1340984 '
PEPTIDYLAMINODIOLS INTERMEDIATES
This is a divisional of copending application
S.N. 527,514 filed January 16, 1987.
Technical Field
ThE: present invention relates to synthetic
intermediates employed in the preparation of compounds
which inhibit re:ni.n.
15
Background A:rt
Renin i_s a proteolytic enzyme synthesized and
stored principally in a specific part of the kidney
called the juxtaglomerular apparatus. Any of three
different physiologic circumstances may cause the
release of renin into the circulation: (a) a decrease in
the blood pressure entering or within the kidney itself;
(b) a decrease in the blood volume in the body; or (c)
a fall in the concentration of sodium in the distal
tubules of the kidney.
When the renin is released into the blood from
the kidney, the renin-angiotensin system is activated,
leading to vasoconstriction and conservation of sodium,
both of which result in increased blood pressure. The
renin acts on a circulating protein, angiotensinogen, to
cleave out ~~ fragment called angiotensin I (AI). AI
x
1340984
2
itself has only alight pharmacologic activity_but..after
additional c:leavage by a second enzyme. angiotensin
converting enzyme (ACE), forms the potent molecule
angiotensin I:I (AII)~. The major pharmacological effects
!s of All are vasoconstriction and stimulation of the
adrenal cortex to release ~aldosterone; a hormone which
causes sodium retention. All is cleaved by an
aminopeptidaser to form angiotensin III (HIII), which,
compared to A:II, is a less potent vasoconstrictor but a
more potent ir~ducer of aldosterone release.
Inhibitors of renin have been sought as agents
.for control o~~ hypertension and as diagnostic agents for
identification, of cases of hypertension due to renin
excess.
With these objectives in mind, the
renin-angioten.sion system has been modulated or
manipulated, is the past, with ACE inhibitors. However.
ACE acts on several substrates other than angiotensin I
(AI), most notably the kinins which cause such
20 desirable s:fde effects as pain, "leaky" capillaries,
prostaglandin release and a variety of behavioral and
aeurologic ef;Eects. Further, ACE inhibition leads to
the accumulation of AI. Although AI has much less
vasoconstrictor activity than AII, its presence may
25 negate some o;E the hypotensive effects of the blockade
of All synthesis.
Inhibition of other targets in the
renin-angiotensin system such as All with compounds such
as saralasia can block All activity, but would leave
30 impaired andl perhaps enhance the :~ypertensive effects
of HIII.
On the other hand, there are no known side
effects which result when renin is inhibited from acting
on its substrate. Considerable research efforts have
3;5 thus been carried out to develop useful inhibitors of
renin. Past research efforts have been directed to
1 34Q gg 4
3
renin antibodies, pepstatin. phospholipids and substrate
analogs such as tetrapeptides and octapeptides to
tridecapeptid~as. These inhibitors either demonstrate
poor activith in inhibiting renin production or poor
'S specificity for inhibiting renin only. However, Boger
et al. have reported that statine-containing peptides
possess potent and specific renin-inhibiting activity
(Nature. Vol. 303, p. 81, 1983). In addition, Szelke
and co-workers have described polypeptide analogs
containing a non-peptide link (Nature, Vol. 299, p. 555,
1982) which also cause potent renin inhibition and show
_ a high specificity for this enzyme.
Disclosure of the Invention
In accordance with the present invention, there
are provided compounds of formula:
OP,
P,NH R'
:'0
wherein R is loweralkyl, cycloalkylmethyl or benzyl;
R' is H, loweralkyl, vinyl or arylalkyl:
Pz and P3 are independently selected from H or
~5
an O-protecting group: and
P~ is H or an N-protecting group; or acid
addition salts thereof.
The compounds of the present invention are
f0 useful intermediates in the preparation of renin
inhibiting compounds of formula:
3a ~ 3 40 9e'~ _
s
:LO
J
R3 H Ra
A i W. N
:;0 U _ (I)
R.1 O ~ RS
R9
wherein A is hydrogen: loweralkyl; arylalkyl: OR10 or
SRlQ wherein R10 is hydrogea, loweralkyl or
amiaoalkyl: NR11R~2 wherein R11 and R12 are
independently selected from hydrogen, loweralkyl,
aminoalkyl, cy~anoalkyl and hydroxyalkyl;
Ri3 ~ B Ri3 ~ / B
or . O~ O
0
whereia H is NFi, alkylamino, S. O, CHZ or CHOH and
R13 is lowErralkyl, cycloalkyl, aryl, arylalkyl,
4 1 3 40 98 4
alkoxy, alksanyloxy, hydroxyalkoxy, dihydroxyalkoxy,
arylalkoxy, arylalkoxyalkyl, amino, alkylamino,
dialkylamino, (hydroxyalkyl)(alkyl)amino, aminoalkyl,
N-protected aminoalkyl, alkylaminoalkyl,
5~ (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl,
(heterocyclic)alkyl or a substituted or unsubstituted
heterocyclic;
W is C=O or CHOH;
U is~ CH2 or NR2, provided that when W is
CHOH then U is CH2; .
' R1 :ls loweralkyl, cycloalkylmethyl, benzyl',
4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl,
(2-naphthyl)methyl, (4-imidazoyl)methyl,
a , a-dimethylbenzyl, 1-benzyloxyethyl, phenethyl,
phenoxy, thiophenoxy or anilino; provided if R1 is
phenoxy, thioyhenoxy or anilino, B is CH2 or CHOH or A
is hydrogen; R2 is hydrogen or loweralkyl; R3 is
loweralkyl, loweralkenyl, [(alkoxylalkoxylloweralkyl,
(thioalkoxy)alkyl, benzyl or heterocyclic ring
substituted methyl; R4 is loweralkyl, cycloalkylmethyl
or benzyl; R5 is vinyl, formyl, hydroxymethyl or
hydrogen; R7 is hydrogen or loweralkyl; Ra andR9
are independently selected from OH and NH2; and R6
is hydrogen, loweralkyl, vinyl or arylalkyl; provided
that when RS and R7 .are both hydrogen and Re and
R9 are OH, the carbon bearing RS is of a "R"
configuration and the carbon bearing R6 is of a "S"
configuration; or pharmaceutically acceptable salts or
esters thereof.
3~) The c:hiral centers of the compounds of the
invention may have either the "R" or "S" configuration
but preferable have an "S" configuration except where
noted. The terms "S" and"R" configuration are as .
defined by the IUPAC 1974 Recommendations for Secticn E,
Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,
13 - 30.
x.
s . 1 3 40 9B 4
The term "N-protecting group" or "N-protected"
as used herein refers to those groups intended to
protect nitrogen atoms against undesirable reactions
during syntheaic procedures or to prevent the attack of
'S exopeptidases on the final compounds or to increase the
solubility oi: the final compounds and includes but is
not limited to aryl, acetyl, pivaloyl, t-butylacetyl,
t-butyloxycarbonyl(Hoc), benzyloxycarbonyl (Cbz)or
benzoyl groups or an L- or D- aminoacyl residue, which
may itself be N-pratected similarly.
The term "loweralkyl" as used herein refers to
straight or branched chain alkyl radicals containing
from 1 to 6 carbon atoms including but not limited to
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
15 sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl,
2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl,
n-hexyl and the like.
The term "loweralkenyl" as used herein refers
to a loweralkyl radical which contains at least one
20 carbon-carbon'~double bond.
The term."arylalkyl" as used herein refers to
an urisubstituted or substituted aromatic ring appended
to an alkyl radical including but not limited to benzyl,
1- and 2-napht:hylmethyl, halobenzyl and alkoxybenzyl.
The i:erm "aminoalkyl" as used herein refers to
-NH2 appended to a loweralkyl radical.
The germ "cyanoalkyl" as used herein ref ers to
-CN appended t:o a loweralkyl radical.
The 'term "hydroxyalkyl" as used herein refers
to -OH appends~d to a loweralkyl radical.
The germ "alkylamino" as used herein ref ers to
a loweralkyl radical appended to an NH radical.
The germ "cycloalkyl" as used herein refers to
an aliphatic ring having 4 to 7~carbon atoms.
The term "cycloalkylmethyl" as used herein
refers to an. cycloalkyl group appended to a methyl
~ ~ 40 98 4
radical, including but not limited to cyclohexylmethyl.
The term "aryl" as used herein refers to a
substituted or unsubstituted aromatic ring including but
not limited to phenyl, naphthyl. halophenyl and
alkoxyphenyl.
The terms "alkoxy" and "thioalkoxy" as used
herein refer: to R1~0- and R14S-, respectively,
wherein RI4 i;~ a Ioweralkyl group.
The term '''alkenyloxy" as used herein refers to
. R1S~ wherein R15 is an unsaturated alkyl group. .
The term "hydroxyalkoxy" as used herein refers
to -OH appendEad to an alkoxy radical.
The term "dihydroxyalkoxy" as used herein
refers to an alkoxy radical which is disubstituted with
~,5 -OH radicals .
The i~erm "arylalkoxy" as used herein refers to
an aryl appended to an alkoxy radical.
The term "arylalkoxyalkyl" as used herein
refers to an aryalkoxy appended to a loweralkyl radical.
The term "(thioalkoxy)alkyl" as used herein
refers to thioalkoxy appended to a loweralkyl radical.
The term "'dialkylamino" as used herein refers
to -NR16R1~ wherein R16 and R1~ are
independently selected from loweralkyl groups.
The term "[(alkoxy)alkoxy]alkyl" refers to an
alkoxy group appended to an alkoxy group which is
appended to a Ioweralkyl radical.
The term "(hydroxyalkyl)(alkyl)amino" as used
herein refers to -NR18RI9 wherein R18 is
hydroxyalkyl a.nd R1~ is Ioweralkyl.
The term "N-protected aminoalkyl" as used
herein refers to NfLR20 is appended to a loweralkyl
group, wherein. R20 s an N-protecting group.
The term "alkylaminoalkyl" as used herein .
refers to ~FiR21 appended to a loweralkyl radical,
wherein R21 is a loweralkyl group.
_. , . 1 3 4th g8 4
The term "(N-protected)(alkyl)aminoalkyl" as
used herein refers to NR20R21, which is appended to
a loweralkyl radical, wherein R20 and R21 are as
def fined above .
The term "dialkylaminoalkyl" as used herein
refers to :DTR22R23 is appended to ' a Ioweralkyl
radical wherein R22 and R23 are independently
selected from loweralkyl.
The i:erm "(heterocyclic)alkyl" as used herein
1.0 . refers to a heterocyclic group appended, to a loweralkyl
radical, including but not limited to imidazoylalkyl. . °
The i:erm "'0-protecting group" as used herein
refers to .a substituent which protects hydroxyl groups
and includes but is not limited to substituted methyl
15 ethers, for example, methoxymethyl, benzyloxymethyl,
2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl
and tehahydropyranyl; substituted ethyl ethers, for
example, 2,2"2-trichloroethyl, t-butyl, benzyl and
triphenylmethy:l; silyl ethers, for example.
trimethylsilyl, t-butyldimethyls~lyl and
t-butyldipheny:lsilyl; cyclic acetals and ketals, for
example, meth~~lene acetal, acetonide and benzylidene
~acetal; cyc:Lic ortho esters, for example,
methoxymethylene; cyclic carbonates; and cyclic
boronates.
The term ":heterocyclic ring" or "heterocyclic"
as used herein ref ers to any 5-, 6-, 9- or 10- membered
ring containing from one to three heteroatoms selected
from the group consisting of nitrogen, oxygen, and
sulfur; having various degrees of unsaturation; wherein
the nitrogen and sulfur heteroatoms may optionally be
oxidized; wherein the nitrogen heteroatom may optionally .
be cruaternized; and including any bicyclic group in
which any of the above heterocyclic rings is fused to a
benzene ring. Heterocyclics in which nitrogen is the
3!i
heteroatom are preferred. Fully saturated heterocyclics
X.
s 1 3 4Q 98 4
are also preferred. Preferred heterocyclics are:
pyrryl, Fyrrvlinyl, pyrrolidinyl, pyrazolyl,
pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl,
imidazolidinyl, pyridyl, piperidinyl, pyrazinyl,
piperazinyl, pyrimidinyl, pyridazinyl~ oxazolyl,
oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl,
thiaxolyl, thiazolidinyl, isothiazolyl,
isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,
benzimidazoly:l, benzothiazolyl, benzoxazolyl, furyl,
.10 thienyi and bE~nzothienyl.
Saturated heterocyclics-may be unsubstituted or
monosubstitutE~d with hydroxy, oxo, amino, alkylamino,
dialkylamino or loweralkyl. Unsaturated heterocyclics
may be unsubstituted or monosubstituted with hydroxy,
:15 amino, alkylanaino, dialkylamino or loweralkyl.
The most preferred heterocyclics are as follows:
_! _! _ _! _
N ~ t I
N N N
s s
OH
O OH
OH
\ \ N ~ HO
vN ~ / ' I / ' ~~X~ zO ' /~X~ 2);
/ -N /'N
wherein n is 7; or 2 and X is N, NH, O, S, provided that
X is the point: of connection only when X is N,
Y
Y
0 wherein Y is NH, N-loweralkyl, 0, S, or S02, or
X
1340984
Z' ~ , Z=' O ~ ~ O ,.
wherein Z1 is N, 0, or S and not the point of
connection arid Z2 is N when it is the point of
connection anti NH, O or S when it is not the point of
connection.
The terms "Ala", "His", "Leu", "Phe", "Tyr",
"Cys", "Gly", "Lys", Sar" and "Pro" as used herein refer
to alamine, histidine, leucine, phenylalanine, tyrosine,
cysteine, glycine, lysine, sarcosine and proline,
l~p respectively.
Most of the compounds of the invention may be
made as shown in Scheme I. The amino diol intermediate
5 represents a transition-state mimic for the Leu-Val
scissile bond of the renin substrate, angiotensinogen.
Incorporation of this amine into the angiotensinogen
sequence in place of Leu-Val Ile-Protein provides potent
inhibitors of human renin. For example, acylation of
amine 5 with. an acyl-Phe-His-OH residue or other
appropriately modified amino acid derivatives produces
2p small peptide analogues which are potent renin
inhibitors.
.. ~~ '.
1340984
a~'
IZ
N
~
IV
Q
O
C
.
V
m
O
d
i
-(r
C
m
t
LL o
m
m
N
C
m
C
' ~ ~r
C7
~
s
~
a o >
a
E
o ,
o m
~
_ C
m
C O L
N t0
.- D N N N tll
M ) ~ ~
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X
/ a ac oc x
a
a
1340984
11
Morn particularly, the process shown in
Scheme I discloses an N-protected-aminoaldehyde 1 (P1
is an N-protecting group) which is treated with an glide
to give the corresponding allylic amine 2. Oxidation
gives diol 3 (PZ and P3 are, both hydrogen).
N-deprotection gives ~; and free-basing gives amine 5.
Either intermediate 4 or S can be converted to 7 by
standard peptide coupling methods. The same sequence
(3 - 7) can be carried out with hydroxy protecting
:LO groups present (where P2 and/or P3 are 0-protecting
groups), thEr final step then being 0-deprotection.
Alternatively, allylic amine 2 may be N-deprotected,
peptide coupled using standard methods to give 6, and
then oxidized to give the desired peptide diols _7.
:LS The protected aminodiol fragment may be
alternatively prepared as shown in Scheme II. Aldehyde
9 (prepared, for example, by oxidation of alcohol 8) is
converted ta~ its cyanohydrin 10. Addition of an
organometallic reagent (such as a Grignard reagent) and
>0 acidic workuF~ provides ketone 12. Reduction of ketone
12 then provides the desired protected- aminodiol 13.
a
Image13 1340gg4
The following Examples will serve to further
illustrate preparation of the novel compounds of the
invention.
- Example 1
2(S)-t-Hutyloxycarbonvlamino-1-cyclohexylbut 3 ene
A 0°C solution of potassium hexamethyl-
disilazide (22.9 mmol in 115 mL of 5:1, tetrahydrofuran
(THF): dimethYl sulfoxide (DMSO) was added dropwise to
triphenylmeth~rlphosphonium iodide (26.81 mmol). After
:LO stirring at 0°C fox 1 hour, the solution was cooled to
-78°C and a solution of Hoc-cyclohexylalaninal (4.90 g,
19.08 mmol, p;~epared by Swern oxidation (Mancuso, A.J.;
Huang " S.-L.; and Swern, D., J. OrQ. Chem. 19?8, _43,
2480) of Hoc-~:yclohexylalaninol~ in dry THF (95 mL) was
added. After stirring at -?8°C for 1 hour, the mixture
was allowed to warm to room temperature. The reaction
mixture was quenched with aqueous ammonium chloride and
extracted with ether (2x300 mL). The combined organic
phase was washed with 10% HC1 (200 mL), saturated
20 NaHS03 (2x2a~0 mL), H20 (2x200 mL), saturated
NaHC03 (2x200 mL), and brine (200 mL), dried
(MgSO~), filtered, and evaporated. The residue was
purified by chromatography (40 m Si02; ether: hexane,
1
15:85) to giver the desired compound in 60% yield. Mass
25 spectrum: (M+.H)+ ~ 254.
Example 2
Hoc-Phe-Ala Amide of (2S)-Amino-1-cyclohexylbut-3-ene
The resultant compound of Example 1 (310 mg,
1.22 mmol) w,as dissolved in 1 M anhydrous HC1 in
anhydrous methanol 1;35 mL). After 22 hours, the solvent
was evaporated to give 230 mg (99%) of the corresponding
amine hydrochloride which was used without further
purification.
1~ 134pg84
To :~ stirred -13°C solution of Boc-Phe-Ala (408
mg, 1.21 mmol) in dry THF (8 mL) containing
N-methylmorpholine (122 mg, 1.21 mmol) was added
isobutyl chloroformate (165 mg, 1.21 mmol) dropwise.
After 3 minutes, a -i3°C solution of the above amine
hydrochloride (230 mg, 1.21 mmol) in 1:1, THF:dimethyl
formamide (D~I~') (4 mL) containing N-methylmorpholine
(122 mg) was added dropwise. The mixture was warmed to
room temperature for 2 hours. Evaporation provided a
residue which was partitioned between ethyl acetate (30
mL) and 0.1 M H3F0! (10 mL). The organic phase was
washed with brine (10 mL), saturated NafiC03 (10 mL),
and brine (10 mL). Drying, filtering, evaporating, and
chromatographing (55 g Si02; 95:5. CH2C12:CH3~H)
LS gave the desi:ced compound (462 mg, 81~).
Example 3
-Ala Amide of 3(S)-Amino-4-cvclohexvi-
;t0 To a stirred solution of the resultant compound
of Example 2 (100 mg, 0.212 mmol) in THF (5 mL) were
added OsO~ solution (0.065 mL of a 2.5 W/V~ solution
in t-butanol) and N-methylmorpholiae N-oxide (57 mg,
0.424 mmol) sequentially. After 4.5 hours, brine (10
;s mL) was added, and the mixture was extracted with ether
(4x8 mL). Tree combined organic phase was washed with
10~ Na2S03 (3 x 6 mL), 0.1 M H3P0~ (5 mL), and
brine (5 mL). Drying, filtering, and evaporating
provided the desired product (97 mg, 91~). Mass
spectrum: M+ » 505.
F.x amp 1 a 4
Sit-Butyloxycarbonylamino-4-cvclohexvl-
an
To a stirred solution of 2(S)-t-butyloxy-
carbonylamino-1-cyclohexylbut-3-ene (1.00 g, 3.95 mmol)
15 ~34pgg4 ,
in THF (20 mL) were added Os04 solution (1.2 mL of a
2.5 W/V~ solution in t-butanol) and N-methylmorpholine
N-oxide (1.07 g, 7.90 mmol). After 24 hours, the
mixture was partitioned between ether (50 caL) and brine
(25 mL). The layers were separated, and the organic
phase was e:~ctracted with ether (3 ° x 25 mL) . The
combined organic phase was washed with 10~ Na2S03
(4x10 mL), 1.0 M H3P04 (2x8 mL), and brine (15 mL).
Drying and e'raporating provided the desired product as
7.0 an oil (1.14 g, 100 0 . 'H NMR shows a 1:1 mixture of
diastereomers (NH 4.~3 and 4.56 ppm).
Example 5
Hoc-Phe-His Amides of 3(S)-Amino-4-cyclohexyl-
15 2 R,S -yydroxy-1-t-butyldimethylsilyloxybutane
The resultant compound of Example 4 (1.10 g,
3.82 mmol) ways treated with anhydrous 1M HCl/CH30H (80
mL) for 16 hours at which time evaporation and drying
provided the corresponding amine hydrochloride (0.85 g,
1000.
To a suspension of the above hydrochloride salt
(344 mg, 1.54 Col) and imidazole (105 mg) in
dichloromethane (15 mL) were added triethylamine (156
mg) and t-butyldimethylsilyl chloride (232 mg). The
25 solvent was evaporated after 31 hours, and the residue
was then re-dissolved in anhydrous dimethylformamide
(DMF, 15 mL). Hoc--Phe-His (619 mg) and 1-hydroxybenzo-
triazole (HOHT~, 312 mg) were then added. After cooling
the stirred solution to -23°C, 1,3-dicyclohexyl-
30 carbodiimide (DCC, 318 mg) was added. The mixture was
warmed to ro«m temperature 3 hours later. After 13
hours the solvent was evaporated in vacuo, and the
residue was dissolved in ethyl acetate (40 mL),
filtered, washed with saturated NaHC03 (2x10 mL) and
35 brine (10 mL), and dried (Na2S0~). Filtration and
evaporation provided a residue which was chromatographed
1 3 4p g$ 4 ,
16
on silica <lel eluting with dichloromethane/methanol
mixtures to give 441 mg (42~) of the desired product.
Mass spectrum: (M+H)+ = 686.
Anal. calcd. for C36H59N506Si:
C. 63.0: H, 8.7; N, 10.2. Found: C.r62.8; H, 9.0; N,
9.9.
Example 6
ides of 3(S)-Amine-4-w~loha~t-
To a. stirred solution of the resultant product
of Example 5 (200 mg, 0.291 mmol) in anhydrous THF (5
mL) at 0°C was added tetrabutylammonium fluoride (0.58
mL of a 1 M solution in THF). The solution was warmed
to room temperature for 4 hours and then evaporated.
The residue was dissolved in chloroform and washed with
water (3X) and brine (iX). Drying and evaporating
provided a giun which was treated with hot ethyl acetate
(8 mL). Cooking and filtration provided 25 mg of the
desired material. Mass spectrum: (M+H)+ = 572.
Anal. Calcd for C30H45N5O6 1/2H20: C,
62.1; H, 8.0; N. 12.1. Found: C. 62.4; H,.8.2; N, 12Ø
Example 7
4S -2,8-Dimethyl-4-((toluenesulfonylZamino7
5-nonanone
To a stirred -78°C solution of toluenesulfonyl
(Ts)-Leu (15 g, 53 mmol) in dry THF (240 mL) was added
butyl lithium (57.8 mL of a 0.91 M_ solution in hexane)
followed 15 minutes later by isopentyl magnesium bromide
(185 mL of a 0.8 M solution in THF). The mixture was
heated at reflux for 3 days, then cooled and poured into
0°C 1 M HC1 (;500 mL;) . The layers were separated and the
aqueous phase was extracted with ether (3x150 mL). The
combined org,3nic layers were washed with saturated
NaHC03 (2x150 mL) and brine (150 mL). Drying and
17 .1 34p 9g 4 .'
evaporating provided a residue which was chromatographed
on silica c~el to give 7.43. g (41%) of the desired
product. Mass spectrum: (M+H)+ - 340.
Anal. calcd, for C18H29N03S: C, 63.7; H,
8.6; N, 4.1. Found: C, 64.0; H, 8.6; N, 4.1.
Example 8
4S)-2,.8-Dimethyl-5-hydroxy-4-((toluenesulfonyl
ammo]-5-vinvlnonane
To a stirred 0°C solution of the resultant
compound .of Example 7 (79 mg, 0.23 mmol) in dry THF
(8 mL) was added vinyl magnesium bromide (1.5 mL of a
1.0 M solution in THF) dropwise. The mixture was. warmed
(room temperature, 10 hours), quenched (8 mL H20 +
1,5 2 mL brine), acidified with 0.1 M H3P04 (pH=7), and
extracted with ether (3 x 4 mL). The combined ether
phase was washed (4 mL brine), dried (Na2S04),
filtered, and evaporated to give 81 mg (95%) of the
desired product as a 4:1 mixture of diastereomers.
Example 9
Boc-Phe-Ala Amide of (4S)-Amino-2,8-dimethyl
5-hvdroxv-5-vinvlnnnanA
To a solution of the resultant compound of
Ex~Ple 8 (400 mg, 1.09 mmol) in liquid ammonia (80 mL)
was added sodium ( 150 mg, 6 . 5 mmol ) . After 6 hours the
ammonia was allowed to slowly evaporate under a stream
of nitrogen. Benzene (50 mL) and 1:1, ethanol: water
(20 mL) were added with stirring. The layers were
separated, and the aqueous phase was extracted with
ether. The combined organic phase was dried
(Na2S04), filtered, and evaporated to give 85 mg
(37%) of the desired product.
Foll~~wing the procedure of Example 2, but
replacing the amine hydrochloride and N-methylmorpholine
with the abovE~ resultant product, gave the desired major
is ~ 1 3 40 9g 4
diastereomer in 35% yield after chromatography. FAH
mass spectrum: (M+R)+ - 570.
Anal. calcd. for C30H49N305: % C, 67.8;
H, 9.3; N, 7.5~. Found: C, 67.7; H, 9.6; N, 7.3.
Example 10 .
Boc-Phew-Ala Amide of (3S)-Amino-2-hydroxy-2
isopentyl-5-methylhexanal
Following the procedure of Example 3 with the
resultant compound of Example 9 except replacing
N-methylmorpholine N-oxide with aqueous NaI04 gave the
desired compound.
Example 11
Hoc-Phe_-Ala Amide of 3-Amino-1,2-dihydroxy
2-iso entyl-5-methylhexane
Treatment of the resultant compound of
Example 10 w:~th one equivalent of NaBH4 in methanol
provided the <iesired compound after aqueous work-up.
Example 12
Boc-Ph_e-Ala Amide of 3-Amino-1,2-dihydroxy-
2-isopentyl-5-methylhexane
ScaIE~ up of the procedure of Example 8 led to
the isolation of the minor diastereomer pure after
ZS chromatograph;i. Treatment as in Examples 9, 10, and 11
provided the desired isomer of the resultant product of
Example 11.
Example 13
2(S)-1~-Butyloxycarbonylamino-1-cyclohexyl-
6-methvlhe~t-3-ene
To a stirred -78°C solution of
Boc-cyelohexy:lalanine methyl ester (40 g, 140 mmol) in
anhydrous toluene (250 mL) was added diisobutylaluminum
hydride (130 M%. 1.5 M solution in toluene, 121.4 mL) at
19 1340984
a rate to keep the internal temperature below -60°C.
After stirring for an additional 20 minutes at -78°C,
the aldehyde solution is used immediately as described
below.
To <i potassium hydride (35%'dispersion in oil,
32.09 g) suspension in a 0°C mixture of anhydrous
THF/DMSO (1(100 mL/200 mL) under dry N2 was added
1,1,1,3,3,3-h.examethyldisilazane (209 M%, 49.07 g)
dropwise. After stirring at 0°C for 1 hour, the
resulting so7.ution was added via cannula to a 0°C flask
containing :isopentyltriphenylphosphonium bromide (209
M%, 125.66 g). .The mixture was stirred vigorously for 1
hour at which time it was cooled to -78°C. The -78°C
aldehyde solution prepared above was then added via
cannula. After stirring at -78°C for 15 minutes, the
mixture was allowed to slowly warm to room temperature
and then heated to 40°C for 12 hours. The mixture was
then cooled to~ room temperature and quenched with
methanol (7.65 mL:) followed by aqueous Rochelle salts
(100 mL sat.urated solution and 500 mL H20). The
mixture was i:hen extracted with ethyl acetate (2x). The
combined extracts were washed with water and brine.
Drying (MgS04) and evaporating provided crude alkene
which was cr~romatographed on silica gel (ether/hexane)
to give 16.5 g (38%) of the desired compound as an 85:15
mixture of cis:trans isomers. Mp=53-55°C. Mass
spectrum: M~~ =309.
Anal,. calcd, for C1gH35N02: C, 73.7; H,
11.4; N, 4.5. Found: C, 73.8; H, 11.4; N, 4.5.
. Example 14
2 S)-t-~Butyloxycarbonylamino-1-cyclohexyl-3,4-
dihvdroxy~-6-methylheptane: The 3(R)4(S); 3(S)4(S
To a solution of the resultant compound of
Example 13 (8.50, 27.5 mmol) in dry THF (150 mL) were
r
134Q984
added Os04 (2..8 mL of a 2.5~ solution in t-butanol and
N-methylmorphol.ine N-oxide (9.28 g, 68.7 mmol). After 4
days the mixture was partitioned between ether (200 mL)
and brine (100 mL). The aqueous layer was back-
'S extracted witri ether (2x100 mL), aid the combined
organic phase was washed with 10~ Na2S03. 0.1 M
H3P04, and brine. Drying (MgS04) and evaporating
provided a re:>idue (10.81 g) which was chromatographed
on -silica gel t:o elute a 60~ yield of the 4 diols in the
:LO following order.
3 R ~~ Mass spectrum: (M+H)+ _ 344.
Anal. calcd. for Ci9H37N04: C' 66.4; H, 10.9; N,
4.1. Found: (:, 66.4: H. 10.8; N, 3.9.
3 S ~~ Mass spectrum: (M+H)+ = 344. Anal.
calcd. for Ci9H37N04: C, 66.4; H, 10.9; N, S.l.
Found: C' 66.4,; H, l:l.i: N, 4Ø
3 R ~~ Mass spectrum: (M+H)+ = 344.
3 S ~~ Mass spectrum: (M+H)+ = 344. Anal.
calcd. for Ci9H37N04: C, 66.4: H, 10.9; N, 4.1.
20 Found: C' 66.0,; H, 10.7; N, 4Ø
Example 15
Boc-Phe-His Amide of 2(S)-Amino-i-cyclohexYl-
The :I(R),4(S) diastereomer of Example 14 was
' deprotected with HC1/methanol, and the resulting product
was coupled to Boc-Phe-His using 1-hydroxybenzo-
triazole and 1,3-dicyclohexylcarbodiimide according to
the procedure of Example 5. The desired product was
obtained in 40~-60~ yield. Mass spectrum: (M+H)+ = 628.
Anal. cal.cd. for C34H53N506 H20~ C,
63.2: H, 8.6: ;N, 10.8. Found: C, 63.2: H, 8.4; N, 10.5.
1340984
21
Example 16
ide of 2(S)-Amino-1-cvclohexvl-
Following the procedure of Example 15, but
replacing the 3(R).~(S) diastereomer with the 3(S).4(S)
diastereomer gave the desired compound. Mass spectrum:
(M+H)+ = 628.
Anal.. calcd. for C3~H53N506 1/2H20:
C. 64.1; H, 8.6: N. 11Ø Found: C. 64.0; H. 8.6: N,
10.6.
Exam Ip a 17
-Ph~e-His Amideof 2(S)-Amino-1-cvclohexvl-
~sm .~wr-amyaroxy-6-mecnylneptane
n
Following the procedure of Example 15, but
replacing thin 3(R).4(S) diastereomer with the 3(R),4(R)
diastereomer gave the desired compound. Mass spectrum:
(M+H)+ = 628.
Anal. calcd. for C34H53N5C6 H2W C.
63.2; H. 8.6; N. 10.8. Found: C. 63.1: H, 8.5: N. 10.7.
Example i8
-Ph~a-His Amide of 2(S)-Amino-1-cvclohexvl-
Following the procedure of Example 15, but
replacing they 3(R),~1(S) diastereomer with the 3(S),4(R)
diastereomer gave the desired compound. Mass spectrum:
(M+H)+= 628.
Anal. calcd. for C34H53N5C6 3/4H20:
C. 63.7; H. 8.6; N. 10.9. Found: C. 63.8: H. 8.8: N.
10.7.
22
Example 19 ~ 3 4 ~ 9 8 4
A. 4(S)-t-Butyloxycarbonylamino-5-cvclohexvl-
ene
To a stirred -78°C solution of
Hoc-cyclohexylalanine methyl ester (10.2 g, 35.8 mmol)
in dry toluene (60 mL) was added diisobutylaluminurn
hydride (34 mL of a 1.5 M solution in toluene). After
30 minutes, vinyl magnesium bromide (108 mL of 1 M_
solution in THF) was added. After stirring for 15 hours
' 10 at 0 °C, thE~ mixture was careful ly quenched ~ with
methanol, treated with Rochelle salts (22 mL of
saturated aqueous solution in 140 mL H20), and
filtered. After extracting the solids 5 times with
ethyl acetate, the extracts and filtrate were combined
and the organic phase was washed with brine, dried,
filtered, and evaporated to an oil (10.2 g).
Chromatograph:Y on silica gel eluting with hexane/ethyl
acetate mixtures provided 6.1 g (60%) of the desired
product.
Anal. calcd. for C16H29N03 1/4H20: C,
66.8; H, 10.3; N, 4.9. Found: C, 66.9; H, 10.2; N, 4.7.
H. _4;S)-Cyclohexylmethyl-5(R,S)-vinyl-2
oxazolidinone
The resultant product of Example 19A (2.80 g,
9.88 mmol) in dry dimethylformamide (DMF) (50 mL) was
added to a starred suspension of NaH (593 mg of a 60%
dispersion in oil, 14.8 mmol, hexane washed) in dry DMF
(50 mL). After 3 :hours, the mixture was quenched (750
mL water + 100 mL brine) and extracted with ether (5x100
~). ~e combined organic phase was washed with brine
(3x50 mL), d:ried I;MgSO4), filtered, and evaporated to
an oil 2.23 c~. The NMR spectrum of the crude product
revealed an 82:18 mixture of 5 S:5 R diastereomers.
Silica gel chromatography gave 80% recovery of pure
1
1340884
23
diastereomers. 5 S:
Anal. calcd. for C12H19N02: C~ 68.9; H.
9.1; N, 6.7. Found: 68. l; N, 9.2; N, 6.5. Mass
spectrum: (M+1)+ ~~ 210. 5 R: Mas s spectrum: (M+1)+
= 210.
C. 5 R -Carboxy-!(S)-cyclohexylmethyl-2-oxazolidinone
To a solution of the compound from Example 19H
( 1 g, ! . 78 m~nol ) di ssolved in 16 mL of benzene and 3 mL
of acetic acid was added a solution of 3.01 g of
potassium pernnanganate in 16 mL of water. The resultant
two-phase mixture was vigorously stirred and treated by
portionwise addition with 153 mg of tetrabutylammonium
bromide. After stirring for 2 hours at room
temperature, the ,mixture was quenched with aqueous
sodium bisulfj.te, acidified to pFi=3, and extracted with
ethyl acetate.. Drying and evaporating gave the desired
product as an oil in 59~ yield.
D. !(S)-Cvclohexylmethvl-5(R)-(3-(3-
l~droxmentyl) -2-oxazolidinone
To a solution of the compound from Example 19C
dissolved in tetrahydrofuran and cooled to -78°C was
added 3.5 equivalents of ethyl magnesium bromide. After
stirring at -i~8°C for 1.5 hours and at room temperature
for 1 hour, the reaction mixture was quenched with water
r
and extracted with ether. The dried ethereal extract was
evaporated to afford a 73~ yield of product.
E. 2(S)-Amino-1-c~rclohexyl-3(R)-3,4-
dihydroxy-!-ethylhexane
A solution of the compound from Example 19D
(1.69 mmol) and barium hydroxide octahydrate (3.38 mmol)
in dioxane (60 mL) and water (40 mL) was heated at
reflex under N2 for 21 hours. The solid barium
carbonate was filtered and the filtrate was partially
~'~4~984
24
evaporated. The residue was diluted with water and the
resulting solution was extracted with ether. The
organic extr:pct was washed with brine solution, dried
over MgS04, and evaporated to give the desired product
in 76~ yield. s .
F. Boc-P:he-His Amide of 2(S)-Amino-1-cvclohexvi-
The resultant product of Example 19E was
coupled to 8oc-Phe-His using 1-hydroxybenzotriazole and
1,3-dicyclohe:ECylcarbodiimide according to the procedure
of Example 5 vto give the desired product in 55~ yield.
Example 20
( ~ Boc-His Amide of 2(S)-Amino-1-cyclohexyl-
3~R~,4(S)-dihydroxy-6-methylheptane
The procedure of Example 15 was followed except
Boc-Phe-His was replaced with Hoc-His. Mass spectrum:
(M)+ = 480.
Ana l, calcd. for C25H44N405 3/4H20:
C. 60.8; H, 9.1; N, 11.3. Found: C, 60.9; H, 9.2: N,
11Ø
Example 21
TBA-CHA-His Amide of 2(S)-Amino-1-cyclohexyl-
»w ~te»;~..a~,.,..._~__~~~,..,t,._~___
The resultant compound of Example 20 was
deprotected w9lth HC1/methanol, and the resulting product
was coupled to t-butylacetyl-cyclohexylalanine (THA-
CHA) using the DCC/HOHT method of Example 5. HRMS
calcd. for C35H61N505' (M+H) 632.4751. Found:
632.4759.
. 1340984
z~s
Example 22
Ami
arDOrlY1-cocx~)Tvr-His Amirla of ~re1_
Using the procedure of Example 21, but
replacing TB~~-CHA with ethoxycarbonyl-f~OCH3)Tyr-His gave
the desired compound. Mass spectrum: (M+H)+ ~ 630.
Example 23
a-His Amide of 2(S)-Amino-1-
Using the procedure of Example 21, but
replacing T~3A-CHA with acetyl-N-methylPhe gave the
desired compound. Mass spectrum: M+ ~ 583.
Example 24
Ac-P1--His Amide of 2(S)-Amino-1-cvclohexvl-
Using the procedure of Example 21, but
replacing THA-CHA with 0-acetyl-L-3-phenyllactic acid
(Ac-P1-OH) gave the desired compound. HRMS calcd. for
C31H46N406' (M+H) 571.349s. Found: s71.3489.
Example 2s
1-His Amide of2~S)-Amino-1-cvclohexvl-3(R).4(S)-
_ __ __~ _____
' The resultant compound of Example 24 (37.4 mg,
0.06s mmol) in MeOH at 0°C was treated with R2C03
(9.1 mg, 0.065 mmol) for 30 minutes at 0°C. Evaporation
provided a residue which was partitioned between ethyl
acetate and water. The organic phase was washed
(brine). dried (MgS04), and evaporated to give the
desired compound (32 mg, 93~). Mass spectrum: (M+H)+
= 529.
Anal. calcd. for C31H46N406 1~2H20:
C. 64.8; H, 8.4; N, 10.4. Found: C. 64.6: H, 8.3: N,
26
10.1.
1340984
Example 26
Boc-1-N;31-His Amide of 2(S)-Amino-1-cyclohexyl
~R ,4S8)-dihydroxv-6-methvl-heotane
Using the procedure' of Example 21, but
replacing TB~~-CHA with Boc-1-naphthylalanine (Boc-1-Nal).
provided the desired compound. Mass spectrum: (M+H)+
= 678.
Example 27
Dba-Ftis Amide of 2(S)-Amino-1-cyclohexyl-
3(R),4(S)-dihydroxy-6-methylheptane
Using the procedure of Example 21, but
replacing TBA-CHA 'with 2,2-dibenzylacetic acid (Dba-OH)
gave the desired compound. HRMS calcd. for
C36H50N4C4' (~K+H) 603.3910. Found: 603.3899.
Example 28
Pp-His Amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-
dihydroxy-6-methylheptane
Usin~~ the procedure of Example 21, but
replacing TBp,-CHA with 3-phenyl-propionic acid (Pp-OH)
gave the desired compound. Mass spectrum: (M+H)+ -
513.
Anal, calcd. for C29H44N404 1/2 H20:
C, 66. 8: H, F3. 7. , N, 10 .7. Found: C, 66. 6; H, 8. 8; N,
10.5.
Example 29
Ethoxycarbonyl-Phe-His Amide of 2(S)-Amino-1
cyclohexYl-3(R),4(S)-dihydroxy-6-ethylhe tane
Using the procedure of Example 21, but
replacing TB~4-CHA with ethoxycarbonyl-Phe gave the
desired produca. Mass spectrum: (M+H)+ - 600.
Anal. calcd. for C32H49N5~6 1/2H20:
X
. 1340984
27
C, 63.1; H, 8.3s N, 11.5. Found: C, 62.8; H, 8.3: N,
11.4
Example 30
ide of 2(S)-Amino-lrcvclohexvl-
Using tha procedure of Example 21, but
replacing TBa~-CHA with acetyl(Ac)-Phe gave the desired
product. Mass spectrum: (M+H)+ = 570.
Anal. calcd. for C31H47N5~5 1/2H20:
C, 64.3: H, 8.2; N, 12.1. Found: C, 64.2: H, 8.3: N,
12Ø
Example 31
c
Boc-Leu-His Amide of 2(S)-Amino-1-cvclohexyl-
31;R),4(S)-dihvdroxv-6-methvlhe~tane
Using the procedure of Example 21, but
replacing T13A-CHA with Boc-Leu gave the desired
product. Mass spectrum: (M+H)+ = 594.
Anal. calcd. for C31H55N5~6 1/2H20:
C, 61.8; H, 9.4; L~, 11.6. Found: C, 61.8; H, 9.3; N,
11.6.
Example 32
-His Amide of 2(S)-Amino-1-cvclohexvl-
Using the procedure of Example 21, but
replacing ~THA-CHA with t-butyl-aminocarbonyl-Phe
(Tbac-Phe) gave the desired product. Exact mass calcd
for C34H55N6~5' 627.4233. Found: 627.4226.
Example 33
Boc-PhE~~-Ala Amide of 2(S)-Amino-1-cvclohexvl-
Using the procedure of 2, but replacing the
resultant compound of Example 1 with the 3(R),4(S)
1 3 40 98 4
28
diastereomer of Example 14 gave the desired compound.
Mass spectrum: (M-H)+ = 560.
Anal. ca:lcd. for C3IHSiN3~6' C~ 66.3:
H, 9.1; N, 7.5. Found: C, 66.0; H, 9.2: N, 7.3.
Example 34
Boc-Phe~-Phe Amide of2(S)-Amino-1-cvclohexvl-
Usin<~ the procedure of Example 33, but
replacing Boc~-Phe-A:la with Boc-Phe-Phe, gave the desired
product. Masr spectrum: (M+H)+ = 638.
Ana l, calcd. for C37H55N306: C, 69.7;
H. 8.7; N, 6.1i. Found C, 69.4: H, 8.8; N, 6.5
Example 35
Boc-Phe--PAla Amide of 2(S)-Amino-1-cvclohexvl-
an
Using the procedure of Example 33, but
replacing Boc:-Phe-Ala with Boc-Phe-(3-pyrazoyl)alanine
(Boc-Phe-PAla)~, gave the desired compound. Mass
spectrum: (M+FI)+ = 628.
Anal. calcd, for C34H53N5~b 1/2H20:
C. 64.1; H, 13.5; N, 11Ø Found: C, 64.1: H. 8.3: N,
11.2.
Example 36
Ethoxy~~arbon~l-Phe-Leu Amide of 2
1-CVCIChe~xvl-3(R) .4(S)-AShv~rn~rts-~-n
Using' the procedure of Example 33, but
replacing Soc-~Phe-Ala with Boc-Phe-Leu, gave the desired
compound. Mass spectrum: (M+H)+ ~ 576.
. Anal. calcd. for C32H53N3~6' C~ 66.7;
H. 9.3: N, 7.3. Found: C, 66.4; H, 9.5; N, 7.2.
1340984
29
Example 37
ino-1-cvclohexvl-
Using the procedure of Example 33, but
replacing Boc:-Phe-Ala with Boc-Phe-(SCH3)Cys, gave the
desired compound. bass spectrum: (M+H)+ = 608.
Anal. calcd. for C32H53N306S' C, 62.8;
H, 8.8; N, 6.'9. Found: C, 62.8; H, 8.9; N, 6.6.
~~ple 38
s-(N Me,Nr~Bn)-His Amide of 2(S)-Amino-1-
Usin~~ the procedure of Example 20, but
replacing eoc~-His with (N tosyl, N methyl, N imidazole
benzyl)-His (Ts-(N Me,NIMBn)-His) (DuVigneau, V.;
Behrens, O.R. J. 8iol. Chem. 1937, 117, 27), gave the
desired compound. Mass spectrum: (M+H)+ = 639.
Example 39
. Ethoxycarbonyl-Phe-MeNis Amide of 2(S)-Amino-1-
To a stirred -78°C solution of the resultant
compound of Example 38 (100 mg, 0.156 mmol) in liquid
NH3 (5 mL) auzd dry tetrahydrofuran (5 mL) was added
sodium until a dark green/brown color persisted for 5
minutes. Sol'.id, powdered NHlC1 was then added, and
the mixture was evaporated. The residue was suspended
in water and extracted several times with chloroform.
The combined extracts were dried (Na2S0!), filtered.
and evaporated to give the Mefiis amide of 2(S)-amino-
1-cyclohexyl-a(R),!(S)-dihydroxy-6-methylheptane. The
material was coupled to ethoxycarbonyl-Phe using to
DCC/H08T method described in Example 5 ~to give the
desired produces. Mass spectrum: (M+H)+ = 61l.
1340984
Example 40
_-t-Hutyloxycarbonylamino-1-cvclohexvl-
Usir.~g the procedure of Example 13, but
5 replacing isopentyltriphenylphosphonium bromide with '
isohexyltripr~enylpr~osphonium bromide, gave the desired
product.
Example 41
10 2 S -~t-Hutyl~carbonylamino-1-cvclohexvl-
Using the procedure of Example 14, but
replacing they resultant compound of Example 13 with the
resultant compound of Example 40, gave the desired
15 compound.
Example 42
Hoc-His Amide of 2(S)-Amino-1-cvclohexyl-
3(R).4(S)-dihydroxy-7-methyloctane
20 Using the procedure of Example 20, but
replacing the 3(R),4(S) diastereomer of Example i4 with
the resultant: compound of Example 41, gave the desired
product. Mass spectrum: (M+H)+ = 495.
Anal. calcd. for C26H46N405 1/2H20:
a
25 C. 62.0: H, 9.4; N. 11.1. Found: C, 62.2; H, 9.4: N.
10.9.
Example 43
TBA-Phe~-His Amide of 2(S)-Amino-1-cvclohexvl-
Using the procedure of Example 15, but
replacing th~a resultant compound of Example 14 and
Boc-Phe-His ~~ith the resultant compound of Example 42
and t-butyla<:etyl('.~HA)-Phe gave the desired compound.
Mass spectrum: (M+H)+ = 640.
1340984
31
Anal. calcd. for C36H57N505 3/4H20:
C, 66.2 H, 9.0: N, 10.7. Found: C, 66.1: H, 9.1; N,
10.6.
Example 44
2 S =t-Hutyloxycarbonvlamino-i-c~r~~nho~1_
Usin~~ the procedure of Example 13, but
replacing ifoopentyltriphenylphosphonium bromide with
isobutyltriphenylphosphonium bromide, gave the desired
product. Mass spectrum: M+ = 295.
Anal, calcd. for C18H33N02 1/4H20: C,
72.0; H, 11.3;; N, 4.7. Found: 71.7; H, 11.1: N, 4.5.
Example 45
2 S -t:-Butyloxycarbonvlamino-1-cvelot~p~~-
Using the procedure of Example 14, but
replacing the resultant compound of Example 13 with the
resultant compound of Example 44, gave the desired
compound.
Example 46
-Phe--His Amide of 2(S)-Amino-1-cvclohexvl-
Using the procedure of Example 15, but
replacing the resultant product of Example 14 with the
resultant product of Example 45, gave the desired
product. Mass spectrum: (M+H)+ = 614.
Example 47
Ethoxyc2~rbonyl-Phe-Leu Amide of 2(S)-Amino-1-
Following the procedures used to make the
resultant connpound of Example 36, but replacing
isopentyltriph~enylphosphonium bromide with propyl-
1
. 32
triphenylpho;sphonium bromide, gave the desired product.
Mass spectrwn: M* ~ 547.
Anal. calcd. for C30H49N3~6 1/4H20:
C, 6s.2; H, li.0; N,, 7.6. Found: C. 65.0; H, 8.9: N. 7.3.
Example 48
-pne-heu Amide of 2(S)-Amino-1-
Following the procedures used to make the
resultant compound of Example 36, but replacing
isopentyltriphenylphosphonium bromide with pheneth-
yltriphenylphosphonium bromide, gave the desired product.
Example 49
Boc-Phe-His Amide of 2(S)-Amino-1-cyclohexyl
3~R~ , 4 ( S ) -d ihydroxypent ane
Following the procedures used to make the
resultant compound of Example 15, but replacing
isopentyltriF~henylphosphonium bromide with ethyltri
phenylphosphonium bromide, gave the desired product.
Mass -spectrwt~: (M+H) ~ 600.
Anal.. calcd. for C3~H49N506 1/4H20:
C, 63.6; H, 8.3; N, 11.6. Found: C. 63.6; H, 8.3; N.
ll.s.
( ~ Example so
2 S -~t-Butsrloxycarbonvlamino-1-cvclohexvl-
To F~ stirred -78°C solution of Boc-cyclohexyl-
alanine meth;~l ~est.er (3s.0 g, 123 mmol) in anhydrous
toluene (200 mL) was added diisobutylaluminum hydride
( 140 M~, 1 . s M solution in toluene, 117 mL) at a rate to
keep the internal temperature below -60°C. After
stirring for an additional 20 minutes at -78°C, allyl
magnesium ch7loride (184 mL of a 2.0 M solution in THF)
35 was added. The mixture was allowed to stand at 0°C for
X340984
33
16 hours and was then quenched with methanol. The
mixture was diluted with ether and then washed
sequentially with .citric acid (aq) and brine. Drying
(MgS04) and evaporating provided ans oil which was
purified by silica gel chromatography to give the
desired compound in 40~ yield.
Example 51
2(S)-t-Butyloxycarbonvlamino-1-cyclohexyl-
3(R),4(S)-dihydroxyhex-5-ene
An allylic oxidation using stoichiometric
Se02 and t-butyl hydroperoxide (Umbriet, M.A. and
Sharpless, R.13. J. Am. Chem. Soc. 1977, 99, 5526) was
performed on the resultant product of Example 50 to give
the desired product after silica gel chromatography.
Example 52
arDOnY~-Phe-Leu Ami de ef 2l S 1-nm; r, r,-~ -
Following the procedure of Example 15, but
replacing the resultant product of Example 14 and
Boc-Phe-His with the resultant product of Example 51 and
ethoxycarbonyl-Phe-Leu, gave the desired product. Anal.
calcd. for C'30H4~.N306: C, 66.03: H, 8.68: N.
7.70. Found: C, b6.10; H, 8.83: N, 7.43.
Example 53
~N-suty~l, 4-OCH3)-Phenylalanine
To a, stirred 0°C suspension of (4-OCH3)-phenylalanine
(1.00 g, 5.12 mmol) and butyraldehyde (0.406 g, 110 M~)
in methanol (10 mL) was added sodium cyanoborohydride
(241 mg, 75M$). The mixture was warmed to room
temperature fo;r 23 h and filtered. The solid was washed
with methanol and suction dried to give 1.07 g (83%) of
the desired p~:oduct. Mass spectrum: M+ = 251. Anal.
' 1 3 40 98 4
34
Calcd for ~=14H21N03.1/3H20: C. 65.3: H, 8.5: N,
5.4 Found: C, 65.1: H, 8.3: N, 5.6.
Example 54
N-Hutv:l~ 4-OCH3)Phe-His Amide of 2(S)-Amino-1-
Using the procedure of Example 21, but replacing THA-CHA
with the resultant product of Example 53 gave the
desired coml>ound. Mass spectrum: (M+H)+ ~ 614.
Anal. Calcd for C34H55N505'1/2 H20: C. 65.6:
H, 9.1; N, 11.2.. Found: C. 65.3: H, 9.0; N, 11.3.
Example 55
H- 4~-OCH3ZPhe-Leu Amide of 2(S)-Amino-1-
......i..v........~ ~~,.w .~.,. ~.~ . _ . __
Using the procedure of Example 33, but replacing
Boc-Phe-Ala ~~ith Cbz-(3-I,4- OCH3)Phe-Leu provided the
protected iodinated product. Deprotection and de-
iodination was achieved by hydrogenating 0.59 g in
methanol (150 mL) with Na0Ac.3H20 (0.40 g), 2.5~
Rh/HaS04 (1.5 g), 20~ Pd/C (0.29 g) at 4 atmospheres
H2 for 2.5, h. Filtration and evaporation provided a
residue which was partitioned between ethyl acetate and
sat. aq. NaHfC03. The organic layer was washed with
dilute Na2S~;03 and brine, dried, filtered, and
evaporated to give a solid. Recrystallization from
CN2C12/hexane provided 260 mg (65~) of the desired
compound. HRMS: M+ Calcd for ~3pH52N305'
534.3907. Measured.. 534.3925.
Ex ~p 1 a 5 6
X1.4-methoxy)-Phe-Leu Amide of 2(S)-Amino-1-
The resultant product of Example 55 (130 mg, 0.243 mmol)
was hydrogenated (1 atmosphere H2) with l0~ Pd/C
(39 mg) in methanol/formalin (12 mL/5 mL) for 8 h.
. 1340984
Filtering an~~ evaporating (high vacuum) provided a
Oesidue which was chromatographed on silica gel to give
43 mg (32~) of the desired compound. HRMS: (M+H)+
calculated for C32H56N305' 562.4220.
5 Measured: 56:! : 4230.
Example 57
H-Phe-Leu Amide of 2(S)-Amino-1-cvclohexvl-
10 Following the procedure of Example 55, but replacing
Cbz-(3-I,4-OCHf3)Phe-~Leu with Cbz-Phe-Leu and omitting
Na0Ac.3H20 and 2.5'~ Rh/BaS04 in the reduction step,
provided the desired compound. Mass spectrum: (M+H)+
504. Anal. Calcd for C29H49N304: C, 69.1; H,
15 9.8; N, 8.3. Found: C, 69.0; H, 10.1; N, 8.3.
Example 58
-cj-C.Yanoetnyl))Phe-Leu Amide of 2(S)-Amino-1-
20 A suspension of the resultant compound of Example 57
(297 mg, 0.~~90 mmol) in acrylonitrile (2 mL) was
refluxed for 3 days. Evaporation provided a residue
which was dlissolv~ed in ethyl acetate, filtered,
evaporated and chromatographed on silica (dichloro-
25 methane/methanol, 97.5/2.5) to give 162 mg (49~) of the
r
desired compound. Mass spectrum: (M+H)+ = 557.
Anal. Calcd for C~32N52N404: C, 69.0; H, 9.4; N,
10.1. Found: C, 68.6; H, 9.5: N, 9.9.
Example 59
3-Aminopropy~l))Phe-Leu Amide of 2(S)-Amino-1-
The resultant compound of Example 58 (75 mg, 0.135 mmol)
was hydrogenated (4 atmospheres H2) over Raney Nickel
(85 mg) in anhydrous methanol/ammonia (20 mL/5 mL) for 3
h. Filtration and evaporation provided the desired
1 3 40 9g 4 '
36
product (68 mg). Mass spectrum: (M+H)+ = 561.
Example 60
N,N-Dimethvl,)Gly-Phe-His Amide of 2(S)-Am
Using the procedure of Example 56, but replacing the
resultant product of Example 55 with the resultant
product of E:Kample 64, gave the desired product. Mass
spectrum: (M+H)+ = 613.
~ Example 61
Cbz-D-Ala-Phe-His Amide of 2(S)-Amino-1-cyclohexvl-
. Using the procedure of Example 21, but replacing THA-CHA
with Cbz-B-AT.a-Phe gave the desired compound. Mass
spectrum: (1K+H)+ = 733. Analysis calculated for
C40H56N6~7' C~ 65.5: H, 7.7; N, 11.5. Found:
C: 65.2; H, 7.7; N. 11.2.
Example 62
H-B-Ala-Phe-His Amide of 2(S)-Amino-1-cyclohexyl-3(F
4(S)-dihyd(roxv-6-methylheptane Diacetic Acid Salt.
The resultant compound of Example 61 (1.00 g, 1.36 mmol)
in acetic acid (14 mL) was hydrogenated at 1 atmosphere
with 10~ Pd/C (0.50 g) for 3 h. Filtration, extraction
of the catalyst with acetic acid, and evaporation of the
combined acetic acid solutions gave a residue which was
dissolved in water (25 mL) and lyopholized to provide
891 mg (91~) of the desired product. Mass spectrum:
(M+H)+ = 599 (free base). Analysis Calculated for
C36H58N6~9~1/2H20: C, 59.4; H, 8.1; N, 11.5.
Found: C, 59.3.. H. 8.0; N, 11.2.
134p9~4
37
Example 63
-Sar-1?he-His Amide of 2(S)-Amino-i-ev~l~hp~i_
~.i - ~ Y \r ~~ ~~rV .
Using the procedure of Example 21, but replacing TeA-CHA
with Cbz-Sa='-Phe gave the desired ' compound. Mass
spectrum: (r~+H)+ ~ 733. Anal. Calcd for C, 64.8; H,
7.7; N, 11.3. Found: 6s.0; H, 7.6; N, 11.3.
Example 64
H-Sar-Phe-His Amide of 2(S)-Amino-1-cvclohexyl-
3(R),4(S)-dihydroxy-6-methylheptane Diacetic Acid Salt.
Using the procedure of Example 62, but replacing the
resultant cornpound of Example 61 with the resultant
compound of ;Example 63 gave the desired product. Mass
spectrum: (~!~+H)+ ~~ s99 (free base) . Anal. calcd for
C36H58N6~9'H2~~' C~ 58.7: H, 8.2; N, 11.4.
Found:
s8.s; H, 8.1; N, 11.4.
Example 6s
z-GABA-Phe-His Amide of 2('S)-Amino-1-cyclohexyl-
4(S)-dihydroxy-6-methvlhe~tane.
Using the procedure of Example 21, but relacing THA-CHA
with Cbz-GABA-Phe (GAHA is 4-aminobutyric acid) gave the
desired compound.
Example 66
-Phe-His Amide of 2(S)-Amino-1-cyclohexyl-3(R),4
dihydroxy-6-methyl-heptane Diacetic Acid Salt.
Using the procedure of Example 62, but replacing the
resultant compound of Example 61 with the resultant
compound of Example 6s gave the desired product.
38 ~34pge4
Example 67
-Isoni ectOyl-Fhe-His Amide of 2(S)-Amino-1-
-3(R),4(S)-d hydroxy-6-methylheptane.
Using the procedure of Example 21, but replacing TBA-CHA
with Cbz-Isonipectoyl-Phe gave the desired compound.
Mass spectrum: (M+H)+ = 773. Analysis calculated for
C43H60N607.H~t0: C. 65.3; H, 7.9: N, 10.6.
Found: 65.4;. H. 7.,6; H, 10.5.
Example 68
H-IsonipectoylPhe-His Amide of'2(S)-Amino-1-cyclohexyl-
3(R),4(S)-d~~hydroxy-6- methylheptane Diacetic Acid Salt.
Using the procedure of Example 62, but replacing the
. resultant compound of Example 61 with the resultant
compund of F;xample 67 gave the desired product. Mass
spectrum: (ri+H)+ = 639 (free base).
Example 69
Cbz-D-Ala-Phe-His Amide of 2(S)-Amino-1-cyclohexyl-3~R).
4 S -dihydroxy-6-methylheptane.
Using the 'prc>cedure~ of Example 21, but replacing THA-CHA
with Cbz-D-p~la-Phe gave the desired compound. Mass
spectrum: ~(M+H)+ = 733. Analysis calculated. for
C40H56N6~7~1.5H20: C. 63.2; H, 7.8; N. 11Ø
Found: C. 63.0: H, 7.4; N. 11Ø
Example 70
H-D-Ala-Phs~-His Amide of 2(S)-Amino-1-cyclohexyl-3(R),
4(S)-dihydroxy-~6-methylhe tape Diacetic Acid Salt.
Using the p~:ocedure of Example 62, but replacing the
resultant compound. of Example 61 with the resultant
compound of Example b9 gave the desired product. Mass
spectrum: (xf+H)+ = 599 (free base).
1340984 '
39
Example 71
3-Henzylo carbonylamino-3-methylbutanoic Acid.
A solution of 2,2-dimethyl-3-carbomethyoxypropionic acid
(LeMaul, Hull. Soc. Chim. Fr., 828 (1965). 20 g, 0.125
mol], diphenylphosphorylazide (34.3 g, 0.125 mol) and
triethylamine~ was heated in toluene (150 mL) at 100°C
for 2 h. Afl:er cooling to 5°C, the toluene solution was
washed successively with 0.5M HC1, aqueous NaHC03 and
brine. Evaporation of the dried solution gave a residue
which was chromatographed on silica gel eluting with
60/!0 hexane-- ether. There was obtained 13 g of methyl
3-isocyanato-3-methylbutanoate as a mobile liquid. A
solution of this material in toluene (20 mL) was treated
with benzyl alcohol (13 mL) and the resulting mixture
heated at re:Elux for !0 h. Evaporation of the toluene
left a residue which was dissolved in methanol (125 mL)
and then treated with a solution of NaOH (6.6 g, 0.165
mol) in 22 mL of water. After 5 h, the reaction mixture
was partially evaporated, washed with ether and
2p acidified with 6N HCl. Extraction with methylene
chloride and evaF~oration gave 21 g of the desired
product. NI~9t (300 MHz, CDC13): 1.42 (s, 6H), 2.78
(s, 2H), 5.08 (s. 2H).
Exam lp a 72
i 25
(:bz= t ( 13 , f3-d i-Me ) -t3-A1 a ] -Phe-OCHa .
A 4.0 g sample of 3-benzyloxycarbonylamino-3-methyl-
butanoic acid was .coupled to phenylalanine methyl ester
hydrochloride (3.13 g) using the mixed anhydride
30 procedure described in Example 2. Purification of the
crude product by flash chromatography eluting with 65/35
ether-hexane gave an 86~ yield of product. NMR (300 MHz,
CDC13): 1.32 (s. 3H), 1.34 (s, 3H), 2.46 (d, 1H),
2.63 (d, 1H), 2.98 (dd, iH), 3.09 (dd, iH), 3.70 (s,
35 3H), 1.86 (dd, 1H), 4.97 (d, 1H), 5.2 (d, 1H), 5.3 (s,
~ 3 ~4 9e 4
1H), 6.13 (d, 1H).
Example 73
Cbz-[(B,B-di-Me)-B-Ala)-Phe-0H
To a 0°C solution of Cbz-[(B,B-di Me)-B-Ala]-Phe-OMe
5 (1.5 g, 3.63 mmol) in dioxane (15 mL) was added a
solution of lithium hydroxide (0.174 g, 4.15 mmol) in
water (7.5 ~r~L) . After stirring for 1 h at 0-5°C, the
reaction mixture was diluted with cold water and
- extracted 2)~ with ether. The aqueous portion was
10 acidified with 6N HC1 and extracted with ether. The
organic extr:~ct was washed with brine and evaporated to
give an 87~ hield of product as a viscous liquid.
Exam le 74
Cbz-[ (B,B-c!i-Me)--B-Ala -Phe-His Amide of 2(S)-Amino-1_-
15 cyclohe~cyl3(R),4(S)- dihydroxy-6-methvlheotane.
Using the procedure of Example 21, but replacing TeA-CHA
with Cbz-[(B,B-di.-Me)-B-Ala]-Phe gave the desired
compound. Mass spectrum: (M+H)+ = 761. Anal. Calcd
for C42H60~46C7 ~ i,/4H20: C, 65. 5; H, 8. 0; N,
20 10.9. Found: C, E~5.6; H, 7.9; N, 11Ø
Example 75
H-[(B,B-di-Me)-t3-Ala]-Phe-His Amide of 2(S)-Amino-1-
cyclohexyl-:3 R ,4(S)-dihydroxy-6-methylhe tare Diaceti
Acid Salt.
Using the procedure of Example 62, but replacing the
resultant compound of Example 61 with the resultant
compound of Example 74 gave the desired product. Mass
spectrum: (~d+H)+ = 627 (free base). Anal. Calcd for
C38H62N6~9~H20: C, 59.7; H. 8.4; N. 11Ø
Found: C, 59.5: H, 8.4; N, 11.3.
41 ~ 3 40 9e ~
Example 7s
-Pro-Phe-His Amide of 2(8)-Amino-1-cyclohexvl
Using the procedure of Example 21, but replacing THA-CHA
with Cbz-Pro-Phe gave the desired r compound. Mass
spectrum: (M+N)+ = 759. Analysis calculated for
C42H58N607~1/2H20: C. 65.7, H, 7.7; N, 10.9.
Found: 65.7, H, 7.7; N, 10.9.
to Example 77
Pro-Phe-l3is Amide of 2(S)-Amino-1-cyclohexyl-
4(S)-dih~~droxv--6-mprl,vtl,ort~"o n,.e.;" r,.;,a ~.,
Using the procedure of Example 62, but replacing the
resultant compound of Example 61 with the resultant
compound of E;xample~ 76 gave the diacetic acid salt as a
tacky solid. A portion of the di-salt was partioned
betwen satd. NaHC0,3 and dichloromethane. The aqueous
layer was further extracted with dichloromethane and the
combined organic layers were dried, filtered and
evaporated to give the desired product. Mass spectrum:
(M+H)+ = s2!i (free base). Analysis calculated for
C36N56N607~2H~;0: C, 60.0: H, 8.4; N, 11.6.
Found: C. 59.51; H, 7.9; N, 11.5.
Example 78
3-Benzyloxy~carbonylamino-2,2-dimethyl ropionic Acid.
3-Carbomethox~~-3-methylbutanoic acid (Bull. Soc. C.him.
Fr., 828 (1965), 7.85 g, 0.049 mold was reacted with
diphenylphosphorylazide and triethylamine as described
in Example 71. After heating the toluene solution for
1.5 h, benzyl alcohol (8 g) was added directly to the
reaction mixture and heating at reflex was continued for
20 h. Work-u.p and purification as in Example 71 gave
methyl 3-benzyloxycarbonylamino-2,2-dimethylpropionate.
NMR (300 MHz. CDC1,~): 1.2 (s, 6H), 3.3 (d, 2H), 3.68
1340984
42
(s, 3H), 5.1. (s, 2H), 5.22 (m, 1H). A sample of the
methyl ester (6.21 g, 0.023 mol) was saponified with 3.1
g (0.78 mol) of NaOH in 100 cnJ ethanol/10 mL H20 at
room temperature fc~r ~8 h. Work-up as in Example 71 gave
the desired product as a liquid.' NMR (300 MHz,
CDC13): 1.2;3 (s. 6H), 3.32 (d, 2H), 5.10 (s, 2H),
5.27 (m, iH).
Example 79
~i>z-( ( a , a -di-Me)-t3-Ala]-Phe-OCH3 .
To a solution of 3-benzyloxycarbonylamino-2,2-dimethyl-
propionic acid (i.:i g, 5.97 mmol) in methylene chloride
(13 mL) was added oxalyl chloride (0.757 g, 5.97 mmol)
and dimethylformami.de (30 ul) . After stirring for 1 h
at room tempE~rature, the reaction mixture was cooled to
0°C and treated successively with phenylalanine methyl
ester hydrochloride (1.29 g, 5.97 mmol) and N-methyl-
morpholine (1,.81 g, 17.9 mmol). Stirring for 1 h at
0-5°C was followed by distribution between CH2C12
and 0.5 N HC1. The organic phase was washed with
aqueous NaH<:03 and brine and dried over MgSO~.
Evaporation of they solvent gave a residue which was
purified by chromatography. There was obtained a
yield of product as a liquid. NMR (300 MHz, CDC13):
l.il (s, 3H), 1.12 (s, 3H), 3.05 (dd. 1H), 3.18 (dd,
iH). 3.23 (d, 1H), 3.24 (d, iH), 3.75 (s, 3H), 4.82 (dd,
1H), 5.08 (s, 2H), 5.37 (broad t, 1H), 6.0~ (d, 1H).
Example 80
C~ Z~( ( a , a -d i -Me ) -t3-A 1 a ] -Phe-OH .
The hydrolysis of the methyl ester was carried out by
the procedur~a described in Example 71 to give the
desired product in 90~ yield as a viscous liquid.
1340984
43
Example 81
Cbz-[ a. _a-di-Me _--!3-Ala]-Phe-His Amide of 2(S)-Amino-1-
..' .
Using the procedure of Example 21. but replacing TBA-CHA
with Cbz-[ a. , a--di-Me)-B-Ala]-Phe gave the desired
compound. Mass spectrum: (M+H)+ = 761.
Example 82
[ ( a, o-Di--Me -B-Ala]-Phe-His Amide of 2(S)-Amino-1-
cyclohexy:l-3 R ,4(S)-dihydroxy-6-methylhe tape Bis
acetic acid salt.
Using the compound from Example 81 and the procedure of
Example 62 gage the desired product in 71~ yield. Mass
spectrum: (M~~H)+ = 627.
Example 83
Cbz-Phe-His Amide of 2(S)-Amino-1-cyclohexyl-3(R),
4 S -dihydroxy-6-methylheptane
Using the pro~~edure of Example 21 but replacing TBA-CHA
with Cbz-Phe gave the desired compound. Mass spectrum:
(M+H)+ = 661.
Example 84
Amide of 2(S)-Amino-1-cvclohexvl-
-v-.i ..r~rrvwl v .v.~.v..yasacY~.oaac.
A solution of the product from Example 83 (180 mg, 0.273
mmol) in methanol 1;50 mL) was hydrogenolyzed in a Parr
Apparatus witlh 90 mg of 20~ Pd/C and 4 atmospheres of
hydrogen. A:Eter the hydrogen uptake ceased, the
catalyst was ~~iltered and the filtrate evaporated to the
desired produ<a (90 mg, 63;t). Mass spectrum: (M+H)+ _
527.
~3'~~g84
44
~xample 85
a -Amino:~sobutyryl-Phe-His Amide of 2(S)-Amino-1_
cyclohexyl-3(it),4(S)-dihydroxy-6-methylhe tape.
A mixture of a -aminoisobutyric acid N-carboxy anhydride
(10.9 mg, 0.1)85 mmol) and the product' from Example 84
(44.6 mg, 0.085 mmol) in dimethylformamide (3 mL) was
stirred at room temperature for 16 h. The dimethyl-
formamide was. evaporated in vacuo and the residue was '
distributed between chloroform and water. The organic
phase was dried arid evaporated to a residue which was
chromatograph~ad ~on silica gel eluting with
methanol-chlo:roform mixtures. There was obtained 35 mg
(68~) of the desired product. Mass spectrum: (M+H)+
= 612.
Example 86
1-sulfonyl)-Phe-His Amide of 2fs)-Amine-i-
..,
Using the procedure of Example 21, but replacing THA-CHA
with (pyrid:ln-3-y:l-sulfonyl)-Ph~e . gave the desired
product.
Example 87
(Pyrazin-2-5~1-carbonyl)-Phe-His Amide of 2(S)-Amino-1
cyclohexyl-3(R),4(S)-dihydroxy-6-methylhe tane.
Using the procedure of Example 21, but replacing THA-CHA
with (pyrazin-2-yl-carbonyl)-Phe gave the desired
product. Mass spectrum: (M+H)+ = 634. Anal. Calcd
for C34H4~rf~05. 1~~4H20: C, 64 . 0; H, 7. 5: N.
30 15.4. Found: C. 6:l.9; H, 7.6; N. 15.2.
Example 88
dazol-4~- 1-acetyl)-Phe-Leu Amide of 2(S)-Amino-1-
yclohexYl-3(R.),4(S)-dihydroxy-6-methylheptane.
35 Using the coupling conditions of Example 21 with
1 3 4 0 9 8 .,~ . .
4-imidazoleacetic acid and the resultant product of
Example 57 provided the desired product. Mass
spectrum: (M+H)+ = 612. Analysis calculated for
C34H53N505'1/2H20: C. 65.9; H. 8.9: N. 11.3.
5 Found: C. 65.9; H, 8.9; N, 11.3
Exampie 89
rroi-z-y~1-carbonyl)-Phe-HisAmide of 2(S)-Amino-1-
10 Using the procedure of Example 21, but replacing THA-CHA
with (pyrrol-2-yl~-carbonyl)-Phe gave the desired
product. Mas;a spectrum: (M+H)+ = 621.
Example 90
15 Allyloxycarbonyl-Phe-Leu Amide of 2(S)-Amino-1-cyclohexyl
-3~1t ,~ S -dihydroxy-6-methvlhectaine.
Using the procedure of Example 33. but replacing
Hoc-Phe-Ala with al.lyloxy carbonyl-Phe-Leu provided the
desired product. Mass spectrum: (M+H)+ = 588. Anal.
20 Calcd for ~33H53N306' C~ 67.4; H, 9.1; N, 7.2.
Found: C. 67,6; H, 9.0; N, 7.1.
Example 91
1_oxycarbonyl-Phe-Leu Amide of 2(S)-Amino-1-
25 ..s ~..,.r"~....~ .
;' To a stirred 0°C solution of the resultant compound of
Example 90 (1..25 g, 2.13 mmol) in dry tetrahydrofuran
(THF, 50 mL) was added 9-borabicyclol3.3.1~- nonane
(9-BBN, 25.5 rtiL of a 0.5M solution in THF). The mixture
30 was warmed to room temperature for 12 h and then cooled
to 0°C. Water (15 inL) and 3M NaOH (4.5 mL) were added
followed 2 .min later by 30~C H202 (5 mL). The
mixture was p<~rtitianed between brine (20 mL) and ethyl
acetate (100 nnL). The organic phase was washed (brine).
35 dried (Na2S04), filtered, and evaporated to a thick
oil. Recryst:allization twice (dichloromethane/ether)
1 3 40 98 4
46
provided 670 mg (52~) of the desired compound. Mass
spectrum: I;M+H)+ ~ 605. Analysis calculated for
CC33H55N307: C, 65.4: H, 9.2; N. 6.9. Found:
C, 65.4; H, 9.1: N, 6.8.
Example 92
the Resultant Comvound of Example 9
To a stirred 0°C suspension of the resultant compound of
Example 91 (60 mg, 0.099 mol), Cbz-Gly-OH (20.7 mg,
0,099 mmol), and 4-dimethylaminopyridine (60 mg, 0.495
mmol) in dichloromethane (10 mL) was added ethyldi-
methylaminopropyl carbodiimide hydrochloride (38 mg,
0.198 mmol). The mixture was warmed at room temperature
for 15 h a:nd than diluted with dichloromethane and
washed sequ~?ntial:ly with 1M H3P04, satd NaHC033
and brine. Drying (Na2S04), filtering, and
evaporating provided 57 mg (72t) of the desired
compound. Mass spectrum: (M+H)+ = 797.
Example 93
H-Gly-Ester of t:he Resultant Compound of Exam le 91 ,
at 3-Hydroxypropyloxy Group).
The resultant compound of Example 92 (13 mg, 0.016 mmol)
was hydrogenated (1 atmosphere H2) with 10~ Pd/C (4
mg) in methanol for 3 h. Filtration, evaporation and
chromatography on silica (dichloromethane/methanol,
95/5- 90/10) provided 4 mg (37~) of the desired
product. fiRMS: (M+H)+ calcd for C35HS8N408:
663.4333. Found: 663.4355.
Example 94
Lysine Ester of the Resultant Compound of Example 91
(at 3-Hycir~iopyloxy Group) Diacetic Acid Salt.
Following the procedure of Example 92 but replacing
Cbz-Gly-OH w~~th a,e-di- Cbz-Lys-OH provide the desired
~3409g4
47
protected pE~ptide. Hydrogenation according to the
procedure of Example 93, but replacing methanol with
acetic acid provide the desired compound.
Example 95
Hemisuccinate Ester of the Resultan~
Using the procedure of Example 92, but replacing Cbz-Gly
with benzyl succinate provided the protected product.
Deprotection was achieved by following the procedure of
Example 103 to give the desired product.
Example 96
er of the Resultant Com and of
;at 3-Hvdroxvpropvloxv GIOUD).
Using the procedure of Example 92, but replacing Cbz-Gly
with dibenzylphosphate provided the protected product.
Deprotection was achieved by following the procedure of
Example 103 to give the desired product.
Example 97
2(R,S),3-DihS~droxypro yloxycarbonYl~Phe-Leu Amide of 2(S
-Amino-1-cYClohexvl-3(R),s(S)-dihvdroxv-6-methvlheDtane.
Following the procedure of Example 14, but replacing the
resultant compound of Example 13 with the resultant
f. 25 compound of l~cample 90, and heating the mixture at SO°C
for 2~ h, gave the desired product. Mass spectrum:
(M+H)+ = 622. Anal. Calcd for C33H55N3~8
.1/2H20: C. 62.8: H, 8.9; N, 6.7. Found: C, 63.0;
H, 8.6: N. 6.7.
Example 98
Using the procedure of Example 92, but replacing the
134pg8,~
48
resultant compound of Example 91 with the resultant
compound of Example 97, provided a mixture of the
desired mono- and diesters. Separation was achieved by
silica gel chromatography.
Exa~le 99
~of Example
c Acid Salt.
Using the p:rocedu:re of Example 93, but replacing the
resultant compound of Example 92 with the resultant
monoester of Example 98 and replacing methanol with
acetic acid, gave t:he desired product.
r EXample 100
H-Gly-Diest er of the Resultant Compound of Example 97
(at the 2,3-Dihydroxypropyl Group) Diacetic Acid Salt.
Using the procedure of Example 93, but replacing the
resultant compound of Example 92 with the resultant
diester of Example 98 and replacing methanol with acetic
acid, provided the desired compound.
' Example 101
Ethoxycarbonvl-~(OBn)Thr-His Amide of 2(S)-Amino-1-
Using the procedure of Example 21, but replacing THA-CHA
i_
with ethoxyc:arbonl~-threonine benzyl ether - [ (OBn)Thr~
gave the desired compound. Mass spectrum: (M+H)+ _
616. Anal. Calcd for C32H~9N507: C, 62.4; H,
8.0; N, 11.x. Found: 62.3: H, 8.0; N, 11.3. ,
Example 102
BenzyloxYace~tvl-Phe-His Amide of 2(S)-Amino-1-cvclohexvl-
Using the procedure of Example 21, but replacing TBA-CHA
with benzyloxyacetyl-Phe gave the desired compound.
Mass spectrunn: (M+H)+ = 676. Analysis calculated for
1340984
49
C38H53N506'1/'~HZO: C. 67.1: H. 7.9: N. 10.3.
Found: 67.0: H, 7.9: N, 10.2.
Example 103
Hydroxvacetyl-Phe-_His Amide of 2(S)-Amino-1-cyclohexyl
~~~(S -dihydroxv-6-methvlheutane.
The resultant compound of Example 102 (250 mg, 0.370
mmol) in acetic acid (3.7 mL) was hydrogenated at 1
atmosphere H,t with 10~ Pd/C (125 mg) for 23 h.
Filtration, extraction of the catalyst with acetic acid,
_ 10 and evaporation of the combined acetic acid solutions
gave a residue which was partitioned between ethyl
acetate and satd. aq. NaHC03. Exhaustive extraction
of the aqueous phase with ethyl acetate, combination of
all organic layers, and evaporation provided crude
product which was recrystallized (ethylacetate/methanol/
methylcyclohe~;ane) to give 157 mg (72~) of the desired
product. Mass spectrum: (M+H)+ = 586. Anal. Calcd
for C3H4~N506.H20: C. 61.7; H. 8.2; N, 11.6.
Found: C. 62.1; H, 8.1; N. 11.4.
Example 104
1-Q-Ala.-Phe-His Amide of 2(S)-Amino-1-cvclohexvl-
Using the procedure of Example 21, but replacing THA-CHA
with Acetyl-D-Ala-Phe provided the entire compound.
Example los
i-Bu-P1-His.i~nide of 2(S)-Amino-1-cyclohexyl-3(R),4~-
_..,_____ . ___~__,~ _
Using the procedure of Example 21, but replacing TBA-CHA
with 0-isobutltl-L-3--phenyllactic acid (i-Bu-P1-OH) gave
the desired compound.
X340984
so
Example 106
Isobutyryl-Homo-Phe methyl ester
To a suspension of (t)- a -amino-!-phenylbutyric acid
(Homo-Phe) methyl ester hydrochloride (0.83 g, 3.61
mmol) in met.hylene chloride cooled in an ice bath was
added successively isobutyric anhydride (0.57 g, 3.61
mol) and N-mEathylmorpholine (0.79 mL, 7.22 mmol). After
stirring for 30 min at 0-s°C, the reaction mixture was
distributed between methylene chloride and O.sN HC1.
The organic layer was washed with aqueous NaHC03 and
brine solution and. then dried over MgSOl. Evaporation
of the solvent gave a solid residue which was triturated
with hexane to provide 700 mg of product, mp 72-73°.
Example 107
Isobutyryl-Homo-Phe
The hydrolys9~s of the methyl ester was carried out by
the procedure described in Example 73 to give the
desired product in 90~ yield.
Example 108
Isobutyryl-Homo-Phe-His Amide of 2(S)-Amino-1-cyclohexyl
~R),!(S)-dihydroxy-6-methvlheotane.
Using the procedure of Example 21, but replacing TBA-CHA
with isobuty~ryl-homo- Phe gave the desired compound.
Mass spectrum: (M+H)+ = 612.
Example 109
-IC(4-rtorpholinyl)carbonylJoxv]-3-phenvlprooioni
acia methyl ester.
To L-phenylla~ctic acid methyl ester (-3.2 g) was added
150 mL of 12..5 phosgene in toluene and 25 drops of
dimethylformamide. After stirring for 16 h at room
temperature, the solvent was evaporated and the residue
1340984
sl
chased several times with benzene. The resulting
product was dissolved in methylene chloride (50 mL),
cooled to 0°C: and treated by dropwise addition with 3.86
g (0.0!! mol.) of morpholine. The reaFtion mixture was
stirred for 2 h at 0-5°C and then distributed between
O.sN HC1 and methylene chloride. The organic phase was
washed with aqueous NaHC03 and brine and evaporated to
a residue. 1?lash chromatography on silica gel eluting
with 2/1 ether-hexane gave a 65~ yield of product. NMR
(300 MHz): 3.08 (dd, 1H), 3.20 (dd, 1H), 3.8 (s. 3H),
5.19 (dd, 1H).
Example iio
2(S)-f(!-Moroholinyl)carbonyl]oxy-3- henylpropionic acid.
Using the hy<irolys:is procedure of Example 73, the title
compound was obtained in 90~ yield.
Example 111
2(S)-[(!-Morpholinyl)carbonyl]oxy-3- henylpro ionyl-His
Amide of 2(S -Amino-1-cyclohexyl-3SR~ ~!(S)-dihydroxy-6
Using the procedure of Example 21, put replacing THA-CHA
with the product from Example 110, gave the desired
product in b0~ yield. Mass spectrum: (M+H)+ = 6l2.
Example 112
2(S)-(C(!-Cbz-1-Pi~erazinvl)carbonvlloxvl-3
Using the F>rocedure of Example 109, but replacing
morpholine with Cbz- piperazine, gave the desired
product in 63~ yield.
Example 113
2(S)-(i~(!-Cbz-1-Piperazinyl)carbonyl]oxy])-3-
phenylpropionic acid.
Using the hydrolysis procedure of Example 73 gave the
134984
s2
desired prod~sct in 93~ yield.
Example 114
10 Example lis
2(S)-(((i-F~i~eraxinyl)carbonyl~oxyJ-3-phenyl ro ionyl
Phe-His A~mde of 2(S)-Amines-i-cv~lehp~t-~ru~~rc~_
Using the ~~rocedure of Example 62 gave the title
compound in 8~s~ yield. M.p. 1s8°-160°C.
Example 116
4-M~~rpholinyl)carbonyl~-Phe methyl ester.
A suspension of L-phenylalanine methyl ester
20 hydrochloride (6 g) in toluene (12s mL) was heated to
100°C while ;phosgene gas was bubbled into the reaction
mixture. After approximately 1-1/2-2 h, the mixture
became homoc~eneoua. The passage of phosgene was
continued for an additional is min, keeping the temp-
25 erature at 90-100°C. The toluene was then evaporated
and the residue chased several times with benzene. A
6.s g (0.03:167 mol) sample of a-isocyanato-L-phenyl-
alanine methyl ester was dissolved in 50 mL of methylene
chloride and cooled to 0°C. Morpholine (2.76 mL,
30 0.03167 mol) dissolved in 5 mL of methylene chloride was
added dropwise. After 10 min at 0-5°C, the reaction
mixture was distributed between O.SN HC1 and methylene
chloride. Ttie organic layer was washed with aqueous
NaHC03 and dried over MgS04. Evaporation of the
35 solvent gave 7 g of product after trituration with
Using the procedure of Example 21, but replacing TBA-CHA
with the resultant compound from Example 113, gave the
title compound. Mass spectrum: (M+H)+ = 77s.
1340984
53
hexane, mp 90-91~.
Example 117
[(4-Morpholinyl)carbonyl]~~Phe.
Using the procedure of Example 73 gave the title
compound in 89~ yield.
ldnyl)caxbonyl -Phe-HisAmide of 2(S)-Amino-1-
..1 _ .. ,.....,. .
Using the procedure of Example 21, but replacing THA-CHA
with [(4-mor;pholin.yl)carbonyl]-Phe, gave the desired
compound. Mass spectrum: (M+H)+ = 6d1.
Example 119
(Dimethylamino)carbonyl]-Phe-His Amide of 2(S)-Amino-1
cyclohexyl3(R~,~(S)-dihydroxy-6-methylhe tape.
Using the procedures of Examples 116, 73, and 21, this
compound was ~?repared. Mass spectrum: (M+H)+= 599.
Example 120
Using the procedures of Examples 116, 73, and 21, the
title compound was synthesized. Anal. calcd for
C32H52N6C6'1-'L/2 H20: C, 60.4: H, 8.~5: N,
12.82. Found.. C, 60.36: H, 8.11; N, 12.77.
Example 121
[(1-Cbz-4-P~ lperazinyl)carbonyl]-Phe methyl ester.
Using the procedure of Example 116, but replacing
morpholine with 1-Cbz-piperazine, gave the desired
product, mp 1114-115" .
1 3 40 9~ 4
s~
Example 122
~(1-Cbz--4-Piperazinyl)carbonyl]-Phe
Using the procedure of Example ~3 gave the desired
product in 89~ yield.
Example 123
[(1-Cbz-4-P~erazinyl)carbonyl]-Phe-His Amide of 2(S)-
Amino-1-cyc:lohexyl-3(R),~(S)-dihydroxy-6-methylhevtane.
Using the procedure of Example 21, but replacing TBA-CHA
with [(1-CY~z-4-piperazinyl)carbonyl]-Phe, gave the
desired compound.
Example 124
[(1-Piperazin 1 carbonyl]-Phe-His Amide of 2(S)-Amino-1
cyclohexy7.-3 R -4(S)-dihydroxy-6-methvlh_eptane His=
Acetic Acid Salt.
IS
Using the procedure of Example 62 gave the desired
compound in 90~ yield. Mass spectrum: (M+H)+ ~ 640
(free base).
Example 125
~(~-Morpholinyl)carbonyl]-(4-OCH~)Phe methyl ester.
Using the procedure of Example 116 but replacing
H-Phe-OCH3.HC1 with L-tyrosine methyl ester methyl
ether.HC1 gave the title compound.
Example i26
[(4-M~orpholinyl)carbonyl]-(4-OCH3 Phe-OH.
Using the procedure of Example 73 gave the title
compound in 9;2~ yie:ld.
X344984
ss
Example 127
((!-Morpholinyl)carbonyl]-(!-OCH3)Phe-His Amide of 2(S)
-Amino-1-cyclohexyl-3(R),!(S)-dihydroxy-6
methylheptane
Using the procedure of Example 21, but replacing THA-CHA
with I(!-morpholinyl)carbonyl]-(!-OCH )Phe gave the
desired compound. Mass spectrum: (M+H)~ = 671.
. Example 128
!- 2-Ox:o~i~er~azinyl)carbonyl )-Phe methyl ester .
Using the F>rocedure of Example 116, but replacing
morpholine with 2-oxopiperazine (Transition Met. Chem.,
11, 27 (1986)] gave the desired compound in 80~ yield.
Example 129
- 2-Oxopiperazinyl)carboayl]-Phe.
Using the procedure of Example 73 gave the desired
compound.
Exam le 130
(!-(2-Oxopi.perazinyl)carbonyl -Phe-His Amide of 2(S)-
Amino-1-cvc7,ohex~l-3(R),!(S)-dihydroxv-6-methvlheptane.
Using the procedure of Example 21, but replacing THA-CHA
with (!-(2- oxopiperazinyl)carbonyl]-Phe, gave the
desired produ~~t in 60~ yield.
Example 131
1-(!-Oxopiperidinyl)carbonyl~-Phe methyl ester.
Using the procedure of Example 116, but replacing
morpholine ~rith 4-oxopiperidine gave the desired
compound.
1340984
ss
EX8mple 132
~1.-(4-Oxopiperidinyl)carbonyl]-Phe.
Using the procedure of Example 73 gave the desired
compund in 91~ yield.
Example 133
-.a~~mrnri~r~orir~inm .rarnnnv. .-vno-r~ic omino r~r vm-
Using the procedure of Example 21, but replacing THA-CHA .
with (1-(4--oxopiperidinyl)carbonyl]-Phe, gave the
desired product.
Example 134
(1-(4-~droxypiperidinyl~)carbonyl]-Phe methyl ester.
Using the procedure of Example 116, but replacing
morpholine with 4--hydroxypiperidine, gave the desired
compound.
Example 135
4-Hyd_roxypiperidinyl)carbonyl]-Phe.
Using the procedure of Example 73, gave the desired
product in 82~ yield.
Example 136
il-(4-Hydrox5rpi~erxdiny])carbonyl]-Phe-His Amide of 2(S)-
Amino-1-cyc7lohexyl-3(R L 4(S -dihydroxy-6-methylheptane.
Using the procedure of Example 21, but replacing THA-CHA
with (1-(4-hydroxypiperidiny])carbonyl]-Phe, gave the
desired compound in. 56~C yield.
Example 137
1-(3-Hydroxy_piperidinyl)carbonyl]-Phe-His Amide of 2(S)-
Amino-1-cvc:lohexvl-3(R),~(S)-dihydroxy-6-methylheptane.
Using the procedures described in Examples i16, 73 and
X340984
57
21, the titl~a compound was synthesized.
Example 138
3-C:arbomethoxy-3-pheno ro iortiic acid.
A solution of 2-phenoxybutyrolactone [Dareman, C., Hull.
Soc . Chim. F:c . . 29~! ( 1971 ) . 4 . 96 g. 0 . 028 mol ] was added
to methanol (125 mL) containing 0.054 mol of sodium
methoxide. After stirring for 3.5 hours at room
temperature, the mixture was quenched, with 5 mL of
acetic acid" and then distributed between ether and
brine solution. The organic layer was washed with brine
and evaporat~ad to a residue (methyl-4-hydroxy-2-phenoxy-
butyrate). A solution of this material in acetone (300
mL) was tre~ited with Jones solution until the orange
color persisted. The acetone was partially evaporated
and the residue wa,s distributed between ether and brine
solution. Evaporation of the dried ether layer gave the
desired product as a waxy solid. NMR (300 NMR,
CDC13): 3.02 (d, 2H), 3.78 (s. 3H), 5.11 (t. iH).
Example 139
-((~-Morpholinvl)carbonvl)-
Using the mixed anhydride procedure described in Example
2, morpholir,~e was coupled to 3-carbomethoxy-3-phenoxy-
propionic acid to give the desired product in 86~ yield.
mp 83-84°C. Ana:L. Calcd for C15H19NC5' C~ 61.2:
H, 6.53; N, ~f.78. Found: C. 61.17; H, 6.50: N, 4.61.
Example 140
3-((4-Morpholin~rl)carbonyl]-2-phenoxypropionic acid.
Using the procedure of Example 73 gave the desired
product in 5!~~ yie:Ld, mp 150-151°C.
' ~ . 1 3 40 9g 4
58
Example 141
Using the procedure of Example 21, but replacing TBA-CHA
with the re~:ultant product of Example 140, gave the
desired product as a mixture of R and S diastereomers.
Chromatograph;Y on silica (dichloromethane/methanol,
95/5) provided the less polar diastereomer (isomer A)
and the more polar diastereomer (isomer H). Isomer A:
Mass spectrum: (M+H)+ = 642. Analysis calculated for
C34HSiN507.1/2H20: C, 62.7; H, 8.0; N, 10.7.
Found: C. 62.7; H, 8.1; N, 10.3. Isomer B: Mass
spectrum: (M+H)+ = 642. Analysis calculated for
C34H51N5C7'H2~3' C~ 61.9; H, 8.1; 10.6.
Found: C, 62.2; H, 7.8; N, 10.4.
Example 142
2~R,,S - 4-Morpholinylcarbonylmethyl)
3~phenylpropionic Acid.
Ethyl a-carboxymeth;ylcinnamate was prepared as reported
(Cohen, S.G. and Milovanovic, A. Biochemistry, 1968,
3495) and hydrogenated according to the procedure of
Example 93. The resulting dihydrocinnamate was coupled
to morpholine using the procedure of Example 21. Ester
hydrolysis according to the procedure of Example 73
provided the desired compound. Mass spectrum: (M+H)+
= 278. Anal. Calcd for Ci5H13N04.1/8H20: C,
64.4: H, 6.9; N, 5Ø Found: C. 64.4; N, 6.8: N, 4.9.
Example 143
2(R,S)-(4-Mor~holinylcarbonylmethyl)-3-phenylpropionyl-
His Amide of 2 S -Amino-1-cyclohexyl-3(R),4(S)-dihvdroxv-
Using the procedure of Example 21, but replacing TBA-CNA
with 2(Ft,S)-(4-morpholinylcarbonylmethyl)-3-phenyl-
X344984
59
propionic acid provided the desired product as a mixture
of R and S diastereomers. Chromatography on silica
(dichloro- mEathane/methanol 95/5 - 90/10) provided the
less polar diastereomer (isomer A) and the more polar
diastereomer (isomer B). Isomer A: Mass spectrum:
(M+H)+ ~ 640.' Anal. Calcd for C35H53N5~6
.1/2H20: C, 64.8: H, 8.4: N, 10.8. Found: C. 65.1:
H, 8.4, N. 10.3. Isomer H: Mass spectrum: (M+H)+
640. Ana:l.Calcd for C35H53NSW 1/2H20: C,
64.8; H, 8.4; N, 10.8. Found: C, 65.0; H, 8.3; N, 10.6.
Example 144
N- Benzyloxyacetyl)morpholine.
Using the mixed anhydride procedure described in Example
2, morpholinEa was coupled to benzyloxyacetic acid to
give the desi~:ed product in 90~ yield.
Exam le 145
Methyl 2-benzyl-3=-benzyloxy-3- (4-mor holinyl)carbonyl
propionate.
A -78°C solution of N-(benzyloxyacetyl)morpholine (1 g,
8.5 mmol) in THF (25 mL) was treated with potassium
bis(trimethyla>ilyl)amide (17 mL of a 0.5M solution).
After stirrin<1 for 10 min at -78°C, a solution of methyl
2-bromo-3-phenylpropionate (8.5 mmol) in TNF (5 mL) was
added dropwi:;e. Stirring at -78°C for 30 min was
followed by warming to 0°C. The reaction was then
distributed between ether and brine solution. The
organic layer was washed with brine and dried over
MgS04. Evaporation and flash chromatography on silica
gel gave the desired product in 63% yield.
Example 146
-Benzyl~-3-hydroxy-3_-[(4-morpholinyl)carbonylJ-
~ro~ionic acid.
Using the procedure of Example 84, the benzyl ether
3 40 98 4
so
protecting group was removed by catalytic hydrogenolysia
to give methyl 2-benzyl-3-hydroxy-3-I(!- morpholinyl)
carbonyl]propionate. The methyl ester function was
hydrolyzed using the procedure in Examgle 73 to give the
title compound.
Example 1!7
15
2-Hen
Example 1!8
2-Hydroxy-~3- !--morpholinyl]carbonyl]propionic acid
acetonide.
A mixture of dl-malic acid (5 g), 2,2-dimethoxypropane
(100 mL) and catalytic p-TsOH was heated at 100°C for 5
h~ After cooling and evaporation the residual solid was
recrystallize~d from carbon tetrachloride to give the
corresponding acet.onide lactone. This material was
coupled to morpholine using the mixed anhydride
procedure of 'Example 2 to give the title compound.
Example 1!9
Methyl 2-hydro -3-((!-morpholinyl)carbonyl]propionate.
A solution of 2-hydroxy-3-(!-(morpholinyl)-carbonyl]
propionic acid acet;onide (5 g) in methyl alcohol (75 mL)
was treated with 1 mL of concentrated sulphuric acid and
the mixture was stirred for 2! h at room temperature.
Partial evaporation of the solvent gave a residue which
was distributed between either and brine solution. The
ether layer was dried over MgSO! and evaporated to
give the desired product.
Using the procedure of Example 21, but replacing THA-CHA
with 2-benzyl-3-hydroxy-3-((!-morpholinyl)carbonyl]
propionic ac id, gave the desired product in 51~ yield.
~ X40984
61
Example 150
Methyl 2-anilino-3-[(4-mor holinyl)carbonyl]propionate.
The trifluoromethanesulfonate of methyl 2-hydroxy-3-
[4-morpholiny:l)carbonyl] propionate wasp prepared by the
method of Shi~osaki [J. Org. Chem. , 46, 3230 ( 1981) ] . A
solution of this compound (7 mmol) in methylene chloride
(25 mL) was added dropwise within S minutes at room
temperature to a stirred solution of aniline (14 mmol)
in methylene chloride (25 mL), and stirring continued
for 30 min at room temperature. The reaction mixture
was filterd, the solution was washed with water, dried
over Na2S04, concentrated and the residue purified
by chromatogr2~phy. Yield of product = 80;.
Example 1s1
ino-3-[(4-morpholinyl)carbonyl]propionyl-His J
!(S)-Amino-1-cvclohexvl-3(R).4(S)-dihvdroxv-6-
Using the product from Example 150 and the methods of
Examples 73 ar,~d 21 gave the title compound.
Example 152
Ethyl 5-p,cetamido-2(R,S)-benzyl-4-oxopentanoate.
Ethyl a-carbo:Kymethylcinnamate was prepared as reported
(Cohere, S.G. and Milovanovic, A. Biochemistry, 1968,
3495) and hy~drogen.ated according to the procedure of
Example 93. The resulting acid was converted to the
desired acetarnidomethyl ketone using the methodology of
Pfaltz et al." (Tetrahedron Lett. 1984, 25, 2977: acid
to acid chloride t:o cyanoketone followed by 2n/acetic
acid/acetic anhydride treatment).
134pgg4
62
Example 153
amido-2(R.S)-benzyl-4-oxo entanoyl-His Ami
)Amino-1-cyclohexyl-3 ( R) , 4 ( S )-dihydroxv-i
The resultant product of Example 152 was hydrolyzed
according to the procedure of Example 73 provided the
corresponding acid which was coupled in place of TBA-CHA
according to the procedure of Example 21. The desired
product was obtained as an (R,S) mixture which was
separated by <;hromatography.
Example 154
-[(4-Morpholin 1 carbonyl]-2-thiophenoxypr
methyl ester.
Using the procedure of Example 139, but replacing
3-carbomethox)r-3-phenoxypropionic acid with 3-carbo-
methoxy-3-thiophenoxypropionic acid, gave the desired
product.
Ex amp 1 a 15 5
-((4-Morpholinyl)carbonyl]-2-(R, S)-thioohenox~rvrooionvl-
6-methylheptane.
Using the procedures of Examples 73 and 21, the title
compound was ~>repared in ~9~ overall yield.
f
Example 156
-t-Buty7loxycarbonylamino-1-cyclohexyl-3-hydroxy-6-
methylheptan-4-one.
To a solution of resultant compound of Example 13 (8.50,
27,5 mmol) in. dry TNF (150 mL) were added OsO~ (2.8 mL
of a 2.5~ so:lution in t-butanol and N-methylmorpholine
N-oxide (9.28 g, 68.7 mmol). After 4d the mixture was
partitioned b~atween either (200 mL) and brine (100 mL).
The aqueous :layer was back-extracted with either (2 x
100mL), and the combined organic phase was washed with
134pg84 .
63
10~ Na2S03, 0.1 M H3P04, and brine. Drying
(MgS04) and evaporating prow;ded a residue (10.81 g)
which was chromatographed on silica gel to remove the
four diastereomeric diols from 0.70f g (7;) of the
desired product. Mass spectrum: (M + H) = 342.
Example 157
Hoc~Phe-His Amide of 2(S)-t-Butyloxycarbonylamino-1
c clohexyl-3-hydroxy-6-methylheptan-4-one.
The resultant product of Example 156 (220 mg, 0:645
mmol) was treated with 4 M HCi/dioxane for 6 hours.
Evaporation ~3nd drying under high vacuum provided the
corresponding amine hydrochloride which was dissolved in
dry dimethyl!'ormamade (DMF, 1.0 mL), treated with Boc-
Phe-His (260 mg), N-methylmorpholine (0.142 mL), and
1-hydroxybenzotriazole hydrate (261 mg), cooled to
-23°C, and then treated with 1-ethyl-3-(dimethyl-
aminopropyl) carbodiimide Hydrochloride (124 mg).
Evaporation after :16 h provided a thick oil which was
partitioned t~betwee~n ethylacetate (60 mL) and saturated
NaHC03 (30 mL). The organic phase was washed with
brine, dried (MgS04), and evaporated to give a residue
which was c:hromatographed on silica gel (dichloro-
methane/methanol) t:o give 161 mg (40~) of the desired
product. Mass spectrum: (M + H)+ = 626. Anal.
calcd. for C34H51N506' ~ C. 65.3: H, 8.3: N.
11.2. Found: ~ C, 65.6: H. 8.3: N. 11.2.
Example 158
Hoc-Phe-His Amide (at N-2) of 1-Cyclohexyl-2(S),4-
(R,SZ-diamino-3-hydroxy-6-methylheptane.
Treatment of the resultant compound of Example 157 with
hydroxylamine followed by reduction of the oxime over
platinum oxide gave the desired product.
134098
4
6!
Example 159
1-Phe-Leu Amide oft-Cyclohexvl-2(S). 3(R
The resultant compound of Example 3'6 was acetylated
using acetic anhydride and the corresponding 3-hydroxy-
!-acetox~ compound was isolated by silica gel
chromatograph;Y. Oxidation to the 3 -one using Jones
reagent, dea~cetylization using sodium methoxide in
methanol, and reductive amination as in Example 158 gave
the desired product.
Example 160
-Phe-His Amide of 2(S)-Amino-1-phenvl-3(R
Using the pr~~cedure of Example 13, but replacing Boc-
cyclohexylalanine methyl ester with Boc-Phe-OCH3 and
then followin~~ the ;procedures of Examples 1! and 29 gave
the desired product.
Example 161
lic Carbonate of 2(S)-t-Hutvloxvcarbonvlamino- -
The 3(R),!(S)~diastereomer of Example 1! was heated with
N,N'-carbonyl~iiimid~azole in benzene to give the desired
compound in 8~5~ yield.
Example 162
D-Ser-Phe-His amide of 2(S)-Amino-1-cyclohexyl-_3(R),!(S)
dihydraxy-6-methylheptane.
Following the procedure of Example 15, but replacing the
resultant product of Example 14 with the resultant
product of Example 161 and replacing Boc-Phe-His with
Cbz-D-Ser-Phe--His gave the desired N,0-diprotected
material. N--deprotection following the procedure of
Ex~ple 62 followed, by 0-deprotection with 0.5M NaOH in
~34~984
ss
s0~ aq:dioxane, gave the desired compound.
Example 163
S(+)-2-mercapto-3-phenylpropionic acid was prepared as
described (Acton, N and Komoriya, A. Organic Preparation
and ProcedurE!s Int. 1982, 14, 381-392.) and acylated
with isobutyric anhydride. Replacing TBA-CHA with this
acid and using the procedure of Example 21, gave the
titled compound.
Example 164
-t(2-Aminoethvl)merca~tol-3-~henv~rooionvl-Phe-Hi
~"°lu~ vL ~w~!-~muv-a-c:ycivriexyt-J\~J.~~~~-ainyarvxy-o-
methvlhe~tane.
2(S)-((2-Aminoethyl)mercapto]-3-phenylpropionic acid was
made using literature methodology (Acton, N. and
Komoriya, A. Or anic Preparations and Procedures Int.
1982, 14, 381-392.) Replacing THA-CHA with this acid
and using thE! procedure of Example 21, gave the titled
compound.
Example 16s
(2S,3R,sP:)-2-(t-HutYloxycarbonylamino)-3-hydroxY-
7-methyl-1-ahp en~rl.octane-s-carboxylic Acid Lithium Salt
A solution of 27.1 mg (0.075 mmol) of (3R,sR,1'S)-5-
((t-butyloxyc~arbonylamino)-2-phenylethyl]-3-isobutyldi-
hydrofuran-2-(3H)-o:ne (D. J. Kempf, J. Orc. Chem. 1986.
51, 3921) in 1 mL of dioxane was treated with 18s ul
(0.092 mmol) of LiOH (O.s.M in H20) and stirred at
ambient temperature for 8 h. Removal of the solvent in
vacuo gave the desired compound as a white solid.
66
134pg84
Example 166
(2S,.3R,5R)-3-(t-Butyldimethylsilyloxy)
2-(t-butyloxycarbonylamino)-7-methyl-I- henyloctane
5-carboxylic Acid t-Butyldimethvlsilvl Ester
A solution of they resultant compound of Example 165
(0.075 mmol), 42 mg (0.28 mmol) of t-butyldimethylsilyl
chloride and 31 mg (0.45 mmol) of imidazole in 0.8 mL of
dimethylformamide was allowed to stand at ambient
temperature f~~r 2 days. Removal of the solvent in vacuo
gave the crude desired compound.
Example 167
2S,3R,5R)-3-(t-Butyldimethylsilyloxy)-
~t-butyloxycarbonylamino)-7-methyl-
1-phenWloctar.~e-5-carboxylic Acid Lithium Salt
A solution o:E the crude resultant compound of Example
166 (0.075 mmol) in 2 mL of dioxane was treated with
0.6 mL (0.3 aanol) of LiOH (0.5 M in H20) and allowed
to stir at ambient temperature for 2 days. After
removal of t:he solvent, purification by flash column
chromato ra h;~ usin 3% methanol/chloroform
g p g gave 18.3 mg
(49%) of the desired compound (Rf 0.10, 2%
methanol/chloroform).
Example 168
(2S,3R,5R,8S,9R,lOS)-7-Aza-
3-(t-butyldimethylsilyloxy)-2-(t-butyloxycarbonyl
amino)-8-(cyclohexylmethyl)-9, I0-dihydroxy-5-isobutyl
I2-methyl-1-phenvltridecane
Using the coupling procedure of Example 21 but replacing
Boc-Phe-His-OFi with the resultant compound of
Example 167 g<ive the desired compound in 62% yield after
purification by MhLC using 6:1 hexane/ethyl acetat a
(Rf 0.50, 2:1 hexane/ethyl acetate).
1344984
67
Example 169
_ 2S 3R,SR,8S,9R,lOS)-7-Aza-
2-(t-butvloxvcarbonvlamino)-8-(cvclohexvlmethvl)-
-iz-metnvi-i-onenvl-3,9,io-trinvar
A solution of 16.5 mg (0.023 mmol) of the resultant
compound of Example 168 in 1 mL of tetrahydrofuran was
treated with 70 mL (0.07 mmol) of tetra-n-butylanmmonium
fluoride (1 M in tetrahydrofuran) and allowed to stir at
ambient temperature for 16 h. After concentration in
vacuo. separation by MPLC using 2:1 hexane/ethyl acetate
gave 10.5 mg (76~) of the desired compound as a white
crystalline solid. Mass spectrum: (M + H)+ = 605.
Example 170
Cbz-6-aminohexanoyl-(4-methoxy)phenylalanine
Benzyl Ester
Using the procedure of Example 72 but replacing
3-benzyloxycarbonylamino-3-methylbutanoic acid with
6-(Cbz-amino)-n-caproic acid and replacing phenylalanine
methyl ester with (4-methoxy)phenylalanine benzyl ester
gave, after ;purification by flash column chromatography
using 9:1 chloroform/ethyl acetate, a 38~ yield of the
desired compound.
Example 171
( 25
Cbz-6-~aminohexanoyl-(4-methoxy)phenylalanine
A solution o1~ 2.66 g (5 mmol) of the resultant compound
of Example 1 ~~0 in X60 mL of tetrahydrofuran was cooled to
0°C, treated with 0.63 g (15 mmol) of LiOH in 30 mL of
H20 and allowed to stir for 2 h. After concentration
of the solvent, 'the mixture was partitioned between
H20 and ether, acidified, extracted with ethyl
acetate, dried over MgS04 and concentrated to give
1.55 g (70~) of the desired compound.
X348984
68
Example 172
Cbz-6-aminohexanoyl-(4-methoxy)Phe-His
AmidE: o.f (2S,3R.~S)-2-Amino-1-cyclohexyl
3,4-d hydroxy-6-methvlheptane.
Using the procedure of Example 21 but replacing TeA-CHA
with the resultant compound of Example 171 gave, after
recrystallization from ethyl acetate, a 79i yield of the
desired compound. '.Mass spectrum: (M + H)+ = 805.
Example 173
6-Aminohexanov7
A mixture of 0.97 g (1.2 mmol) of the resultant compound
of Example 172 and 0.20 g of 20~ palladium on carbon in
150 mL of 95'1 aqueous acetic acid was shaken in a Parr
Apparatus vender four atmospheres of H2. After
filtration to remove catalyst, the solution was concen-
trated in v~acuo, diluted with 75 mL of H20, and
concentrated by lyophilization to give 0.86 g (91~) of
the desired compound as a white solid. Mass spectrum:
(M+H)+ = 671.
Example 17~
Using the procedures of Examples 116. 117 and 118 but
replacing L-Phe-C~CH3 'HC1 with D-Phe-OCH3 'HCl,
gave the title compound. Mass spectrum: (M + H)+ _
6 X11 .
Example 175
Ethyl H. dro en ( a . a -dimethylbenzyl )malonate .
Diethyl ( a , a -dimethylbenzyl)malonate was prepared by
the congugate addition of phenyl magnesium bromide to
- _ 1340984
69
diethyl isopropylidenemalonate as described by
C. Holmberg [Liebiqs Ann. Chem., 748 (1981)]. A
solution of this diester (42.1 g, 0.15 mole) in ethanol
(100 mL) wa:; treated by dropwise addition with a
solution of potassium hydroxide (8.48 g, 0.13 mole) in
100 mL of ethanol. After heating at 90°C for 1 h and at
50°C for 20 h, the reaction mixture was evaporated on
the rotary evaporator to a residue. The residue was
diluted with water' and extracted with ether to remove
unreacted starting material. The aqueous phase was
cooled to 5°C, acidified to pH 3, with 6N HC1 and
extracted with methylene chloride. The organic layer
was washed with brine solution and dried over magnesium
sulfate. Evaporation of the solvent gave 27.3 g (84%)
of liquid product. NMR (CDC13): 1.05 (3H, t),
1.6 (6H, s), 3.78 (1H, s), 3.96 (2H, m), 7.2-7.4 (5H, m).
Example 176
Ethyl 2(R,S)-[[(4-morpholinyl)carbonyl]amino]-
3,3-dimethyl-3-phenylpropionate.
To a solution of ethyl hydrogen ( « , « -dimethylbenzyl)
malonate (4 g, 0.016 mole) in toluene was added
triethylamine (2.23 mL, 0.016 mole) and diphenyl-
phosphoryl azide (4.4 g, 0.016 mole). The reaction
mixture was heated at 100°C for 2.5 h, cooled to 5°C,
and treated with 1.4 mL (0.016 mole) of morpholine.
After stirring overnight at room temperature, the
toluene solution was washed successively with 1N HCI and
aqueous sodium bicarbonate solution. The dried organic
solution was evaporated to a residue which was purified
by column chromatography on silica gel. There was
obtained 3.7 g (69%) of product after trituration with
hexane, mp 93-94°C.
Anal. ca:lcd. for C18H26N204: C, 64.65;
H, 7.84: N, 8.38.
Found: C. 64.72; H, 7.95; N, 8.33.
134pg84
Example 177
2(R,.S)-[[(4-Morpholinyl)carbonyl]amino]
3,:3-dimethvl-3- henyl ropionic Acid.
A solution of the product form Example 176 (2 g,
5 5.99 mmole) in dioxane (10 mL) was treated with 0.26 g
(6.5 mmol) of sodium hydroxide in 5 mL of water. After
stirring for 16 h at 35°C, the reaction was worked up as
described in Example 175 to give a 93% yield of product.
10 Example 178
2 R,:~)-[[(4-Morpholinyl)carbonyl]amino]-
3,3-dimethvl-3-phenylpropionyl-His Amide of
2(S)-Annino-1-cvclohexvl-3(R),4(S)-dihvdroxv-
6-methylheptane.
The product from Example 20 was deprotected with HC1/
15 methanol and coupled to the product from Example 177
using the procedures described in Example 5 but modified
as follows. IaOBT was not used in the coupling and the
reaction time was 20 h. There was obtained an 80% yield
of the desired product. Mass spectrum: (M + H)+ -
20 669.
Example 179
H-Isonipecotyl-(4-OCH3)Phe-His Amide of
2 S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy
6-methyl:heptane Diacetic Acid Salt.
25 --
Using the pro~:edure of Examples 67 and 68, but replacing
Cbz-isonipecot:yl-Phe with Cbz-isonipecotyl-(4-OCH3)
Phe gave the desired product. Mass spectrum: (M + H)+
669 (free b~~se) .
30 Example 180
H-[ 8,13-~di-Me)-?-Ala]-(4-OCH )Phe-His Amide of
2(S)-Amino-1-cyclohexyl-3(R~,4(S)-dihydroxy
6-methylheptane Diacetic Acid Salt.
Using the procedures of Examples 74 and 75, but
. 134984
71
replacing Cbz-[(ti,t3-di-Me)-B-Ala)-Phe with
Cbz-[(D,a-di--Me)-Q-~Ala~-(OCH3)Phe gave the desired
product. iM + H)+ = 657 (free base).
Example 181
2 S --t-Butyloxycarbonylamino-1-cyclohexyl-
3(R)-hydroxy-6-methylheptan-4-one
To ;d stirred -63°C solution of oxalyl chloride
(784 mg, 6.18 mmol) in dry dichloromethane (15 mL) was
added dry dimethylsulfoxide (708 mg, 9.06 mmol) dropwise
over 5 minutes. After another 5 minutes, Boc-cyclo-
hexylalanino7. (l.OSg, 4.12 mmol) in dichloromethane (5
mL) was addsad dropwise over 5 minutes, and 5 minutes
later, triet;hylamine (1.67 g, 16.48 mmol) was added
similarly. 'ZnI2 (300 mg, 0.94 mmol) was added over 5
minutes. After stirring for 2 minutes, trimethylsilyl
cyanide (1.438, 1,.42 mmol) was added and the mixture
was warmed to room temperature for 1 hour. The mixture
was then cooled to 0°C and isobutylmagnesium chloride
(22.0 mL of a 2 M soln. in ether) was added. After
warming to room temperature for 4 hours, the mixture was
poured into 1 I~ H3P04 (40 mL)/ice (SO mL) and
extracted w9lth ethyl acetate. The combined organic
phase was washed sequentially with 1 M H3P04, water,
satd. NaHC:03, and brine. Drying (MgS04),
filtering, and evaporating provided 1.75 g of, an oil
which was dissolved in THF (75 mL) and treated with 1 M
H3P04 (25 m1~) for 18 hours at 5°C. The solution was
partitioned between ethyl acetate/brine, a.nd the
resulting organic phase was washed sequentially with
brine, satd. NaHC03, and brine. Drying (MgS04),
filtering, and evaporating provided the desired product
(1.39 g, 994;) which was used directly in the next step.
. X340984
72
Example 182
-Butyloxycarbonvlamino-1-cvclohexvl-
To a stirred solution of 2(S)-t-Hutyloxy-
carbonylamino-1-cyclohexyl-3(R)-hydroxy-6-methylheptan-
4-one (200 mg, 0.586 mmol) in THF (10 mL) was added
NaHH4 (22 mg,, 0.588 mmol). After 2 hours, the solvent
was evaporated and the residue was partitioned between
ethyl acetate! and brine. The organic~phase was washed
(brine), driE~d (MgS04), filtered and evaporated. The
residue was recrystallized from methylcyclohexane to
give 76 mg (38~) of the desired product. M.p.
130-131°C. The mother liquor was chromatographed
(silica gel, ~ether/Izexane) to afford 43 mg (21~) more.
Example 183
3R,5R,8S.,9R,lOS)-7-Aza-2-(t-Hutyloxycarbonylamino)-
-8- c clohexylmethyl)-12-methyl-5-(4- entenyl)_-
-1~-phenyl-3,9,10-trihvdroxvtridecane
Using the procedures of Examples 165-169, but
re lacin (3R,5R,1'S)-5-E(t-but to
p g y xycarbonylamino)-
-2-phenylethy:l~-3-isobutyldihydrofuran-2-(3H)-one with
(3R,5R,1'S)-5~-[(t-butyloxycarbonylamino)-2-phenylethyl~-3-
(4-pentenyl)d:ihydrofuran-2-(3H)-one (D. J. Rempf, J.
Orq. Chew. 1986, 5:1, 3921) gave the desired compound in
52~ yield ~~fter purification by MPLC using 2:1
hexane/ethyl ~icetate. Mass spectrum: (M+H)+ = 617.
The compounds of the present invention can be
used in the form of salts derived from inorganic or
organic acids. These salts include but are not limited
to the following: acetate, adipate, alginate, citrate,
aspartate, benzoate, benzenesulfonate, bisulf ate.
butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanep~:opionate, dodecylsulfate, ethanesulfonate,
glucoheptanoai:e, glycerophosphate, hemisulfate,
~~~~984
73
heptonate, hexanoate, fumarate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate.
lactate, maleate, methanesulfonate, nicotinate.
2-naphthalene;~ulfonate, oxalate, pactwate, pectinate.
persulfate, 3-phenylpropionate, picrate, pivalate,
propionate, succinate, tartrate, thiocyanate, tosylate.
and undecanoate. Also, the basic nitrogen-containing
groups can be quaternized with such agents as loweralkyl
halides, such as methyl, ethyl, propyl, and butyl
chloride, bromides, 'and iodides; dialkyl sulfates like
dimethyl, diethyl, dibutyl., and diamyl sulfates, long
chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides
like benzyl and phenethyl bromides, and others. Water
or oil-soluble or dispersible products are thereby
obtained.
Examples o:f acids which may be employed to form
pharmaceutica~.ly acceptable acid addition salts include
such inorganic acids as hydrochloric acid, sulphuric
acid and phosphoric acid and such organic acids as
oxalic acid, malefic acid, succinic acid and citric
acid. Other salts include salts with alkali metals or
alkaline earth metals, such as sodium, potassium.
calcium or magnesium or with organic bases.
Z'he <:ompounds of formula I can also
be used in the form of esters. Examples of such esters
include a hhdroxy:l-substituted compound
which has bean acylated with a blocked or unblocked
amino acid residue, a phosphate function, or a
hemisuccinate residue. The amino acid esters of
particular interest are glycine and lysine; however,
other amino acid residues can also be used. These
esters serve as pro-drugs of the compounds of
formula I and serve to increase the solubility
of these substances in the gastrointestinal tract. The
preparation of the pro-drug esters is carried out
. 1340984
74
reacting a .hydroxyl-substituted compound of formula I
with an activated amino acyl, phosphoryl or hemisuccinyl
derivative. The resulting product is then deprotected
to provide the desired pro-drug ester. s
The compounds of formula I
possess an excellent degree of activity and specificity
in treating resin-.associated hypertension in a host. The
ability of the compounds to inhibit
human renal resin can be demonstrated in vitro by
reacting a aelected compound at varied concentrations '
with human renal resin, free from acid proteolytic
activity, a.nd with resin substrate (human angio-
tensinogen) at 37°C and pH 6Ø At the end of the
incubation, the amount of angiotensin I formed is
measured by :radioiunmunoassay and the molar concentration
required to cause 50~ inhibition, expressed as the
IC50, is calculated. When tested in accordance with
the foregoin~~ procedure, the compounds of formula I
demonstrated IC50"s in the range of 10-5 to 10-10
M as seen in Table I.
1340984
Table I
Example Example
Number IC50_,~ Number IC50- (nM)
3 4000 63 0.45
5 6 50 64 3
15 1.5 67 0.8
16 70 68 1
17 35 69 ' 0.81
18 95 70 2.5
21 2 74 0.7
22 1.5 75 0.4
23 10 76 0 . 5
10 24 2 77 0.98
25 20 81 0.6
26 1.5 82 0.6
27 7 83 0.6
28 80 84 10
29 0.6 85 0.4
30 4 . T5 87 0 .~55
31 1 88 0.6
32 2 89 1
33 5 90 0.!
34 1.5 91 0.3
35 1 92 0.5
36 0.4 93 0.55
37 0.5 97 0.3
39 2 101 5
20 !3 5 102 0.6
!6 1.5 103 1
47 1 108 0.55
49 2 111 0.5
54 0.95 114 1.3
55 2 115 1
56 5.5 118 0.5
25 57 7 =i 124 0 . 65
sg 7 127 0.75
61 0.55 141 5.5
62 2 143 0.3
169 6.0 178 2
173 0 . Si 179 1
174 12 180 0.8
183 12
30
1 3 4p gg 4
76
The c;ompounds of formula I also be used
with one or more antihypertensive agents selected from
the group consisting of diuretics, and/or t3-adrenergic
blocking agena:s, central nervous syste~g -acting agents,
adrenergic neuron blocking agents, vasodilators.
angiotensin I converting enzyme inhibitors, and other
antihypertensive agents.
Total daily dose administered to a host in
single or divided doses may be in amounts, for example,
from 0.001 to 10 mg/kg body weight daily and more
usually 0.01 to 1 mg. Dosage unit compositions may
contain such aunounts of submultiples thereof to make up
the dai ly dose .
The amount of active ingredient that may be
combined with the carrier materials to produce a single
dosage form will vary depending upon the host treated
and the particular mode of administration.
It will :be understood, however, that the
specific dose level for any particular patient will
;zp depend upon a variety of factors including the activity
of the specific compound employed, the age, body weight,
general health., sex, diet, time of administration, route
of administration, rate of excretion, drug combination.
and the severity of the particular disease undergoing
( ;~5 therapy.
The compounds of formula I may be
administered ~~rally, parenterally, by inhalation spray.
rectally, or topic: ally in dosage unit formulations
containing conventional nontoxic pharmaceutically
acceptable carriers, adjuvants, and vehicles as
desired. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular,
intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile
injectable aqueous or oleagenous suspensions may be
formulated according to the known art using suitable
1 3 40 98 4
dispersing or wetting agents and suspending agents. The
sterile injectable preparation may also be a sterile
injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, for example,
as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water,
Ringer's solution, and isotonic sodium chloride
solution. 7:n addition, sterile, fixed oils are
conventionall;Y employed as a solvent or suspending
medium. For this, purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
Suppositories for rectal administration of the
drug can be F~repared by mixing the drug with a suitable
nonirritating exci,pient such as cocoa butter and
polyethylene glycols which are solid at ordinary
temperatures but liquid at the rectal temperature and
will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may
include capsules, tablets, pills, powders, and
granules. 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.,~lubricating
agents such as magnesium stearate. In the case of
capsules, ta~~lets, and pills, the dosage forms may also
comprise buffering agents. Tablets and pills can
additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may
include pharmaceutically acceptable emulsions,
solutions, suspensions, syrups, and elixirs containing
inert diluent:s commonly used in the art, such as water.
Such compositions may also comprise adjuvants, such as
wetting agents, emulsifying and suspending agents, and
. 1340984
sweetening, flavoring, and perfuming agents.
The foregoing is merely illustrative
and is not intended to limit the invention to
the disclosed', compounds. Variations and changes which
are obvious to one skilled in the art are intended to be
within the scope and nature of the invention which are
defined in the appended claims.
