Note: Descriptions are shown in the official language in which they were submitted.
CA 02563965 2006-10-31
6-0-SUBSTITUTED KETOLIDES HAVING ANTIBACTERIAL ACTIVITY
This application is a division of Canadian Application
No. 2,263,972, filed September 2, 1997.
Technical Field
This invention relates to novel semi-synthetic macrolides having antibacterial
activity, to pharmaceutical compositions comprising these compounds, and to a
medical
method of treatment. More particularly, this invention concerns to 6-0-
substituted
erythromycin ketolide derivatives, compositions containing these compounds,
and a method
of treating bacterial infections.
Background of the Invention
Erythromycins A through D, represented by formula (I),
CH3 NMe2
O HO..,
A
)6."1".0 C H3 .,. 3
Ho,.,, O CH3 Er ty hrom,ycin R' R`~
q A -OH -CH3
.= 12 H H B -H -CH3
H3C~ CH3 CH3 C -OH -H
,,,,D -H -H
cH3 0 H
O OH
CH3 OR"
(j)
are well-known and potent antibacterial agents, used widely to treat and
prevent bacterial
infection. As with other antibacterial agents, however, bacterial strains
having resistance or
insufficient susceptibility to erythromycin have been identified. Also,
erythromycin A has
only weak activity against Gram-negative bacteria. Therefore, there is a
continuing need to
identify new erythromycin derivative compounds which possess improved
antibacterial
activity, which have less potential for developing resistance, which possess
the desired
Gram-negative activity, or which possess unexpected selectivity against target
microorganisms. Consequently, numerous investigators have prepared chemical
derivatives
of erythromycin in an attempt to obtain analogs having modified or improved
profiles of
antibiotic activity.
-1-
CA 02563965 2006-10-31
.--
~
WO 98/09978 PCT/US97/15506
United States Patent 5,444,051 discloses 6-O-substituted-3-oxoerythromycin A
derivatives in which the substituents are selected from alkyl, -CONH2, -
CONHC(O)alkyl
and -CONHSO2alkyl. PCT application WO 97/10251, published March 20, 1997,
discloses 6-0-methyl 3-descladinose erythromycin derivatives.
European Patent Application 596802, published May 11, 1994, discloses bicyclic
6-
0-methyl-3-oxoerythromycin A derivatives. - - :
PCT application WO 92/09614, published June 11, 1992, discloses tricyclic 6-0-
methylerythromycin A derivatives.
Summary of the Invention
The present invention provides a novel class of 6-0-substituted erythromycin
derivatives possessing increased acid stability relative to erythromycin A and
6-0-methyl
erythromycin A and enhanced activity toward gram negative bacteria and
macrolide resistant
gram positive bacteria.
iS In one embodiment, the present invention provides compounds selected from
the
group consisting of
Y R Rc NMeZ
Z,,.. i
'1".
0
..,,. ,
HOr,.. 6
Ra O
O
(II)
R Rc NMe2
o ~~..
.,,. ,,
.6
O 'p O
O
O
(III)
-2-
CA 02563965 2006-10-31 Y _......... ___,.- --- _.-__.::. _.:..-.--..
~
WO 98l09978 PCT/(TS97115306
D
A \ R Re NMe2
o
1==.
o-C 6
0 o o
..,='
0
0
~ O
D H
r =
Ec
~=.. N R Rc
A
8~,,. O
N&=. 6
O O
O
O
O
(N-A)
S and
R R NMe2
I
O 'l=.
6
Rb o
.~~=''
0
O
(V)
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein
either,
Y and Z taken together define a group X,
wherein
X is selected from the group consisting of
(1) =0,
(2) =N-OH,
-3-
_.._.. ._:._.._.
CA 02563965 2006-10-31
. ~---.
WO 98/09978 PGT/US97113506
(3) =N-O-RI where Rl is selected from the group consisting of
(a) unsubstituted C1-C12-alkyl,
(b) CI-C12-alkyl substituted with aryl,
(c) CI-C12-alkyl substituted with substituted aryl,
(d) C1-C12-alkyl substituted with heteroaryl,
(e) CI-C12-alkyl substituted with substituted heteroaryl,
(f) C3-C12-cycloalkyl, and
(g) -Si-(R2)(R3)(R4) wherein R2, R3 and R4 are each independently selected
from CI-C12-alkyl and Aryl;
and
(4) =N-O-C(R5)(R6)-O-RI where R1 is as previously defined and R5 and R6 are
each independently selected from the group consisting of
(a) hydrogen,
(b) unsubstituted CI-C12-alkyl,
(c) CI-C12-alkyl substituted with aryl,
(d) CI-C12-alkyl substituted with substituted aryl,
(e) CI-C12-alkyl substituted with heteroaryl,
and
(f) CI-C12-alkyl substituted with substituted heteroaryl,
or
R5 and R6 taken together with the atom to which they are attached form a
C3-Ct2-cycloalkyl ring;
or,
one of Y and Z is hydrogen and the other is selected from a group consisting
of
(1) hydrogen,
(2) hydroxy,
(3) protected hydroxy,
and
(4) NR7R8 wherein R7 and Rg are independently selected from hydrogen and '
C1-C6-alkyl, or R7 and R8 are taken with the nitrogen atom to which they are
connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-
membered ring, may optionally contain a hetero'function selected from the
group
consisting of -0-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl)-, -N(aryl-C1-C6-alkyl-)-,
-N(substituted-aryl-Ci-C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-
)-,
-N(substituted-heteroaryl-CI-C6-alkyl-)-, and -S- or -S(O)n-, wherein n is 1
or 2,
Ra is hydrogen or hydroxy;
-4-
CA 02563965 2006-10-31
WO 98/0s978 PCT1US97/15306
Rb is selected from the group consisting of hydroxy, -O-C(O)-NH2 and
-O-C(O)-imidazolyl;
Rc is hydrogen or a hydroxy protecting group;
L is methylene or carbonyl, provided that when L is methylene, T is -0-,
T is selected from the group consisting of -0-, -NH-, and -N(W-Rd)-, wherein
W is absent or is selected from the group consisting of -0-, -NH-CO-, -N=CH-
and
-NH-;
and
Rd is selected from the group consisting of
(1) hydrogen,
(2) C1-C6-alkyl optionally substituted with one or more substituents selected
from the group consisting of
(a) aryl,
(b) substituted-aryl,
(c) heteroaryl,
(d) substituted-heteroaryl,
(e) hydroxy,
(f) C1-C6-alkoxy,
(g) NR7R8, wherein R7 and R8 are as defined previously,
and
(h) -CH2-M-R9
wherein M is selected from the group consisting of:
(i) -C(O)-NH-,
(ii) -NH-C(O)-,
(iii) -NH-,
(iv) -N=,
(v) -N(CH3)-,
(vi) -NH-C(O)-O-
(vii) -NH-C(O)-NH-
(viii) -O-C(O)-NH-
(ix) -O-C(O)-O-
(x) -0-, -5-
.CA 02563965 2006-10-31 ,
~
WO 98l09978 PGT/US97/15506
(xi) -S(O)n-, wherein n is 0, 1 or 2,
(xii) -C(O)-0-,
(xiii) -O-C(O)-,
and
(xiv) -C(O)-,
and
R9 is selected from the group consisting of:
(i) Cl-C6-alkyl, opdonally substituted with a substituent
selected from the group consisting of
(aa) aryl,
(bb) substituted-aryl,
(cc) heteroaryl, and
(dd) substituted-heteroaryl,
(ii) aryl,
iS (iii) substituted-aryl,
(iv) heteroaryl,
(v) substituted-heteroaryl,
and
(vi) heterocycloalkyl,
(3) C3-C7-cycloalkyl,
(4) aryl,
(5) substituted-aryl,
(6) heteroaryl,
and
(7) substituted-heteroaryl;
R is selected from the group consisting of
(1) methyl substituted with a moiety selected from the group consisting of
(a) CN,
(b) F,
(c) -CO2R10 wherein Rt0 is C1-C3-alkyl or aryl substituted C1-C3-allcyl,
or heteroaryl substituted C1-C3-a1ky1,
(d) S(O)nR10 where n is 0, 1 or 2 and R10 is as previously defined,
(e) NHC(O)R10 where R1Q is as previously defined,
(f) NHC(O)NR11R12 wherein R11 and R12 are independently
selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with
aryl, substituted aryl, heteroaryl, substituted heteroaryl,
-6-
CA 02563965 2006-10-31 --- - -=
WO 98109978 PCTlUS97/15506
(g) aryl,
(h) substituted aryl,
(i) heteroaryl,
and
(j) substituted heteroaryl,
(2) C2-Clp-alkyl,
(3) C2-C10-alkyl substituted with one or more substituents selected from the
group consisting of
(a) halogen,
(b) hydroxy,
(c) Cl-C3-alkoxy,
(d) C1-C3-alkoxy-C1-C3-alkoxy,
(e) oxo,
(f) -N3,
(g) -CHO,
(h) O-S02-(substituted C1-C6-a1ky1),
(i) _NR13R14 wherein R13 and R14 are selected from the group
consisting of
(i) hydrogen,
(ii) C VC 12-alkyl,
(iii) substituted Cl-C12-alkyl,
(iv) C1-C12-alkenyl,
(v) s ubstituted C 1-C 12-alkenyl,
(vi) C1-C12-alkynyl,
(vii) substituted CI-C12-alkynyl,
(viii) aryl,
(ix) C3-C8-cycloalkyl,
(x) substituted C3-C8-cycloalkyl,
(xi) substituted aryl,
(xii) heterocycloalkyl,
(xiii) substituted heterocycloalkyl,
(xiv) CI-C12-alkyl substituted with aryl,
(xv) CVC12-alkyl substituted with substituted aryl,
(xvi) CI-C12-alkyl substituted with heterocycloalkyl,
(xvii) Cl-C12-a1ky1 substituted with substituted heterocycloalkyl,
(xviii) Ct-C12-alkyl substituted with C3-Cg-cycloalkyl,
(xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl,
-7-
CA 02563965 2006-10-31 _ ....... ,..._ ~ ..
~
WO 98109978 PCT/US97/15606
(xx) heteroaryl,
(xxi) substituted heteroaryl,
(xxii) CI-C12-alkyl substituted with heteroaryl,
and
(xxiii) CI-C12-alkyl substituted with substituted heteroaryI,
or
R13 and R14 are taken together with the atom to which they are
attached form a 3-10 membered heterocycloalkyl ring which may be -.
substituted with one or more substituents independently selected from the
group consisting of
(i) halogen,
(ii) hydroxy,
(iii) C1-C3-alkoxy,
(iv) C1-C3-alkoxy-C1-C3-alkoxy,
(v) oxo,
(vi) CI-C3-alkyl,
(vii) halo-C1-C3-alkyl,
and
(vii) C 1-C3-alkoxy-C 1-C3-alkyl,
(j) -C02R1b wherein R10 is as previously defined,
(k) -C(O)NR11R12 wherein R1I and R12 are as previously defined,
(1) =N-O-R10 wherein RIO is as previously defined,
(m) -C-N,
(n) O-S(O)nR10 wherein n is 0, 1 or 2 and R10 is as previously defined,
(o) aryl,
(p) substituted aryl,
(q) heteroaryl,
(r) substituted heteroaryl,
(s) C3-C8-cycloalkyl,
(t) substituted C3-C8-cycloaLkyl,
(u) C1-C12-alkyl substituted with heteroaryl,
(v) heterocycloalkyl,
(w) substituted heterocycloalkyl,
(x) NHC(O)R10 where R10 is as previously defined,
(y) NHC(O)NR11R12 wherein R1 I and R12 are as previously defined,
(z) =N-NR13R14 wherein R13 and R14 are as previously defined,
(aa) =N-R9 wherein R9 is as previously defined,
-$-
CA 02563965 2006-10-31---
WO 98109978 PGT1US97/15506
(bb) =N-NHC(O)R10 wherein R10 is as previously defined,
and
(cc) =N-NHC(O)NRi 1RI2 wherein Ri 1 and R12 are as previously
defined;
(4) C3-alkenyl substituted with a moiety selected from the group consisting of
(a) halogen,
(b) -CHO,
(c) -C02R10 where R10 is as previously defined,
(d) -C(O)-R9 where R9 is as previously defined,
(e) -C(O)NR11R12 wherein R11 and R12 are as previously defined,
(f) -C=N,
(g) aryl,
(h) substituted aryl,
(ij heteroaryl,
(j) substituted heteroaryl,
(k) C3-C7-cycloalkyl,
and
(1) C1-C1,)-alkyl substituted with heteroaryl,
(5) C4-C10-a1kenyl;
(6) C4-Cl0,-alkenyl substituted with one or more substituents selected from
the
group consisting of
(a) halogen,
(b) C1-C3-alkoxy,
(c) oxo,
(d) -CHO,
(e) -C02R10 where R10 is as previously defined,
(f) -C(O)NRi1R12 wherein R11 and R12 are as previously defined,
(g) -NR 13R14 wherein R13 and R14 are as previously defined,
(h) =N-O-R10 where R10 is as previously defined,
(i) -C=N,
(j) O-S(O)nR14 where n is 0, 1 or 2 and R10 is as previously defined,
(k) aryl,
(1) substituted aryl.
(m) heteroaryl,
(n) substituted heteroaryl,
(0) C3-C7-cycloalkyl,
(p) Cl-C12-alkyl substituted with heteroaryl,
-9-
, ,...v....,_...__ .,::._
CA 02563965 2006-10-31'
,f-
WO 98/09978 PCT/1JS97/15506
(q) NHC(O)R10 where R10 is as previously defined,
(r) NHC(O)NR11R12 wherein R11 and R12 are as previously defined,
(s) =N-NR13R14 wherein R13 and R14 are as previously defined,
(t) =N-R9 wherein R9 is as previously defined,
(u) =N-NHC(O)R10 where R10 is as previously defined,
and - =
(v) =N-NHC(O)NR11R12 wherein R> > and R12 are as previously
defined;
(7) C3-C10-alkynyl;
and
(8) C3-C10-alkynyl substituted with one or more substituents selected from the
group consisting of
(a) trialkylsilyl,
(b) aryl,
] 5 (c) substituted aryl,
(d) heteroaryl,
and
(e) substituted heteroaryl;
and
= A, B, D and E, with the provision that at least two of A, B, D and E are
hydrogen, are
independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6-alkyl, optionally substituted with one or more substituents selected
from the group consisting of:
(i) aryl;
(ii) substituted-aryl;
(iii) heteroaryl;
(iv) substituted-heteroaryl;
(v) heterocycloalkyl;
(vi) hydroxy;
(vii) Cl-C6-alkoxy;
(viii) halogen consisting of Br, Cl, F or 1; and
(ix) NR7R8, wherein R7 and R8 are as previously defined;
(c) C3-C7-cycloalkyl;
(d) aryl;
-10-
CA 02563965 2006-10-31
WO 98/09978 PGT/US97/15506
(e) substituted-aryl;
(f) heteroaryl;
(g) substituted-heteroaryl;
(h) heterocycloalkyl; and
(i) a group selected from option (b) above further substituted with -M-R9,
wherein M and R9 are as previously defined;
or
any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken
together with the atom or atoms to which they are attached to form a 3- to 7-
membered ring optionally containing a hetero function selected from the
group consisting of-O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-Cj-C6-alkyl-)-,
-N(substituted-aryl-Cl-C6-alkyl-)-, -N(heteroaryl-Ci-C6-allcyl-)-,
-N(substituted-heteroaryl-C1-C6-alkyl-)-, -S- or -S(O)n-, wherein n is
1- or 2, -C(O)-NH-, -C(O)-NR12-, wherein R12 is as previously defined,
i5 -NH-C(O)-, -NR12-C(O)-, wherein R12 is as previously uzfined, and
-C(=NH)-NH-.
The present invention also provides pharmaceutical compositions which comprise
a
therapeutically effective arriount of a compound as defined above in
combination with a
pharmaceutically acceptable carrier.
The invention further relates to a method of treating bacterial infections in
a host
mammal in need of such treatment comprising administering to a mammal in need
of such,
treatment a therapeutically effective amount of a compound as defined above.
In a further aspect of the present invention are provided processes for the
preparation
of 6-0-substituted macrolide derivatives of Formula (II), (III), (IV), (IV-A)
and (V) above.
Detailed Description of the Invention
In one embodiment of the present invention are compounds having the formula
II,
Y R Rc NMe2
,i I
O 01~=.
Z",.
Ra O O
O
O
(II) o
-11-
.. ..z:A4 4i..,...:....... . .
CA 02563965 2006-10-31
~.^ r
WO 98/09978 pCT/US97/15506
wherein X, Y, R, Ra and Rc are as described previously.
A representative compound of formula II is the compound of Formula (II), Ra is
OH, Rc is benzoyl, R is allyl.
In a preferred embodiment of the compounds of formula II of the invention are
compounds wherein Ra is hydroxy and Rc is hydrogen.
In a more preferred embodiment of the compounds of formula II of the invention
are
compounds having the formula VIII,
X R NMe2
* 0 H 0l,,
''=.
H
H O O
0 0
VIII 0
wherein X is 0 or NOH, and R is as defined previously.
Compounds representative of this embodiment include, but are not lirnited to:
Compound of Formula (VIII): X is 0, R is allyl;
Compound of Formula (VIII): X is NOH, R is allyl.;
Compound of Formula (VIII): X is 0, R is propyl;
Compound of Formula (VIII): X is 0, R is -CH2CHO;
Compound of Formula (VIII): X is 0, R is -CH2CH=NOH;
Compound of Formula (VIII): X is NOH, R is -CH2CH=NOH;
Compound of Formula (VIII): X is 0, R is -CH2CN;
Compound of Formula (VIII): X is 0, R is -CH2CH2NH2;
Compound of Formula (VIIII): X is 0, R is -CH2CH2NHCH2-Phenyl;
Compound of Formula (VIII): X is 0, R is -CH2CH2NHCH2CH2-Phenyl;
Compound of Formula (VIII): X is 0, R is -CH2CH2NHCH(CO2CH3)CH2-Phenyl;
2.5 Compound of Formula (VIII): X is 0, R is -CH2CH2NHCH2-(4-pyridyl);
Compound of Formula (VIII): X is 0, R is -CH2CH2NHCH2-(4-quinolyl);
Compound of Formula '(VIII): X is 0, R is -CH2CH=CH-Phenyl;
Compound of Formula (VIII): X is 0, R is -CH2CH?CH2-Phenyl;
Compound of Formula (VIII): X is 0, R is -CH2CH=CH-(4-methoxyphenyl);
Compound of Formula (VIII): X is 0, R is -CH2CH=CH-(4-ch1orophenyl);
-12-
CA 02563965 2008-08-01
Compound of Formula (VIII): X is 0, R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (VIII): X is 0, R is -CH2CH2CH2OH.;
Compound of Formula (VIII): X is 0, R is -CH2C(O)OH;
Compound of Formula (VIII): X is 0, R is -CH2CH2NHCH3;
Compound of Formula (VIII): X is 0, R is -CH2CH2NHCH2OH;
Compound of Formula (VIII): X is 0, R is -CH2CH2N(CH3)2;
Compound of Formula (VIII): X is 0, R is -CH2CH2(1-morpholinyl);
Compound of Formula (VIII): X is 0, R is -CH2C(O)NI-I2;
Compound of Formula (VIII): X is 0, R is -CH2NHC(O)NH2;
Compound of Formula (VIII): X is 0, R is -CH2NHC(O)CH3;
Compound of Formula (VIII): X is 0, R is -CH2F;
Compound of Formula (VIII): X is 0, R is -CH2CH2OCH3;
Compound of Formula (VIII): X is 0, R is -CH2CH3;
Compound of Formula (VIII): X is 0, R is -CH2CH=C(CH3)2;
Compour,d of For;-i;ula ( V IITi): X is 0, R is -CH2CH2CH(CH3)CH3;
Compound of Formula (VIII): X is 0, R is -CH2CH2OCH2CH2OCH3;
Compound of Formula (VIII): X is 0, R is -CH2SCH3;
Compound of Formula (VIII): X is 0, R is -cyclopropyl;
Compound of Formula (VIII): X is 0, R is -CH2OCH3;
Compound of Formula (VIII): X is 0, R is -CH2CH2F;
Compound of Formula (VIII): X is 0, R is -CH2-cyclopropyl;
Compound of Formula (VIIl): X is 0, R is -CH2CH2CHO;
Compound of Formula (VIII): X is 0, R is -C(O)CH2CH2CH3;
Compound of Formula (VIII): X is 0, R is -CH2-(4-nitrophenyl);
Compound of Formula (VIII): X is 0, R is -CH2-(4-chlorophenyl);
Compound of Formula (VIII): X is 0, R is -CH2-(4-methoxyphenyl);
Compound of Formula (VIII): X is 0, R is -CH2-(4-cyanophenyl);
Compound of Formula (VIII): X is 0, R is -CH2CH=CHC(O)OCH3;
Compound of Formula (VIII): X is 0, R is -CH2CH=CHC(O)OCH2CH3;
Compound of Formula (VIII): X is 0, R is -CH2CH=CHCH3;
Compound of Formula (VIII): X is 0, R is -CH2CH=CHCH2CH3;
Compound of Formula (VIIl): X is 0, R is -CH2CH=CHCH2CH2CH3;
Compound of Formula (VIII): X is 0, R is -CH2CH=CHSO2-phenyl;
Compound of Formula (VIII): X is 0, R is -CH2C=C-Si(CH3)3;
Compound of Formula (VIIl): X is 0, R is -CH2C=_CCH2CH2CH2CH2CH2CH3;
Compound of Formula (VIII): X is 0, R is -CH2C-CCH3;
Compound of Formula (VIII): X is 0, R is -CH2-(2-pyridyl);
-13-
CA 02563965 2006-10-31
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WO 98/09978 PCT/US97/15506
Compound of Formula (VIII): X is 0, R is -CH2-(3-pyridyl);
Compound of Formula (VIII): X is 0, R is -CH2-(4-pyridyl);
Compound of Formula (VIII): X is 0, R is -CH2-(4-quinolyl);
Compound of Formula (VIII): X is 0, R is -CH2NO2;
Compound of Formula (VIII): X is 0, R is -CH2C(O)OCH3;
Compound of Formula (VIII): X is 0, R is -CH2C(O)-phenyl;
Compound of Formula (VIII): X is 0, R is -CH2C(O)CH2CH3;
Compound of Formula (VIII): X is 0, R is -CH2C1; -.
Compound of Formula (VIII): X is 0, R is -CH2S(O)2-phenyl;
Compound of Formula (VIII): X is 0, R is -CH2CH=CHBr;
Compound of Formula (VIII): X is 0, R is -CH2CH=CH-(4-quinolyl);
Compound of Formula (VIII): X is 0, R is -CH2CH2CH2-(4-quinolyl);
Compound of Formula (VIII): X is 0, R is -CH2CH=CH-(5-quinolyl);
Compound of Formula (VIII): X is 0, R is -CH2CH2CH2-(5-quinolyl);
Compound of Formula-(VIII): X is i~, R is -CH2CH=CH-(4-benzoxazo1y'1);
Compound of Formula (VIII): X is 0, R is -CH2CH=CH-(7-benzimidazolyl);
Compound of Formula (VIII): X is O, R is CH2-(3-iodophenyl);
Compound of Formula (VIII): X is 0, R is CH2-(2-naphthyl);
Compound of Formula (VIII): X is 0, R is CH2-CH=CH-(4-fluorophenyl); and
Compound of Formula (VIII): X is 0, R is CH2-CH(OH)-CN.
Preferred compounds of formula VIII are selected from the group consisting of:
Compound of Formula (VIII): X is 0, R is allyl;
Compound of Formula (VIII): X is 0, R is -CH2CH=CH-phenyl; and
Compound of Formula (VIII): X is 0, R is -CH2CH=CH-(3-quinolyl).
In one embodiment of the invention is a process for the preparation of 6-0-
substituted macrolide compounds having the Formula:
Y R Rc NMe2
Z i I
O O'".
Ra O O
O
O
(II) o
-14-
_ ..... . . _..~.. _... ...._ .
CA 02563965 2006-10-31
WO 98/09978 PCT/US97/15506
wherein
either,
Y, Z, Ra, Rc, and R are previously defined,
the method comprising:
(a) treating a compound having the formula
V H Rp NMe2
I
O 0~~..
~.,,. ~.
Ra 0 O
O O
H
O 'Q_Re
H3C-O
wherein RP is a hydroxy protecting group and V is =N-O-R1 or =N-O-C(R5)(R6)-O-
R1
wherein R1, R9 and R10 are as previously defined, with a base in an aprotic
solvent
followed bv treatment with an alkylating agent to give a compound having the
formula
v R Rp NMe2
O O~=..
Ra O O
O
O
H
O .O,Rp
H3C-O
wherein Ra and RP are as previously defined, V is =N-O-RI or =N-O-C(R5)(R6)-O-
R1
wherein R1, R5 and R6 are as previously defined, and R is the "alkyl group"
derived from
the corresponding alkylating agent;
(b) deprotecting the 2'- and 4"-hydroxyl groups to give a compound of the
formula
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WO 98/09478 PGT/US97nSS06
OH -
I H NMe2
N~ R
~0
~'~..
Ra 1 0 o
o
O
O H
O H
H3C-O
wherein Ra is as previously defined and R is the "alkyl group" derived from
the
corresponding alkylating agent;
(c) deoximation in the presence of acid in a suitable solvent to give the
desired
intermediate having the formula
O R H NMe2
r
O O'~..
q,, ,=
HO,,,
Ra O O
~~~
` 0,,' O
O
H
O "'O-H
H3C-O
(d) removing the cladinose moiety by hydrolysis with acid, and protecting the
2'.
hydroxyl group by treatment with a hydroxy-protecting reagent to give a 3-
hydroxy
erythromycin compound having the formula
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WO 98/09978 Pcr/US97n5506
0 R Rp NMe2
O
O '~..
..,, ~.
HO,,,
Ra O O
OH
0 ,and
(e) oxidizing the 3-hydroxy group, optionally deprotecting the 2'-hydroxyl
group, and
isolating the desired compound.
In a preferred embodiment of the process immediately above, in step (a) the
base is
selected from the group consisting of potassium hydroxide, cesium hydroxide,
tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium
isopropoxide, potassium tert but;,xide and potassium isobutoxide, the
alkylating agent is
selected from the group consisting of allyl bromide, propargyl bromide, benzyl
bromide, 2-
fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-
methoxybenzyl
bromide, a-bromo-p-tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate,
crotyl
bromide, 1-bromo-2-pentene, 3-bromo-l-propenyl phenyl sulfone, 3-bromo-l-
trimethylsilyi-l-propyne, 3-bromo-2-octyne, 1-bromo-2-butyne, 2-picolyl
chloride, 3-
picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline,
bromoacetonitrile,
epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate,
methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-
butanone,
bromo chloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-l-propene, allyl
0-
tosylate, 3-phenylpropyl-0-trifluoromethane sulfonate, and n-butyl-0-
methanesulfonate,
and the reaction is performed at a temperature from about -15 C to about 50
C for a period
from 0.5 hours to 10 days; in step (b) deprotection is accomplished by use of
acetic acid in
water and acetonitrile; and in step (c) the deoximating reagent is an
inorganic sulfur oxide
compound is selected from the group consisting of sodium hydrogen sulfite,
sodium
pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium
hydrosulfite,
sodium metabisulfite, sodium dithionate, potassium thiosulfate, and potassium
25- metabisulfite, or an inorganic nitrite salt in the presence of acid
selected from the group
consisting of sodium nitrite and potassium nitrite, and the solvent is
selected from the aroup
consisting of water, methanol, ethanol, propanol, isopropanol,
trimethylsilanol or a mixture
of one or more thereof: in step (d) the hydroxy protecting reagent is selected
from the group
consisting of a trialkysilyl halide, an acyl anhydride or an acyl halide; in
step (e), the
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WO 98/09978 PCT/US97/15506
oxidizing is selected from N-chlorosuccinimide-dimethyl sulfide and
carbodiimide-
dimethylsulfoxide, and the optional deprotection is carried out by stirring in
methanol.
In another embodiment of the present invention are compounds having formula
III,
O R (~ NMe2
I O~==
,,= "O
t~. T,=.. g .
O =~r0 O
O
O
(III) o
wherein R, Rc, L and T are as.described previously,
= t
Preferred compounds of formula III are those selected from the group
consisting of:
Compound of Formula (III); Rc is acetyl, L is CO, T is NH, R is -CH2CH=CH2;
Compound of Formula (III): Rc is acetyl, L is CO, T is NH, R is -CH2CH=CH-(3-
quinolyl);
Compound of Formula (III): Rc is benzoyl, L is CO, T is NH, R is -CH2CH=CH-(3-
quinolyl);
Compound of Formula (III): Rc is propanoyl, L is CO, T is NH, R is -CH2CH=CH-
(3-
quinolyl); and
Compound of Formula (III): Rc is ethylsuccinoyl, L is CO, T is NH, R is -
CH2CH=CH-
(3-quinolyl).
In a more preferred embodiment of the compounds of formula III of the
invention
are compounds having the formula IX.
O R NMe2
H O,
O ,..
.,,= "T
L '~=.
O 0 O
~~~=='
O
O
(I}{} O
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WO 98/09978 PCT/US97/15M6
wherein L, T, and R are defined above.
Compounds representative of this embodiment include, but are not limited to:
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH2;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-phenyl;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH2CH2-Phenyl;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-(4-chlorophenyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH2CH3.;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH2NH2.;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=NOH.;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH2CH2OH;
Compound of Formula (IX): L is CO, T is 0, R is -CH2F;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH2-phenyl;
} t5 Compound of rormula (IX): L is CO, T is O, R is--CH2CH2=(4-pyridyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH2-(4-quinolyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH(OH)CN;
Compound of Formula (IX): L is CO, T is 0, R is -CH(C(O)OCH3)CH2-phenyl;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CN;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-(4-methoxyphenyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-(4-fluorophenyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-(8-quinolyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH2NHCH2-phenyl;
Compound of Formula (IX): L is CO, T is 0, R is -CH2-phenyl;
Compound of Formula (IX): L is CO, T is 0, R is -CH2-(4-pyridyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2-(4-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is -CH2CH=CH-(4-pyridyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH2CH2-(4-pyridyl);
Compound of Formula (IX): L is CO, T is O. R is -CH2CH=CH-(4-quinolyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH2CH2-(4-quinolyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-(5-quinolyl);
Compound of Formula (IX): L is CO, T is O. R is -CH2CH2CH2-(5-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is -CH2CH=CH-(4-benzoxazolyl);
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-(4-benzimidazolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH?CH=CH2;
Compound of Formula (IX): L is CO, T is N`H, R is -CH2CH=CH-Phenyl;
Compound of Formula (IX): L is CO, T is N"H, R is -CH-?CH=CH-(3-quinoIyl);
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Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2CH3.;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NH2.;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NOH.;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2CH2OH;
Compound of Formula (IX): L is CO, T is NH, R is -CH2F;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2=phenyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2-(4-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH(OH)CN;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2-(4-quinolyi);
Compound of Formula (IX): L is CO, T is NH, R is -CH(C(O)OCH3)CH2-phenyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CN;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-chlorophenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-fluorophenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2CH2-(4-methoxyphenyl);
!5 Compourrd of Formula (IX): =L is CO; Tis iv`I-i, R is =CH2CH-=C1-1'=(4-
methoxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-chloro-6-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2CH2-(2-
chlorophenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-phenyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2-(4-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2CH,)-(4-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-fluoro-6-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2CH2-(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-cyano-6-
quinolyl);
. ( = .'
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2CH2-(5-quinolyl);
Compound of Formula (IX): L'is CO, T is NH, R is -CH2CH=CH-(4-benzoxazolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-benzimidazotyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-methoxy-6-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-(2-naphthyl);
Compound of Formula (IX): L is CO, T is N(CH3), R is -CH2CH=CH2;
Compound of Formula (IX): L is CO, T is N(CH3), R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is N(CH2CH2N(CH3)2), R is -CH2CH=CH2;
Compound of Formula (IX): L is CO, T is N(CH2CH2N(CH3)2), R is -CH2CH=CH-(3-
quinolyl);
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WO 98/09978 PCT/US97/15506
Compound of Formula (IX): L is CO, T is N(CH2CH=CH2), R is -CH2CH=CH2;
Compound of Formula (IX): L is CO, T is T is N(CH2CH=C-(3-quinolyl)), R is
-CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH-CH-(3-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-isoquinolinyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3,4-
methylenedioxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(8-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-indolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-chloro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3,4-
ethylenedioxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-nitrophenyl);
1,5 Compound of Formul.a (IX): L is CO, i is NH, R is -CH2CH -CH=(6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-nitroquinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-methyl-6-
quinolyl);
Compound of Formula (III): L is CO, T is NH, Rc is acetyl; R is -CH2CH=CH-(3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-isoquinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(7-nitro-6-
quinoxalinyl);
quinoxalinyl);
Compound of Fonnula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-amino-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(1,8-naphthyridin-3-
yl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-(acetylamino)-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-carbazolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-benzimidazolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(-3-hydroxy-2-(N-(2-
methoxyphenyl)amido)-7-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-quinoxalinyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-hydroxy-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-methoxy-3-
quinolyl);
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Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-nitro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-($-nitro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-carboxyl-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-fluoro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-methoxycarbonyl-
3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-aminocarbonyl-3-
.
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-cyano-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-bromo-6-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2C(O)H;
= :.._,>. _;-=
1S Compound of Formuia (ff): L is CO; T is NH, R is -,CHjCH21v"HCHZPfi6nyl`;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2CH2Phenyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2CH2CH2Phenyl;
Compound of Formula (IX): L is CO, T is NH, R is
-CH2CH2NH CH2CH2CH2CH2Phen yI;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2CH2CH2-
(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2(6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NO(phenyl);
Compound of Formula (IX): L is CO, T is Nl-l, R is -CH2CH=NOCH2(phenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NOCH2(4-NO2-phenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NOCH2(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH =NOCH2(2-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NOCH2(3-quinolyl);
Compound of Formula (TX): L is CO, T is NH, R is -CH2CH=NOCH2-(6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NOCH2-(I-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NOCH2-(2-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHOCH2-(phenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHOCH2-(4-NO?-phenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2C(O)-phenyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2C(O)-(4-F-phenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NNHC(O)phenyl;
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. _. ... _._.. .._ . _...._ :~ .
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WO 98/09978 PCT/US97J15506
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2CH2-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-(2-(3-
quinolyl)cyclopropyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C-C-H;
Compound of Formula (IX): L is CO, T is NH, R is -CH-_-)-C=C-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C-C-(6-nitro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C=C-phenyi;
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C=C-naphthyl;
Compound of Formula (IX): L is CO, T is NH, R is -CHi-C=C-(2-naphthyl) ;
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C~C-(6-methoxy-2-
naphthyl);
l0 Compound of Formula (IX): L is CO, T is NH, R is -CH,)-C=C-(6-chloro-2-
naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C=C-(6-quinolyl);
Compound of Formula (IX): L is CO, T is NZ-i, R is -CH2-C=C-(2-methyl-6-
quinolyl);
Compound of Formula (IX): L is CO, T is NH,.R is -CH2-C=_C-(5-(N-(2-
pyridyl) amin o)carbonyl)furanyl );
Compound of Formula (I~X): L is CO; T is iH, R is -CH~=C=C-( l=phenylethehyl);
Compound of Formula (IX): L is CO, T is NH, R is -CHi-C=C-Br;
Compound of Formula (IX): L is CO, T is tiII-1, R is -CH2-(2,2-dimethyl-l,3-
dioxolan-4-
yl);
Compound of Formula (IX): L is CO. T is NH, R is -CH2CH(OH)-phenyl;
20 Compound of Formula (IX): L is CO. T is N3-1, R is -CH2)CH(OH)CH2OH;
Compound of Formula (IX): L is CO, T is N'HNH2, R is -CH2CH=CH2;
Compound of Formula (IX): L is CO. T is NT-INH2, R is -CH2C'H=CH-(3-quinolyl);
Compound of Formula (IX): L is CO. T is NHNH2, R is -CH2CH2CH2-(3-quinolyl);
Compound of Formula (IX): L is CO. T is NH2, R is -CH?CH=CH-naphthyl;
25 Compound of Formula (IX): L is CO, T is ti-H2, R is -CH-_CH=CH-(3-(2-
furanyl)-6-
quinolyl);
Compound of Formula (IX): L is CO. T is NH2, R is -CH~CH=CH-(8-chloro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is'v-H2, R is -CH~CH=CH-(4-chloro-2-
trifluoromethyl-6-quinolyl):
30 Compound of Formula (IX): L is CO. T is \"1-12, R is -CH-)CH=CH-(9-
fluorenone-2-yl);
Compound of Formula (IX): L is CO. T is NH2, R is -CH-CH=CH-(6-benzoyl-2-
naphthyl);
Compound of Formula (IX): L is CO. T is.N`H2, R is -CHiCH=CH-(7-methoxy-2-
naphthyl);
35 Compound of Formula (IX): L is CO. T is N-f-12, R is -CH.7CH=CH-(3-phenyl-6-
quinolyl);
,
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Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(3-(2-pyridyl)-6-
quinolyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(3-(2-thiophenyl)-
6-
quinolyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(4-
methylnaphthyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(6-P-D-
galactopyranosyl-2-naphthyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(7-quinolyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(4-
fluoronaphthyl);
l0 Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(3-biphenyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(5-nitronaphthyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(4-
pyrrolylphenyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(6-methoxy-2-
naphthyl);
t5 Compound of Formula (IX): L is CO, T is N"iI2, R is -CHZC%1=CH=(3;5-
dichloropheriyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2-(3-iodophenyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2-(3-(2-furanyl)phenyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(6-hydroxy-2-
naphthyl);
20 Compound of Formula (IX): L is CO, T is N1-12, R is -CH2CH=CH-(6-(2-
bromoethoxy)-
2-naphthyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(6-(2-
(tetrazolyl)ethoxy-2-naphthyl),
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-naphthyl;
25 Compound of Formula (IX): L is CO, T is N.H, R is -CH2-C_=C-(2-
phenylethenyl);
i:.
Compound of Formula (IX): L is CO, T is NH, R is -CH2-CH=CH-(5-(3-isoxazolyl)-
2-
thiophenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-CH=CH-(1,3-dimethyl-2,4-
dioxo-5-pyrimidinyl); and
30 Compound of Formula (IX): L is CO, T is NH, R is -CH2-CH=CH-(5-(2-
pyridyl)aminocarbonyl-2-furanyl).
Preferred compounds of formula IX are those selected from the group consisting
of:
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH2;
35 Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-Phenyl;
Compound of Formula (IX): L is CO, T is 0, R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH2;
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Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-Phenyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is N(CH3), R is -CH2CH=CH2;
Compound of Formula (IX): L is CO, T is N(CH3), R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is N(CH2CH2N(CH3)2), R is -CH2CH=CH2;
Compound of Formula (IX): L is CO, T is N(CH2CH2N(CH3)2), R is -CH2CH=CH-(3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-naphthyl);
lo Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-
isoquinolinyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3,4-
methylenedioxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(8-quinolyl);
Compound of Formula (IX): L is CO, T is Nt-I, R is -CH2CH=CH-(6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2Cl-I=CH-(6-
nitroquinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-quinolyl); -
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-amino-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(1,8-naphthyridin-3-
YI);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-(acetylamino)-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-quinoxalinyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-hydroxy-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-methoxy-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-nitro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(8-nitro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-carboxyl-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-fluoro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-methoxycarbonyl-
3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-aminocarbony)-3-
quinolyl);
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WO 98/09978 PCT/US97/15506
Compound of Formula (IX): L is CO, T is NH, R is =CH2CH=CH-(6-cyano-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-bromo-6-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2CH2-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-(2-(3-
quinolyl)cyclopropyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C-C-H;
Compound of Formula (IX): L is CO, T`is NH, R is -CH2-C=C-(3-quinolyl);
Compound of Formula (IX): L is CO. T is NH, R is -CH2-C=C-(6-nitro-3-
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C=C-phenyl; =
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C-C-naphthyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C=-C-(2-naphthyl) ;
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C-C-(6-methoxy-2-
naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C=C-(6-chloro-2-
naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C C-(6-quinolyl);
Compound of Formula (IX): L is CO, T is N(NH2), R is -CH2CH=CH2;
Compound of Formula (IX): L is CO, T is N(NH2), R'is -CH2CH CFI=(3-quinolyl);
Compound of Formula (IX): L is CO, T is N(NH2), R is -CH2CH2CH2-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-naphthyl;
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(3-(2-pyridyl)-6-
quinolyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(7-quinolyl); and
Compound of Formula (IX): L is CO, T is NH, R is -CH2-CH=CH-(5-(3-isoxazolyl)-
2-
thiophenyl).
In another embodiment of the invention is a process for the preparation of 6-0-
substituted macrolide compounds having the Formula:
O R RP NMe2
I 0~=.
R H3C,'==
~ N... O
O
O
O
O
O
wherein R and RP
R is selected from the group consisting of
(1) methyl substituted with a moiety selected from the group consisting of
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WO 98/09978 tPCT/US97/YWW
(a) CN,
(b) F,
(c) -C02R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl,
or heteroaryl substituted C1-C3-alkyl,
(d) S(O)nR10 where n is 0, 1 or 2 and R10 is as previously defined,
(e) NHC(O)R10 where R10 is as previously defined,
(f) NHC(O)NR11R12 wherein R11 and R12 are independently
selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with
aryl, substituted aryl, heteroaryl, substituted heteroaryl,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl,
and
(j) substituted heteroaryl,
iS (21 C2-C10-alkyi,
(3) C2-C10-alkyl substituted with one or more substituents selected from the
group consisting of
(a) halogen,
(b) hydroxy,
(c) CI-C3-alkoxy,
(d) C1-C3-alkoxy-C1-C3-alkoxy,
(e) oxo,
(f) -N3,
(g) -CHO,
(h) O-S 02- (substituted C1-C6-alkyl),
(i) -NR13R 14 wherein R13 and R14 are selected from the group
consisting of
(i) hydrogen,
(ii) C1-C12-alkyl,
(iii) substituted C1-C12-alkyl,
(iv) C1-C12-alkenyl,
(v) substituted C1-C12-alkenyl,
(vi) C1-C12-alkynyl,
(vii) substituted C I-C 12-alkynyl,
(viii) aryl,
(ix) C3-C8-cycloalkyl,
(x) substituted C3-C8-cycloalkyl,
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WO 98/09978 PCT/US97/1596
(xi) substituted aryl,
(xii) heterocycloalkyl,
(xiii) substituted heterocycloalkyl,
(xiv) C1-C12-alkyl substituted with aryl,
(xv) C1-C12-alkyl substituted with substituted aryl,
(xvi) C1-C12-alkyl substituted with heterocycloalkyl,
(xvii) C1-C12-alkyl substituted with substituted heterocycloalkyl,
(xviii) C1-C12-alkyl substituted with C3-Cg-cycloalkyl,
(xix) C1-C12-alkyl substituted with substituted C3-Cg-cycloalkyl,
(xx) heteroaryl,
(xxi) substituted heteroaryl,
(xxii) C1-C12-alkyl substituted with heteroaryl,
and
(xxiii) C1-C12-alkyi substituted with substituted heteroaryl,
or
R13 and R14 are taken together with the atom to which they aie
attached form a 3-10 membered heterocycloalkyl ring which may be
substituted with one or more substituents independently selected from the
group consisting of
(i) halogen,
(ii) hydroxy,
(iii) C1-C3-alkoxy,
(iv) C1-C3-alkoxy-Ci-C3-alkoxy,
(v) oxo,
(vi) C1-C3-alkyl,
(vii) halo-C1-C3-alkyl,
and
(vii) C1-C3-alkoxy-C1-C3-alkyl,
(j) -C02R10 wherein R1O is as previously defined,
(k) -C(O)NR11R12 wherein Rll and R12 are as previously defined,
(1) =N-O-R10 wherein R10 is as previously defined,
(m) -C=N, (n) O-S(O)nR10 wherein n is 0, 1 or 2 and R10 is as previously
defined,
(o) aryl,
(p) substituted aryl,
(q) heteroaryl,
(r) substituted heteroaryl,
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WO 98/09978 PGT/US97/15506
(s) C3-C8-cycloalkyl,
(t) substituted C3-C8-cycloalkyl,
(u) C1-C12-alkyl substituted with heteroaryl,
(v) heterocycloalkyl,
(w) substituted heterocycloalkyl,
(x) NHC(O)R10 where R10 is as previously defined,
(y) NHC(O)NR11R12 wherein R11 and R12 are as previously defined,
(z) =N-NR13R14 wherein R13 and R14 are as previously defined,
(aa) =N-R9 wherein R9 is as previously defined,
(bb) =N-NHC(O)R10 wherein Ri0 is as previously defined,
and
(cc) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously
defined;
(4) C3-alkenyl substituted with a moiety selected from the group consisting of
1S (a) halogen,
(b) -CHO,
(c) -C02R10 where R10 is as previously defined,
(d) -C(O)-R9 where R9 is as previously defined,
(e) -C(O)NR11R12 wherein R11 and R12 are as previously defined,
(f) -C=N,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl,
(j) substituted heteroaryl,
(k) C3-C7-cycloalkyl,
and
(1) Ci-C12-alkyl substituted with heteroaryl,
(5) C4-C10-alkenyl;
(6) C4-C10-alkenyl substituted with one or more substituents selected from the
group consisting of
(a) halogen,
(b) C1-C3-alkoxy,
(c) oxo,
(d) -CHO,
(e) -C02R 10 where R 10 is as previously defined,
(f) -C(O)NR11R12 wherein R11 and R12 are as previously defined,
(g) -NR 13R14 wherein R13 and R14 are as previously defined,
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.~
t .
1
WO 98/09978 PCT/US97/15506
(h) =N-O-R10 where R10 is as previously defined,
(i) -C=N,
(j) O-S(O)nR1U where n is 0, 1 or 2 and RiO is as previously defined,
(k) aryl,
(1) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) C3-C7-cycloalkyl,
(p) Ci-C12-alkyl substituted with heteroaryl,
(q) NHC(O)R10 where R10 is as previously defined,
(r) NHC(O)NR11R12 wherein R11 and R12 are as previously defined,
(s) =N-NR13R14 wherein R13 and R14 are as previously defined,
(t) =N-R9 wherein R9 is as previously defined,
(ti) =N-NHC(O)R10 where R10 is as previously defined,
and
(v) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously
defmed;
(7) C3-C10-alkynyl;
and
(8) C3-C10-alkynyl substituted with one or more substituents selected from the
group consisting of
(a) trialkylsilyl,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl,
and
(e) substituted heteroaryl;
Re is H or W-Rd, wherein W is absent or is selected from the group consisting
of -0-,
-NH-CO-, -N=CH- and -NH-, and Rd is selected from the group consisting of
(1) hydrogen,
(2) C1-C6-alkyl optionally substituted with one or more substituents selected
from the group consisting of
(a) aryl,
(b) substituted-aryl,
(c) heteroaryl,
(d) substituted-heteroaryl,
(e) hydroxy,
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r
WO 98/09978 PCT/US97/106
(f) C1-C6-alkoxy,
(g) NR7R8 wherein R7 and R8 are independently selected from
hydrogen and C1-C6-alkyl, or R7 and R8 are taken with the nitrogen
atom to which they are connected to form a 3- to 7-membered ring
which, when the ring is a 5- to 7-membered ring, may optionally
contain a hetero function selected from the group consisting of -0-,
-NH-, -N(C1-C6-alkyl-)-, -N(aryl)-, -N(aryl-C1-C6-alkyl-)-,
-N(substituted-aryl-Cj-C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-
CZ-C6-alkyl-)-, -N(substituted-heteroaryl-Ct-C6-alkyl-)-, and -S- or
-S(O)n-, wherein n is 1 or 2,
and
(h) -CH2-M-R9
wherein M is selected from the group consisting of:
(i) -C(O)-NH-,
>5 (ii)
(iii) -NH-,
(iv) -N=,
(v) -N(CH3)-,
(vi) -NH-C(O)-O-
(vii) -NH-C(O)-NH-
(viii) -O-C(O)-NH-
(ix) -O-C(O)-O-
(x) -0-,
(xi) -S(O)n-, wherein n is 0, 1 or 2,
(xii) -C(O)-0-,
(xiii) -O-C(O)-,
and
(xiv) -C(O)-,
and
R9 is selected from the group consisting of:
(i) C1-C6-alkyl, optionally substituted with a substituent,
selected from the group consisting of
(aa) aryl,
(bb) substituted-aryl,
(cc) heteroaryl, and
(dd) substituted-heteroaryl,
(ii) aryl,
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WO 98/09978 PCIYUS97/15306
(iii) substituted-aryl,
(iv) heteroaryl,
(v) substituted-heteroaryl,
and
(vi) heterocycloalkyl,
(3) C3-C7-cycloalkyl,
(4) aryl,
(5) substituted-aryl,
(6) heteroaryl,
and
(7) substituted-heteroaryl;
the method comprising.
(a) treating a compound having the formula
o R Rp NMez
o~-..
.,,. o
HO O
Ol
O Z'
O
wherein R is as previously defined,RP is a hydroxy protecting group and Z' is
4"-hydroxy-
protected cladinose, with sodium hexamethyldisilazide and carbonyldiimidazole
to give a
compound having the formula
O R RP NMe2
O O'~=.
^ .
N IN O cH3 .I, O
~ %W='
O ~
O
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WO 98/09978 PGT/US97/lSW
(b) treating the compound from step (a) with a reagent selected from the group
consisting of ammonia, Re-NH2, hydrazine, substituted hydrazine,
hydroxylamine, and
substituted hydroxylamine to give a compound having the formula
O R Rp NMeZ
01".
R\ H3C"4=
O~Nil~.. 0 O
O
O , Z'
O
wherein Re is H or W-Rd, wherein W is absent or is selected from the group
consisting of
-0-, -NH-CO-, -N=CH- and -NH-, and Rd is as defined previousl_v,
(c) optionally treating the compound from step (b) wherein Re is H with an
alkylating
agent having the formula Rd-halogen, wherein Rd is as defined previously, to
give a
compound of the formula shown in step (b) wherein Re is W-Rd, W is absent and
Rd is as
defined previously;
(d) optionally treating the compound from step (b) wherein Re is W-Rd and W is
-NH-
and Rd is H, with an alkylating agent selected from the group consisting of Rd-
halogen,
wherein Rd is as defined previously, to give a compound of the formula shown
in step (b)
wherein Re is W-Rd, W is -NH- and Rd.is as defined above;
~ 20
(e) optionally treating the compound from step (b) wherein Re is W-Rd and W is
-NH-
and Rd is H, with an acylating agent selected from the group consisting of Rd-
C(CO)-
halogen or (Rd-C(CO)-0)2 to give a compound wherein Re is W-Rd, W is -NH-CO-
and Rd
is as defined above;
(f) optionally treating the compound from step (b) wherein Re is W-Rd and W is
-NB-
and Rd is H, with an aldehyde having the formula Rd-CHO, wherein Rd as defmed
above to
give a compound wherein Re is W-Rd, W is -N=CH- and Rd is as defined above;
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WO 98/09978 PCT/US97/15506
(g) removing the cladinose moiety by hydrolysis with acid to give a compound
having
the formula
O R Ra NMe2
O ~'..
Re\ HsC...,
N11... .,,O
O O
O
O
O " H
O
(h) oxidizing the 3-hydroxyl group; and
(i) optionally deprotecting, and isolating the desired compound.
_. . _ . ~ . .
In a preferred embodiment of the process immediately above, R is an allyl or
propargyl group substituted with a moiety selected from the group consisting
of 1-
phenylethenyl, 2-chlorophenyl, 2-fluorenyl, 2-methyl-6-quinolyl, 2-naphthyl, 2-
phenylethenyl, 2-quinolyl, 3-(2-furanyl)-6-quinolyl, 3-(2-pyridyl)-6-quinolyl,
3-quinolyl,
3-(2-thiophenyl)-6-quinolyl, 3-biphenyl, 3-bromo-6-quinolyl, 3-carbazolyl, 3-
chloro-6-
quinolyl, 3-cyano-6-quinolyl, 3-fluoro-6-quinolyl, 3-hydroxy-2-(N-(2-
methoxyphenyl)amido)-7-naphthyl, 3-iodophenyl, 3-methoxy-6-quinolyl, 3-
nitrophenyl, 3-
phenyl-6-quinolyl, 3-quinolyl, 4-benzoxazolyl, 4-carboxyl-3-quinolyl, 4-chloro-
2-
trifluoromethyl-6-quinolyl, 4-chlorophenyl, 4-fluoronaphthyl, 4-fluorophenyl,
4-
isoquinolinyl, 4-methoxyphenyl, 4-methylnaphthyl, 4-pyridyl, 4-pyrrolylphenyl,
4-
quinolyl, 5-(2-pyridyl)aminocarbonyl-2-furanyl, 5-(3-isoxazolyl)-2-thiophenyl,
5- ~=
benzimidazolyl, 5-indolyl, 5-isoquinolyl, 5-nitro-3-quinolyl, 5-nitronaphthyl,
5-(N-(2-
pyridyl)amino)carbonyl)furanyl, 5-quinolyl, 6-(acetylamino)-3-quinolyl, 6-(2-
(tetrazolyl)ethoxy-2-naphthyl, 6-(2-bromoethoxy)-2-naphthyl, 6-amino-3-
quinolyl, 6-
aminocarbonyl-3-quinolyl, 6-j3-D-galactopyranosyl-2-naphthyl, 6-benzoyl-2-
naphthyl, 6-
cyano-3-quinolyl, 6-fluoro-3-quinolyl, 6-hydroxy-2-naphthyl, 6-hydroxy-3-
quinolyl, 6-
methoxy-2-naphthyl, 6-methoxy-3-quinolyl, 6-methoxycarbonyl-3-quinolyl, 6-
nitroquinolyl, 6-quinolyl, 6-quinoxalinyl, 7-methoxy-2-naphthyl, 7-nitro-6-
quinoxalinyl, 7-
quinolyl, 8-chloro-3-quinolyl, 8-nitro-3-quinolyI, 8-quinolyl, 9-oxofluoren-2-
yl, 1,3-
dimethyl-2,4-dioxo-5-pyrimidinyl, 1,8-naphthyridin-3-yl, 3,4-
methylenedioxyphenyl, 3,5-
dichlorophenyl, naphthyl, and phenyl, and in step (b) the reagent is selected
from the group
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CA 02563965 2006-10-31
WO 9&M9978 PCT/US97/15506
consisting of ammonia and Re-NI-12; optional steps (c), (d) and (e) are
omitted; and in step
(g) the oxidizing reagent is selected from N-chlorosuccinimide-dimethyl
sulfide and
carbodiimide-dimethylsulfoxide; and in step (h) the optional deprotection is
carried out by
stirring in methanol.
In a more preferred embodiment of the process immediately above, R is an allyl
or
propargyl group substituted with a moiety selected from the group consisting
of 2-methyl-6-
quinolyl, 2-quinolyl, 3-(2-furanyl)-6-quinolyl, 3-(2-pyridyl)-6-quinolyl, 3-
quinolyl, 3-(2-
thiophenyl)-6-quinolyl, 3-bromo-6-quinolyl, 3-chloro-6-quinolyl, 3-cyano-6-
quinolyl, 3-
fluoro-6-quinolyl, 3-methoxy-6-quinolyl, 3-phenyl-6-quinolyl, 3-quinolyl, 4-
carboxyl-3-
quinolyl, 4-chloro-2-trifluoromethyl-6-quinolyl, 4-isoquinolinyl, 4-quinolyl,
5-isoquinolyl,
5-nitro-3-quinolyl, 5-quinolyl, 6-(acetylamino)-3-quinolyl, 6-amino-3-
quinolyl, 6-
aminocarbonyl-3-quinolyl, 6-cyano-3-quinolyl, 6-fluoro-3-quinolyl, 6-hydroxy-3-
quinolyl,
6-methoxy-3-quinolyl, 6-methoxycarbony.l-3-quinolyl, 6-nitroquinolyl, 6-
quinolyl, 7-
j 15 quinolyl, o-chloro-3-quinolyl,*8-nitro=3-quinotyl and 8-quinolyl.
In another embodiment of the invention is a process for preparing a compound
having the formula
iOR'O
N
O Rp NMe2
O'==.
R8\ H3C'1=
~N'f~~. O
O O
O
O
O
wherein Re is H or W-Rd, wherein W is absent or is selected from the group
consisting of
-0-, -NH-CO-, -N=CH- and -NH-, and Rd is as defined previously, and R10 is H
or Cl-
C3-alkyl, aryl substituted CI-C3-alkyl, or heteroaryl substituted CI-C3-alkyl,
the method comprising
(a) treating a compound having the formula
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CA 02563965 2006-10-31
WO 98/09978 rcT/Us97n5506
RP NMe2
O 1
O'".
Re H3C,''= "o
\
~~... ..,i O
O==3<
O O
O
O =
O
with ozone to give a compound having the formula
O
. , I
Rp NMe2
O
Re\ H3C''=.`O
NI~,..
O~ O
O
O
O
O
(b) treating the compound of step (a) with a hydroxylamine compound having the
formula
NH2-O-R10, wherein R10 is as previously defined; and
(c) optionally deprotecting, and isolating the desired compound.
In a preferred embodiment of the process immediately above, Re is H.
In another embodiment of the invention is a process for preparing a compound
having the formula
-36-
CA 02563965 2006-10-31
r
Wo 9sro999s Pcr/US97115506
R13
FIN ~
O ('RP NMe2
O
H3C''= 01~..
~
O=<N,.... O
O
O
0
0
wherein Re is H or W-Rd, wherein W is absent or is selected from the group
consisting of
-0-, -NH-CO-, -N=CH- and -NH-, and Rd is as defined above,
S' is the method comprising
(a) reductively aminating a compound having the formula
O
O RP NMe2
O'~=.
R3CII==
Nil... O
O
O
O
O
O
with an amine compound having the formula NH2-R13, wherein R13 is as
previously
defined; and
(b) optionally deprotecting, and isolating the desired compound.
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WO 98/09978 PCTlUS97115506
In another embodiment of the present invention are compounds having formula IV
D
EN R Rc NMe2
A
B''" ,''== o
~'~..
o Ni,.. 6
~0 0 _
0
o =
(N) o
wherein R, Rc, A, B, D and E are as defined previously.
In a more preferred embodiment of the compounds of formula IV of the invention
are compounds having the formula VII,
. . . D. .... _ . ~
E'~== N M e2
A N R
0 H 0.,,.
B '~~... `
O O O
O CH3
O
(VIII) 0
wherein A, B. D, E, and R are defined previously.
Compounds representative of the embodiment of formula VII include, but are not
limited to:
Compound of Formula (VII): A, B, D, and E are H, R is allyl;
Compound of Formula (VII): A. B, D, and E are H, R is -CH2CH2CH3;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2NH2;
Compound of Formula (VII): A, B, D. and E are H, R is -CH2CH=NOH;
Compound of Formula (VII): A. B, D, and E are H, R is -CH2CH2CH2OH;
Compound of Formula (VII): A, B, D, and E'are H, R is -CH2F;
Compound of Formula (VII): A, B. D, and E are H, R is -CH2CN;
Compound of Formula (VII): A, B. D, and E are H, R is -CH2CH(OH)CN;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2-phenyl;
Compound of Formula (VII): A, B, D, and E are H, R is -CH?-(4-pyridyl);
-38-
... ,~,
CA 02563965 2006-10-31
+_.. ~
WO 98109978 PCT/US9',/15506
Compound of Formula (VIl): A, B, D, and E are H, R is -CH2-(4-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-pyridyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-
chlorophenyl);
Compound of Formula (VII): A, B, D, and E=are H, R is -CH2CH=CH-(4-
fluorophenyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-
methoxyphenyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2CH2-phenyl;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-pyridyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2CH2-(4-pyridyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2CH2-(4-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(5-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2CH2-(5-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-
benzoxazolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-
benzimidazolyl);
} Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(8-
quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2NHCH2-phenyl;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2NHCH2-(4-
pyridyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2NHCH2-(4-
quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2NHCH(CH2-
phenyl)C(O)OCH3=
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2NHCH2CH2-(2-
chlorophenyl);
Compound of Formula (VII): A, B and E are H, D is benzyl, R is allyl;
Compound of Formula (VII): A is benzyl, B, D and E are H, R is allyl;
Compound of Formula (VII): A and E are phenyl, B and D and are H, R is allyl;
Compound of Formufa (VII): A is rriethyl, B, D and E are H, R is allyl;
Compound of Formula (VII): A and D are methyl, B and E arL- H, R is alIyl;
Compound of Formula (VII): A and E taken together is -CH2CH2CH2-, B and D are
H, R
is allyl;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(3-quinolyl);
and
Compound of Formula (VII): A, B, D, and E are H, R is 3-(3-quinolyl)propyl.
Preferred compounds of formula VII are those in the group consisting of:
3.5 Compound of Formula (VII): A, B, D, and E are H, R is allyl;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(3-quinolyl);
and
Compound of Formula (VII): A, B, D, and E are H. R is -CH2CH,7CH2-(3-quinolyl)
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WO 98/09978 PCT/US97/15506
In another embodiment of the invention is the process for preparing a compound
having the formula IV
D
N = R Rc NMez
,~ I I - . . .
O 1".
B,,,.
O O O
O
0
(IV) o
wherein Rc, R, A, B, D and E are as defined previously,
the method comprising:
_ ,..... . _ ~ ..
(a) treating a compound having the formula
O R Rc NMeZ
0~~..
~,,. .
HO,,, ~O
HO
,,",
O
O
(II) o
wherein R is as defined previously, and Rc is a hydroxy protecting group, by
treatment with
methanesulfonic anhydride in pyridine, then treating the methansulfonyl
derivative with an
amine base to give a compound having the formula
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CA 02563965 2006-10-31
WO 98/09978 PCT/US97/15506
Rc NMe2
O R
O'==.
O
HO
CH3 ~~`'=O
O
0
(b) treating the compound from step (a) with an alkali metal hydride base and
carbonytdiimidazole to give a compound having the formula
O R R` NMe2
! 01=,=
N
1 - ~ 'o
N CHs
~ ~~.=.
0 O
O
0
(c) treating the compound of step (b) with a dianline having the formula
D NH2
Er~,=
B'~. NH
A
2
wherein A. B, D and E are as defined previously, to give a compound having the
formula
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CA 02563965 2006-10-31
WO 98/09978 PCr/US97/15506
D NHz R` NMe2
E~~.. O R
01,.
B ,.. H3G... O
rp1,,. 6
O==< =.,tO O
O
O
O
O
(d) cyclizing the compound of step (c) with dilute mineral or organic acid,
optionally
deprotecting, and isolating the desired compound.
An alternate to the process described immediately above is that process
wherein
steps (c) and (d) are replaced by the steps (c)-(f) consisting of
. _ . . . .. .. . . .. .. .. ...... . . . . , ... .,.. i .
(c) treating the compound of step (b) with an amine having the formula
D Y
E ~,..
A
B"' NH
z
wherein A, B, D and E are as defined therein, and Y is hydroxy, to give a
compound having
the forrnula
D Y R R NMez
E ' Z O 0,,, B HP,..
O==< O O
O
00
O
O
(d) treating the compound of step (c) with triphenylphosphine and
diphenylphosphoryl
azide and diethylazodicarboxylate in tetrahydrofuran to give the analogous
compound of
wherein Y is N3, and removing the deprotecting group to give the analogous
compound
wherein Y is N3 and Rc is H;
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CA 02563965 2006-10-31
wO 98/09978 PCT/[JS97/15506
(e) treating the compound of step (d) with a reducing agent selected from the
group
consisting of triphenylphosphine-water, hydrogen with a catalyst, sodium
borohydride, and
dialkylaluminum hydride, to give the compound having the formula
D NH2 R ~-t NMep
E r... O
O O'~=.
,~
8,.. H3C##..
~N,J... O O
O
O
O
O ;and
(f) cyclizing the compound of step (e) with dilute mineral or organic acid,
and isolating
the desired compound.
In another embodiment of the present invention are compounds having formula IV-
A
D N.
N R Rc NMe2
o
O
6
O O O
0"'
O
0
(N-A) 0
1S wherein R, Rc, A, B, D and E are as defined previously.
In a preferred embodiment are compounds having formula IV-A wherein Rc is H,
and R, A, B, D and E are as defined previously.
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CA 02563965 2006-10-31
~ ..
WO 9&109978 Pcr/[rS9'1115506
In another embodiment of the present invention are compounds having formula V'
0. R R NMe2
I Q~=.
O
6
Rd o
O
O
(V) o
S wherein R, Rc and Rd are as defined previously.
In a preferred embodiment of the compounds of formula V of the invention are
compounds having the formula VI
CH3
O = R NMe2
~ H 0,,,
.
/
HO CH3 '1O O CH3
O CH3
O
CH3 CH3
(VI) 0
wherein R is as defined previously.
Compounds representative of compounds of formula VI include, but are not
limited
to:
Compound of formula (VI): R is -CH2CH2CH3,
Compound of formula (VI): R is -CH2CH=CH,
Compound of formula (VI): R is -CH2CH=CH-Phenyl,
Compound of formula (VI): R is -CH2CH2CH2-Phenyl,
Compound of formula (VI): R is -CH2CH=NOH,
Compound of formula (VI): R is -CH2CH2NH2,
Compound of formula (VI): R is -CH2CH2NHCH2-Phenyl,
Compound of formula (VI): R is -CH2CH2NHCH2-(4-pyrdidyl),
Compound of formula (VI): R is -CH2CH2NHCH2-(4-quinolyl),
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CA 02563965 2006-10-31
r
wo 9&W97s PcrIvS97/15SO6
Compound of formula (VI): R is -CH2CH(OH)CN,
Compound of formula (VI): R is -CH2CH2NHCH(CO2CH3)CH2-Phenyl,
Compound of formula (VI): R is -CH2CN,
Compound of formula (VI): R is -CH2CH=CH-(4-methoxyphenyl),
Compound of formula (VI): R is -CH2CH=CH-(4-chlorophenyl),
Compound of formula (VI): R is -CH2CH=CH-(4-fluorophenyl),
Compound of formula (VI): R is -CH2CH=CH-(3-quinolyl),
Compound of formula (VI): R is -CH2CH=CH-(8-quinolyl), and
Compound of formula (VI): R is -CH2CH2NHCH2CH2-(2-chlorophenyl).
Another embodiment of the invention is the process for preparing a compound
having the formula
O R Rc NMe2
o
fRb
O
O
(V) p
wherein R and Rc are as defined previously and Rb is selected from the group
consisting of
hydroxy, -O-C(O)-NH2 and -O-C(O)-imidazolyl;
the method comprising:
(a) treating a compound having the formula
O R R NMep
I 0~..
HO 0 O
O
O
O
wherein Rc is a hydroxy protecting group and R is as previously defined with a
reagent
combination selected from
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r
WO 98/09978 PGT/US97/15506
(1) an alkali metal hydride and a phosgene reagent selected from phosgene,
diphosgene and triphosgene under anhydrous conditions, followed by aqueous
base
catalyzed decarboxylation, and
(2) reaction with methanesulfonic anhydride in pyridine, followed by treatment
with
an amine base, to give the compound of formula V wherein Rb is hydroxy;
(b) optionally treating the 'compound of formula V of step (b) wherein Rb is
hydroxy with
an alkali metal hydride base and carbonyldiimidazole to give the compound of
formula V =
wherein Rb is -O-C(O)-imidazolyl;
(c) optionally treating the compound of formula V of step (a) wherein Rb is -O-
C(O)-
imidazolyl with an amine to give the compound of formula V wherein Rb is -O-
C(O)-NH2;
and
(d) optiorally_deprotecting and isolatIng the uesired-ccrrppunti,
Definitions
As used throughout this specification and the appended claims, the following
terms
have the meanings specified.
The terms "C1-C3-alkyl", "CVC6-alkyl',', and "C1-C12-alkyl" as used herein
refer to
saturated, straight- or branched-chain hydrocarbon radicals derived from a
hydrocarbon
moiety containing between one and three, one and six, and one and twelve
carbon atoms,
respectively, by removal of a single hydrogen atom. Examples of CI-C3-alkyl
radicals
include methyl, ethyl,. propyl and isopropyl, examples of C1-C6-alkyl radicals
include, but
are not Iimited to, methyl, ethyl, propyl, isopropyl, -z-butyl, tert-butyl,
neopentyl and n-
hexyl. Examples of CI-C12-allcyl radicals include, but are not limited to, all
the foregoing
examples as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-
docecyl.
The term "CI-C6-alkQxy" as used herein refers to an Cl-C6-alkyl group, as
previously defined, attached to the parent molecular moiety through an oxygen
atom.
Examples of C1-C6-alkoxy, but are not limited to, methoxy, ethoxy, propoxy,
isopropoxy,
n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term "C1-C12-alkenyl" denotes a monovalent group derived from a
hydrocarbon
moiety containing from two to twelve carbon atoms and having at least one
carbon-carbon
double bond by the removal of a single hydrogen atom. Alkenyl groups include,
for
3.5 example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-l-yl, and the like.
The tenn "C1-C12-alkynyl" as used herein refers to a monovalent group derived
from a hydrocarbon containing from two to twelve carbon atoms and having at
least one
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j'
WO 98/09978 ( PGT/I7S97/15506
carbon-carbon triple bond by the removal of a single hydrogen atom.
Representative
alkynyl groups include ethynyl, 2-propynyl (propargyl), I -propynyl and the
like.
The term "alkylene" denotes a divalent group derived from a straight or
branched
chain saturated hydrocarbon by the removal of two hydrogen atoms, for example
methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene,
and the like.
The term "CI-C3-alkylamino " as used herein refers to one or two C1-C3-allcyl
groups, as previously defined, attached to the parent molecular moiety through
a nitrogen
atom. Examples of C1-C3-alkylamino include, but are not limited to
methylamino,
dimethylamino, ethylamino, diethylamino, and propylamino.
The term "oxo" denotes a group wherein two hydrogen atoms on a single carbon
atom in an alkyl group as defined above are replaced with a single oxygen atom
(i.e. a
carbonyl group).
The term "aprotic solvent" as used herein refers to a solvent that is
relatively inert to
proton activity, i.e., not acting as a proton-donor. Examples include, but are
not limited to,
- i 15 hydrx.arbons; such as -hexane aici-tol.uere, fo-, exampie, halogenated
hydrocarbons, sucli
as, for example, methylene chloride, ethylene chloride, chloroform, and the
like, heteroaryl
compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone,
and ethers
such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known
to those
skilled in the art, and it will be obvious to those skilled in the art that
individual solvents or
mixtures thereof may be preferred for spccific compounds and reaction
conditions,
depending upon such factors as the solubility of reagents, reactivity of
reagents and
preferred temperature ranges, for example. Further discussions of aprotic
solvents may be
found in organic chemistry textbooks or in specialized monographs, for
example: Organic
Solvents Physical Properties and Methods of Purification, 4th ed., edited by
John A.
Riddick et a[., Vol. II, in the Techniques of Chemistry Series, John Wiley &
Sons, NY,
1986.
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 and the like. Aryl groups (including
bicyclic aryl
groups) can be unsubstituted or substituted with one, two or three
substituents
independently selected from loweralkyl, substituted loweralkyl, haloalkyl,
alkoxy,
thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo,
mercapto,
nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. ln addition,
substituted
aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term "C3-C12-cycloalkyl" denotes a monovalent group derived from a
monocyclic or bieyclic saturated carbocyclic ring compound by the removal of a
single
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CA 02563965 2006-10-31
r r
WO 98/09978 PCT/US97/15506
hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl,
bicyclo[2.2.1 ]heptyl, and bicyclo[2.2.2]octyl.
The terms "halo" and "halogen" as used herein refer to an atom selected from
fluorine, chlorine, bromine and iodine.
The term "alkylamino" refers to a group having the structure -NHR' wherein R'
is
alkyl, as previously defined, Examples of alkylamino include methyiamino,
ethylamino,
iso-propylamino and the like.
The term "dialkylamino" refers to a group having the structure -NR'R" wherein
R'
and R" are independently selected from alkyl, as previously defined.
Additionally, R' and
R" taken together may optionally be -(CH2)k- where k is an integer of from 2
to 6.
Examples of dialkylamino include, dimethylamino, diethylaminocarbonyl,
methylethylamino, piperidino, and the like.
The term "haloalkyl" denotes an alkyl group, as defined above, having one,
two, or
three halogen atoms attached thereto and is exemplified by such groups as
chloromethyl,
bromoethyl, trifluorarneihyl, arid the like.
The term "alkoxycarbonyl" represents an ester group; i.e. an alkoxy group,
attached
to the parent molecular moiety through a ca=bonyl group such as
methoxycarbonyl,
ethoxycarbonyl, and the like.
The term "thioalkoxy" refers to an alkyl group as previously defined attached
to the
parent molecular moiety through a sulfur atom.
The term "carboxaldehyde" as used herein refers to a group of formula -CHO.
The term "carboxy" as used herein refers to a group of formula -CO2H.
The term "carboxamide" as used herein refers to a group of formula -CONHR'R"
wherein R' and R" are independently selected from hydrogen or alkyl, or R' and
R" taken
together may optionally be -(CH2)k- where k is an integer of from 2 to 6.
The term "heteroaryl", as used herein, refers to a cyclic aromatic radical
having from
five to ten ring atoms of which one ring atom is selected from S, 0 and N;
zero, one or two
ring atoms are additional heteroatoms independently selected from S, 0 and N;
and the
remaining ring atoms are carbon, the radical being joined to the rest of the
molecule via any
of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl,
pyrrolyl,
pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl,
thiophenyl, furanyl, quinolinyl, isoquinolinyl; and the like.
The term "heterocycloalkyl" as used herein, refers to a non-aromatic partially
unsaturated or fully saturated 3- to 10-membered ring system, which includes
single rings
of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which may include
aromatic six-
membered aryl or heteroaryl rings fused to a non-aromatic ring. These
heterocycloalkyl
rings include those having from one to three heteroatoms independently
selected from
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WO 98/09978 PCT/US97115506
oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms may
optionally
be oxidized and the nitrogen heteroatom may optionally be quaternized.
Representative heterocycles include, but are not limited to, pyrrolidinyl,
pyrazolinyl,
pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl,
isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl.
Specific heterocycloalkyl rings considered useful in preparing compounds of
the
invention include: 3-methyl-4-(3-methylphenyl)piperazine, 3-methylpiperidine,
4-(bis-(4-
fluorophenyl)methyl)piperazine, 4-(diphenylmethyl)piperazine, 4-
(ethoxycarbonyl)piperazine, 4-(ethoxycarbonylmethyl)piperazine, 4-
(phenylmethyl)piperazine, 4-(1-phenylethyl)piperazine, 4-(1,1-
dimethylethoxycarbonyl)piperazine, 4-(2-(bis-(2-
propenyl)amino)ethyl)piperazine, 4-(2-
(diethylamino)ethyl)piperazine, 4-(2-chlorophenyl)piperazine, 4-(2-
cyanophenyl)piperazine,
4-(2-ethoxyphenyl)piperazine, 4-(2-ethylphenyl)piperazine, 4-(2-
fluorophenyl)piperazine,
4-(2-hydroxyethyl)piperazine, 4-(2-methoxyethyl)piperazine, 4-(2-
methoxyphenyl)piperazine, 4=(2-methylphenyl)piper-azir.e, 4-(2-
methylthiophenyl)piperazine, 4-(2-nitrophenyl)piperazine, 4-(2-
nitrophenyl)piperazine, 4-
(2-phenylethyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-
pyrimidinyl)piperazine, 4-(2,3-
dimethylphenyl)piperazine, 4-(2,4-difluorophenyl)piperazine, 4-(2,4-
dimethoxyphenyl)piperazine, 4-(2,4-dimethylphenyl)piperazine, 4-(2,5-
dimethylphenyl)piperazine, 4-(2,6-dimethylphenyl)piperazine, 4-(3-
chlorophenyl)piperazine, 4-(3-methylphenyl)piperazine, 4-(3-
trifluoromethylphenyl)piperazine, 4-(3,4-dichlorophenyl)piperazine, 4-(3,4-
dimethoxyphenyl)piperazine, 4-(3,4-dimethylphenyl)piperazine, 4-(3,4-
methylenedioxyphenyl)piperazine, 4-(3,4,5-trimethoxyphenyl)piperazine, 4-(3,5-
dichlorophenyl)piperazine, 4-(3,5-dimethoxyphenyl)piperazine, 4-(4-
(phenylmethoxy)phenyl)piperazine, 4-(4-(1, 1 -
dimethylethyl)phenylmethyl)piperazine, 4-(4-
chloro-3-trifluoromethylphenyl)piperazine, 4-(4-chlorophenyl)-3-
methylpiperazine, 4-(4-
chlorophenyl)piperazine, 4-(4-chlorophenyl)piperazine, 4-(4-
chlorophenylmethyl)piperazine, 4-(4-fluorophenyl)piperazine, 4-(4-
methoxyphenyl)piperazine, 4-(4-methylphenyl)piperazine, 4-(4-
nitrophenyl)piperazine, 4-
(4-trifluoromethylphenyl)piperazine, 4-cyclohexylpiperazine, 4-
ethylpiperazine, 4-hvdroxy-
4-(4-chlorophenyl)methylpiperidine, 4-hydroxy-4-phenylpiperidine, 4-
hydroxypyrrolidine,
4-methylpiperazine, 4-phenylpiperazine, 4-piperidinylpiperazine, 4-((2-
furanyl)carbonyl)piperazine, 4-((1,3-dioxolan-5-yl)methyl)piperazine, 6-fluoro-
1,2,3,4-
tetrahydro-2-methylquinoline, 1,4-diazacycloheptane, 2,3-dihydroindolyl, 3,3-
dimethylpiperidine, 4,4-ethylenedioxypiperidine, 1.2,3,4-
tetrahydroisoquinoline, 1,2,3,4-
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WO 98/09978 PCT/US97/15506
tetrahydroquinoline, azacyclooctane, decahydroquinoline, piperazine,
piperidine,
pyrrolidine, thiomorpholine, and triazole.
The term "heteroarylalkyl" as used herein, refers to a heteroaryl group as
defined
above attached to the parent molecular moiety through an alkylene group
wherein the
alkylene group is of one to four carbon atoms.
"Hydroxy-protecting.group", as used here.in, refers.to an easily removable
group
which is known in the art to protect a hydroxyl group against undesirable
reaction during
synthetic procedures and to be selectively removable. The use of hydroxy-
protecting
groups is well known in the art for protecting groups against undesirable
reactions during a
synthetic procedure and many such protecting groups are known, cf., for
example, T.H.
Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition,
John
Wiley & Sons, New York (1991). Examples of hydroxy-protecting groups include,
but are
not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl,
ethers such as
methoxymethyl, and esters including acetyl benzoyl, and the like.
The term. "ketone protecting.. group", as used hereinz refers tg an easily
removable
group which is known in the art to protect a ketone group against undesirable
reactions
during synthetic procedures and to be selectively removable. The use of ketone-
protecting
groups is well known in the art for protecting groups against undesirable
reactions during a
synthetic procedure and many such protecting groups are known, cf., for
example, T.H.
Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition,
John
Wiley & Sons, New York (1991). Examples of ketone-protecting groups include,
but are
not limited to, ketals, oximes, 0-substituted oximes for example O-benzyl
oxime, O-
phenylthiomethyl oxime, 1-isopropoxycyclohexyl oxime, and the like.
A the term "protected-hydroxy" refers to a hydroxy group protected with a
hydroxy
protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl,
triethylsilyl,
methoxymethyl groups, for example.
The term "protogenic organic solvent" as used herein refers to a solvent that
tends to
provide protons, such as an alcohol, for example, methanol, ethanol, propanol,
.,
isopropanol, butanol, t-butanol, and the like. Such solvents are well known to
those skilled
in the art, and it will be obvious to those skilled in the art that individual
solvents or
mixtures thereof may be preferred for specific compounds and reaction
conditions,
depending upon such factors as the solubility of reagents, reactivity of
reagents and
preferred temperature ranges, for example. Further discussions of protogenic
solvents may
be found in organic chemistry textbooks or in specialized monographs, for
example:
Organic Solvents Physical Properties and Methods of Purification, 4th ed.,
edited by John
A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley
& Sons, NY,
1986.
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CA 02563965 2006-10-31
The term "substituted aryl" as used herein refers to an aryl group as defined
herein
substituted by independent replacement of one, two or three of the hydrogen
atoms thereon
with Cl, Br, F, I, OH, CN, CI-C3-alkyl, Ci-C6-alkoxy, Ci-Cb-alkoxy substituted
with
aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro,
carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one
substitutent may be an aryl, heteroaryl, or heterocycloalkyl group. Also,
substituted aryl
groups include tetrafluorophenyl and pentafluorophenyl.
The term "substituted heteroaryl" as used herein refers to a heteroaryl group
as
defined herein substituted by independent replacement of one, two or three of
the hydrogen
f0 atoms thereon with Cl, Br, F, 1, OH, CN, CVC3-alkyl, Cl-C6-alkoxy, C1-C6-
alkoxy
substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino,
mercapto,
nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition,
any one
substitutent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term "substituted heterocycloalkyl" as used herein, refers to a
heterocycloalkyl
15 group, as defined-above, substituted by independentreplacement of orie; two
or three of the
hydrogen atoms thereon with Cl, Br, F, I,.OH, CN, Cl-C3-alkyl, Cl-C6-alkoxy,
Cj-C6-
alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino,
dialkylamino,
mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In
addition,
any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group.
20 Numerous asymmetric centers may exist in the compounds of the present
invention.
Except where otherwise noted, the present invention contemplates the various
stereoisomers
and mixtures thereof. Accordingly, whenever a bond is represented by a wavy
line, it is
intended that a mixture of stereo-orientations or an individual isomer of
assigned or
unassigned orientation may be present.
As used herein, the term "pharmaceutically acceptable salt" refers to those
salts
which are, within the scope of sound medical judgment, suitable for use in
contact with the
tissues of humans and lower animals without undue toxicity, irritation,
allergic response and
the like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically
acceptable salts are well known in the art. For example, S. M. Berge, et al.
describe
30 pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences.
66: 1-19 (1977).
The salts can be prepared in situ during the final isolation
and purification of the compounds of the invention, or separately by reacting
the free base
function with a suitable organic acid. Examples of pharmaceutically
acceptable, nontoxic
acid addition salts are salts of an amino group formed with inorganic acids
such as
34; hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or
with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric
acid, citric acid,
succinic acid or malonic acid or by using other methods used in the art such
as ion
-51-
CA 02563965 2006-10-31
exchange. Other phannaceutically acceptable salts include adipate, alginate,
ascorbate,
aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate,
camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,
gluconate,
hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate,
lactate, laurate, lauryl sulfate; mal-ate, maleate, malonate,
methanesulfonate, 2-
naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,
pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate,
sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate
salts, and the like.
io Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium,
calcium, magnesium, and the like. Further pharmaceutically acceptable salts
include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed
using
counterions such as halide; hydroxide, carboxylate, sulfate, phosphate,
nitrate, loweralkyl
sulfonate and aryl sulfonate.
lc As used herein, the term "pharrnaceutically acceptable ester"-refers to
esters which
hydrolyze in vivo and include those that break down readily in the human body
to leave the
parent compound or a salt thereof. Suitable ester groups include, for example,
those
derived from pharmaceutically acceptable aliphatic carboxylic acids,
particularly alkanoic,
alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl
moiety
20 advantageously has not more than 6 carbon atoms. Examples of particular
esters includes
formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term "pharmaceutically acceptable prodrugs" as used herein refers to those
prodrugs of the compounds of the present invention which are, within the scope
of sound
medical judgment, suitable for use in contact with the tissues of humans and
lower animals
25 with undue toxicity, irritation, allergic response, and the like,
commensurate with a
reasonable benefit/risk ratio, and effective for their intended use, as well
as the zwitterionic
forms, where possible, of the compounds of the invention. The term "prodrug"
refers to
compounds that are rapidly transformed in vivo to yield the parent compound of
the above
formula, for example by hydrolysis in blood. A thorough discussion is provided
in T.
30 Higuchi and V. Stella, Pro-drugs as Novel Delivery S sY temA, Vol. 14 of
the A.C.S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug
Design,
American Pharmaceutical Association and Pergamon Press, 1987.
35 Antibacterial Activitv
Representative compounds of the present invention were assayed in vitro for
antibacterial activity as follows: Twelve petri dishes containing successive
aqueous
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---_.......--...__._ __ .. ....,:....,. _ ...---~
CA 02563965 2006-10-31
>^^ r
WO 98/09978 f f f V/ PGT/US97/15506
dilutions of the test compound mixed with 10 mL of sterilized Brain Heart
Infusion (BIE)
agar (Difco 0418-01-5) were prepared. Each plate was inoculated with 1:100 (or
1:10 for
slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up
to 32
different microorganisms, using a Steers replicator block. The inoculated
plates were
incubated at 35-37 C for 20 to 24 hours. In addition, a control plate, using
BHI agar
containing no test compound, was prepared and incubated at the beginning and
end of each
test.
An additional plate containing a compound having known susceptibility patterns
for
the organisms being tested and belonging to the same antibiotic class as the
test compound
was also prepared and incubated as a further control, as weIl as to provide
test-to-test
comparability. Erythromycin A was used for this purpose.
After incubation, each plate was visually inspected. The minimum inhibitory
concentration (MIC) was defined as the lowest concentration of drug yielding
no growth, a
slight haze, or sparsely isolated colonies on the inoculum spot as compared to
the growth
control. The results of this assay, shown below in Table 2 demonstrate the
antibacterial
activity of the compounds of the invention.
-53-
CA 02563965 2006-10-31
wo 98/09rs PCrrtls97nsso6
Table I
Antibacterial Activitv (MIC's) of Selected Compounds
Microorganism Organism Ery. A
code standard
Staphylococcus aureus ATCC 65=38P AA 0.2 =
Staphylococcus aureus A5177 BB 3.1
Staphylococcus aureus A-5278 CC >100
Staphylococcus aureus CMX 642A DD 0.39
Staphylococcus aureus NCTC10649M EE 0.39
Staphylococcus aureus CMX 553 FF 0.39
Staphylococcus aureus 1775 GG >100
Staphylococcus epidermidis 3519 HH 0.39
Enterococcus faecium ATCC 8043 D 0.05
~treptococcusbovis A-5.169 JJ 0.02
Streptococcus agalactiae CMX 508 KK 0.05
Streptococcus pyogenes EES61 LL 0.05
Streptococcus pyogenes 930 MM >100
Streptococcus pyogenes PIU 2548 NN 6.2
Micrococcus luteus ATCC 9341 00 0.05
Micrococcus luteus ATCC 4698 PP 0.2
Escherichia coli JUHL QQ >100
Escherichia coli SS RR 0.78
Escherichia coli DC-2 S S >100
Candida albicans CCH 442 TT >100
Mycobacterium smegmatis ATCC 114 UU 3.1
Nocardia Asteroides ATCC9970 W 0.1
Haemophilis Influenzae DILL AMP R -WW 4
Streptococcus Pneumonia ATCC6303 XX 0.06
Streptococcus Pneumonia GYR 1171 YY 0.06
Streptococcus Pneumonia 5979 ZZ >128
Streptococcus Pneumonia 5649 ZZA 16
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WO 98/09978 PCT/US97/15506
Table 1. continued
Organism Example Example Example Exam le Example Example Example
code 1 2 3 5 7 8 9
AA 12.5 3.1 25 6.2 3.1 25 3.1
BB 50 3.1 >100 6.2 3.1 25 1.56
CC >100 >100 >100 >100 >100 >100 >100
DD 50 3.1 100 12.5 3.1 6.2 6.2
EE 6.2 1.56 25 12.5 3.1 6.2 0.78
FF 25 3.1 25 12.5 3.1 50 3.1
GG >100 >100 >100 >100 >100 >100 >100
HH 50 6.2 50 6.2 3.1 100 3.1
11 12.5 6.2 25 6.2 1.56 6.2 0.78
JJ 25 3.1 25 1.56 0.78 3.1 0.05
Kn 6.2 1.56 25 1.56 0.78 6.2 0.39
LL -* 3.1 100 3.1 1.56 6.2 0.39
MM >100 >100 >100 >100 >100 >100 >100
NN 12.5 3.1 100 6.2 3.1 12.5 0.78
00 3.1 1.56 12.5 0.78 0.39 6.2 0.2
PP 6.2 3.1 100 6.2 1.56 12.5 0.78
QQ >100 >100 >100 >100 >100 >100 25
RR 12.5 3.1 50 6.2 3.1 6.2 0.39
S S >100 >100 >100 >100 100 >100 25
TT >100 >100 >100 >100 >100 >100 >100
U U >100 25 100 >100 100 100 6.2
W .6.2 0.2 12.5 6.2 0.78 12.5 0.2
WW >128 - - >128 - - 16
XX 4 - 8 - - 0.25
YY 4 - - 4 - - 0.25
ZZ >128 - - >128 - - >64
ZZA 8 - - 16 - - 4
missing data is indicated by "-"
-55-
CA 02563965 2006-10-31
wo 9RM99'7R
Ta}~lr, I ~ti~yu~l
C}i >]riitirit F,11A[7= Exaintrle T'um 11r "in te Exym ~ xain Ir; Fxirrnplc
:n= . lC1 R u 11 .jt t? j.~
AA 6.2 6.2 1.56 6.2 1.56 1,56 t).2
J313 .6.2 3,1 1.56 6.2 1.56 1,56 0.2
CC ~I(1(I ~1Ot) >lilfl >100 >l(M5 5i'1 >10(I
an 612 6.2 3.1 fi.Z f,56 1.56 {I12
EB 6.2 6.2 3.1 6.2 1.5f1 1,56 '11.2
l~h fi.~ 6.2 3.1 6.2 1.ifi 1,56 0.2
Ciii >t(Jd) >]{lU ~If10 '.1[10 > Ef)'f) 50 > 100
illl (1.2 12.5 J.56 6.2 1.56 l.ifi 0.2
TJ 6.2 ].16 0,7$ 1.56 0.78 1.5fi 0.2
)J 0.2 ().2 0.2 (J.2 0.2 (139
KK 1.56 0.78 0.2 0.2 {1.39 0.78 (I,2
Ll, 4.34 409 0.39 l1.3s1 0.39 ().78 0,2
1-+WI >11l(l >EUO 50 tlu) > 100 26 1 (A) .
NN I.Sfi 1.56 (t.7?i 3.1 0.78 0.78 0.1
CX~ 0.2' 0.39 U.:i+} 0.78 0.2 fJ.39 -
J'P 1,56 0.7H U.7~ 3.1 0.7$ 0.7K 0.2
Q[,? ~140 >](uJ >100 ~]1)D > I(10 >1(Jd) >100
RR 1.56 0,39 6.2 6.2 6.2 12.5 0.39
1~3 >In(J >I(k} >100 >10(I `=100
~.l~lcl >j(J(I
7'I' .)f)f) >100 A{lu >100 >111I? 50 >100
t)tJ 12.5 - 3.1 6.2 3.2 3.1 -
w 1.Sfi 0,31) 3.1 1.56 115{1 3.1 0.1
Ww fid 32 128 >64 12$ f.ih Ifi
Xx ~ 0.25 t t I ]: (1.(13
YY 2 - (1,25 ]: 0.25 ().5 -
zz. >128 >12 128 32 ' 129 32 128
ZZA 4 2 2 1 2 ~ 0.25
-56-
CA 02563965 2006-10-31
'WA 9$NIq47S PCTfiJ99T~i3SdIG
`1'xb c 1. u} ti~ nacci
( anisrn FSpW~ EzaiiiR le Exampi Fmntvlc Exanip) Cxuma( fixmgple
71 72 72 74 75 103
AA 0.79 0,1 0.39 0.2 0.1 it.78 0. I
BB 0.39 0.1 0.39 0.2 a.1 1.5 F~ 0.1
C:{'. >100 100 100 >100 >10(1 >100 >1N)
17E~ 1.56 0.1 0.39 0.2. (l.l 1.50 0.1
EE 0.78 ii. I 0,39 012 I 0.7iS 0. I
P1~ 3_] 0.2 0.39 0.2 {l,1 1.56 0,1
GU >]{)(I If)(1 100 ?]0 0 >tC1C1 >lil() >If?D
H }1 I,] U.I (1.39 0.2 0.1 1.56 0.1
II 1.56 0,05 0.1 [l, l TJ. l 0.7$ (1105
T.1 Ø2 {}.01 0.05 0.05 41005 012 O.fal
KK 0.2 il.t} 1 0.05 0.(15 0.01 0.2 0.02
LL i}.3r) <0.005 0.03 U.US 0.02 0,2 !t.(J7
h41ti+T >100 50 12.5 50 3.i >tOO 1(1(I
NN 0.39 0.2 0,2 0.39 0.1 0.2 0.1
O0 - 0_0 1 0.1 (1.(15 (yM G.2 0.41
['P 0.78 (111 0.2 0.2 0.2 0.78 0.1
QQ >IUO - A3>at >]()fl 50 > 100 t00
RR 3.1 0.7M 3,2 3.1 0.39 1,56 (1.39
SS >100 >100 >I(lil y14.`1 >]p(l >I00 IC)()
TT >10() >100 >100 >itlil ]oU >100 :y100
UU 215 0.78 0.78 0,19 0.59 2.5 0.2
YV 0.19 U.] 0.39 U.P 0.05 I.56 0.02
wVW 64 $ ]f- 4 2 64 4
xx 0.25 (1.(16 t).125 0.125 0.0 0.5 0.03
YY 0.21 0.06 (1,125 0.125 0,03 0.25 0.03
ZZ >128 64 64 32 64 >64 12$
27A I 015 1 [l.S 0.5 0,25 0.25
-57-
CA 02563965 2006-10-31
WO 981Q997S YCTATLR97tLSaIIEi
'Ialtlc I. j:ontiliuatt
Organimn );xum p . Ln il Fsac.tirui~ egiti gle. G. xanl -amNr, BkWM1c
Mtle IA14 M lu 173 D-4 175 176
AA (1.05 0.1 11117 12.5 3.1 0.2 J.56
BB 0.05 0.05 Intl 5i) 3.1 0:39 0178
>100 >10t1 I0(1 100 >100 2.5 >100
T)1~ 0.05 0.05 100 12,5 3.1 0,78 1.56
FsE 0.1 0,02 101) 12.5 3.1 6.711 0178
RE i1.1 0.05 >104E 12.5 3.1 03}i 4.78
00 lOra >ioc} 100 IN >100 12_5 Jpp
HJ-E 0.05 0.2 10c1 12.5 3.1 t1.78 0.7K
il 0.05 0.05 100 1.56 9.1 0.02 0.2
.fa 0.01 -::4.003 11 0.78 (1.2 0.02 0.05
KK 0.01 0.02 50 0.~t{ 0,39, 0.02 0.05
LL <=0,005 <4.o05 sn u_78 0.34 (l.n 1 0.I15 -
rvlm 1.56 2s 30 it] I M 3.1 51}
NN f?.1 0.2 23 3.1 [.56 0.39 (1,2
00 <=0.00S 0.01 5I) M8 0,39 0.1115 0105
PF' 0105 0139 100 3.1 0175 U. I 0.2
w 50 2.S >100 >100 Atl4) >300 >lW
RR 039 0.39 ylt};P 50 12.5 0.78 3.!
sS .50 25 >1(KI >10(} >I0fl >1011 >100
'I'I' >100 >100 >10(1 lntl >100 >]00 >1N)
lJ[J {},39 0.78 50 3,1 3,1 0.78 t1.79
vV 0.0] 0.0 25 6.2 0.78 0.39 1.56
NAV 2 2 >128 12Ji 12iS 64 fi4
xx 0.03 t11.03 1ei 2 1 0.0 0.25
N'v 0.03 0.03 16 2 1 0.03 0.25
'f 16 >16 64 32 >R28 K 64
M~A ta.ZS 1 32 4 2 2 0.25
--5K-
CA 02563965 2006-10-31
WO MUa4?a aY.'Tll!&J7l15M6
Txbl,~- 1. corttin toc~j
(7r~xo~sm lininnig Ex,Tnr)j 1= inpLe. Rs~Ainp( bxatr, ] = n lr. I-sxumpl
S~S 1? 41 m 1] ~ 1~ ~ K4
141ti, 6.2 11.1 6,2 0.39 25 3,1 {). i
I#i3 6.2 (1,1 6.2 0.2 25 1.56 (5,J
CC "100 }100 >100 ~10(1 ~1l?[) >10(1 > 1(10
T]I=) 6,2 0.T l,.z 0.39 2.5 3.1 0.1
EE 6.2 0.1 U 0.'19 25 3.1 o. ]
1%J4 6.2 (1.1 6.2 0.39 25 1,56 0. 1
(.iC > J170 AI)() >100 Ify() >100 >1UG >100
[[w 1215 0.1 12.5 0.78 25 5.1 0.1
jT ].i6 (}105 0.7K U, ] 3,1 0.2 (1.(15
JJ U,'i() (J.(12 {), L 0.01 0,7~ (1,1 <=(J.(10.5
ICK 0,3() {).05 012 0Ø5 1.56 0,! 0.01
LL 039 0,07 0,1 0.01 1.56 0.1 0.61
UM A(14? 2;i y1(1(1 1(10 >100 25 31()0
NN (1.79 (1.2 {).7~ 039 3. 1.56 0.2
t][) 1.56 0.02 0.78 0.02 6.12 0õ39 0.01
PP 3.1 ().1 1.56 = i09 25 {).7$ 0.1
C~p A(Jd) >100 :-I(1(i 1{10 >100 >100
[tkl
Fi1z 6,2 0.2 1,56 0.39 25 12.5 (1,39
SS >1U(1 >100 >100 >1U() 3(oo >1(10 ]{)()
TT >100 >1(}() > kQ(} ~1(f4) >TCl(I >100 >1{}[}
Uli 12.5 0,2 12.5 11.39 > 1()(1 612 3. ('
}rV 3.1 0,1 0.39 0.2 1.56 3.1 .011
1MI >12:H 4 64 9 -,[2!i >128 K
XX 0,5 {).()3 1 0.125 2 1 0103
YY 0.5 0.03 I . 0.25 2 4.5 t}.(l:i
7Z >12H 128 >12t{ >128 .} 129 32 >128
77% II.S 0.25 2 1. 2 2 [).5
.~+~,
CA 02563965 2006-10-31
WO 98/09978 PCTIUS97/15506
V
Table 1. continued
Organism Examnle Example Exam le Examnle Examnle Examnle Example
code 186 187 188 189 190 191 192
AA 0.1 0.1 0.1 0.2 0.05 0.05 0.1
BB 0.01 0.1 0.1 0.1 0.05 0.05 0.1
CC >100 >100 >100 >100 >100 >100 >100
DD 0.1 0.1 0.1 0.2 0.05 0.05 0.1
EE 0.1 0.1 0.2 0.1 0.02 0.1 0.2
FF 0.01 0.1 0.1 0.1 0.02 0.05 0.1
GG >100 >100 >100 >100 >100 >100 >100
HH 0.1 0.1 0.2 0.2 0.05 0.05 0.1
II 0.05 0.02 0.05 0.05 0.02 0.05 0.02
J7 <=0.005 <=0.005 <=0.005 - <=0.005 <=0.005 - 0.01
_... ~
KK 0Ø1. 0.02 <=0-:005 <=0.005 <=0.005 - 0:05 0.01
LL 0.01 0.01 0.01 <=0.005 <=0.005 0.02 0.01
MM 3.1 25 25 50 12.5 3.1 50
NN 0.1 0.1 0.1 0.2 0.1 0.1 0.1
00 <=0.005 0.01 0.02 - 0.02 0.01 0.01 0.01
P P 0.1 0.02 0.2 0.1 0.1 0.1 0.2
QQ >100 100 >100 100 100 50 >100
RR 0.39 0.39 0.78 0.39 0.2 0.2 0.2
S S >100 >100 >100 50 100 100 100
TT >100 >100 >100 >100 >100 >100 >100
UU 0.2 0.78 0.78 0.78 0.78 0.39 3.1
W 0.1 0.1 0.39 0.05 0.1 0.02 0.1
WW 16 2 8 8 4 2 4
XX 0.03 0.03 0.03 0.125 0.06 0:03 '0.03
YY 0.015 0.03 0.03 0.06 0.03 0.03 0.03
ZZ >128 >16 >64 >32 >128 2 >128
2ZA 1 0.25 1 0.5 0..5 0.25 0.25
-60-
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WO 98/09978 PCT/US97/15506
Table 1. continued
Organism Examvle Example Example Example Examnle Example Exarrrule
c e 19 194 195 196 197 198 199
AA 0.05 0.05 0.05 0.1 0.1 0.05 0.1
BB 0.1 0.05 - - 0.1 0.05 0.1
CC >100 >100 >100 >100 >100 >100 >100
DD 0.1 0.05 0.05 0.1 0.1 0.05 0.1
EE 0.1 0.1 0.05 0.1 0.2 0.05 0.1
FF 0.1 0.05 0.05 0.1 0.2 0.02 0.1
GG >100 >100 >100 >100 >100 >100 >100
HH 0.1 0.05 0.05 0.2 0.1 0.1 0.1
II 0.02 - 0.02 0.05 0.05 0.05 0.02 <=0.05
~ JJ 0.01 <=0.005 0.01 <=0.005 <=0.005 <=0.005 <=0.05
KK 0.01 0.01 0.05 <=0.005 <=0.005 <=0.005 <=0.05
LL <=0.005 0.01 0.02 <=0.005 <=0.005 <=0.005 -
MM 25 0.78 1.56 >100 100 0.39 50
NN 0.05 0.05 0.1 0.2 0.1 0.1 0.1
00 0.01 0.01 0.01 0.01 0.02 <=0.005 0.05
P P 0.1 0.1 0.1 0.1 0.2 0.1 0.1
QQ 100 50 50 >100 100 50 100
RR 0.2 0.39 0.2 0.39 0.2 0.1 0.39
S S >100 100 50 >100 100 50 >100
TT >100 >100 >100 >100 >100 >100 >100
UU 0.39 0.78 0.39 0.2 1.56 0.39 0.78
W 0.05 <=0.005 0.05 0.1 0.1 0.02 0.1
WW 4 1 8 2 1 4
XX 0.03 <=0.004 0.03 0.03 0.03 <=0.004 0.008
YY 0.015 <=0.004 0.015 0.03 0.03 <=0.004 0.008
ZZ >128 64 4 >128 64 4 >128
ZZA 0.25 0.25 0.25 0.25 0.5 0.125 0.25
-61-
._..__.. ,... -õ-..::: :... _ .
CA 02563965 2006-10-31
~ ~ .r..
WO 98/09978 PCT/1JS97/15506
Table 1, continued
Organism Example Example Example Example Example Example Example
code 200 201 202 203 204 205 206
AA 0.1 0.1 - 0.2 0.1 - 0.78
BB 0.1 0.1 - 0.39 0.1 - 0.39
CC >100 >100 - >100 >100 - >100
DD 0.1 0.1 - 0.2 0.1 - 0.78
EE 0.1 0.1 - 0.2 0.1 - 0.78
FF 0.1 0.1 - 0.39 0.1 - 0.78
GG >100 >100 - >100 >100 - >100
HH 0.1 0.1 - 0.2 0.1 - 0.78
II 0.02 0.05 - 0.2 0.05 - 0.39
JJ Ø01 0.01 - <=0.005 0.01 - 0.1 KK 0.02 0.01 - 0.01 0.01 - 0.39
LL - 0.01 - 0.01 0.01 - 0.39
MM 50 1.56 - 1.56 3.1 - >100
NN 0.2 0.2 - 0.39 0.2 - 1.56
00 0.01 0.05 - 0.02 0.02 - 0.2
PP 0.2 0.1 - 0.39 0.1 - 1.56
QQ 50 50 - 100 >100 - >100
RR 0.39 0.2 - 0.39 0.78 - 25
S S 12.5 50 - 100 >100 - >100
TT >100 >100 - >100 >100 - >100
UU 0.78 6.2 - 6.2 0.78 - 3.1
W 0.1 0.2 - 0.39 0.1 - 3.1
WW 2 2 4 4 >128
XX <=0.004 0.03 0.03 0.03 0.06 0.03 0.5
YY <=0.004 0.03 0.03 0.03 0.06 0.06 0.5
ZZ >128 16 32 16 8 >64 >128
ZZA 0.25 1 2 2 0.5 4 4
-62-
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WO 98/09978 PCT/US97/15506
Table 1, continued
Organism Example Example ExamRle ExamQe Exam le Example Example
code 207 208 209 210 211 212 213
AA 0.1 0.1 0.05 0.1 0.05 0.39 0.2
BB 0.1 0.39 - - v.05 0.39 0.2
CC >100 >100 >100 >100 >100 >100 >100
DD 0.1 0.2 0.1 0.1 0.1 0.39 0.2
EE 0.1 0.2 0.1 0.1 0.1 0.39 0.2
FF 0.1 0.2 0.1 0.1 0.1 0.39 0.2
GG >100 >100 >100 >100 >100 >100 >100
HH 0.1 0.2 0.1 0.1 0.05 0.39 0.2
11 0.02 0.1 0.02 0.02 0.01 0.1 0.1
JJ <=0.005 0.01 0.01 <=0.005 0.01 <=0.005 0.05
} KK <=0.005 0.01 0.01 <=0.005 0.01 0.-1 0.05
LL 0.01 0.01 0.01 0.01 0.01 0.05 '0.02
MM 1.56 0.78 3.1 0.78 3.1 25 100
NN 0.2 0.39 0.1 0.2 0.1 0.39 0.39
00 0.01 0.01 0.01 0.02 0.01 0.05 0.05
P P 0.1 0.1 0.2 0.2 0.1 0.39 0.2
QQ 25 25 100 50 25 >100 100
RR 0.2 0.39 0.2 0.2 0.2 0.39 0.39
S S 50 50 >100 >100 50 >100 >100
TT >100 >100 >100 >100 >100 >100 >100
UU 0.39 0.78 0.78 0.78 0.39 0.78 0.39
W 0.02 0.2 0.02 0.02 0.05 0.2 0.39
WW 2 2 2 2 2 8 4
XX 0.015 0.03 0.03 0.015 <=0.004 0.125 0.03
YY 0.015 0.03 0.03 <=0.004 <=0.004 0.25 0.03
ZZ 64 4 4 4 16 128 >128
ZZA 0.5 1 0.5 0.25 0.25 1
-63-
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(~ {
WO 98/09978 PCT/US97/15506
Table 1. continued
Organism Example Example Example Examnle Examnle Example Example
code 214 215 216 217 218 219 221
AA 6.2 0.05 0.2 0.2 0.1 0.2 0.2
BB 25 0.1 0.2 0.39 0.1 0.2 0.39
CC >100 >100 >100 >100 >100 100 >100
DD 12.5 0.1 0.2 0.39 0.1 0.2 0.39
EE 12.5 0.1 0.2 0.1 0.2 0.2
FF 12.5 0.1 0.2 0.2 0.1 0.2 0.2
GG >100 >100 >100 >100 >100 100 >100
HH 25 0.1 0.2 0.39 0.1 0.2 0.2
II 25 0.05 0.05 0.2 0.05 0.05 0.05
JJ 6.2 0.01 0.01 0.02 0.01 <=0.005 <=0.005
K K 3.1 0.01 0.02 0.02- 0.01 0:02 U:02
LL 1.56 0.01 0.02 - 0.02 0.01 0.02 0.01
MM 12.5 0.78 0.78 0.78 6.2 3.1 >100
NN 25 0.1 0.2 0.78 0.2 0.2 0.39
00 12.5 0.01 0.05 0.1 0.05 0.05 0.02
PP 12.5 0.2 0.1 0.39 0.05 0.2 0.2
QQ >100 25 100 50 50 100 12.5
RR 3.1 0.2 0.39 0.39 0.39 0.78 0.1
S S >100 >100 >100 >100 >100 >100 12.5
TT >100 >100 >100 >100 >100 >100 >100
UU 100 0.78 0.78 12.5 0.78 0.39 3.1
W 50 0.02 0.1 0.78 0.05 0.05 0.2
WW 64 2 2 2 2 2
XX 1 0.015 0.015 0.03 0.015 0.03 0.03
YY 1 <=0.004 0.015 0.03 0.015 0.03 0.06
ZZ >128 16 0.5 2 4 2 >128
ZZA 32 0.25 0.25 2 0.25 0.25 2
-64-
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~..
WO 98/09978 PGT/US97/15506
Table 1, continued
Organism Example Exam le Examvle E xamnle Example Exavle Example
code 222 223 224 225 226 227 28
AA 0.2 0.2 0.39 0.2 0.1 0.2 0.39
BB 0.1 0.2 0.2 0.39 0.1 0.2 0.78
CC >100 >100 >100 >100 >100 >100 >100
DD 0.39 0.2 0.2 0.39 0.1 0.2 0.78
EE 0.2 0.2 0.2 0.39 0.1 0.2 0.78
FF 0.2 0.2 0.2 0.2 0.1 0.2 0.78.
GG >100 >100 >100 >100 >100 >100 >100
HH 0.2 0.39 0.39 0.2 0.1 0.2 0.78
Il 0.02 0.05 0.01 0.05 0.05 0.05 0.1
JJ <=0.005 <=0.005 0.01 0.01 0.01 <=0.005 0.02
=KK 0.02 <=0.005 <=0.005 0.01 0.02 0.05 <=0.005
LL <=0.005 <=0.005 0.01 0.01 0.01 0.02 0.0-1
MM >100 >100 >100 >100 6.2 50 25
NN 0.39 0.1 0.2 0.39 0.39 0.39 0.78
00 0.01 0.05 0.02 0.02 0.02 0.05 0.2
PP 0.2 0.2 0.2 0.2 0.1 0.39 0.39
QQ 25 50 25 12.5 6.2 6.2 >100
RR 0.1 0.2 0.2 0.2 0.2 0.2 0.78
S S 25 100 25 12.5 12.5 25 >100
TT >100 >100 >100 >100 >100 >100 >100
UU 0.78 3.1 3.1 3.1 0.78 1.56 3.1
W 0.2 0.2 0.1 0.2 0.05 0.05 0.78
WW 4 4 4 4 2 2 8
XX 0.03 0.03 0.03 0.03 0.03 0.03 0.125
YY 0.06 0.03 0.03 0.06 0.03 0.03 0.125
ZZ >128 >128 >128 >128 >128 >64 >128
ZZA 2 0.5 2 2 2 2 1
-65-
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WO 98/09978 PCT/US97/1M06
Table 1. continued
Organism Examnle Example Exam2le ExaWle Exarnnle Example Examnle
232 233 234 235
c e 229 230 21
AA 0.2 0.1 0.1 0.1 0.1 0.1 0.2
B B 0.2 0.1 0.1 0.1 0.1 0.1 0.2
CC >100 >100 >100 >100 >100 >100 >100
DD 0.2 0.1 0.1 0.2 0.2 0.2 0.2
EE 0.2 0.1 0.1 0.2 0.2 0.2 0.2
FF 0.2 0.2 0.05 0.1 0.1 0.1 0.2
GG >100 >100 >100 >100 >100 >100 >100
HH 0.2 0.1 0.2 0.2 0.2 0.1 0.2
Il 0.05 0.05 0.02 0.02 0.05 0.05 0.05
JJ <=0.005 <=0.005 0.02 0.02 0.02 <=0.005 0.01
KK 0.02 <=0.005 0.02 0.02 0.02 0.05 0.01
LL 0.01 <=0.005 0.02 0.02 0.02 0.01 0.01
MM 50 >100 100 >100 100 100 25.
NN 0.2 0.05 0.1 0.2 0.1 0.2 0.2
00 0.02 0.05 0.02 0.02 0.02 0.01 0.05
PP 0.05 0.2 0.1 0.2 0.2 0.1 0.39
QQ >100 100 100 25 50 50 >100
RR 0.39 0.39 0.39 0.39 0.39 0.39 0.78
S S >100 >100 100 >100 50 50 >100
TT >100 >100 >100 >100 >100 >100 >100
UU 1.56 0.78 0.78 0.39 0.78 0.78 0.78
W 0.2 0.05 0.05 0.05 0.05 0.1 3.1
WW 2 2 2 2 2 2 4
XX <=0.004 0.03 0.03 0.03 0.03 0.03 0.03
YY <=0.004 0.015 0.03 0.03 0.03 0.03 0.03
ZZ >128 128 >128 >128 64 >128 32
ZZA 0.125 0.25 0.5 0.5 0.25 0.25 0.5
-66-
CA 02563965 2006-10-31 'WO 9g/0997g PCT/US97/15306
Table 1. continued
Organism Example Example Examnle Example Example Exarnple Example
code 236 237 238 23-9 240 241 242
AA 0.2 0.39 0.2 6.2 3.1 3.1 0.2
BB 0.2 0.39 0.2 6.2 3.1 - -
CC >100 >100 >100 >100 >100 >100 >100
DD 0.2 0.39 0.39 6.2 6.2 6.2 0.2
EE 0.2 0.39 0.39 6.2 3.1 6.2 0.2
FF 0.2 0.39 0.39 6.2 3.1 6.2 0.2
GG 100 >100 >100 >100 >100 >100 >100
HH 0.2 0.39 0.39 = 6.2 3.1 6.2 0.39
11 0.05 0.1 0.05 1.56 0.78 1.56 0.1
JJ 0.05 0.05 0.02 0.39 0.39 0.39 0.02
KK 0.05 0.05 0.02 0.39 0.39 1.56 0.05
LL 0.01 0.05 0.02 0.39 0.39 0.78 0.01
MM 25 >100 >100 >100 >100 >100 >100
NN 0.2 0.2 0.2 1.56 0.78 6.2 0.2
00 0.05 0.05 0.05 0.39 0.39 0.78 0.05
PP 0.2 0.39 0.2 1.56 1.56 3.1 0.39
QQ 50 >100 100 >100 >100 >100 >100
RR 0.39 0.39 0.39 6.2 3.1 1.56 0.78
S S >100 >100 >100 >100 >100 >100 >100
TT >100 >100 >100 >100 >100 >100 >100
UU 0.39 0.78 0.2 50 6.2 100 0.78
VV 0.2 0.39 0.1 3.1 1.56 6.2 0.39
WW 4 16 8 - 64 32 16 8
XX 0.03 0.03 0.03 0.25 0.25 0.5 0.03
YY 0.03 0.03 0.03 0.25 0.25 0.25 0.03
ZZ 32 >128 >64 >128 >128 >128 >128
ZZA 0 0.5 0.25 1 1 4 0.25
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WO 98/09978 PCT/US97/15506
Table 1, continued
Organism Example Example Example Example Example Example Example
code 243 244 245 246 247 248 249
AA 0.05 0.1 0.1 0.78 0.05 0.05 0.1
BB 0..05 0.2 0.2 0.78 0.05 0.05 0.1
CC >100 >100 >100 >100 >100 >100 >100
DD 0.05 0.2 0.2 0.78 0.05 0.05 0.2
EE 0.1 0.2 0.2 0.78 0.05 0.05 0.2
FF 0.05 0.1 0.2 0.78 0.05 0.02 0.1
GG >100 >100 >100 >100 >100 >100 >100
HH 0.1 0.2 0.1 0.78 0.05 0.05 0.1
II 0.02 0.05 0.05 0.2 0.02 0.02 0.05
JJ 0.02 0.01 0.05 0.1 <=0.005 0.02 0.01
K K 0.02 <=0.005 0.02 0.2 0.01 <=0.005 . 0.02
LL 0.02 0.02 0.02 0.2 0.01 <=0.005 0.02
MM 6.2 1.56 0.78 >100 0.39 0.39 100
NN 0.1 0.2 0.1 0.39 0.1 0.1 0.1
00 0.02 0.02 0.05 0.2 0.01 0.02 0.01
PP 0.02 0.2 0.2 0.78 0.02 0.1 0.1
QQ 50 50 50 >100 25 50 100
RR 0.2 0.1 0.05 0.78 0.2 0.39 0.39
S S 50 25 25 >100 25 50 >100
TT >100 >100 >100 >100 >100 >100 >100
UU 0.39 0.78 0.78 50 0.39 0.39 0.39
w 0.05 0.02 0.05 0.78 0.01 0.02 0.1
WW 4 2 2 16 1 1 4
XX 0.03 0.03 0.03 0.25 <=0.004 0.03 0.03
YY 0.03 0.03 0.03 0.125 <=0.004 0.03 0.03
ZZ 128 64 64 >128 4 4 >128
ZZA 0.25 0.5 0.5 0.5 0.25 0.25 0.25
-68-
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WO 98/09978 PCrtvs97115M
Table 1, continued
Organism Ex e Exanmple Exaniple Example Ex le Examnle Ex e
code 250 251 252 253 254 255 256
AA 0.2 0.1 0.1 0.05 0.1 0.1 0.05
BB 0.2 0.1 0.1 0.05 0.1 0.2 0.05
CC >100 >100 >100 >100 >100 >100 >100
DD 0.2 0.1 0.1 0.05 0.1 0.2 0.05
EE 0.2 0.1 0.1 0.1 0.1 0.2 0.05
FF 0.2 0.1 0.1 0.05 0.1 0.2 0.02.
GG 100 >100 >100 >100 >100 >100 >100
HH 0.2 0.1 0.1 0.05 0.1 0.1 0.1
11 0.05 0.1 0.05 0.05 0.02 0.05 0.02
11 "0.01 0.02 0.02 " 0.02 <=0.005 0.02 0.01
KK 0.01 0.05 0.02 0.02 0.~; 0.02 0.02
'~ -
LL 0.01 0.05 0.05 0.01 0.01 0.02 0.01
MM 6.2 6.2 3.1 0.78 0.78 50 25
NN 0.2 0.2 0.1 0.05 0.1 0.2 0.2
00 0.1 0.02 0.02 0.01 0.02 0.05 0.01
PP 0.2 0.2 0.2 0.1 0.1 0.2 0.1
QQ 100 >100 >100 50 25 100 100
RR 0.39' 1.56 0.78 0.2 0.2 0.2 0.2
SS >100 >100 >100 50 100 >100 >100
TT >100 >100 >100 >100 >100 >100 >100
UU 0.78 0.2 0.2 0.2 0.78 3.1 1.56
W 0.1 0.05 0.05 0.02 0.01 0.05 0.05
WW 4 16 2 2 2 2
XX 0.03 0.125 0.03 0.015 <=0.004 0.03 0.03
YY 0.03 0.25 0.03 0.03 <=0.004 0.03 0.03
ZZ 16 >128 4 1 2 16 16
ZZA 0.5 1 0.25 0.25 0.25 0.25 0.25
-69-
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WO 98/09978 PGT/US97/15506
Table 1. continued
C3rganism Examgle Example Exam le Exa 1 Exam,ple Example Example
ode 257 258 259 26~ 261 A 261 B 262
AA 0.2 0.78 6.2 25 6.2 3.1 0.78
BB 0..2 0.39 6.2 25. ... 6.2 _ 3:1-. 0.78
CC >100 >100 >100 >100 >100 >100 >100
DD 0.2 0.78 12.5 25 12.5 6.2 0.78
EE 0.2 0.39 6.2 25 12.5 3.1 0.78
FF 0.2 0.78 6.2 25 12.5 3.1 0.78
GG >100 >100 >100 >100 >100 >100 >100
HH 0.2 0.78 6.2 25 6.2 6.2 0.78
II 0.1 0.39 0.78 3.1 1.56 0.78 0.39
JJ 0.01 0.05 0.39 0.78 0.39 0.39 <=0.005
KK 0.05 0, l, Ø78 0.7 R 0.39 0.39 ; 0.05
..i .
LL 0.01 0.05 0.39 0.78 0.39 0.39 0.1
1vIM 100 >100 >100 >100 >100 >100 >100
NN 0.2 0.2 1.56 12.5 1.56 0.78 0.78
00 0.05 0.1 0.78 1.56 0.78 0.39 0.1
PP 0.2 0.39 1.56 3.1 3.1 1.56 0.39
QQ >100 >100 >100 >100 >100 >100 >100
RR 0.78 0.78 1.56 6.2 6.2 6.2 1.56
SS >100 >100 >100 >100 >100 >100 >100
TT >100 >100 >100 >100 >100 >100 >100
UU 0.39 12.5 12.5 >100 25 25 6.2
W 0.2 0.39 3.1 50 6.2 6.2 0.39
WW 8 32 128 64 64 32 16
XX 0.125 0.03. 1 2 1 0.5 0.03
YY 0.125 0.03 1 1 1 0.5 0.03
ZZ 128 >128 >128 >64 >128 >128 >128
ZZA 0.5 0.125 4 16 2 1 0.5
-70-
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l-
WO 98/09978 PGT/(JS97/15506
Table 1, continued
Organism Example Example Example Example Example Example Example
code 263 264 265 266 267 268 269
AA 0.1 0.01 0.1 0.2 0.05 0.39 -
BB 0.1 0.01 0.1 0.2 0.05 0.39 -
CC >100 >100 50 >100 >100 25 -
DD 0.1 0.01 0.1 0.2 0.05 0.39 -
EE 0.1 0.01 0.1 0.2 0.05 0.39 -
FF 0.05 0.01 0.1 0.2 0.05 0.39 -
GG >100 >100 25 >100 >100 25 -
HH 0.1 0.05 0.1 0.2 0.05 0.39 -
II 0.02 0.01 0.05 0.1 0.05 0.2 -
JJ . 0.01 <=0.005 <=0.005 0.01 <=0.005 0.1 -
KK 0.02 0.01 <=0.005 01.01 <=0.005 0.1 -
LL 0.02 0.01 0.01 0.01 <=0.005 0.1 -
MM 50 3.1 6.2 6.2 1.56 25 -
NN 0.2 0.2 0.1 0.2 0.1 0.39 -
00 0.02 <=0.005 0.01 0.02 <=0.005 0.1 -
PP 0.2 0.1 0.05 0.2 0.05 0.39 -
QQ >100 100 >100 >100 25 >100 -
RR 0.78 0.1 0.78 0.78 0.2 3.1 -
S S >100 100 >100 >100 25 >100 -
TT >100 >100 50 >100 >100 >100 -
UU 0.78 0.78 0.2 0.39 0.39 0.39 -
W 0.2 0.01 0.2 0.1 0.02 0.39 -
WW 4 2 4 4 2 16
XX 0.015 0.03 0.015 0.06 0.03 0.125 0.06
YY 0.015 0.015 0.015 0.03 0.03 0.125 0.06
ZZ >128 >128 32 2 8 8 2
ZZA 0.25 0.5 0.25 0.25 0.25 1 0.5
-71-
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-- ~'_
WO 98/09978 PCTIUS97/15506
Table I. continued
Organism Examl2le Example Exam le Examnle Example Example Example
code 270 271 272 273 274 275 276
AA 0.1 0.39 0.2 0.2 0.1 0.2 0.39
BB 0.1 0.78 0.1 0.1 0.1 0.2 0.78
CC >100 >100 100 >100 >100 >100 50
DD 0.1 0.39 0.2 0.2 0.1 0.2 0.39
EE 0.2 0.78 0.2 0.2 0.1 0.2 0.78
FF 0.1 0.39 0.1 0.2 0.05 0.2 0.78.
GG >100 100 50 >100 >100 >100 25
HH 0.1 0.39 0.2 0.2 0.1 0.2 0.78
11 0.05 0.39 0.05 0.1 0.05 0.1 0.2
JJ 0.05 0.1 0.02- 0.02 0.01 0.01 0.02
KK.__ 0Ø5. 0.2. 0.02. 0.02 0.01 0.05 .-0.i
LL 0.05 0.1 0.05 0.05 0.01 0.02 0.02
MM 3.1 6.2 3.1 12.5 6.2 12.5 25
NN 0.2 0.39 0.2 0.39 0.1 0.2 0.39
00 0.02 0.2 0.05 0.05 0.01 0.02 0.1
PP 0.2 0.78 0.2 0.39 0.1 0.2 0.39
QQ 50 >100 >100 >100 >100 >100 >100
RR 0.39 3.1 0.78 0.78 0.2 0.78 6.2
SS 50 >100 >100 >100 >100 >100 >100
TT >100 >100 >100 >100 >100 >100 100
UU 0.39 1.56 0.2 0.78 0.78 0.39 0.78
W 0.1 0.78 0.2 0.39 0.05 0.2 1.56
WW 16 64 32 8 4 8 8
XX - 0.03 0.25 0.03 0.03 <=0.004 0.03 0.125
YY 0.03 0.25 0.03 0.03 <=0.004 0.03 0.125
ZZ 2 8 16 16 8 4 16
ZZA 0.25 1 0.25 0.5 0.25 0.5 0.5
-72-
CA 02563965 2006-10-31
~
wo 9s10997s rcr/I1s97/1s5o6
Table 1. continued
Organism Example Exam~le Example Example ExmRie Exam e Ex le
code 277 278 279 280 281 282 283
AA 1.56 0.05 0.39 0.39 0.78 0.2 0.1
BB 1.56 0.05 0.39 0.39 0.78 0.1 0.1
CC >100 >100 50 50 >100 100 100
DD 1.56 0.05 0.78 0.39 0.78 0.2 0.1
EE 1.56 0.05 0.39 0.39 0.78 0.2 0.1
FF 1.56 0.05 0.39 0.39 0.78 0.1 0.1
GG >100 >100 50 25 >100 100 50
HH 1.56 0.1 0.39 0.39 0.78 0.2 0.2
Il 0.78 0.05 0.2 0.2 0.39 0.05 0.05
JJ 0.39 0.01 0.05 0.05 0.05 0.01 0.01
) KK 0.2 0.01. 0.02 0.05 0.1 <=0:005 0.02
LL 0.2 <=0.005 - 0.1 0.1 <=0.005 <=0.005
MM 50 1.56 25 . 12.5 50 25 3.1
NN 1.56 0.2 0.39 0.39 0.39 0.1 0.2
00 0.39 0.01 0.05 0.1 0.2 0.05 0.01
PP 3.1 0.1 0.39 0.78 0.78 0.2 0.2
QQ >100 25 >100 >100 >100 >100 >100
RR 6.2 0.39 1.56 1.56 3.1 0.78 0.78
SS >100 12.5 >100 >100 >100 >100 >100
TT >100 >100 >100 >100 >100 >100 >100
UU 3.1 0.78 0.78 3.1 3.1 1.56 0.39
W 3.1 0.02 0.78 6.2 3.1 0.2 0.2
WW >128 4 8 8 32 8 2
XX 0.5 0.03 0.03 0.06 0.25 0.03 <=0.004
YY 0.5 0.03 0.03 0.06 0.25 0.03 <=0.004
ZZ 32 128 32 16 64 16 4
ZLA 4 0.5 0.5 1 1 0.25 0.125
-73-
CA 02563965 2006-10-31
r
WO 98/09978 PCT/US97/15506
Table 1. continued
Organism Exam le Example Exa=le Exanle Example Example
code 284 285 286 287 288 289
AA 0.2 3.1 6.2 0.1 0.1 0.2
B B 0.2 3.1 6.2 0.1 0.2 0.2
CC 50 >100 >100 >100 >100 >100
DD 0.2 3.1 6.2 0.1 0.39 0.2
EE 0.2 3.1 6.2 0.1 0.39 0.2
FF 0.2 3.1 6.2 0.02 0.39 0.2
GG 50 >100 >100 >100 100 >100
HH 0.2 3.1 6.2 0.1 0.39 0.2
11 0.05 0.39 1.56 0.05 0.39 0.2
JJ . 0.02 0.2 0.39 0.02 0.01 0.02
KK . 0.02 Ø2 ", .. 0.2 0:02 . 0.02 0.1 . i
LL <=0.005 0.05 0.78 0.02 0.1 0.1
MM 25 100 100 3.1 12.5 >100
NN 0.2 0.78 1.56 0.1 0.39 0.39
00 0.05 0.39 1.56 0.02 0.02 0.05
PP 0.2 0.39 3.1 0.2 0.39 0.39
QQ >100 >100 >100 50 >100 >100
RR 1.56 12.5 12.5 0.39 3.1 3.1
S S >100 >100 >100 >100 >100 >100
TT 50 >100 >100 >100 >100 >100
UU 0.2 6.2 25 0.39 0.39 1.56
W 0.78 1.56 12.5 0.05 0.39 0.39
WW 4 >128 128 2 8 64 XX 0.03 0.25 - 1 0.03 0.125 0.25
YY 0.03 0.25 0.5 0.03 0.125 0.25
ZZ 32 64 64 4 16 >128
ZZA 0.25 1 2 0.5 1 1
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WO 98/09978 PGT/US97/15606
Table 1, continued
Organism Example Example Example Exarr-pie
code 290 291 292 293
AA 0.1 0.05 0.1 0.39
BB 0.1 0:05. 0.1 0.39
CC 50 >100 >100 >100
DD 0.1 0.05 0.1 0.39
EE 0.1 0.05 0.1 0.39
FF 0.1 0.05 0.1 0.39
GG 25 >100 >100 >100
HH 0.1 0.05 0.05 0.39
II 0.05 0.02 0.02 0.1
JJ <=0.005 <=0.005 <=0.005 0.02
__
K <=0.005 ~<=0:005 = 0.02 0.05.
LL 0.01 <=0.005 0.01 0.02
MM 6.2 3.1 12.5 >100
NN 0.1 0.1 0.05 0.78
00 0.01 <=0.005 0.02 0.05
PP 0.05 0.05 0.1 0.2
QQ >100 25 50 >100
RR 0.78 0.1 0.2 0.78
SS >100 50 100 >100
TT 50 >100 >100 >100
UU 0.2 0.39 0.78 12.5
W 0.2 0.01 0.02 0.78
WW 4 2 2 16
XX 0.015 <=0.004 0.03 0.03
YY 0.015 <=0.004 0.03 0.03
ZZ 32 1 16 >128
ZZA 0.25 0.125 0.25 0.5
-75-
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WO 98109978 PCT/US97/15506
Pharmaceutical Compositions
The pharmaceutical compositions of the present invention comprise a
therapeutically
effective amount of a compound of the present invention formulated together
with one or
more pharmaceutically acceptable carriers. As used herein, the term
"pharmaceutically
acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid
filler, diluent,
encapsulating material or formulation auxiliary of any type. Some examples of
materials
which can serve as pharmaceutically acceptable carriers are sugars such as
lactose, glucose
and sucrose; starches such as corn starch and potato starch; cellulose and its
derivatives such
as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered
tragacanth; malt; gelatin; talc; excipients such as cocoa butter and
suppository waxes; oils.
such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn
oil and soybean
oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl
laurate; agar;
buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and
phosphate buffer
. solutions, as well .as other-:non=toxic compatible-lubricants such as sodium
iauryi suifate.and
magnesium stearate, as well as coloring agents, releasing agents, coating
agents,
sweetening, flavoring and perfuming agents, preservatives and antioxidants can
also be
present in the composition, according to the judgment of the formulator. The
pharmaceutical compositions of this invention can be administered to humans
and other
animals orally, rectally, parenterally, intracisternally, intravaginally,
intraperitoneally,
topically (as by powders, ointments, or drops), bucally, or as an oral or
nasal spray.
Liquid dosage forms for oral administration include pharmaceutically
acceptable
emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the
active compounds, the liquid dosage forms may contain inert diluents commonly
used in the,
art such as, for example, water or other solvents, solubilizing agents and
emulsifiers such as
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate. benzyl
alcohol, benzyl
benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular,
cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of
sorbitan, and
mixtures thereof. Besides inert diluents, the oral compositions can also
include adjuvants
such as wetting agents, emulsifying and suspending agents, sweetening,
flavoring, and
perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable
dispersing or
wetting agents and suspending agents. The sterile injectable preparation may
also be a
sterile injectable solution, suspension or emulsion in a nontoxic parenterally
acceptable
diluent or solvent, for example, as a solution in 1,3-butanediol. Among the
acceptable
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WO 98/09978 PCT1US97/15506
vehicles and solvents that may be employed are water, Ringer's solution,
U.S.P. and
isotonic sodium chloride solution. 'In addition, sterile, fixed oils are
conventionally
employed as a solvent or suspending medium. For this purpose any bland fixed
oil can be
employed including synthetic mono- or diglycerides. In addition, fatty acids
such as oleic
acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration
through a
bacterial-retaining filter, or by incorporating sterilizing agents in the fonm
of sterile solid
compositions which can he dissolved or dispersed in sterile water or other
sterile injectable
medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the
absorption of
the drug from subcutaneous or intramuscular injection. This may be
accomplished by the
use of a liquid suspension of crystalline or amorphous material with poor
water solubility.
The rate of absorption of the drug then depends upon its rate of dissolution
which, in tum, may depend upon crystal size and crystalline form.
Alternatively, delayed absorption of a
.; _ .
p arenterally'ad:niniste;ed drug form~~s accbinpl.shed'by dissblving'or
susli~ndirt~ the drug
in an oil vehicle. Injectable depot forms are made by forming microencapsule
matrices of
the drug in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the
ratio of drug to polymer and the nature of the particular polymer employed,
the rate of drug
release can be controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also
prepared by
entrapping the drug in liposomes or microemulsions which are compatible with
body
tissues.
Compositions for rectal or vaginal administration are preferably suppositories
which
can be prepared by mixing the compounds of this invention with suitable non-
irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which
are solid at ambient temperature but liquid at body temperature and therefore
melt in the
rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills,
powders,
and granules. In such solid dosage forms, the active compound is mixed with at
least one
inert, pharmaceutically acceptable excipient or carrier such as sodium citrate
or dicalcium
phosphate and/or a) fillers or extenders such as starches, lactose, sucrose,
glucose,
mannitol, and silicic acid, b) binders such as, for example,
carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as
glycerol, d) disintegrating agents such as agar-agar, calcium carbonate,
potato or tapioca
starch, alginic acid, certain silicates, and sodium carbonate, e) solution
retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium compounds,
g) wetting
agents such as, for example, cetyl alcohol and glycerol monostearate, h)
absorbents such as
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WO 98/09978 PCT1US97/15806
kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case
of capsules, tablets and pills, the dosage form may also comprise buffering
agents.
Solid compositions of a similar type may also be employed as fillers in soft
and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as
well as high
molecular weight polyethylene glycols and the'like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can
be
prepared with coatings and shells such as enteric coatings and other coatings
well known in
the pharmaceutical formulating art. They may optionally contain opacifying
agents and can
also be of a composition that they release the active ingredient(s) only, or
preferentially, in a
certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding
compositions which can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft
and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as
well as high
molecular weight-p.oleth.y-leno glyeols and the-like:
The active compounds can also be in micro-encapsulated form with one or niore
excipients as noted above. The solid dosage forms of tablets, dragees,
capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings,
release
controlling coatings and other coatings well known in the pharmaceutical
formulating art. In
such solid dosage forms the active compound may be admixed with at least one
inert diluent
such as sucrose, lactose or starch. Such dosage forms may also comprise, as is
normal
practice, additional substances other than inert diluents, e.g., tableting
lubricants and other
tableting aids such a magnesium stearate and microcrystalline cellulose. In
the case of
capsules, tablets and pills, the dosage forms may also comprise buffering
agents. They may
optionally contain opacifying agents and can also be of a composition that
they release the
active ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally,
in a delayed manner. Examples of embedding compositions which can be used
include
polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this
invention include ointments, pastes, creams, lotions, gels, powders,
solutions, sprays,
inhalants or patches. The active component is admixed under sterile conditions
with a
pharmaceutically acceptable carrier and any needed preservatives or buffers as
may be
required. Ophthalmic formulation, ear drops, eyd ns are also contemplated as
being within
the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active
compound of this invention, excipients such as animal and vegetable fats,
oils, waxes,
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paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols,
silicones,
bentonites, silicic acid, talc anc( zinc oxide, or mixtures thereof.
Powders and sprays-can contain, in addition to the compounds of this
invention,
excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium
silicates and
polyamide powder, or mixtures of these substances. Sprays can additionally
contain
customary. propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery
of a
compound to the body. Such dosage forms can be made by dissolving or
dispensing the
compound in the proper medium. Absorption enhancers can also be used to
increase the
t0 flux of the compound across the skin. The rate can be controlled by either
providing a rate.
controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to the methods of treatment of the present invention, bacterial
infections
are treated or prevented in a patient such as a human or lower mammal by
administering to
IS õthe patient a therapeutically effective amount of acompound of the
invention, in such
amounts and for such time as is necessary to achieve the desired result. By a
"therapeutically effective amount" of a compound of the invention is meant a
sufficient
amount of the compound to treat bacterial infections, at a reasonable
benefit/risk ratio
applicable to any medical treatment. It will be understood, however, that the
total daily
20 usage of the compounds and compositions of the present invention will be
decided by the
attending physician within the scope of sound medical judgement. The specific
therapeutically effective dose level for any particular patient will depend
upon a variety of
factors including the disorder being treated and the severity of the disorder;
the activity of
the specific compound employed; the specific composition employed; the age,
body weight,
25 general health, sex and diet of the patient; the time of administration,
route of administration,
and rate of excretion of the specific compound employed; the duration of the
treatment;
drugs used in combination or coincidental with the specific compound employed;
and like
factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a
human or
30 other mammal in single or in divided doses can be in amounts, for example,
from 0.01 to 50
mg/kg body weight or more usually from 0.1.to 25 mg/kg body weight. Single
dose
compositions may contain such amounts or submultiples thereof to make up the
daily dose.
In general, treatment regimens according to the present invention comprise
administration to
a patient in need of such treatment from about 10 mg to about 2000 mg of the
compound(s)
35 of this invention per day in single or multiple doses.
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Abbreviations
Abbreviations which have been used in the descriptions of the scheme and the
examples that follow are: AIBN for azobisisobutyronitrile; Bu3SnH for
tributyltin hydride;
CDI for carbonyldiimidazole; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DEAD
for
diethylazodicarboxylate; DMF for dimethylformamide; DMSO for
dimethylsulfoxide; DPPA -
for diphenylphosphoryl azide; Et3N for triethylamine; EtOAc for ethyl acetate;
-Et20for
diethyl ether; EtOH for ethanol; HOAc for acetic acid; MeOH for methanol;
NaN(TMS)2 for
sodium bis(trimethylsilyl)amide; NMMO for N-methylmorpholine N-oxide; TEA for
triethylamine; THF for tetrahydrofuran: and TPP for triphenylphosphine.
Synthetic Methods
The compounds and processes of the present invention will be better understood
in
connection with the following synthetic schemes I-VI (to be found following
the text
describing the schemes) which illustrate the methods by which the compounds of
the.
15, invention may be prepared,. The cornpounds of the prrsent inventiqrr are
prepared by the
representative methods described below. The groups A, B, D, E, W, X, Y, Z, Ra,
Rb, Rc,
and Rd are as defined above unless otherwise noted below.
The preparation of the compounds of the invention of formula VIII from
erythromycin A is outlined in Schemes Ia and lb. The preparation of protected
;erythromycin A is described in the following United States patents, US
4,990,602; US
4,331,803, US 4,680,368, and US 4,670,549 which are incorporated by reference.
Also
incorporated by reference is European Patent Application EP 260,938. In
general, the C-9-
carbonyl group of compound 1 is protected as an oxime, (V is =N-O-R3 or
=N-O-C(R8)(R9)-O-R3 where R3 is defined above and Rg and R9 are each
independently
selected from the group consisting of (a) hydrogen, (b) unsubstituted C1-C12-
alkyl, (c) C1-
C12-alkyl substituted with aryl, and (d) C1-C12-alkyl substituted with
substituted aryl, or R9
{; .
and R10 taken together with the carbon to which they are attached form a C3-
C12-cycloallcyl
ring). An especially preferred carbonyl protecting group V is O-(1-
isopropoxycyclohexyl)
oxime.
The 2'- and 4"-hydroxy groups of 2 are protected by reaction with a suitable
hydroxy protecting reagent, such as those described by T.W. Greene and P.G.M.
Wuts in
Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Son, Inc., 1991,
which is
incorporated by reference. Hydroxy protecting groups include, for example,
acetic
anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, or a
trialkylsilyl
chloride in an aprotic solvent. Examples of aprotic solvents are
dichloromethane,
chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone,
dimethylsulfoxide,
diethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,
hexamethylphosphoric
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WO 9a/09978 rcrnJS97115506
triamide, a mixture thereof or a mixture of one of these solvents with ether,
tetrahydrofuran,
1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like.
Aprotic solvents do
not adversely affect the reaction, and are preferably dichloromethane,
chloroform. DMF,
tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. Protection
of 2'- and
4"-hydroxy groups of 2 may be accomplished sequentially or simultaneously to
provide
compound 3 where RP is ahydroxy protecting group. A preferred protecting group
RP is
trimethylsilyl.
The 6-hydroxy group of compound 3 is then alkylated by reaction with an
alkylating
agent in the presence of base to give compound 4. Alkylating agents include
alkyl
chlorides, bromides, iodides or alkyl sulfonates. Specific examples of
alkylating agents
include allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl
bromide, 4-
nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, ec-bromo-
p-
tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, 1-
bromo-2-
pentene, 3-bromo-l-propenyl phenyl sulfone, 3-bromo- l-trimethylsilyl-l-
propyne, 3-
bromo-2-octyne, 1-bromo-2=b~.~tyne,=2-picolyl chloride, 3-picolyl chloride, 4-
picolyl
chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin,
bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl
chloride,
bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromo chloromethane,
bromomethyl pheriyl sulfone, 1,3-dibromo-l-propene, and the like. Examples of
alkyl
sulfonates are: allyl 0-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate,
n-butyl -0-
methanesulfonate and the like. Examples of the solvents used are aprotic
solvents such as
dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, N,N-
dimethylacetamide, N-
methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a
mixture of one
of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane,
acetonitrile, ethyl
acetate, acetone and the like. Examples of the base which can be used include
potassium
hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride,
potassium
hydride, potassium isopropoxide, potassium tert-butoxide, potassium
isobutoxide and the
like.
The deprotection of the 2'- and 4"-hydroxyl groups is then carried out
according to
methods described in literature, for example, by T.W. Greene and P.G.M. Wuts
in
Protective Groups in Or a~ nic Synthesis, 2nd ed., John Wiley & Son. Inc.,
1991, which is
incorporated herein by reference. The conditions used for the deprotection of
the 2'- and
4"-hydroxyl groups usually results in the conversion of X to =N-OH. (For
example, using
acetic acid in acetonitrile and water results in the deprotection of the 2'-
and 4"-hydroxyl
groups and the conversion of X from =N-O-R3 or =N-O-C(R8)(R9)-O-R3 where R3,
R8
and R9 are as defined above to =N-OH.) If this is not the case, the conversion
is carried out
in a separate step.
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WO 98/09978 PCTIUS97/15506
The deoximation reaction can be carried out according to the methods described
in.
the literature, for example by Greene (op. cit.) and others. Examples of the
deoximating
agent are inorganic sulfur oxide compounds such as sodium hydrogen sulfite,
sodium
pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium
hydrosulfite,
sodium metabisulfite, sodium dithionate, potassium thiosulfate, potassium
metabisulfite and
the Iike.. Exam- ples of the solvents used are protic solvents such as water,
methanol,
ethanol, propanol, isopropanol, trimethylsilanol or a mixture of one or more
of the
mentioned solvents and the like. The deoximation reaction is more conveniently
carried out
in the presence of an organic acid such as formic acid, acetic acid and
trifluoroacetic acid.
The amount of acid used is from about I to about 10 equivalents of the amount
of
compound 5 used. In a preferred embodiment, the deoximation is carried out
using an
organic acid such as formic acid in ethanol and water to give the desired
product 6.
The conversion of the 6-substituted erythromycin derivative to the 6-
substituted
ketolide is described in scheme 1 b. The cladinose moiety of macrolide 6 is
removed either
iS bv rnild aqueous aoid hydrolysis or hy enzymatic hydrolysisto .give:7.
Representaave asids
include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic
acid,
dichioroacetic acid or trifluoroacetic acid. Suitable solvents for the
reaction include
methanol, ethanol, isopropanol, butanol and the like. Reaction times are
typically 0.5 to 24
hours. The reaction temperature is preferably -10 to 35 C. The 2'-hydroxy
group of 7 is
protected using a suitable hydroxy protecting reagent such as acetic
anhydride, benzoyl
anhydride, benzyl chloroformate or trialkylsilyl chloride in an aprotic
solvent, as defined
above, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-
methyl
pyrrolidinone or a mixture thereof. A particularly preferred protecting group
RP is benzoate.
It is possible to reverse the order of the steps for removing the cladinose
and protecting the
hydroxy groups without affecting the yield of the process.
The 3-hydroxy group of 8 is oxidized to the ketone 9 using a modified Swem
;-.=
~,.
oxidation procedure. Suitable oxidizing agents are N-chlorosuccinimide-
dimethyl sulfide or
carbod'umide-dimethylsulfoxide. In a typical example, 8 is added into a pre-
formed N-
chlorosuccinimide and dimethyl sulfide complex in a chlorinated solvent such
as methylene
chloride at -10 to 25 C. After being stirred for 0.5-4 hours, a tertiary
amine such as
triethylamine or Hunig's base is added to produce the corresponding ketone.
The 2'
hydroxy protecting group of 9 is then removed by standard methods to give the
desired
ketolide VIII. When RP is an ester such as acetate or benzoate, the compound
may be
deprotected by treatment with methanol or ethanol. When RP is a trialkylsilyl
group, the
compound may be deprotected by treatment with fluoride in THF or acetonitrile.
The oxime derivative may then be prepared by reaction of compound VIII wherein
X
is 0 with hydroxylamine hydrochloride in the presence of base, or
hydroxylamine in the
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WO 98/09978 PCT/US97/15506
presence of acid as described in US Pat. No. 5,274,085, to form the compounds
wherein
R1 is H. Reaction with the substituted hydroxylamine R1ONH2, results in the
formation of
compounds in which RI is other than H. Alternatively, compounds wherein R1 is
other
than H may be prepared by initial formation of the unsubstituted oxime as
described above
followed by reaction with R1X' wherein X' is a suitable leaving group such as
halogen.
The preparation of the compounds of this invention of formula{pC) wherein L is
CO
and T is -NH- or -N(W-Rd)- is outlined in Schemes lc and 4. According to
Scheme lc, the
6-0-substituted compound 6 is first protected with a suitable hydroxy
protecting group to
give compound 6A, by the procedures referenced above. Compound 6A is then
treated with
sodium hexamethyldisilazide and carbonyldiimidazole to give compound 6B. In
particular,
treatment of compound 6B, with aqueous ammonia results in formation of the
cyclic
carbamate 6C wherein Re is H. Likewise, reaction of compound 6B with an amino
compound of the formula H2N-W-Rd results in fomnation of the cyclic carbamate
in which
Re is -W-Rd.
],5 Alxernate or additional procedures may be used to pFepare cempcunds
offo'rmula
(IX) wherein L is CO and T is -N(W-Rd)-. For example, treatment of a compound
6C
wherein Re is H with an alkylating agent having the formula Rd-halogen,
wherein Rd is as
defined previously, gives a compound 6C wherein Re is W-Rd, W is absent and Rd
is as
defined previously.
Reaction of compound 6B with a hydrazine compound of the formula H2N=NH-Rd
results in formation of the cyclic carbamate gives a compound 6C wherein Re is
W-Rd, W is
-NH- and Rd is as defined above. When unsubstituted hydrazine is the reagent
the final
product is a compound 6C wherein Re is -N(W-Rd)- wherein (W-Rd) is (NH2).
Treatment of a compound EC wherein Re is -N(W-Rd)- wherein (W-Rd) is (NH2)
with an alkylating agent having the formula Rd-halogen, wherein Rd is as
defined
previously, gives a compound 6C wherein Re is W-Rd, W is -NH- and Rd is as
defined
previously.
Treatment of compound 6C with an acylating agent selected from the group
consisting of Rd-C(CO)-halogen or (Rd-C(CO)-O)2 gives a compound 6C wherein Re
is W
is -NH-CO- and Rd is as defined previously
Treatment of a compound ~C wherein Re is -N(W-Rd)- wherein (W-Rd) is (NH2)
with an aldehyde Rd-CHO, wherein Rd is as defined previously gives a compound
6C
wherein W is -N=CH- and Rd is as defined previously.
Treatment of a compound of formula (IX) wherein L is CO and T is -N(W-Rd)-
3; wherein (W-Rd) is (NH2), with an alkylating agent having the formula Rd-
halogen, wherein
Rd is as defined previously, gives the compound formula (IX) wherein L is CO.
T is -N(W-
Rd)-, W is absent and Rd is as defined.
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WO 98/09978 PC'lYUS97n5S06
Reaction of compound 6B with a hydroxylamine compound of the formula H2N-O-
Rd results in formation of the cyclic carbamate in which Re is -O-Rd.
Removal of the cladinose moiety by acid hydrolysis as described previously
gives
the compound 6D wherein Z' is H. Compound 6D is then oxidized to 6E by the
modified
Swern oxidation procedure described for Scheme 1 b above for converting
compound 8 to
ketone 9.
Deprotection of the 2'-hydroxy group as described above provides the desired
ketolide IX.
According to the alternate procedure shown in Scheme ld, the compound 2A,
which
is the 9-oxime compound of erythromycin A, is subjected to acid hydrolysis
with dilute
mineral or organic acid as described previously to remove the cladinose moiety
and give
compound 7A. The oxime compound 7A is then converted to the protected oxime
compound 7B wherein V is =N-O-RI (shown) or =N-O-C(R5)(R6)-O-R1 where R1, R5
and
R6 are as defined previously, by reaction with the appropriately substituted
oxime protecting
r.eagent_ Th.e 3 and 2'-hydroxy groups of D are then prote-cted as described
previously,
preferably with a trimethylsilyl protecting group, to give compound 7C.
Compound 7C is
then alkylated as described previously for Scheme la to give compound 7D, and
compound
7D is first deoximated as described above for Scheme 1 a then the deoximated
product is
converted to the compound 7E by the procedures described for preparation of
compound 6C
from compound 6A in Scheme Ic. Compound 7E is then deprotected and oxidized to
the 3-
ketolide derivative compound of formula IX, wherein X is 0, L is CO and T is -
NH- or
-N(W-Rd)- by procedures described previously.
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PCTIUS97/1M
WO 98/09978
Scheme la
H NMe2 H H NMeZ
O - v 1 p1".
OH ',= 0.0
HO,,, 6 HO,~.. 6 o
_
HO O H
- ,~, -r `~~=:
o
0~,,= O 0~~.=,
O
0 0- H 0 ~=~' 0- H
OMe ~OMe
2
~ - ~ NMe2
R NMe2 v H
V RPO', p Rp
~,,,= O '~=..=
HO,,, HO,,, 6 ,
=~, O H ',
O
O
HO
`,~=: f----- ``.='.
00
O p
O =~' ORp 0 ., =~~ ORP
.~~OMe OMe
4 ~
H NMe2
R
OH O
I R H NMe2
N
HO,,, 6
'~-.. '=~~ o
6 HO
HO O O `~=..
,~=,.= -- Oi,,.
O
O
O OH
'=.
0 O-H OMe
~~OMe
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~- r
wo 98/09978 rcr/iTS97l15506
Scheme lb
O R H NMep O R H NMe2
~~.
.,,~. ,.O O`''= ''~=. ~~O
HO O O -_ HO
~~=='' ~ j
OH
Q'~..
0 O
O 0- H O
OMe
_ ,. . , . . ~ ( .
R RP NMe2 R Rp NMe2
O 0
O 0~.., .O
~,,~. ~. ,,,~= ~ ''= .
6 HO,,
.,~ 0 ,.
HO HO
,,.
01
O OH
0 0
0 9 O
$
OR'
t NMe2
= NMeZ N~
O R HO
~ ,,=.
O HO',=. ``''= 6
6 O
HO
="~ O
HO ~~..
0". 0
O O
O
0 VIII, X = NOR'
VIII,XO
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~. ~
WO 98/09978 PGT/US97/15M
Scheme Ic
O R H NMe2 O R Rp NMe2
O 0l'.. O 0~..,
HO ~ HO
,,=. 6 ,,.. 6
~=~ .~
HO O HO
`~~.=. ,~~. ``~.=. _
O ~~'=
00 p O,~=..
0 .~~ ~ H 0 ~ ~ RP
OMe yA OMe
r _ .
p R Rp NMe2
1 0~~.=
^ ~~O
N-~ IN ~
6
Rp NMe2 O p
O R
R e p
~ 0,,,=
~ ~,,.= ~~ ~~~~ O 0/,,,, O
oz=:< w.,, 6 ~f .
O O O =~~~ O R p
OMe
O-Z'
ry
O
6C. Z' is 4"-acetyl-cladinose 6D. Z' is H
p R RR NMe2
Re I O
O '~..
~ .,,,. ,.
O '' N'==. 6
O R R NMe2
R e
O p p~~~=
~~
O 6
O p
6E O
O
O
IX, L is CO, T is -NH- or -N(WR4)-
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,
WO 98/0/978 P(.T/US'47/13506
Scheme Id
v
.j H NMe2 V H H NMe2
o 0~.., a.,.
.,,,= ,,,, o
HO,,, Hp.,,.
=~~~ . : . . . .,,, . ..._. - ~
HO ' O HO p
.~`' --~ ~~`'~=
O o''~=. O p ORZ
O =~' O- H O
2A. OMe
V is N-OH V is N_OH.
RzjLH
RZ NMez
V H v H Rz NMep
. . . O , - ... - ~, {
. .._ ,.
_ ,, ~. .~ ~~ ,=
HOa,. HO,,I .
HO p O
HO
t~`'=- `~~~'=
O ORz ORz
m O
L
V is N-ORl V is N-ORl
3yis hydroxY R~ is H
roo tectinggrouo
z
v R RZ NMe2 e R R NMe2
R p
p 0".= ~ ,,~,= O
Ho,,,.,f,, I` O==< N~''= ,,~ O (
HO O p
ORZ
ORZ -'~ O
O
O
o Ln, Z
V is N- Rl,
Rx is hydroxv
nrotecting group
IX,XisC?,ReisHorWR4
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WO 98/09978 PCT/US9710506
The preparation of the compounds of this invention of formula (IX) wherein L
is CO
and T is 0 and compounds of fonnula VI is outlined in Scheme 2. In Scheme 2,
the
preparation follows the procedure described by Baker et al., J. Org. Chem.,
1988, 53,
2340, which is incorporated herein by reference. In particular, the 2'
protected ketolide
derivative 9, prepared as described in Scheme I above, is converted to the
cyclic carbonate
by reaction with carbonyldiimidazole and sodium hexamethyldisiiazide:
Deprotection as
described above gives compound IX wherein L is CO and T is O.
Compounds of formula VI are prepared from 9 by reaction with sodium hydride or
lithium hydride and phosgene, diphosgene or triphosgene under anhydrous
conditions
l0 followed by aqueous work up (aqueous base catalyzed decarboxylation).
Alternatively, 9 is
converted to its corresponding mesylate by reaction with methanesulfonic
anhydride in
pyridine. The mesylate is then converted to l I by treatment with an amine
base such as
DBU or dimethylaminopyridine in acetone or acetonilrile. The 2' protecting
group is the
removed as described above to give compound VI.
Compounds of formula VI are also prepared from -10 by trcatment with an aminz
base such as 1,8-diazobicyclo[5.5.0]undec-7-ene (DBU) or 4-
dimethylaminopyridine
(DMAP) in a solvent such as benzene or acetonitrile, or by reaction with
sodium or lithium
hydride in tetrahydrofuran or N,N-dimethylformamide (DMF) to give 1 l which is
then
deprotected as described above to give the desired compound.
Compounds of formula VII are prepared as described in Schemes 3a and 3b. In
accordance with Scheme 3a, ketolide 11, prepared as in Scheme 2, is converted
to 12 by
reaction with carbonyldiimidazole and an alkali metal hydride base, such as
sodium hydride,
lithium hydride or potassium hydride in a suitable aprotic solvent at from
about 0 C to *
ambient temperature. Compound 12 may also be prepared by reaction of diol 9,
or cyclic
carbonate 10, prepared as described in Scheme 2 above. by reaction with
carbonyldiimidazole and sodium or lithium hydride under similar conditions.
Compound
12 is then reacted with diamine il having substituents A, B, D and E as
defined above, in a
suitable solvent such as aqueous acetonitrile, DMF or aqueous DMF, to give the
bicyclic
compound 14. Compound 14 is then cyclized by treatment with dilute acid, such
as acetic
acid or HC1 in a suitable organic solvent such as ethanol or propanol and
deprotected as
described above to give the tricyclic ketolide VII. Alternatively, the 2'-
protecting group of
the bicyclic ketolide 14 may be removed prior to cyclization using the methods
described in
Scheme 1. Compounds of formula IV or VII may be reduced to compounds of
formula 1V-
A by treatment with a reducing agent selected 'from hydrogen in the presence
of palladium
catalyst, alkyl borohydride and lithium aluminum hydride in a suitable organic
solvent.
Scheme 3b illustrates an alternative preparation of compounds of formula VII.
Starting material 12 is reacted with a beta-aminoalcohol 15 (Y=OH) in a
suitable solvent
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WO 98/09978 PCT/US97/15506
system such as aqueous acetonitrile, DMF or aqueous DMF at 0 - 70 C to give
16 which is
converted to the azide with a Mitsunobu reaction using triphenylphosphine and
diphenylphosphoryl azide and DEAD in tetrahydrofuran. Alternatively, the
hydroxy group
in h may be activated by treatment with sulfonyl chloride, alkyl or aryl
sulfonic anhydride
S or trifluoromethanesulfonic anhydride in an aprotic solvent. The activated
hydroxy group is
then converted to "the corresponding azide by reaction with-1'ithium azide or
sodium azide in
an aprotic solvent. The 2'-protecting group is then removed as described
above, and the
azide is reduced to the amine 12. Suitable reducing reagents are
triphenylphosphine-water,
hydrogen with a catalyst, sodium borohydride, or dialkylaluminum hydride in
the
appropriate solvent for these reactions, as is well known in the art. Compound
17 is then
cyclized as described in Scheme 3a above.
Compounds of formula IX wherein L is CO and T is NH or N-W-Rd are prepared as
shown in Scheme 4. The preparation follows the procedure described by Baker et
al., J.
Org. Chem., 1988, 53, 2340, which is incorporated herein by reference. In
particular,
trwatrnent of co:npound.Ll Frepared as descri-bed in Scheme 3- above wfth
'aqueous
ammonia results in formation of the cyclic carbamate .].$ wherein Re is H.
Likewise,
reaction of compound 12 with an amino compound of the formula H2N-W-Rd results
in
formation of the cyclic carbamate in which Re is -W-Rd.
Deprotection of the 2'-hydroxy group as described above provides the desired
ketolide IX.
In particular, treatment of compound f
aB, with aqueous ammonia results. in formation of the
cyclic carbamate L wherein Re is H. Likewise, reaction of compound 6B with
an.amino
compound of the formula H2N-W-Rd results in formation of the cyclic carbamate
in which
Re is -W-Rd.
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pGT/US97n5506
WO 98/09978
Scheme 2
= RP NMeZ
O R
O O'~=.
ap NMe2
HOr.,, O R I
HO O
,.
.,,.
`~.=' Oi,,.
0 ="'~--..,= 0~ O
O
O q O O
O
,, _ . =
= R NMe2
O
R
O
O'~==
,. _
NMe2
CH3 O O
O ',,.
HO I HO
.,,, ~=
r='
0,,,.
O O~ 0
O
O
O O O
0 IX,L=CO,T=O
= R NMe2
O
HC-''==
O
,
CH3 =~~ O
HO
O
O
O vi
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c r
WO 98/09978 PCT/US97/13506
Scheme 3a
O R RP NMe2 O R RP NMe2
pl"
H C O H3C ,'O
3 6 ~ N~ N O
HO p p
`,.= _ .. _~ ~ ~.='
O p
O O O
O L2
D NH2
E#,..
A ia
8. NH2
D NH2 O R RP NMe2
E~,.
B ~,. H3C~~.. 6
O
,
0:c3
O~ D O
Er,.. N OH NMep O
A
~ H/ O
g~`' H3Ct... ,= Xl
Nii... O
6
O=< p 14
O
O
O
D H
O
VII Ei,.. pH NMe2
A u
gH3CII,.
0=,< N-,.. 6
O
O
O
IV-B. Rb is H
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WO 98/09978 fl'CT/US97/1SS06
Scheme 3b
Rp NMe2
p R I
H3C
~ `p O',,=
6
- // p O O
oll
O p O D
Eit Y
A
O B~~~~ NH
12 2
ErD, Y O R Rp NMe2
A O O1=..
g~~.. H3G...
Nie,. 6
O
~ =IIr
p
O
O
0 1: Y=OH -- Y=N3
2: deprotect
3: Y= N3 --~ Y= NH2
D
Er~,= R NMe2
N D NH2 NMe2
A p HO,,, Er~.. O R
g:ch6.p g~~.= H3C-~.. 6
O p O p==< Ni - "' O O
O
O
O O
O
O
vii 0
17
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WO 9s/09978 PcT/US97n5506
Scheme 4
Rp NMep
O R 1
H 3C O 0~~..
N g =~~ O O
~, . .. _
O O
O
NH4OH or
0 2 H2NWRd
O R RP NMe2
'
O
R ~. =
II\ H3C~O
.
O==< 0
O
O
O
0
18
Re=HorWRd
R NMe2
O .
O HOt=.
R H3C,''
N1,,,. 6
O =~~ O
O
: O
O
O
IX:L=CO,T=NH
The desired 6-0-substituted compound may be prepared directly as described
above
or obtained from chemical modification of an initially prepared 6-0-
substituted compound.
Representative examples of further elaboration of the 6-position are shown in
Scheme 5.
For example, compound 20 where R is 6-0-CH2CH=CH2 and M' represents the
macrolide
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WO 98/09978 PGT/QS97/15506
ring system can be further derivatized. The double bond of the allyl compound
can be (a).
catalytically reduced to give the 6-0-propyl compound 27; (b) treated with
osmium tetroxide
to give the 2,3-dihydroxypropyl compound 31 which in turn may be
functionalized, such as
by esterification with an acylating agent such as an acyl halide or acyl
anhydride, at each
oxygen atoms to give 32; (c) oxidized with m-chloroperoxybenzoic acid in an
aprotic
solvent to give theepoxy methyl compound 29 which can be opened with
nucieophilic
compounds, for example, amines or N-containing heteroaryl compounds, to give
compounds with N-containing side chains 30; (d) oxidized under Wacker
conditions as
described by Henry in "Palladium Catalyzed Oxidation of Hydrocarbons", Reidel
Publishing Co., Dordrecht, Holland (1980), to give the 6-O-CH2-C(O)-CH3
compound 2$;
and (e) ozonized to give the aldehyde 21 which can in turn be (1) converted to
oximes 22
and 24 by reaction with H2NOR3 or H2NOH respectively, or (2) reductively
aminated, such
as with a suitable amine in the presence of a borohydride reducing agent or by
formation of
the imine and subsequent catalytic reduction,. to give the amine 23. Reaction
of the oxime
24 with diisonropyl carbodiimide in an aprotic solvent in the presence of CuCI
gives the
nitrile 25. Reaction of 20 with an aryl halide under Heck conditioris (Pd(II)
or Pd(O),
phosphine, and amine or inorganic base, see Organic Reactions, 1982, 27, 345-
390) gives
26. Reduction of the double bond in 26, for example using H2 and palladium on
carbon
gives 33.
Scheme 6 describes alternate procedures for preparing compounds of formula XI
wherein L is CO, T is -NH- or -N(W-Rd)- and R is substituted alkenyl. The 6-O-
allyl
erythromycin compound 33 is converted to the compound of formula XI wherein L
is CO,
T is -NH- or -N(W-Rd)- and R is allyl by removing the cladinose and oxidation
of the 3-
hydroxy group as described in earlier Schemes. Subsequent reaction of the
compound of
formula XI wherein L is CO, T is -NH- or -N(W-Rd)- and R is allyl with a
compound
having the formula R**-halogen, wherein R** is aryl, substituted aryl,
heteroaryl or
substituted heteroaryl, under Heck conditions with (Pd(II) or Pd(O),
phosphine, and antine
or inorganic base, (see Organic Reactions, 1982, 27, 345-390) gives the
desired product of
formula XI wherein L is CO, T is N(Rd) and R is substituted alkenyl.
Alternately, compound 33 is converted to the 6-0-(substituted alkenyl)
compound of
formula 34 by reaction with an aryl halide, a substituted aryl halide, an
heteroaryl halide or
substituted heteroaryl halide under Heck conditions with (Pd(II) or Pd(O),
phosphine, and
amine or inorganic base, as just described. Compound 34 may then be converted
to the
desired product of formula XI wherein L is CO, T is -NH- or -N(W-Rd)-, and R
is
substituted alkenyl by removing the cladinose and oxidation of the 3-hydroxy
group as
described in earlier Schemes.
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wo 9s~o9978 rcT/U~7I1s5~
Scheme 5
OR6
r-c
M.-O OH
~ Rs
OH R7
aQ
HO A
r_.L_O
M -O
M'- O OH
~.1. ,. .
O
CH3 -
~ ~- M, O CH3
M'- O
M =-- O
im 2a
R3
N-- O
Ar A/0 ---
M- O
IIIA1
C= N
NHR6 M'- O M- O
2a
M'""O 22
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(WO 98/09978 ?C1'~S97/IM
Scheme 6
Rp NMe2 0 RP NMe2
O
~ ~~..
Re NO O1'== R8 O 0
O< O~
O .,tO O O O O
O-Z' --~ O
O O
O O
XI. R is allvl
6C. R is allvl.
Z' is 4"-acetyl-cladinose
RI isHorW-R-4
R= R,.
I I
RP NMe2 RP NMe2
O O
Re O O~~=. Re O O"=
o`
O~ O =.=<NI.,,
O O O O O
O-Z' O
O O
O O
34 XI. R is substituted allyl
6C. R is substituted allvl.
Z' is 4"-acetvl-cladinose
Representative examples of still further elaboration of the 6-position are
shown in
Scheme 7. The desired 6-0-substituted compound may be prepared by chemical
modification of an initially prepared 6-0-propargyl compound. For example,
compound
35 where R is 6-0-CH2-C=CH and M' represents the macrolide ring system can be
further
derivatized. The triple bond of the alkyne compound 35 can be treated with an
aryl halide, a
substituted aryl halide, an heteroaryl halide or substituted heteroaryl halide
in the presence of
Pd(triphenylphosphine)2C12 and Cul in the presence of an organic amine, such
as
triethylamine, to give the compound 36. Compound 35 may also be treated with a
boronic
acid derivative HB(ORzZ), wherein Rzz is H or Cl-Clp-alkyl, in an aprotic
solvent at 0 C to
ambient temperature to give compounds 37, which are then treated with
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WO 98/09978 PCT/US97/15506
Pd(triphenylphosphine)4 and an aryl halide, a substituted aryl halide, an
heteroaryl halide or
substituted heteroaryl halide under Suzuki reaction conditions to give
compounds 38.
Compound 35 may also be treated with N-halosuccinimide in acetic acid to give
compounds
39. Also, compound 35 may be treated with a substituted alkenyl halide, such
as Ar-
CH=CH-halogen, wherein Ar is aryl, substituted aryl, heteroaryl or substituted
heteroaryl,
in the presence of Pd(triPhenY1PhosPhine)2Cl2 and Cul in the presence of an
organic amine,
such as triethylamine, to give the appropriately substituted compounds 41.
Further,
compound 36 can be selectively reduced to the corresponding cis-olefin
compound 40 by
catalytic hydrogenation in ethanol at atmospheric pressure in the presence of
5% PdBaSO4
and quinoline (Rao et at., J. Org. Chem., (1986), 51: 4158-4159).
Scheme 8 describes alternate procedures for preparing compounds of formula XI
wherein L is CO, T is -NH- or -N(W-Rd)-, and R is substituted alkynyl. The 6-0-
propargyl erythromycin compound 42 may be converted to the compound of formula
XI
wherein L is CO, T is N(Rd) and R is propargyl by removing the cladinose and
oxidation of
the 3-hydroxy.group as described in earlier Schemes. Subsequent reactiott-of-
the comperund
of formula XI wherein L is CO, T is N(Rd) and R is propargyl with a compound
having the
formula R**-halogen, wherein R** is aryl, substituted aryl, heteroaryl or
substituted
heteroaryl, in the presence of Pd(t.riphenylphosphine)2C12 and Cul in the
presence of an
organic amine, such as triethylamine, gives the desired product of formula XI
wherein L is
CO, T is -NH- or -N(W-Rd)-, and R is substituted alkynyl.
Compound 42 is converted to the 6-0-(substituted alkynyl) compound of formula
~
by reaction with a compound having the formula R**-halogen, wherein R** is
aryl,
substituted aryl, heteroaryl or substituted heteroaryl, in the presence of
Pd(triphenylphosphine)2C12 and Cul in the presence of an organic amine, such
as
triethylamine, as just described. Compound 43 is then converted to the desired
product of
formula XI wherein L is CO, T is -NH- or -N(W-Rd)-, and R is substituted
alkynyl by
removing the cladinose and oxidation of the 3-hydroxy group as described in
earlier
Schemes.
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WO 98/o9978 rcr/Q397115506
Scheme 7
Aryl
Aryl M'- O 0-
M'- O 40
36 RBe
B` Rea
~- ~
M'-O M'- O
35 37
Halogen
M'- O
L9
//-Aryl
j.-Aryl
M'-O
M'- O
41 38
=.._~
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WO 98/09978 PGT/[JS97/15506
Scheme 8
Rp NMe2 O Rp NMe2
O
Re =`O R e
., ,~= ,
O~ N'~=. 6 O~N~... O p O O
O O
O p
XI. R is Rooarevl
6C. R is prooarevl.
Z'is 4"-aeetyl-cladinose.
.. -.. _ .. ~ _ . ~
HS?r W
R..
= (I - II
O = RP NMe2 O Rp NMeZ
Re O
R O ~'
~.., ,~O '' ~ .,,,, ,. ''=
0~/ Nq.. 6 O,,.=='
o-z' o
o O
o p
43 XI. R is substituted propargvl
6C. R is substitutedpropargyl.
Z' is 4"-acetvl-cladinose
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The foregoing may be better understood by reference to the following examples
which are presented for illustration and not to limit the scope of the
inventive concept.
Example I
Compound of Formula (VIII): X is O. R is allvl
Sten la: Compound 4 from Scheme la: V is N-O-(1-isoprouoxycvclohexvl). R is
aIlyl. R&
is trimethylsilyl.
To a 0 C solution of 2',4"-bis-O-trimethylsilylerythromycin A 9-[O-(1-
isopropoxycyclohexyl)oxime (1.032 g, 1.00 mmol), prepared according to the
method of.
U.S. Pat. No. 4,990,602 in 5 mL of DMSO and 5 mL of THF was added freshly
distilled
allyl bromide (0.73 mL, 2.00 mmol). After approximately 5 minutes, a solution
of
potassium tert-butoxide (1M 2.0 mL, 2.0 mL) in 5 mL of DMSO and 5 mL of THF
was
added dropwise over 4 hours. The reaction mixture was taken up in ethyl
acetate and
washed with water and brine. The organic phase was concentrated in vacuo to
give the -desired compound (1.062 g) as a white foam.
Step 1 b: Compound 5 from Scheme 1 a: V is NOH. R is allyl.
To a solution of the compound resulting from step la (1.7 g) in 17 mL of
acetonitrile
and 8.5 mL of water was added 9 mL of acetic acid at ambient temperature.
After several
hours at ambient temperature, the reaction mixture was diluted with 200 mL of
toluene and
concentrated in vacuo. The residue obtained was found to contain unreacted
starting
material, so additional acetonitrile (15 mL), water (70 mL) and HOAc (2 mL)
was added.
After 2 hours, an additional 1 mL aliquot of HOAc was added. After
approximately three
more hours, the reaction mixture was placed in the freezer overnight. The
reaction mixture
was allowed to warm to ambient temperature, diluted with 200 mL of toluene and
concentrated in vacuo. The residue was chased twice with toluene and dried to
constant
weight (1.524 g).
Step lc: Compound 6 from Scheme la: R is allyl.
The compound resulting.from step 1 b (1.225 g) in 16 mL of 1:1 ethanol-water
vvas
treated with NaHSO3 (700 mg) and formic acid (141 L) and warmed at 86 C for
2.5
hours. The reaction mixture was allowed to cool to ambient temperature,
diluted with 5-6
mL of water, basified with 1 N NaOH to pH 9-10 and extracted with ethyl
acetate. The
combined organic extracts were washed with brine (2x), dried over MgSO4,
filtered and
concentrated in vacuo. The crude material was purified by column
chromatography eluting
with 1% MeOH in methylene chloride containing 19o ammonium hydroxide to give
686 mg
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WO 98/09978 PCT/US97/1S5 6
(57%) of the title compound. 13C NMR (CDC13) S 219.3 (C-9), 174.8 (C-1), 135.5
(C=
17), 116.3 (C-18), 101.9 (C-1'), 95.9 (C-1"), 79.7 (C-5), 78.8 (C-6), 78.5 (C-
3), 74.1
(C-12), 72.4 (C-3"), 70.6 (C-11), 68.1 (C-5'), 65.5 (C-16), 65.1 (C2'), 49.0
(C-3" 0-
CH3), 45.0 (C-2), 44.1 (C-8), 39.7 (NMe2), 37.9 (C-4), 37.1 (C-10), 34.6 (C-
2"), 28.4
(C-4'), 21.0, 20.6 (C-3" CH3, C-6' CH3), 20.8 (C-14), 18.3 (C-6"), 18.1 (C-8
CH3),
15.7, 15 6- (C-2 CH3, C=6 CH3), 11.9 (C-10 CH3), 10.1 (C-15), 8.9 (C-4 CH3).
MS
(FAB)+ nVe 774 (M+H)+, 812 (M+K)+.
Step 1 d= Compound 7 from Scheme 1 b: R is allvl.
To a suspension of the compound prepared in step Ic (7.73 g, 10.0 mmol) in
ethanol (25 mL) and water (75 mL) was added aqueous I M HC1(18 mL) over 10
minutes.
The reaction mixture was stirred for 9 hours at ambient temperature and then
was left
standing in the refrigerator overnight. Aqueous 2 M NaOH (9 mL, 18 mmol) which
resulted in the formation of a white precipitate. The mixture was diluted with
water and
. . . ; .;
filtered: The solid wag wastterl' with v1%ater`and dried under vacuum to give
the des-
cladinosyl compound 2 (3.11 g).
Step le: Compound 8 from Scheme lb: R is alltil. RD is benzovl.
To a solution of the product of step 1 d (2.49 g, 4.05 mmol) in
dichloromethane (20
mL) was added benzoic anhydride (98%, 1.46 g, 6.48 mmol) and triethylamine
(0.90 mL,
6.48 mmol) and the white suspension was stirred for 26 hours at ambient
temperature.
Aqueous 5% sodium carbonate was added and the mixture was stirred for 20
minutes. The
mixture was extracted with dichloromethane. The organic phase was washed with
aqueous
5% sodium bicarbonate and brine, dried over sodium sulfate and concentrated in
vacuo to
give a white foam. Chromatography on silica gel (30% acetone-hexanes) gave the
title
compound (2.46 g) as a white solid. (=
Step 1 f: ComQound 9 from Scheme I b: R is ally], R'R is benzoyl:
same as Compound of Formula (II). Ra is OH. RQ is benzoyl
To a -10 C solution under N2 of N-chlorosuccinimide (0.68 g, 5.07 mmol) in
dichloromethane (20 mL) was added dimethylsulfide (0.43 mL, 5.92 mmol) over 5.
minutes. The resulting white slurry was stirred for 20 minutes at -10 C and
then a solution
of the compound resulting from step le (2.43 g, 3.38 mmol) in dichloromethane
(20 mL)
was added and the reaction mixture was stirred for 30 minutes at -10 to -5 C.
Triethylamine (0.47 mL, 3.38 mmol) was added dropwise over 5 minutes and the
reaction
mixture was stirred for 30 minutes at 0 C. The reaction mixture was extracted
with
dichloromethane. The organic phase was washed twice with aqueous 5% sodium
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WO 98/09978 PCT/US97/15506
bicarbonate and once with brine, dried over sodium sulfate, and concentrated
in vacuo to
give a white foam. Chromatography on silica gel (30% acetone-hexanes) gave the
title
compound (2.27 g) as a white foam.
i Step I g Compound of Formula (VIII): X is O. R is ally_l.
A solution of the compound resulting from step 1 f(719 mg; T:0 mmol) in
methanol
(20 mL) was stirred at reflux for 6 hours. The reaction mixture was
concentrated in vacuo
and the residue was purified by chromatography on silica gel (95:5:0.5
dichloromethane-
methanol-ammonia) to give the desired compound (577 mg) as a white foam. 13C
NMR
to (CDC13) S 219.2 (C-9), 206.0 (C-3), 169.8 (C-1), 135.3, 117.5, 102.8, 78.4,
78.0, 75.9,
74.4, 70.3, 69.5, 69.0, 65.9, 64.6, 50.6, 45.4, 45.1, 40.2, 38.6, 37.8, 31.6,
28.4, 21.8,
21.3, 20.3, 18.1, 16.5, 14.7, 12.8, 12.3, 10.6. MS (FAB)+ m/e 614 (M+H)+.
Example 2
15 Co*npound-of Formula.("III): X is NOH. R is allvl.
To a solution of the compound resulting from Example 1 (122 mg, 0.2 mmol) in
ethanol was added hydroxylamine hydrochloride (76 mg, 1.1 mmol) and
triethylamine (56
L, 0.4 mmol) and the reaction mixture was stirred overnight at 80 C. The
reaction
mixture was concentrated and the residue was taken up in ethyl acetate. The
organic phase
20 was washed with aqueous 5% sodium bicarbonate and brine, dried over sodium
sulfate, and
concentrated in vacuo. Chromatography on silica gel (95:5:0.5 dichloromethane-
methanol-
ammonia) gave the E oxime (42 mg) and the Z oxime (38 mg) as white foams. 13C
NMR
(CDC13) S 206.3 (C-3), 170.1 (C-9), 169.8 (C-1), 136.1, 116.5, 102.7, 78.6,
78.2, 75.5,
74.1, 70.3, 70.2, 69.4, 65.9, 64.7, 50.6, 45.2, 40.2, 37.3, 33.1, 28.4, 25.4,
21.9, 21.3,
25 20.3, 18.6, 16.5, 14.9, 14.7, 12.8, 10.7. MS (FAB)+ m/e 629 (M+H)+.
Example 3
Compound of Formula (VIIII: X is O, R is pronvl.
A solution of the compound resulting from Example 1(122 mg, 0.2 mmol) in
30 ethanol was flushed with nitrogen and 10% palladium on carbon (20 mg) was
added. The
mixture was then flushed with hydrogen and the reaction mixture was stirred
overnight
under positive hydrogen pressure. The reaction mixture was filtered and
concentrated in
vacuo to give a glass. Chromatography on silica gel (95:5:0.5 dichloromethane-
methanol-
ammonia) gave the title compound as a white solid. 13C NMR (CDC13) S 220.2 (C-
9),
35 206.5 (C-3), 169.9 (C-1), 102.7, 78.1, 77.7, 75.7, 74.1, 70.3, 69.4, 65.9,
64.5, 50.6,
45.4, 44.7. 40.2, 38.8, 37.5, 28.4, 22.3, 21.9, 21.3, 20.3, 18.3, 16.5, 14.9,
14.7, 12.4,
10.6, 10.2. MS (FAB)+ m/e 616 (M+H)+.
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Example 4
Compound of Formula (VIII): X is O. R is -CH2CHO.
Step 4a: Compound of Formula (VIIII: X is O. R is -CH2CHO N-oxide.
Ozone was passed through a-78 G solution in dichloromethane (100 mL) of -the
compound resulting from Example 1 (2.45 g, 4.0 mmol) for 45 minutes. The
reaction
mixture was then flushed with nitrogen for 10 minutes. Dimethyl sulfide (1.46
mL, 20 =
mmol) was added at -78 C and the reaction mixture was stirred for 30 minutes
at 0 C. The
reaction mixture was concentrated in vacuo to give a white foam (2.78 g) which
was used
without further purification.
Step 4b: Compound of Formula (VIII): X is O. R is -CH?CHO.
The desired compound was prepared by heating a solution in THF (40 mL) of the
compound zesttlting from step.4a.(2.78 g, 4Ømmol) and =tripl~er~yphosphine
(2:6-2 g, 10.0
mmol) at 55 C for 2.5 hours. The reaction mixture was concentrated in vacuo
to give a=
white foam. Chromatography on silica gel (1:1 acetone-hexane, then 75:25:0.5
acetone-
hexane-triethylamine) gave the desired compound (1.29 g) as a white solid. MS
(FAB)+
m/e 616 (M+H)+.
Example
Compound of Formula (VIII): X is O. R is -CH?CH=NOH.
To a solution in methanol (5 mL) of the compound prepared in Example 4 (46 mg,
0.08 mmol) was added triethylamine (31 L, 0.225 mmol) and hydroxylaniine
hydrochloride (7.7 mg, 0.112 mmol) and the reaction mixture was stirred for 6
hours at
ambient temperature. The reaction mixture was taken up in ethyl acetate and
washed with
aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, and
concentrated in
vacuo to give a clear glass. Chromatography on silica gel (95:5:0.5
dichloromethane- ,
methanol-ammonia) gave the title compound (29 mg) as a white solid. MS (FAB)+
m/e 631
(M+H)+.
ExamRle 6
Compound of Formula (VIII): X is NOH. R is -CH,)CH=NOH.
The title compound (7.0 mg) was obtained from the chromatography described in
Example 5. MS (FAB)+ m/e 631 (M+H)+. MS (FAB)+ m/e 645 (M+H)+.
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Exam,ple 7
Compound of Formula (VIIT): X is O. R is -CH2CN.
To a solution under nitrogen of the compound prepared in Example 5 (168 mg,
0.267 mmol) in THF (5 mL) was added diisopropylcarbodiimide (83 L, 0.534
mmol) and
CuCI (2.7 mg, 0.027 mmol) and the reaction mixture was stirred overnight at
ambient
temperature. The reaction mixture was taken up in ethyl acetate and washed
with aqueous
5% sodium bicarbonate and brine, dried over sodium sulfate, and concentrated
in vacuo to
give a clear glass. Chromatography on silica gel (95:5:0.5 dichloromethane-
methanol-
ammonia) gave the title compound (63 mg) as a white solid. 13C NMR (CDC13) S
219.5(C-
9), 205.6 (C-3), 169.9 (C-1), 103.4, 81.3, 78.2, 77.4, 77.1, 74.0, 70.2, 69.7,
69.1, ..
65.9, 51.1, 48.6, 46.7, 44.3, 40.2, 38.0, 37.6, 28.2, 23.5, 21.2, 19.7, 17.8,
16.1, 14.4,
11.9, 10.5, 10.5. MS (FAB)+ rn/e 613 (M+H)+.
Example 8
Compound of Formula (VIlI):...X. is O. R is -CHcCH2I~1~:
To a solution in methanol (10 mL) of the compound prepared in Example 4(170
mg, 0.276 mmol) was added ammonium acetate (212 mg, 2.76 mmol) and the mixture
was
cooled to 0 C. Sodium cyanoborohydride (34 mg, 0.553 mmol) was added and the
reaction mixture was stirred for 30 hours at 0 C. The reaction mixture was
taken up in
ethyl acetate and washed with aqueous 5% sodium carbonate, aqueous 2%
tris(hydroxymethyl)aminomethane, and brine, dried over sodium sulfate,
filtered, and
concentrated in vacuo. Chromatography on silica gel (90:10:0.5 dichloromethane-
methanol-
ammonia) gave the title compound (90 mg) as a white solid. 13C NMR (CDC13)5
217.0
(C-9), 206.3 (C-3), 170.6 (C-1), 102.7, 78.9, 78.5, 75.1, 74.9, 70.3, 69.4,
67.8, 65.9.
63.1, 50.8, 45.8, 44.9, 41.7, 40.3, 38.8, 38.2, 28.4, 22.2, 21.3, 20.7, 19.2,
16.6,
14.9, 12.8, 12.4, 10.9. MS (FAB)+ m/e 617 (M+H)+.
Example 9
Compound of Formula (VIIi): X is O. R is -CH,)CH?NHCH-7-Phenyl.
To a 0 C solution in methanol (10 mL) of the compound prepared in Example 4
(121.3 mg, 0.200 mmol) was added acetic acid (114 L, 2.00 mmol) and
benzylamine (218
L, 2.00 mmol) and the mixture was stirred for 10 minutes. Sodium
cyanoborohydride
(24.8 mg, 0.400 mmol) was added and the reaction mixture was stirred for 16
hours.
Additional sodium cyanoborohydride (24.8 mg, 0.400 mmol) was then added and
stirring
was continued for 5 hours. The reaction mixture was taken up in ethyl acetate
and washed
with aqueous 5% sodium carbonate, aqueous 2% tris(hydroxymethyl)aminomethane,
and
brine, dried over sodium sulfate, filtered, and concentrated in vacuo.
Chromatography on
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silica gel (95:5:0.5 dichloromethane-methanol-ammonia) followed by a second
chromatography (50:50:0.5 acetone-hexanes-triethylamine) gave the title
compound (82 mg)
as a white foam. 13C NMR (CDC13) S 216.6 (C-9), 206.3 (C-3), 170.5 (C-1),
139.0,
128.6, 128.3, 126,9, 102.4, 78.9, 78.4, 75.1, 74.8, 70.2, 69.4, 67.8, 65.9,
61.7, 53.2,
s 50.7, 48:2, 45.6, 44.8, 40.2, 38.8, 38.0, 28.3, 21.9, 21.3, 20.6, 18.8,
16.6, 14.6, 12.6,
12.3, 10.7. MS (FAB)+ m/e 707 (M+H)+.
Example 10
Compound of Formula (VIII): X is O. R is -CH-)CH2NHCH2CH2-Phenvl.
To a 0 C solution in methanol (10 mL) of the compound prepared in Example 4
(121.3 mg, 0.200 mmol) was added acetic acid (114 L, 2.00 mmol) and
phenethylamine
(218 L, 2.00 mmol) and the mixture was stirred for 10 minutes. Sodium
cyanoborohydride (24.8 mg, 0.400 mmol) and the reaction mixture was stirred
for 16
hours. The reaction mixture was taken up in ethyl acetate and washed with
aqueous 5%
sodium carbonate, aqueous.2% tris(hydr.oxymethyl)aminomethane, and brine,
dried over
sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica
gel
(90:10:0.5 dichloromethane-methanol-ammonia) gave the title compound (60.1 mg)
as a
white foam. MS (FAB)+ m/e 721 (M+H)+.
Example 11
Compound of Formula (VIII): X is O. R is -CH,)CH2)NHCH(CO2CHa)CH2-Phenvl.
To a 0 C solution in methanol (10 mL) of the compound prepared in Example 4
(121.3 mg, 0.200 mmol) was added L-phenylalanine methyl ester hydrochloride
(129 mg,
0.600 mmol) and the mixture was stirred for l Ominutes. Sodium
cyanoborohydride (24.8
mg, 0.400 mmol) and the reaction mixture was stirred for 22 hours. The
reaction mixture
was taken up in ethyl acetate and washed with aqueous 5% sodium carbonate,
aqueous 2%
tris(hydroxymethyl)aminomethane, and brine, dried over sodium sulfate,
filtered, and
concentrated in vacuo. Chromatography on silica gel (95:5:0.5 dichloromethane-
methanol-
ammonia) gave the title compound (60.1 mg) as a white foam. 13C NMR (CDC13) S
217.8
(C-9), 206.4 (C-3), 170.5 (C-1), 170.4, 137.5, 129.4, 128.2, 126,4, 102.4,
78.8, 78.4,
75.2, 74.9, 70.2, 69.4, 68.5, 65.9, 63.1, 61.6, 51.4, 50.7, 47.1, 45.5, 44.7,
40.2, 39. '-),
38.4, 28.4, 21.8, 21.2, 20.6, 18.7, 16.6, 14.7, 12.6, 12.2, 10.7. MS (FAB)+
m/e 779
(M+H)+.
Example 12
Compound of Formula (VIII): X is O, R is -CH,)CH2NHCH,)-(4-pyridYl).
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The desired compound was prepared according to the method of Example 10,
except
substituting 4-aminomethylpyridine for phenethylamine. 13C NMR (CDC13) S 217.8
(C-9),
206.2 (C-3), 170.6 (C-1), 149.7, 148.2, 123.3, 102.5, 78.9, 78.4, 75.0, 74.9,
70.2,
69.5, 68.4, 65.9, 61.7, 52.4, 50.7, 48.7, 45.7, 44.8, 40.2, 39.2, 38.5, 38.2,
28.4, 21.8,
21.3, 20.6, 18.7, 16.6, 14.6, 12.6, 12.2, 10.7. MS (FAB)+ m/e 708 (M+H)+.
Example 13
Compound of Formula (VIII)= X is 0. R is -CH2CH2NHCH2-(4-c,Iuinolyl).
To a solution of the compound prepared in Example 8 (90 mg, 0.15 mmol) in
methanol (2 mL) was added 4-quinolinecarboxaldehyde (23 mg, 0.15 mmol), acetic
acid.
(8.6 L, 0.15 mmol), and sodium cyanoborohydride (9.4 mg, 0.15 mmol) and the
reaction
mixture was stirred for 15 hours. The reaction mixture was taken up in ethyl
acetate and
washed with aqueous 5% sodium carbonate, aqueous 2%
tris(hydroxymethyl)aminomethane, and brine, dried over sodium sulfate,
filtered, and
concentrated in vacuo. Chromatography on silica gel (90:10:0:5 dichloromethane-
methanol-
ammonia) gave the title compound (32 mg) as an off-white solid. MS (FAB)+ m/e
758
(M+H)+.
Exanm i e 14
Compound of Formula (VIIII: X is O. R is -CH?CH=CH-PhenYl.
Steg 14a: Compound 9 from Scheme 2: X is 0. R is -CH2CH=CH-Phenvl. Rp is
benzoyl.
To a solution under nitrogen of the compound prepared in Example 1, step 6,
(717
mg, 1.00 mmol), palladium(II)acetate (22 mg, 0.100 mmol), and
triphenyphosphine (52
mg, 0.200 mmol) in acetonitrile (5 mL) was added iodobenzene (220 L, 2.00
mmol) and
triethylamine (280 .L, 2.00 mmol) and the mixture was cooled to -78 C,
degassed, and
sealed. The reaction mixture was then warmed to 60 C for 0.5 hours and
stirred at 80 C
for 12 hours. The reaction mixture was taken up in ethyl acetate and washed
twice with
aqueous 5% sodium bicarbonate, once with aqueous 2%
tris(hydroxymethyl)aminomethane, and once with brine, dried over sodium
sulfate, filtered,
and concentrated in vacuo. Chromatography on silica gel (95:5:0.5
dichioromethane-
methanol-ammonia) gave the title compound (721 mg) as an off-white foam.
Step 14b: Compound of Formula (VIII): X is 0. R is -CH2CH=CH-Phenyl.
Deprotection of the compound prepared in step 14a was accomplished by heating
in
methanol according to the procedure of Example 1, step g. 13C NMR (CDC13) S
219.4 (C-
9), 206.0 (C-3), 169.8 (C-1), 137.0, 132.6, 128.3, 127.3, 126.7, 126.6, 102.7,
78.4,
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78.2, 75.9, 74.3, 70.3, 69.5, 69.1, 65.9, 64.2, 50.6, 45.4, 45.3, 40.2, 38.7,
37.7, 28.3,
21.9, 21.2, 20.3, 18.1, 16.5, 14.6, 13.0, 12.3, 10.8. MS (FAB)+ m/e 690
(M+H)+.
Example 15
Compound of Formula (VIII): X is O. R is -CH2CHqCH?-Phenyl.
A solution of the compound prepared in Example 14 (170 mg, 0.247 mmol) in
methanol (10 mL) was flushed with nitrogen. 10% Palladium on carbon (50 mg)
was
added and the mixture was flushed with hydrogen and stirred for 18 hours under
positive
hydrogen pressure. The reaction mixture was-filtered through celite and the
filter cake was
rinsed with dichloromethane. The filtrate was concentrated in vacuo to give a
colorless
glass. The glass was taken up in ether, hexane was added and the solvents were
removed in
vacuo to give the title compound (67 mg) as a white solid. 13C NMR (CDC13) S
220.2 (C-
9), 206.5 (C-3), 170.0 (C-1), 142.3, 128.4, 128.1, 125.4, 102.6, 78.2, 78.0,
75.6, 74.2,
70.3, 69.5, 69.4, 65.9, 62.1, 50.6, 45.4, 44.6, 40.2, 38.8, 37.5, 32.1, 30.3,
28.4, 21.9,
21.3. -20.2, 18.4, 16.5., 14.9, 12.4, 10.6.- MS (FAB)+ m/e 692 (IvI+H)+. - --
_
Example 16
Compound of Formula (VIII): X is O. R is -CH2CH=CH-(4-methoxyphenyl).
The desired compound was prepared according to the method of Example 14,
except
substituting 4-iodoanisole for iodobenzene. MS (FAB)+ m/e 720 (M+H)+.
Examnle 17
Compound of Formula (VIII): X is 0. R is -CH,)CH=CH-(4-chlorophenyl.
The desired compound was prepared according to the method of Example 14,
except
substituting 1-chloro-4-iodobenzene for iodobenzene. 13C NMR (CDC13) S 219.6
(C-9),
206.0 (C-3), 169.8 (C-1), 139.6, 135.5, 131.3, 128.5, 127.9, 127.3, 102.7,
78.4, 78:2,
75.9, 74.2, 70.3, 69.5, 69.2, 65.9, 64.1, 50.6, 45.4, 45.3, 40.2, 38.6, 37.6,
28.4, 21.8,
21.2, 20.3, 18.0, 16.5, 14.6, 13.0, 12.2, 10.8. MS (FAB)+ m/e 724 (M+H)+.
Example 18
Compound of Formula (VIII): X is O. R is -CH2CH=CH-(3-quinolyl).
Step 18a: Compound 9 from Scheme 2; X is 0, R is -CH?CH=CH-(3-cLuinolyl). Rp
is
benzovl.
A mixture of the compound prepared in Example 1, step f, (1.80g, 0.25 mmol),
palladium(II)acetate (11 mg, 0.05 mmol), and tri-o-tolylphosphine (30 mg, 0.10
mmol) and
3-bromoquinoline (68 L, 0.5 mmol) in acetonitrile (2 mL) was cooled to -78
C, degassed,
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and sealed. The reaction mixture was then warmed to 50 C for 2 hours and
stirred at 80 * C
for 16 hours. The reaction mixture was taken up in ethyl acetate and washed
with aqueous
5% sodium carbonate, aqueous 2% tris(hydroxymethyl)aminomethane, and brine,
dried
over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on
silica gel
(98:2 dichloromethane-methanol) gave the title compound (186 mg) as an off-
white foam.
MS (FAB)+ m/e 845 (M+H)+.
Step 18b: Compound of Formula (VIIII: X is 0. R is -CH?CH=CH-(3-quinolyl)
Deprotection of the compound prepared in step 18a was accomplished by heating
in
methanol according to the procedure of Example 1, step g. 13C NMR (CDC13) S
219.7 (G-
9), 205.9 (C-3), 169.8 (C-1), 152.1, 150.0, 147.5, 140.2, 132.6, 130.0, 129.2,
129.1,
128.8, 128.1, 127.9, 126.5, 102.8, 78.5, 78.2, 75.9, 74.2, 70.2, 69.4, 69.2,
65.9, 64.1,
50.6, 45.4, 45.3, 40.2, 38.7, 37.6, 28.4, 21.8, 21.2, 20.3, 18.0, 16.5, 14.6,
1,3.0, 12.2,
10.8. MS (FAB)+ rn/e 741 (M+H)+.
Using the procedures described in the preceding examples and schemes and
methods
known in the synthetic organic chemistry art, the following compounds of
Formula VIII
wherein X is 0 can be prepared. These compounds having the R substituent as
described in
the table below are of the formula
CH3
O = R NMe2
H 0,,,.
H3
C.,., 3
HO,,H O O O CH3
H3C'~' CH3
O
CH3 3
)CH
O
Ex. No. substitutent
19 R is -CH2CH27CH2OH
20 R is -CH2C(O)OH
21 R is -CH2CH2NHCH3
22 R is -CH2CH2NHCH2OH
23 R is -CH2CH2N(CH3)2
24 R is -CH2CH2(1-morpholinyl)
R is -CH2C(O)NH2
26 R is -CH2NHC(O)NH2
27 R is -CH2NHC(O)CH3
28 R is -CH2F
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29 R is -CH2CH2OCH3
30 R is -CH2CH3
31 R is -CH2CH=CH(CH3)2
32 R is -CH2CH2CH(CH3)CH3
33 R is -CH2CH2OCH2CH2OCH3
34 R is -CH2SCH3
35 R is -cyclopropyl
36 R is -CH2OCH3
37 R is -CH2CH2F
38 R is -CH2-cyclopropyl
39 R is -CH2CH2CHO
40 R is -C(O)CH2CH2CH3
41 R is -CH2-(4-nitrophenyl)
42 R is -CH2-(4-chlorophenyl)
43 R is -CH2-(4-methoxyphenyl)
44 R is -CH2-(4-cyanophenyl)
45 R is -CH2CH=CHC(O)OCH3
46 R is -CH2CH=CHC(O)OCH2CH3
47 R is -CH2CH=CHCH3
48 R is -CH2CH=CHCH2CH3
49 R is -CH2CH=CHCH2CH2CH3
50 R is -CH2CH=CHSO2-phenyl
51 R is -CH2C=C-Si(CH3)3
52 R is -CH2C=CCH2CH2CH2CH2CH2CH3
53 R is -CH2C=CCH3
54 R is -CH2-(2-pyridyl)
55 R is -CH2-(3-pyridyl)
56 R is -CH2-(4-pyridyl)
57 R is -CH2-(4-quinolyl)
58 R is -CH2NO2
59 R is -CH2C(O)OCH3
60 R is -CH2C(O)-phenyl
61 R is -CH2C(O)CH2CH3
62 R is -CH2C1
63 R is -CH2S(O)2-phenyl
64 R is -CH2CH=CHBr
65 R is -CH2CH=CH-(4-quinolyl
66 R is -CH2CH2CH2-(4-quinolyl
67 R is -CH2CH=CH-(5-quinolyl
68 R is -CH2CH2CH2-(5-quinolyl
69 R is -CH2CH=CH-(4-benzoxazolyl
70 R is -CH2CH=CH-(7-benzimidazolyl
Example 71
Compound of Formula (IX): L is CO. T is O, R is -CH?CH=CH2
Step 71 a: Compound 10 frurn Scheme 2: R is R is -CH2(:H=CH?. RL is benzoyl.
To a -35 C solution under nitrogen in THF (60 mL) of the compound prepared in
Example 1, step f, (3.58 g, 5.00 mmol) was added sodium hexamethyldisilazide
(1.0 M in
THF, 5.5 mL, 5.5 mmol) and the resulting white suspension was stirred for 30
minutes. A
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solution of carbonyldiimidazole (4.05 g, 25 mmol) in THF (40 mL) was added
dropwise
over 20 minutes at -35 C and then the cold bath was removed and the reaction
mixture was
stirred for 30 minutes. The reaction mixture was taken up in ethyl acetate and
washed with
aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, filtered,
and
concentrated in vacuo. Chromatography on silica gel (30% acetone-hexane) gave
the title
compound (2.6 g) as a white foam. MS (FAB)+ m/e 744 (M+H)+.
Sten 71 b: Compound of Formula (IX): L is 'CO, T is Q. R is -CH2CH=CH?.
Deprotection of the compound prepared in step 71 a was accomplished by heating
in
lo methanol according to the procedure of Example 1, step g. 13C NMR (CDC13) S
212.1 (C-
9), 205.0 (C-3), 168.9 (C-1), 153.8, 134.4, 118.4, 103.1, 84.7, 80.5, 78.7,
77.1, 76.9,
70.3, 69.5, 65.9, 64.8, 50.8, 46.5, 44.1, 40.2, 38.8, 38.1, 28.4, 22.7, 21.2,
20.5, 18.3,
14.5, 13.6, 12.6, 10.6. MS (FAB)+ m/e 640 (M+H)+.
Example 72
Compound of Formula (IX): L is CO. T is O. R is -CH2CH=CH-Phen -l.
Step 72a: Compound 10 from Scheme 2; R is -CH2CH=CH-Phenyl. RRis benzoyl.
A solution of the compound prepared in Example 14, step a (150 mg, 0.20 mmol)
in
20 THF (5 mL) was cooled to -35 C and flushed with nitrogen. Lithium
hexamethyldisilazide
(1.0 M in THF, 0.22 mL, 0.22 mmol) over 2 minutes at -35 C. The reaction
mixture was
stirred for 10 minutes at -35 C and then a solution of carbonyldiimidazole
(162 mg, 1.00
mmol) in THF (3 mL) was added dropwise over 2 minutes. The cold bath was
removed
and the reaction mixture was stirred for 30 nminutes. The reaction nuxture was
cooled to 0
25 C and aqueous 0.5 M KH2P04 was added. The mixture was extracted with ethyl
acetate
and the organic phase was washed with brine, dried over sodium sulfate, and
concentrated
in vacuo. Chromatography on silica gel (30% acetone-hexane) gave the title
compound (87
mg) as a white solid. MS (FAB)+ m/e 820 (IVI+H)+.
30 Sten 72b: Compound of Formula (IX): L is CO. T is 0. R is -CH9CH=CH-Phenvl
Deprotection of the compound prepared in step 72a was accomplished by heating
in
methanol according to the procedure of Example 1, step g. 13C NMR (CDC13) S
212.4 (C-
9), 205.2 (C-3), 168.3 (C-1), 153.3, 136.4,134.9, 128.3, 127.6, 127.0, 124.7,
103.2,
84.5, 80.8, 78.7, 78.0, 70.3, 69.6, 65.9, 64.5, 50.9, 46.9, 44.4, 40.2, 39.1,
37.8, 28.3,
35 23.0, 21.2, 20.4, 18.1, 14.8, 14.4, 13.7, 12.6, 10.8. MS (FAB)+ m/e 716
(M+H)+.
Example 73
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Compound of Formula (IX): L is CO. T is O. R is -CH2CH2CH2-Phenvl.
Step 73a: Compound 8 from Scheme lb: R is -CH2CH2CH9.-Phenyl. Rp is benzovi.
The desired compound was prepared by reaction of the compound of Example 15
with benzoic anhydride according to the procedure of Example 1, step e.
Step 73b: Compound 10 from scheme 1 b: R is -CH2CH2CH2-Phenyl, RD is benzoyl.
A solution of the compound prepared in step 73a (104 mg, 0.13 mmol) in THF (5
mL) was cooled to -35 C and flushed with nitrogen. Sodium
hexamethyldisilazide (1.0 M
in THF, 0.16 mL, 0.16 mmol) over l minute at -35 C. The reaction mixture was
stirred .
for 10 minutes at -35 C and then a solution of carbonyldiimidazole (105 mg,
0.65 mmol) in
THF (3 mL) was added dropwise over l minute. The cold bath was removed and the
reaction mixture was stirred for 30 minutes. The mixture was extracted with
ethyl acetate
and the organic phase was washed with aqueous 5% sodium bicarbonate and brine,
dried
over sodium sulfate, and concentrated in vacuo to give a colorless glass.
Chromatography
on silica gel (30% acetone-hexane) gave the title compound (63 mg) as a white
solid. MS
(FAB)+ m/e 822 (M+H)+.
Step 73c: Compound of Formula (IX): L is CO. T is O. R is -CH,)CH2CH9-Phenvl.
Deprotection of the compound prepared in step 73b was accomplished by heating
in
methanol according to the procedure of Example 1, step g. 13C NMR (CDC13) S
211.8 (C-
9), 205.1 (C-3), 169.6 (C-1), 153.6, 141.9, 128.5, 128.1, 125.5, 102.7, 84.6,
80.5,
78.3, 76.0, 70.2, 69.5, 65.9, 62.4, 50.7, 45.5, 44.5, 40.2, 38,6, 37.9, 31.9,
30.4, 28.4,
22.6, 21.2, 20.3, 18.5, 14.6, 13.4, 13.3, 12.6, 10.4. MS (FAB)+ m/e 718
(M+H)+.
Example 74
Compound of Formula (IX): L is CO. T is 0. R is -CH2CH=CH-(4-chlorophen,till
Sten 74a: Compound 10 from Scheme lb= R is -CH2CH=CH-(4-chlorophenvll RR is
benzoyl.
A solution of the compound of formula 10 (R is -CH2CH=CH-(4-chlorophenyl),
Rp is benzoyl), prepared as in Example 17, (165 mg, 0.20 mmol) in THF (5 mL)
was
cooled to -35 C and flushed with nitrogen. Lithium hexamethyldisilazide (1.0
M in THF,
0.22 mL, 0.22 nunol) over 2 minutes at -35 C. The reaction mixture was
stirred for 10
minutes at -35 C and then a solution of carbonyldiimidazole (105 mg, 0.65
mmol) in THF
(3 mL) was added dropwise over 2 minutes. The cold bath was removed and the
reaction
mixture was stirred for 30 minutes. The mixture was extracted with ethyl
acetate and the
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organic phase was washed with aqueous 5% sodium bicarbonate and brine, dried
over
sodium sulfate, and concentrated in vacuo to give a colorless glass (219 mg)
which was
used without further purification. MS (FAB)+ m/e 854 (M+H)+.
Step 74b: Compound of Formula (IX): L is CO. T is O, R is -CH2CH=CH-(4-
chlorophenyl).
Deprotection of the compound prepared in step 74a was accomplished by heating
in
methanol according to the procedure of Example 1, step g. 13C NMR (CDC13) S
212.4 (C-
9), 205.1 (C-3), 168.6 (C-1), 153.3, 135.0, 133.5, 133.2, 128.5, 128.3, 125.5,
103.2,
84.5, 80.7, 78.8, 78.0, 70.3, 69.6, 66.0, 64.3, 50.9, 46.9, 44.4, 40.2, 39.1,
37.8, 28.4,
23.0, 21.2, 20.4, 18.1, 14.8, 14.4, . 13.6, 12.6, 10.7. MS (FAB)+ m/e 750
(M+H)+.
ExamRle 75
Compound of Formula (IX): L is CO. T is O. R is -CH2CH=CH-(3-quinolyl).
The compound formula 10 (R is -CH2CH=CH-(3-quinolyl), Rp is benzoyl),
. .~
prepared as in Example 18, was converted to the title compound using the
procedure of
Example 71, steps a and b. 13C NMR (CDC13) S 212.4 (C-9), 205.2 (C-3), 168.7
(C-1),
153.4, 150.3, 147.6, 132.7, 131.1, 129.6, 129.0, 128.9, 128.4, 128.1, 127.7,
126.6,
103.2, 84.5, 80.6, 78.9, 77.5, 77.0, 70.3, 69.6, 65.9, 64.3, 50.9, 46.9, 44.5,
40.3,
39.0, 37.8, 28.4, 22.8, 21.2, 20.4, 18.1, 14.7, 14.4, 13.5, 12.6, 10.6. MS
(FAB)+ m/e
767 (M+H)+.
Using the procedures described in the preceding examples and schemes and
methods
known in the synthetic organic chemistry art, the following compounds of
Formula IX
wherein L is CO and T is 0 can be prepared. These compounds having the R
substituent as
described in the table below are of the formula
CH3
O R NMe2
H3C,,, 0~..
O O CH3
H3C%"' CH3
O
)CH3
CH3 O
Ex. No. Substituent
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76 R is -CH2CH2CH.z.
77 R is -CH2CH2NH2.
78 R is -CH2CH=NOH.
79 R is -CH2CH2)CH2OH
80 R is -CH2F
81 R is -CH2CH2-phenyl
82 R is -CH2CH2-(4-pyridyl)
83 R is -CH2CH,)-(4-quinolyl)
84 R is -CH2CH(OH)CN
85 R is -CH(C(O)OCH3)CH2-phenyl
86 R is -CH2CN
87 R is -CH2CH=CH-(4-methoxyphenyl)
88 R is -CH2CH=CH-(4-fluoropheny])
89 R is -CH2CH=CH-(8-quinolyl)
90 R is -CH2CH,)NHCH,)-phenyl
91 R is -CH2-phenyl
92 R is -CH2-(4-pyrid}'l)
93 R is -CH2-(4-quinolyl)
94 R is -CH2CH=CH-(4-pyridyl)
95 R is -CH2CH2CH2-(4-pyridyl)
96 R is -CH2CH=CH-(4-quinolyl)
97 R is -CH2CH2CH2-(4-quinolyl)
98 R is -CH2CH=CH-(5-quinolyl)
99 R is -CH2CH,)CH,)-(5-quinolyl)
100 R is -CH2CH=CH-(4-benzoxazolyl)
101 R is -CH2CH=CH-(4-benzimidazolyl)
Example 102
Compound of Formula (IX): L is CO. T is NH. R is -CH?CH=CH2.
Sten 102a: Compound 11 from Scheme 2: R is -CHICH=CH2. RP is benzovl.
To a solution of compound 10 (R is -CH2CH=CH2, RP is benzoyl), prepared as in
Example 71, step a, (2.59 g, 3.48 mmol) in benzene (100 mL) was added 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 5.0 mL, 34 mmol). The reaction mixture
was
~.=
. ~
flushed with nitrogen, warmed to 80 oC, and stured for 3.5 hours. The reaction
rruxture
was cooled to 0 C and aqueous 0.5 M NaH2PO4 (100 mL) was added. The niixture
was
extracted twice with ethyl acetate and the combined organic layers were washed
with brine,
dried over sodium sulfate and concentrated in vacuo to give a white foam.
Chromatography
on silica gel (30% acetone-hexanes) gave the title compound (1.74 g) as a
white solid. MS
(FAB)+ m/e 700 (M+H)+.
Step 102b: Compound 12 from Scheme 3a= R is -CH2CH=CH~. RP is benzovl.
A solution in THF (30 mL) of the compound prepared in step 102a (1.74 g, 2.49
mmol) was cooled to -10 C and flushed with nitrogen. Sodium hydride (80% in
mineral
oil, 150 mg, 5.00 mmol) was added and the reaction mixture was stirred for 10
minutes. A
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solution of carbonyldiimidazole (1.22 g, 7.50 mmol) in THF (20 mL) was added
over 10
minutes at -10 C. The cold bath was removed and the reaction mixture was
stirred for I
hour. The reaction mixture was extracted with ethyl acetate and the organic
phase was
washed with aqueous 5% sodium bicarbonate and brine, dried over sodium
sulfate, and
concentrated in vacuo to give a white foam. Chromatography on silica gel (30%
acetone-
hexanes) gave the title compound (1.58 g) as a white solid. MS (FAB)+ m/e 794
(M+H)+.
Step 102c: Compound 18 from Scheme 4: R is -CH?CH=CH2, RP is benzoyl.
The compound prepared in step 102b (1.19 g, 1.5 mmol) was dissolved in THF (2
lo mL) and acetonitrile (20 mL) and the solution was flushed with nitrogen.
Aqueous
ammonium hydroxide (28%, 21 mL) was added and the reaction mixture was stirred
under
nitrogen for 24 hours. The reaction mixture was extracted with ethyl acetate
and the organic
phase was washed with aqueous 5% sodium bicarbonate and brine, dried over
sodium
sulfate, and concentrated in vacuo to give a white foam. Chromatography on
silica gel
(30% acetone-hexanes) gave the title compound (0.56 g) as a white solid. MS
(FAB)+ m/e
743 (M+H)+.
Sten 102d: Compound of Formula (IX): L is CO. T is NH, R is -CH2CH=CH2
The title compound was prepared by deprotection of the compound prepared in
step
102c by heating in methanol according to the procedure of Example 1, step g.
13C NMR
(CDC13) S 216.9 (C-9), 205.3 (C-3), 169.5 (C-1), 158.0, 134.4, 118.2, 102.8,
83.7,
78.4, 77.1, 76.1, 70.2, 69.5, 65.9, 64.7, 57.8, 50.8, 45.9, 45.1, 40.2, 38.9,
37.3, 28.3,
22.6, 21.2, 20.2, 18.1, 14.5, 13.8, 13.7, 10.6. MS (FAB)+ m/e 639 (M+H)+.
Example 103
Compound of Formula (IX): L is CO. T is NH, R is -CH?CH=CH-Phenvl
The desired compound was prepared using the procedure of Example 18, except
substituting the compound prepared in Example 102, step c, (which is the
compound 18 of
Scheme 4, wherein R is allyl and RP is benzoyl) for the compound of Example 1,
step f,
used therein, and substituting iodobenzene for 3-bromoquinoline. 13C NMR
(CDC13) S
217.1 (C-9), 205.3 (C-3), 169.5 (C-1), 157.4, 136.5, 133.7, 128.6, 127.8,
126.5, 125.4,
102.9, 83.4, 78.4, 77.7, 76.4, 70.3, 69.5, 65.9, 64.3, 58.2, 50.9, 46.3, 45.1,
40.2,
39.1, 37.3, 31.5, 28.3, 22.8, 21.2, 20.3, 18.1, 14.4, 14.2, 13.7, 10.8. MS
(FAB)+ m/e
715 (M+H)+.
Example 104
Compound of Formula (IX): L is CO T is NH R is -CH CH=CH-(3-quinolyl)
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The desired compound was prepared using the procedure of Example 18, except
substituting the compound prepared in Example 102, step c, (which is the
compound 18 of
Scheme 4, wherein R is allyl and RP is benzoyl) for the compound of Example 1,
step f,
used therein. 13C NMR (CDC13) S 217.4 (C-9), 205.3 (C-3), 169.6 (C-1), 157.7,
149.7,
147.6, 132.5, 129.9, 129.6, 129.2, 129.1, 128.6, 128.1, 126.7, 102.9, 83.5,
78.8, 77.5,
76.5, 70.2, 69.5, 65.9, 64.3, 58.2, 50.9, 46.3, 45.1, 40.2, 39.1, 37.4, 28.2,
22.6, 21.2,
20.2, 18.1, 14.4, 14.2, 13.7, 10.7. MS (FAB)+ m/e 766 (M+H)+.
Using the procedures described in the preceding examples and schemes and
methods
t0 known in the synthetic organic chemistry art, the following compounds of
Formula IX
wherein L is CO and T is NH can be prepared. These compounds having the R
substituent
as described in the table below are of the formula:
CH3
0 NMe2
H~ H3C,,, O H 0''==
O=< N~=,.
O
0 0 CH3
H3C"0 CH3
0
CH3 CH3
0
Ex. No. Substituent
105 R is -CH2CH2CH3.
106 R is -CH2CH2NH2.
107 R is -CH2CH=NOH.
108 R is -CH2CH2CH2OH
109 R is -CH2F
110 R is -CH2CH2NHCH2-phenyl
11 I R is -CH2CH2Nrf-ICH2-(4-pyridyl)
112 R is -CH2CH2NHCH2-(4-quinolyl)
113 R is -CH2CH(OH)CN
114 R is -CH(C(O)OCH3)CH2-phenyl
115 R is -CH2CN
116 R is -CH2CH=CH-(4-chlorophenyl)
117 R is -CH2CH=CH-(4-fluorophenyl)
118 R is -CH2CH=CH-(4-methoxypheny1)
119 R is -CH2CH2CH2-(4-ethoxyphenyl)
120 R is -CH2CH=CH-(3-quinoly1)
121 R is -CI12CH2NHCH2CH2-(2-chlorophenyl)
122 R is -CH2-phenyl
123 R is -CH2-(4-pyridyl)
124 R is -CH2-(4-quinolyl)
125 R is -CH2CH=CH-(4-pyridyl)
126 R is -CH2CH2CH2-(4-pyridyl)
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127 R is -CH2CH=CH-(4-quinolyl)
128 R is -CH2CH2CH2-(4-quinolyl)
129 R is -CH2CH=CH-(5-quinolyl)
130 R is -CH2CH2CH2-(5-quinolyl)
131 R is -CH2CH=CH-(4-benzoxazolyl)
132 R is -CH2CH=CH-(4-benzimidazolyl)
133 R is -CH2CH=CH-(8-quinolyl)
Example 134
Compound of Formula (V1I): A, B, D, and E are H, R is allyl.
Step 134a: Compound of Formula 14 (Scheme 3a): A, B, D, and E are H, R is
allyl, RD is
benzoyl.
To a solution under nitrogen of a compound of formula 12 (R is allyl, Rp is
benzoyl, 385 mg, 0.485 mmol), prepared as in Example 102, step b, in
acetonitrile was
added ethylenediamine (291 mg, 4.85 mmol) and the reaction mixture was stirred
for 67
-.10 hours. The reaction mixture was extracted with ethyl acetate and the
organic phase was
washed with aqueous 5% sodium bicarbonate and brine, dried over sodium
sulfate, and
concentrated in vacuo to give the title compound (401 mg) as colorless oil
which was used
without further purification.
Step 134b: ComQound of Formula (VII): A, B, D, and E are H, R is allyl.
The crude oil prepared in step 134a was dissolved in methanol (5 mL), acetic
acid
(60 L) was added, and the reaction mixture was stirred for 15 hours at
ambient
temperature. The reaction mixture was extracted with ethyl acetate and the
organic phase
was washed with aqueous 5% sodium bicarbonate and brine, dried over sodium
sulfate, and
concentrated in vacuo to give a slightly yellow glass (347 mg). Chromatography
on silica
gel (95:5:0.5 dichloromethane=methanol-ammonia) gave the title compound (126
mg) as a
white foam. MS m/e 664 (M+H)+.
Using the procedures described in the preceding examples and schemes and
methods
known in the synthetic organic chemistry art, the following compounds of
Formula VII
wherein A, B, D and E are H can be prepared. These compounds having the R
substituent
as described in the table below are of the formula:
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CH3
N = R NM92
~0 O
H3C//i.. ~~ CH3
11 n. O
O~ O CH3
H CCH3
3 p
O
CH3 CH3
O
Ex. No. Substituent
135 R is -CH2CH2CH3.
136 R is -CH2CH2NH2.
137 R is -CH2CH=NOH.
138 R is -CH2CH2CH2OH
139 R is -CH2F
140 R is -CH2CN
141 R is -CH2CH(OH)CN
142 R is -CH2-phenyl
143 R is -CH2-(4-pyridyl)
144 R is -CH2-(4-quinolyl)
145 R is -CH2CH=CH-(4-pyridyl)
146 R is -CH2CH=CH-(4-chlorophenyl)
147 R is -CH2CH=CH-(4-fluorophenyl)
148 R is -CH2CH=CH-(4-methoxyphenyl)
149 R is -CH2CH2CH2-phenyl
150 R is -CH2CH=CH-(4-pyridyl)
151 R is -CH2CH2CH2-(4-pyridyl)
152 R is -CH2CH=CH-(4-quinolyl)
153 R is -CH2CH2CH2-(4-quinolyl)
154 R is -CH2CH=CH-(5-quinolyl)
155 R is -CH2CH2CH2-(5-quinolyl)
156 R is -CH2CH=CH-(4-benzoxazolyl)
157 R is -CH2CH=CH-(4-benzimidazolyl)
158 R is -CH2CH=CH-(8-quinolyl)
159 R is -CH2CH2NHCH2-phenyl
160 R is -CH2CH2NHCH2-(4-pyridyl)
161 R is -CH2CH2NHCH2-(4-quinolyl)
162 R is -CH2CH2NHCH(CH2-phenyl)C(O)OCH3
163 R is -CH2CH2NHCH2CH2-(2-chlorophenyl)
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Example 164
Compound of Formula (VII): A. B and E are H. D is benzy], R is al]yl.
Step 614a: 2-(R)-(BOC-amino)-3-phenyl-1-propanol.
To a 5.2 g (23.8 mmol) sample of di-t-butyl dicarbonate in 20 mL of inethylene
chloride held at 0 C was added (R)-2-amino-3-phenyl-l-propanol (3.0 g, 19.8
mmol,
Aldrich), and the reaction mixture was stirred 1.5 hours at room temperature.
The solvent
was removed, and the residue was dried under high vacuum and taken directly to
the next
step.
Step 164b: 2-(R)-(BOC-amino)-1-O-methanesulfonvloxy-3-phenvipropane.
The material from step 164a was dissolved in 20 mL of methylene chloride and 5
mL of THF, and the solution was cooled to (1 C. Triethylamine (4.1 mL, 29.4
mmol) was
added, then methanesulfonyl chloride (1.9 mL, 24.5 mmol) was added slowly. The
mixture was stirred 45 minutes at room temperature, then the solvent was
removed under
vacuum. The residue was dissolved in ethyl acetate, and the solution was
washed with
water and brine, dried (Na2SO4) and filtered. The solvent was removed under
vacuum to
afford 6.38 g of the title compound. MS m/z (M+H)+: 330, MS m/z (M+NH4)+: 347.
Step 164c: 1-azido-2-(R)-(BOC-amino)-3-phenylnropane.
The compound from step 164b above (6.36 g, 193 mmol) was dissolved in 25 mL
of DMF, and 2.5 g (38 mmol) of NaN3 was added. The reaction mixture was
stirred for 24
hours at 62 C. The solution was cooled to room temperature, then extracted
with ethyl
acetate. The organic extract was washed with water and brine, dried (Na2SO4)
and filtered.
The solvent was removed under vacuum to afford 4.34 g of the title compound.
MS nVz
(M+H)+: 277, MS m/z (M+NH4)+: 294.
SIp 164d: I -azido-2-(R)-amino-3-phenYnropane.
The compound from step 164c (4.3 g,15.6 mmol) was dissolved in 30 mL of 4 N
HCI in ethanol, and the reaction mixture was stirred for 1.5 hours at room
temperature. The
solvent was stripped and chased with ether. The residue was dissolved in
water, NaCI was
added, and the mixture was extracted with ethyl ether, which was discarded.
The aqueous
layer was adjusted to pH 12 with.K2C03, saturated with NaCI, then extracted
with CHC13.
The organic extract was washed with brine, dried (Na2SO4) and filtered. The
solvent was
removed under vacuum to afford 2.17 g of the title compound. MS m/z (M+H)+:
177, MS
m/z (M+NH4)j: 194.
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Step 164e: 1. 2-(R)-diamino-3-phenvlpropane.
A sample of the compound from step 164d (1.2 g, 6.8 mmol) was hydrogenated (4
atm) in ethanol over 1.2 g of 10% Pd/C for 21.5 hours at room temperature. The
mixture
was filtered to remove the catalyst, and the solvent was removed to afford the
title
S compound (1.055 g). MS m/z (M+H)+: 151, MS m/z (M+NHd)+: 168.
Step 164f: Compound 14 from Scheme 3a: A, B and E are H, D is benzyl, R is
allyl. RLis
benzoyl
The desired compound is prepared by stirring a solution of compound prepared
as in
1() Example 102, step b, (which is the compound 12 from Scheme 3a, wherein R
is allyl, Rp is
benzoyl), and 1,2-(R)-diamino-3-phenylpropane, prepared as in step 164e above,
in
aqueous acetonitrile for an amount of time sufficient to consume substantially
all of the
starting material.
15 Step 164g: Compound 14 from Scheme 3a: A. B and E are H, D is benzvl R is
allyl Rp is
H.
The title compound is prepared by deprotection of the compound prepared in
step
164f by heating in methanol according to the procedure of Example 1, step g.
20 Stey 164h: Compound of Formula (VII): A. B and E are H, D is benzyl. R is
all~Ll.
The desired compound is prepared by heating a solution of the compound
prepared
in step 164g in ethanol-acetic acid.
Example 165
25 Compound of Formula (VII): A is benzyl. B. D and E are H. R is allvl.
. E.
Step 165a: Compound 16 from Scheme 3b: A is benzyl, B. D and E are H. Y is OH,
R is
Ialtil.Rpisbenzovl.
The desired compound is prepared according to the method of Example 164, step
f,
30 except substituting (S)-2-amino-3-phenyl-l-piopanol (Aldrich Chemical Co.)
for 1, 2-(R)-
diamino-3-phenylpropane.
Sten 165b: Compound 16 from Scheme 3b= A is bozyl B, n and E a.re H. Y is N3 R
is
la lyl. RR is benzovl.
35 The desired compound is prepared by treating a solution in THF of the
compound of
step 165a with triphenylphosphine, diethylazodicarboxylate, and
diphenylphosphorylazide.
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Step 165c: Compound 16 from Scheme 3b: A is benzyl. B. D and E are H Y is N. R
is
atlyl. RIP is H.
The desired compound is prepared by deprotection of the compound prepared in
step
165b by heating in methanol according to the procedure of Example 1, step g.
Step 165d: Compound 17 from Scheme 3b: R is allvl.
The desired compound is prepared by refluxing a solution in THF of the product
of
step 165d and triphenylphosphine.
Step 165e: Compound of Formula (VII): A is benzyl. B. D and E are H. R is
ally].
The desired compound is prepared by heating a solution of the compound
prepared
in step 165d in ethanol-acetic acid.
Example 166
~ompound of Formula (VII): A and E are phenyl. B and D and are H. R is allyl.
The desired compound is prepared according to the method of Example 164, steps
f-
h, except substituting 1,2-diphenyl-1,2-ethylenediamine (Aldrich Chemical Co.)
for 1, 2-
(R)-diamino-3-phen ylpropane.
Example 167
Compound of Formula (VII): A is methvl. B. D and E are H. R is ally].
The desired compound is prepared according to the method of Example 165,
except
substituting (S)-2-amino-l-propanol (Aldrich Chemical Co.) for (S)-2-amino-3-
phenyl-l-
propanol.
Example ] 68
Comnound of Formula (VII): A and D are methvl B and E are H, R is allyl. -
Step 168a: meso-2.3-bis(methanesulfonyloxy)butane.
Samples of meso-2,3-butanediol (10 g, 111 mmol, Aldrich) and triethylamine
(92.8
mL, 666 mmol) were dissolved in methylene chloride. The solution was cooled to
-78 C,
and methanesulfonyl chloride (25.8 mL, 333 mmol) was added dropwise. A
precipitate
formed. The mixture was diluted with additional methylene chloride, and the
mixture was
stirred for 20 minutes at -78 C and at 0 C for 2 hours. The reaction mixture
was warmed to
room temperature, diluted with additional solvent, and washed with H20,
aqueous
i+1a14CO3 and aqueous NaCI. The organic solution was dried over MgSO4, and the
solvent
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was removed to afford the title compound (25.01 g). jH NMR (300 MHz, CDC13) :
S 4:91
(q, 2H), 3.10 (s, 6H), 1.45 (d. 6H).
Step 168b: meso-2.3-diazidobutane.
A sample of the compound from step 168a (25 g) was dissolved in 250 mL of
DMF, and NaN3 (40 g) was added. The mixture was stirred vigorously at 85 C for
24
hours, then cooled to room temperature. The mixture was diluted with 800 mL of
ether,
washed with H20, aqueous NaHCO3 and aqueous NaC1, then dried over MgSO4. The
solution was filtered and concentrated to afford the title compound (13.00 g).
'H NMR
(300 MHz, CDCl3) : S 3.50 (m, 2H), 1.30 (d. 6H).
Step 168c: meso-2.3-butanediamine.
A sample of the compound from step 168b (13.0 g, 125 mmol) wasdissolved in
ethanol and hydrogenated at 4 atm over 10%'Pd/C for 20 hours at room
temperature. The
catalyst was removed by filtration, and the solvent was removed under vacuum
to afford the
title compound. 'H NMR (300 MHz. CDC13) : S 2.70 (m, 2H), 1.45 (br, 4H), 1.05
(d,
6H).
MS (m/z) : 89 (M+H)
Step l 68d: Compound of Formula (VI1): A and D are methXl. B and E are H. R is
all y].
The desired compound is prepared according to the method of Example 164, steps
c-h, except substituting meso-2.3-butanediamine, prepared as in step 168c, for
the 1, 2-(R)-
diamino-3-phenylpropane thereof.
Example 169
Compound of Formula (VII): A and E taken together is -CH2CH2CH,)-. B and D are
HLR
is allvl.
The desired compound is prepared according to the method of Example 168,
except
substituting 1,2-cyclopentane diol (Aldrich Cheniical Co.) for meso 2,3-
butanediol.
Ezanle 170
Compound of Formula (VII)= A B. D and E are H. R is -CH2CH=CH-(3- uinolyl)
The desired compound was prepared by coupling 3-bromoquinoline with the
product of Example 134 according to the method of Example 18. MS (FAB)+ m/e
791
(M+H)+.
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Example 171
Compound of Formula (VII): A. B. D. and E are H. R is -CH2CH')CH')-(3-
quinolyD.
To a sample of the compound from Example 170 (110 mg) in methanol (10 mL)
flushed with nitrogen was added 10% Pd/C (50 mg), and the mixture was stirred
at room
temperature under I atm of hydrogen for 16 hours. The mixture was filtered and
concentrated, and the residue was purified by chromatography on silica gel
eluting with
95:5:0.5 to 90:10:0.5 dichloromethane/methanol/dimethylamine to give the title
compound
(106 mg). High Res. MS m/e (M+H)+ Calcd for C44H64N4O9: 793.4752; Found
793.4766.
Example 172
Compound of Formula (VIIII: X is O. R is CH2-(3-iodonhenyl)
Following the procedures of Example 1, except substituting 3-iodobenzyl
bromide
for the ally] bromide of step If, the title compound was prepared. MS (FAB)+
m/e 949
t5 (M+H)+.
Example 173
Compound of Formula (VIII): X is O. R is CH2-(2-naphth YD
Following the procedures of Example 1, except substituting (2-naphthyl)methyl
bromide for the allyl bromide of step I a and acetic anhydride for the benzoic
anhydride in
step le, the title compound was prepared. MS (FAB)+ m/e 714 (M+H)+; Anal.
Calcd. for
C40H59NO10: C, 67.30; H, 8.33; N, 1.96; Found: C, 66.91; H, 8.29; N, 1.64.
Example 174
Compound of Formula lVIII): X is O. R is CH2-CH=CH-(4-fluorophenyl)
Following the procedures of Example 172, except substituting 4-fluoro-l-
iodobenzene for the iodobenzene of step 14a, the title compound was prepared.
Example 175
Compound of Formula (VIII): X is O. R is CH,)-CH(OH)-CN
The title compound was obtained by chromatographic separation from the
reaction
mixture of the crude product of Example 8. MS (FAB)+ m/e 643 (M+H)+.
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Example 176
Compound of Forinula (IX): L is CO. T is NH, R is -CH?-(2-naphthyl)
Step 176a. Compound 6 from Scheme la: R is -CH?-(2-naphthyl).
S Following the procedures of Example 1, steps a-c. except substituting (2-
naphthyl)methyl bromide for the allyl bromide of step 1 a, the title compound
was prepared.
MS (FAB)+ m/e 874 (M+H)+.
Step 176b. Compound 6A from Scheme lc: R is -CH2-(2-naphthyl), Rp is acetyi
The compound from step 176a (2.0 g) was treated according to the procedure of
Example I step e, except substituting acetic anhydride for the benzoic
anhydride of that
example. MS (FAB)+ m/e 958 (M+H)+.
Step 176c. Compound 6B from Scheme lc: R is -CH?-(2-naphth lv ), Rp is ac~j
The compound of step 176b (500 mg) was treated with NaH and
carbonyldiimidazole according to the procedure of Example 102 step b to afford
the title
compound (58 mg). MS (FAB)+ m/e 1034 (M+H)+.
Step 176d. Compound 6C from Scheme lc: R is -CH?-(2-naphthvl). Rp is acetvl,
Rld is H
The compound of step 176c (58 mg) was treated with ammonia in acetonitrile
according to the procedure of Example 102 step c to afford the title compound.
MS (FAB)+
m/e 983 (M+H)+.
Step 176e. Compound of formula (IX): L is CO. T is NH. R is -CH7-(2-naphthvl)
The compound of step 176d was treated according to the procedures of Example 1
steps 1 d, 1 f and 1 g, to give the title compound. MS (FAB)+ m/e 739 (M+H)f.
Example 177
Compound of Formula (III): Rc is acetvl, L is CO. T is NH, R is -CH,)CH=CH2
Step 177a. Compound 6A from Scheme Ic= R is -CH2CH=CH? RP- is ace 1
To a sample of the compound from Example 1 step c (405.2 g, 528 mmol) in
dichloromethane (20 mL) was added ciimethylTminopyridine(0.488 g, 4 mmol) and
acetic
anhydride (3.39 mL, 36 mmol), and the mixture was stiured at room temperature
for 3
hours. The mixture was diluted with methylene chloride, then washed with 5%
aqueous
sodium bicarbonate and brine and dried over Na2SO4. The residue was dried and
recrystallized from acetonitrile to give the title compound (491 g). MS m/e
857 (M+H)+.
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Step 177b. Compound 6B from Scheme Ic: R is -CH2CH=CH2. RP is ace 1
To a sample of the compound from step 177a (85.8 g, 100 mmol) in dry THF (500
mL) cooled to -40 C and flushed with nitrogen was added sodium
bis(trimethylsilyl)amide
(125 mL, 125 mmol) over 20 minutes, and the mixture was stirred at -40 C for
40 minutes.
To this mixture was added a solution of carbonyldiimidazole (3.65 g, 22.56
mmol) in 5:3
THF/DMF (800 mL) under nitrogen at -40 C over 30 minutes, and the mixture was
stirred
at -20 C for 30 minutes. The mixture was stirred at room temperature for 27
hours, then
diluted with ethyl acetate. The mixture was washed with 5% sodium bicarbonate
and brine,
dried over Na2SO4, and concentrated to give the title compound (124 g), which
was taken
directly to the next step.
Step 177c. Comnound 6C from Scheme lc; R is -CH9)CH=CH2'. Rp is acetyl_Rsl is
H
The compound from step 177b (124 g) was dissolved in 9:1 acetonitrilelTHF
(1100
mL), ammonium hydroxide (28%, 200 mL) was added, and the mixture was stirred
at room
temperature under nitrogen for 8 days. The solvent was removed, and the
residue was
dissolved in ethyl acetate. This solution was washed with 5% sodium
bicarbonate and
brine, dried over Na2SO4, and concentrated to give the title compound. MS
(FAB)+ nve
882 (M+H)+.
Step 177d. Comgound 6D from Scheme I c: R is -CH,7CH=CHq. RIl is acetyl, Rd is
H
To a sample of the compound from step 177c (69.0 g, 78.2 mmol) suspended in
ethanol (200 mL) and diluted with water (400 mL) was added HCI (0.972 N, 400
mL)
dropwise over 20 minutes. The mixture was stirred for 4 hours, and additional
HCI was
added (4 N, 100 mL) over 20 minutes. The mixture was stirred for 18 hours,
cooled to
0 C, then NaOH (4 N, 200 mL) was added over 30 minutes to approximately pH 9.
The
title compound was isolated by filtration (35.56 g)
Step 177e. Compound 6E from Scheme l c: R is -CH2CH=CHq. RII is acetvl, R-d is
H:
ICompound of Formula (III)= Rc is acetyl L is CO T is NH R is -CH&H=M)
To a -10 C solution under nitrogen of N-chlorosuccinimide (2.37 g, 17.8 mmol)
in
dichloromethane (80 mL) was added dimethylsulfide (1.52 mL, 20.8 mmol) over 5
minutes. The resulting white slurry was stirred for 10 minutes at -10 C, a
solution of the
compound from step 177d (8.10 g, 11.9 mmol) in dichloromethane (60 mL) was
added and
3S the reaction mixture was stirred for 30 minutes at -10 to -5 C.
Triethylamine (1.99 mL,
14.3 mmol) was added dropwise over 10 minutes and the reaction mixture was
stirred for I
hour at 0 C. The reaction mixture was extracted with dichloromethane. The
organic phase
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was washed with aqueous 5% sodium bicarbonate and brine, dried over sodium
sulfate, and
concentrated in vacuo to give a white foam. Chromatography on silica gel
(eluting with
50:50:0.5 acetone/hexanes/ammonium hydroxide) gave the title compound (8.27 g)
as a
white foam. Anal. Calcd. for C35H56N201 1: C, 61.75; H, 8.29; N, 4.11; Found:
C,
62.25; H, 8.50; N, 4.28.
Example 178
alternate preparation of
Compound of Formula (IX): L is CO. T is NH, R is -CH?CH=CH-(3-quinolvI)
Step 178a. (Compound of Formula (III): Rc is acetyl, L is CO, T is NH, R is
-CH7CH=CH-(3-quinolyl))
A mixture of the compound from Example 177 (46.36 g, 68.2 mmol),
palladium(II)acetate (3.055 g, 13.6 mmol), and tri-o-tolylphosphine (8.268 g,
27.2 mmol)
in acetonitrile (400 mL) was flushed with nitrogen. To this solution was added
3-
bromoquinoline (18.45 mL, 136 mmol) and triethylamine (18.92 mL, 13.6 mmol)
via
syringe. The reaction mixture was heated at 50 C for 1 hour and stirred at 90
C for 4
days. The reaction mixture was taken up in ethyl acetate and washed with
aqueous 5%
sodium bicarbonate and brine, dried over sodium sulfate, filtered, and
concentrated in
vacuo. Chromatography on silica gel (eluting with 50:50:0.5
acetone/hexanes/ammonium
hydroxide) gave the title compound (46.56 g) as a white foam. MS m/e 808
(M+H)+.
Step 178b: Compound of Formula (IX): L is CO. T is NH. R is -CH2CH=CH-(3-
uinol 1 .
Deprotection of a sample of the compound prepared in step 178a (42.43 g) was
accomplished by stirring overnight in methanol according to the procedure of
Example 1,
step g to give the title product (32.95 g). MS m/e 766 (M+H)+.
Example 179
Compound of Formula (IX): L is CO, T is N(CHy), R is -CH2CH=CH2
Ste 179a: Compound 18 from Scheme 4= R* is meth I R is -CH CH=CH2, R>? is
benzoyl.
A sample of the compound from Example 102, step 102b (Compound (12) from
Scheme 3a; R is -CH2CH=CH2, RP is benzoyl, 320 mg, 0.400 mmol) was dissolved
in
acetonitrile (10 mL) and the solution was flushed with nitrogen. Aqueous
methylamine
(40%, 0.344 mL) was added and the reaction mixture was stirred under nitrogen
for 4 days.
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The reaction mixture was extracted with ethyl acetate and the organic phase
was washed
with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, and
concentrated in vacuo to give a white foam. Chromatography on silica gel (30%
acetone-
hexanes) gave the title compound (277 mg) as a white solid. MS m/e 757 (M+H)+.
S
Step 179b. Compound of Formula (IX): L i's CO. T is N(CH3), R is -CH2CH=CH?
Deprotection of a sample of the compound prepared in step 179a (110 mg) was
accomplished by stirring overnight in methanol according to the procedure of
Example 1,
step g, to give the title product (48 mg). Anal. Calcd. for C34H56N2010: C,
62.56; H,
8.65; N, 4.29; Found: C, 62.23; H, 8.72; N, 4.13.
Example 180
Compound of Formula (IX): L is CO. T is N(CH3 . R is -CH,)CH=CH-(3-quinolyl)
Following the procedure of Example 178, except substituting the compound of
-)15 Example 179 step a for the starting material compound therein (from
Example 177), the title
compound was prepared.
Example 181
Compound of Formula (IX): L is CO. T is N(CH,)CH,)N(CH-)). R is -CHiCH=CH
Sten 181 a. Compound 18 from Scheme 4; R* is 2-(dimethvlamino)ethYl R is
-CH7CH=CH2. R2 is benzoyl.
Following the procedures of Example 179, except substituting N,N-
dimethylethylenediamine for the methylamine thereof, the title compound was
prepared (285
mg). MS m/e 814 (M+H)+.
Sten 181 a. Compound of Formula (IX): L is CO. T is N(CH2CH2N(CH R is
-CH2CH;--CH2
Deprotection of a sample of the compound prepared in step 181a (110 mg) was
accomplished by heating overnight in methanol according to the procedure of
Example 1,
step g, to give the title product (28 mg).
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Example 182
Compound of Formula (IX): L is CO. T is N(CH2CHq N(CH3)')), R is -CH-)CH=CH-(3-
uinol 1
Following the procedures of Example 178, except substituting the compound of
i Example 181 step a (162 mg) for the starting material compound therein (from
Example
177), the title compound was prepared (33.4 mg).
Example 183
Compound of Formula lIX): L is CO. T is N(CH2CH=CH2 , R is -CH2CH=CH2
Step 183a. Compound 18 from Scheme 4: R* is -CH-)CH=CH7), R is -CH2CH=CH2, RR
is
benzovl.
Following the procedures of Example 179, except substituting allylamine for
the
methylamine thereof, the title compound was prepared .
1i Step 183b. Compound of Formula (IX): L is CO, T is N(CH,)CH=CH R is
-CH?CH=CH?
Deprotection of a sample of the compound prepared in step 183a (78 mg) was
accomplished by heating overnight in methanol according to the procedure of
Example 1,
step g, to give the title product (33 mg).
Example 184
Compound of Formula (IX): L is CO. T is T is N(CH,)CH=CH-(3-quinoly))). R is
-CH2CH=CH-(3-quinolvl)
Following the procedures of Example 178, except substituting the compound of
Example 183 step a for the starting material compound therein (from Example
177), the title
compound was prepared. H. Res. M.S. Calcd. for C54H69N4010: 933.5014; Found
933.5052.
Examples 185-219
Following the procedures of Example 178, except substituting the reagent below
for
the 3-bromoquinoline of Example 178, the compounds 185-219 shown in the table
below
the following compounds 185-219 shown in the table below were prepared. These
compounds of Formula IX wherein L is CO and T is 0 having the R substituent as
described in the table below are of the formula
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CH3
~ - R NMe2
N,1. H 0~,,
H H3C11' =`0
O~.
O O CH3
H3CO CH3
O
CH3 CH3
O
Examples 185-219
Ex. reaant substituent data
No.
185 3-bromopyridine R is -CH2CH=CH-(3-pyridyl) MS 716 (M+H)+
186 2-bromonaphthalene R is -CH2CH=CH-(2-naphthyl) MS 765 (M+H)+
187 4-bromoisoquinoline R is -CH2CH=CH-(4-isoquinolinyl) H. Res. M.S.
Calcd. for
C42H60N3010:
766.4279; Found
776.4271.
188 4-bromo-1,2- R is -CH2CH=CH-(3,4- H. Res. M.S.
methylenedioxy- methylenedioxyphenyl) Calcd. for
benzene C40H58N2012:
759.4068; Found
759.4083.
189 8-bromoquinoline R is -CH2CH=CH-(8-quinolyl) MS 766 (M+H)+
190 5-bromoindole R is -CH2CH=CH-(5-indolyl) H. Res. M.S.
Calcd. for
C41H59N3010:
754.4279; Found
754.4294.
191 3-bromo-6-chloro- R is -CH2CH=CH-(6-chloro-3- - H. Res. M.S.
quinoline quinolyl) Calcd. for
C42H58N3010:
800.3889; Found
800.3880.
192 3,4-ethylenedioxy- R is -CH2CH=CH-(3,4- H. Res. M.S.
benzene ethylenedioxyphenyl) Calcd. for
C41 H60N3 012:
773.4225; Found
773.4204.
193 1 -iodo-3- R is -CH2CH=CH-(3-nitrophenyl) H. Res. M.S.
nitrobenzene Calcd. for
C39H58N3012:
760.4020; Found
760.4004.
194 6-bromoquinoline R is -CH2CH=CH-(6-quinolyl) MS 766 (M+H)+
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195 3-bromo-6- R is -CH2CH=CH-(6-nitroquinolyl) H. Res. M.S.
nitroquinoline Calcd. for
C42H59N4012:
811.4129: Found
811.4122.
196 5-bromoquinoline R is -CH2CH=CH-(5-quinolyl) H. Res. M.S.
Calcd. for
C42H60N30i0 :
766.4279; Found
766.4281.
197 2-methyl-6- R is -CH2CH=CH-(2-methyl-6- Anal. Calcd. for
bromoquinoline quinolyl) C43H61N3010:
C, 66.22; H,
7.88; N, 5.39;
Found: C. 66.43;
H, 8.12; N,
5.18.
198 * 3-bromoquinoline Compound of Formula (III): L is CO, H. Res. M.S.
T is NH, Rc is. acetyl; R is Calcd. for
-CH2CH=CH-(3-quinolyi) C44H61N3010:
808.4379; Found
808.4381.
199 5-bromoisoquinoline R is -CH2CH=CH-(5-isoquinolyl) H. Res. M.S.
Calcd. for
C42H59N3010:
766.4279; Found
766.4301.
200 6-bromo-7-nitro- R is -CH2CH=CH-(7-nitro-6- H. Res. M.S.
quinoxaline quinoxalinyl) Calcd. for
C44H57N5012:
812.4082; Found
812.4064.
201 6-amino-3- R is -CH2CH=CH-(6-amino-3- H. Res. M.S.
bromoquinoline quinolyl) Calcd. for
C42H60N4010:
781.4388; Found
781.4386.
202 3-bromo-1,8- R is -CH2CH=CH-(1,8-naphthyridin- H. Res. M.S.
naphthyridine 3-yl) Calcd. for
C41H58N4010:
781.4388; Found
781.4386.
203 6-(acetylamino)-3- R is -CH2CH=CH-(6-(acetylarnino)-3- H. Res. M.S.
bromoquinoline quinolyl) Calcd. for
C44H62N4011 :
823.4493; Found
823.4479.
204 3-bromocarbazole R is -CH2CH=CH-(3-carbazolyl) H. Res. M.S.
Calcd. for
C45H61 N3010-
804.4435; Found
803.4437.
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205 5- R is -CH2CH=CH-(5-benzimidazo]yl) H. Res. M.S.
bromobenzimidazole Calcd. for
C40H58N4010:
755.4231; Found
755.4224.
206 7-bromo-3-hydroxy- R is -CH2CH=CH-(-3-hydroxy-2-(N- H. Res. M.S.
N-(2- (2-methoxyphenyl)amido)-7-naphthyl) Calcd. for
methoxyphenyl)-2- C51 H67N3013:
napthylamide 930.4752; Found
930.4754.
207 6-bromoquinoxaline R is -CH2CH=CH-(6-quinoxalinyl) H. Res. M.S.
Calcd. for
C41H59N4013:
767.4231; Found
767.4236.
208 3-bromo-6- R is -CH2CH=CH-(6-hydroxy-3- H. Res. M.S.
hydroxylquinoline quinolyi) Calcd. for
C42H6ON3011 :
782.4228; Found
782.4207.
209 3-bromo-6- R is -CH2CH=CH-(6-methoxy-3- H. Res. M.S.
methoxyquinoline quinolyl) Calcd. for
C43H62N3011 :
796.4384; Found
796.4379.
210 3-bromo-5- R is -CH2CH=CH-(5-nitro-3-quinolyl) H. Res. M.S.
nitroquinoline Calcd. for
C42H59N4012:
811.4129; Found
811.4146.
211 3-bromo-8- R is -CH2CH=CH-(8-nitro-3-quinolyl) Anal. Calcd. for
nitroquinoline C42H58N4012:
C, 62.21; H,
7.21; N, 6.91;
Found: C, 62.56;
H, 7.48; N,
6.61.
212 2-chloroquinoline R is -CH2CH=CH-(2-quinolyl) MS (M+H)+ 766.
213 4-chloroquinoline R is -CH2CH=CH-(4-quinolyl) MS 766 (M+H)+
214 3-bromoquinoline-6- R is -CH2CH=CH-(4-carboxyl-3- MS (M+H)+ 810.
carboxylic acid quinolyl)
215 3-bromo-6- R is -CH2CH=CH-(6-fluoro-3- Anal. Calcd. for
fluoroquinoline quinolyl) C42H58FN3010:
C, 64.35; H,
7.46; N, 5.36;
Found: C, 64.53;
H, 7.69; N,
5.18.
216 3-bromoquinoline-6- R is -CH2CH=CH-(6- MS (M+H)+ 824.
carboxylic acid methoxycarbonyl-3-quinolyl)
methyl ester
217 3-bromoquinoline-6- R is -CH2CH=CH-(6-aminocarbonyl- MS (M+H)+ 809.
carboxamide 3-quinolyl)
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218 3-bromo-6- R is -CH2CH=CH-(6-cyano-3- MS (M+H)+ 79).
cyanoquinoline quinolyl)
219 3-bromo-6- R is -CH2CH=CH-(3-bromo-6- MS (M+H)+ 844.
iodoquinoline quinolyl)
* without deprotection step
Example 220
Compound of Formula (IX): L is CO. T is NH. R is -CH2C(O)H
The compound from Example 102 (14.0 g) was dissolved in CH2C12 (200 mL) and
the solution was cooled to -78 C under a nitrogen atmosphere. Ozone was then
bubbled
through the solution until a blue color persisted. The reaction was then
purged with N2 until
colorless and dimethylsulfide (14 mL) was added, and the reaction mixture was
warmed to
0 C. After stirring for 90 min, the reaction mixture was concentrated under
reduced
pressure to give a light-yellow foam. This material was dissolved in THF (300
mL) and
treated with triphenylphosphine (8 g) at reflux for 6 hours, then the reaction
mixture was
concentrated under reduced pressure. Chromatography ( l:1 acetone/hexanes to
3:1
acetone/hexanes with 0.5% TEA) gave the product (6.6 g) as an off-white foam.
MS(CI)
m/e 641 (M+H)+.
Example 221
Compound of Formula (IX): L is CO. T is NH. R is -CHgCH2NHCH?Phenyl
The compound from Example 220 (120 mg, 0.187 mmol) and benzylamine (40 L,
0.366 mmol, 2 equiv) were dissolved in 3 mL of dry dichloromethane. Molecular
sieves
(4A) were added and the reaction was stirred overnight. The reaction was then
filtered and
concentrated under reduced pressure. The resulting imine was dissolved in MeOH
(5 mL),
a catalytic amount of 10% Pd on carbon was added, and the reaction was stirred
rapidly
under 1 atm of H2 pressure for 20 hours, The mixture was then filtered through
a Celite
pad, and the solution concentrated under reduced pressure. Chromatography
(Si02, 5%
2S MeOH/dichloromethane with 0.2% NH4OH) gave the desired material (84 mg) as
a white
solid. 13C NMR (CDC13) S 218.3, 205.6, 170.3, 157.9, 140.2, 128.2, 126.8,
102.4,
83.5, 78.2, 76.9, 75.1, 70.1, 69.5, 65.9, 62.0, 58.4, 53.8, 50.6, 48.2, 45.3,
44.8, 40.1,
39.0, 37.4, 28.2, 22.4, 21.2, 20.6, 18.3, 14.6, 13.6, 13.5, 12.7, 10.3. MS(CI)
m/e 732
(M+H)+.
Example 222
Compound of Formula (I3C): L is CO. T is NH, R is -CH2CH2NHCHgCH2Phenyl
The title compound was prepared from the compound of Example 220 (108 mg,
0.169 mmol) and phenethylaniine (42 L, 0.334 mmol, 2 equiv) using the
procedure
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described for Example 221. Chromatography (Si02, 5% MeOH/dichloromethane with
0.5% NI-i4OH) gave the desired material (82 mg) as a white solid. 13C NMR
(CDC13) S
218.1, 205.5, 170.3, 158.0, 140.2, 128.8, 128.2, 125.8, 102.4, 83.6, 78.3,
76.9, 75.1,
70.1, 69.5, 65.9, 61.9, 58.3, 51.5, 50.6, 48.8, 45.2, 44.9, 40.1, 38.9, 37.4,
36.5, 28.2,
s 22.4, 21.2, 20.6, 18.3, 14.6, 13.6, 13.4, 12.8, 10.3. MS(CI) m/e 746 (M+H)+.
Anal
Calcd for C40H63N3010= Found C 64.26, H 8.47, N 5.43.
Exa le 223
Compound of Formula (IX): L is CO. T is NH. R is -CH?CH-)NHCH2CH')CH?Phenvl
The title compound was prepared from the compound of Example 220 (100 mg,
0.1 56 mmol) and 3-phenyl-l-propylamine (40 L, 0.282 mmol, 1.8 equiv) using
the
procedure described for Example 221. Chromatography (Si02, 5%
MeOH/dichloromethane
with 0.5% NH4OH) gave the desired material (45 mg) as a white solid. 13C NMR
(CDC13)
S 218.6, 205.7, 170.4, 158.1, 142.3, 128.4, 128.2, 125.6, 102.4, 83.7, 78.3,
77.0,
]S 75.2, 70.2, 69.5, 65.9, 62.0, 58.4, 50.6, 49.2, 49.0, 45.3, 44.9, 40.2,
39.0, 37.5, 33.7,
31.7, 28.2, 22.4, 21.2, 20.7, 18.3, 14.6, 13.6, 13.5, 12.8, 10.3. MS(CI) m/e
760
(M+H)+. Anal Calcd for C41H65N3010-
Examnle 224
Compound of Formula (IX): L is CO. T is NH, R is
-CH2CH?NHCH2CH2CH2CHgPhenvl
The title compound was prepared from the compound of Example 220 (170 mg,
0.266 mmol) and 4-phenyl-l-butylamine (68 L, 0.431 mmol, 1.6 equiv) using the
procedure described for Example 221. Chromatography (Si02, 5%
MeOH/dichloromethane
with 0.2% NH4OH) gave the desired material (87 mg) as a white solid. 13C NMR
(CDCI3)
S 218.6, 205.6, 170.4, 158.1, 142.6, 128.4, 128.1, 125.5, 102.4, 83.7, 78.3,
77.0,
75.2, 70.2, 69.5, 65.9, 61.9, 58.4, 50.6, 50.0, 49.0, 45.3, 44.9, 40.2, 39.0,
37.5, 35.8,
29.7, 29.1, 28.2, 22.4, 21.2, 20.7, 18.3, 14.6, 13.6, 13.5, 12.7, 10.3. MS(CI)
m/e 774
(M+H)+. Anal Calcd for C42H67N3010. Found C 64.80, H 8.63, N 5.35.
Example 225
Compound of Formula (IX): L is CO. T is NH, R is -CH?CH2NHCH?CH2CH?-
(3-quinoly1)
The compound from Example 220 (135 mg, 0.211 mmol) and 3-(3-quinolyl)-1-
propylamine (70 mg, 0.376 mmol, 1.8 equiv) were dissolved in 4 n-iL of dry
dichloromethane. Molecular sieves (4A) were added and the reaction was stirred
overnight.
The reaction was then filtered and concentrated under reduced pressure. The
resulting imine
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was dissolved in MeOH (5 mL) and treated with NaCNBH3 (about 100 mg) and
enough
AcOH to turn bromocresol green indicator from blue to yellow. After stirring
for 4 hours,
the reaction mixture was poured into saturated NaHCO3 solution and 'extracted
into
dichloromethane. The organic portion was washed with saturated NaHCO3, H20 and
brine, dried (Na2SO4) and concentrated under reduced pressure. Chromatography
(Si02,
5% MeOH/dichloromethane with 0.5% NI-i4OH to 10% MeOH/dichloromethane with 1%
NH4OH) gave the desired material (71 mg) as a white solid. 13C NMR (CDCI3) S
218.8,
205.7, 170.5, 158.2, 152.2, 146.8, 135.0, 134.2, 129.1, 128.4, 128.2, 127.4,
126.4,
102.5, 83.8, 78.4, 77.2, 75.2, 70.2, 69.6, 65.9, 62.0, 58.4, 50.7, 49.5, 49.1,
45.4,
44.9, 40.2, 39.1, 37.6, 31.4, 30.9, 28.3, 22.6, 21.3, 20.7, 18.3, 14.7, 13.6,
13.5, 12.8,
10.3. MS(CI) m/e 811 (M+H)+. Anal Calcd for C44H66N4010. Found C 65.50, H
8.51,
N 6.66.
Example 226
Compound of Formula (IX): L is CO. T is NH. R is -CHqCH2NHCHq(3-quinoIvl)
The title compound was prepared from the compound of Example 220 (150 mg,
0.234 mmol) and 3-(aminomethyl)quinoline (100 mg, 0.633 mmol, 2.7 equiv) using
the
procedure described for Example 225. Chromatography (Si02, 5%
MeOH/dichloromethane
with 0.5% NH4OH) gave the desired material (82 mg) as a white solid. 13C NMR
(CDC13)
S 218.8, 205.5, 170.4, 158.1, 151.6, 147.3, 134.5, 133.0, 129.0, 128.7, 128.0,
127.6,
126.3, 102.4, 83.7, 78.3, 76.9, 75.1, 70.1, 69.4, 65.8, 61.8, 58.4, 51.3,
50.5, 48.5,
45.3, 44.8, 40.1, 39.0, 37.4, 28.2, 22.3, 21.2, 20.6, 18.2, 14.6, 13.6, 13.4,
12.7, 10.2.
MS(CI) m/e 783 (M+H)+. Anal Calcd for C42H62N4010. Found C 64.32, H 8.01, N
7.11.
The 3-(aminomethyl)quinoline reagent was prepared as follows:
Sten 226a. 3-(hydroxYmethyl)guinoline
, Quinoline 3-carboxaldehyde (1.0 g, 6.37 mmol) was dissolved in 20 mL of EtOH
and treated with NaBH4 (70 mg). After stirring for 1 hour, the solution was
treated with 2
mL of 1 N HC1, and after stirring for 10 min the reaction mixture was treated
with enough
IN NaOH to make the solution basic. The reaction mixture was extracted with
Et20 and the
organic portion was washed with H20 and brine. The organic portion was dried
over
Na2SO4 and concentrated under reduced pressure to give the title compound.
MS(CI) nt/c
160 (M+H)+.
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Jten 226b. 3-(azidomethvl)quinoline
3-(hydroxymethyl)quinoline (0.36 g, 2.26 mmol) and triphenyl phosphine (621
mg,
2.37 mmol, 1.05 equiv) were dissolved in 10 mL of dry THF followed by cooling
to 0 C.
The reaction mixture was treated with diphenylphosphoryl azide (570 L. 2.63
mmol, 1.16
equiv) followed by the dropwise addition of diethylazodicarboxylate (405 L,
2.57 mmol,
1.14 equ.iv). The reaction mixture was allowed to warm to room temperature
ovemight.
The reaction mixture was then concentrated under reduced pressure.
Chromatography
(Si02, 2:1 Hexanes/EtOAc) gave the desired material (350 mg) as a colorless
oil. MS(C1)
m/e 185 (M+H)+.
Step 226c. 3-(aminomethyl)guinoline
3-(azidomethyl)quinoline (250 mg, 1.36 nunol) and triphenylphosphine (880 mg,
3.36 mmol, 2.5 equiv) were dissolved in 10 mL THF. The reaction mixture was
treated
with 0.5 mL of H20 and refluxed for 6 hours. The reaction mixture was cooled
and
partitioned between Et20 and IN HC1. The aqueous portion was then treated with
1N
NaOH until basic and extracted into EtOAc. The organic portion was dried over
Na2SO4
and concentrated under reduced pressure to give the title compound (104 mg) as
a brown
oil. MS(CJ) m/e 159 (M+H)+.
Example 227
Compound of Formula (IX): L is CO. T is NH. R is -CH7CH2NHCH?(6-yuinolyl)
The title compound was prepared from the compound of Example 220 (116 mg,
0.181 mmol) and 3-(aminomethyl)quinoline (40 mg, 0.25 mmol, 1.4 equiv) using
the
procedure described for Example 221. Chromatography (Si02, 5%
MeOH/dichloromethane
with 0.5% NH4OH) gave the desired material (62 mg) as a white solid. 13C NMR
(CDC13)
S 218.7, 205.6, 170.4, 158.1, 149.8, 147.8, 138.9, 136.0, 130.3, 129.4. 128.3,
126.2,
121.0, 102.5, 83.7, 78.4, 77.0, 75.2, 70.2, 69.5, 65.9, 62.1, 58.5, 53.7,
50.6, 48.6,
45.4, 44.9, 40.2, 39.1, 37.5, 28.3, 22.4, 21.3, 20.7, 18.3, 14.7, 13.7, 13.5,
12.8, 10.3.
MS(C1) m/e 783 (M+H)+. Anal Calcd for C42H62N4010.
The 6-(aminomethyl)quinoline reagent was prepared as follows:
Step 227a. 6-(hydroxymethvl)auinoline
Quinoline 6-carboxylic acid (1.73 g, 10.0 mmol) was suspended in 40 mL of THF,
under N2 at 0 C, and treated with N-ethyl morpholine (1.3 mL, 10.2 mmol, 1.02
equiv)
followed by the dropwise addition of ethyl chloroformate (1.1 mL, 11.5 mmol,
1.15
equiv). After stirring for 15 min, the solution was filtered, and the
resulting salts were
rinsed with additional THF. The filtrate was then added to a rapidly stirring
solution of
NaBHd (760 mg, 20 mmol) in H20 (50 mL). After stirring for 20 min, the
reaction mixture
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was quenched with saturated NH4CI solution and extracted with EtOAc (2 x 50
mL). The
organic portion was washed with brine, dried over Na2SO4, and concentrated
under
reduced pressure. Chromatography (Si02, 1:3 Hexanes/EtOAc) gave the desired
material
(1.03 g) as a colorless oil. MS(C1) m/e 160 (M+H)+.
Step 227b. 6-(azidomethxl)Quinline
6-(hydroxymethyl)quinoline (0.51 g, 3.21 mmol) and triphenyl phosphine (880
mg,
3.36 mmol, 1.05 equiv) were dissolved in 15 mL of dry THF followed by cooling
to 0 C.
The reaction mixture was treated with diphenylphosphoryl azide (0.81 mL, 3.74
mmol,
1.16 equiv) followed by the dropwise addition of diethylazodicarboxylate (0.57
mL, 3.62
mmol, 1.13 equiv). The reaction mixture was allowed to warm to room
temperature
overnight, then concentrated under reduced pressure. Chromatography (Si02, 30%
EtOAc/Hexanes) gave the desired material (320 mg) as a colorless oil. MS(CI)
m/e 185
(M+H)+.
Step 227c. 6-(aminomethyl)quinoline
6-(azidomethyl)quinoline (320 mg) and triphenylphosphine (880 mg) were
dissolved in 7 mL THF. The reaction mixture was treated with 0.5 mL of H20 and
refluxed
for 7 hours. The reaction mixture was cooled and partitioned between Et20 and
IN HCI.
The aqueous portion was then treated with iN NaOH until basic and extracted
into EtOAc.
The organic portion was dried over Na2SO4 and concentrated under reduced
pressure to
give the title compound (70 mg) as a brown oil. MS(CI) m/e 159 (M+H)+.
Example 228
Comnound of Formula (IX)= L is CO. T is NH. R is -CH2CH-NO(phenyD
The compound from Example 220 (200 mg, 0.313 mmol) and O-
phenylhydroxylamine-HCl (138 mg, 0.948 mmol, 3.0 equiv) were dissolved in 4 mL
of
MeOH. Triethylamine (118 L, 0.847 mmol, 2.7 equiv) was added and the reaction
was
stirred at reflux for 3 hours. The reaction was cooled and quenched with
saturated NaHCO3
solution. The reaction mixture was extracted with dichloromethane (2 x 25 mL)
and the
combined organic portions were washed with H2O and brine. The organic portion
was
dried over Na2SO4 and concentrated under reduced pressure. Chromatography
(Si02, 5%
MeOH/dichloromethane with 0.2% NH4OH) gave the desired material (150 mg, 3:2
mixture
of oxime isomers) as a violet-colorcd solid. 13C NMR (CDC13) S 218.1, 217.4,
205.0,
169.9, 169.8, 159.1, 159.1, 157.9, 157.6, 152.9, 150.8, 129.1, 129.0, 122.2,
122.1,
114.8, 114.6, 103.2, 103.1, 83.5, 83.4, 79.8, 79.6, 77.1, 77.0, 76.9v. 70:2;
69:6, 65:8;
60.3, 58.1, 58.0, 58.0, 50.9, 50.9, 46.6, 46.6, 44.8, 44.7, 40.1, 38.7, 38.5,
37.4, 37.4,
28.2, 22.2, 22.1, 21.1, 21.1, 20.5, 20.1, 18.0, 17.9, 14.6, 14.5, 14.5, 14.4,
13.5, 13.5,
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10.4, 10.2. MS(CI) m/e 732 (M+H)+. Anal Calcd for C38H57N3011. Found C 62.30,
H
7.76, N 5.74.
Example 229
Compound of Formula (IX): L is CO. T is NH. R is -CH?CH=NOCH?(phegvl)
The title compound was prepared from the compound of Example 220 (201 mg,
0.314 mmol) and O-benzylhydroxylamine=HCl (150 mg, 0.940 mmol, 3.0 equiv)
using the
procedure described for Example 228. Chromatography (Si02, 5%
MeOH/dichloromethane
with 0.2% NH4OH) gave the desired material (170 mg, 2:1 mixture of oxime
isomers) as a
1o white solid. 13C NMR (CDC13) S 218.1, 217.2, 205.1, 170.0, 169.8, 158.0,
157.9,
150.5, 147.8, 138.1, 137.8, 128.4, 128.0, 127.8, 103.3, 103.3, 83.7, 83.7,
79.6, 79.5,
77.5, 77.3, 77.0, 76.9, 76.1, 76.0, 70.4, 69.7, 66.0, 60.5, 58.2, 58.1, 58.0,
51.0, 51.0,
46.8, 46.5, 45.0, 44.9, 40.3, 38.9, 38.7, 37.6, 28.4, 22.5, 22.4, 21.3, 20.6,
20.2, 18.2,
18.1, 14.8, 14.7, 14.6, 14.4, 13.7, 13.7, 10.6, 10.5. MS(CI) nve 746 (M+H)+.
Anal
1.5 Calcd for C39H59N301 1. Found C 62.89 H 8.04, N 5.42
Example 230
Comnound of Formula (IX): L is CO. T is NH. R is -CH2CH=NOCH?(4-NO?-UhenY1)
The title compound was prepared from the compound of Example 220 (200 mg,
20 0.313 mmol) and O-(4-nitrobenzyl)hydroxylamine=HCI (192 mg, 0.938 mmol, 3.0
equiv)
using the procedure described for Example 228. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH4OH) gave the desired material (184 mg, 2:1
mixture
of oxime isomers) as a white solid. 13C NMR (CDC13) S 218.2, 217.3, 205.0,
169.9,
169.7, 157.8, 151.2, 148.7, 147.4, 145.7, 145.5, 128.4, 128.1, 123.6, 123.5,
103.2,
25 83.6, 83.5, 79.6, 79.4, 77.1, 76.9, 76.8, 74.5, 74.3, 70.2, 69.6, 65.8,
60.2, 58.0, 57.9,
57.8, 51.0, 50.9, 46.8, 46.6, 44.9, 44.7, 40.2, 38.7, 38.5, 37.5, 37.4, 28.2,
22.4, 22.2,
21.2, 21.2, 20.5, 20.1, 18.1, 17.9, 14.8, 14.5, 14.4, 13.5, 10.5, 10.3. MS(CI)
m/e 791
(M+H)+.
30 Example 231
Comnound of Formula (IX): L is CO T is NH. R is CH2CH-NOCH2(4 quinolyl)
The compound from Example 220 (200 mg, 0.313 mmol) and O-(4-
quinolyl)methylhydroxylamine (200 mg, 0.86 mmol, 2.7 equiv) were dissolved in
4 mL of
MeOH. Catalytic pTSA=H20 was added and the reaction was stirred at reflux for
2 hours.
35 The reaction was cooled and quenched with saturated NaHCO3 solution. The
reaction
mixture was extracted with dichloromethane (2 x 25 mL) and the combined
organic portions
were washed with H20 and brine. The organic portion was dried over Na2SO4 and
concentrated under reduced pressure. Chromatography (Si02, 5%
MeOH/dichloromethane
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w-ith 0.2% NH4OH) gave the desired material (226 mg, 2:1 mixture of oxime
isomers) as a
white solid. 13C NMR (CDCI3) S 218.1, 217.3, 205.0, 205.0, 170.0, 169.8,
158.0,
157.9, 151.3, 150.3, 148.7, 148.0, 143.2, 143.2, 130.1, 130.0, 129.1, 129.1,
126.7,
126.2, 126.2, 123.4, 123.3, 119.9, 119.6, 103.2, 83.7, 83.6, 79.7, 79.5, 77.4,
77.2,
77.1, 77.0, 76.9, 72.6, 72.3, 70.3, 69.6, 65.8, 60.3, 58.1, 58.0, 57.9, 51.0,
50.9, 46.8.
46.6, 44.9, 44.8, 40.2, 38.8, 38.5, 37.5, 37.5, 28.2, 22.4, 22.2, 21.2, 21.2,
20.5, 20.2,
18.1, 18.0, 14.9, 14.6, 14.5, 13.6, 13.6, 10.6, 10.3. MS(CI) m/e 797 (M+H)+.
Anal
Calcd for C42H60N4011. Found C 63.46, H 7.80, N 6.87.
The O-(4-quinolyl)methylhydroxylamine reagent was prepared as follows:
Step 231 a. N-(4-quinolyl)methoxyphthalimide
4-(hydroxymethyl)quinoline (1.20 g, 7.55 mmol), triphenyl phosphine (2.27 g,
8.66 mmol, 1.15 equiv) and N-hydroxyphthalimide (1.42 g, 8.71 mmol, 1.15
equiv) were
dissolved in 40 mL of dry THF. Diethylazodicarboxylate (1.44 mL, 9.15 mmol,
1.21
equiv) was then added dropwise and the reaction was stirred overnight. The
reaction
mixture was then diluted with 50 mL of Et20 and filtered. The resulting solid
was
dissolved in dichloromethane and washed with 1N NaOH, H20 and brine. The
organic
portion was dried over Na2SO4 and concentrated under reduced pressure to give
the title
compound (2.03 g) as a fluffy white solid. MS(C1) m/e 305 (M+H)+.
Step 231 b. O-(4-quinolyl)methxlhvdroxylamine
N-(4-quinolyl)methoxy phthalimide (2.00 g) was suspended in 95% EtOH and
hydrazine (0.30 mL) was added. The reaction mixture was stirred for 3 h and
then filtered.
The filtrate was concentrated under reduced pressure and then taken up in a
small amount of
dichloromethane. The small amount of remaining phthalhydrazide was then
removed by
filtration. The filtrate was concentrated under reduced pressure to give the
title compound
(1.44 g) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Example 232
Compound of Formula (IX): L is CO. T is NH. R is -CH2CH=NOCH,)(2-quinoIyl)
The title compound was prepared from the compound of Example 220 (206 mg,
0.322 mmol) and O-(2-quinolyl)methylhydroxylamine (120 mg, 0.681 mmol, 2.1
equiv)
using the procedure described for Example 231. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH4OH) gave the desired material (185 mg, 3:1
mixture
of oxime isomers) as a white solid. 13C NMR (CDC13) S 217.9, 217.2, 204.9,
204.9,
169.9, 169.8, 159.0, 158.9, 157.8, 151.0, 148.7, 147.6, 136.5, 129.3, 129.2,
129.0,
127.5, 126.1, 126.0, 119.8, 119.6, 103.1, 83.5, 79.6, 79.4, 77.3, 77.0, 76.9,
76.9,
76.8, 76.7, 70.2, 69.5, 65.8, 60.4, 58.0, 58.0, 50.9, 46.5, 46.4, 44.8, 44.7,
40.1, 38.7,
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38.5, 37.4, 37.4, 28.2, 22.3, 22.2, 21.2, 21.1, 20.5, 20.1, 18.1, 18.0, 14.5,
14.4, 14.3,
13.5, 10.4, 10.3. MS(CI) m/e 797 (M+H)+.
The O-(2-quinolyl)methylhydroxylamine reagent was prepared as follows:
Sten 232a. N-(2-quinolyl)methoxyphthalimide
2-(hydroxymethyl)quinoline (1.20 g, 7.55 mmol), triphenyl phosphine (1.00 g,
6.29 mmol, 1.05 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05
equiv) were
dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol,
1.10
equiv) was then added dropwise and the reaction was stirred overnight. The
reaction
lo mixture filtered to give a white solid. The filtrate was concentrated and a
second crop of
material was obtained by triturating with Et20. This was combined with the
original solid
and recrystallization from EtOH gave the desired product (1.53 g) as a fluffy
white solid.
MS(CI) m/e 305 (M+H)+.
Sten 232b. O-(2-auinolXl)methvlhydrox l~ne
N-(2-quinolyl)methoxy phthalimide (1.53 g ) was suspended in 95% EtOH and
hydrazine (0.30 mL) was added. The reaction mixture was stirred for 5 h and
then filtered.
The filtrate was concentrated under reduced pressure and then taken up in a
small amount of
dichloromethane. The small amount of remaining phthalhydrazide was then
removed by
filtration. The filtrate was concentrated under reduced pressure to give the
title compound
(0.91 g) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Example 233
Compound of Formula (IX): L is CO. T is NH. R is -CH2CH=NOCH2(3- uinolvl)
The title compound was prepared from the compound of Example 220 (250 mg,
0.391 mmol) and O-(3-quinolyl)methylhydroxylamine (160 mg, 0.909 mmol, 2.3
equiv)
using the procedure described for Example 231. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH4OH) gave the desired material (202 mg, 2:1
mixture
of oxime isomers) as a white solid. 13C NMR (CDC13) S 217.9, 217.1, 205.0,
169.9,
169.7, 157.9, 157.8, 151.0, 150.9, 150.8, 148.4, 147.8, 135.4, 135.2, 130.6,
130.5,
129.3, 129.2, 128.0, 127.9, 127.9, 126.6, 126.5, 103.2, 83.6, 83.5, 79.5,
79.4, 77.2,
76.9, 76.7, 73.7, 73.4, 70.3, 69.6, 65.9, 60.3, 58.1, 57.9, 51.0, 50.9, 46.7,
46.4, 44.9,
44.7, 40.2, 38.8, 38.6, 37.5, 28.2, 22.4, 22.2, 21.2, 20.4, 20.1, 18.1, 18.0,
14.7, 14.6,
14.4, 14.3, 13.6, 13.5, 10.5, 10.3. MS(CI) m/e 797 (M+H)}. Anal Calcd for
C42H60N4011 . Found C 63.00 H 7.56 N 6.79.
The O-(3-quinolyl)methylhydroxylamine reagent was prepared as follows:
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Step 233a. N-(3-gpinolyl)methoxyphthalimide
3-(hydroxymethyl)quinoline (400 mg, 2.52 mmol), triphenyl phosphine (692 mg,
2.64 mmol, 1.05 equiv) and N-hydroxyphthalimide (430 mg, 2.64 mmol, 1.05
equiv) were
dissolved in 10 mL of dry THF. Diethylazodicarboxylate (0.44 mL, 2.80 mmol,
1.11
equiv) was then added dropwise and the reaction was stirred overnight. The
reaction
mixture placed in a freezer for 2 hours, and then filtered to give the desired
product (0.69 g)
as a fluffy white solid. MS(C1) m/e 305 (M+H)+.
Step 233b. O-(3-quinolvl)methylhvdroxylamine
N-(3-quinolyl)methoxy phthalimide (0.69 g) was suspended in 95% EtOH and
hydrazine (0.10 mL) was added. The reaction mixture was stirred overnight and
then
filtered. The filtrate was concentrated under reduced pressure and then taken
up in a small
amount of dichloromethane. The small amount of remaining phthalhydrazide was
then
removed by filtration. The filtrate was concentrated under reduced pressure to
give the title
compound (0.42 g) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Example 234
Compound of Formula (IX): L is CO. Tis NH, R is -CH?CH=NOCH?(6-quinolYll
The title compound was prepared from the compound of Example 220 (120 mg,
0.186 mmol) and O-(6-quinolyl)methylhydroxylamine (92 mg, 0.529 mmol, 2.8
equiv)
using the procedure described for Example 231. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH4OH) gave the desired material (89 mg, 3:1
mixture
of oxime isomers) as a white solid. 13C NMR (CDC13) S 217.9, 217.1, 204.9,
169.8,
169.6, 157.8, 157.7, 150.6, 150.1, 148.0, 147.8, 136.1, 136.1, 129.6, 129.4,
129.3,
128.0, 126.6, 126.3, 121.0, 103.0, 83.5, 83.4, 79.4, 79.3, 77.4, 77.0, 76.8,
76.7, 76.6,
75.5, 75.3, 70.1, 69.5, 65.7, 60.2, 58.0, 57.9, 57.8, 50.8, 46.6, 46.3, 44.8,
44.6, 40.1,
_.38.6, 38.4, 37:3;- 28.1; ~22-:3; -22.1; 21-.1-,-20:4;. 20:0, -1-8.0, -1=7:8;
14.7;- i4 5; 14.3-, =13:4;
10.4, 10.2. MS(CI) m/e 797 (M+H)+. Anal Calcd for C42H60N4011= Found C 63.03 H
7.60 N 6.69.
The O-(6-quinolyl)methylhydroxylamine reagent was prepared as follows:
Step 234a. N-(6-quinolyl)methoxyphthalimide
6-(hydroxymethyl)quinoline (520 mg, 3.27 mmol), triphenyl phosphine (900 mg,
3.44 mmol, 1.05 equiv) and N-hydroxyphthalimide (560 mg, 3.43 mmol, 1.05
equiv) were
dissolved in 25 mL of dry THF. Diethylazodicarboxylate (574 L, 3.63 mmol,
1.11 equiv)
was then added dropwise and the reaction was stirred overnight. The reaction
mixture
filtered to give a white solid. The filtrate was concentrated and a second
crop of material
was obtained by triturating with Et20. This was combined with the original
solid and
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recrystallization from EtOH gave the desired product (782 mg) as a fluffy
white solid.
MS(CI) m/e 305 (M+H)+.
Step 234b. O-(2-quinolyl)methylhydroxylamine
N-(2-quinolyl)methoxy phthalimide (782 mg) was suspended in 95% EtOH and
hydrazine (0.15 mL) was added. The reaction mixture was stirred overnight and
then
filtered. The filtrate was concentrated under reduced pressure and then taken
up in a small
amount of dichloromethane. The small amount of remaining phthalhydrazide was
then
removed by filtration. The filtrate was concentrated under reduced pressure to
give the title
compound (480 mg) as a yellow oil. MS(Cl) m/e 175 (M+H)+.
Example 235
Compound of Formula (IX): L is CO. T is NH. R is -CH?CH=NOCH?(1-naphthyl)
The title compound was prepared from the compound of Example 220 (117 mg,
0.183 mmol) and O-(1-naphthyl)methylhydroxylamine (80 mg, 0.462 mmol, 2.5
equiv)
using the procedure described for Example 231. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.1% NH4OH) gave the desired material (112 mg, 2:1
mixture
of oxime isomers) as a white solid. 13C NMR (CDC13) S 217.8, 217.0, 205.0,
169.9,
169.7, 157.9, 157.8, 150.3, 147.7, 133.7, 133.1, 131.8, 128.7, 128.6, 128.4,
127.1,
126.8, 126.2, 125.6, 125.3, 124.1, 103.1, 103.1, 83.6, 79.5, 79.3, 77.2, 77.0,
76.9,
74.7, 74.3, 70.3, 69.6, 65.9, 60.5, 58.1, 58.0, 51.0, 50.9, 46.6, 46.3, 44.9,
44.8, 40.2,
38.8, 38.6, 37.5, 28.3, 22.4, 22.3, 21.2, 20.5, 20.0, 14.6, 14.5, 14.1, 13.6,
10.5, 10.3.
MS(CI) m/e 796 (M+H)+. Anal Calcd for C43H61N3011= Found C 64.91 H 7.80 N
5.06.
The O-(1-naphthyl)methylhydroxylamine reagent was prepared as follows:
Step 235a. N-(1-naphthyl)methoxyphthalimide
1-(hydroxymethyl)naphthalene (1.00 g, 6.33 mmol), triphenyl phosphine (1.73 g,
6.60 mmol, 1.04 equiv) and N-hydroxyphthaiinrdde (1.08 g, 6.63 mmol, 1.05
equiv) were
dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol,
1.09
equiv) was then added dropwise and the reaction was stirred overnight. The
reaction
nuxture was diluted with 25 mL of Et20 and placed in a freezer for 2 hours.
The reaction
mixture was then filtered to give a white solid. Recrystallization from EtOH
gave the
desired product (1.21 g) as a white solid. MS(CI) m/e 321 (M+NH4)+.
Step 235b. O-(1-naphth 1)y methvlhvdroxvlamine
N-(1-naphthyl)methoxy phthalimide (1.21 g) was suspended in 95% EtOH and
hydrazine (0.20 mL) was added. The reaction nwcture was stirred overnight and
then
filtered. The filtrate was concentrated under reduced pressure and then taken
up in a small
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amount of dichloromethane. The small amount of remaining phthalhydrazide was
then
removed by filtration. The filtrate was concentrated under reduced pressure to
give the title
compound (480 mg) as a colorless oil. MS(CI) m/e 174 (M+H)+.
Example 236
Compound of Formula (IX): L is CO, T is NH. R is -CH=CH=NOCH')(2-naphthvll
The title compound was prepared from the compound of Example 220 (122 mg,
0.191 mmol) and O-(2-naphthyl)methylhydroxylamine (62 mg, 0.358 mmol, 1.9
equiv)
using the procedure described for Example 231. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.1% NI-i4OH) gave the desired material (100 mg, 3:1
mixture
of oxime isomers) as a white solid. 13C NMR (CDC13) S 217.8, 217.0, 204.9,
169.8,
169.6, 157.8, 157.7, 150.3, 147.8, 135.4, 135.1, 133.2, 132.9, 128.0, 127.9,
127.9,
127.5, 127.0, 126.7, 126.1, 125.8, 125.7, 125.7, 125.6, 103.1, 83.5, 83.5,
79.4, 79.3,
77.1, 76.9, 76.8, 76.1, 75.9, 70.2, 69.5, 65.8, 60.3, 58.0, 57.9, 57.9, 50.9,
46.6, 46.3,
44.8, 44.7, 40.1, 38.7, 38.5, 37.4, 28.1, 22.3, 22.1, 21.1, 20.4, 20.0, 18.0,
17.9, 14.6,
14.5, 14.4, 14.2, 13.5, 10.4, 10.2. MS(Cl) m/e 796 (M+H) . Anal Calcd for
C43H61N3011. Found C 64.59 H 7.72 N 5.14.
The O-(2-naphthyl)methylhydroxylamine reagent was prepared as follows:
Step 236a. N-(2-naphthvl)methoxyphthalimide
2-(hydroxymethyl)naphthalene (1.00 g, 6.33 mmol), triphenyl phosphine (1.73 g,
6.60 mmol, 1.04 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05
equiv) were
dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol,
1.09
equiv) was then added dropwise and the reaction was stirred overnight. The
reaction
mixture was placed in a freezer for 2 h and then filtered, rinsing with Et20,
to give the
product (1.38 g) as a white solid. MS(CI) m/e 321 (M+NH4)+.
. , i. :
Sten 236b. O-(2-nUhthvl)methylhydroxvlamine
N-(2-naphthyl)methoxy phthalimide (1.38 g) was suspended in 95% EtOH and
hydrazine (0.25 mL) was added. The reaction mixture was stirred overnight and
then
filtered. The filtrate was concentrated under reduced pressure and then taken
up in a small
amount of dichloromethane. The small amount of remaining phthalhydrazide was
then
removed by filtration. The filtrate was concentrated under reduced pressure to
give the title
compound (821 mg) as a colorless oil. MS(CI) m/e 174 (M+I-I)+.
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Example 237
Compound of Formula (IX): L is CO. T is NH. R is -CH,)CH2NHOCH?(phenyl)
The compound from Example 229 (120 mg, 0.161 mmol) was dissolved in MeOH
(5 mL) and treated with NaCNBH3 (about 120 mg) and enough AcOH to turn
bromocresol
green indicator from blue to yellow. After stirring for 20 hours, the reaction
mixture was
poured into saturated NaHCO3 solution and extracted into dichloromethane. The
organic
portion was washed with saturated NaHCO3, H20 and brine, dried (Na2SO4) and
concentrated under reduced pressure. Chromatography (Si02: 5%
MeOH/dichloromethane
with 0.2% NH4OH) gave the desired material (51 mg) as a white solid. 13C NMR
(CDCl3)
S 219.0, 205.7, 170.5, 157.8, 138.3, 128.1, 127.5, 102.5, 83.6, 78.6, 77.0,
75.6, 75.2,
70.2, 69.5, 66.0, 58.8, 58.3, 51.4, 50.7, 45.3, 45.0, 40.2, 39.1, 37.7, 28.3,
22.4, 21.3,
20.7, 18.2, 14.7, 13.7, 13.5, 12.8, 10.3. MS(C1) nVe 748 (M+H)+.
Example 238
Compound of Formula (IX): L is CO. T is NH. R is -CH2CH2NHOCH2(4-NO2-ohenyl)
The compound from Example 230 (64 mg) was dissolved in MeOH (3 mL) and
treated with NaCNBH3 (about 100 mg) and enough HCI to turn methyl orange
indicator
red. After stirring for 20 hours, the reaction mixture was poured into
saturated NaHCO3
solution and extracted into dichloromethane. The organic portion was washed
with H20
and brine, dried (Na2SO4) and concentrated under reduced pressure.
Chromatography
(Si02, 5% MeOH/dichloromethane with 0.2% NH4OH) gave the desired material (35
mg)
as a white solid. 13C NMR (CDC13) S 219.5, 205.5, 170.5, 157.8, 147.2, 146.8,
128.3,
123.4, 102.4, 83.6, 78.6, 76.8, 75.0, 74.3, 70.1, 69.5, 65.8, 58.4, 58.1,
51.3, 50.6,
45.3, 45.0, 40.1,. 38.9, 37.7, 28.2, 22.2, 21.2, 20.7, 18.1, 14.6, 13.5, 13.3,
12.8, 10.2.
MS(CI) m/e 793 (M+H)+.
Example 239
Comnound of Formula (IX): L is CO. T is NH. R is -CH2C(O)-nhenvl
Stev 239a. Comnound of Formula (IX): L is CO. T is NH R is -CH?C(OH)-phenvl
The compound from Example 220 (550 mg, 0.87 mmol) was dissolved in 16 mL of
dry THF and cooled to 0 C under nitrogen. Phenylmagnesium bromide (3.0 M
solution in
Et20, 3.0 mL, 6.0 mmol, 6.9 equiv) was then added dropwise via syringe. The
reaction
was stirred for 50 min, then quenched by addition of saturated NH4CI solution.
The
reaction mixture was extracted with EtOAc and the organic portion was washed
with H20
and brine, dried (Na2SO4) and concentrated under reduced pressure.
Chromatography
(SiO2, 5% MeOH/dichloromethane with 0.2% NH4OH) gave the desired material (295
mg)
as a white solid. MS(CI) m/e 719 (M+H)+.
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Step 239b. Compound of Formula (18. Scheme 4): R* is H. RR is Ac, R is -
CH,)C(OH)-
hp evl.
The compound from the previous step (180 mg, 0.250 mmol) was dissolved in 5
mL of dry dichloromethane and treated with acetic anhydride (25 L, 0.269
mmol, 1.08
equiv). After stirring overnight, then reaction was quenched by addition of
saturated
NaHC03 solution. The reaction mixture was extracted with dichioromethane and
the
organic portion was washed with brine, dried (Na2SO4) and concentrated under
reduced
pressure to give the desired material (160 mg) as a white solid. MS(CI) m/e
761 (M+H)+.
Step 239c. Compound of Formula (18. Scheme 4): R* is H, RR is Ac, R is -
CH?C(O)-
hen 1.
DMSO (145 L, 2.04 mmol, 14 equiv) was added to a cooled (-78 C) solution of
oxalyl chloride (145 mL, 1.32 mmol, 9 equiv) in 4 mL of dichloromethane under
a nitrogen
atmosphere. The compound from the previous step (113 mg, 0.149 mmol) was
dissolved
in 2 mL of dichloromethane and added to the reaction, via cannula, over 15
min. After
stirring for I hour. Et3N (0.37 mL, 2.65 mmol, 18 equiv) was added to the
reaction mixture
and the temperature was slowly raised to -20 C. The was quenched by addition
of 5%
KH2PO4 solution and extracted with dichloromethane. The organic portion was
washed
with 5% KH2PO4, H20, and brine, dried (Na2SO4) and concentrated under reduced
pressure. Chromatography (Si02, 1:1 acetone/hexanes) gave the desired material
(42 mg)
as a white powder. MS(CI) m/e 759 (M+H)+.
Sten 239d. Compound of Formula (IX): L is CO T is NH R is -CH9C(O)-nhenYl
The compound from the previous step was dissolved in 5 mL of MeOH and left to
stirred overnight. The reaction mixture was concentrated under reduced to give
the title
compound (38 mg) as a white solid. -13C INMR (CDC13) S 215.4; 206.1,-194.4,
169:6,
157.7, 135.5, 133.0, 128.5, 127.6, 103.0, 83.8, 79.6, 77.1, 77.1, 70.2, 69.5,
65.9,
65.4, 57.6, 50.9, 46.0, 44.6, 40.2, 38.9, 37.9, 28.4, 22.4, 21.3, 20.2, 18.9,
14.9, 13.9,
13.7, 13.6, 10.5. MS(CI) m/e 717 (M+H)+.
Example 240
CoMQound of Formula (IX): L is CO. T is NH R is -CH2 (O)-(4-F-phenvl)
The title compound was prepared from the compound of Exaiciple 220 and
4-fluorophenylmagnesium bromide using the reaction sequence of Example 239.
13C NMR (CDC13) S 215.3, 206.0, 192.8, 169.6, 165.7, 157.7, 131.5, 130.2,
115.6,
103.1, 83.8, 79.7, 77.3, 76.8, 70.3, 69.6, 65.8, 65.1, 57.6, 50.9, 46.0, 44.6,
40.2,
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38.8, 37.8, 28.3, 22.4, 21.3, 20.2, 18.8, 14.8, 13.9, 13.7, 13.5, 10.4. MS(CI)
m/e 735
(M+H)+.
Example 241
Compound of Formula (IX): L is CO, T is NH, R is -CH?CH=NNHC(O)phenvl
The compound from Example 220 (100 mg, 0.156 mmol) and benzoic hydrazide
(50 mg, 0.370 mmol, 2.4 equiv) were dissolved in 3 mL of dry dichloromethane.
Molecular sieves (4A) were added and the reaction was stirred overnight. The
mixture was
filtered, and the filtrate was concentrated under reduced pressure.
Chromatography (Si02,
5% MeOH/dichloromethane with 0.2% NH4OH) gave the desired material (29 mg) as
a
white solid. 13C NMR (CDC13) S 216.9, 204.2, 169.6, 164.3, 159.0, 148.8,
133.4,
131.2, 128.0, 127.7, 103.2, 83.9, 79.6, 77.6, 76.5, 70.1, 69.5, 65.7, 62.7,
57.8, 50.8.
46.9, 44.4, 40.0, 38.4, 37.3, 28.1, 21.9, 21.1, 20.7, 17.8, 15.0, 14.2, 13.3,
13.1, 10Ø
MS(CI) m/e 759 (M+H)+.
Example 242
Compound of Formula (IX): L is CO. T is NH, R is -CH2CHqCH?(3-quinolvl)
A mixture of the compound from Example 104 (230 mg) and 10 % Pd/C (50 mg) in
30 mL of methanol and 15 mL of ethyl acetate was flushed with nitrogen and
stirred under I
atm of hydrogen at room temperature for 22 hours. The mixture was filtered,
and the filtrate
was concentrated under reduced pressure. Chromatography on silica gel (5%
MeOH/dichloromethane with 0.5% NH4OH) gave the desired material (175 mg) as a
white
solid. Anal Calcd for C42H65N3010: C, 65.35; H, 8.49; N, 5.44. Found C, 65.73;
H,
8.77; N, 5.17.
Example 243
Compound of Formula (IX): L is CO. T is NH. R is -CH2(2-(3-
quinolvl)cvclopropyl)
To a solution of diazomethane (0.64 M, 3.12 mL, 2.00 mmol) in ether was added
a
solution of the compound from Example 104 (153 mg, 0.200 mmol) in
dichloromethane (5.
0 mL) at 0 C under nitrogen. A small amount (2 mg) of palladium acetate was
added, and
the mixture was stirred for 20 minutes. Another portion of diazomethane (3 mL)
was
added, and the mixture was stirred for another hour. The solvents were
evaporated, and the
residue was purified by chromatography on silica gel (5% MeOH/dichloromethane
with
0.5% NH4OH) to give the title compound (100 mg) as a white solid. Anal Calcd
for
C43H61N3010: C, 66.22; H, 7.88; N, 5.39. Found C, 66.05; H, 8.08; N, 5.02.
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Example 244
Compound of Formula (III): Rg is propanovl. L is CO, T is NH,
R is -CH?CH=CH(3-quinol +}1)
To a solution of the compound from Example 104 (152 mg) in dichloromethane was
added propionic anhydride (52 L) and triethylamine (56 L), and the mixture
was stirred
for 24 hours at room temperature. The mixture was diluted with ethyl acetate,
and this was
washed with 5% NaHCO3 solution and brine, dried (Na2SO4) and concentrated
under
reduced pressure. The residue was chromatographed on silica gel (1:1
acetone/hexanes) to
give the title compound(I 19 mg) as a white foam. Anal Calcd for C45H63N3011:
C, 65.75;
H, 7.72; N. 5.11. Found C, 65.67; H, 7.92; N, 4.77.
Example 245
Compound of Formula (111): Rg~ is ethylsuccinoyl, L is CO, T is NH,
R is -CH?CH=CH(3-quinol Y1)
To a solution of the compound from Example 104 (153 mg, 0.200 mmol) in
dichloromethane (10 mL) at 0 C was added ethyl succinyl chloride (29 L) and
triethylamine (56 L), and the mixture was stirred for 24 hours at room
temperature. The
mixture was diluted with ethyl acetate, and this was washed with 5% NaHCO3
solution and
brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was
chromatographed on silica gel (1:1 acetone/hexanes) to give the title
compound(I 10 mg) as
a white foam. Anal Calcd for C48H67N3013=H2O C, 63.21; H, 7.63; N, 4.61. Found
C,
63.08; H, 7.50; N, 4.20.
Example 246
Compound of Formula (IX): L is CO, T is NH, R is -CH2-C=C-H
Sten 246a. Compound 4 from Scheme la: V is N-O-(1-isopropoxycyclohexvl) R is -
CH2-
C=-C-H. RPI is trimethylsilyl.
To a solution under nitrogen of 2',4"-bis-O-trimethylsilyierythromycin A 9-[O-
(1-
isopropoxycyclohexyl)oxime (100 g, 96.9 mmol, prepared according to the method
of U.S.
Pat. No. 4,990,602) in THF (200 mL) was added anhydrous DMSO (200 mL) and the
mixture was coolcd to 0 C. To this solutioii stirred under a N2 atmosphere was
added
propargyl bromide (27 mL, 240 mmol, 80 wt. % in toluene), followed by a
solution of dry
KOH (13.6 g, 24o mmol) in anhydrous DMSO (300 mL) over 25 minutes, and the
mixture
was stirred vigorously for 1 hour at 0 C. Additional KOH (10.9 g, 190 mmol)
and
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propargyl bromide (21 mL, 190 mmol) was added, and the mixture was stirred at
0"C
under N2 for 1.5 hours. This addition of KOH and propargyl bromide was
repeated 3
more times at 1.5 hour intervals. The mixture was then extracted with ethyl
acetate, and the
organic phases were washed with water and brine and dried (MgSO4). Removal of
the
solvent under vacuum gave the crude product (108 g), which was taken directly
to the next
step.
SteR246b: Compound 5 flom Scheme la: R is -CH?-CEBC-H
To the compound from Step 246a (108 g) in CH3CN (300 mL) was added water
(150 mL) and acetic acid (glacial, 200 mL), and the mixture was stirred at
room temperature
for about 20 hours. The solvent was then removed under vacuum at 40 "C, and
the residue
was taken up in EtOAc and washed successively with 5% Na2CO3 and brine. The
organic
phase was then dried over MgSO4, filtered and concentrated to give the title
compound (74
g) as a brown foam, which was taken directly to the next step.
Step 246c: Compound 6 from Scheme I a= R is -CH7-C=C-H
The compound from Step 246b (74 g) was dissolved in ethanol (550 mL) and
diluted with water (550 mL). To this solution was added sodium nitrite (33 g,
0.48 mol),
and the reaction mixture was stirred at room temperature for 15 minutes. Next
was added
4M HCl (125 mL, 0.48 mol) at ambient temperature over 15 minutes, the mixture
was
heated to 70 OC for two hours, then cooled to room temperature. The mixture
was extracted
with ethyl acetate, and the organic phase was washed with 5% Na2CO3 and brine,
then
dried over MgSO4, filtered and concentrated. The crude product was purified by
chromatography on silica gel, eluting with 1% methanol/dichloromethane
containing 0.5%
ammonium hydroxide. The compound was crystallized from acetonitrile to give
the title
compound (27 g).
Stn e 246d: Compound 6A from Scheme lc= R~ isace . R is -CH?-C=_C-H
To a solution of 19 grams (246 mmol) the compound from Step 246c in anhydrous
dichloromethane (100 mL) was added 4-dimethylaminopyridine (105 mg) and
triethylamine
(7.16 mL, 52 mmol). The nuxture was cooled to about 15 C in a cold water
bath, and
acetic anhydride (5.5 milliliters, 59 mmol) was added over 5 minutes. After
stirring at 15 C
for 5 minutes, the cold water bath was removed, and the reaction was stirred
at ambient
temperature for 4 hours. The mixture was diluted with ethyl acetate and washed
successively with 5% aqueous sodium carbonate (twice), water (twice) and
brine. The
organic extracts were dried over magnesium sulfate, filtered and concentrated
in vacuo .
Drying to constant weight with high vacuum provided the title compound (21 g).
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Step 246e: Compound 6B from Scheme l c: RR is acetvl, R is -CH2-C=C-H
To a 0 C solution of the compound from Step 246d (21 g, 24.5 mmol) in THF (128
mL) and dimethyl sulfoxide (48 mL) was added 1,1 '-carbonyldiimidazole (14.3
g, 88.3
mmol). After stirring for 5 minutes, sodium hydride (60% dispersion in mineral
oil, 1.3 g,
32.5 mmol) was added portionwise over 1 hour under a nitrogen atmosphere.
After
complete addition, the cooling bath was removed, and the mixture was stirred
at ambient
temperature for 3.5 hours. The reaction was recooled to 0 C, diluted with
ethyl acetate
(-400 mL), and quenched with 5% aqueous sodium bicarbonate (50 mL). The
organic
layers were washed successively with water and brine, then dried over
magnesium sulfate.
The solution was filtered and the filtrate was concentrated in vacuo. and
dried to constant
weight to afford the title compound (23 g), which was taken directly to the
next step.
Step 246f: Compound 6C from Scheme 1 c: RR is acet-yl, R is -CH')-C=C-H
A pressure vessel containing the compound from Step 246e (23 g, 24 mmol) in
acetonitrile (250 mL) was cooled to -78 C. An equal volume of liqaid ammonia
(250
milliliters) was condensed into the reaction vessel which was then sealed and
allowed to
warm to ambient temperature with stirring. After 20 hours the reaction was
recooled to
-780C, the pressure vessel was opened and the reaction was allowed to warm to
ambient
temperature with stirring. When all the liquid ammonia had evaporated, the
acetonitrile was
removed in vacuo , and the residue was dried to constant weight to provide the
title
_compound (21 g).
5tep 246g: Compound 6D from Scheme 1 c= RD is acetyl. R is -CH2-C-=CrH
To a 0 C suspension of the compound from Step 246f (21 g) in 1:1 ethanol/water
(200 mL) was added 4 M hydrochloric acid (125 mL) over 10 minutes. After
removing the
cooling bath, the reaction solution was stirred at ambient temperature for 26
hours. The
mixture was diluted with water, cooled to 0 C and made basic to pH 10 with 2N
sodium
hydroxide. The mixture was then extracted with ethyl acetate (400 mL), and the
organic
layers were washed with brine. The organic extracts were dried over magnesium
sulfate,
filtered, and concentrated in vacuo . Drying to constant weight provided 18 g
of the crude
product which was crystallized from ethyl acetate/hexanes to give the pure
title compound
(8=5 g).
Step 246h: Compound 6E from Scheme lc= RR is acettil. R is -CH?-C=C-H
To a-10 C solution of N-chlorosuccinimide (2.3 g, 0.017 moles) in
dichloromethane (100 mL) was added methyl sulfide (1.47 mL, 0.021 moles) over
5
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minutes. The reaction was stirred at -10 C for 10 minutes. A solution of the
compound
from Step 246g (8.3 g, 0.012 m) in dichloromethane (100 mL) was then added
over 30
minutes, and the mixture was stirred for 25 minutes at -10 C. Triethylamine
(1.6 mL,
0.021 mol) was added over 5 minutes, and the reaction was stirred at -10 C
for 50 minutes.
The reaction was then quenched with 5% aqueous sodium bicarbonate (50 mL), and
extracted with dichloromethane (300 mL). The organic layers were washed with
5%
aqueous sodium bicarbonate followed by brine, dried over magnesium sulfate,
filtered, and
concentrated in vacuo . The crude product was purified on silica gel with
column
chromatography eluting sequentially with 30% acetone/hexanes followed by 50%
acetone/hexanes to provide the title compound (7.35 g).
Step 246i: Compound of Formula (IX): L is CO. T is NH. R is -CH2- -C-H
A sample (72 mg) of the compound from Step 246h was dissolved in methanol (8
mL) and stirred at ambient temperature for 18 hours. After concentrating under
vacuum and
drying to constant weight under high vacuum 65 mg of the pure title compound
was
obtained. liigh Resolution FAB MS: calculated m/e for (M+H)+ :
C33H53N2010=637.3700 Observed m/e =637.3718.
Example 247
Comnound of Formula (IX)= L is CO T is NH. R is -CH,)- -C-(3-quinolxl)
Sten 247a. Compound 6E from Scheme lc= R is -CH2-C=C-(3-quinolyI)
A pressure tube equipped with a stir bar was charged with
dichlorobis(triphenylphosphine)palladium(II) (6.2 mg), degassed triethylamine
(2.5 mL),
degassed N,N-dimethylformamide (0.5 mL), then 3-bromoquinoline (93 .L and a
sample
of the compound from Step 246h (300 mg), and lastly copper (II) iodide (0.84
mg). The
reaction was sealed under a nitrogen atmosphere and heated to 60 C for 2
hours. After
cooling to room temperature, the reaction was diluted with 1:1 ether/ethyl
acetate and was
washed three times with water and brine. The organic extracts were dried over
magnesium
sulfate, filtered and concentrated in vacuo. Drying with high vacuum provided
374
milligrams of crude product. The crude product was purified with silica gel
chromatography using 30% acetone/hexanes to give the title compound (280
mg,78%. MS
(APCI)+ m/e 806 (M+H)+.
Sten 247b. Comnound of Formula (IX)= L is CO. T is NH R is CH,) C=f(3
auinolvll
The compound form step 247a (270 mg) was dissolved methanol and was stirred at
ambient temperature for 18 hours. After concentrating in vacuo and drying to
constant
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weight under high vacuum 260 mg of crude product was obtained. Purification
with silica
gel chromatography eluting with 98:1:1 dichloromethane/methanol/ammonium
hydroxide
gave 221 mg of the title compound. High Resolution FAB MS: calculated m/e for
(M+H)+ :
C42H58N3010=764.4122 Observed m/e =764.4121.
S
Example 248
Compound of Formula (IX): L is CO. T is NH. R is -CH2-C=C-(6-nitro-3-quinolXl)
Following the procedure of Example 247, except substituting 6-nitro-3-
bromoquinoline for 3-bromoquinoline, the title compound was prepared. High
Resolution
io FAB MS: calculated m/e for (M+H)+ : C42H57N4012=809.3973 Observed m/e
=809.3966
Example 249
Compound of Formula (IX): L is CO, T is NH. R is -CH2-C=C-phenyl
Following the procedure of Example 247, except substituting iodobenzene for 3-
1 5 bromoquinoline. High Resolution FAB MS: calculated m/e for (M+H)+ :
C39H57N201Q=713.4013 Observed m/e =713.3998.
Example 250
Compound of Formula (IX): L is CO. T is NH. R is -CH7-C=-C-naphthYl
20 Following the procedure of Example 247, except substituting 1-
iodonaphthalene for
3-bromoquinoline. High Resolution FAB MS: calculated m/e for (M+H)+ :
C43H59N2010=763.4170 Observed m/e =763.4161.
Example 251
25 Compound of Formula (IX): L is CO; T is NH. R is -CH2-C=C-(2-naphthyl)
Following the procedure of Example 247, except substituting 2-bromonaphthalene
for 3-bromoquinoline. High Resolution FAB MS: calculated m/e for (M+H)+ :
C43H59N2010=763.4170 Observed m/e =763.4150.
30 Example 252
Compound of Formula (IX)= L is CO. T is NH, R is -CH?-C=-C-(6-methoxv-2-
naphth,yl)
Following the procedure of Example 247, except substituting 6-methoxy-2-
bromonaphthalene for 3-bromoquinolinc. High Resolutiuii FAB MS: calculated m/e
for
(M+H)+ : C44H61N2O11=793.4275 Observed m/e =793.4256.
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Example 253
Compound of Formula (IX): L is CO. T is NH. R is -CHZC=C-(6-chloro-2-nayhthylI
Following the procedure of Example 247, except substituting 6-chloro-3-
bromoquinoline for 3-bromoquinoline. High Resolution FAB MS: calculated m/e
for
(M+H)+ : C42H57N3O10C1=798.3732 Observed m/e =798.3743.
Example 254
ComQound of Formula (IX): L is CO T is NH. R is -CH3-C--= C-(6-auinolyl)
Following the procedure of Example 247, except substituting 6-bromoquinoline
for
3-bromoquinoline. High Resolution FAB MS: calculated m/e for (M+H)+ :
C42H58N3010=764.4122 Observed m/e =764.4116.
Exampie 255
Compound of Formula (IX): L is CO. T is NH. R is -CH2-C-C-(2-methyl-6-
quinolvl)
~ 5 Following the procedure of Example 247, except substituting 6-bromo-2-
methyiquinoline for 3-bromoquinoline. High Resolution FAB MS: calculated m/e
for
(M+H)+ : C43H60N3O10=778.4279 Observed m!e =778.4282.
Example 256
Compound of Formula (IX): L is CO. T is NH. R is -CH2-C-=C-(5-(N-(2-
pvridyl)amino)carbon 1)y furanvl)
Following the procedure of Example 247, except substituting 5-bromo-furan-2-
carboxylic acid pyridin-2-yl amide for 3-bromoquinoline. MS (FAB+):(M+H)+ @
m/e
823.
Example 257
Comnound of Formula (IX)= L is CO T is NH R is -CH2-C-=C-(1-phenvlethenyl)
Following the procedure of Example 247, except substituting alpha-bromostyrene
for 3-bromoquinoline. MS (ESI) m/e 739 (M+H)+.
Example 258
Compound of Formula (IX): L is CO. T is NH R is -CH-2-C=_C-Br
Step 258a. Compound 6E from Scheme I c: R is -CHZ-C=C-Br
To a solution under nitrogen of the compound of Example 246, Step h (100 mg)
in
acetone (i mL) was added acetic acid (8.4 microliters) at ambient temperature.
A second
solution containing N-bromosuccinimide (39 mg) and silver nitrate (2.5 mg) in
I mL of
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acetone was prepared and then stirred at room temperature under nitrogen for
ten minutes
and was cooled to 0 C. The first solution was then added to the second
solution in one
portion, the cooling bath was removed, and the resulting reaction mixture
stirred at room
temperature under nitrogen for 2 hours. The reaction was then diluted with
ethyl acetate,
~ saturated aqueous sodium bicarbonate was added, and the mixture was stirred
at room
temperature overnight. The organic phase was separated, washed with brine and
dried
(MgSO4). The solvent was removed, and the residue was purified by
chromatography on
silica gel, eluting with 40% acetone/hexanes to give the title compound (50
mg, 46 %).
Step 258b. Compound of Formula (IX): L is CO, T is NH, R is -CH')-C=C-Br
A sample (35 mg) of the compound from Step 258a was dissolved in methanol (2
mL) and stirred at ambient temperature for 16 hours. The solvent was removed,
and the
residue was purified by chromatography on silica gel, eluting with 5:94:1
methanol/dichlormethane/1% NH4OH, to give the title compound (32 mg, 26 %). MS
1 .,
(ESI) m/e 715 (M+H)+.
Example 259
Compound of Formula (IX): L is CO. T is NH.
R is -CH,)-(2.2-dimethyl-1,3-dioxolan-4-yl)
Step 259a. Compound 6D from Scheme lc: R is -CH2CH(OH)CH9OH, RR is ace l
To a sample of the compound from Example 176, Step d (5.0 g, 7.32 mmol,
Compound 6D from Scheme ic, R is -CH2CH=CH2, Rp is acetyl) and N-
methylmorpholine N oxide (1.7 g, 14.5 mmol) in THF (25 mL) at room temperature
was
added 0S04 (4 % in H20, 0.090 mL, 0.0147 mmol), and the mixture was stirred
for 24
hours. The reaction was quenched with sodium bisulfite (1.5 g) and water (10
mL), and the
solvents were removed under vacuum. The residue was dissolved in ethyl
acetate, which
was washed with saturated aqueous sodium bicarbonate, water and brine, and
dried
(Na2SO4). The solvent was removed to give the title compound (3.17 g).
Step 259b. Compound 6D from Scheme lc: R is -CH2-(2.2-dimethyl-l.3-dioxolan-
4^vl).
RPI is acetyl. Rd is H
To a sample of the compound from Step 259a (500 mg, 0.70 mmol) and 2,2-
dimethoxpropane (0.26 mL, 2.1 mmol) in toluene (7 mL) was added p-
toluenesulfonic acid
(160 mg, 0.84 mmol), and the mixture was stirred at 55 C for 3 days. The
mixture was
diluted with ethyl acetate, and this solution was washed with 10 % sodium
carbonate
solution, water and brine. The organic phase was dried (Na2SO4), and the
solvent was
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removed to give the crude product, which was purified by chromatography on
silica gel,
eluting with 2:97:1 methanol/chloroform/ammonium hydroxide to give the title
compound
(363 mg).
i StQp 259c. Compound 6E from Scheme lc: R is -CH~-(2.2-dimethyl-1,3-dioxolan-
4-yl),
RI! is acetyl. Ril is H
A sample of the compound from Step 259b (356 mg, 0.47 mmol) was oxidized with
N-chlorosuccinimide and dimethylsulfide according to the procedure of Example
l,Step f,
to afford the title compound (371 mg).
Step 259d. Compound of Formula (IX): L is CO. T is NH, R is -CH2-(2.2-dimeth l-
y 1.3-
dioxolan-4-vl)
A sample of the compound from Step 259c (100 mg, 0. 13 mmol) was stirred in
methanol (4 mL) overnight at room temperature. The solvent was removed, and
the residue
was purified by chromatography on silica gel, eluting with 0.9:98:1
methanol/chloroforn-i/ammonium hydroxide to give the title compound (87 mg).
MS m/e
713 (M+H)+.
Example 260
Compound of Formula (IX): L is CO. T is NH. R is -CH,)CH(OH)CH22OH
A sample of the compound from Example 259 (100 mg, 0.13 mmol) was stirred at
reflux with p-toluenesulfonic acid (35 mg, 0.18 mmol) in 4:1 THF/water (2.5
mL) for 3
hours. The mixture was diluted with ethyl acetate, and this.solution was
washed with 10 %
sodium carbonate solution, water and brine. The organic phase was dried
(Na2SO4), and
the solvent was removed to give the crude product, which was purified by
chromatography
on silica gel, eluting with 2:97:1 methanol/chloroform/ammonium hydroxide to
give the title
compound (61 mg). MS m/e 689 (M+H)+.
Example 261
Compound of Formula (IX): L is CO. T is NH. R is -CH,)CH(OH) phenYl
To a sample of the compound from Example 220 (550 mg, 0.87 mmol) in dry THF
(16 mL) at 0 C under nitrogen was added dropwise a solution of phenyl
magnesium
bromide (3.0 M, 2.0 mL, 6.0 mmol) in ether. The mixture was stirred for about
1 hour,
and the reaction was quenched with saturated ammonium chloride solution. The
mixture
was extracted with ethyl acetate, and this solution was washed with water and
brine and
dried (Na2SO4). The solvent was removed, and the residue was purified by
chromatography on silica gel, eluting with 10:90:0.5
methanol/dichloromethane/ammonium
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hydroxide to give the title compound (235 mg) as two isoiners. Isomer A: MS
m/e 719
(M+H)+. Isomer B: MS in/e 719 (M+H){.
Example 262
Compound of Formula (IX): L is CO, T is N(NH,)) R is -CH,)CH=CH,)
To a sample of the compound from Example 102, Step b (793 mg, 1.0 mmol) in 9:1
acetonitrile/water (10 mL) was added hydrazine (85 % aqueous solution, 0.50
mL., 10.0
mmol), and the mixture was stirred at room temperature under nitrogen for 4
days. The
mixture was diluted with ethyl acetate, and the organic phase was washed with
water and
brine and dried (Na2SO4). The solvent was removed, and the residue was
purified by
chromatography on silica gel, eluting with 5:95:0.5
methanol/dichloromethane/ammonium
hydroxide to give the title compound (91 mg). MS m/e 654 (M+H)+.
Example 263
Compound of Formula (IX): L is CO, T is N(NHA~ R is -CH9CH=CH-(39uinoIYl)
Following the procedures of Example 178, except substituting the compound from
Example 262 for the compound from Example 177, the title compound was
prepared. MS
m/e 781 (M+H)+. High Resolution FAB MS: calculated m/e for (M+H)+ of
C42H59N3010:
781.4176; Found: 781.4188.
Example 264
Comnound of Formula (IX): L is CO. T is N(NH,)) R is -CH2CH,)CH?-(3-quinolyl)
Following the procedures of Example 3, except substituting the compound from
Example 262 for the compound from Example 3, the title compound was prepared.
MS m/e
768 (M+H)+. High Resolution FAB MS: calculated m/e for (M+H)+ of C42H61N3010:
768.4435; Found: 768.4437.
Example 265
Compound of Formula (IX): Lis CO. T is NH2. R is -CH2CH=CH-naphthyI
Following the procedures of Example 178, except substituting 1-
bromonaphthalene
for the 3-bromoquinoline of Example 178, the title compound was prepared. MS
m/e 764
(M+H)+.
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Example 266
Compound of Formula (IX): L is CO, T is NH2, R is -CH,?CH=CH-(3-(2-furanyl)-6-
uin 1 1
A mixture of a sample of the 2'-acetylated derivative of the compound of
Example
219 (acetylated by the procedure of Example 177, Step a) (177 mg, 0.200 mmol),
2-
(tributylstannyl)furan (78 L, 0.200 mmol) and Pd(triphenylphosphine)4 (23 mg,
0.020
mmol) in dry toluene was heated in a sealed tube at 60 C to 90 C for 20
hours. The
mixture was then diluted with ethyl acetate, which was washed with aqueous 5%
sodium
bicarbonate and brine and dried (Na2SO4). The solvent was removed, and the
residue was
purified by chromatography on silica gel, eluting with 1:1 acetone/hexanes to
give the
acetylated title compound. This material was stirred with methanol for 48
hours, and the
solvent was removed. The residue was purified by chromatography on silica gel,
eluting
with 95:5:0.5 dichlormethane/methanol/dimethylamine to give the title compound
(102 mg).
MS m/e 832 (M+H)+. High Resolution FAB MS: calculated m/e for (M+H)+ of
C46H61N3011: 832=4384; Found: 832.4384.
Example 267
Compound of Formula (IX): L is CO. T is NH7. R is -CH,)CH=CH-(8-chloro-3-
guinolxl)
Following the procedures of Example 178, except substituting 8-chloro-3-
bromoquinoline for the 3-bromoquinoline of Example 178, the title compound was
prepared. MS nVe 800 (M+H){. High Resolution FAB MS: calculated m/e for (M+H)+
of
C42H58C1N3010: 800.3889; Found: 800.3890.
Example 268
Comgound of Formula (IX): L is CO. T is NH,). R is -CH?CH=CH-(4-chloro-2-
triflu orometh yl -6-q uin olyl )
Following the procedures of Example 178, except substituting 6-bromo-4-chloro-
2-
trifluoromethylquinoline for the 3-bromoquinoline of Example 178, the title
compound was
prepared. MS nVe 868 (M+H)}.
Example 269
Comgound of Formula (IX): L is CO. T is NH?, R is -CH?CH=CH-(2-fluoreny))
Following the procedures of Example 178, except substituting 2-bromofluorene
for
the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e
803
(M+H)+.
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Example 270
Compound of Formula (IX): L is CO, T is NH?, R is -CH?CH=CH-(9-fluorenone-2-
vl)
Following the procedures of Example 178, except substituting 2-iodo-9-
fluorenone
for the 3-bromoquinoline of Example 178, the title compound was prepared. MS
ni/e 817
i (M+H)+. Anal Calcd for C46H60N2O1 1 C, 67.63; H. 7.40; N, 3.43. Found C,
68.11; H,
8.08; N, 3.21.
Example 271
Compound of Formula (IX): L is CO. T is NH?. R is -CH,?CH=CH-(6-benzoxl-2-
na hth l
Following the procedures of Example 178, except substituting 6-benzoyl-2-
(trifluoromethylsulfonyloxy)naphthalene (prepared from 6-benzoyl-2-naphthol by
reaction
with trifluoromethylsulfonic anhydride) for the 3-bromoquinoline of Example
178, the title
compound was prepared. MS m/e 869 (M+H)+.
Example 272
ComQound of Formula (IX): L is CO. T is NH2, R is -CH?CH=CH-(7-methoxy-2-
nahthl
Following the procedures of Example 178, except substituting 7-methoxy-2-
(trifluoromethylsulfonyloxy)naphthalene (prepared from 7-methoxy-2-naphthol by
reaction
with trifluoromethylsulfonic anhydride) for the 3-bromoquinoline of Example
178, the title
compound was prepared. MS m/e 795 (M+H)+. Anal Calcd for C44H62N2O1 I.-0.5 H20
C, 65.73; H, 7.90; N, 3.48. Found C, 65.62; H, 8.06; N, 3.49.
Example 273
Compound of Formula (IX): L is CO. T is NH7 R is -CH2CH=CH-(3-phenvl-6-
quinolvl)
A mixture of a sample of the 2'-acetylated derivative of the compound of
Example
219 (acetylated by the procedure of Example 177, Step a) (177 mg, 0.200 mmol),
Pd(triphenylphosphine)4 (11.5 mg, 0.010 mmol), CuBr (1.43 mg) and
(tributylstannyl)benzene (78.3 L) in dioxane (2 mL) was heated in a sealed
tube at 100 C
for 15 hours. The mixture was then diluted with ethyl acetate, which was
washed with
aqueous 5% sodium carbonate and brine and dried (Na2SO4). The solvent was
removed,
and the residue was purified by chromatography on silica gel to give the
acetylated title
compound (77 mg). This material was stirred with methanol for 48 hours, and
the solvent
was removed. The residue was purified by chromatography on silica gel to give
the title
compound (54.2 mg). MS m/e 842 (M+H)+.
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Example 274
Compound of Formula (IX): L is CO. T is NH?, R is -CH2CH=CH-(3-(2-p,vridvl)-6-
uinol 1
Following the procedures of Example 273, except substituting 2-
(triburylstannyl)pyridine for the 2-(tributylstannyl)furan of Example 273, the
title compound
was prepared. MS m/e 841 (M+H)+.
Example 275
Compound of Formula (IX): L is CO. T is NH,). R is -CHZCH=CH-(3-(2-thiophenyl)-
6-
guinolyi)
Following the procedures of Example 273, except substituting 2-
(tributylstannyl)thiophene for the 2-(tributylstannyl)furan of Example 273,
the title
compound was prepared. MS m/e 848 (M+H)+.
] 5 Example 276
Compound of Formula (IX): L is CO. T is NH2. R is -CH2CH=CH-(4-methylnaphthyD
Following the procedures of Example 178, except substituting the 2'-
benzoylated
compound of Example 102, Step c for the 2'-acerylated compound of Example 177
and
substituting 1-bromo-4-methylnaphthalene for the 3-bromoquinoline of Example
178, the
title compound was prepared. MS m/e 779 (M+H)+. High Resolution FAB MS:
calculated
m/e for (M+H)+ of C44H62N2O10: 779.4483; Found: 779.4495.
Example 277
Compound of Formula (IX): L is CO. T is NH2s R is -CH2CH=CH-(6-D-D-
alg actopyranosvl-2-naphthvl)
Following the procedures of Example 178, except substituting the 2'-
benzoylated
compound of Example 102, Step c for the 2'-acetylated compound of Example 177
and
substituting 6-bromo-2-naphthyl-o-D-galactopyranoside (obtained from Sigma
Aldrich) for
the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e
943
(M+H)+.
Example 278
Compound of Formula (IX): L is CO. T is NH?, R is -CH?CH=CH-(7-Quinolyl)
Following the procedures of Example 178, except substituting the 2'-
benzoylated
compound of Example 102, Step c for the 2'-acetylated compound of Example 177
and
substituting 7-(trifluoromethylsulfonyl)quinoline for the 3-bromoquinoline of
Example 178,
the title compound was prepared. MS m/e 766 (M+H)}.
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Example 279
Compound of Formula (IX): L is CO. T is NH?, R is -CH?CH=CH-(4-fluoronaphthvl)
Following the procedures of Example 178, except substituting the 2'-
benzoylated
S compound of Example 102, Step c for the 2'-acetylated compound of Example
177 and
substituting I-bromo-4-fluoronaphthalene for the 3-bromoquinoline of Example
178, the
title compound was prepared. MS m/e 783 (M+H)+. High Resolution FAB MS:
calculated
m/e for (M+H)+ of C43H59FN2010: 783.4227; Found: 783.4223.
Example 280
Compound of Formula (IX): L is CO, T is NH2. R is -CH?CH=CH-(3-binhenvl)
Following the procedures of Example 178, except substituting the 2'-
benzoylated
compound of Example 102, Step c for the 2'-acetylated compound of Example 177
and
substituting 3-bromobiphenyl for the 3-bromoquinoline of Example 178, the
title corrtpound
was prepared. MS m/e 791 (M+H)+. High Resolution FAB MS: calculated nVe for
(M+H)+ of C45H63N2010: 791.4483; Found: 791.4492.
Example 281
Compound of Formula (IX): L is CO, T is NH?. R is -CH2CH=CH-(5-nitronaphthyl)
FoIIowing the procedures of Example 178, except substituting the 2'-
benzoylated
compound of Example 102, Step c for the 2'-acetylated compound of Example 177
and
substituting 1-bromo-5-nitronaphthalene for the 3-bromoquinoline of Example
178, the title
compound was prepared.
Example 282
Compound of Formula (1X): L is CO, T is NH,), R is -CH,?CH=CH-(4-
g,vrrolvhhenyl) i. :
Following the procedures of Example 178, except substituting the 2'-
benzoylated
compound of Example 102, Step c for the 2'-acetylated compound of Example 177
and
substituting 1-(4-iodophenyl)pyrrole for the 3-bromoquinoline of Example 178,
the title
compound was prepared. MS m/e 780 (M+H)+. High Resolution FAB MS: calculated
m/e
for (M+H)+ of C43H61N3010: 780.4430; Found: 780.4424.
Example 283
Compound of Formula (IX): L is CO. T is NH?, R is -CH?,CH=CH-(6-methoxv-2-
na hth 1
FoIlowing the procedures of Example 178, except substituting the 2'-
benzoylated
compound of Example 102, Step c for the 2'-acetylated compound of Example 177
and
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substituting 2-broino-6-methoxynaphthalene for the 3-bromoquinoline of Example
178, the
title compound was prepared. MS m/e 795 (M+H)+. High Resolution FAB MS:
calculated
m/e for (M+H)+ of C44H62N2O11: 795.4426; Found: 795.4426.
Example 284
Compound of Formula (IX): L is CO. T is NH9. R is -CH2CH=CH-(3.5-
dichlorophenyll
Following the procedures of Example 178, except substituting the 2'-
benzoylated
compound of Example 102, Step c for the 2'-acetylated compound of Example 177
and
substituting 1,3-dichloro-5-iodobenzene for the 3-bromoquinoline of Example
178, the title
compound was prepared. MS m/e 783 (M+H)+. High Resolution FAB MS: calculated
m/e
for (M+H)+ of C39H57C12N2010: 783 .3390; Found: 783 .3392.
Example 285
Compound of Formula (IX): L is CO. T is NH2), R is -CH2-(3-iodQphenvl)
Following the procedures of Example 1, steps a-f, except substituting the 3-
iodobenzyl bromide for the allyl bromide of Example 1, Step a, to prepare the
compound 9
from Scheme l b, wherein R is 3-iodophenylmethyl and RP is benzoyl, then
treating that
compound according to the procedures of Example 102, the title compound was
prepared.
MS m/e 815 (M+H)+.
Example 286
Compound of Formula (IX): L is CO, T is NH2. R is -CH2-(3-(2-furanvl)phenvl)
Following the procedures of Example 266, except substituting the compound of
Example 285 for the compound from Example 265, the title compound was
prepared. MS
m/e 689 (M+H)+.
Example 287
Compound of Formula (IX): L is CO. T is NH2, R is -CH2CH=CH-(6-hvdroxy-2-
na hth 1
Following the procedures of Example 178, except substituting the 2'-
benzoylated
compound of Example 102, Step c for the 2'-acetylated compound of Example 177
and
substituting 6-bromo-2-naphthol for the 3-bromoquinoline of Example 178, the
title
compound was prepared. MS m/e 781 (M+H)+.
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Example 288
Compound of Formula (IX): L is CO. T is NH2. R is -CH2CH=CH-(6-(2-bromoethoxy)-
2-naphthv])
Following the procedures of Example 178, except substituting 6-bromo-2-(2-
S bromoethoxy)naphthalene for the 3-bromoquinoline of Example 178, the title
compound
was prepared. MS m/e 887 (M+H)+.
Example 289
Comuound of Formula (IX): L is CO. T is NH2. R is -CH2CH=CH-(6-(2-
(tetrazolyl)ethoxv-2-naphthyD
To a sample of the compound from Example 288 (371 mg, 0.4 mmol) in
acetonitrile
(4 mL) was added tetrazole (138 mg, 2 mmol) and triethylamine (0.556 mL, 4
mmol), and
the mixture was heated at 60 C under nitrogen overnight. The volatiles were
removed
under vacuum, and the residue was dissolved 'in ethyl acetate. This solution
was washed
with 5 % aqueous sodium bicarbonate and brine, dried (Na2SO4), and
concentrated. The
residue was purified by chromatography on silica gel, eluting with 97:3:0.5
dichloromethane/methanol/ammonium hydroxide. This product was stirred in
methanol at
room temperature for 2 days, then the product was purified by chromatography
on silica
gel, eluting with 99:1:0.5 dichloromethane/methanol/ammonium hydroxide. MS m/e
877
(M+H)+.
Example 290
Compound of Formula (IX): L is CO. T is NH2. R is -CH,)CH=CH-naphthvl
Following the procedures of Example 178, except substituting 1-
bromonaphthalene
for the 3-bromoquinoline of Example 178, the title compound was prepared. MS
m/e xxx
(M+H)+.
Example 291
Compound of Formula (IX): L is CO. T is NH. R is -CH2-Q-=C-(2-phen, lev
thenyl)
Following the procedure of Example 247, except substituting beta-bromostyrene
for
3-bromoquinoline. MS (ESI) m/e 739 (M+H)+.
Examnle 292
Compound of Formula (IX): L is CO. T is NH. R is -CH2-CH=CH-(5-(3-isoxazolyl)-
2-
thiohnl
Step 292a. Compound 37 from Scheme 7 wherein RBB is OH
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To 11.8 mL (11.8 mmol) borane-THF complex (1 molar solution in
tetrahydrofuran) at -10 C was added 2-methyl-2-butene (2.7 mL, 24 mmol). The
reaction
was stirred at 0 C for 2 hours and a separately prepared solution containing
the compound
from Example 246, Step h (Compound 6E from Scheme lc; RP is acetyl, R is -CH2-
C=C-
H. 2 g, 2.95 nvnol) in 10 mL tetrahydrofuran was then added in one portion.
The reaction
was stirred at 0 C foT 1 hour and was warmed to ambient temperature. After 3
hours the
reaction was recooled to 0 C and 5% aqueous sodium carbonate was added. The
mixture
was extracted with ethyl acetate, and the organic layers were washed with
brine and dried
over magnesium sulfate. Concentration and drying in vacuo gave 3.6 grams of
crude
iU product which was purified with silica gel chromatography eluting with
acetone/hexanes
(1:1) to provide the title compound (0.85 g, 40%).
Step 292b. Compound of Formula (IX): L is CO. T is NH. Rc is acetvl. R is -CHZ-
CH=CH-(5-(3-isoxazolvl)-2-thiohenyl)
is A pressure tube equipped with a stir bar was charged with 100 mg (0.138
mmol) of
the compound resulting from Step 292a, potassium carbonate (42 mg, 0.3 mmol) 2-
bromo-
5-(isoxazol-3-yl)thiophene (48 mg, 0.21 mmol), palladium (II) acetate (0.15
mg, 0.7
mmol), 0.75 mL acetone and 0.75 mL water. Two freeze-pump-thaw cycles were
performed to degas reaction. The reaction tube was then sealed under nitrogen
and heated at
20 65 OC for 2 hours. The mixture was diluted with ethyl acetate and washed
successively
with water then brine. Organic extracts were dried over magnesium sulfate,
concentrated in
vacuo, and dried to constant weight with high vacuum to provide 140 mg of
crude product.
Step 292c. Compound of Formula (IX): L is CO. T is NH, R is -CHZCH=CH-(5-(3-
25 isoxazolyi)-2-thiophenYl)
The compound resulting from Step 292b (140 mg) was dissolved in 5 mL methanol,
and the solution was stirred at ambient temperature for 20 hours. The solution
was
concentrated in vacuo and dried to constant wei ht. The ru e r t
g c d p oduc was purified with
silica gel chromatography eluting with 98:1:1
dichloromethane/methanol/ammonium
30 hydroxide to give 34 mg of the title compound. High Resolution FAB MS:
calculated m/e
for (M+H)+ : C40H58N3011S: 788.3792 Observed: 788.3809.
Example 293
Compound of Formula (IX): L is CO, T is'NH. R is -CH2-CH=CH-(1,3-dimethvl-2 4-
35 dioxo-5-p3rimidinvl)
Following the procedures of Example 292, except substituting 5-bromo-1,3-
dimethyluracil for 2-bromo-5-(isoxazol-3-yl)thiophene, the title compound was
prepared.
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High Resolution FAB MS: calculated m/e for (M+H)+ : C39H61N4012: 777.4286.
Observed m/e: 777.4291
Example 294
Compound of Formula (IX): L is CO. T is NH. R is -CH,)-CH=CH-(5-(2-
12,vridyl)aminocarbonvl-2-furan,yl)
Following the procedures of Example 292, except substituting 5-bromo-furan-2-
carboxylic acid pyridin-2-yl-amide for 2-bromo-5-(isoxazol-3-yl)thiophene the
title
compound was prepared. MS (ESI)+:(M+H) + @ m/e 825.
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