Note: Descriptions are shown in the official language in which they were submitted.
CA 02297894 2000-O1-21
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CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98115479
ENDOTHELIN ANTAGONISTS
This is continuation-in-part application of U.S. patent application
s Serial No. 081905,913, filed August 4, 1997 which is a continuation-in-
part of U.S. patent application Serial No. 08/794,50fi, filed February 4,
1997 which is a continuation-in-part of U.S. patent application Serial
No. 08/600,625, filed February 13, 1996, which is a continuation-in-
part of U.S. patent application Serial No. 08/497,998, filed August 2,
i o 1995, which is a continuation-in-part of U.S. patent application Serial
No. 08/442,575, filed May 30, 1995, which is a continuation-in-part of
U.S. patent application Serial No. 08/334,717, filed November 4, 1994,
which is a continuation-in-part of U.S. patent application Serial No.
08/293,349, filed August 19, 1994.
Technical Field
The present invention relates to compounds which are endothelia
antagonists, processes for making such compounds, synthetic
intermediates employed in these processes and methods and
2o compositions for antagonizing endothelia.
Background of the invention
Endothelia (ET) is a 21 amino acid peptide that is produced by
endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val
25 bond in the precursor peptide big endothelia (Big ET). This cleavage is
caused by an endothelia converting enzyme (ECE). Endothelia has been
shown to constrict arteries and veins, increase mean arterial blood
pressure, decrease cardiac output, increase cardiac contractility i n
vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro,
ao contract non-vascular smooth muscle including guinea pig trachea,
human urinary bladder strips and rat uterus in vi ro, increase airway
resistance i n viv , induce formation of gastric ulcers, stimulate
release of atrial natriuretic factor i n vitro and i n vivo, increase plasma
levels of vasopressin, aldosterone and catecholamines, inhibit release
3s of renin i n vitr and stimulate release of gonadotropins i n vi ro.
It has been shown that vasoconstriction is caused by binding of
endothelia to its receptors on vascular smooth muscle (Nature 3 2 411
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WO 99106397 - 2- PCT/US98/15479
(1988), FEBS Letters x,31 440 (1988) and Biochem. Biophys. Res.
Commun. 1 54 868 (1988)). An agent which suppresses endothelia
production or an agent which binds to endothelia or which inhibits the
binding of endothelia to an endothelia receptor will produce beneficial
s effects in a variety of therapeutic areas. In fact, an anti-endothelia
antibody has been shown, upon intrarenal infusion, to ameliorate the
adverse effects of renal ischemia on renal vascular resistance and
glomerular filtration rate (Kon, et al., J. Clin. Invest. 83 1762 (1989)).
In addition, an anti-endothelia antibody attenuated the nephrotoxic
o effects of intravenously administered cyclosporin (Kon, et al., Kidney
Int. 37 1487 {1990)) and attenuated infarct size in a coronary artery
ligation-induced myocardial infarction model (Watanabe, et al., Nature
344 114 (1990)).
Clozel et al. (Nature ~5_: 759-761 (1993)) report that Ro 46-
15 2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal
vasoconstriction in rats, prevents the decrease in cerebral blood flow
due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in
sodium-depleted squirrel monkeys when dosed orally. A similar effect
of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber
2o after SAH has also been recently reported (S.Itoh, T. Sasaki, K. Ide, K.
Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. , 195:
969-75 (1993). These results indicate that agents which antagonize
ETIET receptor binding will provide therapeutic benefit in the indicated
disease states.
Agents with the ability to antagonize ET/ET receptor binding have
been shown to be active in a number of animal models of human disease.
For example, Hogaboam et al (EUR. J. Pharmacoi. 1996, X09, 261-269),
have shown that an endothelia receptor antagonist reduced injury in a
rat model of colitis. Aktan et al (Transplant Int 1996, 9_, 201-207) have
so demonstrated that a similar agent prevents ischemia-reperfusion injury
in kidney transplantation. Similar studies have suggested the use of
endothelia antagonists in the treatment of angina, pulmonary
hypertension, Raynaud's disease, and migraine. (Ferro and Webb, Drugs
1996, 51,12-27).
35 Abnormal levels of endothelia or endothelia receptors have also
been associated with a number of disease states, including prostate
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cancer (Nelson et al, Nature Medicine 1995, 1, 944-949), suggesting a
rote of endothelin in the pathophysiology of these diseases.
Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown
that both endothelin and endothelin antagonists bind tightly to plasma
s proteins, e.g., serum albumin. This plasma protein binding can decrease
the effectiveness with which the antagonists inhibit endothelin's
action. Thus, endothelin antagonists with reduced plasma protein
binding may be more effective than highly bound congeners.
~ o Disclosure of the Invention
In accordance with the present invention there are compounds of
the formula (I):
R2 Z~ ~ Ra
N
~CH2)n
R
R' (I)
~s wherein
Z is -C(R18)(R19)-
or -C(O)-
wherein R18
and R1g are
independently
selected from
hydrogen
and loweralkyl;
n is 0 or 1;
R is -(CH2)m-W
wherein m
is an integer
from 0 to
6 and W is
20 (a) -C(O)2-G wherein G is hydrogen or a carboxy protecting
gro up,
(b) -P03H2,
(c) -P(O){OH)E wherein E is hydrogen, loweralkyl or
arylalkyl,
(d) -CN,
2s (e) -C(O)NHR1 ~ wherein R~ 7 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
so (j) alkoxy,
(k) sulfonamido,
(I) -C(O)NHS(O)2R16 wherein R1s is loweralkyl, haloalkyl,
ary l or dialkylamino,
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(m) -S(O)2NHC(O)R~6 wherein R16 is defined as above,
Ho 0
NH
1
(n) O
s.S' O
(0) HO O
OH
~N
i
(p) o ,
O
NH
O
(q) ° ,
.~~ N. o
N
~~H
(r~ O ,
~O
~S= O
N
(S) H
~N
~~-- CFs
N
(t) ~ H , Or
- ~ ~ NHS02CF3
(U) ;
i o R 1 and R2 are independently selected from hydrogen, loweralkyl,
alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl,
haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl,
alkylaminocarbonylalkyl,. dialkylaminocarbonylalkyl,
aminocarbonylalkenyl, alkylaminocarbonylalkenyl,
dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl,
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aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl,
afkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(R~b)N-Roy- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or
alkanoyl and R~~ is afkylene, with the proviso that one or both of R1 and
s R2 is other than hydrogen;
R3 is (a) R4-C(O)-R5- , R4-R5a- ~ R4-C(O)- R5-N{Rs}- , Rs-S{O)2-R7_
or R26-S(O)-R27-
wherein R5 is (i) a covalent bond, (ii) alkylene,
(iii) alkenylene, (iv) -N(R2o)-R8- or -R$a-N(R2o)-R8-
wherein R8 and R8a are independently selected from
the group consisting of alkylene and alkenylene
and R2p is hydrogen, loweralkyl, alkenyl, haloalkyl,
alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl
or (v) -O-R9- or -R9a-O-R9- wherein Rg and Rga are
1 s independently selected from alkyiene;
R5a is (i) alkylene or (ii) alkenylene;
R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or
(iv) -N(R21 )-R~ o- or -R1 oa-N( R2~ )-R~ o- wherein R1 o and
R 1 oa are independently selected from the group
2o consisting of alkylene and alkenylene and R21 is
hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl,
haloalkoxyalkyl, aryl or arylalkyl;
R4 and R6 are independently selected from the group
consisting of
25 (i) (R11)(R12)N- wherein R11 and R12 are
independently selected from
( 1 ) hydrogen,
{2) loweralkyl,
(3} haloalkyl,
so (4) -alkoxyalkyl,
(5} haloalkoxyalkyl,
(6) alkenyi,
(7) alkynyl,
(8) cycloalkyl,
35 (9) cycloalkylalkyl,
(10} aryl,
(11) heterocyclic,
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WO 99/06397 - 6- PCTNS98/15479
(12) arylalkyl,
(13) (heterocyclic)alkyl,
{ 14) hydroxyalkyl,
( 15) alkoxy,
(16) aminoalkyl,
(17) trialkylaminoalkyl,
(18) aikylaminoalkyl,
(19) dialkylaminoalkyl, and
(20) carboxyalkyl,
~o (ii) loweralkyl,
(iii) alkenyl,
(iv) alkynyl,
{v) cycloalkyl,
(vi) cycloalkylalkyl,
i5 (vii) aryl,
(viii) aryialkyl,
(ix) heterocyclic,
(x) (heterocyclic)alkyl,
(xi) aikoxyalkyl,
20 (xii) hydroxyalkyl,
(x i i i ) haloalkyl,
(xiv) haloalkenyl,
(xv) haloalkoxyalkyl,
(xvi) haloalkoxy,
25 (xvii) alkoxyhaloalkyl,
(xviii) alkylaminoalkyl,
(xix) dialkylaminoalkyl,
(xx) alkoxy, and
H
N \ R7a
(XXI)
wherein z is 0-5 and Rya is alkylene;
R26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv)
alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl,
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(ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii)
alkoxy-substituted
haloalkyl;
and
R27 is aikylene or alkenylene;
(b) R22-O-C(O)-R23- wherein R22 a carboxy protecting
is
group or heterocyclic and R23 i) a covalent bond,
is (
(ii) alkylene, (iii) alkenyleneor (iv) -N(R24)-R25-
wherein R25 is afkylene and R24 is hydrogen or
loweralkyl,
(c) loweralkyl,
(d} alkenyl,
(e} alkynyl,
(f) cycloalkyl,
(g) cycloalkylalkyl,
(h) aryl,
~s (i) arylalkyl,
( j ) aryloxyalkyl,
(k) heterocyclic,
(I) (heterocyclic)alkyl,
(m) alkoxyalkyl,
(n) alkoxyalkoxyalkyl, or
(o) R13-C(O)-CH(R14}-
wherein R13 is amino, alkylaminoor dialkylamino and
R14
is aryl or R~ 5-C(O)- wherein is amino, alkylamino
R15 or
dialkylamino;
or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the invention is a compound of formula
R2 Z~ ~ R3
N
R'~~~,. (CH2)n
3o R1
*rB
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wherein the substituents -R2, -R and -R1 exist in a traps, traps
relationship and Z, n, R, R1, R2, and R3 are as defined above.
Another preferred embodiment of the invention is a compound of
s formula (I) or (II) wherein n is 0 and Z is -CH2-.
Another preferred embodiment of the invention is a compound of
formula (I) or (II) wherein n is 1 and Z is -CH2-.
~ o Another preferred embodiment of the invention is a compound of
formula (I) or (11) wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5- ,
Rs-S(O)2-R~- or R26-S(O)-R27- wherein R4, R~, R6, R~, R26 and R2~ are
as defined above.
7 s Another preferred embodiment of the invention is a compound of
formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or
alkoxyalkoxyalkyl.
A more preferred embodiment of the invention is a compound of
2o formula {I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5-
wherein R4 is (R1~){R12)N- as defined above and R5 is alkylene or R3 is
R6-S(O)2-R~- or R26-S(O)-R27- wherein R7 is alkylene, R2~ is alkylene
and R6 and R~6 are defined as above.
25 Another more preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, Z is -CH2- and R3 is
R4-C(O)-N(R2o)-R$- or R6-S(O)2-N(R21)-Rio- wherein R8 and R1o are
alkylene and R4, R6, R2o and R21 are defined as above.
so An even more preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is. 0, R is tetrazolyi or
-C(O)2-G wherein G is hydrogen or a carboxy protecting group or R is
tetrazolyl or R is
-C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is
ss -CH2-,
R 1 and R2 are independently selected from (i) loweralkyl, (ii)
cycloaikyl, (iii) substituted aryl wherein aryl is phenyl substituted
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WO 99106397 - 9- PCT/US98115479
with one, two or three substituents independently selected from
loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv)
substituted or unsubstituted heterocyclic, (v) alkenyl, (vi} heterocyclic
(alkyl), (vii) arylalkyl, (viii) aryloxyalkyl, (ix) (N-alkanoyl-N-
alkyl)aminoalkyl and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5-
wherein R4 is (R~1)(R12)N- wherein R~1 and R~2 are independently
selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl,
arylalkyl, heterocyciic, hydroxyalkyl, alkoxy, aminoalkyl, and
trialkylaminoalkyl, and R5 is alkylene; or R3 is R4-C(O)-N(R2p)-R$- or
1o R6-S(O)2-N(R21)-R1 o- wherein R4 is loweralkyl, aryl, alkoxy,
alkylamino, aryloxy or arylalkoxy and R6 is foweralkyl, haloalkyl,
alkoxyaikyl, haloalkoxyalkyl, aryl or arylafkyl, R8 and R1 o are alkyiene
and R2o and R21 are loweralkyl; or R3 is R6-S(O)2-R~- or R2s-S(O)-R2~-
wherein R6 is loweralkyl or haloalkyl, R~ is alkylene, R26 is loweralkyl
i s and R2~ is aikylene.
A yet more preferred embodiment of the invention is a compound
of formula (i) or (il} wherein n is 0, R is -C(O)2-G wherein G is hydrogen
or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein
R ~ 6 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) loweraikyl, (ii)
alkenyl,
(iii} alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl,
(viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl,
3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methyiphenyl,
2s 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-
methoxyphenyl,
3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,
4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl
or dihydrobenzofuranyi wherein the substituent is selected from alkoxy,
so alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl,
(xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyi, or (xiii)
alkylsulfonyiamidoalkyl, R2 is substituted or unsubstituted
1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,
8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,
35 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and
R3 is R4-C(O)-N(RZO)-R$- or R6-S(O)2-N(R21 )-R10- wherein R$ and R10
are alkylene, R2o and R21 are loweralkyl, R4 is foweraikyl, aryl, alkoxy,
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WO 99/06397 - 1 ~- PCT/US98/15479
alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, hafoalkyl,
alkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a
s compound of formula (I) or (II} wherein n is 0, R is -C(~)2-G wherein G
is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
NHS(O)2R~6 wherein R1s is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri
is (i) loweralkyl, (ii) alkenyi,
(iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl,
~ o (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl,
3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl,
4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-
methoxyphenyl,
3-fiuoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,
1 ~ 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl
or dihydrobenzofuranyl wherein the substituent is selected from alkoxy,
alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl,
(xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii)
alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted
20 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,
8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,
4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and
R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N-
wherein R11 and R~ 2 are independently selected from loweralkyl,
2s haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic,
hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.
Another yet more preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
so is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
NHS(O)2Rls wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1
is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv)
aryloxyalkyl, (v) arylalkyl, (vi) aryl, (vii) (N-alkanoyl-N-
alkyl)aminoalkyl, or (viii) alkyisulfonylamidoalkyl, R2 is substituted or
ss unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-
benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl,
benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or
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difluorophenyl wherein the substituent is selected from loweralkyl,
alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4
is (R~y)(R12)N- wherein R11 is loweralkyl and Rt2 is aryl, arylalkyl,
hydroxyalkyl, alkoxy, aminoalkyl, trialkyiaminoalkyl, or heterocyclic.
Another yet more preferred embodiment of the invention is a
compound of formula (I) or {II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1
o is (i) loweralkyl, (ii) alkenyl, (iii) heterocyciic (alkyl), (iv)
aryloxyalkyl, (v) arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii)
alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or
unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-
ffuorophenyl,
i 5 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,
1,3-benzodioxoiyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein
the substituent is selected from loweralkyl, haloalkyl, alkoxy,
alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-
benzodioxolyl,
20 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,
8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-rnethoxyphenyf,
dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the
substituent is selected from loweralkyl, alkoxy and halogen and R3 is
R6-S(O)2-N(R21)-Rio- wherein R1 fl is alkylene, R6 is loweralkyl,
25 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is
loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
so is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
NHS(O)2R j6 wherein R16 is loweralkyl, haioalkyl or aryl, Z is -CH2-, R~
is (i) substituted or unsubstituted
4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl,
3-fluoro-4-ethoxyphenyi, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl
s5 o r
1,4-benzodioxanyl wherein the substituent is selected from loweralkyl,
haloalkyl, alkoxy and alkoxyalkoxy, (ii} loweralkyl, (iii) alkenyl, {iv)
*rB
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heterocyclic (alkyl), {v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-
alkyl)aminoalkyl, (viii) alkyisulfonylamidoalkyl,or (ix) phenyl, R2 is
substituted or unsubstituted
1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,
s 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl,
dimethoxyphenyl, fiuorophenyl or difluorophenyl wherein the
substituent is selected from loweralkyi, alkoxy and halogen and R3 is
alkoxycarbonyl or R6-S(O)2-N{R21 }-R~ o- wherein R j o is alkylene, R6 is
loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is
~ o loweralkyl, haloalkyl, alkoxyalkyl or haloaikoxyalkyl.
Another yet more preferred embodiment of the invention is a =
compound of formula (I} or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, tetrazolyl or -C(O}-
15 NHS(O)2R~6 wherein Ris is loweralkyl or haloalkyl, Z is -CH2-, R1 is
loweralkyl,aikenyl, heterocyclic (allkyf), aryloxyalkyl, aryaikyi, aryl,
(N-alkanoyl-N-alkyl)aminoalkyl" or alkylsulfonylamidoalkyl, and R3 is
R4-C(O)-RS- wherein R5 is alkylene and R4 is (R~1)(R~2)N- wherein R1y
and R~ 2 are independently selected from alkyl, aryl, hydroxyalkyl,
2o alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
A stilt more preferred embodiment of the invention is a compound
of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen
or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)ZRy6 wherein
25 R~ 6 is loweralkyf or haloalkyl, Z is -CH2-, R1 is substituted or
unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-
methyiphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyi,
4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-
benzodioxoiyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the
so substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,
(ii) foweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl,
(vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii)
alkylsulfonyfamidoalkyl,or (ix) phenyl, R2 is 1,3-benzodioxolyl,
1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-
s~ methoxyphenyi, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3
is R4-C{O)-R5- wherein R5 is alkylene and R4 is (R~ 1 )(R~ 2)N- wherein
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R 11 and R12 are independently selected from loweralkyl, aryl, arylalkyl,
hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Another still more preferred embodiment of the invention is a
s compound of formula (I) or (li) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
NHS(O)2R16 wherein R~6 is loweralkyl or haloalkyl, Z is -CH2-, R1 is
loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (N-
alkanoyl-N-alkyl)aminoalkyl, alkyisulfonylamidoalkyl, phenyl, or
i o alkoxyalkyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl,
dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl,
fluorophenyl or difluorophenyl and R3 is R4-C(O)-R~- wherein R5 is
alkylene and R4 is (R11 )(R12)N- wherein R11 and R12 are independently
selected from foweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy,
15 aminoalkyl, trialkylaminoalkyl, or heterocyclic.
A most highly preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted
20 or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-
methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl,
4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-
benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the
substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2
2s is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl,
benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyi or
difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is
(R11)(R12)N- wherein R~1 and R~2 are independently selected from
loweralkyl.
Another most highly preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted
or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl,
4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl,
4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-
benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the
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substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2
is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl,
benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or
difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is
s (R11)(R~2)N- wherein R11 is loweralkyl and R12 is aryl.
Another most highly preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted
~ o or unsubstituted 4-methoxyphenyl, 3-fluoro-4-rnethoxyphenyl, 3-
fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-
methoxymethoxyphenyl, 1,3-benzadioxolyl, 1,4-benzodioxanyl or
dihydrobenzofuranyl wherein the substituent is selected from
loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is
i~ substituted or unsubstituted 1,3-benzodioxolyl,
7-methoxy-~ ,3-benzodioxolyl, 1,4-benzodioxanyl,
8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl,
dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the
substituent is selected from loweralkyl, alkoxy and halogen and R3 is
2o R6-S(O)2-N(R21)-Rio- wherein R1o is alkylene, R6 is loweralkyl,
haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is ioweraikyl,
haloalkyl or alkoxyalkyl.
Another most highly preferred embodiment of the invention is a
2s compound of formula (!) or (ll) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted
or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl,
3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl,
4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or
so dihydrobenzofuranyl wherein the substituent is selected from
loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is
substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-
benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl,
dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl
ss or difluorophenyl wherein the substituent is selected from loweralkyl,
alkoxy and halogen and R3 is R4-C(O)-R~- wherein R5 is alkylene and R4
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is (R11)(R~2)N- wherein R1 j is alkyl and R12 is selected from aryl,
aminoalkyl, trialkyiaminoalkyl, and heterocyciic.
Another most highly preferred embodiment of the invention is a
s compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, R~ is
loweralkyi,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-
alkanoyl-N-alkyl)aminoalkyi, or alkylsulfonylamidoalkyl, and R3 is
R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R~2)N- wherein R1 ~
i o and R12 are independently selected from alkyl, aryl, hydroxyalkyl,
alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the
proviso that one or R11 and Ry2 is alkyl.
Another most highly preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is
R4-C(O)-R5- wherein R4 is (R1i)(R12)N- as defined therein and R5 is
alkylene.
Another most highly preferred embodiment of the invention is a
2o compound of formula (() or (II) wherein n is 0, Z is -CH2-, R~ is
loweralkyl, and R3 is R4-C(O)-RS- wherein R4 is (R11)(R12)N- as defined
therein and R~ is alkylene.
Another most highly preferred embodiment of the invention is a
25 compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is alkenyl,
and R3 is R4-C(O)-R~- wherein R4 is (R~1)(R~2)N- as defined therein and
R5 is alkylene.
Another most highly preferred embodiment of the invention is a
so compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R~ is
heterocyclic (alkyl), and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N-
as defined therein and R~ is alkylene.
Another most highly preferred embodiment of the invention is a
3s compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is
aryloxyalkyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as
defined therein and R~ is alkylene.
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Another most highly preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R~ is
arylalkyl, and R3 is R4-C(O)-Rs- wherein _R4 is (R11)(R12)N- as defined
therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is aryl, and
R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5
is alkylene.
Another most highly preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R~ is (N-
alkanoyi-N-alkyl)aminoalkyl, and R3 is R4-C(O)-R5- wherein R4 is
~s (R11)(Ry2)N- as defined therein and RS is alkylene.
Another most highly preferred embodiment of the invention is a
compound of formula (I) or (II) wherein n is 0, Z is -CHZ-, R1 is
alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R4 is
2o (R11)(R~2)N- as defined therein and R~ is alkylene.
The present invention also relates to processes for preparing the
compounds of formula (I) and (II) and to the synthetic intermediates
employed in these processes.
The present inventian also relates to a method of antagonizing
endothelia in a mammal (preferably, a human) in need of such treatment,
comprising administering to the mammal a therapeutically effective
amount of a compound of formula (I) or (tl).
The invention further relates to endothelia antagonizing
compositions comprising a pharmaceutical carrier and a therapeutically
effective amount of a compound of formula (I) or (II).
The compounds of the invention comprise two or more
asymmetrically substituted carbon atoms. As a result, racemic
mixtures, mixtures of diastereomers, as well as single diastereomers
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of the compounds of the invention are included in the present invention.
The terms "S" and "R" configuration are as defined by the IUPAC 1974
Recommendations for Section E, Fundamental Stereochemistry, Pure
Appl. Chem. (1976) 45, 13 - 30.
The term "carboxy protecting group" as used herein refers to a
carboxylic acid protecting ester group employed to block or protect the
carboxylic acid functionality while the reactions involving other
functional sites of the compound are carried out. Carboxy protecting
groups are disclosed in Greene, "Protective Groups in Organic Synthesis"
pp. 152-188 (1981 ), which is hereby incorporated herein by reference.
In addition, a carboxy protecting group can be used as a prodrug whereby
the carboxy protecting group can be readily cleaved in vivo , for example
by enzymatic hydrolysis, to release the biologically active parent. T.
Higuchi and V. Stella provide a thorough discussion of the prodrug
y 5 concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S.
Symposium Series, American Chemical Society (1975), which is hereby
incorporated herein by reference. Such carboxy protecting groups are
well known to those skilled in the art, having been extensively used in
the protection of carboxyl groups in the penicillin and cephalosporin
2o fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the
disclosures of which are hereby incorporated herein by reference.
Examples of esters useful as prodrugs for compounds containing
carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers
in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon
2s Press, New York (1987), which is hereby incorporated herein by
reference. Representative carboxy protecting groups are C~ to C8 alkyl
(e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl;
cycioalkyl and substituted derivatives thereof such as cyclohexyl,
cylcopentyl and the like; cycloalkylalkyl and substituted derivatives
so thereof such as cyclohexylmethyi, cylcopentylmethyl and the like;
arylalkyl, for example, phenethyl or benzyl and substituted derivatives
thereof such as alkoxybenzyl or nitrobenzyl groups and the like;
arylalkenyl, for example, phenylethenyl and the like; aryl and
substituted derivatives thereof, for example, 5-indanyl and the like;
as dialkylaminoalkyl (e.g., dimethylaminoethyl and the like);
alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl,
valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-
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(propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1-ethyl, 1-methyl-1-
(propionyloxy)-1-ethyl, pivaloyloxymethyl, propionyloxymethyl and the
like; cycloalkanoyloxyalkyl groups such as
cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl,
s cyclopentyfcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the
like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the
like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-
benzylcarbonyioxyethyl and the like; alkoxycarbonylalkyl, such as
methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-
~o methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl, such as
methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-
ethoxycarbonyloxy-1-ethyl,
1-cyclohexyloxycarbonyloxy-1-ethyl and the like;
alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and
15 the like; alkylaminocarbonylaminoalkyl, such as
methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl,
such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl,
such as 4-methylpiperazinylcarbonyloxymethyl and the like;
dialkyfaminocarbonylalkyl, such as dimethylaminocarbonylmethyl,
2o diethyiaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1 ,3-
dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-
y1)methyl and the like; and {5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl,
such as {5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.
The term "N-protecting group" or "N-protected" as used herein
2s refers to those groups intended to protect the N-terminus of an amino
acid or peptide or to protect an amino group against undersirable
reactions during synthetic procedures. Commonly used N-protecting
groups are disclosed in Greene, "Protective Groups in Organic
Synthesis," {John Whey & Sons, New York (1981 )), which is hereby
ao incorporated by reference. N-protecting groups comprise acyl groups
such as formyl, acetyl, propionyl, pivaioyl,
t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,
trichioroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl,
benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;
ss sulfonyl groups such as benzenesulfonyl, p-tofuenesulfonyl and the like;
carbamate forming groups such as benzyloxycarbonyl,
p-chlorobenzyloxycarbonyl,
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p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,
2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
s 2-vitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-
trimethoxybenzyloxycarbonyl,
1-(p-biphenylyl)-1-methylethoxycarbonyl,
a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyi, benzhydryloxycarbonyl,
t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,
1 o ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,
2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl,
4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl,
cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl,
phenylthiocarbonyl and the like; alkyl groups such as benzyl,
7 5 triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as
trimethylsilyl and the like. Preferred N-protecting groups are formyl,
acetyl, benzoyl, pivaloyf, t-butylacetyl, phenylsulfonyl, benzyl,
t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term "alkanoyl" as used herein refers to an alkyl group as
2o previously defined appended to the parent molecular moiety through a
carbonyl (-C(O)-) group. Examples of alkanoyl include acetyl, propionyl
and the like.
The term "alkanoylamino" as used herein refers to an alkanoyl
group as previously defined appended to an amino group. Examples
alkanoylamino include acetamido, propionylamido and the like.
The term "alkanoylaminoalkyl" as used herein refers to
R43-NH-R44- wherein R43 is an alkanoyl group and R44 is an alkylene
group.
The term "alkanoyloxyalkyl" as used herein refers to Rgp-O-R3i-
so wherein R3p is an alkanoyl group and R3~ is an alkylene group. Examples
of alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.
The term "alkenyl" as used herein refers to a straight or branched
chain hydrocarbon radical containing from 2 to 15 carbon atoms and
also containing at least one carbon-carbon double bond. Alkenyl groups
ss include, for example, vinyl (ethenyl), allyi (propenyl), butenyl, 1-
methyl-2-buten-1-yl and the like.
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The term "alkenylene" denotes a divalent group derived from a
straight or branched chain hydrocarbon containing from 2 to 15 carbon
atoms and also containing at least one carbon-carbon double bond.
Examples of alkenylene include -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, -
s CH2CH=CHCH2-, and the like.
The term "alkenyfoxy" as used herein refers to an alkenyl group, as
previously defined, connected to the parent molecular moiety through an
oxygen (-O-) linkage. Examples of alkenyloxy include allyloxy,
butenyloxy and the like.
i o The term "alkoxy" as used herein refers to R41 O- wherein R41 is a
loweralkyl group, as defined herein. Examples of alkoxy include, but are
not limited to, ethoxy, tert-butoxy, and the like.
The term "alkoxyalkoxy" as used herein refers to R8p0-R$IO-
wherein R8o is loweralkyl as defined above and R81 is alkyfene.
15 Representative examples of alkoxyalkoxy groups include
methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term "alkoxyalkoxyalkyl" as used herein refers to an
alkoxyalkoxy group as previously defined appended to an alkyl radical.
Representative examples of alkoxyalkoxyalkyl groups include
2o methoxyethoxyethyl, methoxymethoxymethyl, and the like.
The term "alkoxyalkyl" as used herein refers to an alkoxy group as
previously defined appended to an alkyl radical as previously defined.
Examples of alkoxyalkyl include, but are not limited to, methoxymethyl,
methoxyethyl, isopropoxymethyl and the like.
25 The term "alkoxycarbonyl" as used herein refers to an alkoxyl
group as previously defined appended to the parent molecular moiety
through a carbonyl group. Examples of alkoxycarbonyl include
methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
The term "alkoxycarbonylalkenyl" as used herein refers to an
3o alkoxycarbonyl group as previously defined appended to an alkenyl
radical. Examples of alkoxycarbonylalkenyl include
methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
The term "alkoxycarbonylalkyl" as used herein refers to
R34-C(O)-R3s- wherein R34 is an alkoxy group and R3s is an alkyfene
35 group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl,
methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
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The term "alkoxycarbonylaminoalkyi" as used herein refers to
R3$-C(O)-NH-R3g- wherein R38 is an alkoxy group and R3g is an alkylene
group.
The term "alkoxycarbonyloxyalkyl" as used herein refers to
s R3s-C(O)-O-R3~- wherein R36 is an alkoxy group and R3~ is an alkylene
group.
The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an
alkoxycarbonyl group as previously defined appended to a thioalkoxy
radical. Examples of (alkoxycarbonyl)thioalkoxy include
~ o methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
The term "alkoxyhaioalkyl" as used herein refers to a haloalkyl
radical to which is appended an alkoxy group.
The terms "alkyl" and "loweralkyl" as used herein refer to straight
or branched chain alkyl radicals containing from 1 to 75 carbon atoms
1 s including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-
butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-
dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the
like.
The term "(N-alkanoyl-N-alkyl}aminoalkyl" as used herein refers
2o to RgSC(O)N(Rgs)Rg7- wherein Rg5 is an alkanoyl as previously defined,
Rgg is loweralkyl, and Rg7 is alkylene.
The term "alkyiamino" as used herein refers to R5~ NH- wherein
R51 is a loweralkyl group, for example, ethylamino, butylamino, and the
Pike.
25 The term "alkylaminoalkyf" as used herein refers to a loweralkyl
radical to which is appended an alkylamino group.
The term "alkylaminocarbonyl" as used herein refers to an
alkylamino group, as previously defined, appended to the parent
molecular moiety through a carbonyl (-C(O)-) linkage. Examples of
ao alkyiaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl,
isopropylaminocarbonyl and the like.
The term "alkylaminocarbonylalkenyl" as used herein refers to an
alkenyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylaminocarbonylalkyl" as used herein refers to a
35 loweralkyl radical to which is appended an alkylaminocarbonyl group.
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The term "alkylaminocarbonylaminoalkyl" as used herein refers to
R4o-C(O)-NH-R41- wherein R4~ is an alkylamino group and R41 is an
alkylene group.
The term "alkylene" denotes a divalent group derived from a
straight or branched chain saturated hydrocarbon having from 1 to 15
carbon atoms by the removal of two hydrogen atoms, for example -CH2-,
-CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH2C(CH3}2CH2- and the like.
The term "alkylsulfonylamidoaikyl" as used herein refers
RggS(O)2NHRgg- wherein Rgg is loweralkyl and Rgg is alkylene.
o The term "alkylsulfonylamino" as used herein refers to an alkyl
group as previously defined appended to the parent molecular moiety
through a sulfonylamino (-S(O)2-NH-) group. Examples of
alkylsulfonylamino include methylsulfonylamino, ethyisulfonylamino,
isopropylsulfonylamino and the like.
i s The term "alkynyl" as used herein refers to a straight or branched
chain hydrocarbon radical containing from 2 to 15 carbon atoms and
also containing at least one carbon-carbon triple bond. Examples of
aikynyl include -C--__C-H, H-C-_-C-CH2-, H-C--_C-CH(CH3)- and the like.
The term "alkynylene" refers to a divalent group derived by the
2o removal of two hydrogen atoms from a straight or branched chain
acyclic hydrocarbon group containing from 2 to 15 carbon atoms and
also containing a carbon-carbon triple bond. Examples of alkynylene
include -C--_C-, -C=C-CH2-, -C--_C-CH(CH3)- and the like.
The term "aminoalkyl" as used herein refers to a -NH2, alkylamino,
25 or dialkylamino group appended to the parent molecular moiety through
an alkylene.
The term "aminocarbonyl" as used herein refers to H2N-C(O}- .
The term "aminocarbonylalkenyl" as used herein refers to an
alkenyl radical to which is appended an aminocarbonyl (NH2C(O}-) group.
so The term "aminocarbonylalkoxy" as used herein refers to
H2N-C(O)- appended to an alkoxy group as previously defined. Examples
of aminocarbonylalkoxy include aminocarbonylmethoxy,
aminocarbonylethoxy and the like.
The term "aminocarbonylalkyl" as used herein refers to a
35 loweralkyl radical to which is appended an aminocarbonyl (NH2C(O)-}
group.
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The term "trialkylaminoalkyl" as used herein refers to
(Rgp)(Rg1)(Rg2)N(Rg3)- wherein Rgp, Rg~, and Rg2 are independently
selected from loweralkyl and Rg 3 is alkylene.
The term "aroyloxyalkyl" as used herein refers to R32-C(O)-O-R33-
s wherein R32 is an aryl group and R33 is an alkylene group. Examples of
aroyioxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
The term "aryl" as used herein refers to a mono- or bicyclic
carbocyclic ring system having one or two aromatic rings including, but
not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl
1 o and the like. Aryl groups can be unsubstituted or substituted with one,
two or three substituents independently selected from loweralkyi, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy,
alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy,
thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl,
i 5 trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy,
alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, vitro,
carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy,
alkylsulfonylamino, cyanoalkoxy, {heterocyclic)alkoxy, hydroxy,
hydroxalkoxy, phenyl and tetrazolylaikoxy. In addition, substituted aryl
2o groups include tetrafluorophenyl and pentafluorophenyl.
The term "arylalkenyl" as used herein refers to an alkenyl radical
to which is appended an aryl group, for example, phenylethenyl and the
like.
The term "arylalkoxy" as used herein refers to R42O- wherein R42
2s is an arylalkyl group, for exampie, benzyloxy, and the like.
The term "arylalkoxyalkyl" as used herein refers to a loweralkyl
radical to which is appended an arylalkoxy group, for example,
benzyloxymethyl and the like.
The term "arylalkyl" as used herein refers to an aryl group as
so previously defined, appended to a loweralkyl radical, for example,
benzyl and the like.
The term "aryloxy" as used herein refers to R45O- wherein R45 is
an aryl group, for example, phenoxy, and the like.
The term "arylalkylcarbonyloxyalkyl" as used herein refers to a
ss loweralkyl radical to which is appended an arylalkylcarbonyloxy group
(i.e., R62C(O)O- wherein R62 is an arylalkyl group).
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The term "aryloxyalkyl" refers to an aryloxy group as previously
defined appended to an alkyl radical. Examples of aryloxyalkyl include
phenoxymethyl, 2-phenoxyethyl and the like.
The term "carboxaldehyde" as used herein refers to a formaldehyde
s radical, -C(O)H.
The term "carboxy" as used herein refers to a carboxylic acid
radical, -C{O)OH.
The term "carboxyalkenyl" as used herein refers to a carboxy group
as previously defined appended to an alkenyl radical as previously
i o defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3-
carboxy-1-ethenyl and the Pike.
The term "carboxyalkoxy" as used herein refers to a carboxy group
as previously defined appended to an alkoxy radical as previously
defined. Examples of carboxyalkoxy include carboxymethoxy,
1 s carboxyethoxy and the like.
The term "cyanoaikoxy" as used herein refers to an alkoxy radical
as previously defined to which is appended a cyano (-CN) group.
Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the
like.
2o The term "cycloalkanoyloxyalkyl" as used herein refers to a
loweralkyi radical to which is appended a cycloalkanoyloxy group (i.e.,
R6o-C(O)-O- wherein R6o is a cycloalkyl group).
The term "cycloalkyl" as used herein refers to an aliphatic ring
system having 3 to 10 carbon atoms and 1 to 3 rings including, but not
25 limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyi,
and the like. Cycloalkyl groups can be unsubstituted or substituted with
one, two or three substituents independently selected from loweralkyl,
haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy,
halo, mercapto, vitro, carboxaldehyde, carboxy, alkoxycarbonyl and
so carboxamide.
The term "cycioalkylalkyl" as used herein refers to a cycloalkyl
group appended to a loweralkyl radical, including but not limited to
cyclohexylmethyl.
The term "dialkylamino" as used herein refers to R56R5~N-
ss wherein R56 and R5~ are independently selected from loweralkyl, for
example diethylamino, methyl propylamino, and the like.
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The term "dialkylaminoaiky(" as used herein refers to a loweralkyl
radical to which is appended a dialkylamino group.
The term "dialkylaminocarbonyl" as used herein refers to a
dialkylamino group, as previously defined, appended to the parent
s molecular moiety through a carbonyl (-C(O)-) linkage. Examples of
dialkylaminocarbonyl include dimethylaminocarbonyl,
diethylaminocarbonyl and the like.
The term "dialkylaminocarbonylalkenyl" as used herein refers to
an alkenyl radical to which is appended a dialkylaminocarbonyl group.
7 o The term "dialkylaminocarbonyialkyl" as used herein refers to
R5o-C(O)-R5~- wherein R5o is a dialkylamino group and R51 is an
alkylene group.
The term "halo" or "halogen" as used herein refers to I, Br, CI or F.
The term "haloalkenyl" as used herein refars to an alkenyl radical
to which is appended at least one halogen substituent.
The term "haloalkoxy" as used herein refers to an alkoxy radical as
defined above, bearing at least one halogen substituent, for example,
2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy,
2,2,3,3,3-pentafluoropropoxy and the like.
2o The term "haioalkoxyalkyl" as used herein refers to a loweralkyl
radical to which is appended a haloalkoxy group.
The term "haloalkyl" as used herein refers to a lower alkyl
radical, as defined above, to which is appended at least one halogen
substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or
2s pentafluoroethyl and the like.
The term "heterocycfic ring" or "heterocyclic" or "heterocycle" as
used herein refers to any 3- or 4-membered ring containing a
heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-
membered ring containing one, two or three nitrogen atoms; one oxygen
so atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen
and one oxygen atom; two oxygen atoms in non-adjacent positions; one
oxygen and one sulfur atom in non-adjacent positions; or two sulfur
atoms in non-adjacent positions. The 5-membered ring has 0-2 double
bonds and the 6- and 7-membered rings have 0-3 double bonds. The
ss nitrogen heteroatoms can be optionally quaternized. The term
"heterocyclic" also includes bicyclic groups in which any of the above
heterocyclic rings is fused to a benzene ring or a cyclohexane ring or
CA 02297894 2000-O1-21
WO 99106397 26 PCT/US98115479
another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl,
isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinoiyl,
decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl
or benzothienyl and the like). Heterocyclics include: aziridinyl,
s azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazoiyl, pyrazolinyl,
pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,
piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,
morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyi,
~ o isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl,
thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyi, isoxazolyl,
oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.
x~
;.
i~
0
Heterocyclics also include compounds of the formula
1 s where X* is -CHZ- or -O- and Y* is -C(O)- or [-C(R")2-lv where R" is
hydrogen or C1-C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl,
1,4-benzodioxanyl and the like. Heterocyclics also include bicyclic
rings such as quinuclidinyl and the like.
Heterocyclics can be unsubstituted or monosubstituted or
2o disubstituted with substituents independently selected from hydroxy,
halo, oxo (=O), alkylimino (R*N= wherein R* is a loweralkyi group),
amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl,
trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S03H,
alkoxycarbonyl, vitro, cyano and loweralkyl. In addition, nitrogen
2s containing heterocycles can be N-protected.
The term "(heterocyclic)alkoxy" as used herein refers to a
heterocyclic group as defined above appended to an alkoxy radical as
defined above. Examples of (heterocyclic)alkoxy include 4-
pyridylmethoxy, 2-pyridylmethoxy and the like.
ao The term "(heterocyclic)alkyl" as used herein refers to a
heterocyclic group as defined above appended to a loweralkyl radical as
defined above.
CA 02297894 2000-O1-21
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The term "heterocycliccarbonyloxyalkyl" as used herein refers to
R46-C(O)-O-R4~- wherein R46 is a heterocyclic group and R4~ is an
alkylene group.
The term "hydroxy" as used herein refers to -OH.
s The term "hydroxyalkenyl" as used herein refers to an alkenyl
radical to which is appended a hydroxy group.
The term "hydroxyalkoxy" as used herein refers to an alkoxy
radical as previously defined to which is appended a hydroxy (-OH)
group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-
o hydroxybutoxy and the like.
The term "hydroxyalkyl" as used herein refers to a loweralkyl
radical to which is appended a hydroxy group.
The term "leaving group" as used herein refers to a halide (for
example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate,
~ s triflate and the like).
The term "mercapto" as used herein refers to -SH.
The terms "methyienedioxy" and "ethylenedioxy" refer to one or
two carbon chains attached to the parent molecular moiety through two
oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring
2o is formed. In the case of ethylenedioxy, a fused 6 membered ring is
formed. Methylenedixoy substituted on a phenyl ring results in the
0
formation of a benzodioxolyl radical. . Ethylenedioxy
substituted on a phenyl ring results in the formation of a benzodioxanyl
0
0
radical .
25 The term "substantially pure" as used herein means 95% or more
of the specified compound.
The term "tetrazolyl" as used herein refers to a radical of the
formula
H
N- N
or a tautomer thereof.
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The term "tetrazolylalkoxy" as used herein refers to a tetrazolyl
radical as defined above appended to an alkoxy group as defined above.
Examples of tetrazolylalkoxy include tetrazolylmethoxy,
tetrazofylethoxy and the like.
s The term "thioalkoxy" as used herein refers to R7pS- wherein Rip
is loweralkyl. Examples of thioalkoxy include, but are not limited to,
methyithio, ethylthio and the like.
The term "thioalkoxyalkoxy" as used herein refers to RgpS-RglO-
wherein R$p is loweralkyl as defined above and R81 is alkylene.
~ o Representative examples of alkoxyalkoxy groups include CH3SCH20-,
EtSCH20-, t-BuSCH20- and the like.
The term "thioalkoxyalkoxyalkyl" as used herein refers to a
thioalkoxyalkoxy group appended to an alkyl radical. Representative
examples of alkoxyalkoxyalkyl groups include CH3SCH2CH20CH2CH2-,
7 s CH3SCH20CH2-, and the like.
The term "trans,trans" as used herein refers to the orientation of
substituents (R1 and R2) relative to the central substituent R as shown
R2 Z~ ~ Rs
N
i
R''~,.. (CH2)n
R1
2o The term "trans,cis" as used herein refers to the orientation of
substituents (R1 and R2) relative to the central substituent R as shown
R2y.... Z~NiR3 2 Z Rs
R ~N/
R~~.~' (CH2)n R~~.~w (CN2)n
R' or R' . This definition encompasses both
the case where R and R2 are cis and R and R1 are trans and the case
where R2 and R are traps and R and R j are cis.
25 The term "cis,cis" as used herein refers to the orientation of
substituents (R1 and R2) relative to the central substituent R as shown
CA 02297894 2000-O1-21
WO 99/06397 - 29- PCTIUS98/15479
R2io,, ZwN/Rs
(CH2)n
~1
Preferred compounds of the invention are selected from the group
consisting of:
frans-frans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1-[3-(N
propyl-N-n-pentanesulfonylamino)propyl]-pyrrolidine-3
carboxylic acid;
traps,traps-2-(4-Methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)--
(2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-
~o carboxylic acid;
traps, traps-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol -5-yl)-1-[2-
(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-
carboxylic acid;
traps, traps-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1-[2-
~ s (N-propyl-N-n-hexanesulfonylamino)ethyl]pyrroiidine-3-
carboxylic acid;
traps, traps-2-(4-Propoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-[2-(N-
propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic
acid;
2o traps,traps-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(3,4-Difluorophenyl)-4-(1 ,3-benzodioxol-5-yl)-1-[2-(N-
propyl-N-n-pentanesuifonylamino)ethyl]pyrrolidine-3-carboxylic
acid;
25 traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3-
carboxylic acid;
traps, traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-propyl-N-(3-chloropropanesuifonyl)amino)ethyl)-
so pyrrolidine-3-carboxylic acid;
traps, traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-isobutyl-N-(3-
chloropropanesulfonyl)amino)ethyl)pyrroiidine-3-carboxylic acid;
CA 02297894 2000-O1-21
WO 99/06397 - 3 ~- PCT/US98/15479
traps, traps-2-(3-Fluoro-4-methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl}-
1-[2-(N-propyl-N-(4-
methylbutanesulfonyl)amino)ethyl]pyrroiidine-3-carboxylic acid;
traps, traps-2-(4-Methoxy-3-fl uorophen.yl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-[2-{N-propyl-N-(n-
pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fiuoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)
1-[2-(N-propyl-N-{2,2,3,3,3-pentafluoropropoxyethanesulfonyl}-
amino)ethyl]pyrrolidine-3-carboxylic acid;
io trans,trans-2-(1 ,4-Benzodioxan-6-yl)-4-{7-methoxy-1 ,3-benzodioxol-
5-yl)-1-[2-(N-propyl-N-(n-
pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)
1-(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3-
75 carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyi}-4-(1 ,3-benzodioxol-5-yl)-
1-(2-(N-(2-methoxyethyl)-N-(3-chioropropanesulfonyl)amino)-
ethyl)pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
20 1-(2-{N-(2-methoxyethyl}-N-
(pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)
1-(2-(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino)-
ethyl]pyrrolidine-3-carboxylic acid;
2s traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-(2-methoxyethyl}-N-{butanesulfonylamino)ethyl)-
pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl}-4-(1,3-benzodioxol-5-
yl)-1-[2-(N-propyl-N-(2-
3o methylpropanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl}-
1-(2-(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2-Methylpentyl)-4-( 1,3-benzodioxoi-5-yl}-1-(N,N-di (n-
35 butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2-D imethylpentyl)-4-( 1,3-benzodioxol-5-yl)-1-(N, N-
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
CA 02297894 2000-O1-21
WO 99/06397 3 ~ - PCT/US98/15479
traps, traps-2-(2-( 1,3-Dioxo-2-yl)ethyl)-4-(1 ,3-benzodioxo I-5-yl)-1-
(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps,traps-2-(2-(2-Tetrahydro-2H-pyran)ethyl}-4-(1 ,3-benzodioxol-
5-yl)-1-(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1,3-benzodioxol-5-yl)-
1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
~o traps,traps-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-
benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl}-
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(1 ,3-Dioxo-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-
[[N-4-heptyl-N(2 methyl-3-fluorophenyl}] amino carbonylmethyl]-
i s pyrrolidine-3-carboxylic acid;
traps, traps-2-{2-(1 ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
traps,traps-2-((2-Methoxyphenoxy)-methyl)-4-(i ,3-benzodioxol-5-yl)-
20 1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
(2S, 3R, 4S)-2-(2,2-Dimethyipentyl)-4-(1,3-benzodioxo I-5-yl)-1-(N-4-
heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
25 traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-
yl)-1-{N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2-( 1 ,3-Dioxo!-2-yl)ethyl)-4-{7-methoxy-1 ,3-
benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-
ao methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps,traps-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5-
yl}-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
ss traps,traps-2-(2,2-dimethylpentyl)-4-(2,3-dihydro-benzofuran-5-yl)-
1-(N,N-di{n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
CA 02297894 2000-O1-21
WO 99/06397 - 32- PCTIUS98I15479
traps, traps-2-(2,2,-Dimethyi-2-(1 ,3-dioxolan-2-yl)ethyl)-4-{7-
methoxy-1,3-benzodioxol-5-yi)-1-(N,N-di(n-
butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1 ,3-benzodioxol-5-yl)-
1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps,traps-2-{2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
io traps,traps-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-{2-oxopyrrolidin-1-yl)ethy!)-4-(1 ,3-benzodioxol-5-
yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
i5 (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-
yl)-1-(N-4-heptyl-N-(4-fluoro-3-
methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-( 1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N, N-
2o di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-j(N-
butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
(2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)1-
25 (2-(N-propyl-N-pentanesu Ifonylamino)ethyl)-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2,2-Dimethylpentyl}-4-{ 1,3-benzodioxol-5-yl)-1-((N-
butyl-N-{4-dimethylamino)butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
so traps,traps-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-
yl)-1-(N-4-heptyl-N-(4-fluoro-3-
methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-
35 yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acrd;
*rB
CA 02297894 2000-O1-21
W O 99106397 - 3 3 - PCT/US98115479
traps,traps-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-
(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonyfmethyl)-
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2-Dimethylpent-3-enyl}-4-(1,3-benzodioxol-5-yl}-1-
s ((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2,2-Dimethy!pent-3-enyl}-4-(7-methoxy-1,3-
benzodioxol-5-yl)-1-(N, N-di{n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
~o traps,traps-2-(2,2-Dimethy!pent-3-enyl)-4-(7-methoxy-1,3-
benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-
methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps,traps-2-(2,2-Dimethy!pent-3-enyl)-4-(7-methoxy-1,3-
~ s benzodioxol-5-yl)-1-((N-butyl-N-(4-
dimethylamino)butyl)aminocarbonyimethyl)-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2,2,4-Trimethylpent-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-
1-(N-4-heptyl-N-(4-fluoro-3-
2o methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps,traps-2-(2,2,4-Trimethylpent-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-
1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
2s traps,traps-2-(2,2,4-Trimethy!pent-3-enyl)-4-(7-methoxy-1,3-
benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2,4-Trimethylpe nt-3-enyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-
so methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2,2,4-Trimethy!pent-3-enyl)-4-(7-methoxy-1 ,3-
be nzodioxol-5-yl)-1-{(N-butyl-N-(4-
dimethylamino)butyl)aminocarbony!methyl}-pyrrolidine-3-
ss carboxylic acid;
CA 02297894 2000-O1-21
WO 99106397 - 34- PCT/US98/15479
traps, traps-2-(2-( 1,3-Dioxol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1
[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-
benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrofidine-3-
carboxylic acid;
traps, traps-2-(2,2,-Dimethy I-2-.(1 ,3-Dioxol-2-yi)ethyl)-4-( 1,3-
benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3
~o methylphenyl)}aminocarbonylmethyl)-pyrrofidine-3-carboxylic
acid;
traps,traps-2-(2,2-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1 ,3-
benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
1 s carboxylic acid;
traps,traps-2-(2,2,-Dimethyl-2-(1 ,3-Dioxol-2-yl)ethyl)-4-(7-
methoxy-1 ,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-
methylphenyl))aminocarbonyfmethyl)-pyrrolidine-3-carboxylic
acid;
2o traps,traps-2-(2,2-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-
methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps,traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 ,3-benzodioxol-5-yl)-
1-(N-4-heptyl-N-(4-fluoro-3-
methylphenyl))amino)carbonylmethy(]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 ,3-benzodioxol-5-yl)-
1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-
so pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-
benzodioxol-5-yl)-1- (N,N-di(n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1 ,3-
ss benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-
methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
CA 02297894 2000-O1-21
WO 99/06397 - 35- PCT/US98I15479
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methcxy-1,3-
benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps, traps-2-((2-Methoxyphenoxy)-methyl)-4-( 1,3-benzodioxol-5-yl)-
1-(N-4-heptyl-N-(4-fluoro-3-
methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-
i o 1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
traps,traps-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1- (N,N-di(n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
15 traps,traps-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-
methyiphenyl})amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-
2o benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2-{2-Oxo 1,2-dihydro pyridin-i -yl)-ethyl)-4-{1 ,3-
benzodioxol-5-yl)-1-(N,N-di(n-butyl}aminocarbonylmethyl)-
25 pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(1 ,3-benzodioxol-5-
yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
so traps,traps-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-
yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyridin-i -yl)-ethyl)-4-(7-methoxy-1,3-
benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-
35 pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-((N-4-heptyl-N-(4-fluoro-3-
CA 02297894 2000-O1-21
W O 99/06397 - 3 6 - PCT/US98/15479
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2(-2-Oxopiperidin-1-yi)-ethyl)-4-(1 ,3-benzodioxol-5
yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3
carboxylic acid;
1o traps,traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-
yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-
1s benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
2o traps, traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1 ,3
benzodioxol-5-yl)-1-j(N-4-heptyl-N-(4-fluoro-3
methyiphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-
2s benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethyiaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-
yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-
so pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-
yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-
35 yl)-1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
CA 02297894~4~2000-O1-21
WO 99/06397 37- PCT/US98115479
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-
yl)-1-[(N-butyl-N-(4-
trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl}-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl}-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-[(N-butyl-N-(3-
~ o hydroxypropyl}amino)carbonylmethyl]-pyrroiidine-3-carboxylic
acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-
benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonyimethyl]-pyrrolidine-3-carboxylic
i s acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-[(N-butyl-N-
(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3-
2o benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylis acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-[(N-butyl-N-(4-
trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydro-
benzofuran-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
so traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydro-
benzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethyi]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl}-4-(2,3-dihydro-
ss benzofuran-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
*rB
CA 02297894 2000-O1-21
WO 99/06397 - 38- PCTlUS98/15479
traps,traps-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-
benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-
yrrolidine-3-carboxylic acid;
traps, traps-2-(2-(3,3-Dimethyl-2-oxopyrrol idin-1-yl)ethyl)-4-( 1 ,3-
benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps,traps-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-
benzodioxol-5-yl)-1-[(N-butyl-N-(4-
1 o dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps,traps-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-
benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
is traps,traps-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-{1,3-
benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps,traps-2-{2-{4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-
2o benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps,traps-2-(2-{1-propanesuitamyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-
1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic
25 acid;
traps, traps-2-(2-( 1-propa n esu lta my l) ethy l)-4-( 1 , 3-be nzodioxo l-5-
y l)-
1-[{N-4-heptyl-N-(4-fl uo ro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
so traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-
1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonyl methyl]-
pyrrolidine-3-carboxylic acid;
traps, traps-2-{2-{ 1-propanesultamyl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-
1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-
ss carboxylic acid;
*rB
CA 02297894 2000-O1-21
WO 99/06397 - 3g- PCTIUS98/15479
traps,traps-2-(2-{1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-
1-[(N-butyl-N-(4 dimethyiaminobutyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1,3-
benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
traps,traps-2-{2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethylJ-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydro-
benzofuran-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl}-
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydro
benzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3
2o methylphenyl)amino)carbonylmethylJ-pyrrolidine-3-carboxylic
acid;
traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydro-
benzofuran-5-yl)-1-[(N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethylj-pyrrolidine-3-
25 carboxylic acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl}-1-j(N-
4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonyfmethyl]-
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-
so butyl-N-{3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2-(1-pyrazo lyl)ethyl)-4-(1,3-be nzodioxol-5-yl)-1-(N-
butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
35 traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-
butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
CA 02297894 2000-O1-21
WO 99/06397 - 4~- PCT/US98115479
traps, traps-2-(2-( 1-pyrazolyl)ethyl)-4-(7-methoxy-1 ,3-benzodioxo l
5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3
carboxylic acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(7-rnethoxy-1 ,3-benzodioxol-
5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-
5-yl)-1-[(N-butyl-N-(4-
~ o dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-
1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
i5 traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-
1-( (N-4-h eptyl-N-(4-fl a o ro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(1-pyrazolyl)ethyl}-4-(2,3-dihydro-benzofuran-5-yl)-
2o i -j(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-oxazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N,N-
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Oxazol-2-yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-1 -[(N-
25 4-heptyl-N-(4-fluoro-3-methyiphenyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-i -[(N-
butyl-N-(3-hydroxypropyl)amino)carbonylmethylj-pyrrolidine-3-
carboxylic acid;
3o traps, traps-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[(N-
butyl-N-(~propoxy)amino)carbonylmethylJ-pyrrolidine-3-carboxylic
acid;
traps,traps-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-
butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-
35 pyrrolidine-3-carboxylic acid;
CA 02297894 2000-O1-21
WO 99/06397 - 41 - PCTIUS98/15479
traps, traps-2-(2-(Oxazol-2-yl)ethyl)-4-{7-methoxy-1,3-benzodioxol-
5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2-(Oxazol-2-yi)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-
5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl}amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-
5-yl)-1-((N-butyl-N-{4-
~o dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
carboxylic acid;
traps, traps-2-{2-(5-Methyrloxazol-2-yl)ethyl}-4-( 1 ,3-benzodioxol-5
yl)-1-{N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3
carboxylic acid;
1~ traps,traps-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-
yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-( i ,3-benzodioxol-5-
2o yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-
5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
2s traps,traps-2-{2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-
5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps,traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-
so 5-yl)-1-[(N-butyl-N-{3-hydroxypropyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2, 5-Dioxopyrro lidin-1-yl) ethyl)-4-( 1,3-benzodioxol-
5-yl)-1-[{N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-
3-carboxylic acid;
ss traps,traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-
5-yl)-1-[{N-butyl-N-(4-dimethylaminobutyl)
amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
CA 02297894 2000-O1-21
WO 99/06397 - 4'2- PCTJUS98115479
traps, traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3
benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-{Pyridin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-
4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-
~ o pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-
butyl-N-(3-hydroxypropyl)amino)carbonylmethylj-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2-(Pyridin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-
15 butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-
butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
2o traps,traps-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-
5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
traps,traps-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-i ,3-benzodioxol-
5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-
2s methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-
5-yl)-1-((N-butyl-N-(4-
dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-
so carboxylic acid;
traps, traps-2-(2-(Pyrimidin-2-yl)ethyl)-4-( 1,3-benzodioxol-5-yl)-1-
(N,N-di{n-butyl)aminocarbonyfmethyl)-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-
35 [(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-
pyrrolidine-3-carboxylic acid;
CA 02297894 2000-O1-21
WO 99/06397 - 43- PCTJUS98I15479
trans, traps-2-(2-(Pyrimidin-2-yl)ethyl)-4-( 7 ,3-benzodioxol-5-yl)-1
[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-( 1, 3-be nzod ioxo I-4-yl)ethy I }-4-{ 1,3-be nzod ioxo I-5
yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3
carboxylic acid;
traps,traps-2-(2-(1,3-benzodioxol-4-yl)ethyl}-4-(1,3-benzodioxol- 5-
yl)-1-[(N-4-heptyl-N-(4-fiuoro-3-
methyiphenyl)amino}carbonylmethyl]-pyrrolidine-3-carboxylic
1 o acid; and
traps, traps-2-(2-(1,3-benzodioxol-4-yl}ethyl)-4-(1 ,3-benzodioxol-5-
yl)-1-((N-butyl-N-(4 dirnethylaminobutyl}amino)carbonyfmethyl]-
pyrrolidine-3-carboxylic acid;
(2S,3R,4S}-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-
~s di(n-butyl)aminocarbonylmethyl}-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-
1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1 ,3-
2o benzodioxol-5-yl}-1-(N,N-di{n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl}-4-(1,3-benzodioxol-5-yi)-
1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
2s (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl}-1-
(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
or a pharmaceutically acceptable salt.
so Most preferred compounds of the invention are selected from the group
consisting of:
traps,traps-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl}-1-
(N,N-di(n-butyl)aminocarbonylmethyi)-pyrrofidine-3-carboxylic
35 acid;
CA 02297894 2000-O1-21
WO 99/06397 44 PCTIUS98/15479
traps,traps-2-(2,2,-Dimethyl-2-(1 ,3-dioxoian-2-yl)ethyl)-4-(1 ,3-
benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-
pyrroiidine-3-carboxylic acid;
traps, traps-2-(2-( 1 ,3-Dioxol-2-y ()ethyl)-4-( 1 , 3-benzodioxol-5-yl)-
-1-[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)]
aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1,3-Dioxo!-2-yl)ethyl)-4-(7-methoxy-1,3-
benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
7 o traps, traps-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-
1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5
yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3
i ~ carboxylic acid;
traps, traps-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-
methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
2o traps,traps-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-
yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
traps, traps-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yl)ethyl)-4-(7-
methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-
25 butyl)aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1,3-benzodioxol-5-yl}-
1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrroiidine-3-carboxylic
acid;
traps, traps-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1,3-
ao benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yi)ethyl)-4-(1,3-benzodioxoi-5-
35 yl}-1-(N,N-di(n-butyl)aminocarbonyfmethyl)-pyrrolidine-3-
carboxylic acid;
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(2S, 3R, 4S}-2-(2,2 Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-
yl)-1-(N,N-di(n-butyl)aminocarbonyfmethyl)-pyrrolidine-3-
carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-
s yl)-1-(N-4-heptyl-N-{4-fluoro-3-
methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
traps, traps-2-(2-( 1-pyrazolyl)ethyl)-4-( 1,3-benzodioxol-5-yl)-1-(N, N-
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
~o (2R, 3R, 4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-[((N-propyl-N-pentanesulfonyl}amino)ethyl]-pyrrolidine-3-
carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpentyl}-4-(1,3-benzodioxol-5-yl)-1-(N,N
di(n-butyl)aminocarbonyimethyl}-pyrrolidine-3-carboxylic acid;
i5 (2S,3R,4S)-2-{2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl)
1-(N,N-di(n-butyl}aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
(2S,3R,4S)-2-{2,2-Dimethylpent-(E)-3-enyl}-4-(7-methoxy-1 ,3-
benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyi)-
2o pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1 ,3-benzodioxol-5-yl)-
1-(N,N-di(n-butyl)aminocarbonylmethyi)-pyrrolidine-3-carboxylic
acid; and
(2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-
2s (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic
acid;
or a pharmaceutically acceptable salt thereof.
Methods for preparing the compounds of the invention are shown in
Schemes I-XV.
Scheme I illustrates the general procedure for preparing the
compounds of the invention when n and m are 0, Z is -CH2- and W is
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-C02H. A [i-ketoester ~, where E is loweralkyl or a carboxy protecting
group is reacted with a vitro vinyl compound ~, in the presence of a
base (for example, 1,8-diazabicyclo[5.4.0]undec-7-eve (DBU) or sodium
ethoxide or sodium hydride and the like) in an inert solvent such as
s toluene, benzene, tetrahydrofuran or ethanol and the like. The
condensation product $ is reduced (for example, hydrogenation using a
Raney nickel or platinum catalyst). The resulting amine cyclizes to give
the dihydro pyrrole 4_. Reduction of 4_ (for example, sodium
cyanoborohydride or catalytic hydrogenation and the like) in a erotic
1 o solvent such as ethanol or methanol and the like gives the pyrrolidine
compound $ as a mixture of cis-cis, traps, traps and cis, traps products.
Chromatographic separation removes the cis-cis isomer leaving a
mixture of the trans,trans and cis,trans isomers which is further
elaborated. The cis-cis isomer can be epimerized (for example, using
1 ~ sodium ethoxide in ethanol) to give the traps, traps isomer and then
carried on as described below. The pyrrolidine nitrogen is (1) acylated
or sulfonylated with R3-X (R3 is R4-C(O)- or Rs-S(O)2- and X is a
leaving group such as a halide {CI is preferred) or X taken together with
R4-C(O)- or R6-S(O)2- forms an activated ester including esters or
2o anhydrides derived from formic acid, acetic acid and the like,
alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide,
N-hydroxybenzotriazoie, N-hydroxy-5-norbornene-2,3-dicarboxamide,
2,4,5-trichlorophenol and the like) or (2) alkylated with R3-X where X is
a leaving group (for example, X is a halide (for example, CI, Br or I) or X
25 is a leaving group such as a sulfonate (for example, mesylate, tosylate,
triflate and the like)) in the presence of a base such as diisopropyl
ethylamine or triethyiamine and the like to give the N-derivatized
pyrrolidine $ which is still a mixture of traps, traps and cis, traps
isomers. Hydrolysis of the ester $ {for example, using a base such a
ao sodium hydroxide in EtOHIH20) selectively hydrolyzes the trans,trans
ester to give a mixture of 7 and $, which are readily separated.
Scheme II illustrates a general procedure for preparing the
compounds of the invention when n is 1, m is 0, Z is -CH2- and W is
-C02H. A substituted benzyl chloride $ is reacted with a lithio dithiane
35 1~ in an inert solvent such as THF or dimethoxyethane to give the
alkylated adduct j 1. The anion of compound 1 1 is formed using a base
such as n-butyliithium and then reacted with R1-CH2-X' wherein X' is a
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leaving group such as a halide or sulfonate to give compound 1 2. The
dithiane protecting group is cleaved (for example, using a mercuric salt
in water) to give the keto compound 1 3. Reaction of ketone 1 3 with
benzyl amine and formaldehyde gives the keto piperidine compound 1 4.
s Treatment of compound 14 with an activated nitrite such as
trimethylsilyl cyanide followed by a dehydrating agent such as
phosphorous oxychloride provides the isomeric ene nitrites 1_~.
Reduction of the double bond (for example, using sodium borohydride)
affords the piperidinyl nitrite 16. Hydrolysis of the nitrite using
hydrochloric acid in the presence of a carboxy protecting reagent (for
example, an alkyl alcohol) affords ester 17 (where E is a carboxy
protecting group). Debenzylation by catalytic hydrogenation under
acidic conditions affords the free piperidine compound 1 8. Compound
1 8 is further elaborated by the procedures described in Scheme I for
15 compound 5_ to give the final product compound 1 9.
Scheme III illustrates a general procedure for preparing the
compounds of the invention when m and n are 0, Z is -C(O)- and W is
-C02H. ~i-Keto ester 20 (wherein E is loweralkyl or a carboxy
protecting group) is reacted with an a-haloester ~ 1_ (where J is lower
2o alkyl or a carboxy protecting group and the halogen is bromine, iodine or
chlorine) in the presence of a base such as NaH or potassium tert-
butoxide or lithium diisopropylamide in an inert solvent such as THF or
dimethoxyethane to give diester 22. Treating compound 22 with R3-NH2
and heating in acetic acid gives the cyclic compound ~ 3. The double
2s bond is reduced (for example, by catalytic hydrogenation using a
palladium on carbon catalyst or sodium cyanoborohydride reduction) to
give pyrrolidone 24. Epimerization with sodium ethoxide in ethanol to
give the desired trans,trans configuration, followed by sodium
hydroxide hydrolysis of the ester, affords the desired trans,trans
so carboxylic acid 25.
Scheme IV illustrates a general procedure for preparing the
compounds of the invention when n is 0, m is 1, Z is -CH2- and W is
-C02H. The trans,trans compound 7, prepared in Scheme I, is
homologated by the Arndt-Eistert synthesis. The carboxy terminus is
as activated (for example, by making the acid chloride using thionyl
chloride) to give compound 52, where L is a leaving group (in the case of
an acid chloride, L is CI). Compound ,5~ is treated with diazomethane to
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give the diazo ketone ,~3. Rearrangement of compound 5 3 (for example,
using water or an alcohol and silver oxide or silver benzoate and
triethylamine, or heating or photolysis in the presence of water or an
alcohol) affords the acetic acid compound 54 or an ester which may be
s hydrolyzed. Compounds where m is from 2 to 6 can be obtained by
repetition of the above described process.
A preferred embodiment is shown in Schemes V and Vl. A benzoyl
acetate ~ is reacted with a vitro vinyl benzodioxolyl compound 27
using 1,8-diazabicyclo[5.4.0]undec-7-eve (DBU) as the base in toluene to
give compound 2 8. Catalytic hydrogenation using Raney nickel leads to
reduction of the vitro group to an amine and subsequent cyclization to
give the dihydropyrrole ~. The double bond is reduced with sodium
cyanoborohydride to give the pyrrolidine compound 3~( as a mixture of
cis-cis, traps, traps and cis, traps isomers. Chromatography separates
~ s out the cis-cis isomer, leaving a mixture of the traps, traps and
cis, traps isomers (31 ).
Scheme VI illustrates the further elaboration of the traps, traps
isomer. The mixture (31 ) of traps, traps and cis, traps pyrrolidines
described in Scheme IV is reacted with N-propyl bromoacetamide in
2o acetonitrile in the presence of ethyldiisopropylamine to give the
alkyiated pyrroiidine compound 32, still as a mixture of trans,trans and
cis,trans isomers. Sodium hydroxide in ethanol-water hydrolyzes the
ethyl ester of the traps, traps compound but leaves the ethyl ester of
the cis,trans compound untouched, thus allowing separation of the
25 traps, traps carboxylic acid 3 3 from the cis, traps ester 3 4.
Scheme V!I illustrates the preparation of a specific piperidinyl
compound. Benzodioxolyl methyl chloride 3 5 is reacted with lithio
dithiane ~ to give the alkylated compound ~7. Treatment of compound
~7 with 4-methoxybenzyl chloride in the presence of lithium
3o diisopropylamide gives compound ~$,. Cleavage of the dithiane
protecting group using a mercuric salt in aqueous solution gives ketone
3 9. Treatment of 3 9 with benzylamine and formaldehyde gives the keto
piperidine 4Q. Treatment of compound 40 with trimethylsilyl cyanide
followed by phosphorous oxychloride gives the eve nitrite as a mixture
35 Of isomers 41. Sodium borohydride reduction of the double bond gives
the piperidinyi nitrite 42. Hydrochloric acid hydrolysis in the presence
of ethanol gives ethyl ester 43. The N-benzyl protecting group is
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removed by catalytic hydrogenation to give the free piperidine
compound 44. Compound 44 is further elaborated by the procedures
described in Scheme V for compound 31 resulting in the formation of
the N-derivatized carboxylic acid ~.
s A preferred embodiment of the process shown in Scheme III is
shown in Scheme VIII. 4-Methoxybenzoylacetate 4_C (wherein E is
loweralkyl or a carboxy protecting group) is reacted with an
benzodioxolyl a-bromoacetate 47 (wherein E is lower alkyl or a carboxy
protecting group) in the presence of NaH in THF to give diester 4 $,.
i o Treating compound 4~ with ethoxypropylamine and heating in acetic
acid gives the cyclic compound 49. The double bond is reduced by
catalytic hydrogenation using a palladium on carbon catalyst to give
pyrrolidone ,5~. Epimerization with sodium ethoxide in ethanol to give
the desired traps, traps configuration is followed by sodium hydroxide
1 s hydrolysis of the ester to afford the desired traps, traps carboxylic acid
51.
Scheme IX illustrates the preparation of compounds where n is 0,
Z is -CH2-, and W is other than carboxylic acid. Compound 5 5, which can
be prepared by the procedures described in Scheme IV, is converted (for
2o example, using peptide coupling condition, e.g. N-methylmorpholine,
EDCI and HOBt, in the presence of ammonia or other amide forming
reactions} to give carboxamide 56. The carboxamide is dehydrated (for
example, using phosphorus oxychloride in pyridine) to give nitrite ,~7.
Nitrite ~7 under standard tetrazole forming conditions (sodium azide
2s and triethylamine hydrochloride or trimethylsilylazide and fin oxide) is
reacted to give tetrazole 58. Alternatively nitrite 57 is reacted with
hydroxylamine hydrochloride in the presence of a base (for example,
potassium carbonate, sodium carbonate, sodium hydroxide,
triethylamine, sodium methoxide or NaH) in a solvent such as DMF,
so DMSO, or dimethylacetamide to give amidoxime ~9. The amidoxime
is allowed to react with a methyl or ethyl chloroformate in a
conventional organic solvent (such as, chloroform, methylene chloride,
dioxane, THF, acetonitrile or pyridine) in the presence of a base (for
example, triethylamine, pyridine, potassium carbonate and sodium
ss carbonate) to give an O-acyl compound. Heating of the O-acyl
amidoxime in an inert solvent (such as benzene, toluene, xylene,
dioxane, THF, dichloroethane, or chloroform and the like) results in
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cycfization to compound 6 0. Alternatively reacting the amidoxime
with thionyl chloride in an inert solvent (for example, chloroform,
dichloromethane, dixoane and THF and the Pike) affords the
oxathiadiazoie F 1_.
Scheme X illustrates the preparation of compounds in which R3 is
an acylmethylene group. A carboxylic acid 6 2 (where R4 is as
previously defined herein) is treated with oxalyl chloride in a solution
of methylene chloride containing a catalytic amount of N,N-
dimethylformamide to give the acid chloride. Treatment of the acid
1 o chloride with excess ethereal diazomethane affords a diazoketone, and
then treatment with anhydrous HCI in dioxane gives the a-chloroketone
6 3. Pyrrolidine ester 5_ where E is lower alkyl or a carboxy protecting
group, prepared in Scheme I, is alkylated with the a-chloroketone 6 3 to
provide alkylated pyrrolidine 6 4. Carboxy deprotection (for example,
i s hydrolysis of an alkyl ester using lithium or sodium hydroxide in
ethanol-water) gives the alkylated pyrrolidine acid 6 5.
Scheme XI illustrates the preparation of "reverse amides and
sulfonamides". The carboxy protected pyrrolidine 5_, prepared in Scheme
I, is reacted with a difunctionalized compound X-R$-X where R8 is
2o alkylene and X is a leaving group (for example a halide where Br is
preferred) to give N-alkylated compound 6 6. Treatment of C~6 with an
amine (R2pNH2) affords secondary amine 67. This amine (67) can be
reacted with an activated acyl compound (for example, R4-C(O)-CI) and
then carboxy deprotected (for example, hydrolysis of an ester or
25 hydrogenation of a benzyl moiety) to afford amide 68. Alternatively
amine ~7 can be reacted with an activated sulfonyl compound (for
example, R6-S(O)2-CI) and then carboxy deprotected (for example,
hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford
sulfonamide ~9.
so Scheme XII illustrates a method for synthesizing pyrrolidines by
an azomethine yfide type [3+2]-cycloaddition to an acryiate. General
structures such as compound 70 are known to add to unsaturated esters
such as 71 to provide pyrrolidines such as compound 72 (O. Tsuge, S.
Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S.
ss Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 5 2 2523-30 (1987), and
S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. ~ 1960-68
(1989)). A specific example is also shown in Scheme XII. Sifyiimine 73
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is reacted with acrylate 74 in the presence of trimethylsilyl triflate
and tetrabutylammonium fluoride to give the desired pyrrolidine 7 5 as a
mixture of isomers. This method can be modified to provide the N-
acetamido derivatives directly by reacting ~ and 7 4 with the
s appropriate bromoacetamide (for example, dibutyl bromoacetamide) in
the presence of tetrabutylammonium iodide and cesium fluoride to give
compound 7~.
Scheme XI11 illustrates a method for producing an
enantiomerically pure pyrrolidine $_0, which can be further elaborated
io on the pyrrofidine nitrogen. intermediate racemic pyrrolidine ester 77
(for example, prepared by the procedure described in Scheme V) is Boc-
nitrogen protected (for example, by treatment with Boc20) and then the
ester is hydrolyzed (for example, using sodium or lithium hydroxide in
ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid
~ s ~. The carboxylic acid is converted to its (+)-cinchonine salt, which
can be recrystallized (for example from ethyl acetate and hexane or
chloroform and hexane} to afford the diastereomerically pure salt. This
diastereomerically pure salt can be neutralized (for example, with
sodium carbonate or citric acid) to afford enantiomerically pure
2o carboxylic acid 79. The pyrrolidine nitrogen can be deprotected (for
example, using trifluoroacetic acid} and the ester reformed by the use
of ethanolic hydrochloric acid to give salt 8 0. Alternatively one can use
ethanol HCI to cleave the protecting group and form the ester in one
step. The pyrrolidine nitrogen can be further elaborated (for example,
2s by treatment with the dibutyl amide of bromoacetamide in acetonitrile
in the presence of diisopropylethylamine) to give optically active
compound ~1,. The use of (-)-cinchonine will give the opposite
enantiomer.
Scheme XIV describes another procedure for preparation of
so pyrrolidines. Pyrrolidines may be synthesized by the use of an
azomethine ylide cycloaddition to an acrylate derivative as described by
Cottrell, I. F., et.al., J. Chem. Soc., Perkin Trans. 1, 5: 1091-97 (1991 ).
Thus, the azomethine ylide precursor ~2 (where R55 is hydrogen or
methyl) is condensed with a substituted acryfate ~3 (wherein R2 is as
35 described herein and R~s is loweralkyl) under acidic conditions to
afford the substituted pyrrolidine ~4. The N-protecting group can be
removed (for example, by hydrogenolysis of an N-benzyl group) to give
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$_5, which can be alkylated under the conditions described above to
provide the N-substituted pyrrolidine $6. Standard ester hydrolysis of
86 produces the desired pyrrolidine carboxylic acid $,7.
A preferred process is shown in Scheme XV. Nitro vinyl compound
s (8 8) is reacted with beta-keto ester 8 9 in the presence of a base such
as sodium ethoxide and the like or a trialkylamine such as triethylamine
or diisopropylethylamine and the like or an amidine such as DBU and the
like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl
acetate, isopropyl acetate or methylene chloride and the like at a
1 o temperature of from about 0° C to about 100° C for a period
of time
from about 15 minutes to overnight to give compound ~0. Reduction of
the vitro group followed by cyclization was effected for example by
catalytic hydrogenation with a hydrogen pressure of from about
atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day
15 Of compound ~0_ in an inert solvent such as THF, ethyl acetate, toluene,
ethanol, isopropanol, DMF or acetonitrile and the like, using a
hydrogenation catalyst such as Raney nickel, palladium on carbon, a
platinum catalyst, such as platinum oxide, platinum on carbon or
platinum on alumina and the like, or a rhodium catalyst, such as rhodium
20 on carbon or rhodium on alumina and the like, and the like affords
intermediate nitrone 9~ or a mixture of nitrone 91 a and imine 91 b.
The reaction mixture comprising the nitrone or nitrone/imine mixture
is treated with an acid such as trifluoroacetic acid or acetic acid or
sulfuric acid or phosphoric acid or methanesulfonic acid and the like,
2s and the hydrogenation is continued to give pyrrolidine compound 92 as
the cis,cis-isomer. Epimerization at C-3 is effected by treatment of
compound ~2 with a base such as sodium ethoxide, potassium
t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or
a trialkylamine such as triethylamine or diisopropylethylamine and the
so like or an amidine such as DBU and the like in an inert solvent such as
ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the
like at a temperature of from about -20° C to about 120° C to
give the
traps, traps compound ~3. Compound 9 3 itself can optionally be resolved
into enantiomers prior to reacting with X-R3. The substantially pure
3s (i.e., at feast 95% of the desired isomer} optically active (+)-isomer of
compound ~3 is obtained by treatment of a mixture of the (+)-isomer
and the (-)-isomer of 9 3 with S-(+)-mandelic acid, D-tartaric acid or
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D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile,
ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like.
The (+)-isomer of 9 3 selectively crystallizes as the salt, leaving the
(-)-isomer of ~ in solution. Alternatively, the substantially pure (i.e.,
s at least 95% of the desired isomer) optically active (-)-isomer of
compound 9 3 can be selectively crystallized by reaction of a mixture of
the
(+)-isomer and the (-)-isomer of ~ 3 with L-tartaric acid, L-dibenzoyl
tartaric acid or L-pyroglutamic acid and the like, leaving the desired
i o (+)-isomer of compound ~3, in solution.
Compound ~3, (racemic or optically active) is reacted with X-R3
{where X is a leaving group (for example, a halide or a sulfonate) and R3
is as previously defined) using a base such as diisopropylethylamine,
triethylamine, sodium bicarbonate or potassium carbonate and the like
i s in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and
the like at a temperature of from about 0° C to about 100° C to
give the
intermediate ester ~4. The ester can be isolated or converted in situ
to the carboxylic acid {9~5 using hydrolysis conditions such as a base
such as sodium hydroxide or lithium hydroxide or potassium hydroxide
2o and the like in a solvent such as ethanol-water or THF-ethanol and the
like.
A more detailed description of the preparation of some specific
analogs is provided in Schemes XVI-XX1. Aliphatic p-ketoesters
(Scheme XVl) may be prepared by copper-catalyzed addition of a
25 Grignard reagent (for example, propylmagnesium bromide) to an
unsaturated ester, for example, ethyl 3,3-dimethylacrylate. The
resultant ester is hydrolyzed, for example with sodium hydroxide in
aqueous alcohol, and is homologated in stepwise fashion to the
corresponding ~3-ketoester, for example by activation using
so carbonyldiimidazole and condensation with magnesio-ethoxymalonate.
Alternatively, olefinic (i-ketoesters may be prepared by Claisen
rearangement of the corresponding allylic alcohols; hydrolysis and
homologation as described above produce the desired ~i-ketoester.
N-alkyl,0-alkyl bromohydraxamates are prepared according to
$s Scheme XVII. N-Boc-O-aliyl hydroxylamine is alkylated with and alkyl
halide, for example using sodium hydride as base; the double bond is
selectively reduced, for example using hydrogen and a palladium
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catalyst. After removal of the Boc protecting group, for example with
TFA, the resultant amine is acylated, for example using bromoacetyl
bromide.
The ~i-ketoesters described in Scheme XVI may be converted to
s pyrroiidine derivatives as described in Scheme XVIII. Michael addition
onto a nitrostyrene derivative can be catalyzed with base, for example
DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for
example using Raney Nickel as catalyst, to give an imine, which is
reduced further, for example using sodium cyanoborohydride under
1 o controlled pH. A mixture of isomers are generated, in which the trans-
trans is generally preferred.
Scheme XIX describes several strategies for resolving the racemic
pyrrolidines described above. Treatment with a chiral acid, for example
(S)-(+)-mandelic acid, may provide a crystalline derivative, which can
15 be further enriched through recrystallization. The salt may be washed
with base to extract the resolving agent and return the optically active
pyrrolidine product. Alternatively, the amino ester can be N-protected
(for example with Boc-anhydride) and hydrolyzed (for example with
sodium hydroxide) to give the corresponding N-protected amino acid.
2o Activation of the acid, for example as the pentafluorophenyl ester,
followed by coupling with a chiral nonracemic oxazolidinone anion,
provides the corresponding acyloxazolidinone diastereomers, which may
be separated chromatographically. Alcoholysis of one acyloxazolidinone
diastereomer, followed by cleavage of the N-protecting group, returns
2s an optically enriched amino ester. A similar transformation may be
accomplished through coupling of the protected amino acid with a chiral
nonracemic amino alcohol. After chromatographic separation of the
resultant diastereomers, the amide is cleaved and the protecting group
is removed to provide optically enriched product.
so Optically active amino esters prepared as described above may be
alkylated (Scheme XX) with a variety of electrophiles, for example
dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4-
heptyl)-N-(3-methyl-4-fluorophenyl} bromoacetamide, or N-(S2-
hydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultant ester,
35 for example using sodium hydroxide in aqueous alcohol, provides the
product.
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For one particular class of electrophile, N-(S2-hydroxyalkyl)-N-
alkyl haloacetamides, further transformations of the alkylation product
are possible (Scheme XXI). Activation (for example using
methanesulfonyl chloride) of the alcohol, followed by displacement with
halogen (for example, using lithium bromide) provides the corresponding
halide. Displacement of halide with an amine, for example
dimethylamine, provides the corresponding amino ester, which may be
hydrolyzed as previously described to provide product.
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Scheme I
R' p R2~N02 R C02E
~J/~ C02E
R2
2
N02
[HJ
~H
N N
R
R~
C02E C02E
Mixture of 4
Cis-Cis
Traps-Traps
Cis-Traps
X_Rs iRs
N
R2~'~-R~ 7
C02H
N
R 1 Trans~Trar~s
[ H20J
$ C02E
,Ra
Mixture of N
Traps-Traps
Cis-Traps C02E _B
Cis-Traps
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Scheme 11
S _ S
R2~C1 +
R
Li S Z~S
11
O~ S
Rz~R' ~ Rz S
R~
13
I \ N Rz ~ \ N ~ Rz
---a- 1~
/ O ~ CN
R~ R~
+ ISOMER
\ N R2 \ N R2
C02E ~ I / C N
R~ R~
17
1~
R2 Rs,N R2
HN
C02E ~''C02H
R~ R~
18 19
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Scheme
Halo
R O R2~OJ C02E
t~C02E '~ O ,~ R1
J02C _ R2
Hafo = CI, Br, or I 22
O R3
O
R N~ ~- N.Rs
2
Rt R2 i
C02E Rt
C02E
24
O .Rs
N
R2 Rt
C 02H
Trar>.s-Trans
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Scheme IV
N ERs N ERs
R2'~-R~ --.-T R2~'R~
C02H
CH2N2
N ~R3 N ERs
R2 R~ . R2~R~
~ CO H O ~CHN2
2
5;i
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Scheme V
O ~ N OZ O
cH3o ~ ~ + ~ ~ ~ ~ cooEt
Et02C O ~ D-~ ~ ~
C H30
a Np2
H2
N~ r O N
/ ~ / OCR O ~ / ~ / OC
COOEt ~ COOEt
fVaCNBH3
Mixture of
Cis-Cis
Traps Traps Chromatographic separation
Cis-Traps
Cis-Cis + Mixture of Traps-Traps and Cis-Traps
31
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Scheme VI
r0 . H
N- _
O ~ ~ "" ~ ~ OCH3 O
COOEt O ~ N H CsH~
Cis Traps ~ N
~ BrCH2CONHC~7 O ~ ~ OCH
and
O H iPr2fV Et COO Et
N Traps-Traps and Cis-Traps
O ~ ~ ~ ~ OCH3 3Z
COOEt
Trar~Trans
NaOH , H20, EtOH
O O
NHC3H7 ~NHC3H~
00 N 00 .. N
OCH3 + ~ ~ " ~ ~ OCH3
U
COOH COOEt
Traps-Traps Cis-Traps
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Scheme VII
C~ + S --~ ~ I \ S
o ~ o ~ S
Li~S
~'1
OMe
O ~ O ~ .~----
O
M
O
O
ISOMER
OMe OMe
w
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Scheme VII cont.
O ~ ~ o
I/ I/
OMe -- OMe
41
HN ~ O I ~ N ~ /O
C02Et / C02Et
~I ~ ~l
_4~
OMe ~ OMe
O'
R3 - OO
OMe
*rB
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/ ~ O
CH30
C02E
9~
Scheme VII!
_- CH3
Br - o'/
OE
o
0
O ~O/''_CH3 r0 O ~O/~CH3
O
C02E ~ / OCH CO E OCH3
3
~-CHa
~O
/~/O
O
O /
~OCH3
C02 ~H
Traps-Traps
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Scheme IX
iRs ~R3
N N
R R2~R
~
2 ~
R~
(CH2)m (CH2)m
C02H CONH2
iRs iRs
N N
R2~Ri RZ--~.R~
(CH2)m ~Ct"~2)m
CN
~ NH
N=N
~1
N~R3 ~R3 N~Rs
/~ ~ /- N
R2_'~-R~ R2._( 1 R~ R2'~-Ri
(CH2)m -E- (CH2~)m ---~... (CHz)m
~N ~NOH "N
HN , H2N HN~ ,
g-O
p~~ ~ O
fit
*rB
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Scheme X
R, O H o R ~
+ Cyc~ R°~CI HN
O '' ---- C02E
o O +
R2
R~
Rs l1 N i
O C02H R4' ~N
CO2E
R2 O
R2
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Scheme XI
NCH NLRB-X
Rs ~ R2
C02E C02E
O
/ Rd
N,Rs-~ NLRB-NHR2o
R2 R ~ E----- R2 R t
C02H C02E
67
O.SiRs
i Rs / 00
N
R2 R~
C02H
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Scheme XIl
R~ COZEt R~
N+ + ' R3 ~ C02Et
R2 N
CHZ '
R2
Me Si~N~ ~ \ O \ \ C02Et
/ _
OCH3
74
OCH3
f3u2N' ~N C02Et
~O
~ O
O
7~
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Scheme XIII
OCH3 OCH3
/ \
1. BOCpO
C02Et ~N
2. NaOH, EtOH -C02H
HZO
/
'O~
(t) ZZ (~) 1$
t . (+)-cinchonine
2. recrystallize fro
EtOAc/hexane
3. Na2C03
OCH3 OCH3
/ \ / \
HCI ~ ~ -C02Et BocN -C02H
HCI
EtOH
-_ O 1 O
of of
(+) ~ (+) z~
Bu2NC(O)CH2Br
EtNiPr2, CH~CN
OCH3
/ \
- C02H
O
O
(+) ~t o-J
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Scheme X!V
R55
R55
R2~CO2R5s ~~N
Ph~N ~O M a C02R5s
TFA, CH2CI2 R2
Me3SiJ
H R3Br
Pd(OH)21C H N BuaNl or Nal
COzRSs
CH3CN
R2
NaOH or LiOH R
R3 ~ CO R EtOH, H20 3 \N CO2H
2 56
R2 R2
$L
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Scheme XV
R2~ N02
+ EO
~$
O
N N
R2 1 R~ R2 1 R~ 02N O
f
C02E C02E R2 R~
C02E
NH NH
R2 R~ ~ R2~ Ri
C02E C02E
92 93
R3 /Rs
N~ N
R2i..~R~
R2~R~
COZH C02E
94
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SCHEME XVI
O. M
COOEt ~pr~ NaOH i - CDI ~OEt
.-,ate ----~ .~.nr
....rr O
cat CuCI HOOC
EtOOC
a M$~
OH ~pEt NaOH ~ CDI O~oEt
--..~. -~.
-s --~ ...girl 1
H+, heat HOOC O
EtOOC
SCHEME XVII
BrCH2COBr p
BocHN'O~ N--~ --Y BocN'O~ TFA ~ --~. Br~N.O~
R-X p~-C R
F
SCHEME XVIII
~~~u
p w~~u + OpN / ( ~ p DBU H2 Na8H3CN HN .,nCOOEt
_ _
or cat. KOtBu Ra-N pH4-5
EtOOC R
R O
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SCHEME XIX
R (s)-(+)_ R
HN mandelic
~~nCOOEt acid recrystallization neutralization HN ~nCOOEt
/ \ O / \
v
o R=
~..p ~~n
(racemic) %~' 1 ''~ (single enantiomer)
1. EDAC,
F5-pheno~ R
R
i N 0 1. NaOMe, HN
HN *,COOEt Z ~ Boc20 '~ ~ MeOH wiCOOMe
2. NaOH 3. separate 2. TFA
diastereomers ~ \
_ O
OJ CH30 O
CH30
(racemic) R = (single enantiomer)
..nr ~~ar
w. ~
I~ I
-~ N 1. EDAC, HOOBt : N
2
HN .nCOOEt ~- B°c20 w ~ H N OH 1. HCI, heat HN ~nCOOEt
2. NaOH 3. separate 2. HCl, EtOH
diastereomers / \
O
J o~
0
(racemic) (single enantiomer)
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SCHEME XX
O
Br~ ~ R~
R2 NaOH R~
NR~H2 -
R3~O.~, ~ ~-
SCHEME XXI
O
R
~ . nnsci
HN .",COOEt
2. Liar
_ O
~R of ~cl-
NaOH /
~1 ~R
'N~N~N ..nCOOH
O
O
.R _ J
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Compounds which are useful as intermediates for the preparation
of compounds of the invention are:
R2
NH
(CH2)n
(CH2)m
W Ri
(III)
wherein n is 0 or 1;
m is 0 to 6;
to W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group,
(b) -P03H2,
(c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
(e) -C(O)NHR~7 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
20 (k), sulfonamido,
(I) -C(O)NHS(O)2R ~ s where R~ 6 is loweralkyl, haloalkyl,
phenyl or dialkylamino,
(m) -S(O)2NHC(O)R~s.
Ho 0
NH
(n) ° ,
s.l" o
25 (~) HO
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OH
\ N
i
(p) o ,
O
' NH
O
(q)
.~~NwO
N
~~H
(r) O ,
N, O
~S=O
N
(S) H ,
N
~~-- CF3
N
(t) H , Or
- ~ ~ NHSOpCF3
(u) ; and
R ~ and R2 are independently selected from hydrogen, loweralkyl,
alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl,
haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyaikyl,
~o cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl,
alkylaminocarbonylalkyl, dialkylaminocarbonyialkyl,
aminocarbonylalkenyl, alkylaminocarbonylalkenyl,
dialkylaminocarbonyialkenyl, hydroxyalkenyl, aryl, arylalkyl,
aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl,
~s alkylsulfonylamidoalkyi, heterocyclic, (heterocyclic)aikyl and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or
atkanoyl and Rcc is alkylene, with the proviso that one or both of R ~ and
R2 is other than hydrogen;
or a salt thereof;
20 or a compound of the formula:
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R2 i~.,. NH
R2 ~H
y (CH2)n w (CH2)n
(CH2)m (CH2)m
W Rt or W R
t
(IV) (U)
wherein n is 0 or 1;
s m is 0 to 6;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group,
(b) -P03H2,
(c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
~o (e) -C(O)NHR» where R~~ is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyi,
(h) tetrazolyl,
(i) hydroxy,
i 5 (j) alkoxy,
(k) sulfonamido,
(1) -C(O)NHS(O)2R~6 where R16 is loweralkyl, haloalkyl,
phenyl or dialkyfamino,
(m) -S(O)ZNHC(O)R~s,
HO O
NH
20 (n) O
s.5' O
(O) HO O
OH
~N
(p) O ,
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O
' NH
O
(q) O
.~~NwO
N--r(
~~H
( r)
N,. O
~S=O
N
(S) H
N
N
(t) ~ H
or
NHSO2cF3
(u) ; and
R ~ and R2 are independently selected from hydrogen, loweralkyl,
alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyi, hydroxyalkyl,
haloalkyl, haloalkoxyalkyl, alkoxyaikoxyalkyl, . thioaikoxyalkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aminocarbonylalkyi,
~o alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,
aminocarbonylalkenyl, alkylaminocarbonylalkenyl,
dialkylarninocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl,
aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl,
aikylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or
alkanoyl and R~~ is alkyfene, with the proviso that one or both of R~ and
R2 is other than hydrogen;
or a salt thereof.
Preferred intermediates include compounds of formula (lll), (IV)
2o and (V) wherein
m is zero or 1;
W is -C02-G wherein G is hydrogen or a carboxy protecting group,
and Ri and R2 are as defined above; or
the substantially pure (+).- or (-)-isomer thereof.
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Particularly preferred intermediates are compounds of formula
(III), (lV) and (V) wherein
n and m are both 0;
W is -C02-G wherein G is hydrogen or a carboxy protecting group;
s and R~ is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl,
(v) phenyl,
(vi) pyridyl, (vii) furany! or (viii) substituted or unsubstituted 4-
methoxyphenyl,
4-fluorophenyl, 3-fluorophenyl; 4-ethoxyphenyl, 4-ethylphenyl, 4-
~o methylphenyl,
4-trifluoromethylphenyl, 4-pentafiuoroethylphenyl, 3-fluoro-4-
methoxyphenyl,
3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,
4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl
or dihydrobenzofuranyl wherein the substituent is selected from
loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix)
aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-
alkyl)aminoalkyl, and (xiii) alkylsulfonyfamidoalkyl, and R2 is
substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-
2o benzodioxolyl,
1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl,
benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fiuorophenyl or
difluorophenyl wherein the substituent is selected from loweralkyl,
alkoxy and halogen; or
2s the substantially pure (+)- or (-)-isomer thereof.
Other compounds which are useful as intermediates for the
preparation of compounds of the invention are:
(
W R,
(VI)
~Rsb-D
'N
(CH2)n
CH2)m
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wherein n is 0 or 1;
m is 0 to 6;
R 5b is alkylene;
D is a leaving group;
s W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group,
(b) -P03H2,
(c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
(e) -C(O)NHRi~ where R~7 is loweralkyi,
~o (f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
~ s (k) sulfonamido,
(I) -C(O)NHS(O)2R i s where Ri 6 is loweralkyl, haloalkyl,
phenyl or dialkylamino,
(m) -S(O)2NHC(O)R~6,
Ho 0
NH
(n) o ,
s.S' o
20 (O) HO O
OH
~~ \ N
i
(p) O ,
O
_~ ' NH
O
(q) O ,
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.~~ Nw O
N
~~H
{r) O ,
N~ O
~S= O
N
{s) " ,
~N
~~-- CFA
N
{t) H , Or
- ~ ~ NHSOzCF~
{u) ; and
s R~ and R2 are independently selected from hydrogen, loweralkyl,
alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi,
haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl,
alkylaminocarbonylalkyf, dialkylaminocarbonylalkyl,
~o aminocarbonylalkenyl, alkylaminocarbonylalkenyl,
dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl,
aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl,
alkytsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
{Raa){Rbb)N-Rcc- wherein Raa is aryl or arylafkyl, Rbb is hydrogen or
~ s alkanoyl and Rcc is alkylene, with the proviso that one or both of R 1 and
R2 is other than hydrogen;
or a salt thereof;
or a compound of the formula:
R2 ~RSb-Q R2y.... N~R5b-O
'N
(Cl"'~2)n (CH2)n
v
(CH2)m
(CH2)m
W R, or W R~
(Vll) (VIII)
wherein n is 0 or 1;
m is 0 to 6;
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Rsb is alkylene;
Q is a leaving group;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group,
(b) -P03H2,
s (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
(e) -C(O)NHR~7 where R» is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
~o (h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(I} -C(O)NHS{O)2R ~ 6 where Ri s is loweralkyl, haloalkyl,
~ s phenyl or dialkylamino,
(m} -S{O)2NHC(O)R~6,
HO O
NH
(n) O ,
O
(~) HO O
OH
~N
{p) O
O
' NH
O
20 (q) O
N\ '
O
N--r(
~~H
( r)
*rB
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N, O
~S= O
N
(S) H ,
N
~>-- CFA
N
(t) H , Or
- ~ ~ NHS02CF3
(u) ; and
R ~ and R2 are independently selected from hydrogen, loweralkyl,
s alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl,
haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl,
alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,
aminocarbonylalkenyl, alkylaminocarbonylalkenyl,
~o dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl,
aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl,
alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(R~b)N-R~~- wherein Raa is aryl or arylalkyl, Rib is hydrogen or
alkanoyl and R~~ is aikylene, with the proviso that one or both of R j and
~s R2 is other than hydrogen;
or a salt thereof.
Preferred intermediates include compounds of formula (VI), (VII)
and (VIII) wherein
m is zero or 1;
2o R5b is alkylene;
Q is a leaving group;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group,
and R~ and R2 are as defined above; or
the substantially pure (+)- or (-)-isomer thereof.
2s Particularly preferred intermediates are compounds of formula
(Vi), (Vil) and (Vl.ll) wherein
n and m are both 0;
R 5b is alkylene;
Q is a leaving group;
3o W is -C02-G wherein G is hydrogen or a carboxy protecting group;
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and Ri is (i) loweralkyl, (ii) alkenyi, (iii) alkoxyalkyl, (iv) cycloalkyl,
(v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or
unsubstituted 4-methoxyphenyl,
4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-
s methylphenyl,
4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-
methoxyphenyl,
3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,
4-hydroxyphenyl, 4-t-butylphenyf, 1,3-benzodioxolyl, 1,4-benzodioxanyl
~o or dihydrobenzofuranyl wherein the substituent -'ss selected from
loweralkyl, haloalkyl, aikoxy, alkoxyalkoxy and carboxyalkoxy, (ix)
aryalkyl, (x) aryioxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-
atkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is
substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-
~s benzodioxolyi,
1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl,
benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or
difluorophenyl wherein the substituent is selected from loweralkyl,
alkoxy and halogen; or
2o the substantially pure (+)- or (-)-isomer thereof.
Other compounds which are useful as intermediates for the
preparation of compounds of the invention are:
R2 N~ Rsb - NHR2oa
(CFi2)n
~C~"~2)m
R~
W
2s (IX)
wherein n is 0 or 7 ;
m is 0 to 6;
Rsb is alkylene;
ao Rzoa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl,
haloalkoxyaikyl, cycloaikyl, cycloalkylalkyl, aryl or aryfalkyl;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group,
(b) -POgH2,
*rB
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(c) -P(O){OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
(e) -C(O)NHR~~ where Rig is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
o (I) -C(O)NHS(O)2Ry6 where R~6 is toweralkyl, haloalkyl,
phenyl or dialkylamino,
(m) -S(O)2NHC(O)Ris,
Ho 0
NH
(n) O ,
O
(O) HO O
OH
~N
i
(p~ O
15 ,
O
O
(q) o ,
.~~ Nw O
N
~~H
( r) O ,
~O
~S= O
H
(S) ,
*rB
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N' ~
-- CFy
N
(t) ~ H , Or
- ~ ~ NHSOZCF3
(u) ; and
R ~ and R2 are independently selected from hydrogen, loweralkyl,
alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyaikyl,
s haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl,
cycloatkyl, cycloalkylalkyl, aminocarbonylalkyl,
alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,
aminocarbonylalkenyl, alkylaminocarbonyfalkenyl,
dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl,
~o aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl,
alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or
alkanoyl and R~~ is alkylene, with the proviso that one or both of R 1 and
R2 is other than hydrogen;
~ s or a salt thereof;
or a compound of the formula:
R2 N~RSb - NHR2oa R2~n... NiRSb - NHR~a
w (CH2)n w (CH2)n
(CH2)m (CH2)m
W R
W R~ or '
(X) (XI)
wherein n is 0 or 1;
m is 0 to 6;
R5b is aikylene;
R2oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl,
haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group,
(b) -P03H2,
(c) -P(O)(OH)E where E is hydrogen, foweralkyl or arylalkyl,
(d) -CN,
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(e) -C(U)NHRi7 where R» is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(I) -C(O)NHS(O)2Ri6 where R~6 is loweralkyl, haloalkyl,
phenyl or dialkylamino,
(m) -S(O)2NHC(O)R~s,
HO O
NH
I
(n) o ,
S.s' o
(o) Ho 0
OH
~N
i
(p) o ,
O
_~ NH
O''
(q) o '
.~~ Nw O
N
~~H
O
(r) ,
~O
~S= O
N
(g) H ,
~. N
~~-- CF3
N
(t) H , Or
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- ~ ~ NHS02CF3
(u) ; and
R ~ and R2 are independently selected from hydrogen, loweralkyl,
alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyfalkyi, hydroxyalkyl,
haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl,
s cycloalkyl, cycloalkylatkyl, aminocarbonylalkyl,
alkylaminocarbonylalkyl, dialkylaminocarbonylaikyl,
aminocarbonylalkenyl, alkylaminocarbonylalkenyl,
dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl,
aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl,
~o aikylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyf and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or
alkanoyl and R~~ is alkyiene, with the proviso that one or both of Ri and
R2 is other than hydrogen;
or a salt thereof.
~s Preferred intermediates include compounds of formula (lX), (X)
and (XI) wherein
m is zero or 1;
R5b is alkylene;
R2oa is hydrogen, loweralkyi, alkenyl, haloalkyl, alkoxyalkyl,
2o haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is -C02-G wherein G is hydrogen or a carboxy protecting group,
and R~ and R2 are as defined above; or
the substantially pure (+)- or (-)-isomer thereof.
Particularly preferred intermediates are compounds of formula
25 (1X), (X) and (XI) wherein
n and m are both 0;
R5b is alkylene;
R2oa is hydrogen, loweralkyl, alkenyl, haloalkyl, aikoxyalkyl,
hatoalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
so W is -C02-G wherein G is hydrogen or a carboxy protecting group;
and R1 is (i) loweralkyl, (ii) alkenyl, (iii) atkoxyalkyl, (iv) cycloalkyl,
(v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or
unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-
ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-triffuoromethylphenyl,
ss 4-pentafluoroethyiphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-
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ethoxyphenyi, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-
hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyi, 1,4-benzodioxanyl
or dihydrobenzofuranyf wherein the substituent is selected from
loweralkyl; haloalkyl, alkoxy, alkoxyalkoxy and carboxyatkoxy, (ix)
s aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-
alkyl)arninoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is
substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-
benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl,
dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl,
fluorophenyl or difluorophenyl wherein the substituent is selected from
loweralkyl, alkoxy and halogen; or
the substantially pure (+)- or (-)-isomer thereof.
The foregoing may be better understood by reference to the
following examples which are provided for illustration and not intended
~ s to limit the scope of the inventive concept. The following abbreviations
are used: Boc for tert-butyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU
for 1,8-diazabicyclo[5.4.0]undec-7-ene, EDCI for 1-(3-
dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, EtOAc for
ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazote, Et3N
2o for triethyiamine, TFA for trifluoroacetic acid and THF for
tet rahyd rofu ran.
_Examole 1
2s r n r n - 2- 4-Methox h n I -4- 1 nz i x I- I -1-
r ~(aminocarbonvlmethvl) avrrolidine-3-carboxylic acid
Example 1 A
h I - 4-m h n I -4-nitr meth I- - 1 nz i x I - I r
so To ethyl (4-methoxybenzoyl)acetate (23.0 g, 0.104 mol), prepared
by the method of Krapcho et al., Org. Syn. 47, 20 (1967), and 5-(2-
nitrovinyf)-1,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of
toluene and heated to 80 °C was added 1,8-diazabicyclo[5,4,0] undec-7-
ene (DBU, 0.65 g) with stirring. The mixture was heated until all the
3s vitro starting material dissolved. The solution was stirred without
heating for 30 minutes (min) and then an additional 0.65 g of DBU was
added. After stirring an additional 45 minutes, thin layer
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chromatography (5% ethyl acetate in methylene chloride) indicated the
absence of vitro starting material. Toluene (200 mL) was added, and
the organic phase was washed with dilute hydrochloric acid and NaCI
solution. The organic phase was dried over sodium sulfate and then
s concentrated under reduced pressure. The residue obtained was
chromatographed on silica gel eluting with 3:1 hexane-ethyl acetate to
give 21.22 g of the desired product as a mixture of isomers and 9.98 g.
of recovered ethyl (4-methoxybenzoyl}acetate.
Example 1 B
~h_yl 2-y4-m ethoxypheny~-4-( 1.3-benzodioxol-5-yl)-4.5-dihyrdro-3H-ovrrole-3
~arboxylate
The compound resulting from Example 1A (21 g) in 500 mL of
ethanol was hydrogenated under 4 atmospheres of hydrogen pressure
~ s using a Raney nickel 2800 catalyst (51 g). (The Raney nickel was
washed with ethanol three times before use.) The catalyst was
removed by filtration, and the solution was concentrated under reduced
pressure. The residue obtained was chromatographed on silica gel
eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of
2o the desired product.
Example 1 C
Ethyl 2-(4-methoxyphenyl-4-(1 3-benzodioxol-5-yl)-pvrrolidine-3-carbox~ate~
~~ a mixture of cis-cis: trans.trans: and cfs.trans-isomers
25 The compound resulting from Example 1 B (11.89 g, 0.324 mol) was
dissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol. Sodium
cyanoborohydride (2.35 g, 0.374 mot) and 5 mg bromocresol green were
added. To this blue solution was added dropwise a solution of 1:2
concentrated HCI in ethanol at such a rate that the color was kept at
so fight yellow-green. After the yellow color persisted without additional
HCI, the solution was stirred an additional 20 minutes. The solution
was concentrated in vacuo and then partitioned between chloroform and
an aqueous potassium bicarbonate solution. The organic phase was
separated, dried over sodium sulfate, and concentrated under reduced
3s pressure. The residue was chromatographed on silica gel eluting with
85:15 ethyl acetate-hexane to give 5.96 g. of a mixture of 64%
traps, traps-compound and 34% cis, traps-compound. Further elution
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with pure ethyl acetate gave 0.505 g of an unknown solid followed by
3.044 g of pure cis,cis-compound.
Example 1 D
~rans irans 2 {_4 Methoxvpheny_I)-4-l1 3-benzodioxol-5-vll-1-
~ro~ylaminocarbonvlmethy~-oyrrolidine-3-carboxylic acid
The mixture of 64% irans,trans- and 34% cis,trans-pyrrolidines
(the mixture resulting from Example i C) (5.72 g, 15.50 mmol},
ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl
~ o bromoacetamide (3.42 g, 19.0 mmol), prepared by.-the method of Weaver,
W.E. and Whaley, W.M., J. Amer. Chem. Soc., ~~: 515 (1947), in 30 mL of
acetonitrile was heated at 50 °C for 1 hour. The solution was
concentrated in vacuo. The residue was dissolved in toluene, shaken
with potassium bicarbonate solution, dried over sodium sulfate and
t s concentrated in vacuo to give 7.16 g of product as a mixture of
traps, traps- and cis, traps- ethyl esters.
This mixture was dissolved in a solution of 50 mL of ethanol and
15 mL of water containing 5.00 g of sodium hydroxide and stirred for 3
hours at room temperature. The ~ solution was concentrated in vacuo and
20 60 mL of water added. The mixture was extracted with ether to remove
the unreacted cis,irans- ethyl ester. The aqueous phase was treated
with hydrochloric acid until slightly cloudy. It was then further
neutralized with acetic acid to give the crude acid product. The crude
product was filtered and purified by dissolving it in tetrahydrofuran,
zs drying over sodium sulfate, concentrating in vacuo, and crystallizing
from ether to give 3.230 g of the title compound. m.p. 15i-'153 °C. ~ H
NMR (CD30D, 300 MHz) 8 0.87 (t, J = 7 Hz, 3H), 1.49 (sextet, J = 7 Hz,
2H), 2.84 ( d, J = 16 Hz, 1 H), 2.95-3.20 (m, 4H), 3.20 (d, J = i 6 Hz, 1 H),
3.34-3.42 (m, i H), 3.58-3.66 (m, 1 H), 3.78 (s, 3H), 3.88 (d, J = 10 Hz,
so 1 H), 5.92 (s, 2H), 6.75 (d, J = 8 Hz, 1 H), 6.86 (dd, J= 8 Hz, J = 1 Hz, 1
H),
6.90 (d, J = 9 Hz, 2H), 7.02 (d, J = 1 Hz, 1 H), 7.40 (d, J = 9 Hz, 2H}.
Examale 2
r n r n - - 4-M hox hen I -4- 1 nzo i x !- I -1- min r n Im h i -
s5 p~rrrolidine-3-carboxylic acid
Using the method described in Example 1 D, 300 mg of the mixture
of 64% trans,trans- and 34% cis,trans-pyrrolidines (the mixture
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resulting from Example 1 C), 220 mg of diisopropylethylarnine and 184
mg iodoacetamide were reacted at 45 °C in 1 mL acetonitrile to give
291 mg of a mixture of mans, traps- and cis, traps- N-alkylated esters.
A portion (270 mg.) was hydrolyzed with 200 mg NaOH in 1 mL of water
s and 3 mL of ethanol; a chloroform extraction was used to remove the
unreacted cis,rrans- ethyl ester. The isolation and purification
procedures described in Example 1 D were used to give 134 mg of the
title compound. m.p. 246-248 °C. 1 H NMR (DMSO-ds, 300 MHz) 8 2.61 (d,
J = 16 Hz, 1 H), 2.71 (t, J = 9 Hz, 1 H), 2.90 (t, J = 9 Hz, 1 H), 2.98 (d, J
=
~ 0 16 Hz, 1 H),3.25-3.35 (m, 1 H), 3.45-3.55 (m, 1 H), 3:71 (s, 3H), 3.75 (d,
J =
Hz, 1 H), 6.00 (s, 2H), 6.81 (s, 2H), 6.90 (d, J = 8 Hz, 2H), 7.10 (s, 1 H),
?.17 (s, 1 H), 7.34 (s, 1 H), 7.38 (d, J = 8 Hz, 2H).
Example 3
~s traps.traps-2-~-Methoxynhenyl~-4-(1.3-benzodioxQl-5-YIL1-(4-fluorobenz~,L
p_vrrolidine-3-carbolic acid
Using the method described in Example 1 D, 300 mg of the mixture
of 64% trans,l'rans- and 34% cis,trans- pyrrolidines (the mixture
resulting from Example 1 C), 220 mg of diisopropylethylamine and 185
2o mg of 4-fluorobenzyl bromide were reacted at room temperature for 3
hours in 1 mL of acetonitrile to give 387 mg of a mixture of
trans,trans- and cis,trans-N-alkylated esters. A portion (360 mg) was
hydrolyzed with 250 mg NaOH in 7 mL of water and 4 mL of ethanol to
give 160 mg of the title compound as an amorphous powder. iH NMR
2s (CDC13, 300 MHz) 8 2.74 (t, J = 9 Hz, 1H), 2.95 (t, J = 7 Hz, 1H), 2.98 (d,
J
= 14, 1 H), 3.07 (dd, J = 9 Hz, 1 Hz, 1 H), 3.42-3.53 (m, 1 H), 3.70 (d, J = 9
Hz, 1 H), 3.78 (d, J = 14, 1 H), 3.81 (s, 3H), 5.92 (s, 2H), 6.70 (d, J = 8
Hz,
1 H), 6.77 (dd, J = 8 Hz, 1 Hz, 1 H), 6.91 (d, J = 9 Hz, 2H), 6.94 -7.00 (m,
3H), 7.20 - 7.25 (M, 1 H), 7.44 (d, J = 9 Hz, 2H).
Exam lp a 4
frans. frans-2-(4-Methox,~~phen~l-4-(1. 3-ben zodioxol-5-vl)-1-(2-eth
oxyethvll
~yrrolidine-3-carbox~rlic acid
Using the method described in Example 1 D, 300 mg. of the mixture
3s of 64% traps, traps- and 34% cis, traps-pyrrolidines (the mixture
resulting from Example 1 C), 220 mg of diisopropylethylamine and 152
mg of 2-bromoethyl ethyl ether were refiuxed in 1.5 mL acetonitrile fog
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3 hours (bath temperature at 95 °C) to give 346 mg of a mixture of
traps, irans- and cis, traps-esters. Hydrolysis with 250 mg NaOH in 1
mL of water and 3 mL of ethanol afforded 14'0 mg of the title compound.
m.p. 88 - 90 °C. ~H NMR (CDC13, 300 MHz) 8 1.25 (t, J = 7 Hz, 3H), 2.21-
2.32 (m, 1 H), 2.70-2.80 (m, 1 H), 2.85-2,94 (m, 2H), 3.38-3.55 (m, 6H),
3.67 (d, J = 10 Hz, 1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J = 8 Hz, 1 H),
6.84 (m, 1 H), 6.84 (d, J = 9 Hz, 2H), 7.08 (d, J = 1 Hz, 1 H), 7.33 (d, J = 9
Hz, 2H).
1 o Exarnale 5 --
r n r n - - 4-M hox hen 1 -4- 1 -b nz i x I- i -1- 2- r x h I
pyrrolidine-3-carboxylic acid
Using the method described in Example 1 D, 520 mg of the mixture
resulting from Example 1 C, 364 mg of diisopropylethylamine, 50 mg
~ s potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted
at 125 °C in 0.5 mL acetonitrile for 4 hours to give 517 mg of a
mixture
of trans,trans- and cis,trans-esters. A portion (500 mg) was
hydrolyzed with 315 mg NaOH in 1 mL of water and 4 mt_ of ethanol to
give 225 mg of the title compound as an amorphous powder. ~H NMR
20 (CDC13, 300 MHz) 8 0.87 (t, J = 7 Hz, 3H), 1.53 (sextet, J = 7 Hz, 2H),
2.28-2.41 (m, 1H), 2.71-2.83 {m, iH), 2.92-3.08 (m, 2H), 3.30 (t, J = 7
Hz, 2H), 3.40-3.60 {m, 4H), 3.72-3.83 (m, 1 H), 3.76 (s, 3H), 5.92 (s, 2H),
6.71 (d, J = 8 Hz, 2H), 6.74 (dd, J = 8 Hz, 1 Hz), 6.71 (d, J = 9 Hz, 2H),
7.07 (d, J = 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H).
Example 6
~rans;raps 2 f4 Methoxvaheny~-4-(1 3-benzodioxol-5-vl)-1-f2-f2
methoxyethoxy~eth~lt-a_ ry rolidine-3-carboxylic acid
so ExamRle 6A
~Jhyl traps traps 2 (4 methoxvohenyl)-4-ji 3-benzodioxol-5-vl) savrrolidine-3-
carboxvlate_
To the pure cis,cis-compound resulting from Example 1C (3.02 g)
dissolved in 10 mL of ethanol was added 20 drops of a solution of 21
ss sodium ethoxide in ethanol. The reaction mixture was refluxed
overnight, at which time thin layer chromatography in ethyl acetate
indicated the absence of starting material. The NaOEt was neutralized
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with HCi in ethanol, and the solution was concentrated in vacuo. The
residue was taken up in toluene and extracted with potassium
bicarbonate in water. The toluene was dried over sodium sutfate and
concentrated under reduced pressure to give 2.775 of the title compound
s which was pure by TLC (ethyl acetate).
Example 68
~rartc traps 2 (4 Methoxvohenyl-Z 4-(1 3-benzodioxol-5-vll-1-f2-(2
methoxvethoxy~ethyll-oyrrolidine-3-carboxylic acid
s o Using the method described in Example 1 D, .250 mg of the
compound resulting from Example 6A, 150 mg of 2-(2-
methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1
mL acetonitrile were heated at 100 °C for 3 hours to give 229 mg of
the irans, traps-ester. A portion (200 mg) was hydrolyzed with 125 mg
~ s NaOH in 1 mL of water and 2 ml- of ethanol to give 151 mg of the title
compound as an amorphous powder. iH NMR (CD30D, 300 MHz) 8 2.9-3.9
(m, 13H), 3.81 (s, 3H), 4.49 (d, J = 10 Hz, 1 H}, 5.94 (s, 2H), 8.79 (d, J = 8
Hz, 1 H}, 6.89 (dd, J = 8 Hz, 1 Hz, 1 H), 7.00 (d, J = 9 Hz, 2H), 7.05 (d, J =
1
Hz, 1 H), 7.49 (d, J = 9 Hz, 2H).
Example 7
traps frans 2 (4 Methoxyphenyl)-4-(7 3-benzodioxo(-5-vl)-1-f2-(2-
ovridvllethvll
~y-rrolidine-3-carboxylic acid
The compound resulting from Example 6A (250 mg), 2-vinyl
pyridine (355 mg) and one drop of acetic acid were dissolved in 2-
methoxyethanol, and stirred at 100 °C for 2.5 hours. Toluene was added,
and the solution was washed with potassium bicarbonate solution. The
solution was dried over potassium bicarbonate and concentrated in
vacuo. Toluene was added and the solution re-concentrated. This was
so done until the odor of 2-vinylpyridine was gone. The residue was taken
up in hot heptane, filtered to remove a small amount of insoluble
impurity, and concentrated in vacuo to give 225 mg of intermediate
ester. The ester was hydrolyzed by the method described in Example 1 D
to give 202 mg of the title compound as the dihydrate. m.p. 77-80 °C.
1H NMR (CD30D, 300 MHz) S 2.8 - 3.3 (m, 6H), 3.55-3.70 (m, 2H}. 3.76 (s,
3H}, 3.99 (d, J = 10 Hz, 1 H), 5.92 (d, J = 1 Hz, 2H), 6.72 (d, J = 8 Hz, 1
H),
R Rc7 ldd. J = 8 Hz. 1 Hz), 6.85 (d, J = 9 Hz, 2H), 6.92 (d, J = 1 Hz, 1 H},
*rB
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7.20 (d, J = 9 Hz, 2H), 7.20-7.32 (m, 2H), 7.70-7.80 (m, 2H), 8.40 (d, J =
4 Hz, 1 H).
Exam I
~~'nC traps 2 f4 Methoxvvhenvll 4 f1 3-benzodioxol-5-vl?-i-(morpholin-4
ylcarbonvll-c"rrolidine-3-carboxylic acid
To the compound resulting from Example 6A (300 mg) and 164 mg
triethylamine dissolved in 2 mL of methylene chloride and cooled in an
ice bath was added 146 mg 1-morpholinocarbonyl chloride. The mixture
was stirred 3 hours at room temperature. Toluene was added and the
solution was washed with potassium bicarbonate solution, dried over
sodium sulfate and concentrated in vacuo to give the intermediate
ester. The ester was hydrolyzed by the method described in Example 1 D
to give 288 mg of the title compound. m.p. 244-246 °C. i H NMR (DMSO-
~ s ds, 300 MHz) 8 2.96 (dd, J = l2.Hz, 13 Hz, 1 H), 3.03-3.13 (m, 2H), 3.20-
3.30 {m, 2H), 3.40-3.60 (m, 5H), 3.74 {s, 3H), 3.70-3.85 (m, 3H), 5.10 {d,
J = 10 Hz, 1 H), 5.99 (d, J = 1 Hz, 2H), 6.80-6.90 (m, 2H), 6.87 (d, J = 9 Hz,
2H), 7.07 (s, 1 H), 7.25 (d, J = 9 Hz, 2H).
Example 9
ran raps-2- 4-M thox hen ( -4- 1 3-benzodiox le-5- I -1- bu lamin c r n I
~rrolidine-3-carboxylic acid
To the compound resulting from Example 6A (300 mg) dissolved in
2 mL tetrahydrofuran and cooled in an ice bath was added 88 mg of butyl
25 isocyanate. After 40 minutes at room temperature, toluene was added, '
and the solution was concentrated in vacuo to give the intermediate
ester. The ester was hydrolyzed by the method described in Example 1 D
to give 232 mg of the title compound. m.p. 220-221 °C. ~ H NMR (DMSO-
d6, 300 MHz) 8 0.78 (t, J = 7 Hz, 3H), 1.10 (sextet, J = 7 Hz, 2H), 1.22
30 (quintet, J = 7 Hz, 2H), 2.78-3.05 (m, 3H), 3.40-3.56 (m, 2H), 3.74 (s,
3H), 3.95-4.05 (m, 1 H), 4.93 (d, J = 9 Hz, 1 H), 5.80 (t, broad, J = 7 Hz,
1 H), 5.99 (s, 2H), 6.78-6.86 (m, 2H), 6.88 (d, J = 9 Hz. 2H), 7.00 {d, J = 1
Hz, 1 H), 7.12 (d, J = 9 Hz, 2H).
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Example 1
mans traps 2 (4 Methoxy~henvl) 4- 1 3-benzodioxol-5-v!)-1-(4-
methoxX~.henylaminocarbon,~l~-3-~yrrolidine-3-c ra boxvlic acid
The compound resulting from Example 6A (300 mg) was treated
s with 133 mg of 4-methoxyphenyl isocyanate by the procedure described
in Example 9. The resulting ester was hydrolyzed with NaOH using the
method described in Example 1 D to give 279 mg of the title compound.
m.p. 185-187 °C. ~ H NMR (CDC13, 300 MHz) b 3.23 (dd, J = 12 Hz, 13 Hz,
1 H), 3.55-3.68 (m, 2H), 3.72 (s, 3H), 3.83 (s, 3H), 4.50-4.65 (m, 1 H),
s o 5.06 (d, J = 10 Hz, 1 H), 5.90 (s, 1 H), 5.95 (s, 1 H~f 6.72 (d, J = 9 Hz,
2H),
6.7-6.8 (m, 3H), 6.92 (d, J = 9 Hz, 2H), 6.97 (d, J = 9 Hz, 2H), 7.37 (d, J =
9 Hz, 2H).
Example 11
is traps traps 2 (4 Methoxvphenyl) 4 (1 3 benzodioxol-5-vl)-1-
acetvlovrrolidine-3-
carboxylic acid
The compound resulting from Example 6A (250 mg) in 0.5 mL of
toluene was treated with 200 mg of acetic anhydride. After stirring 2
hours at room temperature, water was added and the acetic acid
2o neutralized with potassium bicarbonate. The mixture was extracted
with toluene to give 273 mg of the intermediate ester. A portion of the
ester (200 mg) was hydrolyzed using the method of Example 1 D to give
211 mg of the title compound. m.p. 248-250 °C. Rotational isomers are
seen in the NMR. ~ H NMR (DMSO-d6, 300 MHz) S 1.55 and 2.00 (s, 3H),
zs 2.94 and 3.03 (dd, J = 12 Hz, 13 Hz, 1 H), 3.3-3.6 (m, 2H), 3.72 and 3.76
(s, 3H), 4.12 and 4.28 (dd, J = 12 Hz, 7 Hz, 1 H), 4.95 and 5.04 (d, J =
1 OHz, 1 H), 6.00 (s, 2H), 6.75-6.87 (m, 3H), 6.95 and 7.04 (d, J = 9 Hz,
2H), 7.18 and 7.32 (d, J = 9 Hz, 2H).
3o Examale 12
r n raps- - 4-Methox hen ! -4- 1 3-benzodioxol- L -1- 2-f ro I - rr 1i in
carboxyfic acid
To the compound resulting from Example 6A (300 mg) and 164 mg
triethylamine dissolved in 2 mL methylene chloride and cooled in an ice
3s bath was added 138 mg of 2-furoyl chloride. The mixture was stirred
30 minutes at room temperature and then worked up by the procedures
described in Example 8 to give the intermediare ester. The ester was
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hydrolyzed by the procedure described in Example 1 D to give 269 mg of
the title compound as an amorphous powder. ~ H NMR (DMSO-d6, 300
MHz} b 3.06 (dd, J = 12 Hz, 13 Hz, 1 H), 3.3-3.6 {m, 2H}, 4.25 (m, 1 H),
5.19 ( d, J = 10 Hz, 1 H), 6.67.4 (m, 8H), 7.8-7.9 (m, 1 H).
Example 13
traps frans 2 t4 MethoxvohenvlL4-!1 3-benzodioxol-5-vll-1
~ph~nylaminocarbonvll t~vrrolidine-3-carboxylic acid
Starting with the compound resulting from Example 6A, phenyl
~ o isocyanate and the procedures described in Exana~ple 9, the title
compound was prepared. m.p. 209-211 °C. ~ H NMR (DMSO-ds, 300 MHz)
8 3.03 (dd, 1 H), 3.55 (m, 1 H), 3.70 (m, 1 H), 3.72 (s, 3H), 4.15 (m, 1 H),
5.13 (d, 1 H), 6.00 (s, 2H), 6.88 (m, 5H), 7.07-7.20 (m, 3H), 7.30 (d, 2H),
7.38 (d, 2H), 8.20 (bs, 1 H).
is
Example 14
_trans traps 2 (4 Methoxvohenvl)-4-(1 3-benzodioxol-5-vl)-1
~ ll laminocarbonvlmethvl)-ovrrolidine-3-carboxylic acid
Using the procedures described in Example 1 the title compound
2o was prepared. m.p. 138-140 °C. i H NMR {CDC13, 300 MHz) 8 2.84 (d,
1 H), 2.90-3.i 0 (dt, 2H), 3.28 (d, 1 H), 3.35 (dd, 1 H), 3.62 {m, 1 H), 3.72-
3.97 (m, 3H), 3.80 {s, 3H), 5.13 {bd, 2H), 5.80 (m, 1 H), 5.97 (s, 2H), 6.74-
6.97 (m, 5H), 7.38 (d, 2H).
25 Exam-ple 1
r n. - - 4-M thox h n I -4- 1 n i x i- I -1- n-
bntvlaminocarbonkmeth~rl)-nyrrolidine-3-~arboxvlic acid
Using the procedures described in Example 1 the title compound
was prepared. m.p. 105-107 °C. ~ H NMR (CDC13, 300 MHz) 8 0.90 (t, 3H),
30 1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, 1 H), 2.87-3.35 (m, 6H), 3.62 (m, 1
H),
3.80 (s, 3H), 5.97 (s, 2H), 6.75-6.92 (m, 5H), 7.28 (d, 2H).
Example 16
r n . - 4-M th x h n I -4- 1 nzo i x (- I -1- N- n- r I -N-
35 methvlaminocar nklmeth~l-~yrrolidine-3-carboxylic acid
Using the procedures described ire Example 1 the title compound
was prepared as an amorphous solid. Rotational isomers are seen in the
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NMR. ~ H NMR (CDC13, 300 MHz) S 0.73, 0.84 (2t, 3H), 1.49 (m, 2H), 2.80
(dd, 1 H), 2.85 (2s, 3H), 2.95-3.20 (m, 3H), 3.20-3.40 (m, 1 H), 3.40 (d,
1 H), 3.60 (m, 1 H), 3.79 (s, 3H), 5.93 (s, 2H), 6.73 (d, 1 H), 6.86 (m. 2H),
7.03 (m, 1 H), 7.32 (d, 2H).
s
Example 17
r n r n - - 4-M th x h n I -4- 1 en odiox 1- I -1- rr li in-1
~r r~a bonvlmethyl_)-ovrro(idine-3-carboxylic acid
Using the procedures described in Example 1 the title compound
~ o was prepared as an amorphous solid. ~ H NMR (CLlCl3, 300 MHz) s 1.40-
1.70 (m, 6H), 2.80 {d, 1 H), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m, 2H),
3.73 (d, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d, 1 H), 6.80-6.90 {m, 3H),
7.04 (d, 1 H), 7.30 (d, 2H).
~ s Examc~le 18
~~ns irans 2 (4 Methoxvohenyl)-4~1 3-benzodioxol-5-vl)-1-
~isobutylaminocarbonylmethxl~yrrolidine-3-carboxylic acid
Using the procedures described in Example 1 the title compound
was prepared. m.p. 175-177 °C. 1 H NMR (CD30D, 300 MHz) 8 0.87 (dd,
20 6H), 1.75 (septet, 1 H), 2.85 (d, 1 H), 2.90-3.10 (m, 4H), 3.23 (d, 1 H),
3.40
(m, 1 H), 3.58-3.67 (m, 1 H), 3.78 (s, 3H), 3.89 (d, 1 H), 5.92 (s, 2H), 6.76
(d, 1 H), 6.86 (dd, 1 H), 6.91 (d, 2H), 7.02 (d, 1 H), 7.40 (d, 2H).
Example 19
25 ~r~.ns trans-2-(4-Methoxvohenyi)-4-(1 3-benzodioxoi-5-yl)-1-
(cvclooentvlaminocarbonKlmethvl)-ovrrolidine-3-carboxylic acid
Using the procedures described in Example 1 the title compound
was prepared. m.p. 137-139 °C. ~ H NMR (CDC13, 300 MHz) 8 1.34 (m,
2H), 1.62 (m, 4H), 1.90 (m, 2H), 2.76 (d, 1 H), 2.90 (t, 1 H), 3.04 (dd, 1 H),
30 3.22 (d, 1 H), 3.28 (dd, 1 H), 3.40 (m; 1 H), 3.80 (s, 3H), 4.15, (m, 1 H),
5.97
(d, 2H), 6.75-6.95 (m, 5H), 7.27 (m, 2H).
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Fxamnle 20
r n r n - - 4-M h x h n I -4- 1 n i x I- I -1- m h lip-4
yl~minocarbonylmethvll-ovrrofidine-3-carboxylic acid
Using the procedures described in Example 1 the title compound
was prepared as an amorphous solid. ~ H NMR (CDC13, 300 MHz) b 2.82 (d,
1 H), 3.00 (m, 2H}, 3.24 (m, 1 H), 3.30-3.52 (m, 4H), 3.52-3.75 (m, 8H),
3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1 H), 6.84 (d, 3H), 7.00 (s, 1 H), 7.28
(d,
2H).
Example 21 --
r ~ n r n - - 4-Methox h n I -4- 1 -benzodi x I- ! -1- 2- h n x h I
gyrrolidine-3-carboxylic acid
Using the procedures described in Example 4 the title compound
was prepared as an amorphous solid. ~ H NMR (CD30D, 300 MHz) 8 2.82
~ s (m, 1 H), 2.96 (dd, 1 H), 3.13 (m, 1 H), 3.32 (m, 1 H), 3.51-3.70 (m, 2H),
3.77
(s, 3H), 4.00 (d, 1 H), 4.07 (m, 2H), 5.91 (s, 2H), 6.72 (d, 1 H), 6.80-6.95
(m, 6H), 7.03 (d, 1 H), 7:22 {dd, 2H), 7.39 (d, 2H).
Example 22
2o frans traps 2 (4 Me hoxyphenvl)-4- 1 3-benzodioxo~vl)-1-(2-
methoxvethyl_aminocarbonvlmethvl)-avrrolidine-3-carboxylic acid
Using the procedures described in Example 1 the title compound
was prepared. m.p. 107-109 °C. ~ H NMR (CD30D, 300 MHz) b 2.82 (d,
1 H); 2.97 (q, 2H), 3.21 (d, 1 H), 3.38 (m, 1 H), 3.32 (s, 3H), 3.44 (m, 4H),
3.62 (m, 1 H), 3.79 (s, 3H), 3.86 (d, 1 H), 5.93 (s, 2H), 6.76 (d, 1 H), 6.85
(dd, 1 H}, 6.91 (d, 2H), 7.01 (d, 1 H), 7.38 (d, 2H).
Example 23
r n r n - - 4-M thox hen 1 -4- 1 -b n i x I- I -1- x h l -
so gyrrolidine-3-carboxylic acid
Using the procedures described in Example 4 the title compound
was prepared. m.p. 53-55 °C. ~ H NMR (CDC13, 300 MHz) b 0.88 (t, J=7Hz,
3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (tt, J=6Hz,
6Hz, 1 H), 2.92 (q, J=1 OHz, 2H), 3.35 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H),
3.68 (d, J=lOHz, 1 H), 3.78 (s, 3H), 5.94 (s, 2H}, 6.73 (d, J=8Hz, 1 H), 6.83
(d, J=9Hz, 2H), 6.82-6.87 (m, 1 H), 7.06 (d, J=2Hz, 1 H), 7.32 (d, J=9Hz,
2H}. MS m/e 442 {M+H)+.
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Examofe 24
traps traps 2 ( 1 3 Benzodioxol-5-vl1-4-(4-methoxvphenvll-1
(propvlaminocarbon~lmethvl)-ovrrolidine-3-carboxviic acid
Using the procedures described in Example 1 and substituting
ethyl {1,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4-
methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisote for 5-(2-
nitrovinyl)-1,3-benzodioxol-5yl afforded the title compound. m.p. 97-
99 °C. 1 H NMR (CDC13, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 1.39 (sextet,
~ o J=7Hz, 2H), 2.72 (d, J=16Hz, 1 H), 2.74 (t, J=1 OHz; 1 H), 2.80-3.10 (m,
4H),
3.26-3.38 (m, 1 H), 3.53 {m, 1 H), 3.73 (s, 3H), 3.80 (d, J=1 OHz, 2H), 7.80
(t, J=6Hz,. 1 H). MS (DCI/NH3) mle 441 (M+H)+.
Example 25
n r n - - 1 -B n i x I- I -4- 4-m h x h n I -1- r x h I -
pyrroiidine-3-carboxylic acid
Using the procedures described in Example 5 and substituting
ethyl (1,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4-
methoxybenzoyl)acetate and 4-(2-nitrovinyl}anisole for 5-(2-
2o nitrovinyl)-1,3-benzodioxol-5yl afforded the title compound. m.p. 67-
69 °C. ~ H NMR (CDC13, 300 MHz) S 0.89 (t, J=7Hz, 3H), 1.56 (sextet,
J=7Hz, 2H), 2.33 (m, 1 H), 2.78-3.00 (m, 3H), 3.32 (t, J=7Hz, 2H), 3.45-
3.57 (m, 4H), 3.73 (m, i H), 3.79 (s, 3H), 5.93 (s, 2H), 6.22 (d, J=8Hz, 1 H),
6.85 (d, J=8Hz, 3H), 6.98 (s, 1 H}, 7.37 (d, J=8Hz, 2H). MS (DCIlNH3) m/e
2s 428 {M+H)+.
Example 26
traps traps 2 l1 3 Benzodioxol-5-vl)-4-f4-methoxvohenvll-1-f2-(2
methoxvethoxv)ethyl)Lpvrrolidine-3-carboxylic acid
so Using the procedures . described in Example 4 and substituting the
starting materials described in Example 25 and using 2-(2-
methoxyethoxy)ethylbromide to alkylate the pyrrolidine nitrogen
afforded the title compound. m.p. 85-86 °C. ~ H NMR (CD30D, 300 MHz) 8
3.18-3.90 (m, 15H), 3.79 (s, 3H), 4.57 (d, J=1 OHz, 1 H), 6.02 (s, 2H), 6.91
35 (d, J=BHz, 1 H), 6.95 (d, J=9Hz, 2H), .7.06 (dd, J=8Hz, 1 H), 7.12 (dd, J=1
Hz,
1 H), 7.37 (d, J=9Hz, 2H). MS (DCIINH3) mle 444 (M+H)+.
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Example 27
r n r n -2- 1 3-Ben odioxol- I -4- 4-meth h n 1 -1- x th I
pyrrolidine-3-carboxylic acid
Using the procedures described in Example 4, substituting the
starting materials described in Example 25 and using 2-
ethoxyethylbromide to alkylate the pyrrolidine nitrogen afforded the
title compound. m.p. 54-56 °C. 1 H NMR (CDC13. 300 MHz) b 0.89 (t, J-
7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (m,
~0 1H), 2.74-2.98 (m, 3H), 3.46 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H), 3.68 {d,
J=1 OHz, 1 H), 3.80 (s, 3H), 5.93 (dd, J=6Hz, 1 Hz, 2H), 6.72 (d, J=8Hz, 1 H),
6.74 {dd, J=9Hz, 3H), 6.96 (s, 1 H), 7.36 (d, J=9Hz, 2H).
Example 28
~r ns traps 2 (4 Methoxvohenvl)-4-(1 4-benzodioxan-6-vl)-1-
~proavlaminocarbon~rlmeth~)-pvrrolidine-3-carboxylic acid
Using the procedures described in Example 1 and substituting 6-
(2-nitrovinyl)-1,4-benzodioxane. for 5-(2-nitrovinyl)-1,3-benzodioxole
afforded the title compound. m.p. 80-81 °C. ~ H NMR (CDC13, 300 MHz) 8
20 0.89 (t, J-7Hz, 3H), 1.49 (sextet, J=7Hz, 2H), 2.78 (d, J=16Hz, 1 H), 2.92
(t, J=1 OHz, 1 H), 3.05-3.43 (m, 5H), 3.24 (d, J=16Hz, 1 H}, 3.52-3.62 (m,
1 H), 3.80 (s, 3H), 3.80 (t, J=1 OHz, 1 H), 4.27 (s, 4H), 6.74-6.93 (m, 5H),
7.29 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 455 (M+H)+.
25 Exam~~lg 29
~rans traps 2 (4 Methoxyphenvl) 4 (1 4 benzodioxan-6-vll-1-(N-methyl-N
~rogylaminocarbonylmethKl~-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1, substituting 6-(2-
nitrovinyl)-1,4-benzodioxane for 5-(2-nitrovinyl)-1,3-benzodioxole and
so alkylating the pyrrolidine nitrogen with N-methyl-N-propyl
bromoacetamide afforded the title compound. m.p. 74-76 °C.
Rotational isomers are seen in the NMR. ~ H NMR (CDCl3, 300 MHz) 8
0.73, 0.83 {2t, J=7Hz, 3H), 1.48 (m, 2H), 2.78 (dd, 1 H), 2.85 {2s, 3H),
2.96-3.15 (m, 3H), 3.27-3.42 (m, 3H), 3.52-3.60 {m, 1 H), 3.75 (d, 1 H),
35 3.78 (s, ~ 3H), 4.22 (s, 4H), 6.80-6.98 (m, 5H), 7.32 (d, 2H}. MS (DClINH3)
mle 469 (M+H)+.
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FYamole 30
r -4- i I- -1- - h _N
but~nlaminocarbonvlmethvl)-oy_rrolidine-3-cari~o_ ~ li '
Using the procedures described in Example 1, the title compound
s was prepared. Rotational isomers are seen in the NMR. ~ H NMR (CD30D,
300 MHz) 8 0.86 (2t, 3H), 1.04-1.50 (m, 4H}, 2.85 (2s, 3H), 2.93-3.20 (m,
4H), 3.40 (m, 2H), 3.52 (dd, 1 H), 3.60 (m, 1 H), 3.80 (s, 3H}, 3.85 (m, 1 H),
5.91 (s, 2H), 6.74 {d, 1 H), 6.83-6.95 (m, 3H), 7.03 (dd, 1 H), 7.35 (dd, 2H).
Fxamole 31
-4- I-4-1 n i I- I-1-N-
I- 1 my n I h 1 - rr li in - r li i
F_xam Qle 31 A
1 s h I - 4- h h m h h n I-4- 1 i x I- i - rr li in -
~,-carbox Iv atel
Using the procedures described in Examples 1 A and 1 B and
substituting ethyl (4-methoxy-2-methoxymethoxybenzoyl)acetate for
ethyl (4-methoxybenzoyl)acetate afforded ethyl 2-(4-methoxy-2-
2o methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H-
pyrroie-3-carboxylate.
The above dihydro pyrrole carboxylate (3.0 g, 7.0 rnmol) was
dissolved in 20 mL of methanol, treated with 500 mg of 10% PdIC and
placed under hydrogen atmosphere for 32 hours. The catalyst was
25 removed by filtration and the filtrate was concentrated under reduced
pressure and chromatographed on silica gel eluting with ethyl acetate
to afford the title compound (1.9 g, 63%) as the cis-cis isomer.
~Ya_mgle 31 B
ao r n r n - - 4- h x - -m m .~h x h n I -4- 1 n x I- I -1- N-
methyl N butvlaminocarbonvlmethvl) ovrrolidine-3-carboxylic acid
The compound resulting from Example 31 A was epimerized by the
procedure described in Example 6A. The resulting rrans, traps compound
(100 mg, 0.23 mmol) was then reacted by the procedures described in
ss Example 1 D substituting N-methyl-N-butyl bromoacetamide for N-
propyl bromoacetamide to give the title compound (75 mg, 62%). m.p.
65-67 °C. Rotational isomers are seen in the NMR. ~ H NMR (CDC13. 300
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MHz) 8 0.64, 0.68 (2t, J=7Hz,3H),1.14, 1.12 (2 sextet, J=7Hz, 2H),
1.40-
1.48 (m, 2H), 2.86, 2.89 3H),2.95-3.42 (m, 6H), 3.50 (s, 3H),
(2s, 3.43-
3.65 (m, 2H), 3.78 (s, 3H), J=7Hz, 1 H), 5.09 (q, J=7Hz, 2H),
4.30 (t, 5.92
(s, 2H), 6.55 (dd, J=3Hz, 6.68(s, 1 H), 6.72 (s, 1 H), 6.85
1 H), (2t, J=1 Hz,
1 H), 7.04 (t, (dd,J=3Hz, 1 H).
J=1 Hz, 1 H),
7.42
Example 32
ran r n - - 4-M h h n I -4- 1 -benz i xol- I -1- tho ro I
pyrrrolidin-~-one-3-carbaxvlic acid
~o
Example 32A
_Ethvl 2 (4 methoxvbenzovl) 3 c rbomethoxv-1 3-benzodioxole-5-propionate
To ethyl (4-methoxybenzoyl)acetate (4.44 g, 0.02 mmol) dissolved
in 20 mL of anhydrous THF was added in portions 480 mg of NaH. The
mixture was stirred .for 30 minutes under nitrogen at ambient
temperature. Methyl (1,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02
mol) in 5 mL of THF was added. The mixture was stirred overnight at
ambient temperature, diluted with 200 mL of EtOAc, and washed with
water and brine. The organic phase was dried over sodium sulfate and
2o concentrated in vacuo to afford the title compound (7.67 g, 92%) which .
was used without further purification.
_Examole 32B
Eth I 1- 3- ho r ! -2- 4- h h n I -4- 1 -benzodi xol- I -4 5-dih dro-
2s 5-oxo-1 H-pyrrole-3-carboxylate
A mixture of the compound resulting from Example 32A {700 mg,
1.69 mmol), 3-ethoxypropytamine (348 mg, 3.38 mmol) and 1 mL of
acetic acid in a sealed tube was heated for 18 hours at 125 °C. After
cooling the contents of the tube to ambient temperature, 5 mL of water
so was added and the mixture extracted with ethyl acetate (2x100 mL).
The. combined organic extracts were washed with saturated sodium
bicarbonate solution, water and brine, dried over sodium sulfate and
concentrated under reduced pressure. The residue obtained was
chromatographed on silica gel eluting with 3:2 hexane-ethyl acetate to
s~ give 330 mg (42%) of the title compound:
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_Fxamnle 32C
- 4- n I -4- 1 I - rr li in-
nnca-~-carb0
The compound resulting from Example 328 (300 mg, 0.64 mmol) in
s 15 mL of methanol was reduced with 100 mg of 10% Pd/C under
hydrogen for 3 hours at ambient temperature. The catalyst was
removed by filtration and the filtrate was concentrated under reduced
pressure to give the title compound.
Example 32D
r rn--4- h I-4-1 n i x I- I-1- r I
~yrrolidin-5-one-:~-carboxylic acid
To the compound resulting from Example 32C (100 mg, 0.21 mmol)
dissolved in 1 mL of ethanol was added 3 drops of a solution of 21
~ s sodium ethoxide in ethanol. The mixture was heated to 70-80 °C for
3
hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of
water was added and heating was continued for 1 additional hour. The
reaction mixture was cooled to ambient temperature, the ethanol was
removed under reduced pressure, and water was added to the residue
2o which was washed with ether. The aqueous layer was neutralized with
3 M HCI and allowed to stand overnight. The white crystalline solid was
collected by filtration to give the title compound (60 mg, 64%). m.p.
134-140 °C. ~ H NMR (DMSO-ds, 300 MHz) 8 1.04 (t, J=7Hz, 3H), 1.55
(sextet, J=7Hz, 2H), 2.48-2.56 (m, 1 H), 2.93 (dd, J=9Hz, 1 H), 3.25 {t,
2s J=7Hz, 2H), 3.28-3.40 (m, 2H), 3.48-3.57 (m, 1 H), 3.78 {s, 3H), 3.88 (d,
J=1 OHz, 1 H), 4.72 (d, J=1 OHz, 1 H), 6.02 (s, 2H), 6.74 (dd, J=8Hz, 1 Hz,
1 H), 6.87 (d, J=BHz, 2H), 6.98 (d, J=SHz, 2H), 7.38 (d, J=BHz, 2H). MS
(DCIlNH3) m/e 442 (M+H)+.
3o Example 33
_trans traps 2 (4 Methoxyphenvll 4 t1 3 benzodioxol-5-vll-1-f3-methoxvbenzvl)-
pyrrolidin-5-one-3-carboxylic acid
Following the procedures described in Example 32 and
substituting 3-methoxybenzylamine for 3-ethoxypropylamine afforded
35 the title compound (123 mg, 65%). m.p. 150-152 °C. 1H NMR (CD30D,
300 MHz) 8 2.96 (dd, J=SHz, 1 OHz, 1 H), 3.72 (s, 3H), 3.80 _ (s, 3H), 4.06
(d,
. nu_ , w .t gist « .WRH~ 1 Hl. 4.92 (4. J=l6Hz, 2H), 5.92 (s, 2H),
"_ "" ,~, .. .,, ..__ ,_, _ . ,
*rB
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6.55-6.63 (m, 2H), 6.82 (d, J=8Hz, 4H), fi.94 {d, J=8Hz, 2H), 7.15-7.22 {m,
3H). MS (DCI/NH3) mle 475 (M+H)+.
FYamole 34
- 4- h n I -4- n i x I- I -1- N N-
ii yl_aminocarbonvtmethvl)-~ inP ~~ar ooYlic acid
The title compound was prepared as an amorphous soiid using the
procedures described in Example 1. ~ H NMR (CDC13, 300 MHz) 8 0.70 -
0.90 (m, 12H), 1.10-1.60 (m, 1 OH), 2.75 (d, J=13Hz, 1 H), 2.90-3.10 (m,
4H), 3.15 - 3.30 (m, 2H), 3.40 (d, J=lOHz, 1 H), 3.40 - 3.52 (m, 2H), 3.55
- 3.62 (m, 1 H), 3.75 (d, J=12 Hz, 1 H), 3.79 (s, 3H), 5.93 (dd, J =1 Hz, 3
Hz, 2H), 6.72 (d, J=BHz, 1 H), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, 1 H),
7.30 (d, J=9Hz, 2H).
t s F.xamole 35
r - 4_ -4_ n i I- -1- N N
~~~~~tvlaminocarbonvlmethvl) Ryrrolidine-3-carboxylic acid
The title compound was prepared as an amorphous solid using the
procedures described in Example 1. i H NMR (CDC13, 300 MHz) b 0.82 (t, J
20 = 7Hz, 6H), 0.95-1.03 (m, 2H), 1.10-1.30 (m, 8H), 1.40-1.51 (m, 2H),
2.72 (d, J=13Hz, 1 H), 2.90-3.08 (m, 4H), 3.25-3.50 (m, 3H), 3.37 (d,
J=13Hz, 1 H), 3.52-3,60 (m, 1 H), 3.70 ( J=1 OHz, 1 H), 3.75 (s, 3H), 5.92
(dd, J=2Hz, SHz, 2H), 6.72 (d, J=BHz, 7 H), 6.80-6.88 (m, 3H), 7.03 (d,
J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
F.xam~le 36
r n ~ -4- h h n 1-4-1 i x 1-1-NN- i
h h i in r n I h I - rr i in - li i
The title compound was prepared using the procedures described
so in Example 1. m.p. 120-122 °C. ~ H NMR (CDCl3, 300 MHz) S 2.82 {d,
J=13, 1 H), 2.94-3.08 (m, 2H), 3.12 (s, 3H), 3.23 (s, 3H), 3.20-3.70 (m,
11 H), 3.73 (d, J=I OHz, 1 H), 3.79 (s, 3H), 5.92 (dd, J= 2Hz. 2Hz, 2H), 6.72
(d, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.04 (d, J=2Hz, 1 H), 7.30 (d, J=9Hz,
2H).
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Fxamole 37
- 4- i 1 - r I' i
r r
'~-carboxv is acid
Using the procedures described in Example 4, 200 mg. of the pure
s trans,trans isomer, the compound resulting from Example 6A was
reacted with 109 mg of 1-bromo-2-hexyne, prepared by the method
described in Perkin i, , 2004 (1987), for 1 hour at 55 °C, to give 226
rng
of the intermediate ester. The ester was hydrolyzed using NaOH in
ethanol-water for 3 hours at room temperature to give 175 mg of the
i o title compound. t H NMR (CDCI3, 300 MHz) 8 1.OOr(t, J=7Hz, 3H), 1.54 (m,
2H), 2.14-2.22 (m, 2H), 2.96 (dd, J=7Hz, 13Hz, 1 H), 3.07 (dd, J=18Hz,
2Hz, 1 H), 3.15 (dd, J=9Hz, 2Hz, 1 H), 3.26 (t, J=9Hz, 1 H), 3.36 (dd, J = 18
Hz, 2Hz, 1 H), 3.47-3.55 (m, 1 H), 3.79 (s, 3H), 3.88 (d, J=9Hz, 1 H), 5.95
(s, 2H), 6.72 (d, J=8Hz, 1 H), 6.80-6.88 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.22
(d, J=9Hz, 2H).
Fxamole 38
r n r - 4- h h n I -4- 1 nz i x I- I -1- N- 1 r Im h i-
,~ o,~o~~~~a~ninocarbonvlmethyll-ovrrolidine-3-carboxylic
2o The title compound was prepared using the procedures described
in Example 1. m.p. 167-169 °C. Rotational isomers were seen in the
NMR. ~ H NMR (CDC13, 300 MHz) b -0.1 (m), 0.05 (m), 0.12-0.25 (m), 0.32-
0.51 (m), 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 (m), 1.20-1.55 (m),
2.72 {d, J=13Hz, 1 H), 2.85--3.29 (m, 4H), 3.30-3.50 (m, 3H), 3.52-3.62
2s (m, 1 H), 3.65-3.73 (2 doublets, J=1 OHz, 2Hz, i H), 3.78 (s, 3H), 5.95 (2
singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (m, 3H), 7.00 and 7.05 (2
doublets, J=9Hz, 2H).
Exams
so r n r n - - 4-M h x h n I -4- 1 nz i x I- 1 -1- N-m h I-N-
p~ntvlaminocarbonvlmethvll-ayrrolidine-3-carboxylic acid
The title compound was prepared as an amorphous solid using the
procedures described in Example 1. Rotational isomers were seen in the
NMR. ~ H NMR (CDC13, 300 MHz) b 0.85 (t, J=7Hz, 3H), 1.00-1.08 (m),
3s 1.13-1.32 (m), 1.35-1,50 (m), 2.72-2.82 (2 doublets, J=13Hz, 1 H), 2.83
and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52
.... ,_ a m n -» /~ .~1.",hlotc ~ H~ 3.75 and 3.76 (2 singlets, 3H), 5.92
J.OG ~~~~, ~~ ~~, v.. ~ ~.... .....-.,...._, .. ."
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(2 singlets, 2H), 6.72 (d, J=BHz, 1 H), 6.80-6.87 (m, 3H), 7.03 (2
doublets, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
Fxamole 40
h x h -4- n i I- 1 -1- N N-
_di~sobutvlaminocarbonylmethvll Qyrroiidine-3- r oocylic acid
The title compound was prepared using the procedures described
in Example 1. m.p. 141-143 °C. ~ H NMR (CDCI3, 300 MHz) s 0.54 (d,
J=7Hz, 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (m, 1 H), 1.90-
2.02 (m, 1 H), 2.67 (d, J=l3Hz, 1 H), 2.70 (d, J=13Hz, 1 H), 2.84 (dd,
J=6Hz, lSHz, 1 H), 2.96-3.06 (m, 2H), 3.20 (dd, J=9Hz, 1 SHz, 1 H), 3.35
(dd, J=2Hz, 1 OHz, 1 H), 3.44-3.60 (m, 4H), 3.70 (d, J=9Hz, 1 H), 3.79 (s,
3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 (d, J=9Hz, 1 H), 6.82-6.90 (m, 3H),
7.03 (d, J=2Hz, 1 H), 7.31 {d, J=9Hz, 2H).
~s
FxamDle 41
r n I -4- 1 n i x 1 - - N-m h l-N-
p~gynvl)aminocarbonkmeth~)-uyrrolidine-3-carboxylic acid
The title compound was prepared as an amorphous solid using the
2o procedures described in Example 1. Rotational isomers were seen in the
NMR. ~ H NMR (CDCI3, 300 MHz) 8 2.09 and 2.32 (2 triplets, J=2Hz, 1 H),
2.80-3.10 (m, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (m, 2H),
3.52-3.fi2 (m, 1 H), 3.78 (s, 3H), 4.03 (d, J=13Hz, 1 H), 4.00-4.30 (m, 3H),
5.93 (s, 2H), 6.72 (2 doublets, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.02 and
2s 7.11 (2 doublets, J = 2Hz, 1 H), 7.30 (2 doublets, J=9Hz, 2H).
Example 42
traps traps 2 (4 Methoxv~henvl) 4 (1 3-benzodioxol-5-vl)-1-(N-methyl-N-(n
h~PY~I)aminocarbonvimethvl)-oyrroiidine-3-carboxylic acid
3o The title compound was prepared as an amorphous solid using the
procedures described in Example 1. ~ H NMR (CDCl3, 300 MHz) 8 0.85 (2
triplets, J=7Hz, 3H), 1.00-1.50 (m, 8H), 2.72-2.82 (2 doublets, J=l3Hz,
1 H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m,
3H), 3.52-3.fi2 (m, 1 H), 3.72 {2 doublets, 1 H), 3.75 and 3.76 (2 singlets
ss 3H), 5.94 (2 singlets, 2H), 6.72 (d, J=8Hz, 1 H), 6.80-6.87 (m, 3H), 7.03
(2 doublets, J=2Hz, 1 H), 7.30 (d, J=9~Hz, 1 H).
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Fxamnle 43
n i x I- I- -NN- in-
b~c tX!)aminoc r~ bonvlmet~yrrolidine-3-carboxylic acid
The title compound was prepared using the procedures described
s in Example 1. m.p. 123-125 °C. ~ H NMR (CDC13, 300 MHz) b 0.79 (t,
J=7Hz, 3H), 0.85 (t, J=7Hz, 3H), 7.00-1.50 (m, 8H), 2.74 (d, J=13Hz, 1 H),
2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, J=13Hz, 1 H), 3.52-3.62
(m, 1 H), 3.75 (d, J=10 Hz, 1 H), 3.78 (s, 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71
(d, J=8Hz, 1 H), 6.81-6.89 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.30 (d, J=9 Hz,
~0 2H). MS (DCUNH3) m/e 511 (M+H)+. Anal calcd for C29H3sN2Os: C,
68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.
Example 44
traps traps 2 (4-Methox Iphenvl~-4-i;1 3-benzodioxol-5-vll-1-(N,N-
~ s diethvlaminocarbonylmethvl)-p~rrrolidine-3-carboxylic acid
The title compound was prepared using the procedures described
in Example 1. m.p. 132-134 °C. ~ H NMR (CDC13, 300 MHz) 8 0.98 (t,
J=7Hz, 3H), 1.06 (t, J=7Hz, 3H), 2.78 (d, J=13 Hz, 1 H), 2.95-3.20 (m,
4H), 3.30-3.50 (m, 4H), 3.55-3.65 (m, i H), 3.76 (d, J=12 Hz, 1 H), 3.79
20 (s, 3H), 5.93 (s, 2H), 6.72 (d, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.02 (d,
J=2Hz, 1 H), 7.32 (d, J=9Hz, 2H).
Example 45
tr_ans irans 2 (4 Methoxvoheny~ 4 (1 3 benzodioxol-5-yrl)-1-(N-methyl-N-
2s QhP~,nvlaminocarbonyrlmethx~~-RYrro(idine-3-carboxylic acid
The title compound was prepared as an amorphous solid using the
procedures described in Example 1. t H NMR (CD30D, 300 MHz) 8 2.75-
2.85 (m, 2H), 3.05-3.13 (m, 1 H), 3. i 8 (s, 3H), 3.40-3.58 (m, 2H), 3.78
(s, 3H), 3.88 (d, J=l2Hz, 1 H), 5.92 (s, 2H), 6.72 (d, J=BHz, 1 H), 6.75-
30 6.85 (m, 3H), 7.00-7.12 (m, 5H), 7.82-7.92 (m, 3H).
Example 46
~r~nS irans 2 (4 Methoxy,Rhenvf)-4-(1 3-benzodioxol-5-vl)-1-(N-methyl-N
~y 1c ohexyiaminocarbonvimethvl)-~yrrolidine-3-carboxylic acid
35 The title compound was prepared as an amorphous solid using the
procedures described in Example 1. Rotational isomers were seen in the
mn~A ~ H NrUA IC;D~OD. 300 MHz) 8 1.00-1.85 (m, 1 OH), 2.72 and 2.78 (2
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singlets, 3H), 2.75-2.82 (2 doublets, J=l2Hz, 1 H), 2.96-3.22 (m, 3H),
3.40-3.65 (m, 3H), 3.68 and 3.82 (2 doublets, J=1 OHz, 1 H), 3.77 and 3.78
(2 singiets, 3H), 5.92 (s, 2H), 6.72 (2 doublets. J=BHz, 1 H), 6.82-6.88
(m, 3H), 7.02 (2 doublets, J=2Hz, 1 H), 7.30-7.40 (2 doublets, J=9Hz,
s 2H).
~xamole 47
rn rn- n -1 n i I- I-1-NN- in-
nronvllaminocarbonKmethvl) nvrrolidine-3-carbo i t
The title compound was prepared using the-procedures described
in Example 1. m.p. 170-172 °C. ~ H NMR (CDC13, 300 MHz) 8 0.69 (t,
J=7Hz, 3H), 0.85 (t, J=7Hz, 3H), 1.20-1.55 (m, 4H), 2.72 (d, J=13Hz, 1 H),
2.90-3.10 (m, 4H), 3.25-3.47 (m, 4H), 3.35-3.62 (m, 1 H), 3.72 (d, J=9Hz,
1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, d, J=8Hz, 1 H), 6.80-6.90 (m, 3H),
~ s 7.02 (d, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
Example 48
r - 4- h x h n I -4- 1 -be i I- -1- N-m h I-N
~sob ~tvia~ninocarb~nylmeth I -~yr_rolidine-3-carboxylic acid
2o The title compound was prepared as an amorphous solid using the
procedures described in Example 1. Rotational isomers were seen in the
NMR. ~ H NMR (CD30D, 300 MHz) S 0.65-0.85 (4 doublets, J=7Hz, 6H),
1.75-1.95 (m, 1 H), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 (m, 4H),
3.10-3.65 (m, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=1 OHz, 1 H),
2s 5.93 (s, 2H), 6.72 (d, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.02 (2 doublets,
J=2Hz, 1 H), 7.80-7.90 (2 doublets, J=9Hz, 2H).
F~xamole 49
Alternate Pre~~ration of
ao Ethyl 2 L methoxvbenzovl) 4 nitromethvl-3-(1 3-benzodioxole-5-vl)butvrate
Example 49A
E 2 (3 4 Methvlenedioxvnhenvl)-1-nitroethene
To a stirred solution of piperonal (75g, 500 mmol) in methanol
(120 mL) at 10 °C was added nitromethane (27.1 mL, 500 mmol, 1 eq)
followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol,
1.05 eq) in sufficient water to achieve a total volume of 50 mL while
*rB
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maintaining the temperature between 10-15 °C. The reaction mixture
became cloudy, turning to a thick paste. The mixture was stirred for 30
minutes upon completion of the addition, and the mixture was then
diluted with ice-water 0350 mL) maintaining the temperature below 5
s °C, until solution was achieved. The resultant solution was poured in
a
narrow stream (such that it just failed to break into drops) into a
rapidly stirred solution of 36% hydrochloric acid (100 mL) in water
(150 mL). A yellow solid precipitated (nitrostyrene), and this was
collected by filtration, washed with water (1.5 L) until the filtrate was
neutral. The filter cake was air dried and then.-fecrystallized from hot
ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow
needles (53 g, 55%). ~ H NMR (300MHz, CDCI3) 8 7.94 (1 H, d, J=13.5Hz),
7.47 (1 H, d, J=13.5Hz), 7.09 (1 H, dd, J=7.5&2Hz), 7.01 (i H, d, J=2Hz),
6.87 (1 H, d, J=7.5Hz), 6.06 (2H, s). MS (DCIINH3) mle 194 (M+H)+, 211
(M+H+NH3)+.
Exam lie 49B
Ethyl 2 (4 methoxvohenvl)oxo 4 vitro-3-(:3 4-methvlenedioxvohenvllbutvrate
2o To a stirred solution of the nitrostyrene resulting from Example
49A (14.17 g, ?3.34 mmol, 1.2 eq) in a mixture of propan-2-of (75 mL)
and tetrahydrofuran (175 mL) at room temperature was added
successively a solution of ethyl (4-methoxybenzoyl)acetate (11.5 g,
51.7 mmol) in THF (50 mL) followed by 1,8-diazabicyclo[5,4,0)undec-7-
2s eve (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was
stirred at room temperature for 1 hour, then additional DBU (0.45 mL,
3.0 mmol, 0.05 eq) was added. The mixture was stirred a further 1 hour,
then the volatiles were removed in vacuo and the residue purified by
flash chromatography on 500 g silica gel, eluting with 20% ethy4
so acetate-hexanes changing to 25% ethyl acetate-hexanes as the product
eluted. The solvents were removed in vacuo to yield the nitroketoester
{19.36 g, 76%) as a viscous oil. Diastereomers were seen in the NMR.
~ H NMR (300 MHz, CDC13,) s 8.06 (2H, d, J=9Hz), 7.89 (2H, d, J=9Hz), 6.96
(2H, d, J=9Hz), 6.91 (2H, d, J=9Hz), 6.77 (1 H, dd, J=9Hz,3Hz), 6.73 (1 H, d,
ss J=9Hz), 6.65 (1 H, d, J=3Hz), 5.95 {2H, s), 5.89 (1 H, d, J=4Hz), 5.88 (1
H, d,
J=4Hz), 4.90-4.60 (3H, m}, 4.39 (1H, m), 4.18 (2H, q, J=7Hz), 3.94 (2H,
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m), 3.80 {3H,- s), 3.78 (3H, s), 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz), MS
(DCIlNH3) m/e 416 (M+H)+, 433 (M+H+NH3)+.
FYam~le 50
r - 4- t -4- 1 n i I- - I -1 _
~~~ ,r~~~ on~ethl~l)-ovrrolidine-3-, r~ boxvi'~c acid
To a stirred solution of the compound resulting from Example 1 C
(100 mg, 0.27 mmol) in acetonitrile (2 mL) was added successively
diisopropylethylamine (70 ~L, 0.40 mmol, 1.5 eq) and t-butyl
~ o bromoacetate (48 ~L, 0.29 mmol, 1.1 eq). The mixture was stirred 2
hours, then the solvent was removed in vacuo to yield the crude diester.
To a stirred solution of the diester in ethanol (1 mL) at room
temperature was added 50% w/w sodium hydroxide (300 mg, 3.75mmol)
in water. The mixture was stirred 2 hours; then the volatiles were
1 s removed in vacuo. The residue was dissolved in water (5 mL), and the
solution was washed with ether. The aqueous phase was acidified with
acetic acid (300 ~L), and then extracted with ethyl acetate (2x). The
combined organic extracts were dried (Na2S04), filtered, and
concentrated to yield the title compound (74 mg, 60%) as a white solid.
2o j H NMR (300 MHz, CDC13) 8 7.36 (2H, d, J=8Hz), 7.13 (1 H, d, J=3Hz), 6.90
(1 H, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=8Hz), 6.76 (1 H, d, J=8Hz), 5.96 (2H,
s), 3.96 (1 H, d, J=9Hz), 3.81 (3H, s), 3.58 (1 H, ddd, J=12, 10Hz,3Hz),
3.52 (1 H, dd, J=9Hz,3Hz), 3.32 (1 H, d, J=i 7Hz), 3.08 (1 H, t, J=i 0Hz),
2.92 (1H, dd, J=9Hz,7Hz), 2.83 (1H, d, J=l7Hz). MS (DCllNH3) mle 456
2s (M+H)+.
Anal calc for C2sH29N0~ - 0.3 H20: C, 65.07; H, 6.48; N, 3.04. Found: C,
65.02; H, 6.42; N, 2.93.
Exa_mgle 51
so r -M I -4- 1-n h h I - -m I-
oroovl)aminoc~vlmeth~cE~-~~~rr~~~~~~p_~.car oxvlic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting naphthalene-1-carboxatdehyde for
piperonyt in Example 49A. Rotational isomers are seen in the NMR. ~ H
ss NMR (300 MHz, CDCI3) 8 8.29 (1 H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75
(1 H, d, J=8Hz), 7.49 (3H, m), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd,
J=9Hz,2Hz), 4.50 {1,H, m), 3.94 (1H, dd, J=9Hz,2Hz), 3.78 (3H, s), 3.65
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s
(1 H, m), 3.49 (1 H, d, J=l4Hz), 3.40-2:93 (5H, m), 2.91, 2.83 (3H, s), 1.48
(2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz}. MS (DCUNH3) mle 461
(M+H)+. Anal caicd for C2sH29N0~ - 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71.
Found: C, 70.95; H, 7.00; N, 5.46.
~~amole 52
-4- r I - I-N-
orow!~~minocarbonvlmethvll oyrroiidine-3-carboxvlic acid
o ~xam~le 52A
3 Dihvdrobe zof~ran-5-carboxaiaenvae
To a stirred solution of a,a-dichloromethyl methyl ether (2.15 g,
19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 °C was added
successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes
~s later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2C12
(5 mL) maintaining the temperature at or below -35 °C. The mixture
was warmed to 0 °C, stirred 1 hour, then poured into ice-water, and
stirred a further 30 minutes. The mixture was diluted with ether, and
the phases separated. The organic phase was concentrated in vacuo, and
2o the residue purified by vacuum distillation to yield the title compound
(1.25 g, 60%) as a colorless liquid. b.p. 119-121 °C at 0.3 mm Hg.
FY~m~le 52B
r n - x h n I -4- ih r n f r n- I -1- N-m h I-N-
2s ~ proovllarriinocarbon~lmethvl oyrrolidine-3-carboxvli~ acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting the compound resulting from Example
52A for piperonal in Example 49A. Rotational isomers are seen in the
NMR. ~ H NMR (300 MHz, CDCI3) S 7.33 (1H, d, J=8Hz), 7.28 (1 H, m), 7.19
30 (1 H, m), 6.87 ( 1 H, d, J=8Hz}, 6.73 (1 H, d, J=8Hz), 4.56 ( 1 H, t,
J=8Hz),
3.83 (1 H, d, J=lOHz), 3.80 (3H, s), 3.63 (1 H, m), 3.4-3.0 (9H, m), 2.87,
2.84 (3H, s), 1.51 (2H, septet, J=7Hz), 0.88, 0.78 (3H, t, J=7Hz). MS
(DCIINH3) mle 453 (M+H)+. Anal calc for C2sHs2N20s - 0.25 H20: C,
68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.
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~mnle 53
4- n I- I h I -
pyrrrolidine-3-carbox lic aci
The title compound was prepared by the procedures described in
s Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in
Example 49A. Rotational isomers are seen in the NMR. ~ H NMR (300
MHz, CDC13) 8 7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, m),
3.83 (1 H, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (1 H, m), 3.48-2.97 (6H, m),
2.87, 2.83 (3H, s), 2.85 (1H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz).
o MS (DCI/NH3) mle 441 (M+H)+. Anal calc for C25ki32N2~s ~ 0.5 H20: C ,
66.80; H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31; N, 6.00.
Fxamole 54
n - - 4- n I -4- 4- im h h n I - - N- h I-N-
~roov~~aminocnrbonxlmethvl)~-oyrrolid~ir e-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 3,4-dimethoxybenzaldehyde for
piperonal in Example 49A. Rotational isomers are seen in the NMR. ~ H
NMR (300 MHz, CDCI3) b 7.33 (2H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz),
Zo 6.98 {1 H, m), 6.85 (1 H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, s),
3.86
(3H, s), 3.83 (i H, m), 3.79 (3H, s), 3.64 (1 H, m), 3.50-2.95 (6H, m), 2.87
(1 H, m), 2.85, 2.83 (3H, s), 1.45 {2H, m), 0.84, 0.74 {3H, t, J=7.5 Hz). MS
(DCI/NH3) mle 471 (M+H)+. Anal calc for C2gH34N2~6 ~ 0.5 H20: C,
65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.
Fxample 55
_ 4- h I -4- h h -1- N- h -N-
QroQyrllaminocarbonlrlmethy~-oyrrolidine-3-carboxvli i
The title compound was prepared by the procedures described in
3o Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in
Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300
MHz, CDC13) 8 7.33 (2H, d, J=7.5 Hz), 7.24 (1 H, t, J=7.5 Hz), 7.05 (2H, m),
6.85 {2H, dd, J=7.5&2 Hz), 6.76 (1 H, m), 3.83 (1 H, rn), 3.81 (3H, s), 3.79
(3H, s), 3.64 {1 H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 ( 1 H, m),
1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz): MS (DCI/NH3) mle 441 (M+H)+.
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Anal calc for C25H32N20s ~ 0.5 H20: C, 66.80; H, 7.40; N, 6.23. Found: C,
66.76; H, 7.36; N, 6.05.
Example 56
s ~rwrans rrans-2-(4-Methoxvohen~)-4-(2-naohthy!_)-1-(N-methvl-N-
proQyl)aminocarbonvlmethvll~,oyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for
piperonal in Example 49A. Rotational isomers are seen in the NMR. ~ H
o NMR (300 MHz, CDCI3) S 7.82 (4H, m), 7.69 (1 H, m~, 7.47 (2H, m), 7.37
(2H, dd. J=7.5&2 Hz), 6.85 (2H, dd, J=7.5&2 Hz), 3.90 (1H, d, J=8 Hz), 3.78
(3H, s), 3.57 (1 H, m), 3.52-2.97 (6H, m), 2.93, 2.85 (3H, s), 2.90 (1 H, m),
1.52 (2H, m), 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCIlNH3) mle 461 (M+H)+.
Anal calc for C2sH32N2O4 - 0.5 H2O: C, 71.62; H, 7.08; N, 5.97. Found: C,
1 s 71.58; H, 7.11; N, 6.01.
~xamcle 57
r - 4- l -4- 1 i x I- I - h lfin I I -
p~yrrrolidine-3-carboxylic acid
zo To the compound resulting from Example 1 C (100 mg, 0.27 mmol)
and 2-chloroethyl ethyl sulfide (67.5 mg, 0.5 mmol, 2 equivalents}
dissolved in 6 mL of acetonitrile was added 10 mg of KI and 0.5 ml_ of
diisopropylethylamine. The mixture was refiuxed for 4 hours and then
concentrated in vacuo. The residue obtained was purified by flash
2s chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to
afford 93 mg (75%) of the ethylthioethyl compound.
To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH2C12 in an
ice bath was added 68 mg of 3-chloroperoxybenzoic acid. The mixture
was stirred for 40 minutes in the ice bath and for 3 hours at room
ao temperature. A 10% solution of sodium hydroxide (2 mL) was added, and
the mixture was extracted with EtOAc (2 x 50 mL.). The combined
organic extracts were washed with water and brine, dried over sodium
sulfate and concentrated in vacuo. The residue obtained was
chromatographed on silica gel eluting with EtOAc and 10% MeOH in
ss CHzCl2 to afford the sulfoxide (62 mg, 65%).
The ethyl ester was hydrolyzed by the procedure described in
FYamnlP 1 D to afford the title compound as a diastereomeric mixture.
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m.p. 61-fi3 °C. MS (DClINH3) mle 446 (M+H)+. ~H NMR (CDC13, 300 MHz)
8 1.25, 1.32 (t, J=9Hz, 3H), 2.45-2.75 (m, 4H), 2.84-2.96 (m, 3H), 3.02-
3.08 (m, 1 H), 3.32, 3.36 (d, J=3Hz, 1 H), 3.47-3.58 (m, 2H), 3.65, 3.68 (d,
J=7.5Hz, 1 H), 3.76, 3.80 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1 H), 3.84-
s 3.89 (m, 3H), 7.02 (d, J=6Hz, 1 H), 7.30, 7.34 (d, J=7.5Hz, 2H).
Example
h -4- 1 n I- I -1-
~j"SQ~~roovlsulfonvlaminolethvl) pyrrolidine-3-carboxvlic acrd
To 2-bromoethylamine hydrobromide (1 mm''ol) suspended in
anhydrous CH3CN was added 1 equivalent of Et3N. The mixture was
stirred for 30 minutes and then 1 equivalent of isopropyl sulfonyl
chloride and 1 equivalent of EtsN were added. The resulting mixture
was stirred for 2 hours at room temperature and then added to. a
s solution of the compound resulting from Example 1 C (185 mg, 0.5 mmol)
in 3 mt_ of CH3CN. The mixture was warmed at 50-60 °C for 2 hours,
cooled to room temperature, treated with water and extracted with
EtOAc. The combined organic extracts were washed with water and
brine, dried and concentrated in vacuo. The residue obtained was
2o chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give
195 mg (75%) of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol)
was hydrolyzed by the procedure described in Example 1 D to afford the
title compound (133 mg, 88%). m.p. 94-96 °C. 1 H NMR (CD30D, 300
MHz) S 1.2fi (d, J=6Hz, 6H}, 1.97 {s, i H), 2.38 (m, 1 H), 2.77 {m, 1 H}, 2.88
(t, J=9Hz, 1 H), 3.04 (m, 1 H), 3.14 (t, J=7.5Hz, 2H), 3.35 {m, 2H), 3.46 {m,
1 H), 3.58 (m, 1 H), 3.78 (s, 3H), 5.92 {s, 2H), 6.74 (d, J=9Hz, 1 H), 6.86
{dd,
J=9Hz,3Hz, 1 H), 6.92 (d, J=9Hz, 2H), 7.00 (d, J=3Hz, 1 H), 7.36 (d, J=9Hz,
2H). MS {DCl/NH3) mle (M+H)+.
3o Example ~9_
rn r -4- x n -1 n i x I- I-1- -i h~l'
p~,rrrolidine-3-carboxyrlic acid
The title compound was prepared by the procedures described in
Example 1 D from the compound resulting from Example 1 C and 2-
35 (isobutoxy)ethyl bromide. m.p. 68-70 °C. ~ H NMR (CDC13, 300 MHz) S
0.88 (d, J=6Hz, 6H), 1.82 (quintet, J=6Hz, 1 H), 2:22 (m, 2H), 2.72-2.79
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(m, 1 H), 2.86-2.95 (m, 2H), 3.13 (d, J=6Hz, 2H), 3.45-3.56 (m, 4H), 3.68
(d, J=9Hz, 1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1 H}, 6.85 (dd,
J=9Hz, 7.5 Hz, 3H), 7.08 (s, 1 H), 7.34 (d, J=9Hz, 2H}. MS (DC11NH3) mle
442 (M+H)+.
Example 60
tr n r ns-2- 4-Me ho h n I -4- 1 nz diox I- I -1- ut Isulf n 1
,pyrrolidine-3-carboxylic acid
To 100 mg (0.271 mmol) of the compound resulting from Example
1 C dissolved in 10 mL of THF was added 1-butanesulfonyl chloride {46.7
mg, 1.1 equivalents) and diisopropylethylamine (53 mg, 1.5 equivalents).
The resulting mixture was stirred for 2.5 hours at room temperature
and then the solvent evaporated. The crude product was purified by
flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to
1 s afford 120 mg (90%) of the ethyl ester.
The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtOH,
and a solution of 100 mg of NaOH in 1 mL of water was added. The
mixture was stirred for 3 hours at room temperature and then
concentrated under reduced pressure. Water (5 mL) was added and the
2o solution was washed with ether to remove any unhydrolyzed traps-cis
isomer. The aqueous solution was acidified to pH--6 with acetic acid
and then extracted with EtOAc (2 x 50 mL). The combined organic
extracts were washed with brine, dried over sodium sulfate and
concentrated under reduced pressure to afford the pure title compound
25 (60 mg, 53%) as a white solid. m.p. 67-69 °C. 1 H NMR (CDC13, 300
MHz)
b 0.82 (t, J=7.5Hz, 3H), 1.20-1.33 (m, 2H), 1.58-1.68 (m, 2H), 2.48-2.69
(m, 2H), 3.28 (dd, J=9Hz, 1 H), 3.49 (t, J=12Hz, 1 H), 3.65 (dd, J=12Hz, 1 H),
3.82 (s, 3H), 4.32 (dd, J=l2Hz, 1 H), 5.17 (d, J=9Hz, 2H), 5.95 (s, 2H),
6.70-6.78 (m, 3H), 6.92 (d, J=9Hz, 2H), 7.35 (d, J=9Hz, 2H). MS (DCIINH3)
3o m/e 462 (M+H)+.
Fxamole 61
r n n - - 4- h x h n -4- n i x I- I -1- - N-m h I-N
i~ooropyl ~! carbon~Lamino)ethvll-R~rolidine-3-carboxylic acid
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Example ~1 A
r n - 4-M x h n I -4- i n i I- I -i - m h 1
o~~~rrolidine 3 carboY~~~~r arid ethyl ester
To the mixture of cis,trans and traps, traps pyrroiidines resulting
s from Example 1 C (400 mg) dissolved in 9 mL of 1,2-dibromoethane was
added 0.7 mL of diisopropylethylamine and 30 mg of sodium iodide. The
resultant mixture was heated at 100 °C for 1 hour, and then the
solvents were removed in vacuo. The residue was taken up in EtOAc and
washed sequentially with water and brine, dried and concentrated under
~ o reduced pressure. The crude product was purified by flash
chromatography on silica gel eluting with 4:1 hexane-EtOAc to give 470
mg of the title product.
IExamQle 61 B
1s I - n I_ _1_ _ m h I in
wrrolidin°-~-~~~hoxvlic acid ethyl ester
To the compound resulting from Example 61 A (450 mg) dissolved
in 10 mL of EtOH was added 0.5 mL of 40% aqueous methylamine and 50
mg of sodium iodide. The mixture was heated at 80 °C for 1 hour, and
zo then the solvents were removed in vacuo. The residue was taken up in
EtOAc and' washed sequentially with water and brine, dried and
concentrated in vacuo. The resultant product was carried on without
further purification.
2 s -~
r _ : 4- h -4- I_ . I _.1- _ N_m h I-N-
j,°~~»tvrvlamino~ethvll nvrrolidine-3-carboxvli t
To the compound resulting from Example 61 B (--150 mg) dissolved
in 5 mL of 1,2-dichloroethane was added 0.3 mL of
so diisopropylethylamine. The solution was cooled to -40 °C, isobutyryl
chloride (0.17 mL) was added, the bath was removed, and the solution
was allowed to warm to ambient temperature and stirred for 15 hours.
The solvent was removed in vacuo; the residue was taken up in EtOAc
and washed sequentially with 1:1 sodium bicarbonate solutionlwater
3s and brine, dried and concentrated in vacuo. The product was purified by
flash chromatography on silica gel eluting with a gradient 1:1 EtOAc-
hexanes going to EtOAc and finally using 10% MeOH-EtOAc.
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The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17%
aqueous NaOH solution was added, and the resultant mixture was stirred
at ambient temperature for 3 hours. The solvents were removed in
vacuo; the residue was taken up in water and washed with ether. The
s aqueous phase was acidified with 1 N H3P04 to pH 3 and extracted twice
with ether. The combined organic extracts were washed with brine and
dried over NazS04. The solvents were removed in vacuo to provide 82
mg of the title compound as a white foam. Rotamers were seen in the
NMR. ~ H NMR (CDC13. 300 MHz) of the major rotamer b 1.06 (d, 3H, .
~ o J=1 OHz), 1.12 (d, 3H, J=1 OHz), 2.15 (m, 1 H), 2.5-3:0 (m, 3H), 2.91 (s,
3H),
3.32 (m, 2H), 3.50 (m, 2H), 3.65 (m, 2H), 3.77 (s, 3H), 5.92 (s, 2H), 6.73
(d, 1 H, J=8Hz), 6.75-6.9 (m, 4H), 6.96 (d, 1 H, J=2Hz), 7.29 (m, 1 H). MS
(DCI/NH3) mlz 469 (M+H)+. Analysis calcd for C2sHs2N20s ~ 0.3 TFA: C,
63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71; N, 5.24.
Example 62
trans traps 2 l4 Methoxy,~,henvl)-4-(1 3-benzodioxol-5-vl)-1-(2-(N-methyl-N
propionvlamino)ethyl_~oyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
2o Example 61 substituting propionyi chloride for isobutyryl chloride in
Example 61 C. ~ H NMR (CDC13, 300 MHz) of the major rotamer 8 1.13 (t,
3H, J=8Hz), 2.19 (m, 1 H), 2.30 (m, 2H), 2.65-3.0 (m, 3H), 2.85 (s, 3H),
3.25-3.4 (m, 2H), 3.5-3.7 (m, 3H), 3.79 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1 H,
J=SHz), 6.75-6.9 (m, 4H), 7.00 (bd s, 1 H), 7.29 (bd s, 1 H). MS (DCI/NH3)
mlz 455 (M+H)+. Analysis calcd for C25H3pN20s ~ 1.0 H20: C, 63.55; H,
6.83; N, 5.93 . Found: C, 63.55; H, 6.52; N, 5.73.
Example 63
r - 4-M h n I -4- 1 n i I- I -1- N-m h I-N-
so benzvlaminocarbonvlmethvl)-~yrrolidine-3-carboxylic acid
Using the procedures described in Example 1 the title compound
was prepared. 1 H NMR {CDC13, 300 MHz) of the major rotamer 8 2.79 (s,
3H), 2.8-3.2 (m, 2H), 3.48 (m, 2H), 3.61 (m, 2H), 3.77 {s, 3H), 3.78 (m,
1 H), 4.3-4.5 (m, 2H), 5.95 (d, 2H, J=2Hz), 6.7-6.9 {m, 4H), 7.00 (m, 1 H),
3s 7.15-7.35 (m, 7H). MS (FA8/NBA) m/z 503 (M+H)+. Anal calcd for
C29H3oN2Os ~ 0.5 H20: C, 68.36; H,5.74; N, 5.50. Found: C,68.41; H, 5.74;
N, 5.36 .
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Fxam~le 64
I _ _ 1 i x - -1- N- h I-N-
r
~~tylaminocarbonY m thyll wrrolidine-3-carboxvl~c acid
s Using the procedures described in Example 1 the title compound
was prepared. i H NMR (CDC13, 300 MHz) of the major rotamer 8 0.88 (t,
.3H, J=7Hz), 1.06 (t, 3H, J=7Hz), 1.27 (m, 2H), 1.45 (m, 2H), 2.8-3.6 (m,
11 H), 3.79 (s,3H), 3.80 (m, 1 H), 5.92 (bd s, 2H), 6.75 (d, 1 H, J=8Hz), 6.85
(d, 1 H, J=8Hz), 6.92 (d, 2H, J=SHz), 7.03 (s, 1 H), 7.33 (d, 1 H, J=8Hz). MS
~o (DCllNH3) mlz 483 (M+H)+. Anal calcd for C27H34~12C6 - 0.5 HOAc: C,
65.61; H,7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66.
~xam~le 65
n n - - 4-M n -4- 1 i x I- - N-m h I-N-
~ s im h I r t min r n im h I - rr 1' in - r li i
Using the procedures described in Example 1 the title compound
was prepared. ~H NMR (CDCl3, 300 MHz) of the major rotamer S 0.90 (s,
9H), 2.8-3.1 (m, 4H), 2.94 (s, 3H), 3.3-3.5 (m, 3H), 3.61 (m, 1 H), 3.80 (s,
3H), 3.82 (m, 1 H), 5.94 (bd s, 2H), 6.74 (d, 1 H, J=8Hz), 6.86 (d, 2H,
2o J=8Hz), 6.87 (m, 1 H), 7.03 (d, 1 H, J=2Hz), 7.33 (d, 2H, J=8Hz). MS
(DCIINH3) m/z 483 (M+H)+.
Fxamnle 66
r r I . _ 1 n I- I -1- - N- I-N-
2s l~~,yl°~ulfonvtamino)ethvll ovrrolidine-3-carboxylic acid
To the compound resulting from Example 61 B (60 mg, 0.13 mmol)
dissolved in 5 ml. of CH3CN was added 0.2 mL of Et3N and 22 mg (0.143
mmol, 1.1 equivalents) of 1-butanesulfonyl chloride. The mixture was
stirred for 1 hour at room temperature and then concentrated in vacuo.
so The crude product was purified by column chromatography on silica get
eluting with 1:1 EtOAc-hexane to yield 64 mg (90%) of the ester. Ester
hydrolysis by the procedure described in Example 1 D afforded the title
compound. m.p. 64-66 °C. j H NMR (CDC13, 300 MHz) 8 0.92 (t, J=7.5Hz,
3H), 1.39 (hexad, J=7.5Hz, 2H), 1.68-1.76 (m, 2H), 2.16-2.25 (m, 1 H),
ss 2.72 (s, 3H), 2.75-2.92 (m, 5H), 3.12-3.20 (m, 1 H), 3.25-3.34 (m, 1 H),
3.46-3.55 (m, 2H), 3.65 (d, J=9Hz, 1 H), 3.78 (s, 3H), 5.53 (s, 2H), 6.72 (d,
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J=7.5Hz, 1 H), 6.82 (dd, J=7.5Hz,3Hz, 1 H), 6.86 (d, J=9Hz, 2H), 7.02 (d,
J=3Hz, 1 H), 7.34 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 519 (M+H}+.
~,~,~nole s7
s
p~oovh, sulfonylamino)ethyl.)-oyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Example fib substituting 1-propanesulfonyl chloride for 1-
butanesulfonyl chloride. m.p. 69-70 °C. ~ H NMR (CDCI3. 300 MHz) b 1.02
~ o (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2:26 (m, 1 H), 2.72 (s,
3H}, 2.75-2.95 (m, 6H), 3.13-3.22 (m, 1H), 3.25-3.35 (m, 1 H), 3.47-3.58
(m, 2H), 3.66 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.96 (s, 2H}, 6.74 (d, J=7.5Hz,
1 H), 6.84 (d,d, J=7.5Hz, 3Hz, 1 H), 6.87 (d, J=9Hz, 2H), 7.04 (d, J=3Hz, 1
H),
7.43 (d, J=9Hz, 2H). MS (DCI/NH3) mle 505 (M+H)+.
is
Fxam~lg 68
rr~na traps-2-(4-0.",e h~~yo~~ylZ-4-(1.3-benzodioxol-5-vl)-1-(2
~~ronvlsulfonyl)ethyl)-Ryrrolidine-3-carboxylic acid
To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of
2o anhydrous THF was added 632 mg (26.32 mmol) of NaH in portions under
a nitrogen atmosphere. The mixture was heated at 60-70 °C for 1 hours.
To this mixture was added the compound resulting from Example 61 A
(180 mg, 0.38 mmol} in 2 mL THF. Heating was continued at 60-70 °C
for an additional 2 hours, and then the volatiles were removed under
2s reduced pressure. The crude propylthioethyl adduct was purified by
flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to
give 170 mg (95%).
To a solution of 170 mg (0.36 mmol) of the sulfide and 93 mg (0.8
mmol) of N-methyimorpholine N-oxide (NMO) in a mixture of 20 mL of
so acetone and 5 mL of H20 was added a solution of osmium tetroxide (10
mg) in 0.3 mL of t-butanol. The resulting mixture was stirred overnight
at room temperature and then concentrated under reduced pressure. The
residue was partitioned between EtOAc and H20. The organic phase was
washed with brine, dried over Na2SOa and concentrated in vacuo. Flash
s5 chromatography afforded i77 mg (98%) of the ethyl ester which was
hydrolyzed by the procedures described in Example 1 D to afford the title
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compound. m.p. 73-75 °C. ~ H NMR (CDC13, 300 MHz) 8 1.04 (t, J=7.5Hz,
3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 (m, 1 H), 2.84-3.08 (m, 7H),
3.43 (dd, J=9Hz, 3Hz, 1 H), 3.53-3.60 (m, 1 H), 3.68 (d, J=9Hz, 1 H),, 3.82
(s,
3H), 5.96 (s, 2H), 6.75 (d, J=7.5Hz, 1 H), 6.82 (dd, J=7.5Hz, 3Hz, 1 H), 6.88
s (d, J=9Hz, 2H), 6.99 (d, J=3Hz, 1 H), 7.32 (d, J=9Hz, 2H}. MS (DCI/NH3)
m/e 476 (M+H)+.
_EZcamp~e fig
r - 4- I -4- I- ! -1-N- r n -m Ih
2-enyy-wrrolidine-3-carboxylic acid
Exam I~~e 69A
fans-5-Methylhex-2-encZc acid ethy_I ester
Oil dispersion sodium hydride (0.85 g} was washed with hexanes
and suspended in THF (20 mL), and the mixture was cooled in an ice bath
to 0 °C. Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was
added slowly and the mixture stirred for 20 minutes at 0 °C.
Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five
minutes. The ice bath was removed and the mixture stirred for 18 hours
2o at ambient temperature. Saturated ammonium chloride solution (50 mL)
was added and the mixture extracted with diethyl ether (3 x 50 mL).
The ether extracts were combined, dried with Na2S04, and evaporated to
give a colorless oil which was purified by flash chromatography on
silica gel eluting with hexanes. The title compound was isolated as a
2s colorless oil (2.1 g).
Example 69B
traps-5-Methylhex-2-en-1-of
The compound resulting from Example fi9A (2.0 g) was dissolved in
3o toluene and cooled to 0 °C in an ice bath. Diisobutylaluminum
hydride
(1.5 N in toluene, 20 mL) was added dropwise and the solution stirred at
0 °C for two hours. Citric acid solution (25 mL) was added very slowly
to the cooled solution. The resulting mixture was stirred for 18 hours
at ambient temperature. Diethyl ether (50 mL) was added, the solids
ss removed by filtration and washed with additional ether (2 x 25 mL).
The filtrate was extracted with ether (2 x 25 mL). The ether
~...~.,..+c.,.,e onri Wachinas were combined, dried, and evaported to give a
W111.aW .v..v ~..~ .. _.
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colorless oil which was purified by flash chromatography on silica gel
eluting with 25% EtOAc-hexanes. The title compound was isolated as a
colorless oil (1.25 g).
Example 69C
traps-1-Bromo-5-methylhex-2-ene
The compound resulting from Example 69B (1.0 g) was dissolved in
diethyl ether and cooled to 0 °C in an ice bath. Phosphorus tribromide
(2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 °C
for
~ o two hours. The solution was poured onto ice, the.-layers separated, and
the aqueous layer extracted with additional ether (3 x 25 m~). The
ether layers were combined, dried, and evaporated to give a colorless
oil which was used without further purification (0.95 g).
- 4- n - 1 i x I h x-
2-enYl_1-pYrrolidine-3-carboxylic acid
The title compound was synthesized using the methods detailed in
Example 1 D but substituting the compound resulting from Example 69C
2o for N-propyl bromoacetamide. ~ H NMR (CDC13, 300 MHz) b 0.84 {d, 6H,
J=8Hz), 1.57 (heptet, 1 H, J=8Hz), 1.87 (t, 2H, J=6Hz), 2.60 (dd, 1 H,
J=8Hz,14Hz), 2.86 (t, 1 H, J=1 OHz), 2.96 (dd, 1 H, J=BHz, lOHz), 3.20 (dd,
1 H, J= 5Hz,14Hz), 3.29 (dd, 1 H, J=3Hz,10Hz), 3.50 (m, 1 H), 3.70 (d, 1 H,
J=1 OHz), 3.78 (s, 3H), 5.47 (m, 2H), 5.93 (s, 2H), 6.71 (d, 1 H, J=8Hz),
6.83 (d, 3H, J=9Hz), 7.05 (s, 1 H), 7.32 {d, 2H, J=9Hz). MS (DCIINH3) m/e
438 (M+H)~. Anal calcd for C26H3t NO~: C, 71.37; H, 7.14; N, 3.20. Found:
C, 71.16; H, 7.24; N, 3.17.
Example 70
3o r - 4- h h n I -4- 1 n i I- I -1-N- r n -
dimethyhex-2-enyil-oKrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
_ Example 69 but substituting 4-methyl-2-pentanone for
isovaleraldehyde in Example 69A, which gave -7:1 mixture of trans/cis
s5 olefins. The crude product was purified by preparative HPLC (Vydac
uC i 8) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The
~ ____.:...... ...crc Imnnh;li7afl tn f7iVe, the product (and its
11CJ11GU W avaw"" ....... .~..r......._ _ - ~
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diastereomer) as a white solid. ~ H NMR of the major (traps) isomer:
{CDC13. 300 MHz) 8 0.83 (d, 6H, J=8Hz), 1.56 (s,3H), 1.74 (m, 1 H), 1.92 {d,
2H, J=6Hz), 3.3-3.5 (m, 3H), 3.6-3.8 (m,4H), 3.78 (s, 3H), 3.9-4.0 (m, 1 H),
5.22 (m, 1 H), 5.90 (d, 2H, J=l2Hz), 6.63 (m, 1 H), 6.78 (m, 3H), 6.95 (s,
s 1 H), 7.45 (d, 3H, J=8Hz). MS (DCI/NH3) m/e 438 (M+H)+. Anal calcd for
C2~H33NO5 ~ 1.0 TFA: C, 61.59; H, 6.06; N, 2.48. Found: C, 61.36; H, 6.10;
N, 2.34.
mole 71
lrans traps-2-{4-Methoxvoheny~,l-4-{1 3 benzodioxol-5-vl)-1-~4
h~eotvlcarbon~,~lmethyrll-o~rrrolidine-3-carboxyrlic acid
Example 71 A
1-Chloro-3-ps~vi-2-hexanone
is To 2-propylpentanoic acid (156.6 pl, 1.00 mmol) dissolved in
anhydrous dichloromethane (2 mL) was added DMF (3 pL, 4 mole %), and
the solution was cooled to 0 °C under a nitrogen atmosphere. To the
solution was added oxalyl chloride (94.3 p.L, 1.08 mmol) dropwise over a
few minutes. The reaction was stirred 18 hours while warming to
2o ambient temperature. The mixture was cooled to 0 °C and excess -0.3
f~
ethereal diazomethane solution was added. The reaction mixture was
stirred 18 hours while warming to ambient temperature. The reaction
mixture was washed with 1 ~, aqueous sodium carbonate solution (30
mL), dried over anhydrous sodium sulfate, filtered and concentrated
2s under reduced pressure. The residue was dissolved in ether (2 mL) and
cooled to 0 °C under a nitrogen atmosphere. Hydrogen chloride as a 4 N
solution in dioxane (275 ~.L, 1.10 mmol} was added dropwise over a few
minutes. The reaction was stirred 18 hours while warming to ambient
temperature. The reaction mixture was concentrated under reduced
3o pressure and the residual oil was used in the next step without further
purification.
Exampe 71 B
n I - 4-m h h n I -4- 1 i x I- 1 -1- 4-
ss Jl~gp~,ylcarbon,~,rlmethyrl)-oyrrolidine-3-carboxy Ir ate
To the compound resulting from Example 71A (1.00 mmol,
maximum theoretical yield) was added a solution of the traps, traps
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ethyl carboxylate from Example 1 C (295 mg, 0.80 mmol as a 50
solution in toluene), diisopropylethylamine (700 p.L, 4.00 mmol) and
acetonitrile (4 mL). To the resulting solution was added sodium iodide
(12 mg, 10 mole %), and the reaction mixture was stirred 18 hours
s under a nitrogen atmosphere at ambient temperature. Additional sodium
iodide (24 mg, 20 mole %) and acetonitrile (4 mL) were added, and the
reaction mixture was heated at 45-50 °C with stirring for 18 hours.
The reaction mixture was concentrated under reduced pressure, and the
residue was chromatographed on silica gel eluting with 1:9 ethyl
~ o acetate-hexane to give 237 mg (46%) of the title -compound as a yellow
oil.
Exam~~e 71~
Lran~.trans-2-(4-Methoxyr~ henyl)-4-(1.3-benzodioxol-5-~rly-1-j4-
~s hep~,yricarbonyyl)-pyrrolidine-3-carboxxlic acid
To the compound resulting from Example 71 B (231 mg, 0.4532
mmol) dissolved in ethanol (10 mL) was added a solution of lithium
hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was
stirred for 18 hours under a nitrogen atmosphere, additional lithium
2o hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and
stirring was continued 24 hours. The reaction mixture was
concentrated under reduced pressure to remove the ethanol, and the
aqueous residue was diluted with water (45 mL) and washed with ether
(50 mL). The aqueous layer was neutralized with 1 N hydrochloric acid
2s to cloudiness and then 10% aqueous citric acid was added to adjust the
pH to -5. This solution was then extracted with 10% ethanol in
chloroform (4 x 25 mL). The combined organic extracts were dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by preparative TLC on silica gel
3o eluted with 1:1 ethyl acetate-hexane to give 86 mg (39%) of the title
compound as an off white powder. ~ H NMR (CDCi3, 300 MHz) b 0.73-0.97
(m, 6H), 1.03-1.33 (m, 6H), 1.36-1.58 (m, 2H), 2.46 (m, 1 H), 2.80-2.98
(m, 3H), 3.38-3.64 (m, 3H), 3.75-3.90 (m, 1 H), 3.79 (s, 3H), 5.94 {s, 2H),
6.75 (d, 1 H), 6.86 (d, 2H), 6.92 (d, 1 H), 7.7 2 (s, 1 H), 7.32 (d, 2H). MS
35 (FAB) m/e 482 (M+H)+. Ana! calcd for C28H3$NO6: C, 69.83; H, 7.32; N,
2.91. Found: C, 69.57; H, 7.41; N, 2.73.
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Example 72
traps tran~2 ~~4 Methoxvohenyrl 4 j1 3 benzodioxol 5 y1 -1-lvalP~lmethvf)
Qyrrrolidine-3-carbox~rlic acid
Example 72A
1-rhloro-2-hexanone
Using the procedure described in Example 71 A and substituting
pentanoic acid for 2-propylpentanoic acid afforded the title compound
as an oil which was used in the next step without further purification.
~o
Example 72B
Lrans traps-Ethyl, 2-~4-methoxvoTh,enyl~-4-~(1.3-benzodioxole-5-vl)-1
~valervimethyrl)-ovrrolidine-3-carboxyrlate
Substituting the compound resulting from Example 72A for i
~ s ~chloro-3-propyl-2-hexanone and using the procedure described in
Example 71 B, except deleting the first addition of sodium iodide,
stirring 18 hours at ambient temperature and purifying by silica gel
chromatography eluting with 3:17 ethyl acetate-hexane, the title
compound 305 mg (65%) was obtained as a yellow oil.
Examp~ 7?
fr~n~ traps 2-~-Methox~rohen~)~-4-(1.3-benzodioxol-5-vll-1-
~,valeryl_m~thy[~rrroli inP,~ 3-cartzoxyrlic acid
By substituting the compound resulting from Example 72B for
traps, traps-Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-
heptylcarbonylmethyl)-pyrrolidine-3-carboxylate and using the
procedure described in Example 71 C, except only one solution of
lithiurrr hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added
followed by stirring for 18 hours, the title compound 130 mg (46%) was
obtained as an off white powder. ~H NMR (CDC13, 300 MHz) b 0.87 (t,
3H), 1.26 (m, 2H), 1.49 (m, 2H), 2.37 (m, 2H), 2.79-2.98 (m, 3H), 3.31-
3.49 (m, 2H), 3.56 (m, 1 H), 3.77, 3.79 {d,s, 4H), 5.94 (s, 2H), 6.75 (d, 1
H),
3s 6.81-6.93 (m, 3H), 7.09 (d, 1 H), 7.33 (d, 2H). MS (FAB) m/e 440 (M+H)+.
Anal. calcd for C2sH29NO6: C, 68.32; H, 6.65; N, 3.19. Found:
C. 67.95: H. 6.64; N, 3.05.
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FYample 73
_trans aans-2 (4 Methoxvt~henvll-4-(1 3-benzodioxol-5-vll-1-(N-(3.4
rlmethoxvb~nz~l N-methylaminocarbonlrlmethvl)ovrrolidine-3-carboxylic acid
Exam~ie 73A
h I -4- 1 n i
kt~~,(3 4-dimethoxybenzyrl)aminocarbonylmethvl)ovrrolidine-3-
~ ra boxyiic acid ethyrt ester
Using the procedure of Example 1 D, paragfaph 1, substituting 3,4-
dimethoxybenzyl bromoacetamide for dipropyl brornoacetamide, the
desired product mixture was obtained as a white foam in 81 % yield.
E, xam-ole 73B
t5 t;an s cans- and cis trans 2-l~-Methoxymhenyrl)-4-(1.3-benzodioxol-5-
yl)-1-~(N~(3 4-dimethoxybenzyrl)-N-
methylaminocarbonvlmethvl)nvrrolidine-3-carboxylic acid ethyl ester
The resultant product from Example 73A (220 mg, 0.404 mmol)
was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled
20 (0 °C) suspension of sodium hydride (23 mg of a 60% by weight
mineral
oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon
atmosphere. The resulting mixture was stirred at 0 °C for 1 hour, then
methyl iodide (28 pL, 64 mg, 0.45 mmo!) was added. The reaction
mixture was stirred at 0 °C for 45 minutes. TLC (Et20) indicated
25 incomplete reaction. An additional portion of methyl iodide (28 pL, 64
mg, 0.45 mmol) and dry 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1 H)pyrimidinone (50 pL, 0.41 mmol) were added. The reaction
mixture was stirred at ambient temperature for 2 days. The reaction
was poured into 25 mL of 0.5 M aqueous citric acid and extracted with 2
so x 25 mL EtOAc. The combined organic extrracts were washed
sequentially with 30 mL water and 30 mL brine, then dried (Na2S04),
filtered and concentrated under reduced pressure to produce 270 mg of
crude material. Flash chromatography on silica gel eluting with Et20
gave the title compounds as an inseparable mixture in 43% yield. ~ H
ss NMR (CDC13, 300 MHz) S 2.79 (s) and 2.81 (s), for the N-CHa signals. MS
mlz 591 (M+H)+.
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Example 73C
dimeth~~cvbenzyll-N-methylaminocarbonyrlm~ hvllovrrolidine-3
carboxyrlic acid
s To the resultant compound from Example 73B (98 mg, 0.17 mmol)
dissolved in 1 ml_ EtOH and cooled to 0 °C was added a solution of
lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H20. The
resulting solution was stirred under a nitrogen atmosphere for 16
hours. The solution was concentrated in vacuo, and the residue was
~ o partitioned between i 5 mL H20 and 15 mL Et20. ~'he aqueous phase was
extracted with 5 mL Et20, then the aqueous phase was acidified with
10% aqueous citric acid. The acidic aqueous phase was saturated with
NaCI and extracted with 3 x 15 mL EtOAc. The EtOAc extracts were
combined, dried (Na2S04), then filtered and concentrated in vacuo to
~ s give 40 mg (42%) of the title compound as a white foam. ~ H NMR
(CD30D, 300 MHz, two rotameric forms) 8 2.85 (s, 3H), 2.94-3.25 (br m,
3H), 3.35-3.70 (br m) and 3.64 (s, 4 H total), 3.70-3.97 (br m), 3.74 (s),
3.76 (s), 3.78 (s), 3.79 (s), 3.81 (s), and 4.03 (br d, J=i 4 Hz, 8H total),
4.43 (AB, 1 H), 5.91 (s) and 5.93 (s, 2H total), 6.50-6.60 (m, 1 H), 6.67-
20 7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for
C3~ H35N2O8 {M+H)+: 563.2393. Found: 563.2385.
example 74
franc franc-~-{ -Methoxvuhe~~ nvl~-4-~1 ~ benz2dioxol-girl)-1-(N-(3_.4-
2s dimethoxvbenzvl)~aminocarbonylmethvl)wrrolidine-3-carboxylic acid
The procedure of Example 73C was used, with the substitution of
the resultant compound from Example 73A for the resultant compound
from Example 738, to provide the title compound. ~ H NMR (CD30D, 300
MHz) 8 2.85 (d, J=16Hz, 1 H), 2.92 (br t, J=9Hz, 1 H), 2.98 (br t, J=1 OHz,
so 1 H), 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1 H), 3.67 (s, 3H), 3.78 (s,
3H), 3.80 (s, 3H), 3.85 (d, J=10 Hz, 1 H), 4.21 (d, J=1 SHz, 1 H), 4.41 (d, J
=
l5Hz, 1 H), 5.91 (s, 2H), 6.67 (d, J=8Hz, 1 H), 6.75-6.95 (m, 7H), 7.33-7.40
(m, 2H). HRMS calcd for C3oHs2N208 (M+H)+: 549.2237. Found:
549.2224.
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i xample 75 ,
j2R 3R 4R)-~l4-Methoxvo'~~lly~~L1 3-benzodioxol-5-vl)-1-((iR)-1-IN.N
diQrooviaminocarbonyly-1-butvl)nvrrolidine-3-carboxylic acid
IExamnle 75A_
traps traps-2-(4- etho~ohenvl)-4-(1.3-benzodioxol-5 vl)-1-lli R)~,
~benzyloxvcarbonvl)buityl)ovrrolidine-3-carboxylic acid ethyl ester
The procedure of Fung, et. at., J. Med. Chem., 35(10): 1722-34
(1992) was adapted. The resultant compound from Example 6A (103 mg,
~ 0 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of H20 ,
and ammonium carbonate (34 mg, 0.35 mmol) and (2S)-benzyl 2-
bromopentanoate (78 mg, 0.30 mmol) were added. The reaction was
refluxed for 24 hours. The reaction was partitioned between 15 mL of 1
M aqueous Na2C03 and 25 mL of CH2C12. The aqueous phase was
1 s extracted with 2 x 10 mL CH2CI2, and the combined organic phases were
washed with 15 mL brine, dried (Na2S04), then filtered and
concentrated under reduced pressure to a brown oil (169 mg). The crude
product was purified by silica gel chromatography eluting with 3:1
CH2C12-hexane to produce 106 mg (68%) of the title compound as a waxy
zo solid. ~ H NMR indicated the presence of two diastereomeric products.
xama~le 75B
Ir~3ns traps-2-~4-Methoxy~henyl)-4-~1 3-benzodioxol-5-vl)-1-lllR)-1-IN.N-
~p~~yrlaminocarbonyrl~~-1-butyl)ovrrolidine-3-carboxylic acid ethyl ester .
2s The resultant compound from Example 75A (101 mg, O.i80 mmol)
and 30 mg of. 10°l° palladium on charcoal were stirred in 2 mL
EtOAc
under 1 atmosphere of H2 for 4 hours. The reaction mixture was
filtered through a plug of Celite, using 15 mL MeOH to wash the
catalyst., The combined filtrate and wash were concentrated in vacuo to
3o give 81.4 mg (96%) of the crude acid as a white solid.
The above crude acid was combined with HOBt hydrate (41 mg,
0.27 mmol), dipropylamine (26 mg, 0.26 mmot), and 4-methylmorpholine
(37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 °C,
then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochioride (44
as mg, 0.23 mmol) was added. The mixture was stirred at -15 °C and
allowed to warm slowly to room temperature overnight. The solvent
was removed by distillation under reduced pressure, and the residue
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was partitioned between 20 mL EtOAc and 10 mL of 1 M aqueous Na2C03.
The organic phase was washed with 10 mL of brine, dried (Na2S04), then
filtered and concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel, eluting with 1:2 Et20-hexane.
s Further purification of overlap fractions by preparative TLC eluting
with 1:2 Et20-hexane yielded 32 mg (34%) of a less polar product, and
44 mg (46%) of a more polar product.
Example 75C
~0 2R R 4R - - 4- h h n I -4- 1 n x I- t -1- 1 R -1-
,~N N dipropylaminocarbonyl)-1-butyl)pvrrolidine-3-carboxylic acid
The procedure of Example 73C was followed, with the substitution
of the less polar isomer from Example 75B for the resultant product
from Example 73B, to provide the title compound in 94% yield. [a]p = -
i s 52° (c=0.235, CH30H). 1 H NMR {CD3OD, 300 MHz) 8 0.55 (t, J=7Hz,
3H),
0.87 (t, J=7Hz) and 0.87-0.94 (m, 6H total), 1.03-1.25 (br m, 2H), 1.25-
1.68 (br m, 4H), 1.90-2.07 (br m, 1 H), 2.75-2.94 (br m, 2H), 2.94-3.02
(br m, 2H), 3.20-3.40 (m, overlapping with CD2HOD signal), 3.40-3.60 (br
m, 2H), 3.79 (s, 3H), 4.04 (br d, J=9 Hz, 1 H), 5.92 (dd, J=3,5 Hz, 2H), 6.72
20 (d, J=8 Hz, 1 H), 6.79 (dd, J=1.5,8 Hz, 1 H), 6.92-6.98 (br m, 3H), 7.29-
7.39
(m, 2H). MS m/z 525 {M+H)+.
Example 76
~2S 3S 4S) 2 ~~4 Methoxvohenyl)-4-(1 3-benzodioxol-5-vl)-1-((1 R)-1-
2s {N N dioroQyrlaminocarbonvl~-1-butyl_)pyrrolidine-3-carboxylic acid
The procedure of Example 73C was followed, with the substitution
of the more polar isomer from Example 75B for the resultant product
from Example 73B, to provide the title compound in 88% yield. [a]p =
+58° (c=0.37, CH30H). ~ H NMR (CD30D, 300 MHz) S 0.57 (br t, J=7Hz,
3H),
3a 0.88-0.98 (m, 6H), 1.08-1.35 (br m, 2H), 1.35-1.68 (br m, 4H), 1.75-1.90
{br m, 1 H), 2.75-2.86 (br m, 2H), 3.10-3.30 (br m, 2H), 3.51-3.65 (br m,
2 H), 3.69 (s, 3H), 4.03-4.16 (br m, 2H), 5.91 (s, 2H), 6.71-6.83 (m, 2H),
6.86-6.97 (m, 3H), 7.32 (br d, J=9Hz, 2H). MS mlz 525 (M+H)+.
*rB
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F,xam~le 77
- 4- -4- n i I- _ 1- N-
~nroovlaminocarbonyl_)-1-butyl)pyrroJidine-3-carboxylic acid
Examol~ 77A
#~ans tram-2-~(~-Methox~!-4-~1 3-benzodioxoLS-vl)-1-l(1 S)-1
jN N-di~ron I~amin~,rarbonyrl)-1-butyrl)~yrrrolidine-3-carboxyrlic acid
ethXl ester
(2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol,
~ o made by standard procedure) was dissolved in 2 rgL THF under an argon
atmosphere, diisopropylethytamine (75 mg, 0.58 mmol) was added, then
the solution was cooled to -20 °C. Trifluoromethanesulfonic anhydride
(95 pL, 159 mg, 0.565 mmol) was added to the cooled solution over 1
minute, and the reaction mixture was stirred at -20 °C for 1 hour, and
~ s at room temperature for an additional 1 hour. The resulting slurry was
recooled to 0 °C, and a solution of the resultant compound from Example
6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 ~.L, 75 mg,
0.58 mmol) in 3 mL of CH2C12 was added. The reaction was stirred at 0
°C for 3 hours and for an additional 2 days at room temperature. TLC
zo (Et20-hexane 1:2) indicated starting materials remained, so the mixture
was warmed to reflux for 4 hours. The reaction was cooled, then
partitioned between 30 mL EtOAc and 15 mL of 1 M aqueous Na2C03. The
aqueous phase was extracted with 15 mL EtOAc, then the combined
organic phases were washed with 20 mL brine, dried (Na2S04), filtered
zs and concentrated in vacuo to a yellowish oil. Purification by flash
chromatography on silica gel eluting with 1:2 Et20-hexane gave 19.9 mg
(7%) of a less polar product and 20.1 mg (7%) of a more polar product.
~ H NMR spectra and MS were the same as those of Example 76B.
so Exam Ip a 77B
4 - 4-M I -4- 1 n i x I- I -1- 1 -1- N N-
ioroQy~aminocarbonSrl)-1-butvl~gyrrolidine-3-carboxylic acid
The procedure of Example 73C was followed, with the substitution
of the less polar isomer from Example 77A for the resultant product
35 from Example 73B, to provide the title compound in 100% yield. i H NMR
(CD30D, 300 MHz) and MS identical to those of Example 75C.
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F_xamole 78
(~R 3R 4R) 2 (~ Mpthoxvohenvil-4-(1 3-benzodioxol-5-vl)-1-((1S -1- N
di~ro~,~laminocarbony~_ -butvl)Ryrrolidine-3-carb~~~rlic acid
The procedure of Example 73C was followed, with the substitution
s of the more polar isomer from Example 77A for the resultant product
from Example 73B, to provide the title compound in 88% yield. ~ H NMR
(CD30D, 300 MHz) and MS identical to those of Example 76.
~;~amote 79
o prd:,s aran~s-2 ~4 Methoxv~gn~~4-(1 3-benzor~ioxol-5-yl)-1-lN.N-di~n-
hr~yJ),~minocarbon I~~~I~ 3-(5-tetr I I rrolidin
Carbonyldiimidazole (510 mg, 3.148 mmol) was added to i .020 g
(2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THI=,
and the mixture was heated for 40 minutes at 50 °C. The reaction
~ s mixture was cooled in an ice bath, and 25% solution of ammonia in
methanol was added. After 30 minutes, the solid which had formed was
filtered, washed with ethanol and finally with ether to yield 850 mg
(83%) of the 3-carboxamide compound. m.p. 194-196 °C.
Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL
20 of pyridine, and the mixture was stirred 1 hour at room temperature.
Dichloromethane was added, and the solution was washed with
potassium bicarbonate solution, dried over sodium sulfate, and
concentrated. The residue was chromatographed on silica gel eluting
with 2:1 hexane-ethyl acetate to give 790 mg (96%) of the 3-
2s carbonitrile compound.
To this nitrite in 5 mL toluene was added 385 mg of trimethyl tin
chloride and 126 mg sodium azide. The mixture was heated 20 hours at
125 °C (bath temp). After cooling, methanol (5 mL ) was added, and
the solution was concentrated in vacuo. To the resulting residue was
so added 6 mL of methanol and f mL of water containing 0.2 g phosphoric
acid. After stirring 1 hour at room temperature, water was added and
the mixture extracted with dichtoromethane. The combined organic
extracts were dried and concentrated, and the resulting residue was
crystallized from ether to give a solid. The solid was dissolved in
as sodium hydroxide solution, filtered from insoluble material and
acidified with acetic acid to get 532 mg (62%) of the title compound.
m.p. 165-167 °C. i H NMR (CDC13, 300 MHz) b 0.85 (t, J=7Hz, 3H), 0.87
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(t, J=7Hz, 3H), 1.10-1.50 (m, 8H), 3.0-3.6 (m, 8H), 3.70 (s, 3H), 3.7-3.8
(m, 7 H), 3.90 (t, J=9Hz, 1 H), 4.37 (d, J=9Hz, 1 H), 5.86 (s, 2H), 6.62 (d,
J=BHz, 1 H), 6.65-6.73 (m, 3H), 6.95 (d, J=2Hz, 1 H), 7.11 (d, J=9Hz, 2H).
Example 80
traps traps-2-~4-Fl~;,oro~n_yjl-4-l1 3-benzodioxol-5-vl)-1-IN.N-di~n
b~r ~rl)aminoc~,rbonvlmethyl_lpyrrolidine-3-carboxylic acid
The title compound was prepared as an amorphous solid from
methyl (4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-1,3-benzodioxole
using the procedures described in Examples 1 and .43. ~ H NMR (CDC13,
300 MHz) 8 0.8i (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.0-1.55 (m, 8H),
2.81 (d, J=13 Hz, 1 H), 2.90-3.10 (m, 4H), 3.15-3.30 (m, 1 H), 3.32-3.45
(m, 3H), 3.55-3.65 (m, 1 H), 3.86 (d, J=lOHz, 1 H), 5.94 (dd, J=2Hz, 4Hz,
2H), 6.72 (d, J=8 Hz, 1 H), 6.86 (d, J= 8 Hz, 1 H), 6.95-7.07 (m, 3H}, 7.32-
~ s 7.45 (m, 2H).
Exam I~e 81
- 4- h n ! -4- 1 nz x I- f -1- N N- ' n-
b_~t~)aminocarbon~l_methyl)nvrrolidine-3-carboxyrlic acid
2o N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method
of Bowman, R.E., J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was
treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for
30 minutes at 50 °C. After cooling to room temperature, 250 mg
(0.678 mmol) of ethyl traps,traps-2-(4-methoxyphenyl)-4-(1,3-
2s benzodioxol-5-yl)-pyrrolidine-3-carboxylate, the compound resulting
from Example 6A, was added, and the mixture was heated at 45 °C for
30 minutes. The product was chromatographed on silica gel, eluting
with 1:1 hexane-ethyl acetate to give 306 mg of the intermediate ethyl
ester.
3o The ester was hydrolyzed with sodiumhydroxide in waterand
ethanol as a white powder.~ H
to give
265 mg
of the
title compound
NMR (CDC13, 300 MHz) 8 rotational isomers0.75 and 0.85 J=7Hz,
- (2 t,
3H), 1.05-1.5 (m, 8H}, 2.65-3.20 (m, (s, 3H),
6H) 3.43-3.70 (m, 3H}, 3.72
3.87 (d, J=l5Hz, 1 H), 4.49 (dd, J=12Hz,and 5.23 (dd, z, 8Hz}
6Hz) J=l2H
35 2H, 5.90 (dd, J=2Hz, 4Hz, 2H), 6.63-6.783H), 6.86 and (d,
(m, 7.04
J=9H z, 2H), 7.22 (d, J=9Hz, 2H).
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FxamDIe 82
ans traps-2-(,4-Methoxy h~n~~)~~ 3-benzodioxol-5-yll-1-lN-n-butyl)-N-(n
Qroovl)amin~ar~onvimet vl)~oyrrolidine-3-carboxylic acid
The title compound was prepared using the procedures described
s in Example 1. m.p. 160-162 °C. ~ H NMR (CDC13, 300 MHz) rotational
isomers 8 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 (m,
6H), 2.63 and 2.66 (two doublets, J=13Hz, 1 H), 2.90-3.10 (m, 4H), 3.23-
3.61 (m, 5H), 3.71 and 3.75 (two doublets, J=1 OHz, 1 H), 3.78 (s, 3H),
5.92-5.96 (m, 2H), 6.72 (d, J=8Hz, 1 H), 6.83-8.89 (m, 3H), 7.03 (d, J=2Hz,
~ 0 1 H), 7.81 (d, J=9Hz, 2H).
Exarn 1~3_
traps traps-2 (4 Methoxvnhenyl~ 4-~(,1 3-benzodioxol-5-yrl)-1-j,?~N N-diln
~Ryrllaminoc3rbonyllethvllovrr li in -~sarboxylic acid
~ s The compound resulting from Example 6A (250 mg, 0.677 mmol),
205 mg (1.36 mmol) dialtyl acrylamide (Polysciences, Inc.), and 10 mg
acetic acid were heated at 85 °C in 0.75 mL of methoxyethanol for one
hour. Toluene was added, and the solution was washed with bicarbonate
solution, dried, and concentrated. Chromatography on silica gel eluting
zo with 3:1 hexane-ethyl acetate gave 283 mg (80%) of the diallyl
compound.
The diallyl compound was hydrogenated using 10% Pd/C catalyst
(27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere. The
catalyst was removed by filtration, and the filtrate was concentrated
2s to afford the dipropyl amide ethyl ester in 100% yield.
The ester was hydrolyzed to the title compound by the method of
Example 1 D in 83% yield. ~ H NMR (CDCl3, 300 MHz) b 0.82 and 0.83 (two
triplets, J=7Hz, 6H), 1.39-1.54 (m, 4H), 2.35-2.60 (m, 3H), 2.80-3.07 (m,
5H), 3.14-3.21 (m, 2H), 3.31-3.38 (m, 1H), 3.51-3.61 (m, 1H), 3.73 (d,
so J=12H, 1 H), 3.75 (s, 3H), 5.94 (s, 2H), 6,71 (d, J=9Hz, 1 H), 6.79-6.85
(m,
3H), 7.04. (d, J=2Hz, 1 H)< 7.32 (d, J=9Hz, 2H).
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Exa P~,84
traps.traps-2-(4-Methox~tR~pyrl -~4-(1.3-benzodioxol-5-yrl)-~N.N-di(n
b~l)a~ninoca~bo~r y~,Ryrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
s Example 8 using dibutyl carbamoyl chloride, prepared by the method of
Hoshino et al., Syn. Comm., 17: 1887-1892 (1987), as a starting
material. ~ H NMR (CDC13, 300 MHz) 8 0.86 (t, J=7Hz, 6H), 1.14-1.28 (m,
4H), 1.35-1.48 (m, 4H), 2.81-2.94 (m, 2H), 3.11 (t, J=l2Hz, 1 H), 3.30-
3.41 (m, 2H), 3.59-3.68 (m, 2H}, 3.76 (s, 3H), 3.78-3.85 (m, 1 H), 5.81 (d,
~ o J=9Hz, 1 H), 5.94 (s, 2H), 6.73-6.86 (m, 5H), 7.24 (d, J=9Hz, 2H}.
Exam I~~ a 8_5
traps.traps-2-~(4-Methoxvohenyl~-4-(1.3-benzodioxol-5-yl}-1-(N N-dijn-
butyl~aminocarbonvlmethvl,~yrrrolidin~-3-carboxv(ic acid s~ium sad,
~ s Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 mmol) in 2 mL of
MeOH was added to the compound resulting from Example 43 (610 mg,
1.196 mmol.) in 5 mL MeOH. The solution was concentrated to dryness,
and the resulting powder was stirred with heptane. The heptane was
removed in vacuo to give a powder which was dried in the vacuum oven
2o for 2 hours at 60 °C to yield 627.5 mg of the title compound.
ExamRle 86
traps.traps-2-(4-Methoxvc~henyr~-4~(1 3-benzodioxol-5-y~-1-[2-(N N-di(n
butyrllamino)ethyrl]~~rrrolidine-3-carboxyrlirt acid
2s A solution of the bromoethyl compound resulting from Example
61A (150 mg), dibutylamine (150 mg} and sodium iodide (18 mg) in 0.75
mL ethanol was heated at 80 °C for 1 hour. After cooling, toluene was
added, and the solution was washed with potassium bicarbonate
solution, dried over Na2S04 and concentrated. More toluene was added,
so and the solution was again concentrated to get rid ~of excess
dibutylamine. The residue was dissolved in warn°S heptane and filtered
from a small amount of insoluble material. The hepane was removed in
vacuo to give 143 mg (87%) of the intermediate ethyl ester.
The ester was hydrolyzed by the method of Example 1 D to give the
35 title compound as a white powder. ~ H NMR (CD30D, 300 MHz) 8 0.89 (t,
J=7Hz, 6H}, 1.16-1.30 (m, 4H), 1.44-1.56 (m, 4H), 2.48-2.57 (m, 1 H),
2.80-3.08 (m, 8H), 3.14-3.25 (m, 1 H), 3.31-3.38 (m, 7 H), 3.59-3.60 (m,
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1 H), 3.74 (s, 3H), 3.75 (d, J=lOHz, 1 H), 5.89 (s, 2H), 6.71 (d, J=9Hz, 1 H),
6.81 (dd, J=9Hz, 2Hz, 1 H), 6.90 (d, J=1 OHz, 2H), 6.96 (d, J=2Hz, 1 H), 7.37
(d, J=lOHz, 2H).
s F,,~~ olc a 87
traps.traps-2-(4-Methoxy~heny~-4-(1.3-benzodioxo!-5- I)-~, 1-~2-jN-IN.N-di n-
butyl)aminocarbonyJl~-N-met~rlaminoj.~thyl)gyrrolidine-3-carboxyriic acid
Dibutyl carbamoyl chloride (135 mg) was added to the compound
resulting from Example 6i B (250 mg) and 150 mg triethylamine in 1 mL
~ o dichloromethane. After stirring 1 hour at room temperature, toluene
was added, and the solution was washed with potassium bicarbonate
solution, dried over Na2S04 and concentrated. The residue was
chromatographed on silica gel, eluting with a mixture of 38% EtOAc and
62% hexane to give 194 mg of the ethyl ester intermediate.
~ s The ester was hydrolyzed by the method of Example 1 D to afford
i41 mg of the title compound. ~H NMR (CD30D, 300 MHz) 8 0.92 (t,
J=7Hz, 6H), 1.21-1.32 (m, 4H), 1.42-1.53 (m, 4H), 2.62 (s, 3H), 2.65-2.7fi
(m, 1 H), 3.00-3.20 (m, 8H), 3.44-3.55 (m, 1 H), 3.62-3.78 (m, 2H), 3.80
(s, 3H), 4.07 (d, J=12 Hz, 1 H), 5.93 (s, 2H), 6.75 (d, J=9Hz, 1 H), 6.87 (dd,
2o J=9Hz, 2Hz, 1 H), 6.94 (d, J=10 Hz, 2H), 7.04 (d, J=2Hz, 1 H), 7.40 (d,
J=lOHz, 2H).
Exam I
traps. traps-2-(4-Methoxvohen~rl)-4-X1.3-benzodioxol-5-,yrl)-1-(N. N-diln-
2s butyl)aminocarbonylmethyl, rrolidine-3- N-methanesulfonvl)carboxamide
Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg
(0.294 mmol) of the compound resulting from Example 43 in 0.4 mL of
tetrahydrofuran, and the solution was stirred at 60 °C for 2 hours.
After cooling, 50 mg (0.52fi mmol) of methanesulfonamide and 68 mg
3~ (0.447 mmol) of DBU in 0.3 mL of THF were added. The mixture was
stirred at 45 °C for 2 hours. The solvents were removed in vacuo, and
the residue was dissolved in water. A few drops of acetic acid were
added, and the solution was lyophilized to give 121 mg (70%} of the
title compound. m.p. 170-173 °C. ~ H NMR (CDC13, 300 MHz) 8 0.82 (t,
ss J=7Hz, 31-i), 0.88 (t, J=7Hz, 3H), 1.05-1.51, (m, 8H), 2.75-2.86 (m, 2H),
2.83-3.25 (m, 4H}, 3.17 (s, 3H), 3.32-.3.50 (m, 3H), 3.70-3.78 (m, 1 H),
3.80 (s, 3H), 3.87 (d, J=1 OHz, 1 H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d,
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J=9Hz, 1 H), 6.84 (dd, J=9Hz, 2Hz, 1 H), 6.90 (d, J=10 Hz, 2H), 7.01 (d,
J=2Hz, 1 H), 7.34 {d, J=lOHz, 2H).
Example 89
s trans.tran~2-(4-Methoxvo, henyl)-4-(1.3-benzodioxol5~rl)-1- .N-diln-
butK)aminocarbonxlmethlrl)~yrrolidine-3-lN-benzenesulfonyljcarboxamide
The compound resulting from Example 43 was converted to the
title compound by the method of Example 88 substituting
benzenesulfonamide for methanesuifonamide. m.p. 169-171 °C for a
~ o sample recrystallized from acetonitrile. ~ H NMR ~CDC13, 300 MHz) S
0.81 (t, J=7 Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.02-1.50 {m, 8H), 2.65-2.80 (m,
2H), 2.90-3.25 (m, 4H), 3.80-3.95 (m, 3H), 3.50-3.60 (m, 1 H), 3.65 (d,
J=1 OHz, 1 H), 3.81 (s, 3H), 5.94 (s, 2H), 6.70 (s, 2H), 6.81-6.90 (m, 3H),
7.17 (d, J=lOHz, 2H), 7.55 (t, J=7 Hz, 2H), 7.66 (t, J=7Hz, 1 H), 8.95 (d,
~ s J=7Hz, 2H).
Exam~fe 90
traps.traps-2-y4-Methoxvohenvl)-4-(i.3-benzodioxol-5_yll-1-[N.N-di(n~t-
~tyrl~~
aminosulfon I,~,yl)-~yrrolidine-3-carboxylic acid
2o Chloromethyl sulfenyl chloride, prepared by the method of
Brintzinger et. al., Chem. Ber. $~: 455-457 (1952), is reacted with
dibutylamine by the method of E. Vilsmaier described in Liebigs Ann.
Chem. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyl
chloride. Alternatively dimethyl(methylthio)sulfonium
2s tetraflouroborate is reacted with dibutylamine to give N,N-dibutyl
methylsulfenyl chloride which is chlorinated with N-chlorosuccinimide
to give chloromethyl sulfenyl chloride by the method of E. Vilsmaier,
described in the above reference.
The N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the
so compound resulting from Example 6A to give ethyl traps, traps-2-(4-
Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-[N, N-di(n-
butyl)aminosulfenylmethylJ-pyrrolidine-3-carboxylate. This is oxidized
with osmium tetroxide and N-methyl morpholine N-oxide by the method
of S. Kaldor and M. Hammond, Tet. Lett. ~?: 5043-5045 (1991) to give
35 the title compound after hydrolysis of the ethyl ester.
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exam to a 91
~~ns. traps-2-t 4=Methoxvohenyl)-4-(,1.3-benzodioxol-5-vl)-1-((N. N-di (n
b~tyrl)aminocarbonyl-i-,~?~~-ethyl~Qyrrolidine-3-carboxylic acid
~QIp 91 A
{~)-_Dibutyl 2-bromoorooanamide
2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methyimorphoiine (0.74
mL, 6.73 mmol) were dissolved in 10 mL of CH2Ci2, the solution was cooled to 0
°C
under a N2 atmosphere, and then treated dropwise with isobutyl chloroformate
~ o (0.45 mL , 3.5 mmol). After 10 minutes at 0 °C, dibutytam~ne (0.57
mL, 3.4 mmol)
was added. The reaction was stirred at 0 °C for i hour and for an
additional 16
hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M
aqueous Na2C03 solution, then the organic phase was washed sequentially with
25 mL of i LVI aqueous NaHS04 and 25 mL brine, dried (Na2S04), filtered, and
~ s concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 %) of
the
crude bromoamide as a colorless oil. ~ H NMR (CDC13, 300 MHz) 8 0.93 (t,
J=7Hz)
and 0.97 (t, J=7.5Hz, 6H total}, 1.26-1.60 (m, 7H), 1.60-1.78 (m, 1 H), 1.82
(d, J=6Hz,
3H), 3.04-3.27 {m, 2H}, 3.42-3.64 (m, 2H), 4.54 (q, J=7H, 1 H). MS (DC11NH3)
m/e
264 and 266 (M+H)+.
Example 91 B
h I -4- 1 I -1-
~(n-buty~a~r irlo)Ecarbon~-1-L S1-ethyl) rrolidine-3-carboxyrlic acid ethyrl
ester
A solution of the resultant mixture of trans,irans and cis,trans compounds
2s from Example 1 C (232 mg, 0.628 mmol) and the resultant compound from
Example
91A {183 mg, 0.693 mmol) in 2 mL of CH3CN was treated with
diisopropylethylamine (0.22 mL, 1.3 mmol). The solution was stirred at 60-80
°C
under a N2 atmosphere for 16 hours. The reaction was concentrated under
reduced pressure, then the residue was partitioned between 30 mL Et20 and 10
mL
so of 1 ~I aqueous Na2C03 solution. The organic phase was washed with 20 mL
water and 20 mL brine, dried over Na2S0a, filtered and concentrated under
reduced pressure to afford the crude amino amide as a brown oil (339 mg, 98%
crude). The product was obtained by flash chromatography on silica gel eluting
with
20% EtOAc-hexane to provide 224 mg (70%) of the title compounds as a mixture
of
35 4 diastereomers. ~ H NMR {CDC13, 300 MHz) 8 0.66-1.55 (several m, i 9H),
2.63-
3.00 (m, 3H), 3.05-3.39 (m, 2H), 3.40-3.76 (m, 4H), 3.78-3.80 (4 s, 3H), 3.84-
4.25
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(m, 2.6H), 4.38 (d, J=10.5Hz. 0.2H) and 4.58 (d, J=10.5Hz, 0.2H), 5.90-5.97
(m, 2H),
6.68-6.96 (m, 5H). 7.38-7.43 (m, 2H). MS (DCI/NH3) m/e 553 (M+H)+.
Example 91C
s #rans traps-2-~4~Methoxvnheny~-4-(1.3-benzodioxol-5-vl)-1-l(N.N
dibutyfamino)carbonyl-1-{RSV-ethyl)pyrrolidine-3-carboxylic acid
The procedure of Example 73C was used, substituting the resultant
compound from Example 91 B for the resultant compound from Example 738 to give
the title compound in 61 °~ yield. ~ H NMR (CD30D, 300 MHz) 8 0.70-1.05
(several
~ o m, 8H), 1.14 (d, J=6Hz, 2H), 1.17-1.55 (m, 6H), 2.79-3.031m, 3.5H), 3.20-
3.65 (br m,
4.6H plus CD2HOD), 3.70-3.78 (m, 0.4H), 3.79 (s, 3H), 3.98 (d, J=BHz, 0.6H),
4.06
(t, J=7.5Hz, 0.4H), 4.25 (d, J=BHz, 0.4H), 5.92 (s) and 5.94 (s, 2H total 6H),
6.73 (d,
J=2.5Hz) and 6.75 (d, J=3Hz, 1 H total), 6.78-6.85 (m, 1 H), 6.91-7.00 (m,
3H), 7.30-
7.38 (m, 2H). MS {DCI/NH3) m/e 525 {M+H)+. Anal calcd for C3oHaoN20s~0.5H20:
~ s C, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65; N, 5.21.
traps traps-2-(Penl~ll-4-(1.~'oenzodioxol-5-yl)-1-{N.N-di(n-
~~rllaminocarbonyrlmeth"",~,~I~-yrrolidine-3-carboxyrlic acid
Example 92A
Methyl 2-(4-hexenoyll-4-nitro-3-L .3-benzodioxole-5-yl)but~ rr ate
A solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL of
isopropanol was added to a solution of 5-(2-nitrovinyl}-1,3-benzodioxole (712
mg,
2s 3.69 mmol) in 10 mL THF, then DBU (22 ~L, 0.15 mmol) was added. The
resulting
reddish solution was stirred at room temperature for 20 minutes. TLC {ethyl
acetate-hexane, 1:3) indicated complete consumption of ketoester. The solution
was concentrated in vacuo and flash chromatographed on silica gel eluting with
18% ethyl acetate in hexane to produce 879 mg {2.42 mmof, 82%} of the title
so compound as a mixture of diastereomers in a 1:1 ratio. ~H NMR (CDC13, 300
MHz)
8 1.55-1.66 (m, 3H), 2.02-2.17 (br m, 1 H), 2.20-2.37 (m, 1.5H), 2.49-2.76 (m,
1.5H),
3.57 (s, 1.5H}, 3.74 (s, 1.5H), 3.97 (d, J=7.5H, 0.5H) and 4.05 (d, J =BHz,
0.5H),
4.10-4.20 (m, 1 H), 4.68-4.82 (m, 2H), 5.06-5.52 (m, 2H), 5.95 {2s, 2H), 6.65
(m, 1 H),
6.68 (br s, 1 H), 6.75 (d, 7.5Hz, 1 H). MS (DCI/NH3) mle 381 (M+NH4)+. Anal
calcd
35 for C~8H2~N0~: C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N,
3.72.
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Example 92B
i I- rr i in - I
The procedures of Example 18 and Example 1 C were followed, with the
substitution of the resultant compound from Example 92A for the resultant
s compound from Example 1 A, and the substitution of the this resultant
compound for
the resultant compound from Example 1 B, to provide the title compound in
crude
form as a yellow oil. This crude compound was epimerized under the following
conditions. A solution of the crude compound (660 mg, 2.07 mmol) in 3 mL
methanol was treated with a solution of sodium rnethoxide (made by the
addition of
~o sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol). T_he resultant
solution was
heated at reflux for 18 hours. The reaction was concentrated under reduced
pressure, and the residue was partitioned between 25 ml- saturated NaHC03
diluted with 70 mL water and 30 mL of CH2C12. The aqueous phase was extracted
(2 x 30 mL CHZC12), then the combined organic phases were washed with 20 mt-
i s brine, dried over Na2S04, filtered and the filtrate concentrated under
reduced
pressure to afford the crude product. Purification by flash chromatography on
silica
gel eluting with 3.5% methanol in CH2C12 gave 336 mg (57%) the title compound
as a yellow oil. ~ H NMR (CDCI3, 300 MHz) b 0.90 (br t, 3H), 1.25-1.70 (br m,
8H),
1.83-2.02 (br s, 2H), 2.58 (dd, J=8,9Hz, 1 H), 2.99 (dd, J=8,14Hz, 1 H), 3.34-
3.45 (m,
zo 2H), 3.53 (q, J=9Hz, 1 H), 3.66 (s, 3H), 5.94 (s, 2H), 6.65-6.75 (m, 3H).
MS
(DCI/NH3) m/e 320 (M+H)+. Anal calcd for Ci 8H25N04: C, 67.69; H, 7.89; N,
4.39.
Found: C, 67.39; H, 7.84; N, 4.37.
fix. ample 92C
25 traps tran~2-(Penty~)-4-(~ 3-benzodioxol-5-yrl)-1-(N.N-di(n-
~~yll,~~minoc rbonKmeth~lyrrrolidine-3-carboxylic acid
The procedures of Exampte 1 B-1 D were used, with the substitution of the
resultant compound from Example 92A for the resultant compound from Example
1 B, to provide the title compound as a white foam. ~ H NMR (CDCI3, 300 MHz) 8
30 0.87 (br t) and 0.89 (br t, 6H total), 0.97 (t, J=7.5Hz, 3H), 1.21-1.42 (br
m, 10), 1.43-
1.78 (br m, 6H), 2.76 (t, J=7Hz, 1 H), 3.02-3.30 (br m, 6H), 3.40-3.60 (m,
3H), 3.73 (d,
J=l4Hz, 1 H), 5.98 (AB, 2H), 6.70 (d, J=7Hz, 1 H), 6.77 (dd, J=1.5,7Hz, 1 H),
6.89 (d,
J=1.SHz, 1 H). MS (DCIINH3) mle 475 (M+H)+. Anal cafcd for C2~H42N205-0.5H20:
C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.
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~s.;~.m I~e 93.
tranc tran~~.lPentvl)~-j1.3-benzodioxol-5-yl)-1-j2-(N-orooyrl-N
QroQ,ylsulfonylamiyolethvt~vrrolidine-3-carboxyrlic acid
~~ple 93A
Methyl trans.traps-2-~(penty~-4-y1.3-benz ioxol-5-yrl)-1-(2-
bromoethyl)oyrrolidine
3-carboxvlate
The procedure of Example 61 A was used, with the substitution of the
resultant compound from Example 92B for the resultant compound from Example
~ 0 1 C, to provide the title compound as a yellow oil. ~ H NMR (CDCl3, 300
MHz) 8 0.89
(br t, J=7Hz, 3H), 1.24-1.40 (br m, 6H), 1.fi0-1.80 (br m, 2H), 2.61-2.75 (m,
2H), 2.76-
2.91 (m, 2H), 3.i0-3.22 (m, 2H), 3.36-3.47 (m, 2H), 3.68 (s, 3H), 5.92 (s,
2H), 6.69-
6.77 (m, 2H), 6.90-6.94 (m, 1 H). MS (DCI/NH3) m/e 426, 428 (M+H)+.
~ s Exam I
Methvl traps ns-2-(Pent)-4-(1_,3-benzodioxol-5-yl)-1-(~N-orooyrl-N-
~r"~ylsutfonylamino~t~,~lj~yrrolidine-3-carboxy_late
A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol)
and tetrabutylammonium iodide (6 mg, 16 pmol) in 1 mL EtOH was treated with
2o propylamine (60 ~L, 0.73 mmol). The solution was warmed to 80 °C for
4 hours.
The reaction was concentrated under reduced pressure, then the residue was
dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL of 1 M aqueous
Na2C03. The organic phase was washed with 15 mL brine, then dried over
Na2S04, filtered and concentrated under reduced pressure to provide the crude
2s secondary amine as a yellow oil (94.2 mg). The crude amine was dissolved in
1 m ~L
of CH2C12, diiosopropylethylamine (65 ~zL, 0.373 mmol) was added, followed by
propylsulfonyl chloride (29 ~L, 0.26 mmol}. The solution was stirred at room
temperature for 4 hours. The reaction was quenched with 10% aqueous citric
acid
(to pH 4), and the mixture was extracted with 2 x 3 m~ CH2C12. The combined
so organic extracts were washed with 2 mL brine, then dried over Na2S04,
filtered,
concentrated in vacuo. Purification by flash chromatography eluting with 20%
ethyl
acetate in hexane provided 65.0 mg (53%} of the title compound as a waxy
solid. Rt
= 0.17 (20%EtOAc-hexane). MS (DCI/NH3) m/e 511 (M~H)+.
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Example 93C
tr~n~ franc ~ (p~yj~1 3-benzodio~~,-yl)-1-[~(,N-orooyl-N
Qroovl,~sutfonylamino}ethy~]ovrrolidine-3-carboxylic acid
The procedure of Example 71 C was followed, with the substitution of the
s resultant compound from Example 93B for the resultant compound from Example
71 B, to provide the title compound as a white foam (47 mg, 80%), Rf = 0.14
(5%MeOH-CH2C12). ~ H NMR (CDC13, 300 MHz) S 0.88 (br t) and 0.92 (t, J=7Hz, 6H
total), 1.22-1.52 (br m, 6H), 1.63 (sextet, J=BHz, 2H), 1.75-2.10 (br m, 4H),
2.89-2.98
(m, 2H}, 3.05 (br t, J=9Hz, 1 H), 3.10-3.30 (m, 3H), 3.30-3.80 (br m, 7H),
5.94 (s, 2H),
~ 0 6.71 (t, J=BHz, 1 H), 6.77 (dd, J=1.5,8Hz, 1 H), 6.89 (d, J=1.SHz, 1 H).
MS (DCI/NH3)
m/e 497 (M+H)+.
Example 94
~rans traps-2-(]Proovl}-4 ~(1 3-benzodioxol-5-yl)-1-(N.N-di(n-
~ 5 ~~!)aminocarbonXlmeth,~,I)ovrrolidine-3-carboxylic acid
Exam l~ 94A
Fthy~4-butanQyl)-4-nitro-3-(1 3-benzodinxole-5-yrl)butyrrate
The procedure of Example 92A was followed, with the substitution of ethyl
2o butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound
as a
mixture of traps and cis isomers (47 mg, 80%), Rf = 0.28 (25%EtOAc-hexane). ~
H
NMR (CDCl3, 300 MHz) S 0.74 (t, J=7.5Hz) and 0.91 (t, J=7.5Hz, 3H total), 1.08
(t,
J=7Hz) and 1.28 (t, J=7Hz. 3H total), 1.45 (sextet, J=7Hz, 1.5H), 1.63
(sextet, J=7Hz,
approx. 1.5H}, 2.77 (t, J=7Hz) and 2.24 (t, J=7Hz, 0.5H total)2.40-2.54 (m,
1H), 2.60
2s (t, J=7.5Hz) and 2.67 (t, J=7.5Hz, 0.5H total), 3.93-4.09 (m, 2H), 4.10-
4.20 (br m,
1 H), 4.23 (q, J=7Hz, 1 H), 4.67-4.85 9m, 2H), 5.94 (s, 2H), 6.62-6.75 (m,
3H). MS
(DCIINH3) m/e 369 (M+NH4)+. Anal calcd for C»H2~N0~: C, 58.11; H, 6.02; N,
3.99. Found: G, 58.21; H, 5.98; N, 3.81.
3a ExamQle 94B
I I -4- nz x I- I rr li i r i
The procedure of Example 92B was followed, with the substitution of the
resultant compound from Example 94A for the resultant compound from Example
92A, to afford the title compound. MS (DCI/NH3) mle 306 (M+H)+.
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,~xamole 94C
mans. traps-2-(proRyrl)-4-{1.3-benzodioxol-5-yll-1-f (N. N-diln-
b~yl[}aminocarbon, lyr m~th,ypyrrolidine-3-carbom,rlic acid
The procedure of Example 92C was followed, with the substitution of the
s resultant product from Example 94B for the resultant product from Example
92B, to
give the title compound. ~H NMR {CDCI3, 300 MHz) b 0.89 (t, J=7.5Hz), 0.92 (t,
J=7.5Hz), and 0.97 {t, J=7.5H, 9H total), 1.22-1.80 {br m, 12H), 2.83 {t,
J=7.5Hz, 1 H),
3.40-3.55 (br m, 2H), 3.55-3.68 (m, 1 H), 3.78 (d, J=1 SHz, 1 H), 5.92 (q, J=1
Hz, 2H),
6.70 (d, J=BHz, 1 H), 6.79 (dd, J=1 Hz,BHz, 1 H), 6.90 (d, J=1 Hz, H). MS
(DC1/NH3)
~ o mle 447 (M+H)+. Anal calcd for C25H38N205~0.5 HZO: CJ 65.91; H, 8.63; N,
6.15.
Found: C, 65.91; H, 8.68; N, 5.94.
Exams ~
~( R.2 3R.4,~~-f+)-2-(4-Methoxvohenyl}-4-(I.3-benzodioxol-5-yl}-1-(tert-
~ s fly,~o_xycarbonyl-aminocarbonyrlmeth5r(}-pyrrQlidine-3-carboxylic acid
~x~mr~Ie 95A
traris.tran_~2_~4-Methoxyphenyl)-4-(1.3-benzodioxoi-5-yl)-1-(jtert
butylo~,rcarbony~aminocarbonylmethyllpyrrolidine-3-carboxylic acid
2o The resulting mixture of 64% traps, traps- and cis, trans-
pyrrolidines resulting from Example 1 C (3.01 g, 8.15 mmol) was
dissolved in 50 mL of methylene chloride. To this was added dropwise a
solution of di-tert-butyl Bicarbonate (1.96 g, 8.97 mmol) in 20 mL
methylene chloride under a nitrogen atmosphere, and the resulting
is solution was stirred 30 minutes at which point TLC (ethyl
acetate:hexane, 1:1 ) indicated that all of the starting material was
consumed. The reaction mixture was concentrated and dried under high
vacuum to give 3.94 g of the ethyl ester as a yellow-brown oil. ~ H NMR
(CDCL3, 300 MHz) 8 0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1.11-1.62 (several
3o br m, 9H), 3.05 (br m, 1 H), 3.44-3.95 (m, 3H), 3.81 (s, 3H), 4.04 (q, J=7
Hz, 1 H), 4.14-4.28 (br m, 1 H), 4.89-5.24 (br m, 1 H), 5.94 (d, J=3 Hz, 2H),
6.69-6.90 (m, 5H), 7.06-7.20 (m, 2H). MS (DCI/NH3) m/e 470 (M+H)+.
To the ethyl ester dissolved in 170 mL of ethanol was added a
solution of lithium hydroxide (1.06 g, 25.17 mmol) in 60 mL of water.
3s The reaction mixture was vigorously stirred for 18 hours under a
nitrogen atmosphere. The reaction mixture was concentrated to remove
ethanol, diluted with 250 mL of water and extracted three times with
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250 mL of ether. The organic phase acidified to slight cloudiness (pH
-7) with 1 ~ hydrochloric acid, then to pH 4 with 10 % citric acid and
extracted with 5 % ethanol in methylene chloride (3 x 100 mL). The
combined organic layers dried (NazS04), filtered, concentrated and dried
on high vacuum to give the title compound as a white foam (2.19 g, 60
}. ~ H NMR (CDC13, 300 MHz) 8 1.16 (v br s, 9H), 3.11 (br m, 1 H), 3.50-
3.64 (m, 2H), 3.81 (s, 3H), 4.24 (br m, 1 H), 4.96 (br m, 1 H), 5.94 (s, 2H),
6.71-6.79 (m, 3H), 6.84-6.91 (m, 2H), 7.19 (d, J=9 Hz, 2H). MS (DCI/NH3)
m/e 442 (M+H)+.
~o
F,xample 95B
(2R.3R,4Sy-(+1-2-~(4-Methoxy~henyl)-4-y1.3-benzodioxol-5-yl)-1-(tert-
butyloxyc~3r onylaminocarbonvlmethyILQyrrolidine-3-carboxylic acid
The compound resulting from Example 95A (2.15 g, 4.86 mmol) and
~5 (+)-cinchonine (1.43 g, 4.86 mmol) were added to 100 mL of methylene
chloride; this suspension was swirled with warming as necessary to get
all solids to dissolve. The solution was then concentrated and dried on
high vacuum to a white foam. This material was crystallized from a
mixture of refluxing chloroform (64 mL) and hexane (360 mL). The
2o resulting crystals were isolated by filtration and recrystallized under
the same conditions seven additional times. Each time the resulting
crystals and filtrate were monitored by ~ H NMR and chiral HPLC. The
amount of (2S,3S,4R)-(-)- enantiomer decreased first in the crystals
and then in the filtrate with the predetermined endpoint achieved when
z5 the (2S,3S,4R)-(-)- enantiomer could no longer be detected in the
filtrate. The pure (2R,3R,4S)-(+}- enantiomer thus obtained was
partitioned between 100 mL of 10% citric acid and 100 mL of ether.
The aqueous layer was further extracted twice with 100 mL of ether.
The combined ether layers were washed with brine, dried (Na2S04},
3o filtered, concentrated and dried on high vacuum to a white powder (550
mg, 55 % of theoretical 50 % maximum; >99.5 ee). ~ H NMR (CDC13, 300
MHz) 8 1.05-1.50 (br m, 9H), 3.12 (br m, 1 H), 3.50-3.65 (m, 2H), 3.81 (s,
3H), 4.24 (m, 1 H), 4.96 (br m, 1 H), 5.95 (s, 2H), 6.70-6.79 (m, 3H), 6.86
(d, J=9 Hz, 2H), 7.19. (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+.
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Example 95C
ii
carbo gate
The compound resulting from Example 95B (251 mg, 0.568 mmol}
s was dissolved in 20 mL of a saturated solution of anhydrous HCl(g) in
anhydrous ethanol. The resulting solution was heated at 50 °C. with
stirring for 18 hours at which point all of the precipitated solid had
dissolved. The reaction mixture was concentrated to a solid which was
partitioned between 0.8 1~1 aqueous sodium carbonate (50 mL) and
~ o . methylene chloride {50 mL). The aqueous layer was further extracted
with methylene chloride (2 x 50 mL). The combined organic layers were
dried (Na2S04), filtered, concentrated and dried under high vacuum to
give the title compound as an almost colorless oil (158 mg, 69%). ~ H
NMR {CDC13, 300MHz) S 1.11 (t, J=7 Hz, 3H), 2.18 (v br s, 1 H), 2.93 (t, J=
9 Hz, 1 H), 3.19,3.22 (dd, J=7 Hz, 1 H), 3.50-3.69 (m, 2H), 3.80 (s, 3H),
4.07 (q, J=7 Hz, 2H), 4.49 (d, J=9 Hz, 1 H), 5.94 (s, 2H), 6.73 (d, J=2 Hz,
2H), 6.81-6.92 (m, 3H), 7.34-7.41 (m, 2H). MS (DCI/NH3) m/e 370
(M+H)+.
2o Example 95D
{,2R.3R.4S)-l+)-2-y4_-Methoxyrphenyl)-4-(1.3-benzodioxol-5-y1)-1-(tert-
butyrl~,ycarbonyl-aminocarbonyrtmethyl)-~yrrolidine-3-carboxvriic acid
To the resulting compound from Example 95C (131 mg, 0.355
mmot) was added, diisopropylethylamine (137 mg, 185 p.L, 1.06 mmot).
2s acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetarnide (133 mg, 0.531
mmol), and the mixture was heated at 50 °C. for 1.5 hours. The reaction
mixture was concentrated to a solid, dried under high vacuum, and
purified by chromatography on silica gel eluting with 1:3 ethyl acetate-
hexane to give pure ester as a colorless oil. ~ H NMR (CDC13, 300MHz) S
so 0.81 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.10 (t, J=7 Hz, 3H), 1.00-1.52
(m, 8H), 2.78 (d, J=14 Hz, 1 H), 2.89-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71
(d, J=9 Hz, 1 H), 3.80 (s, 3H), 4.04 (q, J=7 Hz, 2H), 5.94 (dd, J=1.5 Hz, 2H),
6.74 (d, J=9 Hz, 1 H), 6.83-6.90 (m, 3H), 7.03 (d, J=2 Hz, 1 H), 7.30 (d, J=9
Hz, 2H). MS (DCI/NH3) m/e 539 (M+H)+.
To the ethyl ester dissolved in 7 mL of ethanol was added a
solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The
mixture was stirred for 1 hour at ambient temperature and then warmed
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slowly to 40 °C. over 2.5 hours at which point all of the starting
material had been consumed. The reaction mixture was concentrated to
remove the ethanol, diluted with 60 mL water and extracted with ether
(3 x 40 mL). The aqueous solution was treated with 1 N aqueous
s hydrochloric acid until cloudy, and the pH was then adjusted to -4-5
with 10% aqueous citric acid. This mixture was extracted with 1:19
ethanol-methylene chloride {3 x 50 mL). The combined extracts were
dried (Na2S04), filtered, concentrated and dried under high vacuum to
give the title compound as a white foam (150 mg, 83%}. ~ H NMR (CDC13,
~ 0 300MHz) 8 0.80 {t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3.ki), 1.08 (m, 2H), 1.28
(m, 3H), 1.44 (m, 3H), 2.70-3.77 (svr br m, 12H), 3.79 (s, 3H), 5.95 (m,
2H), 6.75 (d, J=8 Hz, 1 H), 6.87 (br d, J=8 Hz, 3H), 7.05 ( br s, 1 H), 7.33
(v
br s, 2H). MS (DCI/NH3) m/e 511 (M+H}+. (a)22 = +74.42°. Anal calcd
for C29H38N206 ~ 0.5 H20: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H,
~ s 7.59; N, 5.33.
~xamole 95E
A_ Iternate Preparation of l2R 3R 4S)~+)-2-(4-Methoxvohenv!?-4-(1.3-
benzodioxol-5
~~;tert butyloxvc~rbonvlamingcarbon~methy!)-oyrroiidine-3-carboxylic acid
2o The product of Example 95A (2.858 g) was suspended in 10 mL of
EtOAc. 0.7833 g of R (+) alpha methyl benzylamine in 3 mL ethyl acetate
was added. On swirling all of the solids were dissolved. The ethyl
acetate was removed in vacuum. Ether (13 ml) was added to the
residue. When all of the residue had .dissolved, 5 mg of seed crystals
2s were added and these crystals were crushed with a metal spatula while
cooling in ice. The product crystallized very slowly. After 1 hour the
solid was filtered and washed with ether giving 1.4213 g, m.p. 163-
167°. The filtrate was concentrated, cooled and scratched with a
spatula to give a second crop 0.1313 g, m.p. i 64-i 68°. The filtrate
so was concentrated again and put in the refrigerator and let stand
overnight giving 1.6906 g, m.p. 102-110°. (HPLC of this showed 20%of
the desired enantiomer and 80% of the unwanted enantiomer.)
The first two batches of crystallized material were combined and
suspended in 20 mL dichloromethane (Note: the unwanted isomer is more
3s soluble in dichloromethane) and stirred for 2 minutes. The mixture was
concentrated, but not to dryness, and ether (10 mL) was added. After
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stirring for a few minutes the crystals were filtered. Yield: 1.401 g,
m.p. 164-172°.
Treatment of the crystalline product with 10% citric acid and
ether according the method described in Example 95B provided the title
s compound.
Example 96
~tyrvl__-ar~inyettayllQyrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
Example 61, but substituting propylamine for methylamine in Example
61 B and butyryl chloride for isobutyryl chloride in Example 61 C. The
product was purified by preparative HPLC (Vydac ~C18) eluting with a
15 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were
lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300
MHz) b 0.80 (m, 3H), 0.90 {t, 3H, J=8Hz), 1.42 (m, 2H), 1.58 (heptet, 2H,
J=8Hz), 2.20 (t, 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m,
4H), 3.76 (br m, 2H), 3.78 (s, 3H), 4.30 (br s, 1 H), 5.95 (s, 2H), 6.75 (d,
20 1 H, J=8Hz), 6.84 (m, 1 H), 6.85 (d, 2H, J=8Hz), 7.04 ~(d, 1 H, J=1 Hz),
7.40
(d, 2H, J=8Hz). MS (DCI/NH3) m/e 497 (M+H)+. Anal calcd for .
C28Hs6N206 ~ 1.0 TFA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30;
N, 4.42.
Exam! to a 97
tranc rranG~-~4-Methoxvohen~rll-4;~1.3-benzodioxo!-5-yl)~-1-[2-(N-oroovl-N
jgth,~rlaminocarbonyl)amino)ethyl]~yrroiidine-3-carboxvlic acid
The title compound was prepared by the methods described in
Example 61, but substituting propylamine for methylamine in Example
61 B and ethyl isocyanate for isobutyryl chloride in Example 67 C. The
3o crude product was purified by trituration with 1:1 diethyl ether-hexane.
The resulting solid was dissolved in CH3CN and water and lyophilized to
give the product as a white solid. i H NMR (CDC13, 300 MHz) mixture of
rotamers s o.80 (t, J=8Hz) and 1.05 (t, J=8Hz) and 1.20 (m) and 1.42 (m)
total of SH for the four peaks, 2.35 (br s, 1 H), 2.70 (m, 1 H), 3.0 (m, 3H),
3s 3.2 (m, 3H), 3.25 (dq, 1 H, J=l,8Hz), 3.42 (m, 1 H), 3.6 (m, 1 H), 3.75 (m,
1 H), 3.78 (s, 3H), 4.8 (br s, 1 H), 5.95 (s, 2H), 6.74 (d, 1 H, J=8Hz), 6.85
(m, 3H), 7.00 (s, 1 H), 7.30 (d. 2H, J=8Hz). MS (DCI/NH3) mle 498 (M+H)ø.
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Anal calcd for C27H35N3O6 ~ 0.75 H20: C, 63.45; H, 7.20; N, 8.22. Found: C,
63.38; H, 7.29; N, 8.44.
exam In a 98
s ::a~s ara ~a-2-(4-Methoxyloheny~~-4-(1 3-benzodioxol-5-yl)-1-!2-(N-butyl-N-
~,y~r l~ amin~~thvllovrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
Example 61, but substituting butylamine for methylamine in Example
6iB and butyryl chloride for isobutyryl chloride in Example 61C. The
~ o crude product was purified by trituration with 1:.~ diethyl ether-hexane.
The resulting solid was dissolved in CH3CN and water and lyophilized to
give the product as a white solid. 1 H NMR (CDC13, 300 MHz) 8 0.80 (m,
3H), 0.90 (t, 3H, J=8Hz), 1.45 (m, 4H), 1.6 (m, 2H), 2.20 (t, 3H, J=8Hz),
2.94 (br m, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s,
t s 3H), 4.30 (br s, 1 H), 5.95 (s, 2H), 6.75 (d, 1 H, J=8Hz), 6.84 (m, 1 H),
6.85
(d, 2H, J=8Hz), 7.04 (d, 1 H, J=1 Hz), 7.40 (d, 2H, J=8Hz). MS (DCIINH3) '
mle 511 (M+H)+. HRMS calcd for C2sH3aN206: 511.2808. Found:
511 .2809
2o Exam I~e 99
n I- I -1- r (-
ethoxy a~rbonylamino)ethy_llpyrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
Exampte 61, but substituting propylamine for methylamine in Example
2s 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by trituration with 1:1 diethyl ether-
hexane. The resulting solid was dissolved in CH3CN and water and
lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300
MHz) 8 0.80 (t, 3H, J=8Hz), i .05 (m, 2H), 1.22 (m, 3H), 1.45 (m, 3H), 2.08
so (br s, 1 H), 2.75 (m, 1 H), 2.88 (br q, 2H, J=8Hz), 3.08 (br rn, 2H), 3.27
(br
m, 2H), 3.44 (m, 1 H), 3.54 (dt, 1 H, J=1,BHz), 3.63 (d, 1 H, J=8Hz), 3.78 (s,
3H), 4.02 (br d, 2H), 5.93 (s, 2H), 6.72 (d, 1 H, J=8Hz), 6.81 (dd, 1 H,
J=1,BHz), 6.85 (d, 2H, J=8Hz), 7.00 (s; 1 H), 7.30 (d, 2H, J=SHz). MS
(DCIlNH3) mle 499 (M+H)+. Anal calcd for C27H34N2O7 ~ 0.5 H20: C,
~s 63.89; H, ~ 6.95; N, 5.52. Found: C, 64.03; H, 6.71; N, 5.30.
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Examnl
g~,yr uty~~,rl)amino)ethX[ioyrrolidine-3-carboxylic acid
To the compound resulting from Example 61 B (190 mg) dissolved
s in THF (2 mL) was added HOBt (60 mg), EDCI (85 mg), N-
methylmorpholine (50 pL), and DMF (2 mL). 2-Ethylbutyric acid was
added and the solution stirred overnight at ambient temperature. Water
(10 mL) was added, and the mixture was extracted with EtOAc (2 x 25
mL). The combined organic extracts were washed with saturated
sodium bicarbonate solution, 1 ~. H3P04, and brine, dried with Na2S04,
and evaporated to give an oil which was purified by flash
chromatography on silica gel eluting with 1:3 EtOAc-hexane. The
resulting ethyl ester was saponified by the procedure described in
Example 61 C. The crude product was dissolved in CH3CN and water and
~ s lyophilized to give the product as a white solid. 1 H NMR (CDC13, 300
MHz) (mixture of rotamers) 8 0.66, 0.74, 0.80, 0.88 (all triplets, total of
6H, J=8Hz), 1.05 (m, 2H), 1.25-1.75 (m, 5H), 2.16 (m, 1 H), 2.32 (m, 1 H),
2.45 (m, 1 H), 2.70 (m, 1 H), 2.86, 2.94 (s, total 3H), 2.95 (m, 1 H), 3.35
(m,
1 H), 3.52 (m, 2H), 3.65 (m, 1 H), 3.80 (s, 3H), 5.94, 5.96 (s, total 2H),
Zo 6.73 (m, 1 H), 6.84 (m, 3H), 6.97 (m, 1 H), 7.30 (m, 2H). MS (DCIINH3) m/e
497 (M+H)+. Ana( calcd for CZ8H36N206 ~ 0.25 H20: C, 67.11; H, 7.34; N,
5.59. Found: C, 67.13; H, 7.24; N, 5.56.
Example 101
2s r - 4- I - i I -1- - N-m h I-N-
oropylvalery_I)amino)ethyllpyrrolidine-3-carboxylic acid
The title compound was prepared by the procedure described in
Example 100, but substituting 2-propylpentanoic acid for 2-
ethylbutyric acid. The crude product was purified by preparative HPLC
ao (Vydac pCl8) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The
desired fractions were lyophilized to give the product as a white solid.
~ H NMR (CDCi3, 300 MHz) 8 0.79 {t, 3H, J=8Hz), 0.82 (t, 3H, J=8Hz), 1.10
(m, 4H), 1.2-1.5 (m, 4H), 2.55 (m, 1 H), 2.96 (s, 3H), 3.15 (br m, 1 H), 3.32
(br m, 1 H), 3.56 (m, 2H), 3.68 (m, 1 H) 3.68 (s, 3H), 3.70 (m, 1 H), 3.80 (m,
3s 2H), 4.65 (br d, 1 H), 5.92 (s, 2H), 6.75 (d, 1 H, J=8Hz), 6.84 (m, 1 H),
6.85
(d, 2H, J=8Hz), 7.05 (s, 1 H), 7.42 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 525
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(M+H)~. Anal calcd for C3oH4oN2O6 ~ 1.25 TFA: C, 58.51; H, 6.23; N, 4.20.
Found: C, 58.52; H, 6.28; N, 4.33. .
Example 102
I - I-
~yj~ ac rbor~,ylmethvl)amino,}~ t~ hvlloyrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
Example 61, but substituting propylamine for methylamine in Example
618 and t-butyl bromoacetate for isobutyryl chloride in Example 61 C.
~o The crude product was purified by trituration with 1:1 diethyl ether-
hexane. The resulting solid was dissolved in CH3CN and water and
lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300
MHz) 8 0.82 (t, 3H, J=8Hz), 1.18 (m, 2H), 1.19 (s, 9H), 2.12 (m, 1 H), 2.46
(m, 2H), 2.70 (m, 3H), 2.85 (m, 2H), 3.20 (s, 2H), 3.40 (dd, 1 H, J=2,8Hz),
~ s 3.50 (dt, 1 H, J=2,8Hz), 3.62 (d, 1 H, J=8Hz), 3.78 (s, 3H), 5.95 (s, 2H),
6.72 (d, 1 H, J=8Hz), 6.84 (m, 1 H), 6.85 (d, 2H, J=8Hz), 7.05 (s, 1 H), 7.16
(d, 2H, J=8Hz). MS (DCIlNH3) m/e 541 (M+H)+. Anal calcd for
C3oHaoN207 ~ 1.0 H20: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35;
N, 4.86.
Exams a 103
- 4- h -4- i I- I -1- r I-N- n-
oroQyl~lnocarbony~methy,~~amin~~~ethyrllQ~rrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
Example 61, but substituting propylamine for methylamine in Example
61 B and N-propyl bromoacetamide for isobutyryl chloride in Example
61 C. The crude product was purified by preparative HPLC (Vydac ~C 18)
eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired
fractions were lyophilized to give the product as a white solid. ~ H NMR
so (CDC13, 300 MHz) 8 0.78 (t, 3H, J=8Hz), 0.88 (t, 3H, J=8Hz), 1.45 (m, 2H),
1.48 (m, 3H, J=8Hz), 2.55-2.7 (m, 2H), 2.90 (m, 1 H), 3.04 (m, 1 Hj, 3.15
(m, 3H), 3.28 (t, 1 H, J=8Hz), 3.45 (t, 1 H, J=8Hz}, 3.60 (m, 2H), 3.70 (d,
2H, J=8Hz), 3.75 (m, 1 H), 3.80 (s, 3H), 4.25 (d, 1 H, J=8Hz), 5.95 (s, 2H),
6.75(d, 1 H, J=8Hz), 6.86 (dt, 1 H, J=1,BHz), 6.88 (d, 2H, J=8Hz), 7.04 (d,
3s 1 H, J=1 Hz), 7.40 (d, 2H, J=8Hz). MS (DCILNH3) m/e 526 (M+H)+. Anal
calcd for C2gH3gN3Og ~ 1.85 TFA: C, 53.32; H, 5.59; N, 5.70. Found: C,
53.45; H, 5.62; N, 5.63.
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Example 104
I- - 4_
~,gthoxvo,~ heno~,rcarboniy)~~amino~,yllQyrrolidine-3-carboxylic acid
s The title compound was prepared by the methods described in
Example 61, but substituting propylamine for methylamine in Example
61 B and 4-methoxyphenylchloroformate for isobutyryl chloride in
Example 61C. The crude product was purified by trituration with 1:1
diethyl ether-hexane. The resulting solid was dissolved in CH3CN and
~o water and lyophilized to give the product as a while solid. ~H NMR
(CD30D, 300 MHz) mixture of rotamers 8 0.88 (m,3H), 1.57 (m, 2H), 2.45
(br s) and 2.60 (br s, total of 1 H), 2.90-3.15 (m, 4H), 3.42-3.7 (m, 5H),
3.78 (s, 3H), 3.80 (s, 3H), 3.85 (m) and 4.0 {m, total of 1 H), 5.95 (s) and
5.98 (s, total of 2H), 6.63(m, 1 H), 6.72 (d, 1 H, J=8Hz), 6.81 (m, 2H), 6.93
~ s (m, 5H), 7.40 (m, 2H). MS {DCt/NH3) m/e 577 (M+H)+. Anal calcd for
C32H3sN2O8 ~ 1.0 H2O: C, 64.63; H, 6.44; N, 4.7i . Found: C, 64.70; H, 6.38;
N, 4.63.
Example 105
2o tram tran.~~-f4-Methoxl_ -~4-.(1 3-benzodioxo(-5-yll-1-(2-fN-~rooyl-N- 4-
methoxybenzoyE),aminoleth~Q~,yrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
Example 61, but substituting propylamine for methylamine in Example
61 B and anisoyl chloride for isobutyryl chloride in Example 61 C. The
is crude product was purified by trituration with 1:1 diethyl ether-hexane.
The resulting solid was dissolved in CH3CN and water and lyophilized to
give the product as a white solid. ~H NMR (CDC13, 300 MHz) mixture of
rotamers 8 0.78 (m) and 0.98 (t, J=8Hz) total of 3H, 1.47 (m) and 1.52 (q,
J=8Hz) total of 2H, 2.25 (br s, 1 H), 2.78 (br s, 1 H), 2.90 (br t, 2H), 3.12-
so 3.68 (m, 7H), 3.80 (s, 3H), 3.82 (s, 3H), 5.94 (s, 2H), 6.75(d, 1 H,
J=8Hz),
6.83 (m, 5H), 6.94 (m, 1 H), 7.22 (m, 4H). MS (FAB) m/e 561 (M+H)+. Anal
calcd for C32HssN247 ~ 0.75 H20: C, 66.94; H, 6.58; N, 4.88. Found: C,
67.00; H, 6.38; N, 4.59.
*rB
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Fxam 1
I - r I-
benzovlamino)ethy[lwrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
s Example 61, but substituting propylamine for methylamine in Example
61 B and benzoyl chloride for isobutyryl chloride in Example 61 C. The
crude product was purified by trituration with 1:1 diethyl ether-hexane.
The resulting solid was dissolved in CH3CN and water and lyophilized to
give the product as a white solid. ~ H NMR (CDC13, 300 MHz) mixture of
1 o rotamers & 0.65 and 0.9 (m, total of 3H) , 1.4 and 1.55 (m, total of 2H),
2.05 and 2.15 (m, total of 1 H), 2.6 - 3.6 {m, 8H), 5.92 (s, 2H), 6.70(d, 1 H,
J=8Hz), 6.82 (m, 4H), 7.2 - 7.4 (m, 6H). MS (DCI/NH3) mle 531 (M+H)+.
Anal calcd for Cgt H34N2~6 ~ 0.3 H20: C, 69.46; H, 6.51; N, 5.23. Found: C,
69.48; H, 6.19; N, 4.84.
example 107
fans frans-2 y-~f ",ethoxy~l-4-~,~I 3-benzodioxol-5-vl)-1-f2-(N-oroovl-N
ben7,~loxvcarbonylamino~~ethylloyrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
2o Example 61, but substituting propylamine for methylamine in Example
61 B and benzyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by preparative HPLC (Vydac ~C 18)
eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired
fractions were lyophilized to give the product as a white solid. ~ H NMR
{CDC13, 300 MHz) 8 0.8 {m, 3H) 1.45 (m, 2H), 2.20 (br m, 1H), 2.75 (m,
1 H), 2.93 (m, 1 H), 3.15 (m, 2H), 3.32 (m, 3H), 3.52 (m, 2H), 3.66 (m, 1 H),
3.78 (s, 3H), 5.00 (m, 2H), 5.94 (s, 2H), 6.72(d, 1 H, J=8Hz), 6.82 (m, 3H),
7.0 (br d, 1 H, J= 15Hz), 7.2 {s, 4H), 7.30 {m, 3H). MS (FAB) m/e 561
(M+H)+. Anal calcd for C32H36N2~7 ~ 1.0 TFA: C, 60.53; H, 5.53; N, 4.i5.
3o Found: C, 60.66; H, 5.34; N, 4.28.
~xamote 108
r n r - 4- h n I -4- 1 n i I- I -1- - N- I-N- 4
methox enzvloxy~arbonyl~rniPolethYllwrrolidine-3-carboxylic acid
The title compound is prepared by the methods described in
Example 61, substituting propylamine for methylamine in Example 61 B
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and 4-methoxybenzyl chloroformate for isobutyryl chloride in Example
61 C.
Example 109
s - 1 i-
~thoxvcarbonvlamino)eth~lovrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
Example 61, but substituting butylamine for methylamine in Example
61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C.
~ o The crude product was purified by preparative HPLC (Vydac ~.C 18)
eluting with a 10-70°/° gradient of CH3CN in 0.1 % TFA. The
desired
fractions were lyophilized to give the product as a white solid. ~ H NMR
{CDC13, 300 MHz) 8 0.82 (t, 3H, J=8Hz), 1.20 (m, 5H), 1.34 (m, 2H), 3.08
(m, 2H), 3.17 (m, 2H), 3.52 (m, 2H), 3.75 {m, 2H), 3.78 (s, 3H), 4.06 {q,
~ s 2H, J=8Hz), 4.35 (br s, 1 H), 5.94 (s, 2H), 6.76 (d, 1 H, J=8Hz), 6.92 (d,
2H,
J=8Hz), 7.03 (br s, 1 H), 7.17 (br s, 1 H), 7.7 (br s, 2H). MS (FAB) mle 513
(M+H)+. Anal calcd for C28H3sN20~ ~ 0.5 TFA: C, 61.15; H, 6.46; N, 4.92.
Found: C, 60.99; H, 6.80; N, 4.93.
20 ~,xamQle 110
I -4- 1 i I -1- - N- I-N-
! ra ODOXycarb nyr mino)eth~~rrolidine-3-carboxylic acid
The title compound was prepared by the methods described in
Example 6i; but substituting butylamine for rnethyiamine in Example
2s 61 B and propyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by trituration with 1:1 diethyl ether-
hexane. The resulting solid was dissolved in CH3CN and water and
lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300
MHz) 8 0.80 (br s, 1 H), 0.85 (t, 3H, J=8Hz), 0.92 (br s, 1 H), 1.22 (m, 3H),
30 1.40 (m, 3H), 1.62 (br m, 1 H), 2.15 (br s, 1 H), 2.72 (m, 1 H), 2.87 {m, 1
H),
3.1-3.45 (m, 5H), 3.55 (m, 1 H), 3.64 (d, 1 H, J=8Hz), 3.79 (s, 3H), 3.88 (br
s, 1 H), 3.97 (br s, 1 H), 5.95 (s, 2H), 6.73(d, 1 H, J=8Hz), 6.85 (m, 3H, 7.0
(s, 1 H), 7.30 (d, 2H, J=8Hz). MS (FAB) m/e 527 (M+H)+. Anal calcd for
C29Hs8N20~ ~ 0.15 H20: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H,
35 7.30; N, 5.21.
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Example 111
r -4- 1 n -N
ploDOXV ac rbon_yrl_~lmino~~thyljRyrrrolidine-3-carboxylic acid .
The title compound was prepared by the methods described in
s Example 61, but substituting propylamine for methylamine in Example
61 B and propyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by trituration with 1:1 diethyl ether-
hexane. The resulting solid was dissolved in CH3CN and water and
lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300
~o MHz) S 0.80 (t, 3H, J=8Hz), 093 (m, 3H), 1.43 (m, 3H), 1.62 (m, 1H), 2.15
(br s,. 1 H), 2.68-3.45 {m, 8H), 3.54 (m, 1 H), 3.66 (m, 1 H), 3.78 (s, 3H),
3.94 (m, 2H), 5.94 (s, 2H), 6.72 (d, 1 H, J=8Hz), 6.82 (m, 7 H), 6.84 (d, 2H,
J=8Hz), 7.00 (br s, 1 H), 7.33 (m, 2H). MS (DCUNH3) m/e 513 (M+H)+.
Anal calcd for C28H36N20~ ~ 0.15 H20: C, 65.26; H, 7.10; N, 5.44. Found:
~ s C, 65.22; H, 6.74; N, 5.06.
Fxamole 112
n I - 4- i 1 i I-
y_I~Qyrrolidine-3-carboxylic acid
2o Ethyl (3,4-methylenedioxybenzoyl)acetate, prepared by the method
of Krapcho et al., Org. Syn. ~, 20 (1967) starting with 3,4-
methylenedioxyacetophenone instead of 4-methoxyacetophenone, was
reacted by the procedures described in Example 1 to give the title
compound as a white solid. m.p. 58-60 °C. 1 H NMR (CDC13, 300 MHz) 8
25 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (m, 6H),
2.80 (d, J=13Hz, 1 H), 2.94-3.12 (m, 4H), 3.28-3.50 (m, 4H), 3.58-3.62
(m, 1 H}, 3.78 (d, J=9Hz, 1 H), 5.95 (s, 4H), 6.73 (dd, J=8Hz, 3Hz, 2H),
6.84-6.89 (m, 2H), 6.92 (d, J=1 Hz, 1 H), 7.01 (d, H=1 Hz, 1 H). MS
(DCI/NH3) m!e 525 (M+H)+.
Examgle 113
r n r n - 1 -N- r I if mi I - - 4-m h h n I -4
,(1_ 3 benzodioxol-5-~~ovrrofidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
3s was prepared as a white solid. m.p. 64-65 °C. ~ H NMR (CDC(3, 300
MHz)
b 0.83 (t, J=7Hz, 3H), 0.98 (t, J=7Hz, 3H), 1.12-1.25 (m, 2H}, 1.32-1.41
(m, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (m, 2H}, 2.72-3.32 (m, 8H),
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3.43 (dd, J=9Hz, 3Hz, 1 H), 3.53-3.59 (m, 1 H), 3.65 (d, J=9Hz, 1 H}, 3.80 (s,
3H), 5.95 (s, 2H), fi.73 (d, J=BHz, 1 H), 6.83 (dd, J=BHz, 1 Hz, 1 H), 6.88
(d,
J=9Hz, 2H), 7.02 (d, J=7 Hz, 1 H}, 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e
547 (M+H)+.
s
Example 114 .
r n 1- N N- i n- I min car on Im h I -2- 4-me h hen I -4- 1
benzodioxol-5-vi)pvrrolidine-3-carboxylic acid
Using the procedures described in Examples 28 and 43, the title
compound was prepared as a white solid. m.p. 74;]6 °C. ~ H NMR
(CDC13, 300 MHz) b 0.80 (t, J=6Hz, 3H}, 0.88 (t, J=BHz, 3H), 1.08 (sextet,
J=SHz, 2H}, 1.21-1.48 (m, 6H), 2.75 (d, J=l2Hz, 1 H), 2.95-3.09 (m, 4H),
3.26-3.59 (m, 5H), 3.75 (d, J=9Hz, 1 H), 3.79 (s, 3H), 4.28 (s, 4H), 6.78 (d,
J=9Hz, 1 H), 6.85 (d, J=9Hz, 2H), 6.91 (d,d, J=3Hz, 9Hz, 1 H}, 6.98 (d,
v s J=3Hz, 1 H), 7.32 (d, J=9Hz, 2H). MS (DCIlNH3) m/e 525 (M+H)+.
Example 115
r n r 1- I- r 1 If n I min h I - - 4- h x h n 1 -4
L1 ,'~-benzodi2xol-5-vl~ovrroiidine-3-carboxylic acid
2o Using the procedures described in Exampie 66, the title compound
was prepared as a white solid. m.p. 72-73 °C. ~ H NMR (CDC13, 300 MHz)
S 0.79 (t, J=SHz, 3H), 0.98 (t, J=8Hz, 3H), 1.43 (sextet, J=8Hz, 2H), 1.75
(sextet, J=BHz, 2H), 2.22-2.32 (m, 1 H), 2.69-3.32 (m, 9H), 3.42 (dd,
J=3Hz, 12Hz, 1 H), 3.52-3.58 (m, 1 H), 3.64 (d, J=12Hz, 1 H), 3.80 (s, 3H),
2s 5.95 (s, 2H}, 6.73 (d, J=11 Hz, 1 H), 6.83 (dd, J=1 Hz, 1 i Hz, 1 H}, 6.87
(d,
J=11 Hz, 2H), 7.0 (d, J=2Hz, 1 H), 7.32 (d, J=11 Hz, 2H). MS (DCIINH3) m/e
533 (M+H)+.
Example 116
so ~ traps traps 1 (2 LN Butyl-N-butvlsulfonylamino)ethyl)-2-(4-methoxvphenvl)-
4-(1.3-
benzodioxoi-5-vl)wrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 62-63 °C. ~ H NMR (CDC13, 300 MHz)
b 0.82 (t, J=6Hz, 3H), 0.9i )t, J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33-
35 1.42 (m, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (m, 1 H), 2.70-3.28 (m,
9H), 3.41 (d, J=BHz, 1 H), 3.52-3.58 (m, i H), 3.65 (d, J=BHz, 1 H), 3.79 (s,
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3H), 5.95 (s, 2H), 6.72 (d, J=BHz, 1 H), 6.82 (d, J=8Hz, 1 H), 6.87 (d, J=8Hz,
2H), 7.01 (s, 1 H), 7.32 (d, J=BHz, 2H). MS (DCI/NH3} m/e 561 (M+H)+.
Example 117
s trans.tran~l -(2-(N.N-Dln-butyljaminocarbonylmethyl)-2-(4-
methoxvmetho~ynhenvl)-4-r(1.3-benzodioxol-5-yl)~y~olidine-3-carboxylic acid
4-Hydroxyacetophenone was treated with chloromethyl methyl
ether and triethylamine in THF at room temperature to give ethyl 4-
methoxymethoxybenzoylacetate which was treated by the procedures
~ o described in Example 1 to afford the title compotmd as a white solid.
m.p. 48-49 °C. ~ H NMR (CDC13, 300 MHz) 8 0.81 (t, J=7Hz, 3H), 0.88 (t,
J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 {m, 4H), 1.44 (quintet,
J=7Hz, 2H), 2.75 (d, J=l2Hz, 1 H), 2.94-3.10 (m, 4H), 3.25-3.35 (m, 1 H),
3.40 (d, J=l2Hz, 1 H), 3.43-3.52 (m, 2H), 3.47 (s, 3H), 3.55-3.62 (m, 1 H),
~ s 3.77 (d, J=9Hz, 1 H), 5.15 (s, 2H), 5.94 (m, 2H), 6.73 (d, J=8Hz, 1 H),
6.86
(dd, J=1 Hz, BHz, 1 H), 7.0 (d, J=BHz, 2H), 7.04 (d, J=1 Hz, 1 H), 7.32 (d,
J=SHz, 2H). MS (DCIlNH3) m/e 541 (M+H)+.
Example 118
2o r n - N i n- 1 mi r n Im h - 4-h r h n I -4- 1
benzor~li~ol-5-yl~yrrolidine-3-carboxylic acid hydrochloride salt
The compound resulting from Example 116 was treated with
concentrated HCI in 1:1 THF-isopropanol to give the title compound as a
white solid. m.p. 211-212 °C. ~H NMR (CD30D, 300 MHz) S 0.90 (t,
2s J=BHz, 6H), 1.12-1.27 (m, 6H), 1.36-1.45 (m, 2H), 3.04 (bs, 1 H}, 3.14-
3.35 (t, J=9Hz, 1 H), 3.90 (bs, 3H), 4.17 (d, J=1 SHz, 1 H), 5.96 (s, 2H),
6.82-6.93 (m, 4H), 7.03 (d, J=1 Hz, 1 H), 7.42 (bs, 2H). MS (DCIlNH3) m/e
497 (M+H)+.
so Example 119
r n r 1- r If n I I - - 4- h h n I -4
(1.3-benzodioxol-5-yl),~yrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 73-74 °C. ~ H NMR {CDC13, 300 MHz)
8 0.80 (d, J=6Hz, 6H), 0.98 (t, J=BHz, 3H), 1.62 (sextet, J=6Hz, 1 H), 1.74
{sextet, J=8Hz, 2H), 2.23-2:34 (m, 1 H), 2.68-2.98 {m, 7H), 3.08-3.18 (m,
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1 H), 3.26-3.42 (m, 2H), 3.52-3.58 (m, 1 H), 3.65 (d, J=9Hz, 1 H), 3.80 (s,
3H), 5.90 (s, 2H), 6.74 (d, J=8Hz, 1 H), 6.82 {d, J=BHz, 1 H), 6.86 (d, J=BHz,
2H), 6.98 .(d, J=1 Hz, 1 H), 7.33 {d, J=SHz, 2H). MS (DCI/NH3) mle 547
{M+H)+.
Exampl-a 120
#~ans rran~t-(2-~,N-Benzenesulfonyi-N~ropylamino}ethyl)-2-(4-methoxwhenvi)-4
~1 3-benzodioxol-5 yi)ovrrotidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
to was prepared as a white solid. m.p. 89-91 °C. ~H-NMR (CDCI3, 300
MHz)
b 0.74 (t, J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (m, 1 H), 2.62-
2.72 (m, 1 H), 2.85-3.05 (m, 4H), 3.12-3.22 (m, 1 H), 3.38 {dd, J=3Hz, 9Hz,
1 H), 3.49-3.57 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.82 (s, 3H), 5.96 (s, 2H),
6.73 (d, J=8Hz, 1 H), 6.84 (dd, J=1 Hz, BHz, 1 H), 6.85 (d, J=9Hz, 2H), 7.02
~ s (d, J=7 Hz, 1 H), 7.28 (d, J=9Hz, 2H), 7.39-7.54 (m, 3H}, 7.70 (d, J=7Hz,
2H). MS (DCI/NH3) m/e 567 (M+H)+.
Exam Ip a 121
r n r n - 4- h x n If n I -N- r I m in h I - - 4-
2o methoxvohen~}-4-(13-benzodioxol-~yl)~~rrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 96-97 °C. ~ H NMR (CDCl3, 300 MHz)
8 0.73 (t, J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1 H), 2.62-
2.71 (m, 1 H), 2.82-3.03 (m, 4H), 3.08-3.18 (m, 2H), 3.38 (dd, J=3Hz, 9Hz,
25 1 H), 3.48-3.56 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.81 (s, 3H), 3.86 (s, 3H),
5.95 (s, 2H), 6.73 (d, J=BHz, 1 H), 6.81-6.89 (m, 5H), 7.01 (d, J=1 Hz, 1 H),
7.28 {d, J=8Hz, 2H), 7.62 (d, J=BHz, 2H). MS (DCt/NH3) m/e 597 (M+H)+.
Example 122
ao r~,r~s trans-1-SIN N-Di,L-buty~)aminocarbonyilmeth~)-~ -methoxyrethoxy-4-
n -4- 1 z x I- I rr i in - r li i
2-Hydroxy-5-methoxyacetophenone was treated with sodium
hydride and bromoethyl methyl ether in THF at 70 °C to provide ethyl 2-
methoxyethoxy-4-methoxybenzoylacetate which was treated by the
35 procedures described in Example 7 . to provide the title compound as a
white solid. m.p. 63-65 °C. ~H NMR (CDC13, 300 MHz} s 0.84 (t, J=7Hz,
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3H), 0.89 (t, J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz,
2H), 1.45-1.52 (m, 4H), 2.87-2.94 (m, 2H), 3.00-3.16 (m, 3H), 3.26-3.36
(m, 2H), 3.43 (s, 3H), 3.47-3.54 (m, 3H), 3.66-3.72 (m, 2H), 3.78 (s, 3H),
3.76-3.84 (m, 1 H), 4.02-4.10 (m, 2H), 4.25 (d, J=9Hz, 1 H), 5.92 (s, 2H),
s 6.40 {d, J=2Hz, 1 H), 6.52 (dd, J=2Hz, 9Hz, 1 H), 6.70 (d, J=8Hz, 1 H), 6.B3
(dd, J=1 Hz, 8Hz, 1 H), 5.98 (d, J=2Hz, 1 H), 7.53 (d, J=9Hz, 1 H). MS
(DCIINH3) mle 585 (M+H)+.
ExamQle 123
l0 4- i I 1- -4-
etho yD~ hEnVl),~(~benzodioxol-5-yl)Qyr~tidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 88-90 °C. ~ H NMR (CDCi3, 300 MHz)
b 0.69 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1 H), 2.32
~ s (s, 3H), 2.47 (s, 3H), 2.62-2.69 (m, 1 H), 2.78 (t, J=9Hz, 1 H), 2.89 {dd,
J=8Hz, 1 H), 3.02 {sextet, J=9Hz, 2H), 3.15-3.32 (m, 3H), 3.46-3.55 (m,
1 H), 3.60 (d, J=9Hz, 1 H), 3.82 (s, 3H), 5.96 (s, 2H), 6.72 {d, J=7Hz, 1 H},
6.80 (dd, J=1 Hz, 9Hz, 1 H), 6.86 (d, J=9Hz, 2H), 6.97 (d, J=1 Hz, 1 H), 7.03
(bs, 2H}, 7.29 (d, J=9Hz, 1 H). MS (DCIINH3) m/e 595 (M+H)+.
ExamplP"124
trans.trans-1-(2-(N-Propyl-N- ~ ~hlorooroo) Isr ulfonvl)amino]ethyl)-2-(4-
methoxvohenyl~l,;~-ben,~odioxol-5-yl)~yrrolidine-3-carboxSLc acid
Using the procedures described in Example 66, the title compound
2s was prepared as a white solid. m.p. 75-76 °C. ~ H NMR (CDCI3, 300
MHz}
b 0.80 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (m, 3H), 2.70-
2.80 (m, 1 H), 2.85-3.10 {m, 6H), 3.23-3.31 (m, 2H), 3.43 (bd, J=9Hz, 1 H),
3.55-3.66 (m, 4H), 3.81 (s, 3H), 5.94 {s, 2H), 6.73 {d, J=BHz, 1 H), 6.82 (d,
J=BHz, 1 H), 6.86 (d, J=8Hz, 2H), 7.00 (s, 1 H), 7.33 (d, J=BHz, 2H). MS
so (DCI/NH3) mle 567 (M+H)+.
ExamQ"le 125
r n r n -1- - N- I- -m th h I If n I mi I - - 4-
methox~yll-4-11.3-benzodioxol-5-yl)~Qyrrolidine-3-carboxylic acid
35 Using the procedures described in Example 66, trans,trans-1-{2-
(N-Propyl-N-(vinylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl}-4-(1 ,3-
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benzodioxol-5-yl)pyrrolidine-3-carboxylic acid was prepared. Ester
hydrolysis using aqueous sodium hydroxide in methanol afforded the
title compound as a white solid. m.p. 62-64 °C. ~ H NMR (CDC13, 300
MHz) S 0.78 (t, J=7Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (m, 1 H),
s 2.72-2.79 (m, 1 H). 2.86-3.05 (m, 4H), 3.10-3.27 (m, 4H), 3.32 (s, 3H),
3.43 (dd, J=3Hz, 9Hz, 1 H), 3.53-3.58 (m, 1 H), 3.65 (d, J=9Hz, 1 H), 3.69 (t,
J=6Hz, 2H), 3.80 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.82 (dd,
J=1 Hz, BHz, 1 H), 6.87 (d, J=BHz, 2H), 7.02 (d, J=1 Hz, 1 H), 7.33 (d, J=BHz,
2H). MS (DCIINH3) m/e 549 (M+H)+.
~o
Examale-126
~,rans traps-1 ~2~lN-Prowl-N- 2-ethoxvethylsulfonyl)amino)ethvl)-2-(4-
metho,~,~hen~)-4-(1 3-benzodioxol-5-ylhyrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
~ s was prepared as a white solid. m.p. 58-60 °C. ~ H NMR (CDC13, 300
MHz)
b 0.78 (t, J=7Hz, 3H), 1.18 {t, J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.24-
2.33 (m, 1 H), 2.70-2.80 (m, 1 H), 2.87-3.05 (m, 4H), 3.13-3.20 (m, 2H),
3.22-3.32 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, 1 H), 3.46 (q, J=7Hz, 2H), 3.52-
3.58 (m, 1 H), 3.65 {d J=9Hz, 1 H), 3.72 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.95
20 (s, 2H), 6.73 (d, J=7Hz, 1 H), 6.83 {dd, J=1 Hz, 7Hz, 1 H), 6.8? (d, J=8Hz,
2H), 7.00 (d, J=1 Hz, 1 H), 7.32 {d, J=BHz, 2H). MS (DC1/NH3) m/e 563
(M+H)+.
xam lp a 127
2s traps tran~l (2 (N-Proovl-N-(5-dimethylamino-1-
naohthylsulfonyllamino)ethyl)-2-
j4-methoxvohenvl)-4-{1 3-benzodioxo!-5-yl)oyrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a yellow solid. m.p. 102-104 °C. 1 H NMR {CDC13, 300
MHz) S 0.62 (t, J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1 H),
30 2.78 (t, J=9Hz, 1 H), 2.88 {s, 6H), 2.72-2.89 (m, 1 H), 3.05-3.12 (m, 2H),
3.26-3.45 (m, 3H), 3.45-3.52 (m, 1 H), 3.58 (d, J=9Hz, 1 H), 6.97 (d, J=1 Hz,
1 H), 7.13 (d, J=7Hz, 1 H), 7.26 (d, J=8Hz, 1 H), 7.42-7.50 (m, 2H), 8.08 (dd,
J=1 Hz, 7Hz, 1 H), 8.20 (d, J=BHz, i H), 8.48 (d, J=8Hz, 1 H). MS (DCIINH3)
mle 660 (M+H)+.
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Example 128
r I I -4-m h I-
Li 3-benzodioxol-5-vl)wrrolidine-3-carboxyrlic acid
Using the procedures described in Example 66, the title compound
s was prepared as a white solid. m.p. 70-72 °C. 1 H NMR (CDCl3, 300
MHz)
8 0.79 (t, J=8Hz, 3H), 1.28 (t, J=7Hz, 3H}, 1.43 (q, J=8Hz, 2H), 2.22-2.30
(m, 1 H), 2.71-2.80 (m, 1 H), 2.82-3.10 (m, 6H), 3.18-3.32 (m, 2H}, 3.43
(dd, J=3Hz, 9Hz, 1 H), 3.53-3.60 (m, 1 H), 3.65 (d, J=9Hz, 1 H), 3.80 (s, 3H),
5.96 (s, 2H), 6.73 (d, J=7Hz, 1 H), 6.82 (dd, J=1 Hz, 7Hz, 1 H), 6.88 (d,
~o J=BHz, 2H), 7.00 (d, J=1 Hz, 1 H),. 7.32 (d, J=BHz, 2~!). MS (DCIINH3) mle
i 9 (M+H)+.
Example 129
trarra tran~l_(2-~N-Pro~rl-N-,L,4-methylbenzenesulfonyrl)amino)ethvl)-2-(4-
~s ' metho~rhen~yrl)-4-(1 3-benzodioxo(-5-vl)ovrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 78-79 °C. 'H NMR (CDCI3, 300 MHz)
8 0.73 (t, J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1 H}, 2.40
{s, 3H), 2.61-2.72 (m, 1H), 2.83-3.05 (m, 4H), 3.08-3.i9 (m, 2H), 3.48
20 (dd, J=3Hz, 9Hz, 1 H), 3.49-3.57 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.81 (s,
3H),
5.95 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.82 (d, J=8Hz, 1 H), 6.87 (d, J=8Hz, 2H),
7.00 (s, 1 H), 7.21 (d, J=BHz, 2H), 7.29 (d, J=8Hz, 2H), 7.57 (d, J=BHz, 2H).
MS (DCIlNH3) m/e 581 (M+H)+.
2s Example 130
r~~4.t~ns- -(~! N-Di(n-butyl)aminocarbonylmethy()-2-(3-oyrid~rll-4-11.3
~ nzo I~xol-5-v,Vovrrolidine-3-carboxylic acid
Methyl nicotinoyl acetate was prepared by the method of Wenkert,
et al., J. Org. Chem. 48: 5006 (1983) and treated by the procedures
so described in Example 1 to provide the title compound as a white solid.
m.p. 167-168 °C. 1 H NMR (CDCl3. 300 MHz) 8 0.82 (t, J-7Hz, 3H}, 0.89
(t, J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (m, 6H), 2.86-3.20
(m, 6H}, 3.34-3.43 (m, 2H), 3.57 (dd, J=3Hz, 9Hz, 1 H), 3.75-3.83 (m, 1 H),
4.08 (d, J=9Hz, 1 H), 5.93 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.90 (dd, J=2Hz,
3s 8Hz, 1 H), 7.03 (d, J=2Hz, 1 H), 7.38 (dd, J=4Hz, SHz, 1 H), 8.04 (d,
J=BHz,
1 H), 8.48 (dd, J=2Hz, 4Hz, 2H). MS (DCIlNH3) m/e 482 (M+H)+.
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Example 131
I If h h n
,~1 3-benzodioxol-5-y~ovrrolidine-3-carboxylic acid
s Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 65-66 °C. ~ H NMR (CDCI3, 300 MHz)
8 0.78 (t, J=7Hz, 3H), 0.92 (t, J=7Hz, 3H), 1.3'1-1.46 (m, 4H}, 1.68
(quintet, J=7Hz, 2H), 2.21-2.32 (m, 1 H), 2.70-3.08 (m, 7H), 3.12-3.23 (m,
2H), 3.42 (dd, J=2Hz, 9Hz, 1 H), 3.52-3.58 (m, 1 H), 3.64 (d, J=9Hz, 1 H),
~ 0 3.80 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7Hz, 1 H), 6.83- (dd, J=1 Hz, 7Hz,
1 H),
6.86 (d, J=SHz, 2H), 7.00 (d, J=1 Hz, 1 H), 7.32 (d, J=BHz, 2H). MS
(DCI/NH3) mle 547 (M+H)+.
,~xamc~le 132
r -4- h If n I i I- -4-
methoxvc~heny~,Z-4-(1 3-benzodioxol-5-yl~~oyrrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 105-106 °C. ~ H NMR (CDC13, 300
MHz) b 0.72 (t, J=7Hz, 3H), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (m, 1 H),
20 2.78-2.86 (m, 1 H), 2.96-3.03 (m, 3H), 3.13-3.26 (rn, 3H), 3.51 (dd, J=SHz,
9Hz, 1 H), 3.62-3.68 (m, 1 H), 3.80 (s, 3H), 3.94 {d, J=9Hz, 1 H), 5.92 (s,
2H), 6.75 (d, J=8Hz, 1 H), 6.84 (dd, J=2Hz, 8Hz, 1 H), 6.94 (d, J=8Hz, 2H),
6.98 (d, J=2Hz, 1 H), 7.36 (d, J=BHz, 1 H), 7.49 (d, J=8Hz, 1 H}, 7.68 (d,
J=8Hz, 1 H). MS (DCIINHs) m/e 601 (M+H)+.
2s
Example 133
traps traps-1-(2-(N-Proayl-N-(benz,~ Is~ ulfon,yllamino)ethoil-2-(4-
methoxvphenvl)-4
L 3-benzodioxol-S~IIp_yrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
3o was prepared as a white solid. m.p. 88-89 °C. ~ H NMR (CDC13, 300
MHz)
S 0.72 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (m, 1 H), 2.56-
2.67 (m, 1 H), 2.75-3.10 (m, 6H), 3.30 (dd, J=2Hz, 9Hz, 1 H), 5.95 (s, 2H),
6.73 (d, J=7Hz, 1 H), 6.80 (dd, J=1 Hz, 7Hz, 1 H), 6.86 (d, J=8Hz, 2H), 6.97
(d, J=1 Hz, 1 H), 7.27-7.35 (m, 7H). MS (DCI/NH3) mle 581 {M+H)+.
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Fxam~le 134
r I- - 4- f I m i I - - 4-
methoxy~~~ 4 (1.3 benzodioxol-5-vl)~y~rolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 91-93 °C. ~ H NMR {CDC13, 300 MHz)
b 0.73 (t, J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 (m, 1 H}, 2.56-
2.67 (m, 1H), 2.78-2.87 (m, 2H), 2.97 {septet, J=8Hz, 2H), 3.11-3.16 {m,
2H), 3.33 {dd, J=2Hz, 9Hz, 1 H), 3.43-3.50 (m. 1 H), 3.57 (d, J=9Hz, 1 H),
3.78 (s, 3H), 7.08 (t, J=BHz, 2H), 7.24 (d, J=BHz, 2H), 7.69 (dd, J=SHz,
~0 8Hz, 2H). MS (DCI/NH3) mle 585 {M+H}+.
Example 135
traps transl-[N-Methyl-N- r~op.~rlaminocarbonylmethyl)-2-(4-methoxvuhenvi)-4-
(4
benzofuran~)ovrrolidine-3-carboxylic acid
example 135A
Benzofuran-4-carboxaldehyde
To a suspension of 60% sodium hydride in mineral oil (4.00 g, Z 00
mmol, 1.25 eq) in DMF (60 mL} at 0 °C was added a solution of 3-
2o bromophenol (13.8 g, 80 mmol} in DMF (5 mL). After 10 minutes,
bromoacetaldehyde diethyl acetal { 14.9 mL, 96.6 mmol, 1.24 eq) was
added, and the resultant mixture then heated at 120 °C for 2.5 hours.
The mixture was cooled to room temperature and was poured into
water, and extracted once with ether. The organic solution was dried
2s over MgS04, filtered, evaporated and vacuum distilled to yield a
colorless liquid (17.1 g, 74%). b.p. 160-163 °C at 0.4 mm Hg.
To warm polyphosphoric acid (15.3 g) was added a solution of the
above compound (17.1 g, 59.3 mmol) in benzene (50 mL). The resultant
mixture was heated under reflux with vigorous stirring for 4 hours,
so after which time the benzene layer was carefully decanted off, and the
lower layer washed once with hexanes. The combined organic solutions
were concentrated in vacuo, and then vacuum distilled to yieid a
colorless liquid (8.13 g, 70%). b.p. 62-72 °C at 0.6 mm Hg.
To a solution of the above compounds (8.11 g, 41.5 mmol) in ether
(80 mL) at -78 °C was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2
eq) such that the temperature did not exceed -70 °C. After stirring for
~ ~ man"to~, a c~lntion of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL}
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was added, and the mixture allowed to warm to room temperaure over 2
hours. The mixture was poured into water and the phases separated.
The organic solution was dried over MgS04 and concentated in vacuo.
The residue was purified by flash chromatography on silica gel eluting
s with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde {1.22
g) and benzofuran-4-carboxaldehyde (1.86 g), both as colorless oils.
Example 1358
~rans tran~l-(N-Methyl-N-orooylaminocarbQ,~~ylmethyrlZ~4-methoxyphenyl,)-4-l4-
~ o ~enzofurany,~m~rrrolidine-3-carboxvli~c acid
The title compound was prepared using the procedures described
in Examples 1 and 49 substituting the compound resulting from Example
135A in Example 49A for piperonal. ~ H NMR (300 MHz, CDCl3) {minor
rotamer) 8 7.59 ( 1 H, t, J=3Hz), 7.4-7.2 (6H, m), 6.8 {2H, d, J=8Hz), 4.03
~ s (1 H, m), 3.94 {1 H, dd, J=8Hz, 3Hz), 3.77 (3H, s), 3.61 (1 H, dd, J=8Hz,
7
3Hz), 3.42 {1 H, dd, J=11 Hz, 5Hz), 3.40-2.90 {5H, m), 2.82 (2.81 ) (3H, s),
1.50 (2H, septet, J=7Hz), 0.82 (0.75) (3H, t. J=7Hz). MS (DCI/NH3) mle
451 {M+H)+. Anal.calc. for C26H3oN205 ~ AcOH: C, 65.87; H, 6.71; N ,5.49.
Found: C, 66.04; H, 6.42; N, 5.60. s
example 136
traps tr~n_~N-Meth_yr1-N-Q~flSrlaminocarbon,~rlmethvl)- S4-methoxyr~yl)-4-(6
benzofuranvllovrr2idine-3-carboxvis; acid
The title compound was prepared using the procedures described
2s in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde,
prepared as described in Example 135A, in Example 49A for piperonal.
~ H NMR (300 MHz, CDC13) (minor rotamer) S 7.65 (1 H, bd), 7.60 (1 H, d,
J=2Hz), 7.55 (1 H, d, J=8Hz), 7.35 {3H, m), 6.85 {2H, dd, J=BHz, 3Hz), 6.75
(1 H, dd, J=3Hz, 2Hz), 3.83 (2H, m), 3.79 (3H, s), 3.60-3.0 (7H, m), 2.91
ao {2.83) (s, 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz). MS
(DCI/NH3) m/e 451 (M+H)+. Anal.caic. for C26H3oN2O5 ~ 0.5 H20: C,
67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.
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Example 137
I I -4-
benzo-2 3-dihydrofuranvllovrrolidine-3-carboxvlic~acid_
The title compound was prepared by catalytic hydrogenation (4
s atmospheres of H2 in AcOH, followed by preparative hplc) of the
compound resulting from Example 136 ~H NMR (300 MHz, CDC13) (minor
rotamer) b 7.49 (7.47) (2H, d, J=8Hz), 7.19 (iH, d, J=8Hz), 7.00 (1H, m),
7.82 (3H, m), 5.40 (1 H, dd, J=11 Hz, 7Hz), 4.58 {2H, t, J=8Hz), 4.18 (1 H,
m), 4.10 (1 H, m), 3.88 (1 H, m), 3.79 (3H, s), 3.fi0 (1 H, m}, 3.35 (1 H, m),
io 3.19 (2H, t, J=8Hz), 3.00 (4H, m), 2.91 (2.78) (s, 3t-i), 1.53 (1.40) (2H,
septet, J=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DCIINH3} mle 453 (M+H)+.
Anal.calc. for C2sHs2N20s - 1.25 TFA: C, 57.53; H, 5.63; N, 4.71. Found:
C, 57.fi8; H, 5.68; N, 4.70.
f5
traps traps-LAN N-Di(n-bu~yyaminocarbonyimethyf -u4-methoxvohenvl?-4-(4
~benzofuranyl_lovrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in
2o Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide
for N-methyl-N-propyl bromoacetamide. 1 H NMR. (300 MHz, CDC13) 8
7.62 (1 H, d, J=3Hz), 7.39 (1 H, dt, J=8Hz, 2Hz), 7.34 {3H, m), 7.26 (1 H, d,
J=2Hz), 7.23 (1 H, d, J=8Hz), 6.84 (2H, d, J=8Hz), 4.02 (1 H, ddd, J=8,
6Hz,4Hz), 3.89 (1 H, d, J=9Hz) 3.79 (3H, s), 3.67 (1 H, dd, J=lOHz, 3Hz),
25 3.44 (2H, m), 3.35-3.15 (3H, m), 3.00 (2H, m), 2.84 (1 H, d, J=l4Hz), 1.43
(3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t,
J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C3oH38N205: C,
71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5:24.
3o Examp el 13_9
r n -1- N N- i r I - 4- h n I -4- 4
b~nzof~ranarl~~rrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared
s5 by the procedures described in Example 135A substituted 4-
bromophenol for 3-bromophenol, in Example 49A for piperonal and
w w J:~...a,.t Lwnmn~notwmlf~P fir N-methyl-N-propel
SuU~.'UIlUlilllJ, lv,W -u,u..~ .. ".......,_...
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bromoacetamide. ~ H NMR (300 MHz, CDCI3) S 7.64 (1 H, bd), 7.59 (1 H, d,
J=2Hz), 7.43 (2H, m), 7.33 (2H, d, J=SHz), 6.85 (2H, d. J=8Hz), 6.73 (1 H,
dd, J=3Hz, 1 Hz), 3.82 ( 1 H, d, J=11 Hz), 3.89 ( 1 H, d, J=9Hz) 3.79 (3H, s),
3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, m), 3.30 (1H, m), 3.20-2.95 (5H, m),
s 2.82 (1 H, d, J=l4Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H,
t, J=7Hz}, 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc.
for C3pHggN205: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N,
5.29.
Exams '
traps traps-1 JJ .N N-Di(n-bu~y(laiminocarbonximethyl)-2_(4-methoxvohenvll-4-
(6
benzofuranYl,)p~rrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting benzofuran-6-carboxaldehyde in
~s Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide
for N-methyl-N-propyl bromoacetamide. ~ H NMR (300 MHz, CDC13) S
7.63 (1H, bd), 7.59 (1H, d, J=2Hz), 7.53 (1H, d, J=8Hz), 7.36 (3H, m),
6.85 (2H, d, J=8Hz), 6.73 (1 H, dd, J=3Hz, 1 Hz), 3.82 (1 H, d, J=11 Hz), 3.89
(iH, d, J=9Hz) 3.79 (3H, s), 3.53 {iH, dd, J=lOHz, 3Hz), 3.44 (2H, m),
20 3.30 (1H, m), 3.20-2.95 (5H, m), 2.80 (iH, d, J=l4Hz), 1.43 (3H, m),
1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS
(DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C3oH38N2O5 - 0.75 H20: C,
69.28; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32.
2s Example 141
traps traps-1~,N N-Di(n-butyl}aminocarbonylmethyl)-2~,4-methoxyphemL-4-(6
han7o-2 3-dihydrofuranyl)pyrrolidine-3-carboxviic acid
The title compound was prepared by catalytic hydrogenation of the
compound resulting from Example 140 (4 atmospheres of H2 in AcOH,
so followed by preparative hp!c). ~ H NMR (300 MHz, CDC13} 8 7.40 (2H, d,
J=8Hz}, 7.16 (1 H, d, J=8Hz), 6.97 (1 H, dd, J=8Hz, 2Hz), 6.89 (3H, m),
5.90 (1 H, bs) 4.57 (2H, t, J=9Hz}, 4.93 (2H, m), 3.80 (3H, s), 3.70-3.58
(2H, m), 3.40 (i H, m), 3.30-2.90 (8H, m), 1.40 (2H, m), 1.29 (3H, m),
1.08 (2H, m}, 0.92 (3H, t, J=7Hz), . 0.82 (3H, t, J=7Hz). MS (DCI/NH3)
s5 m/e 509 (M+H)+. Anal.calc. for C3oHaoN2~s - 0.85 TFA: C, 62.88; H,
6.80; N, 4.fi3. Found: C, 63.04; H, 6.66; N, 4.60.
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Exam I
r n r n 1- h r min r n 1 -m h n I -4-
j~danvl)oyrrrQ~~,ine-3-carboxvfic acid
Example 142A
jpd~3~,P-,~ 5-ca_rlboxaldehvde
Indane-5-carboxaldehyde was prepared by formylation of indane
under the conditions described for 2,3-dihydrobenzofuran in Example
~ 0 52A. The resultant mixture of 4- and 5-carboxahiehydes was purified
as follows: to a 6:1 mixture of indane-4-carboxaldehyde and indane-5-
carboxaldehyde (3.46 g, 23 mmol) was added aniline (2.20 g, 23 mmol, 1
eq). The resultant solution slowly solidfied to a mixture of imines
which was recrystallized from hot acetonitrile to yield the 5-aldimine
~ s as a white solid. The aldimine (2.65 g) was suspended in water (6 mL),
and treated with 4 N hydrochloric dioxane (10 mL). The mixture was
boiled for 1 hour, cooled to room temperature, and poured into ether.
The organic solution was dried over MgS04, filtered, and concentated in
vacuo. Vacuum distillation of the residue afforded indane-5-
2o carboxaldehyde (1.54 g, 88%) as a colorless liquid. b.p. 88-90 °C at
0.9
mm Hg.
~xam~le 1,~2B
n 1- -N- I min I h I - - 4- h h n I -4-
2s indanvlloyrrrolidine-3-carboxyrlic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting indane-5-carboxaldehyde for piperonat
in Example 49A. ~ H NMR (300 MHz, CDC13) (minor rotamer) S 7.25-7.1
(5H, m), 6.78 (2H, d, J=8Hz), 3.89 (1H, d, J=8Hz), 3.75 (3H, s), 3.50-
so 2.90 (6H, m), 2.88 (6H, t, J=6Hz), 2.82 (2.80) (3H, s), 2.04 (2H, t,
J=8Hz),
1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DC1/NHg) m/e
451 (M+H)+, 473 (M+Na)+. Anal.calc. for C2~H34N204 - 2.5 H20 ; C, 65.44;
H, 7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53.
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Example 143
~ran~ tra~~1-~(N-Methyt-N-or~vlaminocarbonyrlme yrl)-2-{4-methoxwhenvl)-4-(6
~ndolyrl)Qyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
s Examples 1 and 49 substituting indole-6-carboxaldehyde, prepared by
the method of Rapoport, J. Org. Chem. 51: 5106 (1986), for piperonal in
Example 49A. ~ H NMR (300 MHz, CDC13) (minor rotamer) 8 8.43 (1 H, brs),
7.57 ( 1 H, d, J=8Hz), 7.43 (1 H, s), 7.31 (2H, dd, J=6Hz, 3Hz), 7.22 (t H, d,
J=8Hz), 7.1 (1 H, t, J=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (1 H, m), 3.93
~ o ( t H, dd, J=6Hz, 3Hz), 3.80 {1 H, m), 3.73 (3H, s), 3.60-2.90 (6H, m),
2.86
(2.82) {3H, s), 1.47 (2H, septet, J=7Hz), 0.83 (0.73 (3H, t, J=7Hz). MS
(DCI/NH3) m/e 450 (M+H)+. Anal.calc. for C26H3i N3O4 ~ 0.75 H20: C,
67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.
~ s xam~le 144
~an~ rans_1-(N-Met(~,yl-N-~oovlaminocarbonyr-Imethyl~~-2-(4-methoxvchenvll-4
(3 4-difluorotahenv!)ovrrolir~ine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 3,4-difluorobenzatdehyde for piperonal
2o in Example 49A. ~ H NMR (300 MHz, CDC13) (minor rotamer) 8 7.60-7.3
(4H, m), 7.13 (1 H, q, J=9Hz), 6.90 (2H, d, J=8Hz}, 3.90 (1 H, m), 3.79 (3H,
s), 3.60-2.95 (6H, m), 2.92 (2.78) (3H, s), 1.55 (2H, septet, J=7Hz), 0.88
(0.73) (3H, t, J=7Hz). MS (DCI/NH3) mle 447 (M+H)+. Anal.caic. for
C24H2aF2N204 ~ 1.80 H20: C, 60.19; H, 6.fi5; N, 5.85. Found: C, 60.13; H,
2s 6.34; N, 5.84.
ExamQle 145
r n r n -1- N- I-N- I min r n Im h I - - 4-m h x h n I -4
(oheny~~Ry_rrolidine-3-carboxxli~ acid,
3o The title compound was prepared by the procedures described in
Examples 1 and 49 substituting benzaldehyde for piperonal in Exampie
49A. ~ H NMR (300 MHz, CDC13) (minor rotamer) 8 7.53 (4H, d, J=6Hz),
7.40-7.20 (3H, m), 6.88 (2H, d, J=8Hz), 3.90 ( 1 H, m), 3.79 (3H, s), 3.70-
2.95 (8H, m), 2.90 (2.79) (3H, s}, 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H,
35 t, J=7Hz}. MS (DCIlNH3) mle 411 (M+H)+. Anal.calc. for C24H3oN2~a
2.00 H20: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.
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Example 146
i -4. 4_
~,vdroxyoheny,~ovrrolidi -3-carboxy i acid
s The title compound was prepared by the procedures described in .
Examples 1 and 49 substituting 4-hydroxybenzaldehyde for piperonat in
Example 49A. ~ H NMR (300 MHz, CDC13-CD30D) (minor rotamer) 8 7.35
(2H, d, J=8Hz), 7.28 (2H, dd, J=7Hz, 3Hz), 6.90 (2H, dd, J=7Hz, 3Hz), 6.89
(2H, d, J=8Hz), 3.8i (3H, s), 3.65 (i H, d, J=8Hz), 3.70-3.00 (8H, m), 2.92
~ o (2.83) (3H, s), 1.50 {2H, septet, J=7Hz), 0.87 (0.77). {3H, t, J=7Hz). MS
{DCi/NH3) mle 427 (M+H)+. Anal.calc. for C24H3oN2O5 - 1.00 H20: C,
64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.
Examele 147
-N- r m'n r n Im h 1 - - 4-m n I -4-
,(2 4-dimethoxv~,ohenyl)ovrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for
piperonal in Example 49A. ~ H NMR (300 MHz, CDCl3-CD30D) (minor
2o rotamer) S 7.61 (i H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (2H, d, J=8Hz},
6.55 (1 H, d, J=8Hz), 6.45 (1 H, d, J=3Hz), 3.90 {1 H, m), 3.81 (3H, s), 3.79
(3H, s), 3.77 {3H, s), 3.70-2.90 (8H, m), 2.85 (3H, s}, 1.50 (2H, sept,
J=7Hz), 0.87 (0.77) (3H, t, J=?Hz). MS (DCIINH3) m/e 471 (M+H)+.
Anal.calc. for C26H34N20s - 0.75 H20: C, 64.51; H, 7.39; N, 5.79. Found:
2s C, 64.65; H, 7.07; N, 5.75.
F.xam~le~l 48
h - 4-m n 1 -4-
b~n~-2-~dihvdro,_ furanyl~rrolidine-3-carboxylic acid
so The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 2,3-dihydrobenzofuran-5-
carboxaldehyde for piperonal in Example 49A. ~ H NMR (300 MHz, CDC13)
8 7.31 (2H, d, J=8Hz), 7.27 (1 H, d, J=2Hz), 7.18 (1 H, dd, J=7Hz, 3Hz},
6.86 (2H, d, J=8Hz), 6.72 (1 H, d, J=8Hz), 4.56 (2H, t, J=7Hz), 3.78 {3H, s);
35 3.62 (i H, m), 3.50-3.25 (4H, m), 3.17 (2f-!, t, J=7Hz), 3.15-2.90 (5H, m),
2.79 (1 H, d, J=l4Hz), 1.43 {3H, m), i .26 (3H, m), 1.08 (2H, m), 0.87 (3H,
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t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCIlNH3) mle 509 (M+H)+. Anal.calc.
for C3oH4pN205 - 0.25 H20: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21; H,
7.92; N, 5.36.
f=Yamnle 149
~,rans traps-1 IN N-Di(n,-bu aminocarbony~mP !~yr~-.2_-~4-methox~rohenvl)-4-f4
methoxvt~henvtl~ rrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in
~o Example 49A. ~H NMR (300 MHz, CDCI3) 8 7.38 (2~i, d, J=8Hz), 7.30 (2H,
d, J=SHz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, s), 3.76 (3H, s), 3.63 (1 H,
m), 3.50-3.20 {4H, m), 3.15-2.90 (5H, m), 2.78 (1H, d, J=l4Hz), 1.43
(3H, m), 1.27 {3H, m), 1.09 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t,
J=7Hz). MS (DCI/NH3) mle 497 (M+H)+. Anal.calc. for C29H4oN205: C,
~ s 70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.
Example 150
- N I r n m I - - 4- h n I -4- 4-
difluorophen,~)pvrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal
in Example 49A: ~H NMR (300 MHz, CDC13) S 7.35 (1H, m), 7.30 (2H, d,
J=8Hz), 7.20-7.00 (2H, m), 6.87 (2H, d, J=8Hz), 3.78 (3H, s), 3.79 (1H,
m), 3.62 (1 H, m), 3.50-3.30 (3H, m), 3.23 (1 H, m), 3.15-2.90 {4H, m),
2s 2.78 (1 H, d, J=l4Hz), 1.43 (2H, m), 1.27 (4H, m), 1.08 {2H, m), 0.85 (3H,
t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCIINH3) mle 503 (M+H)+. Anal.calc.
for C28H36F2N204- ~ 1 H20: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H,
7.20; N, 5.35.
so Example 151
rn rn-1-NN- in- I min c r n I h I- -4-m h x h n 1-4-24
~limethoxxph~n_~)ovrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 2,4-dirnethoxybenzaldehyde for
35 piperonal in Example 49A. ~ H NMR (300 MHz, CDC13) S 7.37 (2H, d,
J=8Hz), 7.20 (1H, d, J=8Hz), 6.92 (2H, d, J=8Hz), 6.60 (1H, d, J=3Hz),
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6.49 (1 H, dd, J=6Hz, 2Hz), 5.35 (1 H, d, J=8Hz), 4.20 (3H, m), 4.10 (3H, s),
3.83 (3H, s), 3.81 (3H, s), 3.75 (3H, m), 3.17 (2H, hep, J=7Hz), 3.05 (2H,
t, J=7Hz), 1.30 (4H, m), 1.07 (4H, m), 0.87 {3H, t, J=7Hz}, 0.80 (3H, t,
J=7Hz). MS (DCI/NH3) m!e 527 (M+H)+. AnaLcalc. for C3oHa2N2~s - 1.30
s TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.
ExamQle 7 52
n
y~~yrrrolidine-3-carboxyrlic acid
~ o The title compound was prepared by the procedures described in
Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B.
~ H NMR (300 MHz, CDCI3) b 7.50-7.25 (5H, m), 7.04 (1 H, d, J=3Hz), 6.87
(1 H, dd, J=7Hz, 3Hz), 6.74 (1 H, d, J=8Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H,
d,
J=4Hz), 3.85 (1H, d, J=8Hz), 3.64 (1H, m), 3.42 (3H, m), 3.27 (2H, m),
~s 3.20-2.90 (5H, m), 2.81 (1H, d, J=l4Hz), 1.43 (2H, m), 1.27 (4H, m),
1.05 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS {DCIINH3)
m/e 481 (M+H)+. Anal.calc. for C28H3sN2O5: C, 69.98; H, 7.55; N, 5.83.
Found: C, 69.69; H, 7.63; N, 5.71.
r n 1- N I min car n Im h I - h n I-4- n -2
dihydrofurany,~,ovrrolidine-3-carboxlrlic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B
2s and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example
49A. t H NMR (300 MHz, CDCI3) b 7.53 (2H, m), 7.40 (4H, m), 7.13 (1 H,
dd, J=7Hz, 3Hz), 6.72 (1H, d, J=8Hz), 5.40 (1H, d, J=lOHz), 4.56 (2H, t,
J=8Hz), 4.18 {1 H, d, J=l4Hz), 4.07 (2H, m), 3.79 (2H, m), 3.48 {1 H, d,
J=l4Hz), 3.35 (1 H, m), 3.28 (3H, m), 2.95 (2H, m), 1.47 (2H, m), 1.28
(4H, m), 1.10 (2H, m), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS
(DCI/NH3) m/e 479 (M+H)+. Anal.calc. for C2gH38N204 - 1.10 TFA: C,
62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.
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Fxam~le 154
I -4-
2s3 dihvdrof~ranyf)ovrrolidine-3-carb~xvlic acid
The title compound was prepared by the procedures described in
s Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the
method of Krapcho et al., Org. Syn. 47:20 (1967} starting from 4-t-
butylacetophenone, in Example 49B and 2,3-dihydrobenzofuran-5-
carboxaldehyde for piperonal in Example 49A. ~ H NMR (300 MHz, CDCl3)
b 7.60-7.30 (6H, m), 6.90 (1 H, m), 4.50 (2H, m), 3.95 (1 H, m}, 3.85-2.95
~ o (11 H, m), 2.90 (1 H, d, J=14Hz), 1..58 (2H, m), 1 ~0 (7H, m), 1.41 {6H,
s), 1.10 (2H, m), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH3)
m/e 535 (M+H)+. Anal.calc. for C33H46N2~4 ~ 0.25 H20: C, 73.50; H, 8.69;
N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.
15 ~xamole 155
r r N- in 1 h - 4-m h n i -4- 4-
fluoroohenyrl)oyrrrolidine-3-carboxvlic~acid_
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 4-fluorobenzaldehyde far piperonal in
2o Example 49A. ~H NMR (300 MHz, CDCI3) 8 7.50 (1H, m), 7.42 (1H, dd,
J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1 H, d, J=8Hz),
3.83 (1 H, m), 3.8 (3H, s), 3.67 (1 H, m), 3.47 (3H, m), 3.30-2.90 (5H, m),
2.82 (1 H, d, J=l4Hz), 1.43 (2H, m), 1.28 {4H, m), 1.08 (2H, m), 0.90 (3H,
t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCIlNH3) mle 485 (M+H)+. Anal.calc.
25 for C28H3~FN204: C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N,
5.74.
Example 156
r r - N ' n- min r n im I - -f r I -4- 1 n t x 1-
30 ~y!)~ovrrolidine-3-carboxvlic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting p-oxo-3-furanpropionate in Example
498. ~ H NMR (300 MHz, CDC13) 8 7.41 (2H, m), 6.97 (1 H, d, J=3Hz), 6.85
(1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=8Hz), 6.42 (1 H, s), 5.94 (1 H, d,
3s J=4Hz), 5.92 (1 H, d, J=4Hz), 3.90 (1 H, m), 3.70-3.25 (5H, m), 3.20-2.90
{4H, m), 2.85 (1 H, d, J=l4Hz), 1.43 (2H, m), 1.40-1.05 (6H, m), 0.90 (6H,
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m). MS (DCIINH3) m/e 471 (M+H)+. Anal.calc. for C26H3aN20s: C, 66.36;
H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.
Exam !e 157
r i m i n r -4-
benzodioxol-5-vl)wrrolidine-3-carboxvlic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B.
~ H NMR {300 MHz, CDCI3) 8 6.85 (1 H, d, J=2Hz), 6.76 (1 H, dd, J=6Hz, 2Hz),
6.71 (1 H, d, J=8Hz), 5.92 (2H, s), 3.75 (1 H, d, J=141-Iz), 3.66 (1 H, q,
J=7Hz). 3.42 (3H, m), 3.25 (3H, m), 3.11 {2H,m), 2.83 (1 H, t, J=7Hz), 1.88
(1 H, m), 1.55 (4H, m), 1.32 {4H, m), 0.92 (12H, m). MS {DCI/NH3) m/e
447 (M+H)+. Anal.calc. for C2~H3gN2O5 ~ 0.50 H20: C, 65.91; H, 8.63; N,
6.15. Found: C, 66.07; H, 8.10; N, 6.03.
Exams
h - 4- - I h n 1 -4-
b~n,~odioxof-5-vl)ovrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
zo Examples 1 and 49 substituting ethyl 4-t-butylbenzoyiacetate, prepared
by the method of Krapcho et al., Org. Syn. 47: 20 {1967) starting with 4-
t-butylacetophenone), in Example 498. ~ H NMR (300 MHz, CDC13) 8 7.32
{4H, d, J=3Hz), 7.04 (1 H, d, J=2Hz), 6.87 {1 H, dd, J=8Hz, 3Hz), 6.74 (1 H,
d,
J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.77 (1 H, d, J=l4Hz),
2s 3.65-3.25 (5H, m), 3.15-2.85 (4H, m), 2.73 (1 H, d, J=l4Hz), 1.45 (2H, m),
1.29 (13H, s), 1.00 (2H, m), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz). MS
(DCI/NH3) mle 537 (M+H)+. Anal.calc. for Cs2HaaN205: C, 71.61; H, 8.26;
N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.
3o ExamQle 159
r n n 1- I mi n Im - 4-- h n I -4-
~,~-dihvdrofuranylhyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B
35 and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example
49A. i H NMR {300 MHz, CDCI3) 8 7.30 (1 H, s), 7.13 (1 H, dd, J=7Hz, 2Hz),
*rB
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6.82 (1 H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1 H, s), 3.19 (3H, m), 3.80
(3H, m), 3.48 {2H, m), 3.3 (5H, m), 2.41 (1H, m), 1.65 {4H, m), 1.44 (4H,
m), 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, m). MS (DCI/NH~)
m/e 445 (M+H)+. Anal.calc. for C26HaoN2~4 ~ 1.2 TFA: C, 58.67; H, 7.14;
s N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.
Exam p,[e 160
traps tran~l-(N N~Di(n-butyl)aminocarbonlrlmethyr_[)~(anti-4-metho,~c_yrclo
4-~1 3-benzodioxol-5-yl)Qyrrolidine-3-carboxylic acid
4-
Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6
mmol) and carbonyldiimidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred
1 s in anhydrous tetrahydrofuran (50 mL) for 6 hours at room temperature.
At the same time, magnesium chloride (3.01 g, 31.6 mmoi) and ethyl
malonate potassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were
stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 °C. The
mixture was cooled to room temperature, and the imidazole-acid
2o mixture added to it. The reaction stirred overnight at room temerature.
The solvents were removed under reduced pressure, and the residue was
taken up in chloroform/water. The organic phase washed with 5%
potassium bisulfate, water, and brine, dried with magnesium sulfate,
filtered, and concentrated under reduced pressure. The residue was
2s purified by flash chromatography on 175 g silica gel, eluting with 20%
ethyl acetate in hexanes. Pure fractions of the syn and anti
methoxycyclohexyl ~-keto esters were obtained. The solvents were
removed under reduced pressure to yield the traps-4-methoxycyclohexyl
~-keto ester (914 mg) as a colorless oil and the cis 4-
3o methoxycyclohexyl ~ keto ester (1.07 g) as a colorless oil.
Exam I~e.160B
n r N- i I i r n Im h I - n '-4- h I h I -
35 ~;~1 ~-ben~ndinxol-5-yl)nyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Fxamoles 1 and 49 substituting the anti-compound resulting from
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Example 160A in Example 49B. ~ H NMR (300 MHz, CDC13) 8 6.84 (1 H, d,
J=2Hz), 6.76 (1 H, dd, J=7Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 (2H, s), 3.69
(2H, m), 3.50-3.27 (5H, m), 3.26 (3H, s), 3.25-3.00 (3H, m), 2.88 (1 H, m),
1.95 (2H, m), 1.62 (7H, m), 1.33 (9H, m), 0.97 (3H, t, J=7Hz), 0.92 (3H, t,
s J=7Hz). MS (DCI/NH3) mle 517 (M+H}+. Anal.calc. for C2sH44N2Os - 0.50
H20: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50; N, 5.13.
Example 161
n r n - i i r n m h -4- I h I -
0 4-j,~3-benzodioxol-5-X("~vrrolidine-3-cartroxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting the syn-compound resulting from
Example 160A in Example 498. ~H NMR (300 MHz, CDC13) b 6.84 (1H, d,
J=2Hz), 6.77 (1 H, dd, J=6Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 (2H, s), 3.65
~ s (2H, m), 3.42 (2H, m), 3.32 (3H, s), 3.30-3.00 (6H, m), 2.82 (1 H, m),
2.10
(2H, m), 1.83 (2H, m}, 1.52 (6H, m), 1.33 (4H, m), 1.20-1.00 (4H, m), 0.96
(3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCI/NH3) m/e 517 (M+H)+.
Anal.calc. for C2gH44N2Og ~ 0.30 H20: C, 66.72; H, 8.61; N, 5.37. Found:
C, 66.76; H, 8.65; N, 5.28.
Example 162
~rans iran~l-fN N-Di(n-bu rllaminocarbonylmethyrl~-2.4-di(5-benzo-2.3
~ihvdrofuranyl~ovrrolidine-3-carboxyrtic acid
~xam~lg 162A
5-Acetvl-2.3-dihydrobenzofuran
To a 0 °C solution of acetyl chloride (1.64. mL, 23.0 mmol, 1.3
equivalents) in methylene chloride (30 mL) was added stannic chloride
(2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature
ao below 5 °C. The solution was stirred 15 minutes at 0 °C, and
then a
solution of 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride
(5 mL) was added dropwise while maintaining the temperature below
8 °C. The dark red solution was stirred 1 hour at 2 °C and then
poured
into 50 mL of ice water. The reaction was stirred an additional 30
ss minutes, and the layers were separated. The organic layer was washed
with water and aqueous sodium bicarbonate, dried over magnesium
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sulfate, filtered, and concentrated under reduced pressure. The residue
was purified by flash .chromatography on 150 g silica gel, eluting with
18% ethyl acetate in hexanes. The solvents were removed under reduced
pressure ~to yield the title compound (2.68 g, 93%) as a yellow solid.
xa ale 1628
~rans traps-1 (jjN-Diln-butyl)aminocarbonytmethytl-?.4-di(,~-benzo-2.3
dihydrofurany~yvrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
~ o Examples 1 and 49 substituting the compound resulting from Example
162A in Example 498 and 2,3-dihydrobenzofuran-5-carboxaldehyde for
piperonal in Example 49A. 1H NMR (300 MHz, CDCl3) 8 7.43 {1H, s), 7.38
(1 H, s), 7.06 (2H, m), 6.75 {1 H, d, J=6Hz), 6.70 (1 H, d, J=6Hz), 5.40 (1 H,
d, J=9Hz), 4.58 (4H, q, J=7Hz), 4.16 (1 H, d, J=l4Hz), 4.09 {2H, m), 3.82
~ s (2H, m), 3.57 (1 H, d, J=l4Hz), 3.38 (1 H, m), 3.30-3.05 {6H, m), 2.95
(2H,
q, J=6Hz), 1.50 (2H, m), 1.30 (4H, m), 1.15 (2H, m), 0.94 (3H, t. J=7Hz),
0.83 (3H, t, J=7Hz). MS (DCIINH3) mle 521 (M+H)+. Anal.calc. for
C3~ H4oN2O5 - 1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Found: C, 60.49; H,
6.18; N, 4.13.
ExamQle 163
r 1- ' n- I min n im I - -f -4- nz -
~,ihvd~rofu_rany~ovrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in
2s Examples 1 and 49 substituting ethyl p-oxo-3-furanpropionate in
Example 498 and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal
in Example 49A. ~ H NMR (300 MHz, CDC13) 8 7.42 (1 H, m), 7.38 (1 H, m),
7.13 (1H, s), 7.16 (1H, dd, J=7Hz, 3Hz), 6.70 (1H, d, J=8Hz), 6.41 (1H, m),
4.57 {2H, t, J=7Hz), 3.95 (1 H, d, J=8Hz), 3.63 (1 H, m), 3.55 (1 H, d, J=14),
so 3.50-3.25 {4H, m), 3.18 (2H, t, J=6Hz), 3.15-2.95 {3H, m), 2.87 (1 H, d,
J=l4Hz), i .45 (4H, m), 1.35-1.10 (4H, m), 0.85 (6H, m). MS (DCI/NH3)
mle 469 {M+H)+. Anai.calc. for C27H3gN2O5 ~ 0.25 H20: C, 68.55; H, 7.78;
N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.
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Fxamole 164
I I I-
fluoro~t~,Q~yl~yrrolidine-3-carbox~rlic acid
The title compound was prepared by the procedures described in
s Examples 1 and 49 substituting 3-fluorobenzenecarboxaldehyde for
piperonal in Example 49A. ~ H NMR (300 MHz, CDCI3} b 7.30 (2H, d,
J=8Hz), 7.22 (2H, m}, 6.91 (1 H, m), 6.86 (2H, d, J=8Hz), 3.79 (1 H, m),
3.78 (3H, s), 3.68 (1 H, m}, 3.55-3.37 (3H, m), 3.29 (1 H, m), 3.15-2.90
(5H, m), 2.78 (1 H, d, J=l4Hz), 1.43 (2H, m), 1.25 (4H, m), 1.07 (2H, m},
0 0.87 (3H, t, J=7Hz}, 0.80 (3H, t, J=7Hz). MS (DCtLNH3) mle 485 (M+H)+.
Anal.calc. for C2gH37FN2O4 ~ 0.25 H20: C, 68.76; H, 7.73; N, 5.73. Found:
C, 68.87; H, 7.69; N, 5.67.
,~xamflle 165
~ s N- min n I h f - - 4-m h I -4-
p~,rrl~yrl)~Qyrrotidine-3-carboxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonat
in Example 49A. The vitro styrene was prepared by the method of
o Bourguignon ,et at., Can. J. Chem. 63:.2354 (1985). ~ H NMR (300 MHz,
CDC13) 8 8.82 (1 H, bs), 8.73 (1 H, bd, J=9Hz), 8.62 (1 H, bd, J=7Hz), 7.78
(i H, bdd, J=9Hz, 3Hz}, 7.38 (2H, d, J=1 OHz), 6.90 (2H, d, J=1 OHz), 4.39
( 1 H, d, J=12Hz), 3.95 ( 1 H, m), 3.80 (3H, s), 3.79 ( 1 H, m}, 3.68 ( 1 H,
d,
J=l8Hz), 3.50-3.30 (3H, m), 3.25-2.90 (6H, m}, 1.47 (2H, m), 1.31 (4H,
2s m), 1.20 (2H, m), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCIlNH3)
m/e 468 (M+H)+. Anal.catc. for C27H37N304 ~ 1.65 TFA: C, 55.50; H, 5.94;
N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.
ExamQle 166
so traps tran~l_(N N-Di(n-buy(lam'nocarbonvlmethyly-2-(2-fluorooh~n~rJ~l,_1~
~enzodioxol-5-y~~,ovrrolidine-3-carbox~~lic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting ethyl 2-ftuorobenzoytacetate in
Example 498. ~ H NMR (300 MHz, CDCl3) S 7.52 (1 H, dt, J=7Hz, 3Hz), 7.25
ss (1 H, m), 7.13 (1 H, dt, J=7Hz, 3Hz), 7.02 (2H, m), 6.88 (1 H, dd, J=7Hz,
3Hz), 6.73 (1 H, d, J=8Hz), 5.93 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 4.25
( 1 H, d, J=9Hz), 3.68 ( 1 H, m), 3.42 (3H, m), 3.39 ( i H, m), 3.20-2.95 (4H,
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m), 2.91 (1 H, d, J=l4Hz), 1.45 (3H, m), 1.26 {3H, m), 1.08 (2H, m), 0.87
(3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCIlNH3) mle 499 (M+H)+.
Anal.caic. for C28H35FN205 ~ 0.25 H20: C, 66.85; H, 7.11; N, 5.57. Found:
C, 66.51; H, 6.67; N, 5.18.
s
Exam 1
-f
benz, ~'ioxol-5-yj~ovrrolidine-3-ca oxylic acid
The title compound was prepared by the procedures described in
Examples 1 and 49 substituting ethyl 3-fiuorobenzoyiacetate in
Example 49B. ~H NMR (300 MHz, CDCI3) 8 7.38 (1H, m), 7.18 (1H, d,
J=7Hz), 7.15 (1 H, m), 7.00 {1 H, d, J=2Hz), 6.95 (1 H, m), 6.86 (1 H, dd,
J=7Hz, 2Hz), 6.75 (1 H, d, J=8Hz), 5.93 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz),
3.94 (1 H, d, J=l4Hz), 3.63 (1 H, m), 3.42 (3H, m)~ 3.35-2.95 (5H, m), 2.87
~ s {1 H, d, J=14Hz), 1.44 (3H, m), 1.27 (3H, m), 1. i 0 (2H, m), 0.88 (3H, t,
J=7Hz), 0.81 {3H, t, J=7Hz). MS (DCIINH3) m/e 499 (M+H)+. Anal.calc.
for C28H35FN20$: C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N,
5.40.
franc.traps-1-(4-N.N-Di(n-butyl)amino~henyly-2-(4-methoxvohenyl -4-(1.3
benzodioxol-5-yl)yXrrolidine-3-carboxylic acid
4-Nitro-1-fiuorobenzene, ethyl irans,irans-2-(4-
methoxyphenyl)-4-{1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate
is (the compound resulting from Example 6A), and diisopropylethylamine
are heated in dioxane to give ethyl traps,mans-2-(4-methoxyphenyl)-4~
( 1, 3-benzodioxol-5-yl)-1-(4-nitrophenyi)-pyrrolidine-3-carboxylate.
The vitro compound is hydrogenated to give the corresponding
aminophenyl compound. The aminophenyl compound is reacted with
so butyraldehyde and sodium cyanoborohydride according to the method of
Borch, J. Am Chem. Soc. 93: 2897 (1971) to give the corresponding N,N-
dibutylaminophenyl compound. Hydrolysis with sodium hydroxide using
the method of Example 1 D affords the title compound.
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Example 169
traps tran~l-~Dibutylamino~yrimidi.-4-yl)-2-(4-methomrphenvl)-4-(1.3
benzodioxol-5-y~~yrrolidine-3-carboxlrlic acid
2-(Dibutylamino)-4-chloropyrimidine is prepared from 2,4
s dichloropyrimidine according to the method of Gershon, J. Heterocyclic
Chem. 24: 205 (1987) and reacted with ethyl trans,trans-2-(4-
methoxyphenyl}-4-(i ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate
(the compound resulting from Example 6A} and diisoproplyethylamine in
dioxane with heating to give the intermediate ethyl ester, which is
~ o hydrolyzed with sodium hydroxide using the method of Example 1 D to
the title compound.
Exann~les 70-266
Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 and
~ s Scheme X, the following compounds can be prepared.
Ex. No. Name
170 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-
(isopropylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
i71 traps,traps-2-{4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(ethylaminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
172 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-( 1-
methylpropylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
173 traps,irans-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(phenylaminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
174 traps, traps-2-{4-Methoxyphenyl)-4-( 1,3-
benzodioxol-5-yl)-1-(piperidinylcarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
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175 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-
benzodioxol-5-yi)-1-( 1-
(propylaminocarbonyl)ethyl)-pyrrolidine-3-
carboxylic acid;
176 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(a-
(propylaminocarbonyl)benzyl)-pyrrolidine-3-
carboxylic acid;
177 traps,traps-2-(4-Methoxyphenyl}-4-(1,3-
benzodioxol-5-yl)-1-(bis-
(propylaminocarbonyl)methyl)-pyrrolidine-3-
carboxytic acid;
178 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(2-
(propylaminocarbonyl)ethyl)-pyrrolidine-3-
carboxylic acid;
179 traps, traps-2-(4-Methoxyphenyl)-4-( 1,3-
benzodioxol-5-yl)-1-(propylaminosulfonylmethyl)-
pyrrolidine-3-carboxylic acid;
180 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(2-phenethyl}-pyrrolidine-3-
carboxylic acid;
181 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(pentan.oylmethyl)-
pyrrolidine-3-carboxylic acid;
182 traps,traps-2-(4-Methoxyphenyl}-4-(1,3-
benzodioxol-5-yl)-1-(benzoylmethyi)-pyrrolidine-
3-carboxylic acid;
183 traps,frans-2-(4-Methoxyphenyl)-4-(1,3~
benzodioxol-5-yl)-1-(hexyl)-pyrrolidine-3-
carboxylic acid;
184 traps, traps-2-(4-Methoxyphenyl)-4-( 1,3-
benzodioxol-5-yl)-1-(2-hexynyl)-pyrrolidine-3-
carboxylic acid;
185 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-
benzodioxol-5-yl)-1-(propoxymethylcarbonyl-
pyrrolidine-3-carboxylic acid;
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18fi traps,traps-2-(4-Methoxyphenyi)-4-(1,3-
benzodioxol-5-yl)-1-(phenyl acetyl)-pyrrolidine-3-
carboxylic acid;
187 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(anilinylcarbonyl)-
pyrrolidine-3-carboxylic acid;
188 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(2-acetylaminoethyl)-
pyrrolidine-3-carboxylic acid;
189 traps, traps-2-(4-Methoxyphenyl)-4-( 1,.3-
benzodioxol-5-yl)-1-{2-phenoxyethyi)-pyrrolidine-
3-carboxylic acid;
190 traps,traps-2-(4-Methoxyphenyl)-4-{1,3-
benzodioxol-5-yl)-1-(2-benzodioxanylmethyl)-
pyrrolidine-3-carboxylic acid;
191 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(2-tetrahydrofuranylmethyl)-
pyrrolidine-3-carboxylic acid;
192 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(2-
(propylaminocarbonylamino)ethenyl)-pyrrolidine-3-
carboxylic acid;
193 traps,traps-2-{4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(2-
(propylaminocarbonylamino)ethyl)-pyrrolidine-3-
carboxylic acid;
194 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-y!)-1-(3-oxohex-1-enyi)-
pyrrolidine-3-carboxylic acid;
195 traps,traps-2-(2,4-Dimethoxyphenyl)-4-( 1,3-
benzodioxol-5-yl)-1-(propylaminocarbonyimethyl)-
pyrrolidine-3-carboxylic acid;
196 traps,traps-2-(2-Carboxy-4-methoxyphenyl)-4-
( 1,3-benzodioxol-5-yl)-1-
(propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
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i 97 traps,traps-2-(2-Aminocarbonyl-4-
methoxyph.enyl)-4-( i ,3-benzodioxol-5-yl)-1-
(propylaminocarbonyimethyl)-pyrrolidine-3-
carboxylic acid;
198 traps,traps-2-(2-Methanesulfonamido-4-
methoxyphenyl)-4-( 1,3-benzodioxol-5-yl}-1-
(propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
199 traps,traps-2-(2-Aminocarbonyimethoxy-4-
methoxyphenyl)-4-( i ,3-benzodioxol-5:.y1)-1-
(propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
200 traps,traps-2-(2-Methoxyethoxy-4-
methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-1-
(propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
201 traps,traps-2-(2-Carboxymethoxy-4-
methoxyphenyl}-4-( 1, 3-benzodioxol-5-yl)-1-
{propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
202 trans,trans-2-(4-Methoxy-2-
tetrazolylmethoxyphenyl)-4-( 1 ,3-benzodioxol-5-
yl)-1-~propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
203 traps,traps-2-(2-Atlyloxy-4-methoxyphenyl)-4-
( 1,3-benzodioxol-5-yl)-1-
(propyiaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
204 trans,trans 2,4-Bis(4-methoxyphenyl)-1-
(propylaminocarbonyl methyl)-pyrrolidine-3-
carboxylic acid;
205 trans,trans 2,4-Bis(1,3-benzodioxol-5-yl)-1-
(propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
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206 traps, traps-2-(4-Methoxyphenyl)-4-( 7 ,3-
benzodioxol-5-yl)-1-(N-methyl-N-
propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
207 traps, traps-2-(4-Methoxyphenyl)-4-{ 1,3-
benzodioxole-5-yl)-1-(N-methyl-N-
butylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
208 traps,traps-2-(4-Methoxyphenyl)-4-{1,3-
benzodioxol-5-yl)-1-(N-methyl-N-(4-
methoxyphenyl)aminocarbonyl)-3-pyrralidine-3-
carboxylic acid;
209 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-
phenylaminocarbonyl)-pyrrolidine-3-carboxylic
acid;
210 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-
allylaminocarbonylmethyl)-pyrrolidine-3-
carboxyiic acid;
21 i traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-(n-
butyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
2 7 2 traps,traps-2-{4-Methoxyphenyl)-4-{ 1,3-
benzodioxol-5-yt)-1-(N-methyl-N-
isobutylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
213 traps,traps-2-(4-Methoxyphenyl)-4-{ 1,3-
benzodioxol-5-yl)-1-(N-methyl-N-
cyclopentylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
214 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-(2-
methoxyethyl)aminocarbonyl)-pyrroiidine-3-
carboxylic acid;
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215 traps,traps-2-(4-Methoxyphenyi)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-
butoxyethyiaminocarbonyl)-pyrrolidine-3-
carboxylic acid;
216 traps,traps-2-(1,3-Benzodioxol-5-yi)-4-(4-
methoxyphenyl)-1-(N-methyl-N-
propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid; .
217 traps,traps-2-(4-Methoxyphenyl)-4-(1,4-
benzodioxan-6-yl)-1-(N-methyl-N-
propylaminocarbonylmethyf)-pyrrolidine-3-
carboxylic acid;
218 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-
isopropylaminocarbonylmethyl)-pyrrolidine-3-
carboxytic acid;
219 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-
ethylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
220 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-(1-
methylpropyl)aminocarbonylmethyi)-pyrroiidine-3-
carboxylic acid;
221 traps,traps-2-(4-Methoxyphenyl)-4-( 1.3
benzodioxol-5-yl)-1-(N-methyl-N
phenylaminocarbonylmethyi)-pyrrolidine-3-
carboxylic acid;
222 franc,traps-2-(4-Methoxyphenyl)-4-{1,3-
benzodioxol-5-yl)-i -( 1-(N-methyl-N-
propylaminocarbonyl)ethyl)-pyrrolidine-3-
carboxylic acid;
223 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(a-(N-methyl-N-
propylaminocarbonyl)benzyl)-pyrrolidine-3-
carboxylic acid;
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224 traps,traps-2-(4-Methoxyphenyl}-4-(1,3-
benzodioxol-5-yl)-1-(N-ethyl-N-
propylaminocarbony!methyl}-pyrrolidine-3-
carboxylic acid;
225 traps,traps-2-{4-Methoxyphenyl}-4-(1,3-
benzodioxole-5-yl}-1-( N-ethyl-N-
butylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
226 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl}-1-(N-ethyl-N-(4-
methoxyphenyl)aminocarbonyl)-3-pyrr~lidine-3-
carboxylic acid;
227 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yi)-1-(N-ethyl-N-
phenylaminocarbonyl)-pyrrolidine-3-carboxylic
acid;
228 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-
benzodioxol-5-yl)-1-{N-ethyl-N-
allylaminocarbony!methyl)-pyrrolidine-3-
carboxylic acid;
229 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-
benzodioxol-5-yl)-1-{N-ethyl-N-
isobutylaminocarbony!methyl)-pyrrolidine-3-
carboxylic acid;
230 traps,traps-2-(4-Methoxyphenyl)-4-(1,3
benzodioxol-5-yl)-1-(N-ethyl-N
cyclopentylaminocarbony!methyl)-pyrrotidine-3-
carboxylic acid;
231 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl}-1-(N-ethyl-N-
methoxyethylaminocarbonyl)-pyrrolidine-3-
carboxylic acid;
232 . traps,traps-2-(4-Methoxypheny()-4-(1,3-
benzodioxoi-5-yl)-1-(N-ethyl-N-
butoxyethylaminocarbonyl)-pyrrolidine-3-
carboxylic acid;
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233 traps,!raps-2-(1,3-Benzodioxol-5-yl)-4-(4-
methoxyphenyl)-1-(N-ethyl-N-
propylaminocarbonyfmethyl)-pyrrolidine-3-
carboxylic acid;
234 irans,traps-2-(4-Methoxyphenyl)-4-( 1,4-
benzodioxan-6-yl)-1-(N-ethyl-N-
propylaminocarbonylmethyl)-pyrroiidine-3-
carboxylic acid;
235 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-i -(N-ethyl-N-
isopropylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
236 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N,N-
diethylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
237 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-ethyl-N-( 1-
methylpropyl)aminocarbonylmethyl)-pyrrolidine-3-
carboxyiic acid;
238 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-
benzodioxol-5-yl)-1-(N-ethyl-N-
phenylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
239 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-( 1-(N-ethyl-N-
propylaminocarbonyl)ethyl)-pyrrolidine-3-
carboxylic acid;
240 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(a-(N-ethyl-N-
propylaminocarbonyl)benzyl)-pyrrolidine-3-
carboxyiic acid;
241 traps,traps-2-(4-Methoxyphenyl)-4-{1,3-
benzodioxol-5-yl)-1-(N-methyl-N-
isobutylaminocarbonylmethy!)-pyrrolidine-3-
carboxylic acid;
*rB
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242 traps,traps-2-{4-Methoxyphenyl}-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-
cyclohexylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
243 traps.traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N,N-
dipropylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
244 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl}-1-(isobutyloxyethyL}-
pyrrolidine-3-carboxylic acid;
245 irans,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(butylsuifonyl)-pyrrolidine-3-
carboxylic acid;
246 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-
(isopropylsulfonylaminoethyl)-pyrrolidine-3-
carboxylic acid;
247 traps,traps-2-{4-Methoxyphenyl)-4-(i,3-
benzodioxol-5-yl)-1-
(ethoxymethylcarbonylmethyl)-pyrrolidine-3-
carboxyiic acid;
248 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(2-ethylbutyrylmethyl)-
pyrrolidine-3-carboxylic acid;
249 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-(3,4-
dimethoxybenzyl}aminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
250 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-[(1 R)-1-(N-methyl-N-
propylaminocarbonyl)butyl]-pyrrotidine-3-
carboxylic acid;
251 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl}-1-[( i S)-1-(N-methyl-N-
propylaminocarbonyf)butyl]-pyrrolidine-3-
carboxylic acid;
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252 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yt)-1-(3-isopropoxypropyl)-
pyrrolidine-3-carboxylic acid;
253 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxot-5-yl)-1-(5-methylhexyl)-pyrrolidine-
3-carboxylic acid;
254 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-
benzodioxol-5-yl)-1-(5-methyl-2-hexenyl)-
pyrrotidine-3-carboxylic acid;
255 traps, traps-2-(4-Methoxyphenyl)-4-( i ,.3-
benzodioxol-5-yl)-1-(5-methyl-4-hexenyl)-
pyrrolidine-3-carboxylic acid;
256 irans,traps-2-(4-Methoxyphenyi)-4-(1,3-
benzodioxol-5-yl)-1-(3,5-dimethyl-2-hexenyl)-
pyrrolidine-3-carboxylic acid;
257 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(2-(N-methyl-N-
isobutyrytamino)ethyl)-pyrrolidine-3-carboxylic
acid;
258 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-(2,2-
dimethylpropyl)aminocarbony!methyl)-pyrrolidine-
3-carboxylic acid;
259 traps,traps-2-(4-Methoxyphenyl)-4-(1,3
benzodioxol-5-yl)-1-(N-ethyl-N
butylaminocarbony!methyl)-pyrrolidine-3-
carboxylic acid;
260 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-
benzodioxol-5-yl)-1-(N-methyl-N-
benzylaminocarbony!methyl)-pyrrolidine-3-
carboxylic acid;
262 traps,traps-2-(4-Methoxyphenyl)-4-{5-indanyl)-1-
(N-methyl-N-propylaminocarbonylmethyl)-
pyrrolidine-3-carboxylic acid;
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262 traps,traps-2-(4-Methoxyphenyl)-4-(2,3-
dihydrobenzofuran-5-yl)-1-(N-methyl-N-
propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
263 traps,irans-2-(4-Methoxyphenyl)-4-(1-
methylindoi-5-yl)-1-(N-methyl-N-
propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
264 traps,traps-2-(4-Methoxyphenyl)-4-{2-naphthyl)-
1-(N-methyl-N-propylaminocarbonylmathyl)-
pyrrolidine-3-carboxylic acid;
265 traps,traps-2-(4-Methoxyphenyl)-4-(1,2-
dimethoxy-4-phenyl)-1-(N-methyl-N-
propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
266 traps,traps-2-(4-Methoxyphenyl)-4-(1-methoxy-3-
phenyl)-1-(N-methyl-N-
propylaminocarbonylmethyl)-pyrrolidine-3-
carboxylic acid;
,exam iii es 267-288
Following the procedures described in Example 1 and Scheme II,
s the following compounds can be prepared.
267 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-i-(propylaminocarbonylmethyl)-
piperidine-4-carboxylic acid;
268 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(aminocarbonylmethyl)-
piperidine-4-carboxylic acid;
269 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(4-fluorobenzyl)-piperidine-
4-carboxylic acid;
270 traps,traps-3-(4-Methoxyphenyl)-5-( 1,3-
benzodioxol-5-yl)-1-(2-ethoxyethyl)-piperidine-4-
carboxylic acid;
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271 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-y!)-1-(2-propoxyethyl)-piperidine-
4-carboxylic acid;
272 traps,traps-3-(4-Methoxyphenyl)-5-( 1,3-
benzodioxol-5-yl)-1-[2-(2-methoxyethoxy)ethyl)-.
piperidine-4-carboxylic acid;
273 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-[2-(2-pyridyl)ethyl}-
piperidine-4-carboxylic acid;
274 traps,traps-3-(4-Methoxyphenyl)-5-(1,~-
benzodioxol-5-yl)-1-(morpholin-4-ylcarbonyl)-
piperidine-4-carboxylic acid;
275 traps,traps-3-(4-Methoxyphenyl}-5-(1,3-
benzodioxole-5-yl)-1-(butylaminocarbonyl}-
piperidine-4-carboxylic acid;
276 traps,traps-3-(4-Methoxyphenyl)-5-( 1,3-
benzodioxol-5-yl)-1-(4-
methoxyphenytaminocarbonyl)-3-piperidine-4-
carboxyiic acid;
277 traps,traps-3-{4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl}-1-acetylpiperidine-3-carboxylic
acid;
278 traps,traps-3-(4-Methoxyphenyl)-5-( 1,3-
benzodioxol-5-yl)-1-(2-furoyl)-piperidine-3-
carboxylic acid;
279 traps,irans-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(phenylaminocarbonyl)-
piperidine-4-carboxylic acid;
280 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(allylaminocarbonylmethyl)-
piperidine-4-carboxylic acid;
281 traps,traps-3-{4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(n-
butylaminocarbonylmethyl)-piperidine-4-carboxylic
acid;
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282 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(N-n-butyl-N-
methylaminocarbonylmethyl)-piperidine-4-
carboxylic acid;
283 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(pyrrolidin-1-
ylcarbonylmethyl)-piperidine-4-carboxylic acid;
284 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-
(isobutylaminocarbonylmethyl)-piperid~ne-4-
carboxyiic acid;
285 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-
(cyclopentylaminocarbonylmethyl)-piperidine-4-
carboxylic acid;
286 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(morpholin-4-
ylaminocarbonylmethyl)-piperidine-4-carboxylic
acid;
287 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(2-phenoxyethyl)-piperidine-
4-carboxylic acid;
288 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-
benzodioxol-5-yl)-1-(methoxyethylaminocarbonyl)-
piperidine-4-carboxylic acid.
Example 289
traps traps= 2-(4-MethoxX~he-n~11-4-x(1.3-benzodioxol-5-yrl)-1- (4
dibutXlaminoQhenyll-nvrrolidine-3-carboxylic acid
s 4-Nitro-fluorobenzene, ethyl traps,traps-2-(4-methoxyphenyl)-4-
(1,3-benzodioxoi-5-yl)-pyrrolidine-3-carboxylate (example 6A) and di-
isopropyl ethyfamine are heated in dioxane to give ethyl traps, irans-2-
(4-methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-1-(4-nitrophenyl)-
pyrrolidine-3-carboxylate. The vitro compound is hydrogenated to the
~ o corresponding aminophenyl compound. This is reacted with
butyraldehyde and sodium cyanoborohydride according to the method of
Borch (J. Am Chem. Soc., 93, 2897, 1971 ) to' give the corresponding N,N-
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dibutylaminophenyl compound, which is hydrolyzed with sodium
hydroxide using the method of example 1 D to give the title compound.
Example 290
s fans rrans-~~4-MetI~Q~y~yl)-4-(1.3-benzodioxol-5-yl)-1-(2-
ct~~~ ino-ovrimidine-4-yl)-Qyrrolidine-3-carboxvlic acid
2-(Dibutylamino) 4-chloropyrimidine is prepared from 2-4-
dichloropyrimidine according to the method of Gershon (J. Heterocyclic
Chem. 24, 205, 1987). This compound, ethyl traps, irans-2-(4-
so methoxyphenyt)-4-(1,3-benzodioxol-5-yl)-pyrroJdine-3-carboxylate
(example 6A), and di-isopropyl ethylamine are heated in dioxane to give
the intermediate ethyl ester, which is hydrolyzed with sodium
hydroxide using the method of example 1 D to give the title compound.
~ s (Exam I
traps.traps-2-(4-Methoxyrhenyl)-4-(1.3-benzodioxol-5-yl)-1-lN-butyl-N-
phenviaminocarbonylmeth~rl)-~,yrrrolidine-3-carboxylic acid
The title compound was prepared according to the general
procedure of Example 1. ~H NMR (CD30D) : b 0.87 (t,3H,J=8); 1.2-1.35
20 (m,2H}; 1.35-1.5 (m,2H); 2.78 (m, 2H); 3.10 (t,1 H, J=9}; 3.26 (d,1
H,J=15}:
3.44 (dd,1 H,J=5,10); 3.5-3.7 (m,3H); 3.77 (m,1 H); 3.78 (s,3H); 5.93
(s,2H); 6.7-6.9 (m,4H); 7.0-7.2 (m,SH); 7.4 (m,3H). MS (DCilNH3): mle
531 (M+H)+. Anal calcd for C3~H3aN2~s: C, 70.17; H, 6.46; N, 5.28.
Found: C,70.36; H, 6.52; N, 4.99.
~xameg 292
Sodium traps frans-2-~4-Methoxyahenvl)-4-~1.3-benzodioxot-5-~~-1-~N.N-di~n
~srfvl)aminocarbonylmefhyl)-pyrrolidine-3-carboxylate
so Example 292A
Ethyl 3-(4-methoxyphenyl)-3-oxopropionate
Simultaneous reactions were run in both a 65-L reactor and a 35-
L reactor that share the same reflux system. A nitrogen atmosphere
was maintained in both. 4.0 kg (100 moles} of 60% sodium hydride in
ss mineral oil and 32 L toluene were charged into the ambient
temperature reactors. The mixture was agitated for 5 minutes and
an~wPd to settle. 20 L of the toluene solution was aspirated. 28 L of
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toluene was added, agitated for 5 minutes, allowed to settle and 28 L
of the toluene solution was aspirated. 68 L of toluene and 8.4 L (69.7
moles) diethyl carbonate were added. The agitation was begun and the
flow of Syltherm (Note 4) in reactor jackets was initiated. A solution
s of 5.0 kg (33.3 moles) 4-methoxyacetophenone in 12 L toluene was
added over 20 minutes. When additions were complete, the jacket
temperaturewas reduced to 10° C and stirring continued for 16 hours.
A solution of 6.7 L (117 moles) glacial acetic acid in 23 L deionized
water was fed at the same rate that was previously used for the
to acetophenone solution. When addition was complete, agitation was
stopped and the layers separated. The aqueous Payer was washed once
with 13 L toluene. The combined organic layers were washed twice
with 6.7 L portions of 7% (w:w) aqueous sodium bicarbonate. The
toluene solution was washed once with 6.7 L of 23% (w:w) aqueous
1 s sodium chloride . The organic solution was dried over 10 kg sodium
sulfate, filtered, and the solvent removed on the rotary evaporator to
provide the desired product.
Example 2928
20 3 4- P,~hylenedioxv-1-(,2-nitroethenyl)-benzene
In a 45-L cryogenic reactor with a contoured, anchor stirrer was
dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg
(36.9 moles) nitromethane at 15°-20° C. The jacket temperature
was
set to -5° C and the reaction solution cooled to a temperature of
+3.5°
25 C. A 21 ° C solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodium
hydroxide diluted with 3.7 L water was pumped in. The reaction
temperature was maintained between 10°-15° C. When addition was
complete, the jacket temperature was reset to 1 ° C and stirring
continued for 30 minutes. A mixture of 7 kg ice in 19 L water was
so added to dissolve most of the solid. The reaction mixture was filtered
through canvas and then a 27R10SV Honeycomb filter. The filtered
solution was metered into a 21 ° C mixture of 7.4 L concentrated
hydrochloric acid in 11.1 L deionized water. The final reaction
temperature was 26° C. The resulting product was centrifuged and
as washed until the wash pH rose to at least 6 (by pH indicating paper).
The crude product was dissolved in . 92 L dichloromethane and the layers
separated. The aqueous layer was washed once with 8 L
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dichtoromethane. The combined organics were dried over 1.32 kg
magnesium sulfate and filtered through Whatman #1 paper. The volume
was reduced to 20% and the solution cooled to 4° C. Filtration through
Whatman #t paper, followed by ambient temperature drying in vacuo
s with an air leak afforded 1.584 kg (22%) of a first crop Concentration
of the MLS to 25% followed by similar cooling, filtration, and drying
afforded 0.262 kg (4%) of a second crop. The yellow product darkened on
standing in light and air.
~o
~,kl 2-y4-methoxK en~oyl)~-3-{1.3-benzodioxol-5-yl)-4-nitro
butanoate
Into a 45-L stirred reactor at ambient temperature were charged
5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene
1 s and 24 L ethyl acetate . A solution of 5.355 kg (24.1 motes) ethyl 3-(4
methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280
g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.OJundec-7-ene in four
equal portions was added over a 2.5 hour period. The reaction mixture
was filtered through dicalite and the resulting filtered solution was
2o used in the next step without any further purification.
Example 292D
~h~,rl 2-(4-methox~rohenyl)-4-~( 1.3-benzodioxol-5-yll-4.5-dihyrdro-3H
~yrrol-3-carboxyl ate
2s The product of Example 292C (1316 ml solution consisting of 300
g Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4
nitrobutanoate in ethyl acetate) was added to a glass reactor
containing RaNi # 28 (300 g). The reaction mixture was shaken under a
hydrogen environment of 4 atm at room temperature for 18 hoursand
so filtered through a nylon 0.20 micron 47 mm millipore.
The filtrate was concentrated to 1.4 kg of dark solution and
purified by normal phase silica gel chromatography eluting with 85:15,
hexanes: ethyl acetate. The pure fractions were combined and
concentrated (as above) until crystals formed. The solution was cooled
as to 0° C and filtered. The solid was washed with 2 L of 85:15,
hexane:
ethyl acetate (0° C). The solids were dried in vacuo at 50° C to
a
constant weight of 193.4 g (21 % yield, melting point 80-81 ° C) of the
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title compound. A further 200 g (23% yield) of product was obtained
from the mother liquors.
Fxam~le 292E
s '~,t vl 2 (4 methox~y11~4-~. ~-h°~'~~ioxol-5-vll-ovrrolidine S-
car o riate
Into a 12-L flask equipped with magnetic stirring, addition funnel,
temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4-
methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro-3H -
~ o pyrrole-3-carboxylate (1.25 mol). The reaction vessel was degassed
with nitrogen. Absolute 3.7 L ethanol and 1.12 L of THF were added. 31
mg bromocresol green and 94.268 sodium cyanoborohydride (1.5 moI)
were added. A solution containing 400 mL absolute ethanol and 200 mL
of 12 M HCI was then added. The reaction mixture was stirred for 30
~ s minutes after addition was complete. After the starting material was
consumed, 0.5 L of 7% aq. NaHC03 was added. The reaction mixture was
concentrated and diluted with 5 L ethyl acetate. The organic layer was
washed twice with 2 L of 7% aq. NaHC03 and once with 2.5 L of 23% aq.
NaCI, the dried over 1908 MgS04, filtered, and concentrated to give 447
2o g of the title compound as a thick yellow oil.
Examohe 292F
~hyl 2-( -methoxvo~ heny,~-4-~ 3-benzodioxol-5-yll-1-IN.N-di(n-
l ino~arbo lyrlmethvll pvrrolidine 3-carboxvlate
zs Into a 22-L flask equipped with overhead stirring, nitrogen inlet,
and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3,4-
methylenedioxyphenyl)-pyrrolidine-3-carboxylate (2.223 kg,6.02 mol).
The reaction vessel was degassed with nitrogen. 13.2 L ofacetonitriie,
3.66 L diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg
so dibutylamidomethyl bromide (6.26 mol) were added. The mixture was
refluxed at 78° C for 17 hrs. After the disappearance of starting
material , the mixture was concentrated until crystals formed. The
solid was filtered and washed with 4 L ethyl acetate (0° C).
Concentrating of the filtrate was continued as above until all volatiles
ss were removed. The residue was diluted with 40 L ethyl acetate and
washed with 20 L deionized water. The organic layer was washed with 8
L of 23% aq. NaCI nad dried over 0.399 kg MgS04 and filtered.
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Concentration as above provided 3.112 kg (96 % yield) of the title
compound as a dark oil.
Example 2 ~12G
3-ca~b"Y~ ata and ~gnaration of tran,~. frans 2-(4-methoxvohenvl)-4
~3 4-dioxvohenkl,l-olrrrolLdine-3-carboxylic acid ethv( ester
Into a 35-L reactor equipped with overhead stirring, nitrogen
inlet, and condenser was charged 3.112 kg ethyl 2-(4-methoxyphenyl)-
~0 4-(3,4-methylenedioxyphenyl)-pyrrolidine 3-carboxylate (5.78 mol).
16.4 L of absolute ethanol was added and the reaction vessel was
degassed with nitrogen. 0.115 kg of sodium ethoxide (1.69 mol) was
added and the mixture was refluxed at 79° C for 1 hr. The mixture was
cooled to 15° C and 5 L of 7.6 M NaOH solution (38.1 mol) was added.
The
~ s mixture was stirred at 15° C for 18 hrs. The solvent was evaporated
and
the residue dissolved in 15.8 L of deionized water and extracted with
28 L of ether. The ether solution was washed with 9.5 L deionized
water. The aqueous wash was extracted with 3 L ether. 0.340 L of 12 M
HCI was added to the aqueous layer. The aqueous layer was extracted
2o with 24 L of ethyl acetate. The organic layer was washed with 9 L of
23% aq. NaCI, dried with 0.298 kg MgS04 , filtered, and concentrated to
give 2.132 kg of a dark oil. The oil was triturated with 18 L ether. The
undesired solids were filtered and saved for later use. The mother
liquors were concentrated to obtain i .102 kg of tight foam. The foam
zs was dissolved in 5.5 L ethyl acetate with heating to 65° C. 14 L
hexane
was added slowly enough to keep the solution refluxing. The reaction
mixture was cooled to 10° C and filtered. The crystals were washed
with 2 L ether (0° C) and dried to constant weight in vacuo at
50° C to
give 0.846 kg (43% yield, melting point 119-120) of crude product,
3o which was further purified by normal phase silica gel chromatography.
Examr~le 292H
Sodium rrans rrans-2-~4-mpthoxyr~henyll-4-( 1 .3-benzodioxol-5-vl)-1
(N N-di(n- utx_Ilaminocarbonylmethyll Dyrrolidine 3-carboxvlate
35 Into a 20-L flask was charged rrans,trans 2-(4-methoxyphenyf)-
4-(3,4-methyledioxyphenyl)-1-,(N,N-dibutylamino- carbonyl methyl)
i-U 1 ~ viiGi . r~ ~Wuuvm ~,
pyrrotidine 3-carboxyic ac~o (u.9~7 icy, ' ""' ') " '"'""' "'
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0.0720 kg NaOH (1.80 mol) dissolved in 4.65 L methanol was added. The
reaction mixture was concentrated to an oil. Pentane (4 L) was added
and the solution concentrated again. Pentane {4 L) was added again and
concentration of this solution gave a tight tan foam. The foam was dried
s in vacuo at 50° C to a constant weight of 0.937 kg (97% yield) of the
title compound.
~xamp~e 293
~r an s arans-2 ~4 Mei~hoxvohenvll-4-(1 3-benzodioxol-5-vll-1-
[~ ecahysiroisoa,uinolin-2- carbonyimethvll-ovrroJidine-3-carboxylic
acid:
The title compound was prepared using the procedures described
in example 1. NMR (CD30D, 300 MHz) shows a mixture of isomers. MS
(DCl/NH3) mlz 521. Anal calcd for C3oH3sN2Os ~. 1.3 TFA: C, 58.54; H,
~ s 6.62; N, 4.19 . Found: C, 58.34; H, 5.58; N, 4.00 .
Examohe 294
n h I - I -1_
dimethvloioeridinyl- carbonylmethyl~-~yrrolidine-3-carboxylic acid.
zo The title compound was prepared using the procedures described
in example 1. NMR (CD30D, 300 MHz) indicates presence of rotamers. &
0.84 (s, 3H), 0.86 (s, 3H), 1.35-1.6 (m, 4H), 3.83 (s, 3H), 5.96 (s, 2H),
6.81 (d, 1 H, J=8), 6.90 (dd, 1 H, J=1,8), 7.01 (d, 2H, J=9), 7.03 (s, 1 H),
7.47 (d, 2H, J=9). MS (DC11NH3) m/z 495. Anal calcd for C28Hs4N24s .
25 1.4 TFA: C, 56.55; H, 5.45; N, 4.28 . Found: C, 56.52; H, 5.83; N, 4.26 .
~xamDle~29-5
traps traps 2 ~(,4 Methoxvo.~henyl?-4-~1 3-ben~odioxol-5-yrll-1-f2-(N
prnnvl-N-iso-butoxycarbonvlaminolethylj-~yrrolidine-3-carboxylic acid
ao The title compound was prepared by the methods detailed in
Example 61, but substituting propyiamine for methylamine in Example
61 B and isobutyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by trituration with 1:1 diethyl ether/
hexane. The resulting solid was dissolved in CH3CN and water and
35 lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300
MHz) 8 0.80 (t, 3H, J=7), 0.92 (m, 3H), 1.43 (h, 2H, J=7Hz), 1.7-1.9 (m,
1 H), 2.72 (m, 1 H), 2.90 (m, 2H), 3.10 (m, 2H), 3.25 (m, 2H), 3.40 (m, 1 H),
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3.55 (m, 1 H), 3.62 (m, 1 H), 3.7-3.9 (m, 2H) 3.78 (s, 3H), 5.95 (s, 2H), 6.72
(d, 1 H, J= 8Hz), 6.82 (m, 3H), 7.00 (s, 1 H), 7.30 {d, 2H, J=8Hz). MS
(DCIINH3) m/e 527 (M+H)+. Anal calcd for C29H38N2O6 ~ 0.5 H20: C,
65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.
s
FxamQle 296
_1-
tetrahKdroiso~«innlin-2- carbonylmethvll-wrrolidine-3-carboxylic
acid.
z o The title compound was prepared using therprocedures described
in example 1. NMR (CD30D, 300 MHz) indicates presence of rotamers. S
2.97 (m, 2H), 4.68 (s, 3H), 5.97 {s, 2H), 6.83 (d, 1 H, J=8), 6.9-7.0 {m, 3H),
7.03 (d, 1 H, J=2), 7.1-7.3 (m, 4H), 7.4-7.5 (m, 2H). MS (DCI/NHa) m/z
515.
~s
Example 297
Lrans traps-2-~4-Methoxvohenyh(~. 3-benzodioxol-5-vll-1-f2-(N
~~,Ryl N dimethy,~aminoc~rbonyrlaminoyethylj-pvrrolidine-3-carboxylic
acid
2o The title compound was prepared by the methods detailed in
Example 61, but substituting propylamine for methylamine in Example
61 B and dimethylcarbamyf chloride for isobutyryl chloride in Example
61 C. The crude product ~ was purified by preparative HPLC (Vydac p.C 18)
eluting with a 10-70% gradient of CHgCN in O.i% TFA. The desired
Zs fractions were lyophilized to give the product as a white solid. ~ H NMR
(CDC13, 300 MHz) S 0.70 (t, 3H, J=7), 1.28 (m, 2H), 2.75 {s, 3H), 2.82 (m,
2H), 3.1-3.45 (m, 4H), 3.70 (m, 1 H), 3.80 (s, 3H), 3.90 (m, 3H), 4.72 (m,
1 H), 5.95 (s, 2H), 6.75 (d, 1 H, J= 8Hz), 6.87 (m, 3H), 7.05 (s, 1 H), 7.40
(d,
2H, J=8Hz). MS (DCIINH3) m/e 498 (M+H)+. Anal calcd for C27Hg5N3Og
30 1.25 TFA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71; N, fi.41.
Example 298
I~rans traps-2 (4 Methox~ohenvl)-4-y1 3-benzodioxol-5-vll-1-(2-(N
Qrgp~rl N (4-nitrobenzenesulfonyl amino ethyll-oyrrolidine-3
35 Sarboxvlic acid
Using the procedures described in Eample 66, the title compound
....,~. n~cnarc~ ac a vPllow solid. m.p. 85-87°C. 1 H NMR (CDC13, 300
MHz)
.. aw ~,.. ..,,..... _ _ _. _ ,
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8 0.77 (t, J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (m, 1 H),
2.57-2.66 {m, 1 H), 2.82-3.15 (m, 4H), 3.22 (t, J=7.5Hz, 2H) 3.38 (dd,
J=3Hz,J=9Hz, 1 H), 3.49-3.57 (m, i H), 3.59 (d, J=9Hz, 1 H), 3.83 (s, 3H),
5.96 (s, 2H), 6.73 (d, J=BHz, 1 H), 6.82 (dd, J=i Hz,J=8Hz, 1 H), 6.87 (d,
s J=9Hz, 2H), 6.98 (d, J=1 Hz, 1 H), 7.27 (d, J=9Hz, 2H), 7.82 (d, J=9Hz, 2H),
8.23 (d, J=9Hz,2H). MS (DCIlNH3) mle 612 (M+H)+~
Example 299
traps tran~2-(,4-Methoxyphenvl~-4-( 1 3-benzodioxol-5-vl)-1-(2-(N-
~o Q~ov'~'I N n pentanesulfonylaminolethkl)-ovrrolidine-3-carbox5rlic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 59-61 °C i H NMR (CDC13, 300MHz) 8
0.79 (t, J=7.5Hz, 3H), 0.90 (t, J=6Hz, 3H), 1.26-1.32 (m, 4H), 1.43
(sextet, J=7.5Hz, 2H), 1.67-1.76 (m, 2H), 2.23-2.32 (m, 1 H), 2.70-3.08
i s (m, 7H), 3.15-3.32 (m,2H), 3.42 (dd, J=3Hz,J=9Hz, 1 H), 3.52-3.57 (m,
i H), 3.63 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7.5Hz, 1
H),
6.83 (dd, J=1 Hz,J=7.5Hz, 1 H), 6.87(d, J=8Hz, 2H), 7.00 (d, J=1 Hz, 1 H),
7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 561 (M+H)+~
2o Example 300
traps traps-2-(4-Methoxy~henyl~-4-(i.3-benzodioxol-5-vl)-1-(2-lN
~r Q,yrl-N-~(4-trifluoromethoxKbenzenesulfonyl)amino)ethvl)
Qyrrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
2s was prepared as a white solid. m.p.122-124°C. 1 H NMR (CD30D,
300MHz}
& 0.75 (t, J=7.5Hz, 3H), 1.26-1.45 (m, 2H), 2.96-3.08 (m, 2H), 3.23 (bs,
2H), 3.35-3.45 (m, 2H), 3.52 (t, J=1 OHz, 1 H), 3.81 (d, J=9Hz, 2H), 3.86 (s,
3H), 3.92 (t, J=9Hz, 1 H), 4.63 (d, J=1 OHz, 1 H), 5.97 {s, 2H), 6.82 {d,
J=9Hz, 1 H), 6.93 (dd, J=3Hz,J=9Hz, 1 H), 7.06-7.08 (m, 3H}, 7.46 (d,
3o J=9Hz, 2H), 7.56 (d, J=9Hz, 2H), 7.89 (d, J=9Hz, 2H). MS (DCIINHs), m/e
651 (M+H)+.
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Example 301
aranj trany2 ~4-Methoxvohenv_I)=4-(1 3-benzodioxol-5-vl)-1-(2-(N
~,~,~~2~methart-2-orooenesulfony~,)amin0,~~~ethvl)-ovrrolidine-3
carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 69-71 °C.. 1 H NMR (CDCfs, 300MHz)
8
0.79 (t, J=7.5Hz, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 (s, 3H), 2:25-2.35
(m, 1 H), 2.68-2.77 (m, 1 H), 2.85-3.28 (m, 7H), 3.40 (d, J=9Hz, 1 H), 3.52-
3.68 (m, 2H), 3.66 (d, J=9Hz, 1 H), 3.80 (s, 3H), 4.92 (s, 1 H), 5.07 (s, 1
H),
5.97 (s, 2H), 6.74 (d, J=7Hz, 1 H), 6.82-6.89 (m,3H), 7.01 (s,1 H), 7.33 (d,
J=9Hz, 2H). MS (DCllNH3), m/e 545 (M+H)+.
Example 302
traps-trarz~2-~(4-MethoxVD~y_I)-4-(1 .3-benzodioxol-5-yll-1-i2
15 ~thytQioeridin~-carbony,Imethylj-Ryrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described
in example 1. NMR (CD30D, 300 MHz) shows a mixture of isomers. 8
0.75 (t, 3H, J=7), 1.4-1.7 (m, SH), 3.84 (s, 3H), 5.96 (s, 2H), 6.83 (d, 1 H,
J=8), 6.91 (d, 1 H, J=8), 7.0-7.1 (m, 3H), 7.52 (d, 2H, J=9). MS (DCl/NH3)
2o m/z 495. Anal calcd for C28H34N2Os . 1.6 TFA: C, 55.35; H, 5.30; N, 4.14.
Found: C, 55.26; H, 5.37; N, 4.01 .
Exam i!~ a 303
~rans tran~2 ~4-Methoxy,~h~n_yll-4S1 3-benzodioxol-5-yrll-1-l2-tN-
25 Qr~t -m th~rlorooanesutfon~~)amino ethlrl)-ovrrolidine-3-
~arboxy,~ic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p. 72-73°C. 1 H NMR (CDC13, 300 MHz) 8
0.82 (t, J=7.5Hz, 3H),1.04 (d, J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.15-2.33
30 (m,2H), 2.57-2.75 (m, 2H), 2.84-3.08 (m, 3H), 3.12-3.21 (m, 1 H), 3.23-
3.45 (m, 1 H), 3.43 (d, J=11 Hz, 1 H), 3.55-3.62 (m, 1 H), 3.66 (d, J=9Hz,
1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 {d, J=9Hz, 1 H), 6.83 (dd, J=1
Hz,J=9Hz,
1 H), 6.87(d, J=9Hz, 2H), 7.02 (d, J=1 Hz, 1 H), 7.33 (d, J=9Hz, 2H). MS
(DC1/NH3) mle 547 M+H)+.
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Fxam~le 304
traps irans-2 ~4 Methoxvo~henKl) 4-(1 3-benzodaoxol-5-yl)-1-(2-f N-
r -h n If n f min I - rr li r ti i
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p.58-59°C. 1 H NMR (CDC13, 300MHz) 8
0.80(t, J=7.5Hz, 3H), 0:88 (t, J=7Hz, 3H), 1.23-1.36 (m, SH), 1.94 (q,
J=7.5Hz, 2H), 1.71 (quintet, J=7Hz, 2H), 2.23-2.32 (m, 1 H), 2.70-3.09(m,
7H), 3.13-3.32 (m,2H), 3.43(dd, J=3Hz,J=9Hz, 1 H), 3.52-3.58(m,1 H),
3.65(d, J=9Hz, 1 H), 3.80 (s, 3H), 5.96(s, 2H), 6.73 (d, J=7Hz, 1 H), 6.83
(dd, J=1 Hz, J=7Hz, 1 H), 6.87(d, J=9Hz, 2H), 7.01 (d; J=1 Hz, 1 H), 7.32(d,
J=9Hz, 2H). MS (DC1/NH3) m/e 589 M+H)+.
~,xam Ip a 305
tram-traps-~-(4-Methox~yl)-4- 1 3-benzodioxol-5-y1)-1-f2-(N
~s ethyl-N-ethoxycarbonylamino)ethyl-oyrrrolidine-3-carboxylic acid
Prepared by the methods detailed in Example 61, but substituting
ethylamine for methylamine in Example 61 B and ethyl chloroformate for
isobutyryl chloride in Example 61 C. The crude product was purified by
preparative HPLC (Vydac ~C18) eluting with a 10-70% gradient of CH3C N
2o in 0.1 % TFA. The desired fractions were lyophilized to give the product
as a white solid. ~H NMR (CDC13, 300 MHz) 8 0.90 (t, 3H, J=7), 1.22 (m,
3H), 3.0-3.2 (m, 4H), 3.42 (m, 2H), 3.78 (s, 3H), 3.82 (m, 4H), 4.10 (q, 2H,
J=7Hz), 3.5 (br s, 1 H), 5.97 (dd, 2H, J=1,7Hz), 6.72 (d, 1 H, J= 8Hz), 6.84
(m, 3H), 7.00 (s, 1 H), 7.42 (d, 2H, J=8Hz). MS (DCIlNH3) mle 485 (M+H)+.
2s Anal calcd for C26H32N20~ ~ 1.2 TFA: C, 54.90; H, 5.39; N, 4.51. Found: C,
55.01; H, 5.36; N, 4.56.
ExamQle 306
Lran~ tr~n~~_~4-MethoxVD~,~ h2nyr_t)~-4-l1 .3-benzodioxol-5-vl)-1-(3'f N-
3o r I n I 'n h I - r i i r x li. i
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p.59-60°C. 1 H NMR (CDCIs, 300MHz) 8
0.80(t, J=7.5Hz,3H), 0.89(t, J=7Hz, 3H), 1.25-1.36(m, 6H), 1.53(sextet,
J=7.5Hz; 2H), 1.72(quintet, J=7Hz, 2H), 2.23-2.32(m, 1 H), 2.72-3.08(m,
35 7H), 3.15-3.32(m, 2H), 3.43(d, J=9Hz, 1 H), 3.55-3.62(m, 1 H), 3.65 (d,
J=lOHz, 1 H), 3.80(s, 3H), 5.96(s, 2H), 6.74(d, J=7.5Hz,1 H), 6.82(d,
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J=7.5Hz,1 H), 6.87(d, J=9Hz, 2H), 7.01 (s,1 H), 7.32(d, J=9Hz,2H). MS
(DCIINHs), m/e 575 (M+H)+.
~xamnle 307
s traps traps-2 ~4 Eth~,rt~he~rl)-4-(1 3-benzodioxol-5-yl)-1-fN N-diln-
1Q,~ tyrl)aminocarbonylmethyl]-~yrrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described
in examples 1 and 49, substituting ethyl 4-ethylbenzoylacetate
(prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967)
~o starting with 4'-ethylacetophenone) in procedure 49B. NMR (CDCI3, 300
MHz) b 7.31 (2H, d, J=8Hz), 7.16 (2H, d, J=8Hz), 7.03 (1 H, d, J=3Hz), 6.86
(1 H, dd, J=8&3Hz), 6.73 (1 H, d, J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d,
J=4Hz), 3.77 (1 H, d, J=9Hz), 3.60 (1 H, m), 3.53-3.23 (5H, m), 3.13-2.90
(4H, m), 2.73 (1 H, d, J=l4Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, m), 1.40-
~ s 1.10 (6H, m), 1.02 (2H, m), 0.87 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). mle
(DCI, NH3) 509 (MH+) AnaLcalc. for C3oHaoN2~s C 70.84, H 7.93, N 5.51.
Found C 70.80, H 7.85, N 5.25 .
Example 308
tr~ns-traps-2-j4-Methox~rphen~,rl)-4-(1.3-benzodioxol-5-yl)-1-f2-(N
prop_yl-N-y2-chloroethoxyycarbonylamino)ethyl]-pyrrofidine-3
carboxxlic acid
Prepared by the methods detailed in Example 61, but substituting
propylamine for methylamine in Example 618 and 2-chloroethyl
2s chloroformate for isobutyryl chloride in Example 61 C. The crude product
was purified by trituration with 1:1 diethyl ether/ hexane. The resulting
solid was dissolved in CH3CN and water and lyophilized to give the
product as a white solid. ~ H NMR (CDC13, 300 MHz) S 0.80 (t, 3H, J=7),
1.22 (m, 3H), 2.15 (m, 1 H), 2.75 (m, 1 H), 2.85 (m, 1 H), 3.1 (m, 2H), 3.25
so (m, 2H), 3.5 (m, 3H), 3.65 (m, 2H), 3.80 (s, 3H), 4.18 (m, 1 H), 4.30 (m,
1 H), 5.98 (s, 2H), 6.72 (m, 1 H), 6.82 (m, 3H), 7.00 (m, 1 H), 7.30(m, 2H).
MS (DCIlNH3) mle 533 (M+H)+. Anal calcd for C27H33N2O7C1: C, 60.84; H,
6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.
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Fxam~le 309
r _ h I - 1 i - N N- i n
~~t~llaminoc ra bonXlmethvll"~oyrrrolidine~3-carboxylic acid.
The title compound was prepared using the procedures described in
s example 1, substituting ethyl 5-methoxy-3-oxopentanoate for ethyl 4-
methoxybenzoylacetate in Example 1 A. The title compound is a yellow foam. ~ H
NMR {CDC13, 300 MHz) b 0.91 (t, J=7Hz) and 0.95 (t, J=7Hz, 6H total), 1.28-
1.41 (br
m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m, 2H), 3.06 (br t, J=9Hz, 1 H),
3.30 (s)
and 3.20-3.68 (br m, 11 H total), 3.72-4.10 (br m, 4H), 5.92 {s, 2H), 6.72 (d,
J=8.5Hz,
~ 0 1 H), 6.82 (dd, J=1.5, 8.5Hz, 1 H), 6.91 (d, J=1.SHz, 1 H); M~S (FAB) m/e
463 (M+H)+.
Anal calcd for C25H3gN205~H2O: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H,
8.15; N, 5.69.
~xamr~le 310
~s r h n -4- 1 n x I- -1- N
~th~ri N n nentanesulfony_lamino)ethyll-pvrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was prepared as a white solid. m.p.57-58°C. 1 H NMR (CDCIs, 300MHz) b
0.89(t, J=7Hz, 3H), 1.06(t, J=7.5Hz, 3H), 1.26-1.37(m, 4H), 1.72(quintet,
2o J=7.5Hz, 2H), 2.22-2.32(m,iH), 2.71-2.96{m,SH), 3.08-3.30{m,4H),
3.95(d, J=9Hz, 1 H), 3.53-3.60(m, 1 H), 3.67{d, J=9Hz,1 H), 3.80(s, 1 H),
5.97{s, 2H), 6.73(d, J=9Hz, 1 H), 6.82(d, J=9Hz,1 H), 6.88(d, J=9Hz,
2H),7.02(s,lH), 7.33(d, J=9Hz, 2H). MS (CDI/NH3) mle 547 (M+H)+.
is Example 311
r n - 4- h n I -4- 1 n i x i- -1- N-
din~,vcl, ohexylamino carbonvlmethvll-oyrrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described
in example 1. ~ NMR (CD30D, 300 MHz) 8 1.0-2.0 (m, 20H), 3.0-3.1 (m, 2H),
30 3.80 (s, 3H}, 5.95 (s, 2H), 6.75 (d, 1 H, J=8), 6.86 (dd, 1 H, J=2,8), 6.95
(d,
2H, J=9), 7.04 (d, 1 H, J=2), 7.38 (d, 2H, J=9). MS (DCI/NH3) m/z 563.
Anal calcd for CssH42N2Os . 0.5 H20: C, 69.33; H, 7.58; N, 4.90 . Found: C,
69.42; H, 7.29; N, 4.78.
*rB
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Example 312
!ra~s-mans-2-(4-Methoxvo, henyrl)-4-(1.3-benzodioxo(-5-vl)-1-f2-(N
Q~,~k,~-N-tert-butoyc~rbonXfamino ethyrll-oyrrrolidine-3-carboxylic
s The title compound was prepared using the procedures described
in example 61, substituting propylamine for aqueous methylamine in
Example 61 B and di-tert-butyldicarbonate for isobutyryl chloride in
Example 61C. NMR (CD30D, 300 MHz} suggests presence of rotamers 8
0.81 (t, 3H, J=7), 1.2-1.5 (m, 11 H), 3.78 (s, 3H), 5.92 (dd, 2H, J=1,2),
~ 0 6.74 (d, 1 H, J=8), 6.84 (dd, 1 H, J=2,8), 6.92 (d, 2H; J=9), 6.99 (bd s,
1 H),
7.35 (d, 2H, J=9}. MS (DCtlNH3} m/z 527. Anal calcd for C2gH3gN2O7 : C,
66.14; H, 7.27; N, 5.32 . Found: C, 66.,05; H, 7.36; N, 5.15.
Example 313
~s traps-traps-2-(4-Methoxy-3-fluoronhenyrl)-4-(1.3-benzodtoxol-5-vl)
1-fN N-di(n-butyrilaminocarbonyrlmethvtl-Ryrrofidine-3-carboxlrlic acid.
The title compound was prepared using the methods described in
examples 1 and 43, using 4-methoxy-3-fluoro acetophenone in place of
4-methoxy acetophenone. m.p. 142-143 °C. NMR (CDC13, 300 MHz) 8 0.82
20 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.03-1.50 (m, 8H), 2.82 (d, J=l3Hz,
1 H), 2.90-3.13 (m, 4H), 3.20-3.50 (m, 3H), 3.39 (d, J=13H, 1 H), 3.55-3.65
(m, 1 H), 3.82 (d, J=1 OHz, 1 H), 3.87 (s, 3H), 5.91 (dd, J=2Hz, 4Hz, 2H),
6.72 (d, J=8Hz, 1 H), 6.83-6.91 (m, 2H), 6.99 (d, J=2Hz, 1 H), 7.06 (m, 2H).
Anal calcd for C29H3~N206F : C, 65.89; H, 7.06; N, 5.30 . Found: C, 65.82;
2s H, 7.13; N, 5.29.
Exam~,IP,~314
traps traps-2-~ProQyll-4- j.3-benzodioxol-5-yl)-1-(2-(N-orooYl_
oentanesulfonvl~minolethyl)pyrrolidine-3-carboxylic acid
Example 314A
Proovl ioentanesulfonamide
Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL
CHZC12 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82
mmol)
as and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mt_ CH2C12 under a
nitrogen
atmosphere. The reaction was stirred at 0 °C for 30 min, then at 25
°C for 4 h. The
.......".,., ~n ".,i ~f ~ n M ananiic NaH~I~~ anti 25 mL
SOIUt~Ul1 wd5 EJG~VUVmu vcv..cc." ~... ...~ ... .-- - ,
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CH2CI2. The organic phase was washed sequentially with 25 mL H20 and 25 mL
brine, then dried (Na2S04), filtered, and concentrated in vacuo to provide 739
mg
(3.83 mmot, 95%) of the title compound as a white solid. TLC (25% EtOAc-
hexane)
Rf 0.23; ~H NMR (CDCi3, 300 MHz) 8 0.92 (t, J=7Hz, 3H), 0.97 (t, J=7Hz, 3H),
1.28-
s 1.50 (br m, 4H), 1.52-1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (m, 2H),
3.08 (q,
J=6Hz, 2H), 4.10-4.23 (br m, 1 H); MS (DCI/NH3) mle 211 (M+NH4)+.
Example 31498
h I -4- n i x I- I -1- r h I - r I rr li in -
carboxvlate
The title compound was prepared according the procedure of Example 61 A,
substituting the compound of Example 948 for the pyrrolidine mixture.
,~"xampfe 314C
t5 ,~y~tl8l7c trana_~_(~~y~(1 3-..-.benZOdIOXQI-5-yl)-1-(2-(N-DfOI?yl-
~entanesutfonyll~,mino)eth~)Qyrrolidine-3-carboxvtate
A solution of the compound of Example 314A (6.6 mg, 34 pmol) in 0.1 mL
DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, 50
~mol). The resulting mixture was stirred at room temperature for 15 min, then
a
2o solution of the compound of Example 1898 (9.0 mg, 22 ~.mol) in 0.1 mL DMF
was
added, followed b y 0.5 mg of tetra-n-butylammonium iodide. The reaction was
sealed under argon and stirred at 60 °C overnight. The reaction was
concentrated
under high vacuum, and the residue was partitioned between 2 mL of saturated
aqueous NaHC03, 1 mL water and 5 mL EtOAc. The organic phase was washed
2s with 1 mL brine, dried by passing through a plug of Na2S04, and the
filtrate
concentrated in vacuo to an pit. The crude product was purified by preparative
TLC
(silica gel, 8 x 20 cm, 0.25 mm thickness, eluting with 20% EtOAc-hexane,
providing
8.4 mg (73%) of the title compound as a wax.
so . ExamQ a 314D
trar,~ tranG4:(1 3-benzodioxol-5-yl)-2-(ProDVI)-1-(2-(N-oroovl
pentanesulfonylamino)ethyl)oyrrotidine-3-carboxylic acid
The title compound was prepared according to the procedure of
Example 71C. ~H NMR (CDCl3, 300 MHz) s 0.88-1.00 (m, 9H), 1.20-1.55
35 (br m, 6H), 1.55-1.68 (m, 3H), 1.70-1.85 .(br m, 2H), 1.90-2.16 (br m, 2H),
2.84-3.26 (br m, 6H), 3.26-3.90 (br m, 6H), 5.95 (s, 2H), 6.76 (d, J=8Hz,
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1 H), 6.79 (m, 1 H), 6.93 (br s, 1 H); HRMS (FAB} calcd for C25H4~ N2OsS
(M+H)+ 497.2685, found 497.2679.
Exarr~~le 315
s r - 4- n t ~ 1 n i xol- I -1- N-
pro~,rt-N-dimethylsulfamoylaminolethyl)-ovrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound
was preapred as a white solid. m.p.59-61°C. 1 H NMR (CDCIs, 300MHz) 8
0..79 (t, J=7.5Hz, 3H}, 1.45(sextet, J=7.5Hz, 2H), 2.22-2.31 (m,1 H), 2.65(s,
6H), 2.70-2.79(m, 1 H), 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d,
J=9Hz, 1 H),3.55 (t, J=9Hz,1 H), 3.65(d, J=9Hz,1 H), 3.81 (s, 3H), 5.96(s,2H),
6.75(d, J=9Hz, 1 H), 6.83{d, J=9Hz, 1 H), 6.88(d, J=9Hz, 2H), 7.02{s, 1 H),
7.34(d, J=9Hz, 2H). MS (DCilNHs) m1e534 (M+H)+.
ExamQle 316
fans-traps-2-y4-Methoxohenyly-4-{1.3-benzodioxot-5-vll-1-f2-(N
r~~yrl-N-[4-methoxVD~, h2nyrl]sulfonyrlaminoloroovll-ovrrolidine-3
carboxvlic acid
~thvl traps-traps and cis-traps 2-~4-Methoxyr~ohenyrll-4-(1.3-benzodiox
5-yll -1-(3-brom~QyILoyrrolidine-3-carboxvlate
A 2:1 mixture of frans-traps and cis-traps ethyl 2-(4
methoxyphenyl)-4-(1,3-benzodiox-5-yl) -pyrrolidine-3-carboxyl ate
2s {4.00 g; prepared according to example 1C), 32 ml dibromopropane, and
200 mg sodium iodide, were heated at 100° for 1.25 hrs. The excess
dibromopropane was removed in vacuo and the residue was dissolved in
toluene. After shaking with potassium bicarbonate, the solution was
dried (Na2S04) and the solution concentrated. The residue was
ao chromatographed on silica gel elufing with 5:1 hexane:EtOAc. yielding
5.22 (98%) of the title compound.
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~xamnle 3168
h n - r - 4-M h . I -4- i
~yp~ (3 proQylaminoprooyl~yrrolidine-3-carboxvtate
The compound described in Example 316A (5.22 g) was heated at
s 80° for 2 hrs.with 35 ml. ethanol, 2.5 g. propylamine and 35 mg.
sodium
iodide. The solvents were removed in vacuo. The residue was dissolved
in toluene, shaken with potassium bicarbonate solution and dried
( Na~S04). The soilution was concentated in vacuum to give 4.96 g of the
title compound as an orange oil. This was used in the next step without
~o purification.
xampl_e 316C
traps tran~2 (4 Methoxph null-4-(1 3-benzodioxol-5-vll-1-f2-lN-
per Qyl N [4 methoxy~henyllsulfonylamino)oroovll-ovrrolidine-3-
ls sarboxkic acid
Using the method described in example 66, the compound prepared
in Example 3168 was reacted with 4-methoxybenzenesulfonyl chloride
in acetonitrile containing diisopropylethylamine. The resulting product
was chromatographed on silica gel (30% EtOAc in hexane), and
2o hydrolyzed to the title compound by the method of example 1D. NMR
(CDC13, 300 MHz) 8 0.83 (t, J=7Hz, 3H), 1.40-1.52 (m, 2H), 1.56-1.70 {m,
2H), 2.00-2.11 (m, 1 H), 2.40-2.51 (m, 1 H), 2.69-2.78 (m, 1 H), 2.84-3.03
(m, 4H), 3.19-3.34 (m, 2H), 3.48-3.59 (m, 2H), 3.80 {s, 3H), 3.86 (s, 3H),
5.95 (s, 2H), 6.74 (d, J=BHz, 1 H), 6.85 (d, J=BHz, 3H), 6.93 (d, J=SHz, 2H),
2s 7.02 (d, J=2Hz, 1H), 7.29 (d, J=BHz, 2H), 7.69 (d, J=BHz, 2H). Anal calcd
for C32H38N20aS : C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39; N,
4.45.
~,xam,ple 317
3o tr_ans traps-2 l4 Metho~hen~rll-4-(1 3-bertzodioxol-5-yll-1-f2-(N
~,~y~~r~Q, I nXlaminol r~ooyl)-oyrrolidine-3-carboxylic acid
Using the method described in example 66, the propylamino
compound prepared in Example 3168 was reacted with propanesulfonyl
chloride in acetonitrile containing diisopropylethylamine. The residing
ss product wias chromatographed on silica gel (30% EtOAc in hexane) and
hydrolyzed to the title compound by the method of example 1 D. N1~1R
(CDC13, 300 MHz) 8 0.85 (t, J=7Hz, 3H), 1.02 (t, J=7Hz, 3H), 1.47-1.60
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(m, 2H), 1.65-1.85 (m, 4H), 2.04-2.16 (m, 1 H), 2.42-2.57 (m, 1 H), 2.72-
3.11 (m, 5H), 3.25-3.41 (m, 2H), 3.50-3.62 (m, 2H), 3.80 {s, 3H), 5.85 {s,
2H), 6.72 .(d, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1 H), 7.30 (d,
J=9Hz, 2H). Anal calcd for C2gH3gN2O7S: C, 61.52; H, 7.01; N, 5.12 .
s Found: C, 6 i .32; H, 7.01; N, 5.0 i .
Example 318
,~r~»~ r~~j ~_2-~~-Fluoro-4-me,~ o~,yr~yl)-4-(i.3-benzodioxol-5-
-2 (N-~oovl-N-oentanesulfony,~laminolethvl)-ovrrolidine-3-
~ o carboxylic acid
Using the procedures described in Example 313 and Example 66,
the title compound was prepared as a white solid. m.p.66-68°C. 1 H NMR
(CDC13, 300MHz) S 0.81(t,J=7.5Hz, 3H), 0.89(t, J=7Hz, 3H), 1.26-1.35(m,
4H), 1.45(sextet, J=7.5Hz, 2H), 1.68-1.76(m, 2H), 2.25-2.33(m, i H),
zs 2.72-2.92(m, 5H), 2.97-3.12(m, 2H), 3.16-3.33(m,2H), 3.43(dd,
J=3Hz,J=9Hz,1 H), 3.53-3.60(m, 1 H), 3.66(d, J=1 OHz, 1 H), 3.88(s, 3H),
5.95(s, 2H), 6.74(d, J=BHz, 1 H), 6.82(dd, J=1 Hz,J=BHz,1 H), 6.92(t,
J=BHz,1 H), 6.97(d, J=1 Hz, 1 H), 7. i 2(d, J=BHz, 1 H), 7.18(dd,
J=1 Hz,J=l2Hz, 1 H). MS (DC1/NH3) m/e 579 (M+H)+.
Example 319
trans-traps-2-(4-Pvridinyll-4-~1.3-benzodioxol-5-yl)-1-fN.N-di(n
~~rl~minocarbonylmethyrll-ovrrolidine-3-carboxylic acid.
The title compound was prepared using the methods described in
2s examples 1 and 43, using methyl 3-oxo-3-(4-pyridyl)propanoate (J. Am.
Chem. Soc. 7 993, t t 5, 11705) in place of ethyl (4-
methoxybenzoyl)acetate. m.p. 131-132 °C. NMR (CDC13, 300 MHz) & 0.82
(t, J+7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50 (m, 8H), 2.90 (dd, J= 7Hz,
9Hz, 1 H), 2.97~(d, J=13Hz, 1 H), 3.00-3.25 (m, 4H), 3.32 (m, 1 H), 3.39 (d,
3o J=l3Hz, 1 H), 3.45-3.52 (m, 1 H), 3.67-3.78 (m, 1 H), 4.10 (d, J=9Hz, 1 H),
5.92 {dd, J=2Hz, 4 Hz, 2H), 6.75 (d, J=9Hz, 1 H), 6.90 (dd, J=9Hz, 2Hz, 1 H),
7.02 (d, J=2Hz, 1 H), 7.45 (d, J=BHz, 2H), 8.50 (d, J=8Hz, 2H). Anai calcd
for G27H3~N3~5 : C, 67.34; H, 7.33; N, 8.73 . Found: C, 67.39; H, 7.45; N,
a.si.
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~xamole 320
I -4- i I -1-
Rrcmvi N diethkaminocarbonvl~minolethvll-ovrrolidine-3-carboxylic
acid.
The title compound was prepared using the procedures described
in example 61, substituting propylamine for aqueous methylamine in
Example 61 B and diethylcarbamyl chloride for' isobutyryl chloride in
Example 61C. NMR (CD30D, 300 MHz) b 0.74 (t, 3H, J=7), 1.09 (t, 6H,
J=7}, 1.33 (m, 2H), 3.17 (q, 4H, J=7), 3.78 (s, 3H), 4.04 (m, 1 H), 5.93 (s,
~ 0 2H), 6.86 (d, 1 H, J=8}, 7.06 (dd, 1 H, J=2,8), 6.94 (d-, 2H, J=9), 7.04
(d, 1 H,
J=2}, 7.40 (d, 2H, J=9). MS (DCIINH3) mlz 526. Anal cafcd for
C29H39N3O6 . 0.1 TFA: C, 65.31; H, 7.34; N, 7.82 . Found: C, 65.33; H, 7.43;
N, 8.14.
is
~rans-traps-2-(,4-Methoxvoheny~,L4~ 1.3-benzodioxol-5-vl )-1-f 3.5-
dim t ~~ ridi ri- carbonxlmeth~l-oyrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described
in example 1. NMR {CD300, 300 MHz) shows mixture of isomers. 8 0.88
20 (d, 3H, J=7), 0.93 (d, 3H, J=7), 3.82 (s, 3H), 5.95 (s, 2H), 6.82 (d, 1 H,
J=8}, 6.89 (dd, 1 H, J=1,8), 7.00 d, 2H, J=9), 7.03 (m, 1 H), 7.47 (d, 2H,
J=9). MS {DCIINH3) mlz 495.
FxamRle 322
2s ~r an s-ar an r2 ~4 Methox~,mhenyrll-4-L1 3-benzodioxol-5-vl)-1-fN.N-
in n I 1 - r li in - x
The title compound was prepared using the procedures described
in example 1. NMR (CD30D, 300 MHz} suggests a mixture of isomers. 8
O.B3 {t, 6H, J=8), 1.27 (d, 6H, J=7), 1.6 (m, 2H), 3.79 (s, 3H}, 5.93 (s, 2H),
30 6.75 (d, 1 H, J=6}, 6.86 (d, 1 H, J=8), 6.94 (d, 2H, J=9}, 7.03 (d, 1 H,
J=2),
7.35 (d, 2H, J=9). MS (DCI/NH3) m/z 511.
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Exam$le 323
I- i
i m I- r
acid.
s The title compound was prepared using the procedures described
in example 1. MS (DCIlNH3) mlz 545. Anal calcd for C32HssN24s . 0.9
H20: C, 68.53; H, 6.79; N, 4.99 . Found: C, 68.56; H, 6.62; N, 4.71.
Exannnle 324
~o ~rans-traps-2-(4-Metho~yrohe XI_~(1.3-benz-odioxol-5-vl)-1-fN-(3
MethX'i[D~y -N-butlrlamino carbonylmeth~)-oyrrolidine-3-carboxylic
acid
The title compound was prepared using the procedures described
in example 1. NMR (CD30D, 300 MHz) d 0.88 (t, 3H, J=7), 1.2-1.5 (m, 4H),
~ s 2.31 (s, 3H), 2.8 (m, 2H), 3.14 (t, 1 H, J=10), 3.3 {m, 1 H), 3.44 (dd, 1
H,
J=5,10), 3.53 (m, 1 H), 3.60 (t, 2H, J=7), 3.79 (s, 3H), 3.82 (m, 1 H), 5.93
{s, ~2H), 6.74 (d, 1 H, J=8), 6.8-6.9 (m, 5H), 7.06 (d, 1 H, J=2), 7.09 (d,
2H,
J=9), 7.18 (d, 1 H, J=7), 7.27 (t, 1 H, J=7). MS (DCIINH3) mlz 545. Anal
calcd for Cg2H36N2~6 . 0.8 H20: C, 68.75; H, 6.78; N, 5.01 . Found: C,
20 68.70; H, 6.67; N, 4.85.
Exam~e 325
~ran° mans-4-(1 3-Benzodioxoi-5-v,f~-2-(benzyloxymethyl)-1-((N.N
dibutYaminoc rbonylmethvllRyrrolidine-3-~t ra boxvlic acid
E~xam~te 325A
h I r 4-1 n i x I- n I x m h I-1- NN- in-
b_~llyllam inocarbonyrlm~~hyiloyrrolidine-3-carboxvlate
The procedures of Example 1 A-1 D were followed, substituting ethyl 4-
3o benzyloxy-3-oxobutyrate for 4-methoxybenzoylacetate in Example 1 A, to
afford the
title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf 0.18; ~ H NMR
(CDCi3, 300 MHz) S 0.88 (t, J=7Hz, 6H), 1.17 {t, J=7Hz, 3H), 1.20-1.34 (br m,
4H),
1.40-1.56 (br m, 3H), 2.85 (t, J=BHz, 1 H), 2.98-3.30 (m, 5H), 3.39-3.60 (m,
3H), 3.64-
3.75 (m, 2H), 3.92 (d, J-14Hz, 1 H), 4.10 {two overlapping q, J=6.5Hz, 2H),
4.53 (s,
3s 2H), 5.91 (m, 2H), 6.69 (d, J=9Hz, 1 H), 6.77 (dd, J=1.5. 9Hz, 1 H), 6.91
(d, J=1.SHz,
1 H); MS (DCI/NH3) mle 553 (M+H)+.
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Fxamole 3258
I -1- N i
b~t~)a,. minocarbony~m~~t_flyl)Qyrrolidine-3-carboxylic acid
The title compound was prepared according to the procedure of Example
s 71C, as a colorless glass. TLC (5% MeOH-CH2CI2) Rf 0.13; 1H NMR (CDC13, 300
MHz) S 0.86 (t. J=7Hz), and 0.90 (t, J=7Hz, 6H total), 1.15-1.52 (br m, 8H),
2.96-3.35
(br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3, l3Hz, 1 H), 3.88-4.40 (br m,
6H), 4.45
(AB, 2H), 5.90 (s, 2H), 6.70 (d, J=8Hz, i H), 6.84 (dd, J=1,8Hz, 1 H), 6.93
(d, J=1 Hz,
1 H), 7.28-7.39 (m, 5H); MS (DCIINH3) m/e 524 (M+H)+.
15
Exam i
~~rt~frans-4 (1 3 Benzodioxol-5-vi)-2-(~vdroxvmethyl)-1-j(N N-di(n
_b~ty~aminocarbonylmethy,~yrrolidine-3-carboxylic acid
~~-yttrans,trans-4-(,1 3-Benzodioxol-5~,rl~~hydf roxymethyrl)-1-(IN.N-di(n
~ty[)am inocarbonylmethyl)pyrrolidine-3-carboxvlate
The resultant product from Example 325A (128 mg, 0.232 mmol) and 25 mg
of 20% Pd(OH)2 on charcoal in 7 mL EtOH was stirred under 1 atm hydrogen for
48
2o h. The mixture was filtered through a plug of celite, and the catalyst was
washed
with 2 x 10 mL EtOH, then the combined filtrate and washes were concentrated
under reduced pressure to afford the crude product. Purification by flash
chromatography (40%EtOAc-hexane) provided the title compound.
Example 3268
has franc-4-y 3-Benzodioxol-5-yll-2-(h, dy roxymethvl)-1-((N.N
di{butyl)aminocarl~r~ylmethy!)ovrrolidine-3-carboxr~rlic acid
The title compound was prepared according to the procedure of Example
71 C.
(Example 327
I - - N-m h I I -1- N N- i n-
bsty~aminocarbony~methy_i},pXrrolidine-3-carboxylic acid
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Fly,~trans.traps--4-(1.3-Benzodioxol-5-y1l-2-~(, or yrl)~-1-(,(N.N-di(n
butyl)~aminocarbonyrlmet yJ[)~p~rrolidine-3-carboxyrlate
The title compound is made by selective oxidation (e.g. using the Swern
s oxidation with DMSO, oxalyl chloride, ethyldiisopropylamine or using the
Dess-
Martin periodinane) of the compound of Example 326A.
I~,xamole 3278
Ethyrl traps.traps--4-(1.3-Benzodioxol-5-yrl)-2-(O-tert-butyl~rooenoat-3-yl)-1-
{lN.N-
~ o di(n-but~~~aminocarbonylmeth~~)Ryrrolidine-3-carbo~,vlate
The title compound is produced by condensing the compound of Example
327A with tert-butyl triphenylphosphoranylidine acetate in CH2C12 solution.
Exan~nle 327C
~s ~tby~ traps.traps--4-(1.3-Benzodioxol-5-vl)-2-(~oenoic acid-3-y~-1-~(N.N-
di(n-
butyrl)aminocarbon I~_m_ethyrllpyrrrolidine-3-rarboxy,rlate
The title compound is produced by reacting the compound of Example 327B
with trifluoacetic acid in CH2C12 (1:1).
2o Examc~le 27D
Ethyl traps.traps--4-11.3-Benzodioxol-5-vl)-2-(N-methylorocenamid-3-yr~-1_(N.N
di(n-buty~)am inocarbonylmethy)pyrrolidine-3-carboxylate
The title compound is produced by condensing the compound of Example
327C with methylamine hydrochloride in the presence of a carbodiimide (e.g. N-
2s ethyl-N-(3-dimethylamino)propylcarbodiimide, DCC).
Example 327E
traps.franc--4-~(,~~enzodioxol-5-y~,)-2-(N-mP,~hvlnrooenamid-3-yl)-1-~ N-di,(n
bui~yl)aminocarbonylmethyll~yrrrolidine-3-carboxylic a~id_
3o The title compound is produced by reacting the compound of Example 327D
with lithium hydroxide according to the procedure of Example 71 C.
Examl to a 328
traps.traps--4-r(1.3-Benzodioxol-5-yl)-2-(1-hydroxy-2~oen-3-vl)-1-(N N-diL
35 ~ I aminocarbon~rlmethvl)wrrolidine-3-c~rboxvlic acid
*rB
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example 328A
I- I-1-NN- in-
~,~tvl)am inocarbonyrlmethy~)pyrrolidine-3-carboxvlate
The title compound is produced by reacting the compound of Example 327C
s with borane methyl sulfide complex.
example 3288
traps. traps--4-( 1.3-Benzodioxol-5-yrly-~ 1-hydrox-2-orooen-3-yl)~-1-(N . N-
di(n
~~yrf~minocarbon~rlmethyl}pyrrolidine-3-carboxylic acid
~ o The title compound is produced by condensing the compound of Example
328A with lithium hydroxide according to the procedure of Example 71 C.
~,le 329
traps.traps--4-~1.3-Benzodioxol-5-yl)-~N-benzyiaminomethyl)-~N.N-di(n-
~ s bui~yrl~aminocarbonylmethyrl)~yrrrolidine-3-carboxylic acid
Examr~le 329A
Ethyl traps.traps--4-(1.3-Benzodioxol-5-yl)-2-(N-benzyrlaminomethyl)~-1-(N.N-
di(n
butyrl)~aminocarbonyrlmethyrl,~~Ryrrrolidine-3-carboxylate
2o The title compound is produced by condensing the compound of Example
327A with benzylamine in the presence of sodium cyanoborohydride in ethanol.
Example 3298
traps.tram-4-(7.,~I~enzor,~joxol-5-yl~~-2 ~N-benzyrlaminomethvi)-1-(N.N-di(n
2s bul~yllaminocayQ,gyimethyl~~rrrolidine-3-carboxyrlic acid
The title compound is produced by reacting the compound of Example 329A
with lithium hydroxide according to the procedure of Example 71 C.
Example 330
so irans.traps--4-~(~.3-Benzodioxol-5-yrl)-2-(N-acetyrl-N-benzyrlaminomet~rl)-
1 jN.N-
~(i(n-butyl)~aminocarbonyrlmethyrl)Ryrrolidine-3-carboxylic acid
Exammle 330A
i I- I- -N- 1 min m h 1-1-
35 (N.N-di(n-bu yl)~aminocarbon~ li methyrl)pyrrrolidine-3-carboxvlate
The title compound is produced by reacting the compound of Example 3294A
with acetic anhydride in the presence of pyridine or triethylamine.
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WO 99/06397 PCT/US98/15479
-212-
Examc~le 3308
traps.traps--4~~.3-Benzodioxol-5-yl)-2-(N-acel~yl- -benzylaminomethyrl)-1-(N.N
dl(n-butyl)aminocarbonylmethy~,Qynrolidine-3-carboxylic acid
s The title compound is produced by reacting the compound of Example 330A
with lithium hydroxide according to the procedure of Example 71 C.
Exa~nle 33i
traps. tram-4-(1.3-Benzodioxol-5-yrl)-2-(ethy~yt)-1-(N. N-dE,(n-
~ o butyl)~aminocarbonyrlmeth)tl)pyrrrolidine-3-carboxyriic acid
Exam~nle 331 A
Ethyl traps.tram-4-~(1.3-Benzodioxol-5-vIL2_~ethynv~-1-(N.N-di(,n-
1 s b~t~~)aminocarbon, ly methyrllovrrolidine-3-carboxy to
The title compound is made by employing the procedure of Corey and Fuchs
(Tetrahedron Lett. 1972, 3769-72), using the compound of Example 327A.
Example 331 B
2o traps. traps--4-( 1.3-Benzodioxol-5-yl)-2-(eth~rnyl)-1-(N.N-di~n-
butyf)~aminocarbonylmethyllpyrr~olidin~ 3-carboxylic aci
The title compound is produced by reacting the compound of Example 331 A
with lithium hydroxide according to the procedure of Example 71C.
2s Exam I
traps.traps--4-(1.3-Benzodioxol-5-yrl)-2 ji-pent~~n_yl)~-1-~N.N-di n-
butyrl)aminocarbonylmethyl)pyrrrolidine-3-carboxylic acid
Exam I~A
3o Ethyrl traps.traps--4-l1.3-Benzodioxol-5-yr()-2-~ entynvi)-1~N N-di(n-
bu;yl)aminocarbonylmethyri)~pyrrolidine-3-cart,~2yrlate
The title compound is made by palladium-catalyzed coupling of the
compound of Example 206A and propyl iodide, employing the procedure of Taylor,
et. al. (J. Org. Chem. 1989, 54(15), 3618-24).
*rB
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-213-
Example 3328
~ra~~s traps--4-~ 3-Benzodioxol-5-y~-2-i(1-penty!~.yrl)-1-(N.N-di(n
b~tyl_)aminocarbonkmethvl)ovrrolidine-3-carboxylic acid
The title compound is produced by reacting the compound of
s Example 332A with lithium hydroxide according to the procedure of
Example 71 C.
Example 333
~~ans-irana2-~,4-Methoxohenvl?-4-(1 3-benzodioxol-5-vl)-1-f2-(2:6
dioxoQ,ioe,~ ridinyl) eth~l~-~yrrolidine-3-carboxylic acid -
The compound of example 61 A is added to a solution of the sodium
salt of glutarimide in dimethylformamide. After stirring 24 hours,
water is added and the mixture is extracted with ether. The resultant
glutarimide is hydrolyzed to the title compound by the method of
~ s example 1 D.
Example 334
rrans-tran~~-(4-Methox h nvl ~-4-~~1 .3-benzodioxol-5-yl)-1-f N.N-
di~>LaminocaL~nylmethxl]-Qyrrolidine-3-carboxylic acid.
2o The title compound was prepared according to the procedures
described in Example 1. ~ H NMR (300 MHz, CD30D} S 2.83 (dd, 1, J = 8.1,
9.7), 2.99 (d, 1, J = 15.4), 3.19 (t, 1, J = 9.5), 3.49 (d, 1, J = 7 5.3},
3.51
(dd, 1, J = 4.6, 9.5), 3.57 (m, 1 ), 3.79 (s, 3), 3.85 (d, 1, J = 9.5), 5.90
(s,
2), 6.71 (d, 1, J = 8.0), 6.84 (m, 3), 7.04 (d, 1, J = 1.6), 7.14-7.16 (m, 6),
25 7.19-7.34 (m, 6); MS (DCIINH3) m!z 551; Anal Calcd for
C33H3oN2~s~0.65H20Ø35C2H50COCH3: C, 69.77, H, 5.77, N, 4.76. Found:
C, 69.75, H, 5.55, N, 4.64.
Example 335
so traps-traps 2-(4-Methoxvnhenyl)-4-(1.3-benzodioxol-5-yrl)-1-(N.N-
diisooroQyrlaminocarbony methy_f]-~yrrolidine-3-carboxyrlic acid.
The title compound was prepared according to the procedures
described in Example 1. ~ H NMR (300 MHz, CD30D) b 0.95 (d, 3, J = 6.5),
1.24 (d, 3, J = 6.4), 1.30 (d, 6, J = 6.8), 2.85 (d, 1, J = 12.5), 3.04 (dd,
1,
s~ J = 8.1, 9.8), 3.14 (t, 1, J = 9.7), 3.32-3.55 (m, 3), 3.63 (m, 1 ), 5.92
(s,
2), 6.75 (d, 1, J = 8.1 ), 6.85 {dd, 1, J = 1.7, 8.1 ), 6.93 {m, 2), 7.02 (d,
1,
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
-214-
J = 1.7), 7.35 (m, 2). MS (DCI/NH3} mlz 483. Anal Calcd for C27Hs4N20s
~ 0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52.
Example 336
irans,traps-2-(3-Fluoro-4-methoxyrhhenyrl)~-4-( 1.3-benzodioxol-5-yrty-
~2-N-~r_~vl-N-butar~esulfonvlar minx)ethyrl,)-pyrrrofidine-3-carboxyrlic
acid
Using the procedures described in Example 313 and Example 66,
the title compound was prepared as a white solid. m.p.65-66°C. 1 H NMR
(CDC13, 300MHz) 8 0.82(t, J=7.5Hz, 3H), 0.92(t, J=7.5Hz, 3H}, 1.34-
1.52(m, 4H), 1.72(quintet, J=7.5Hz,2H), 2.25-2.35(m,1 H), 2.72-2.94(m,
5H), 2.97-3.12(m, 2H}, 3.19-3.46(m, 2H}, 3.44(d, J=9Hz,lH), 3.53-
3.60(m, '1 H), 3.67(d, J=9Hz, 1 H), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz,
1 H), 6.82(d, J=BHz, 1 H), 6.92(t, J=9Hz, 1 H), 6.97(s, 1 H), 7.12(d, J=9Hz,
1 H), 7.18(d, J=12Hz, 1 H). MS (DCIINHs) mle 565 (M+H)+.
Exam !p a 337
Using methods described in the above examples, the compounds
2o disclosed in Table 1 can be prepared.
Table 1
R R R
"Z
~ I~
1. 2. 3.
CA 02297894 2000-O1-21
WO 99106397 PCT/US98/15479
-215-
Table 1 cost.
R R R
J
4. J
s. s.
~I
I N OH~~ H3CO.F OS.ON~ ~S.ON~
7. 8. 9.
os
0 0 0'' o
10. 11. 12.
o c
Or . s / I
I ~ s. ~
O .O
H5C0
14. 18.
13.
w i ~ w I .S!"~'~
o'o~ do
16. 17. 1 S.
oz
19. 20. 21.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98115479
-2~s-
Table 1 cont.
R R R
0
~
s~~ ~ cue:
~
o"''o 0 0 0
o
22. 23. 24.
H~
C0 F
H
3 a
~ O O
O~rO O O
25. 26. 27.
Fa~;~ FH2C~~S~~ FHZC~~S~
O O O O O O
28. 29~ 30.
FHzC. ~ FH2C'C~S I~.~ F2HG
F ~'~'O~ F2 O O FZ OH'.
31. 32. 33.
F2HC. ~ . N~ FCC. . N~/.~ F3C. ~~' t~,~.~
FZ p~' O F O ~~O F2 O O
34. 35. 36.
~S; ~ .S. F3C~,
O O ~ O O O
37. 38. 39.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
-217-
Table 1 cont.
R R R
F CO F3~
FsC~~~ w I ~ w I ..
On O ..'~J~O ~ O O
O
40. 41. 42.
Ha~ ~ ~ ~ N, N~ ~ N~ S.'N
Os~p~ O ~ O 04 O
43. 44. 45.
N I / N~ N
O
46. 47. 48.
N
49. 51.
50.
N N
O ~ ~[ TO
52. 53.
54.
55. 56. 57.
w.o~~ n.o ~ ~o
0 0 0
58. 59. 60.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98115479
-218-
Table 1 coot.
R R R
0
O
61. 62.
63.
0
64. 65. 66.
w
w
" ~ ~ °~ ~ ~ . °~ N
°
° °
67. 68. 69.
O O '~i N O
70. 7 i . 72.
°1(N~
o ~%~ o
73. 74. 75.
1
wN
0 0 0
76. 77. 78.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
-219-
Tabie 1 cont.
R R
H3C0
Ct~° ~ CI~° N
79. 80~ 81.
O N O N
~O~N~ ~ o ~ CI~
1IO
82. 83. 84.
~~N~/'~ /~°~Nw/'~ Ct'~°~N~
85. 86. 87.
0
88. 89. 90.
I I
° ° o
91. 92. 93.
~°~N~ ~° O N~ CI~° O N
'O'
94. 95~ 96.
*rB
CA 02297894 2000-O1-21
WO 99/06397 PCTILJS98/15479
- 220-
Table 1 cont.
R R R
J..
0 0
99.
97. 98.
o ~o 0
100. 101. 102.
~.'~lf'~'~
0 0
103. 104. 105.
W N II
p
0
106. 107, 1 OB.
CHs ~_ CH3
a Q' o
0
109. 110. 111.
"~'~ i v " ~ i '''l~ ~
0
112. 113. 114.
Cilia ~ C(Ha
W O.$~O ~ 1 i O ~O
O
115. 1 i 6. 117.
CA 02297894 2000-O1-21
WO 99/06397 PCTNS98/15479
-221-
Table 1 cont.
R
I, o
118. 119 120.
w
I, o I., o
121. 122. 123.
o I ~ ~'
F O F
F
124. 125. 126.
i~ o
c
128. 129.
127.
I ~ li ~ y
p~ 0
OCH3 OCH H~CO
3
130. 131. 132.
w
I I~ 0 0
o ~I ~I
133. 134. 135.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 222-
Table 1 cont.
R R R
p E ~ ,i
136. 137. ~ 38~
U\/~ N_ ~ ~SN~
O Oa Q ~ p O
139. i Q0. 141.
0 0 0 0 0 0
142. 143. 144.
Oy$.'O ~ Fa~.~ ~ OJ' O O
145. 146. 147.
~~~3
Ow O O O O O
148. 149. i 50.
H
FhGr NS~~ \ \ N
0 0 ~ ,N o ' ~ o
151. 152. 153.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98I15479
- 223-
Table 1 cont.
R R R
° I ~ '~'~ O
154. 155, 15s.
o ° -~ o
0
0
157. 158, 159.
I ~ ~ i ~,
I ° ~ o
160. 161. 162.
I
O O
i 63. 164. 165.
Fa~ ~ Faw~gf ~
O O FF O O O O
166. 167. 168.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
- 224-
Tabie 1 coot.
R R R
"1 Y Y
F3~0~~
O O O p O O
169. 170. 171.
0 0 0'"0 ~ o' o
172. 173. 174.
Y Y Y
Fad ~ ~./' Fa ~ ~/'' P~/'
S ~S.
O" 'O F F. O O
175. 176. 177.
_Y F _Y
F3~0 O O~~ F3~0 p'~'~'O~~ F3~,,~ ~
FF O p
178. 179. 180.
FawO~ ~/' F F O ~ H3C" I
O~. p ~ F3~
18i. 182. 183.
H~CO
C1~~~~ H3C~ ~ H3C'
O' O
184. d ° ~o" o~~
185. 186.
H~CO~ H3C~ H3C0
~~~O~~ Fa~~ ~/'~ Fa- F ' .~/'
O'SO
187. 1 g8. 189.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
-225-
Table 1 cont.
R R
,,w,,~~~ H CO~ F ~_3~
FaCv~g~~ Fa~° O .O
O O
190. 191. 192.
o G~i' s; ~ ~~ s,;
o' 0 0 0
193. 194. 195.
p p O~O ~ Fa~gO
196. 197.
198.
Fa~ ~~ ~
F~O~ ~y~0~ FaCv~
O~ ~O
199. 200.
201.
F
Fa~~ .~° ' f' G ~ Ct
202. ~ ° I
203.
204.
G
CI
° / ° I / O
205. 2~. 207.
CA 02297894 2000-O1-21
WO 99106397 PCT/tJS98115479
- 226-
Table 1 cont.
R R R
I ~''~ I ~'.,~ "
0
208. 209. 210.
ci
I o I~ ~ I~
211. 212. 213.
H
H
o I ~ ~ f o
214. 215. 216.
H/~ OH ~ H
\ r~
r~
I I ~ I\
0
217. 218. 219.
H
CF3 ~ CF3
I ~~ o I \ Nl~'~ o I \
O ~O
220. 221, 222.
CA 02297894 2000-O1-21
WO 99106397 PCTNS98/15479
- 227-
Table 1 coot.
R R R
~F3
~r~ O~~r~
223. ~4, X225.
CF
3
o I ~~: I~ ~~ !~
226. 227. 228'
I
0
229. 230. 231.
cF~~~ ci i
232. 233.
234.
ci
CF~ ~r~
jl~J O
235. 23fi. 237.
CA 02297894 2000-O1-21
WO 9910b397 PCTIUS98115479
- 228-
Table 1 cont.
R R R
I
o ~ o
238. 239.
240.
O I .~ I
O O
241.
242. 243.
F I/ ~.~ I
F O
245. 24fi.
F I ~.~ I ~~ F I
247. 248. 249.
I / O ( / O
F ~~ N~~f : N I
O
250. 251.
252.
CA 02297894 2000-O1-21
WO 99106397 PCTIUS98/15479
- 229-
Table 1 cont.
R R R
N N
''~'~ I ~ '''1r'.~ "
o ~ o ~ o
253. 254.
255.
N ~ r~
''l~' ~~~
I.N o
256. 257.
258.
259. 260. 261.
F F
i
2~, 263.
264.
I ~~,~
F N O F
265. 2ss. 2s~.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 230-
Table 1 coat.
R
Fa
~r ~r
I N I
268. 269. 270.
c
~'~ P I
O F
271.
272. 273.
N
' o I '~''~'
I
N O rL
274. F N
275.
276.
I ~~
N o I
I ~~
277.
278. 279.
~'lY~~t
I ~~ .N o
280. 282.
281.
CA 02297894 2000-O1-21
WO 99106397 PCTIUS98/15479
-231-
Table 1 cont.
R R R
p
283. 284. 285.
~ .N o
286.
287- 288.
N O
289. 290. 291.
i~~~ i~
292.
293. 294.
,~
~'~"N°' '
~N O ~N
295.
296. 297.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98115479
- 232-
Table 1 cont.
R R
''~N~'~ ,''~'"~
N O
298. 299. 300.
~r ,~
~N ''' o ' ~"' N "' or''
~gN O
301. 302. 303.
I ~"~'v
~N O ~N O
304. 305.
306.
~~N~ I ~ N
~N O
307. 308. 309.
p
~N O
310. 311. 312.
CA 02297894 2000-O1-21
WO 99106397 PCT/US98115479
-233-
Table 1 cont.
R R R
1
313. 314. 315.
°
316. 317. 318.
° ~,~-.~
'°
319.
320. 321.
0
322.
323. 324.
. '''~'~
r~ o
~g~ 326. 327.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 234-
Table 1 coot.
R R R
i
o ~ o
328~ 329. 330.
1
1 ~ 332. 333.
0
334. 335.
336.
r
o r,,~~ r
. o
337. 338. 339.
~ ~ N.~.~
~N ~N
340. 341. 342.
CA 02297894 2000-O1-21
WO 99106397 PC'T/EJS98/15479
- 235-
Table 1 cont.
R R R
N
343. 344. 345.
I ~1'"~'~
iN F iN
346. 347. 348.
I n~ N'~..,~ I
F
349. 350. 351.
F I ~~ I ~Y~.~ I ~'l1'~~
F F N
352. 353. 354.
N
I ~ ~~ I ~~ ~r~
N iN (
355. 356.
357.
*rB
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 236-
Table 1 coot.
R R R
N I ~~-~ i ~t'~,4
355. N
359. 360.
'~ I "h' ~ I ''~'~,~
iN
361. 362.
363.
N
I iN ~r~ I NyY~''~
iN
364. 365.
366.
N
I ~~'~ I ~Y~'~
N ~N I ,T
iN
367. 368.
368.
I i N I N '~' ( Y N~.r~r
~N
370. 371.
372.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 237-
Table 1 cont.
R R R
~N ~N
373.
374.
375.
376. 377. 378.
N ~N
379. 380. 381.
E
382. 383. 384.
385. 386. 387.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 238-
Table 1 coot.
R R R
I N
388.
389. 390.
I ~ ~~
'~ N
391. 392.
393.
I r~N'',.~
N ~/'~ ~/'~
394. 395.
396.
397. 398.
399.
00.
401. 402.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 239-
Table 1 cost.
R R
N w/' N
403. 404. 405.
40fi. 407. 408.
N..,.~
409. 410. -
411.
G
vl
4i2. 413.
414.
r
415. 416. 417.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 240-
Table 1 cont.
R R R
COOEt - _v 'COOEt
418. 419. 420.
'~ I'~
,~~ Nv 'COOEt Cv _NO
~COOEt
421. 422. 423.
I ~ I ~.~ I
~~ NO
z ~~ NO N
2 Op
424. 425. 426.
CN ~ CN I
~~
CN
427. 428. 429.
i
CN Oz Oz
430. 431. 432.
CA 02297894 2000-O1-21
WO 99/06397 PCTNS98/15479
-24'i-
Table 1 cont.
R R R
I .~ N~.~ ~~.~
o K~ I ~ °
2 °21~~~
433. 434. 435.
N
o °
436. 437. 438.
I o
439. 440. 441.
I ° 1 ~ I~ o
442. 443. 444.
I o I
o ~ ~ o
445.
446. 447.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 242-
Table 1 cont.
R R p
F~ ~ O
F
448. 449. 450.
w
F~ O F ~ / ~ ~ r~
F
451. 452. 453.
Me0 ~ M
MeOI v v ~~' Me0 I / r~
F~ O O
O
454. 455. 456.
Ma0 ~ Mep
~ Me0
Me0' v v ~ ~
Me0_ y v ~ ~
O ~ Me0
457. ° o
458. 459.
Me0 ~/~ Me ~ ~ Me0
MeO~ ~ MeO~ r~: w
Me0 r~
O
4so. 4s ~ . 4s2.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 243-
Table i cont.
R R R
~I - ~ ~
Ma0- v v ~ Me0 I ~ r~ MeO~ r~
463. 464. 465.
~(~ ~ ~~
Me0- v v r~ Me0_
466. 467- 468.
~I i
I
Moo ~ ,,~ I ~
M.o "~' ,~
0
469. 470. 47 i .
372. 473. 474.
I 1~
,~ ,~ I
475. 476. 477.
CA 02297894 2000-O1-21
WO 9910b397 PCT/US98/15479
- 244-
Table 1 cont.
R R R
ci
c~
cl ~'~ ~~
478. 0 479.
0
480.
ci
~ cl ~~ cl
c~~ ~ I ~ I ~
cl ~~ cl~~~
481. 482. ° o
483.
cl
cl i
cl ~'~~ c r~.,~
O O CI
484. 485. °
486.
F ~ F
~I ~ F
F '''~-~' I
F~ r~
° F r~
487. 488.
489.
F ~~ F ~J ' ~~ F W
F I ~ rC~ F' v v ~ F I ~ iL
490. 491. 492.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 245-
Table 1 cont.
R R R
F
~( F
F
493. 494. 0 495. ~
~'~' I
w
0
496. o
497. 498.
I
,~ .~
'''~'
0
499. 500. 501.
w w
I I I
,,,~'
502. 503. 504.
,4 I
M.o'
0
o~
505. 506.
507.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
- 246-
Tabte 1 cont.
R R R
I
MaO~~~ Me0 ~ I
Me0 r~
OMB O
OMe O . OMa O
508. 509.
510.
I
Moo ~ M~ ~ ,t I
Ma0 r~
OMo ~ OMe O
OMe
511. 512. 513.
Me0 Me
MaO~ ~~ ( ~ I ~'
OMa O OMe O OMe O
514. 515. 516.
Mo0 ~ Me0
M
t ~ I ~ ~: I
i
OMo O OMe
OMe
517. 518. 51 g.
Mo ~ Ma0
I ~ Me0
.~ y I
OMo O OMe
OMe O
520. 521.
522.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 247-
Table 1 cont.
R R R
Ma
H
I H i ~ H~'~ I H
Mop Ma0
0~ O
523. 524. 525.
Ma
I H
r~ Br ~ N~r~ Br
0../i. p I / ~O[
526. 527.
528.
Br~H~~ Br~ ~ gr~~~r
I ~o )I~i' . (~ 1~5(i
529. 530. 531.
Br
Br I ~.~r I f' Br , ~~,
O
532. 533. 534.
I w ~~
FO FO
535. 536. 537.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 248-
Table 1 cont.
R R R
I F I~ Fo I o r~
~F
538. 539.
540.
o I ~ ~ a I ~ .
540. 542. 543.
o B
B
544. 545. 546.
I "~'~ I w ~~.~ w ~.4
e~ ° a~ ° B I ~ o
547. 54g. 549.
a~~ F I ~ ,~~ I
c
F~ C1 °
550.
551. 552.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 249-
Tabie 1 cont.
R R R
"~' I
F CIO / CIO F~CIO
553. 554. 555.
I w ~.r:
F , ~O F / CIC F I / CIO
556. 557. 558.
8r~Br~~~ Br i
F F FF
559. 560. 561.
Br
Br y r~
Br
O
F
562. 563.
564.
F
8r~~.~r Br i ~ 1~,~ CI I ~'~
FF'' ~~ ~O F ~O~ F / O
565. 566. 567.
*rB
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98115479
- - 250-
Tabie 1 cont.
R R R
F
F
CI ~ Ct I ~ ~~r C~ ~r~r
0 0O
F F
568. 569. 570.
F ~ F F
C
C~ ~ ~~ C1 ~r~r
O
O ~ O
F ~ F
57 ~ . 572. 573.
F
Ci~~~r
574. 575. 576.
0 0
° 578. 579.
577.
w
0
580. 581. 582. o
o ~
583. 584. 585.
CA 02297894 2000-O1-21
WO 99!06397 PCT/US98115479
-251-
Table 1 cont.
R R R
0 0 0
586. 587. 588.
592. 593. 594.
595. 596. 597.
598. 599. 600.
so 1. sot. so3.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 252-
Table 1 cont.
R R
H
° i '''~.~' I
l
0
604.
605. 606.
H
~ I ~.
i o ~ o
soy. soa. sos.
f
! H~'r'- I ~~. I ~.
° ° . o
610. 611. 612.
H H
l ~: l , '''~'~ p '''
0
613. 614' 615.
H H H
l I ~ N~, I ~
O
616. 617' 618.
H
H
l
y '~'~ . ~~ H
o l
619. ~ o
620.
621.
CA 02297894 2000-O1-21
WO 99/06397 PCTNS98/15479
- 253-
Tabie 1 cont.
R R R
o~ ~
H O H N II '
' ~ O '
O
622. 623, 624.
1 ~ ~ ~ I
o I~ 0 0
625. 626. 627.
J
H H
H
I i O i O
_ O
628. 629. 630.
0
O H
'''1~ I " ot'~
I ~~ o
631. 632. 633,
634. 635. 636.
o ~~ o
637. 638' 639.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 2 54-.
Table 1 cont.
R R R
0
%~ 0 0
640. ~1. 642.
0
0
643. 644 ~ 645.
0
0 0
- 646. 647.
ci I ~.~ c t ~.~
o ~ o ~ o
649. 650. 651.
I ~ ci ci
o I w .~ I w
o ~ o
652.
653. 654.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 255-
Table 1 cont.
R R R
655. 656. 657.
,~ I w
o I o 0
658. 659. 660.
I ''~ I I
o ~ o
661. 662. 663.
b b-
ss5. sss.
I ~~ i
o ~o ~o
ss7. s6a. sss.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
-256-
Table 7 cont.
R R R
I 1 '4 I
o a
670. 671. 672.
o I ~ o .4
F F I / O
673. 674.
675.
I '~ I '~
o i
F
s7s. 677 s78.
FI o I~ o
679. 680' 681.
682. 683. 684.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
- 257-
Table 1 cont.
R
w
1 1
0 0
O F
ss5. sas, ss7.
i ~ ~~
O F~ O I
O
688. 689.
690.
y
F~ . F~ O ~ O
691. 692. 693.
t
F~ ° E o ~ o
694. 695. 696.
H ~ H
Me0 ~~' Ma0 N'~r~
O O O
698. 699.
607.
CA 02297894 2000-O1-21
WO 99/06397 PCTlIJS98/15479
- 258-
Table 1 cont.
R R R
H
AAoO ' H ~ Me0 ' ~~ ~ H ~r
O Ma0
O O
701. 702.
700.
Moo "~~~ ~ ~ ,t
o ~ o
/F O
703. 704.
705.
pO ~FO O
706. 707. 708.
~~~'~ O r~
O O
709. 710. 711.
W ~~ F3C~S'~r~
O ~ O O'~O
712. 713. 714.
F3~,S: ~~
O O
715.
CA 02297894 2000-O1-21
WO 99/06397 - Q 59- PCT/US98/15479
~xamole 338
Using methods described in the above examples, compounds
comprising a parent structure selected from those disclosed in Table 2A
and an R substituent selected from those disclosed in Table 2B can be
s prepared.
Table 2A
F
F
1. L. 3.
F
~,COOH
R-
r \ O
4.
F
v. ...
7.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
-260-
Table 2A cont,
H~
~,.COOH
~ OCH3
OCH3
. _. ~ ~ . 12.
F F
~,,COOH
R-
OCH~
JCH3
t 3. 14. 15.
F
,,COON
R-
i
O
OCH3 OCHy
1 O.
17. 18.
H3 F
~COOH
20. ~ o
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
-261-
Table 2A coot.
CH3
~,,COOH ~'~H
R- R-
1
23. 0 24.
F
GI.
cv.
F
a
,,,COON
R-
F
w~
29. ~ 30.
28.
H3 F
,~COpH ~COOH
R-N
r r
31. ~ 32. 33.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
-262-
Table 2A cont.
CHI
MOM
~~H ~COOH R_ ,,.COON
R_ R_ ~ 1
1 I 36.
34. 35.
CH3
MOM
\ /
~,,COOH
",COON R-N O
R-
I
37. ~ I . 38. ~H3
MOM CHI
\ / \
,,"COON ~N ,.COON
~I
OCH
OCH3 42.
40.~ 41. _
OMOM OCH~
\ \ \ /
~COOH ",COON R- ,,.COON
R-N ~ 1 R' ~ ..
v1 v1 wI
OCH3
43. 44. 45.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98115479
- 263-
Table 2A cont.
F
CH3
\
xCOOH
~,COOH
R-
R- ~ 1 ~ - 1
\~ \!
47. 48.
\ / 1
~cooH ~cooH
R-
! ~ i
50. ~ 51.
1
R- ~..COOH ~ ~,,COOH
\ O f \
"" , 53. 54.
\~
~~H ~.COOH ~ ,,.COOH
R'
OCH3
3
55.0 56. i ~ F 57. ocH
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 2fi4-
Table 2A cont.
~~H ~COOH
R- R-
O
O
5s. so.
58.
,~COOH
R-
I \
62. vo.
61.
...
~,COOH ~ ,,.COOH
' \ OCH3
sa. ~ s5. ' o~H3 .....
v y
~,,COOH ~ ~,,COOH
r \ ~ \ 0
s7. ' o ss.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 265-
Table 2A cont.
,~cooH
F
F
71 . ~ F r ~.. vvn3
'\ / O~ COON
O~ COON
~_COOH
73. ~o~ r -~. 75.
CH3 OCH3 OCH3
\ O~ COON \ O~' COON \ / O~ COON
~~H R- ~,.COOH ~ ,,,COON
R-
! o I
! '~ ~ 77. ~ 78.
76.
CH3 CH3 .
O~ COON \ O~ COON
- ~,cooH ~ ~cooH
! F ! \ OCH3
~ F 8O. ' OCH3
*rB
CA 02297894 2000-O1-21
WO 99!06397 PCT/US98/15479
- 266-
Table 2A cont.
OCH3
NOH
O
,,COOH
r
83. o _ ..
CH3
OH
O~
~,COOH
R'
r F
7.
vv.
OCH~
CH3
NOH , O~OCH3
O
~COOH F ~ ~,,COOH
r \
r OCH3 .
OCH3
88. 89. 90.
93.
91.
CA 02297894 2000-O1-21
WO 99106397 PCT/US98115479
- 267-
Table 2A cont.
NOCH3
F
Ff-
'~ 3
'J' 7. w.n3 96.
F F F
~OCH3 ' ~ ~ CH3
,,.COOH ,,.COOH
R'
R- F
\ ~ ~ w
97. 98.
F F F
~OCH3 ' -NOCH3
~
~COOH r,,
COOH
F R' R-
F
~
1 101. ~ 102.
F
F
F
V 1113
103. l U4. ~ vv.
CA 02297894 2000-O1-21
WU 99106397 PCT/US98/IS479
-268-
Table 2A cont.
. ,,".,.
OCH3
111. JcH,
1 ~9. . . ".
",,COOH ,,,COOH
R R- ,.cooH
~,' i ~ v o
112. 113. 114.
R- ,~cooH R-N ,,~cooH
o)
115. 116.
,,cooH
R- ,~cooH
R-
118. 119. ' 120.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98115479
- 269-
Table 2A cont.
R- ,,cooH R_ ~.cooH R- ,,cooH
0
121. ~ o~ 122. 123. !
OCH3
,, COOH
R-
! w o
i
126.
125.
OOCH3 OOCH3
~COOH .,C~H R_ ,,.COON
R R ! ~ o
! ° ! v o~
0 128. ~ ° 129. ~ °
127.
/OCH3
,~COOH
~COOH R-
R-
132.
130. ,
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 270-
Table 2A cont.
~~3
~.cooH F
R-
o,
0
135.
133. ' "'~'
F
1:iti.
137.
H OCH~
3
~COOH ,~COOH
R-N
l ' N .-...
139. F 140. ' o
OCH3 OCH3
~,COOH ,a~H
R_ R_
H,co w ~
143. °"'
144.
CA 02297894 2000-O1-21
WO 99!06397 PCTlUS98115479
-271-
Table 2A coot.
OCH3 F
~,COOH
R- F
F
1
CH3
146. ~H3
145.
F F
1 / ~ /
~,.COOH ~ ~,.COOH
F ~ \ \ o
H3C0 I ~ OCH 1 i
s
148. 150.
149.
F F
,"COON
R- F
I ~
152.
OMOM
,.COON
I \
H3C0 ~' OCH
3
156.
154. 155.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
- 272-
Table 2A cont.
MOM
~,cooH F
R-N
F
I
158.
" °cH~ .
0
". ° 162.
161.
OCH3 H
a
OCH3
O~
,,COOH ~COOii
F ~N R-
w:n3 164. ~ F 165.
163.
..,.... 1~/. IDG7.
CA 02297894 2000-O1-21
WO 99106397 PCT/US98/15479
- 273-
Table 2A cont.
F F
H
K
..
169. ~O .
.... ~ r v.
F MOMO
~N.N ' ~ N .
~' N ~ ~ N
o I w
173. ' ~ 174.
! /L.
F
F
K
~ N
~~N
I~ F
177. ~~F
175. _
F
H
~N
s
w.n3 ~ OcH3
11 ts. 179. 18~.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98I15479
- 274-
Table 2A cont.
H
t NH
..... 182. ~ iVV.
MOMO
0 0 - ~ ~ ,p
r..
H S,CH3 R-~ H S.CH3
1 s~. ~0 18s.
~...
MOMO
~0..~ ~' ~~,0
~~,~.S.CH3 ~ ~ ~ S'CH3 ~ ~'CH3
H
l ~ ~ l ~
187. I o 188. ~ 0 189.
o't o p . . ~ osp
~ .,~ _
H ~CH3 ~~ ~H S.CS3 ~ H~ CH3
t 91. 192.
190.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98l15479
- 275-
Table 2A cont.
F
F MOM
1 ~ O~ O
O O
a0 ~~"~ N CH a
~~ S'CHa R_ ~~CH3 ~' H
~F
j '~\
F
193. 194. 195.
-' ~g,p ' ~oao
H ~'CH3 R- H'S~CHa R- J~H S.CHa
F ~ \ OCHa ' \ OCHa
i
196. 197. °cHa 198. °cHa
°~ a_o ~ ~ o o - ~ o, o
s
H'S CHa R- H~S.CHa R- H CFa
° ~\ °
i 99. ~ 200. °~ 201.
00 ~°°
p a z a ~ ~~ CH2CFa f~" H ~ H(CHa)z
H S' CH CH
O
202. ~ Q~ 203. ' ° 204.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98I15479
- 276-
Table 2A cont.
r"COOH ~ ~,,COOH
,,cooH l q o
' o, ' o~
I g
o- 206. 207.
205.
~Ha
N, CH3
~,COOH ~H
r
j \ ) ~O
p i
208. 209. 210.
y
0
212. ocH, 213. ocH~
zip. -
ocH, ~~ 5. "'"3 216. ocH
214.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
- 277-
Table 2A cont.
217. 218. 219.
221. 222.
220.
0
OCH3
223. 224. 225.
226. 227.
CA 02297894 2000-O1-21
WO 99106397 PCT/US98/15479
- 278-
Table 2A cont.
229. 230. 231. ocH,
232.
233. 234.
235. 236. 237.
ocH3 239. 240.
238.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US9$115479
- 279-
Table 2A cont.
241. 242. 243.
244. 245, ocH3 246.
248. 249.
247.
252. ocH3
250. 251.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
-280-
Tabte 2A cont.
F F F F
rpppH ~,COOH ~COOH
O ~ ~ O
253. 254. 255.
F
\ \
'~H fcooH
R' ~ o R'H
1 1 /~
257. 258.
~COOH fCOOH
R' '
O
z59. 2so. 2s i .
~COOH ~COOH ~,COOH
R' ' O R'N ' / / R' N , O
262. 263. 264.
~,COOH
R'
265. ~..... 267,
CA 02297894 2000-O1-21
WO 99106397 PCTIUS98115479
-281-
Table 2A cont.
268. 269. 270.
~COOH
R' \
273. "''"'
271. 272.
~COOH ,~H ~,COOH
\ ~ f1 \
o ~ / o
274. 275. 276.
fCOOH ~COOH ~CC~H
' R' t R'N
277. 278. 279 ,~.
*rB
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98115479
- 282-
Table 2A cont.
~,OOOH
~,COOH fCOOH
w
O ~ , O
280. ~cH'
281. 282.
~~H ~,COOH ~COOH
R- ~ O R. O
0 1 / / 1
283. 284, 285.
~COOH ~COOH ~COOH
R'
v ~
0
28s. 28~. ~~H3 2ss.
~COOH ~COOH ~COOH
~ O
R' ~ O R' 1 w O 1 / /
289. 290. 291.
~COOH ~COOH
y R' y
/ O
OCH3
292. 293. 294.
CA 02297894 2000-O1-21
WO 99106397 PCT/US98/15479
- 283-
Table 2A cont.
~COOH ~COOH
R'
1 R' 1 0 1
295. ~ 296. 297.
p" ~COOH rCOOH
R. ~ o R~ ~ o R_ ~t~
t 1 / 1~/
298' 2gg. 300.
~COOH ,,~H ~CC~OH
R' R' w ~N
1 / O 1
301. °~H' 302. 303.
v
COOH ~ ~.~H ,,COOH
_ R' r
R'N ~ R'N I / / N 1
~O
306.
304.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
-284-
Table 2A coot.
~COOH ,~~H
R
0
307. ocH 309.
308. z
1
~COOH ~CCiOH iCOOH
R R' ~ R_ ~ o
310. i ~ 1
311. 312.
~COOH O ~ COOH ~,COOH
R_ 1 w o R' 1,. ~ R_ ~ o~
i o 1
OCH3
313. 314. 315.
~CC?OH ,COOH ~,COOH
R 1 R' ~ ~ R' ..
316. 1~~ 1 i 7
317. 318.
,~cooH
rCOOH ~COOH
R, 1 i / R_ ~ o R_ ~ o ,
319. 320. 1 / 32 i .
CA 02297894 2000-O1-21
WO 99!06397 PCT/US98115479
- 285-
Table 2A cont.
.o t r
ICppH ICOOH ~,COOH
w ~ w
~ / O
322. °°H' 323. 324.
t ~ t cooH
I~H ICOOH r
O
t /
O
325. 32fi. 327.
t/
ICOOH ~,COOH
O
329. ocH,
328. .~~u.
~,COOH .COOH rCOOH
R" ~ R- t \ O R' v /
° 333.
331. 332.
IOOOH I~H ~,COOH
v ~ w
~O
334. 335. 33fi.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 286-
Table 2A cont.
'o
iCOOH
~C°OH ~,COOH
R'
' O
O ~ O ~ / /
337. 338, 339.
0
,~cooH r ~H ,COOH
1~- o R. R' ~.
1 t / ~ t / o
340. 341. 342. ocH3
~~H , ~COOH ~COOH
R. O
w ~ R'
O ~~ ~ / O
343. 344. 345.
0
~COOH ~,COOH
O R-
/ O
346. 347. Wig.
E
O
~ / o o. ° ~ / oo,~~
a Hs-CH3 ~H CH3
f;' ~O~
/ O ~ / O
349. ocH3 350.
351.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
-287-
Table 2A cont.
_ o - ~o
O Oi9-CH3 ~ O NS~CH3 ~ ~N~ CH3
' ~N ~-H H
H R. w O R' ~ Ov
R' ~ ~ / O ~ / O
O
ocH3 354. ocH3
352. ~ 353.
CH3
' / O
356. 357.
355. ocH3
OCH3
358. 359. 360.
o / ono
CH3 ~HS-CH3
H .~ a 4 .~ ~O_
- ~ . v--
362. 363.
av i .
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 288-
Table 2A cont.
H3C H~ . .,,_
/ o ;~g-CH' ° 4 o O °ss-CH3
~N ~ rS'CH3
H H ~ O.
R" 1 O R' I ,.. O ~O.
364. 365. 366.
H H3C Ha
3
O N~CH3 ~ / '~NH / ~~NH
,L.H
/ / ~ ~ /
367. 368. 369.
HOC
H~ H~
ty ~ / ~~ NH
~~NH ~ / ' NH I N
I ~'N
R' ~ R' ~ ~ ~ / O
O ~ / O
370. 371. 372.
v / ~~ ~ / ° °'s-cH / ° °;~~-cH
I' N1NH N a ~ N a
H H
R- w R- w
F ~ / O ~ / /
373. 374. 375.
CA 02297894 2000-O1-21
WO 99/Ob397 PCT/US98/15479
- 289-
Table 2A cont.
o mss. \ / o°'s-cH3 / ° °,
CH3 ~H ~H CH3
O ~ ~ O
376. 3n. 378.
° °r$CH \ / ° °'SrCH3 \ 'HNH
,L H / N
ft' ~. R' w F (~-
F
379. 380. 381.
Na~'l \ / N'nINH N%N
,~NNH /LAN ,' ~NH
R- R' ~~ R-
~ / ~ / O
382. 383. 384.
NH '~NH
' ~'NNH / N !~N
~ F
O ~ /
385. 386. 387.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 290-
Table 2A cont.
00
s
Ors" CH ~~NH ~ H CH3
~N ~ ~/~N O
R, H o~ R~ ~~o~ R' 1 0
~'' 0
388. 3gg, 390.
F Fa
3
~NH \ / ~COOH
/~N , COON
..O ~ 1 ~ / O
/ 0 393.
391. 392.
F3 F3 F3
\ /
~COOH sCOOH ~,COOH
R-N R'N w O F.;.N ~. O
O ~ / ~ ~ /
394. 395. 396.
OCH3
397. 398. 399.
CA 02297894 2000-O1-21
WO 99/06397 PCTNS98/15479
-291-
Table 2A cont.
F2CF3 FzCF3 F2CF3
~,COOH ~COOH ~,COOH
R. R. w. R- '
400. ~ 401. ~ 402.
403. 404. 405.
~COOH ~COOH
_ 1 '~ R' 1 '
407. 408.
40fi.
~,,COOH
~~H ~,COOH ~ ' O
R' F~' -w IV\~O
411.
409. 410.
f --/
~COOH ~COOH ,,,COON
1'
412. 413. 414.
CA 02297894 2000-O1-21
WO 99/06397 PCTIUS98/15479
- 292-
Table 2A cant.
-~o ~o
~COOH ~,COOH ~COOH
_
R. o R_K~~ R . 1
417:
415. 416.
~COOH ~,COOH ~COOH
R_ 1 0, R, 1 / o, R.
418. 419. 424.
~COOH ~H ~COOH
R.~ R..N ~ 1 R_nt 1
/ O
421. 422. 423.
rCOOH ,COOH rC00H
R_N O R'H
1 p O ~O
424. 425. 42fi.
f~H ,COOH sGOOH
R.N ~ R,.N ~ O
7 1
/O /o
427. 428. 429.
CA 02297894 2000-O1-21
WO 99/Ob397 PCTNS98/15479
- 293-
Table 2A coot.
~,COOH COOH
~~H O ~N O
R
430. 431. 432.
~o
~,COOH
~COOH ~COOH O
_N ~ O R_ .~ O R' w
R 1 / ~ > > ~ / o
433. 435.
434.
~o
~COOH ~,COOH rCOOH
R. o~
l R
436. 437. 438.
~,~H ~COOH
439. 440. 441.
~~H ~COOH ~COOH
O
R' ~ , ~ R 1 / O~ R.N~O
442. 443. ~4'
CA 02297894 2000-O1-21
WO 99106397 PCT/US98/i5479
- 2 94-
Table 2A cont.
~,COOH ~,COOH lCOOH
R-~l~°o
447 0.
445. 446.
,r~H dCOOH ~COOH
448. 450.
449.
O ~,COOH
~COOH ,~COOH
f3'
R'N~ R'N 1~ ' / O
O
451. 452. 453.
\ /
~,COOH
~ O
/ O
454. 455. 456.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 295-
Table 2A cont.
o~
0
~,COOH ~ COOH ~COOH
/ O , / O ' O
457. 458. 459.
0
0
~COOH ~COOH
jCOOH
O
w ~ w ~ w
O ~t,~'/ 'O ~ / O
~J- 461. 462.
460.
fcooH
1 0 0
463. 464. 465.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 2ss-
Table 28
R , R R
w
1. 2~ 3.
l
o g s~ ~'
4. 5.
6.
8. s.
°'1
°
10. 11. 12.
cW°~
0 0
13. 14. 15.
H3C / HOC
w I w N~.
p v ~' p O
1fi. 17. 18.
cW',s~ "~'~
~o~ os~''o 00
0
19. 20. 21.
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 297-
Table 2B cost.
R R R
H3C0.~ H3C
i ~ ~
'
'S.
p
O O
22. 23. 24.
~ 0~ F
H ~
'
H'O 3 s
N~ ~y/ ~O
~ O
O O
25. 26. 27.
F FH
N.
3 ~~0~ N~ z O~'O
FHzC~~
O
O
28. 29. 30.
FH ~ '
C.
/'
z N~ FzHC
F O~~O ~ FHzC. ~ C
~
Fz O O Fz O O
31. 32. 33.
z ~ N
F HC.~ F
.
~
_~
4$ F3~ a0'G~S,.'
O ~ ~
z0
F20~ O Fz0 O
34.
35. 36.
N
~ ~ ~
O ~ ..
O O
O O
! O
37. 38. 39.
N
S,.'N~ /~ . ~ S
'~' O
O O O
O
40. 41. 42.
*rB
CA 02297894 2000-O1-21
WO 99/06397 PCT/US98/15479
- 298-
Table 2B cont.
R R
F~
F3~a~r~ Fa~.~~ W I
O O O O O~' O
43. 44. 45.
F3~ H3 ~ (
.s; ~~
0 0 0 0
46. 47. 48.
w
o I~ o I~ o
49. 50. 51.
w
o I~ o
i~
52. 53. 54.
I~ ~ I~ ~ I~
F
F
55. 56. 57.
I
ci i ~ o
58. c~ 59. 60.
CA 02297894 2000-O1-21
DEMANDES OU BREVETS VOLUMlNEUX
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COMPREND PLUS D'UN TOME.
CECI EST LE TOME ~ DE
NOTE. Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
JUMBO APPL1CATIONSIPATENTS
THiS SECTION Of= THE APP~ICATION/PATENT CONTAINS MORE
THAN ONE VOLUME
THIS IS VOLUME ~ I - OF
NOTE: For additional volumes-pf~ase contact the Canadian Patent Ofific~ . I'
