U.S. patent application number 11/835017 was filed with the patent office on 2008-02-07 for [beta]-lactamyl vasopressin v1a antagonists and methods of use.
Invention is credited to Robert F. JR. Bruns, Gary A. Koppel.
Application Number | 20080033165 11/835017 |
Document ID | / |
Family ID | 23283669 |
Filed Date | 2008-02-07 |
United States Patent
Application |
20080033165 |
Kind Code |
A1 |
Koppel; Gary A. ; et
al. |
February 7, 2008 |
[Beta]-Lactamyl Vasopressin V1a Antagonists and Methods of Use
Abstract
Novel 2-(azetidin-2-on-1-yl) alkanedioic acid derivativies and
2-(azetidin-2-on-1-yl) alkoxyalkanoic acid derivativies are
described for use in the treatment of disease states responsive to
antagonism of the vasopressin V.sub.1a receptor.
Inventors: |
Koppel; Gary A.;
(Indianapolis, IN) ; Bruns; Robert F. JR.;
(Carmel, IN) |
Correspondence
Address: |
BARNES & THORNBURG LLP
11 SOUTH MERIDIAN
INDIANAPOLIS
IN
46204
US
|
Family ID: |
23283669 |
Appl. No.: |
11/835017 |
Filed: |
August 7, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11442788 |
May 30, 2006 |
7268125 |
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11835017 |
Aug 7, 2007 |
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10492323 |
Jun 15, 2004 |
7119083 |
|
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PCT/US02/32433 |
Oct 11, 2002 |
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11442788 |
May 30, 2006 |
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60329054 |
Oct 12, 2001 |
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Current U.S.
Class: |
540/200 |
Current CPC
Class: |
A61P 17/06 20180101;
A61P 19/08 20180101; A61P 17/04 20180101; A61P 25/06 20180101; C07D
403/14 20130101; A61P 25/16 20180101; A61P 1/06 20180101; A61P
25/00 20180101; A61P 25/24 20180101; A61P 37/06 20180101; A61P 9/00
20180101; A61P 37/08 20180101; A61P 25/22 20180101; A61P 13/10
20180101; A61P 13/02 20180101; A61P 29/02 20180101; A61P 3/10
20180101; A61P 15/00 20180101; A61P 25/04 20180101; A61P 15/06
20180101; A61P 13/08 20180101; A61P 19/00 20180101; A61P 21/00
20180101; A61P 7/02 20180101; A61P 31/18 20180101; A61P 1/04
20180101; A61P 25/18 20180101; A61P 25/36 20180101; A61P 11/02
20180101; A61P 11/00 20180101; A61P 9/04 20180101; C07D 409/14
20130101; A61P 7/00 20180101; A61P 25/32 20180101; A61P 9/10
20180101; C07D 401/14 20130101; A61P 35/00 20180101; A61P 25/28
20180101; A61P 1/02 20180101; A61P 29/00 20180101; A61P 1/00
20180101; A61P 9/08 20180101; C07D 403/04 20130101; A61P 19/04
20180101; A61P 43/00 20180101; A61P 27/02 20180101; A61P 1/12
20180101; A61P 17/00 20180101; A61P 37/02 20180101; C07D 417/14
20130101; A61P 25/08 20180101; C07D 413/14 20130101; A61P 11/06
20180101; A61P 19/10 20180101; A61P 19/02 20180101; C07D 413/04
20130101; A61P 1/08 20180101 |
Class at
Publication: |
540/200 |
International
Class: |
C07D 413/14 20060101
C07D413/14 |
Claims
1. A compound of the formula ##STR35## and pharmaceutically
acceptable salts, hydrates, and solvates thereof.
2. A compound of the formula ##STR36## wherein X' is optionally
substituted aryl(C.sub.1-C.sub.4 alkyl); and pharmaceutically
acceptable salts, hydrates, and solvates thereof.
3. The compound of claim 2 wherein X' is
3-fluoro-5-trifluoromethylbenzyl.
4. The compound of claim 2 wherein X' is
4-chloro-3-trifluoromethylbenzyl.
5. A compound of the formula ##STR37## wherein R.sup.5 is H or
C.sub.1-C.sub.6 alkyl; and X is optionally substituted
aryl(C.sub.1-C.sub.4 alkyl); and pharmaceutically acceptable salts,
hydrates, and solvates thereof.
6. The compound of claim 5 wherein R.sup.5 is H; and X is
(R)-.alpha.-methylbenzyl.
7. The compound of claim 5 wherein R.sup.5 is CH.sub.3; and X is
3-trifluoromethylbenzyl.
8. A compound of the formula ##STR38## wherein X is
1,2,3,4-tetrahydronaphth-1-yl or optionally substituted
aryl(C.sub.3-C.sub.7 cycloalkyl); and pharmaceutically acceptable
salts, hydrates, and solvates thereof.
9. The compound of claim 8 wherein X is
(R)-1,2,3,4-tetrahydronaphth-1-yl.
10. The compound of claim 8 wherein X is 1-phenylcyclopent-1-yl.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel
2-(azetidin-2-on-1-yl)alkanedioic acid derivatives as vasopressin
V.sub.1a receptor antagonists. The present invention also relates
to methods of treating mammals in need of relief from disease
states associated with and responsive to the antagonism of the
vasopressin V.sub.1a receptor.
BACKGROUND OF THE INVENTION
[0002] Vasopressin, a neurohypophyseal neuropeptide produced in the
hypothalamus, is involved in water metabolism homeostasis, renal
function, mediation of cardiovascular function, non-opioid
mediation of tolerance for pain, and regulation of temperature in
mammals. In addition to being released into the circulation via the
posterior pituitary, vasopressin acts as a neurotransmitter in the
brain. Three vasopressin receptor subtypes, designated V.sub.1a,
V.sub.1b, and V.sub.2 have been identified. The human V.sub.1a
receptor has been cloned (Thibonnier et al., The Journal of
Biological Chemistry, 269(5), 3304-3310 (1994)), and has been shown
by radioligand binding techniques to be present in vascular smooth
muscle cells, hepatocytes, blood platelets, lymphocytes and
monocytes, type II pneumocytes, adrenal cortex, brain, reproductive
organs, retinal epithelium, renal mesangial cells, and the A10,
A7r5, 3T3 and WRK-1 cell lines (Thibonnier, Neuroendocrinology of
the Concepts in Neurosurgery Series 5, (Selman, W., ed), 19-30,
Williams and Wilkins, Baltimore, (1993)).
[0003] Structural modification of vasopressin has provided a number
of vasopressin agonists (Sawyer, Pharmacol. Reviews, 13, 255
(1961)). In addition, several potent and selective vasopressin
peptide antagonists have been designed (Lazslo et al.,
Pharmacological Reviews, 43, 73-108 (1991); Mah and Hofbauer, Drugs
of the Future, 12, 1055-1070 (1987); Manning and Sawyer, Trends in
Neuroscience, 7, 8-9 (1984)). Their lack of oral bioavailability
and short half-life, however, have limited the therapeutic
potential of these analogs. While novel structural classes of
non-peptidyl vasopressin V.sub.1a antagonists have been discovered
(Yamamnura et al., Science, 275, 572-574 (1991); Serradiel-Le Gal
et al., Journal of Clinical Investigation, 92, 224-231 (1993);
Serradiel-Le Gal et al., Biochemical Pharmacology, 47(4), 633-641
(1994)), a clinical candidate has yet to be identified.
[0004] The general structural class of substituted
2-(azetidin-2-on-1-yl)acetic acid esters and amides are known as
synthetic intermediates for the preparation of .beta.-lactam,
antibiotics (see e.g. U.S. Pat. No. 4,751,299).
SUMMARY OF THE INVENTION
[0005] It has been found that certain compounds within the general
class of 2-(azetidin-2-on-1-yl)alkanedioic acid derivatives elicit
activity at the vasopressin V.sub.1a receptor. The present
invention describes novel 2-(azetidin-2-on-1-yl)alkanedioic acid
esters and amides useful for treating disease states that are
associated with and responsive to antagonism of a vasopressin
V.sub.1a receptor in a mammal.
[0006] The invention also describes a method for treating a disease
state responsive to the antagonism of a vasopressin V.sub.1a
receptor, in a mammal in need of such treatment, comprising the
step of administering to the mammal a pharmaceutically effective
amount of such 2-(azetidin-2-on-1-yl)alkanedioic acid
derivatives.
[0007] In particular, the present invention describes compounds
having the formula I: ##STR1## wherein:
[0008] n is an integer from 0 to 2;
[0009] A is R.sup.6O--, monosubstituted amino, or disubstituted
amino;
[0010] A' is R.sup.6'O--, monosubstituted amino, or disubstituted
amino;
[0011] R.sup.2 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0012] R.sup.3 is a structure selected from the group consisting of
##STR2##
[0013] R.sup.4 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.9 cycloalkenyl, limonenyl, pinenyl, C.sub.1-C.sub.3
alkanoyl, optionally-substituted aryl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), optionally-substituted
aryl(C.sub.2-C.sub.4 alkenyl), or optionally-substituted
aryl(C.sub.2-C.sub.4 alkynyl);
[0014] R.sup.6 and R.sup.6' are each independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, (C.sub.1-C.sub.4 alkoxy)-(C.sub.1-C.sub.4 alkyl),
optionally-substituted aryl(C.sub.1-C.sub.4 alkyl), a first
heterocycle Y--, Y--(C.sub.1-C.sub.4 alkyl), a second heterocycle
Y'--, Y'--(C.sub.1-C.sub.4 alkyl),
R.sup.7R.sup.8N--(C.sub.2-C.sub.4 alkyl), and
R.sup.7'R.sup.8'N--(C.sub.2-C.sub.4 alkyl); [0015] where the first
heterocycle Y and the second heterocycle Y' are each independently
selected from the group consisting of tetrahydrofuryl, morpholinyl,
pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or
quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl,
piperazinyl, homopiperazinyl, or quinuclidinyl is optionally
N-substituted with C.sub.1-C.sub.4 alkyl or optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl);
[0016] R.sup.7 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0017] R.sup.8 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, optionally-substituted aryl, or optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl); or [0018] R.sup.7 and R.sup.8 are
taken together with the attached nitrogen atom to form an
heterocycle selected from the group consisting of pyrrolidinyl,
piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where
said piperazinyl or homopiperazinyl is optionally N-substituted
with R.sup.12;
[0019] R.sup.7' is hydrogen or C.sub.1-C.sub.6 alkyl;
[0020] R.sup.8' is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, optionally-substituted aryl, or optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl); or [0021] R.sup.7' and R.sup.8' are
taken together with the attached nitrogen atom to form an
heterocycle selected from the group consisting of pyrrolidinyl,
piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where
said piperazinyl or homopiperazinyl is optionally N-substituted
with R.sup.12';
[0022] R.sup.10 and R.sup.11 are each independently chosen from the
group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.4 alkoxycarbonyl,
C.sub.1-C.sub.5 alkanoyloxy, benzyloxy, benzoyloxy,
diphenylmethoxy, triphenylmethoxy, optionally-substituted aryl, and
optionally-substituted aryl(C.sub.1-C.sub.4 alkyl); [0023] where
the C.sub.1-C.sub.6 alkyl or the C.sub.3-C.sub.8 cycloalkyl is
optionally monosubstituted with a substituent selected from the
group consisting of hydroxy, protected carboxy, carbamoyl,
thiobenzyl and C.sub.1-C.sub.4 thioalkyl; and, [0024] where the
benzyl of said benzyloxy or said benzoyloxy is optionally
substituted with one or two substituents independently selected
from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, hydroxy, cyano, carbamoyl, amino,
mono(C.sub.1-C.sub.4 alkyl)amino, di(C.sub.1-C.sub.4 alkyl)amino,
C.sub.1-C.sub.4 alkylsulfonylamino, and nitro;
[0025] R.sup.12 and R.sup.12' are each independently selected from
the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.4 alkoxycarbonyl,
optionally-substituted aryloxycarbonyl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), and optionally-substituted aryloyl;
and
[0026] hydrates, solvates and pharmaceutically acceptable acid
addition salts thereof; and
[0027] providing that:
[0028] a) when A is R.sup.6O--, then A' is not benzylamino or
substituted benzylamino;
[0029] b) when A is R.sup.6O-- and the integer n is 0, then A' is
not R.sup.6'O--; and
[0030] c) when A is monosubstituted amino and the integer n is 0,
then A' is not anilinyl, substituted anilinyl, benzylamino, or
substituted benzylamino.
[0031] In addition, the present invention describes compounds
having the formula II: ##STR3## wherein:
[0032] n' is an integer from 1 to 3;
[0033] A is R.sup.6O--, monosubstituted amino, or disubstituted
amino;
[0034] R.sup.2 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0035] R.sup.3 is a structure selected from the group consisting of
##STR4##
[0036] R.sup.4 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.9 cycloalkenyl, limonenyl, pinenyl, C.sub.1-C.sub.3
alkanoyl, optionally-substituted aryl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), optionally-substituted aryl(halo
C.sub.1-C.sub.4 alkyl), optionally-substituted aryl(alkoxy
C.sub.1-C.sub.4 alkyl), optionally-substituted aryl(C.sub.2-C.sub.4
alkenyl), optionally-substituted aryl(halo C.sub.2-C.sub.4
alkenyl), or optionally-substituted aryl(C.sub.2-C.sub.4
alkynyl);
[0037] R.sup.6 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.4
alkoxy)-(C.sub.1-C.sub.4 alkyl), optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), a first heterocycle Y--,
Y--(C.sub.1-C.sub.4 alkyl), and R.sup.7R.sup.8N--(C.sub.2-C.sub.4
alkyl); [0038] where the first heterocycle Y is selected from the
group consisting of tetrahydrofuryl, morpholinyl, pyrrolidinyl,
piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where
said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl,
homopiperazinyl, or quinuclidinyl is optionally N-substituted with
C.sub.1-C.sub.4 alkyl or optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl);
[0039] R.sup.6' is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.4
alkoxy)-(C.sub.1-C.sub.4 alkyl), optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), Y'--(C.sub.1-C.sub.4 alkyl), where
Y'-- is a second heterocycle, and
R.sup.7'R.sup.8'N--(C.sub.2-C.sub.4 alkyl); [0040] where the second
heterocycle Y' is selected from the group consisting of
tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl,
piperazinyl, homopiperazinyl, or quinuclidinyl; where said
morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl,
homopiperazinyl, or quinuclidinyl is optionally N-substituted with
C.sub.1-C.sub.4 alkyl or optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl);
[0041] R.sup.7 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0042] R.sup.8 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, optionally-substituted aryl, or optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl); or [0043] R.sup.7 and R.sup.8 are
taken together with the attached nitrogen atom to form an
heterocycle selected from the group consisting of pyrrolidinyl,
piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where
said piperazinyl or homopiperazinyl is optionally N-substituted
with R.sup.12;
[0044] R.sup.7' is hydrogen or C.sub.1-C.sub.6 alkyl;
[0045] R.sup.8' is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, optionally-substituted aryl, or optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl); or [0046] R.sup.7' and R.sup.8' are
taken together with the attached nitrogen atom to form an
heterocycle selected from the group consisting of pyrrolidinyl,
piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where
said piperazinyl or homopiperazinyl is optionally N-substituted
with R.sup.12';
[0047] R.sup.10 and R.sup.11 are each independently chosen from the
group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.4 alkoxycarbonyl,
C.sub.1-C.sub.5 alkanoyloxy, benzyloxy, benzoyloxy,
diphenylmethoxy, triphenylmethoxy, optionally-substituted aryl, and
optionally-substituted aryl(C.sub.1-C.sub.4 alkyl); [0048] where
the C.sub.1-C.sub.6 alkyl or the C.sub.3-C.sub.8 cycloalkyl is
optionally monosubstituted with a substituent selected from the
group consisting of hydroxy, protected carboxy, carbamoyl,
thiobenzyl and C.sub.1-C.sub.4 thioalkyl; and, [0049] where the
benzyl of said benzyloxy or said benzoyloxy is optionally
substituted with one or two substituents independently selected
from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, hydroxy, cyano, carbamoyl, amino,
mono(C.sub.1-C.sub.4 alkyl)amino, di(C.sub.1-C.sub.4 alkyl)amino,
C.sub.1-C.sub.4 alkylsulfonylamino, and nitro;
[0050] R.sup.12 and R.sup.12' are each independently selected from
the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.4 alkoxycarbonyl,
optionally-substituted aryloxycarbonyl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), and optionally-substituted aryloyl;
and
[0051] hydrates, solvates and pharmaceutically acceptable acid
addition salts thereof.
[0052] Illustrative compounds of formula I and II are described,
wherein A is an acyclic disubstituted amino.
[0053] Illustrative compounds of formula I and II are described 1,
wherein A is a cyclic disubstituted amino.
[0054] Illustrative compounds of formula I and II are described,
wherein A is a monosubstituted amino having the formula XNH--,
where X is selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.4
alkoxy)-(C.sub.1-C.sub.4 alkyl), optionally-substituted aryl,
optionally-substituted aryl(C.sub.1-C.sub.4 alkyl), the first
heterocycle Y, Y--(C.sub.1-C.sub.4 alkyl), R.sup.7R.sup.8N--, and
R.sup.7R.sup.8N--(C.sub.2-C.sub.4 alkyl).
[0055] Illustrative compounds of formula I and II are described,
wherein A is a disubstituted amino having the formula R.sup.5XN--;
where R.sup.5 is selected from the group consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxycarbonyl, and benzyl;
and where X is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.4
alkoxy)-(C.sub.1-C.sub.4 alkyl), optionally-substituted aryl,
optionally-substituted aryl(C.sub.1-C.sub.4 alkyl), the first
heterocycle Y, Y--(C.sub.1-C.sub.4 alkyl), R.sup.7R.sup.8N--, and
R.sup.7R.sup.8N--(C.sub.2-C.sub.4 alkyl).
[0056] Illustrative compounds of formula I and II are described,
wherein A is a disubstituted amino having the formula R.sup.5XN--,
where R.sup.5 and X are taken together with the attached nitrogen
atom to form an heterocycle selected from the group consisting of
pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl; [0057]
where the heterocycle is optionally substituted with R.sup.10,
R.sup.12, R.sup.7R.sup.8N--, or R.sup.7R.sup.8N--(C.sub.1-C.sub.4
alkyl) as defined above.
[0058] Illustrative compounds of formula I and II are described,
wherein R.sup.5 and X are taken together with the attached nitrogen
atom to form piperidinyl optionally substituted at the 4-position
with hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, (C.sub.1-C.sub.4 alkoxy)carbonyl,
(hydroxy(C.sub.2-C.sub.4 alkyloxy))-(C.sub.2-C.sub.4 alkyl),
R.sup.7R.sup.8N--, R.sup.7R.sup.8N--(C.sub.1-C.sub.4 alkyl),
diphenylmethyl, optionally-substituted aryl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), or piperidin-1-yl(C.sub.1-C.sub.4
alkyl).
[0059] Illustrative compounds of formula I and II are described,
wherein R.sup.5 and X are taken together with the attached nitrogen
atom to form piperazinyl optionally substituted at the 4-position
with C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
optionally-substituted aryl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), .alpha.-methylbenzyl,
N--(C.sub.1-C.sub.5 alkyl)acetamid-2-yl, N--(C.sub.3-C.sub.8
cycloalkyl)acetamid-2-yl, R.sup.7R.sup.8N--, or (C.sub.1-C.sub.4
alkoxy)carbonyl.
[0060] Illustrative compounds of formula I and II are described,
wherein R.sup.5 and X are taken together with the attached nitrogen
atom to form homopiperazinyl optionally substituted in the
4-position with C.sub.1-C.sub.4 alkyl, aryl, or
aryl(C.sub.1-C.sub.4 alkyl).
[0061] Illustrative compounds of formula I and II are described,
wherein A is a disubstituted amino having the formula R.sup.5X'N--,
where R.sup.5' and X' are taken together with the attached nitrogen
atom to form an heterocycle selected from the group consisting of
pyrrolidinonyl, piperidinonyl,
2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl,
1,2,3,4-tetrahydroisoquinolin-2-yl.
[0062] Illustrative compounds of formula I are described, wherein
A' is an acyclic disubstituted amino.
[0063] Illustrative compounds of formula I are described, wherein
A' is a cyclic disubstituted amino.
[0064] Illustrative compounds of formula I are described, wherein
A' is a monosubstituted amino having the formula X'NH--; where X'
is selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.4
alkoxy)-(C.sub.1-C.sub.4 alkyl), optionally-substituted aryl,
optionally-substituted aryl(C.sub.1-C.sub.4 alkyl), the second
heterocycle Y', Y'--(C.sub.1-C.sub.4 alkyl), R.sup.7'R.sup.8'N--,
and R.sup.7'R.sup.8'N--(C.sub.2-C.sub.4 alkyl).
[0065] Illustrative compounds of formula I are described, wherein
A' is a disubstituted amino having the formula R.sup.5'X'N--; where
R.sup.5' is selected from the group consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxycarbonyl, and benzyl;
and X' is selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.4
alkoxy)-(C.sub.1-C.sub.4 alkyl), optionally-substituted aryl,
optionally-substituted aryl(C.sub.1-C.sub.4 alkyl), the second
heterocycle Y', Y'--(C.sub.1-C.sub.4 alkyl), R.sup.7'R.sup.8'N--,
and R.sup.7'R.sup.8'N--(C.sub.2-C.sub.4 alkyl).
[0066] Illustrative compounds of formula I are described, wherein
A' is a disubstituted amino having the formula R.sup.5'X'N--, where
R.sup.5' and X' are taken together with the attached nitrogen atom
to form an heterocycle selected from the group consisting of
pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl; [0067]
where the heterocycle is optionally substituted with R.sup.10,
R.sup.12', R.sup.7'R.sup.8'N--, or
R.sup.7'R.sup.8'N--(C.sub.1-C.sub.4 alkyl) as defined above.
[0068] Illustrative compounds of formula I are described, wherein
R.sup.5' and X' are taken together with the attached nitrogen atom
to form piperidinyl optionally substituted at the 4-position with
hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, (C.sub.1-C.sub.4 alkoxy)carbonyl,
(hydroxy(C.sub.1-C.sub.4 alkyloxy))-(C.sub.1-C.sub.4 alkyl),
R.sup.7'R.sup.8'N--, R.sup.7'R.sup.8'N--(C.sub.1-C.sub.4 alkyl),
diphenylmethyl, optionally-substituted aryl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), or piperidin-1-yl(C.sub.1-C.sub.4
alkyl).
[0069] Illustrative compounds of formula I are described, wherein
R.sup.5' and X' are taken together with the attached nitrogen atom
to form piperazinyl optionally substituted at the 4-position with
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
optionally-substituted aryl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), .alpha.-methylbenzyl,
N--(C.sub.1-C.sub.5 alkyl)acetamid-2-yl, N--(C.sub.3-C.sub.8
cycloalkyl)acetamid-2-yl, R.sup.7'R.sup.8'N--, or (C.sub.1-C.sub.4
alkoxy)carbonyl.
[0070] Illustrative compounds of formula I are described, wherein
R.sup.5' and X' are taken together with the attached nitrogen atom
to form homopiperazinyl optionally substituted in the 4-position
with C.sub.1-C.sub.4 alkyl, aryl, or aryl(C.sub.1-C.sub.4
alkyl).
[0071] Illustrative compounds of formula I are described, wherein
A' is a disubstituted amino having the formula R.sup.5'X'N--, where
R.sup.5' and X' are taken together with the attached nitrogen atom
to form an heterocycle selected from the group consisting of
pyrrolidinonyl, piperidinonyl,
2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl,
1,2,3,4-tetrahydroisoquinolin-2-yl.
[0072] Illustrative compounds of formula I and II are described,
wherein R.sup.4 is optionally-substituted aryl(C.sub.1-C.sub.4
alkyl), optionally-substituted aryl(C.sub.2-C.sub.4 alkenyl), or
optionally-substituted aryl(C.sub.2-C.sub.4 alkynyl).
[0073] Illustrative compounds of formula I and II are described,
wherein R.sup.3 is the structure ##STR5##
[0074] Illustrative compounds of formula I and II are described,
wherein R.sup.2 is hydrogen.
[0075] Illustrative compounds of formula I and II are described,
wherein A is a disubstituted amino having the formula R.sup.5XN--,
where R.sup.5 and X are taken together with the attached nitrogen
atom to form an heterocycle selected from the group consisting of
pyrrolidinyl, piperidinyl, and piperazinyl; where said heterocycle
is optionally substituted with C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, R.sup.7R.sup.8N--,
R.sup.7R.sup.8N--(C.sub.1-C.sub.4 alkyl), optionally-substituted
aryl, or optionally-substituted aryl(C.sub.1-C.sub.4 alkyl).
[0076] Illustrative compounds of formula I and II are described,
wherein A is a monosubstituted amino having the formula XNH--,
where X is optionally-substituted aryl(C.sub.1-C.sub.4 alkyl).
[0077] Illustrative compounds of formula I and II are described,
wherein: [0078] R.sup.4 is optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), optionally-substituted
aryl(C.sub.2-C.sub.4 alkenyl), or optionally-substituted
aryl(C.sub.2-C.sub.4 alkynyl); [0079] R.sup.3 is the structure
##STR6## [0080] and, [0081] R.sup.2 is hydrogen
[0082] Illustrative compounds of formula I are described, wherein
A' is R.sup.6'O--, where R.sup.6' is C.sub.1-C.sub.6 alkyl.
[0083] Illustrative compounds of formula I are described, wherein
A' is a monosubstituted amino having the formula X'NH--, where X'
is optionally-substituted aryl(C.sub.1-C.sub.4 alkyl), the second
heterocycle Y', Y'--(C.sub.1-C.sub.4 alkyl), R.sup.7'R.sup.8'N--,
or R.sup.7'R.sup.8'N--(C.sub.2-C.sub.4 alkyl).
[0084] Illustrative compounds of formula I are described, wherein
X' is R.sup.7'R.sup.8'N-- or R.sup.7'R.sup.8'N--(C.sub.2-C.sub.4
alkyl).
[0085] Illustrative compounds of formula I are described, wherein
X' is the second heterocycle Y' or Y'--(C.sub.1-C.sub.4 alkyl),
where the second heterocycle Y' is selected from the group
consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,
and homopiperazinyl, where said second heterocycle is optionally
N-substituted with optionally-substituted aryl(C.sub.1-C.sub.4
alkyl).
[0086] Illustrative compounds of formula I and II are described,
wherein R.sup.8' is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, and
aryl(C.sub.1-C.sub.4 alkyl).
[0087] Illustrative compounds of formula I and II are described,
wherein R.sup.7' and R.sup.8' are taken together with the attached
nitrogen atom to form an heterocycle selected from the group
consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,
and homopiperazinyl, where said piperazinyl or homopiperazinyl is
optionally substituted at the 4-position with (C.sub.1-C.sub.4
alkyl), (C.sub.3-C.sub.8 cycloalkyl), or aryl(C.sub.1-C.sub.4
alkyl).
[0088] Illustrative compounds of formula I are described, wherein
A' is a disubstituted amino having the formula R.sup.5'X'N--.
[0089] Illustrative compounds of formula I are described, wherein
R.sup.5' is aryl(C.sub.1-C.sub.4 alkyl), and X' is selected from
the group consisting of optionally-substituted aryl(C.sub.1-C.sub.4
alkyl), the second heterocycle Y', Y'--(C.sub.1-C.sub.4 alkyl),
R.sup.7'R.sup.8'N--, and R.sup.7'R.sup.8'N--(C.sub.2-C.sub.4
alkyl).
[0090] Illustrative compounds of formula I and II are described,
wherein R.sup.8' is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, and
aryl(C.sub.1-C.sub.4 alkyl).
[0091] Illustrative compounds of formula I and II are described,
wherein R.sup.7' and R.sup.8' are taken together with the attached
nitrogen atom to form an heterocycle selected from the group
consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,
and homopiperazinyl, where said piperazinyl or homopiperazinyl is
optionally substituted at the 4-position with (C.sub.1-C.sub.4
alkyl), (C.sub.3-C.sub.8 cycloalkyl), or aryl(C.sub.1-C.sub.4
alkyl).
[0092] Illustrative compounds of formula I are described, wherein
R.sup.5' and X' are taken together with the attached nitrogen atom
to form an heterocycle selected from the group consisting of
pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and
homopiperazin-1-yl; where said heterocycle is substituted with
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
optionally-substituted aryl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), the second heterocycle Y',
Y'--(C.sub.1-C.sub.4 alkyl), R.sup.7'R.sup.8'N--,
R.sup.7'R.sup.8'N--(C.sub.1-C.sub.4 alkyl), or
R.sup.7'R.sup.8'N--C(O)--(C.sub.1-C.sub.4 alkyl).
[0093] Illustrative compounds of formula I are described, wherein
R.sup.5' and X' are taken together with the attached nitrogen atom
to form an heterocycle selected from the group consisting of
piperidin-1-yl and piperazin-1-yl, where the heterocycle is
substituted with C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
optionally-substituted aryl(C.sub.1-C.sub.4 alkyl),
R.sup.7'R.sup.8'N--, or R.sup.7'R.sup.8'N--(C.sub.1-C.sub.4
alkyl).
[0094] Illustrative compounds of formula I and II are described,
wherein R.sup.7' and R.sup.8' are taken together with the attached
nitrogen atom to form an heterocycle selected from the group
consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,
and homopiperazinyl, where said piperazinyl or homopiperazinyl is
optionally substituted at the 4-position with (C.sub.1-C.sub.4
alkyl), (C.sub.3-C.sub.8 cycloalkyl), or aryl(C.sub.1-C.sub.4
alkyl).
[0095] Illustrative compounds of formula I are described, wherein
R.sup.5 and X' are taken together with the attached nitrogen to
form piperazin-1-yl, where said piperazin-1-yl is substituted with
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, or
aryl(C.sub.1-C.sub.4 alkyl).
[0096] Illustrative compounds of formula I are described, wherein
the integer n is 1.
[0097] Illustrative compounds of formula I are described, wherein
the integer n is 2.
[0098] Illustrative compounds of formula II are described, wherein
the integer n' is 1.
[0099] Illustrative compounds of formula II are described, wherein
the integer n' is 2.
[0100] The present invention also describes a pharmaceutical
comprising a compound selected from those described above, and a
pharmaceutically acceptable carrier, diluent, or excipient.
[0101] The general chemical terms used in the formulae above have
their usual meanings. For example, the term "alkyl" includes such
groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl,
hexyl, heptyl, octyl and the like.
[0102] The term "cycloalkyl" includes such groups as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and
the like.
[0103] The term "alkenyl" includes such groups as ethenyl,
propenyl, 2-butenyl, and the like.
[0104] The term "alkynyl" includes such groups as ethynyl,
propynyl, 1-butynyl, and the like.
[0105] The term "aryl" refers to an aromatic ring or heteroaromatic
ring and includes such groups as furyl, pyrrolyl, thienyl,
pyridinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,
imidazolyl, pyrazolyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl,
thiadiazolyl, oxadiazolyl, naphthyl, indanyl, fluorenyl,
quinolinyl, isoquinolinyl, benzodioxanyl, benzofuranyl,
benzothienyl, and the like.
[0106] The term "optionally-substituted" refers to the replacement
of one or more, preferably from one to three, hydrogen atoms with
one or more substitutents. Such substituents include such groups as
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
alkylthio, hydroxy, nitro, halo, carboxy, cyano, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, amino, carboxamido, amino,
mono(C.sub.1-C.sub.4 alkyl)amino, di(C.sub.1-C.sub.4 alkyl)amino,
C.sub.1-C.sub.4 alkylsulfonylamino, and the like.
[0107] The term "heterocycle" refers to a saturated cyclic
structure possessing one or more heteroatoms, such as nitrogen,
oxygen, sulfur, and the like, and includes such groups as
tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl,
piperazinyl, homopiperazinyl, quinuclidinyl, and the like.
[0108] The term "alkoxy" includes such groups as methoxy, ethoxy,
propoxy, isopropoxy, butoxy, tert-butoxy and the like.
[0109] The terms "acyl" and "alkanoyl" include such groups as
formyl, acetyl, propanoyl, butanoyl, pentanoyl and the like.
[0110] The term "halo" means fluoro, chloro, bromo, and iodo.
[0111] The term "alkanoyloxy" includes such groups as formyloxy,
acetoxy, n-propionoxy, n-butyroxy, pivaloyloxy, and like lower
alkanoyloxy groups.
[0112] The terms "optionally-substituted C.sub.1-C.sub.4 alkyl" and
"optionally-substituted C.sub.2-C.sub.4 alkenyl" are taken to mean
an alkyl or alkenyl chain which is optionally substituted with up
to two methyl groups or with a C.sub.1-C.sub.4 alkoxycarbonyl
group.
[0113] The term "(C.sub.1-C.sub.4 alkyl)" as used in for example
"aryl(C.sub.1-C.sub.4 alkyl)", "(C.sub.1-C.sub.4
alkoxy)-(C.sub.1-C.sub.4 alkyl)", and the like, refers to a
saturated linear or branched divalent alkyl chain of from one to
four carbons bearing for example aryl, C.sub.1-C.sub.4 alkoxy, and
the like, as a substituent and includes such groups as for example
benzyl, phenethyl, phenpropyl, .alpha.-methylbenzyl, methoxymethyl,
ethoxyethyl, and the like.
[0114] The term "optionally-substituted phenyl" is taken to mean a
phenyl radical optionally substituted with one or two substituents
independently selected from the group consisting of C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, hydroxy, halo, nitro,
trifluoromethyl, sulfonamido, cyano, carbamoyl, amino,
mono(C.sub.1-C.sub.4 alkyl)amino, di(C.sub.1-C.sub.4 alkyl)amino,
C.sub.1-C.sub.4 alkylsulfonylamino, and indol-2-yl.
[0115] The term "protected amino" refers to amine protecting groups
used to protect the nitrogen of the .beta.-lactam ring during
preparation or subsequent reactions. Examples of such groups are
benzyl, 4-methoxybenzyl, 4-methoxyphenyl, or trialkylsilyl, for
example trimethylsilyl.
[0116] The term "protected carboxy" refers to the carboxy group
protected or blocked by a conventional protecting group commonly
used for the temporary blocking of the acidic carboxy. Examples of
such groups include lower alkyl, for example tert-butyl,
halo-substituted lower alkyl, for example 2-iodoethyl and
2,2,2-trichloroethyl, benzyl and substituted benzyl, for example
4-methoxybenzyl and 4-nitrobenzyl, diphenylmethyl, alkenyl, for
example alkyl, trialkylsilyl, for example trimethylsilyl and
tert-butyldiethylsilyl and like carboxy-protecting groups.
[0117] The term "antagonist", as it is used in the description of
this invention, is taken to mean a full or partial antagonist. A
compound which is a partial antagonist at the vasopressin V.sub.1a
receptor must exhibit sufficient antagonist activity to inhibit the
effects of vasopressin or a vasopressin agonist at an acceptable
dose. While a partial antagonist of any intrinsic activity may be
useful, partial antagonists of at least about 50% antagonist effect
are preferred and partial antagonists of at least about 80%
antagonist effect are more preferred. Full antagonists of the
vasopressin V.sub.1a receptor are most preferred.
DETAILED DESCRIPTION OF THE INVENTION
[0118] Certain classes of compounds of the present invention having
formula I or formula II are preferred. Illustrative classes of such
compounds are described in the following paragraphs.
[0119] A class of compounds having formula I, wherein:
[0120] (aa) A is R.sup.6O--;
[0121] (ab) R.sup.6 is C.sub.1-C.sub.6 alkyl;
[0122] (ac) R.sup.6 is optionally-substituted aryl(C.sub.1-C.sub.4
alkyl);
[0123] (ad) A is a monosubstituted amino of the formula XNH--;
[0124] (ae) A is a disubstituted amino having the formula
R.sup.5XN--;
[0125] (af) A' is a monosubstituted amino having the formula
X'NH--;
[0126] (ag) A' is a disubstituted amino having the formula
R.sup.5'X'N--;
[0127] (ah) A' is R.sup.6'O--;
[0128] (ai) R.sup.6' is C.sub.1-C.sub.6 alkyl;
[0129] (aj) R.sup.6' is optionally-substituted aryl(C.sub.1-C.sub.4
alkyl);
[0130] (ak) X is optionally-substituted aryl(C.sub.1-C.sub.4
alkyl);
[0131] (al) X is R.sup.7R.sup.8N--(C.sub.1-C.sub.4 alkyl);
[0132] (am) R.sup.7 and R.sup.8 are taken together with the
attached nitrogen atom to form an heterocycle;
[0133] (an) R.sup.5 and X are taken together with the attached
nitrogen atom to form an heterocycle;
[0134] (ao) the heterocycle is optionally substituted with an
optionally-substituted aryl(C.sub.1-C.sub.4 alkyl), the first
heterocycle Y, or C.sub.3-C.sub.8 cycloalkyl;
[0135] (ap) R.sup.2 is hydrogen;
[0136] (aq) R.sup.2 is C.sub.1-C.sub.6 alkyl;
[0137] (ar) R.sup.2 is C.sub.1-C.sub.2 alkyl;
[0138] (as) R.sup.3 is 4-substituted oxazolidin-2-on-3-yl;
[0139] (at) R.sup.3 is 4,5-disubstituted oxazolidin-2-on-3-yl;
[0140] (au) R.sup.3 is 2-substituted oxazolidin-4-on-3-yl;
[0141] (av) R.sup.3 is 2-substituted imidazolidin-4-on-3-yl;
[0142] (aw) R.sup.3 is 1,2-disubstituted
imidazolidin-4-on-3-yl;
[0143] (ax) R.sup.3 is 5-substituted imidazolidin-2-on-1-yl;
[0144] (ay) R.sup.3 is 4,5-disubstituted
imidazolidin-4-on-1-yl;
[0145] (az) R.sup.4 is optionally-substituted 2-aryleth-1-yl;
[0146] (ba) R.sup.4 is optionally-substituted 2-arylethen-1-yl;
[0147] (bb) R.sup.5' is benzyl;
[0148] (bc) X' is the heterocycle Y;
[0149] (bd) X is optionally-substituted aryl(C.sub.1-C.sub.4
alkyl);
[0150] (be) aryl is optionally-substituted phenyl;
[0151] (bf) X' is R.sup.7'R.sup.8'N--(C.sub.1-C.sub.4 alkyl);
[0152] (bg) X' is R.sup.7'R.sup.8'N--;
[0153] (bh) R.sup.7' is C.sub.1-C.sub.6 alkyl;
[0154] (bi) R.sup.8' is C.sub.1-C.sub.6 alkyl;
[0155] (bj) R.sup.7 and R.sup.8 are taken together with the
attached nitrogen atom to form an heterocycle;
[0156] (bk) R.sup.7 and R.sup.8 are the same and are
C.sub.1-C.sub.6 alkyl;
[0157] (bl) R.sup.5' and X' taken together with the nitrogen to
which they are attached form pyrrolidinyl, piperidinyl,
piperazinyl; where said pyrrolidinyl, piperidinyl, or piperazinyl
is optionally substituted with the second heterocycle Y' or with
R.sup.7R.sup.8N--(C.sub.1-C.sub.4 alkyl);
[0158] (bm) R.sup.5' and X' taken together with the nitrogen to
which they are attached form piperidinyl optionally substituted at
the 4-position with hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.4 alkoxy, (C.sub.1-C.sub.4
alkoxy)carbonyl, (hydroxy(C.sub.1-C.sub.4
alkyloxy))-(C.sub.1-C.sub.4 alkyl), R.sup.7R.sup.8N--,
R.sup.7R.sup.8N--(C.sub.1-C.sub.4 alkyl), phenyl,
phenyl(C.sub.1-C.sub.4 alkyl), optionally-substituted
phenyl(C.sub.1-C.sub.4 alkyl), furyl(C.sub.1-C.sub.4 alkyl),
pyridinyl(C.sub.1-C.sub.4 alkyl), thienyl(C.sub.1-C.sub.4 alkyl),
or piperidin-1-yl(C.sub.1-C.sub.4 alkyl),
[0159] (bn) R.sup.5' and X' taken together with the nitrogen to
which they are attached form piperazinyl optionally substituted at
the 4-position with C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, optionally-substituted phenyl, optionally-substituted
phenyl(C.sub.1-C.sub.4 alkyl), N--(C.sub.1-C.sub.5
alkyl)acetamid-2-yl, N--(C.sub.3-C.sub.8 cycloalkyl)acetamid-2-yl,
R.sup.7R.sup.8N--, or (C.sub.1-C.sub.4 alkoxy)carbonyl; and
[0160] (bo) R.sup.5' and X' taken together with the nitrogen to
which they are attached form homopiperazinyl optionally substituted
in the 4-position with C.sub.1-C.sub.4 alkyl, phenyl, or
phenyl(C.sub.1-C.sub.4 alkyl).
[0161] It is appreciated that the classes of compounds described
above may be combined to form additional illustrative classes. An
example of such a combination of classes may be a class of
compounds wherein A is a monosubstituted amino having the formula
XNH--, where X is optionally-substituted aryl(C.sub.1-C.sub.4
alkyl), and A' is a disubstituted amino having the formula
R.sup.5'X'N--, where R.sup.5' and X' are taken together with the
attached nitrogen atom to form an heterocycle, such as piperidine,
peperazine, and the like. Further combinations of the classes of
compounds described above are contemplated in the present
invention.
[0162] Further illustrative classes of compounds are described by
compounds having formula III: ##STR7## wherein:
[0163] Ar is optionally-substituted phenyl, optionally-substituted
pyridinyl, optionally-substituted furyl, or optionally-substituted
thienyl;
[0164] R.sup.2 is hydrogen;
[0165] A is XNH--;
[0166] A' is X'NH--;
[0167] A' is R.sup.5'X'N--;
[0168] n is 0, 1, or 2;
[0169] X is optionally-substituted aryl(C.sub.1-C.sub.4 alkyl), and
aryl is substituted phenyl;
[0170] A' is R.sup.6'O--;
[0171] R.sup.6' is C.sub.1-C.sub.6 alkyl;
[0172] X' is R.sup.7'R.sup.8'N--;
[0173] X' is optionally-substituted aryl(C.sub.1-C.sub.4
alkyl);
[0174] X' is the second heterocycle Y';
[0175] R.sup.5' and X' are taken together with the attached
nitrogen atom to form piperidinyl, piperazinyl, or homopiperazinyl;
where said piperidinyl, piperazinyl, or homopiperazinyl is
optionally substituted with C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, the second heterocycle Y', optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl), R.sup.7R.sup.8N--,
R.sup.7R.sup.8N--(C.sub.1-C.sub.4 alkyl), or
R.sup.7R.sup.8N--C(O)--(C.sub.1-C.sub.4 alkyl);
[0176] R.sup.8' is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, optionally-substituted aryl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl); and
[0177] R.sup.7' and R.sup.8' are taken together with the attached
nitrogen atom to form an heterocycle selected from the group
consisting of pyrrolidinyl, piperidinyl, morpholinyl, and
piperazinyl; where said piperazinyl is optionally substituted at
the 4-position with C.sub.1-C.sub.4 alkyl.
[0178] Further illustrative classes of compounds are described by
compounds having formula IV: ##STR8## wherein:
[0179] Ar is optionally-substituted phenyl, optionally-substituted
pyridinyl, optionally-substituted furyl, or optionally-substituted
thienyl;
[0180] R.sup.2 is hydrogen;
[0181] A is XNH--;
[0182] n' is 1, 2, or 3;
[0183] X is optionally-substituted aryl(C.sub.1-C.sub.4 alkyl), and
aryl is substituted phenyl;
[0184] R.sup.6' is
[0185] R.sup.8' is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, optionally-substituted aryl, optionally-substituted
aryl(C.sub.1-C.sub.4 alkyl); and
[0186] R.sup.7' and R.sup.8' are taken together with the attached
nitrogen atom to form an heterocycle selected from the group
consisting of pyrrolidinyl, piperidinyl, morpholinyl, and
piperazinyl; where said piperazinyl is optionally substituted at
the 4-position with C.sub.1-C.sub.4 alkyl.
[0187] The following Tables 1-5 are illustrative of compounds
contemplated to be within the scope of the present invention.
TABLE-US-00001 TABLE 1 ##STR9##
2-[3-(Oxazolidin-2-on-3-yl)azetidinon-1-yl]alkanedioic acid
derivatives. n R.sup.2 R.sup.10 R.sup.11 A A' Ar 0 H benzofur-2-yl
3-iodophenyl 2-(piperidin-1-yl)ethylamino
4-(pyrrolidin-1-yl)piperazin-1-yl fur-3-yl 0 methyl benzofur-7-yl
4-fluorophenyl 4-(piperidin-1-yl)piperidin-1-yl
4-(3-trifluorophenyl)piperazin-1- pyrrol- yl 2-yl 0 ethyl
benzothien-5-yl 4-cyanophenyl 4-(phenylethyl)piperain-1-yl
4-(benzyloxycarbonyl)piperazin- pyrrol- 1-yl 3-yl 1 methyl
benzothien-3-yl phenyl fur-2-ylmethylamino 4-[2-(2- pyridin-
hydroxyethoxy)ethyl]piperazin-1- 2-yl yl 1 H thien-2-yl
methoxycarbonyl 4-(3- 4-(3,4- pyridin-
trifluoromethylphenyl)piperazin- methylenedioxybenzyl)piperazin-
4-yl 1-yl 1-yl 1 H naphth-2-yl 4-ethylaminophenyl
4-(benzyloxycarbonyl)piperazin- 4-phenylpiperazin-1-yl thiazol-
1-yl 2-yl 2 methyl 3-phenylprop-1- 2-isobutoxycarbonyl 4-[2-(2-
4-(3-phenylprop-2-enyl)piperazin- thiazol- yl
hydroxyethoxy)ethyl]piperazin-1- 1-yl 4-yl yl 2 ethyl
2-pheneth-1-yl 2- 4-benzylpiperazin-1-yl 4-ethylpiperazin-1-yl
thiazol- methanesulfonylaminophenyl 5-yl 2 methyl 3- cyclohexyl
4-(3,4- 2-(dimethylamino)ethylamino oxazol- isopropylbenzyl
methylenedioxybenzyl)piperazin- 2-yl 1-yl
[0188] TABLE-US-00002 TABLE 2 ##STR10##
2-[3-(Oxazolidin-4-on-3-yl)azetidinon-1-yl]alkanedioic acid
derivatives. n R.sup.2 R.sup.10 A A' Ar 0 ethyl 4-fluorobenzyl
4-phenylpiperazin-1-yl
4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1- oxazol-4-yl yl 0 H
benzyl 4-(3-phenylprop-2-enyl)piperazin-1-yl
4-(1-methylpiperidin-4-yl)piperazin-1-yl oxazol-5-yl 0 methyl
4-methoxyphenyl 4-ethylpiperazin-1-yl 4-butylpiperazin-1-yl
isoxazol-3-yl 1 H 3-chlorophenyl 2-(dimethylamino)ethylamino
4-isopropylpiperazin-1-yl isoxazol-4-yl 1 methyl 2-ethylphenyl
4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-
2-(piperidin-1-yl)ethylamino isoxazol-5-yl yl 1 ethyl phenyl
4-(1-methylpiperidin-4-yl)piperazin-1-yl
4-(2-phenylethyl)piperazin-1-yl imidazol-2- yl 1 methyl cyclopropyl
4-butylpiperazin-1-yl 4-(piperidin-1-yl)piperidin-1-yl imidazol-4-
yl 2 H cyclobutyl 4-isopropylpiperazin-1-yl
2-(pyridin-2-yl)ethylamino imidazol-5- yl 2 H cyclopentyl
4-pyridylmethylamino morpholin-4-ylamino pyrazol-3-yl 2 H
cyclohexyl 3-(dimethylamino)propylamino
4-(pyrrolidin-1-yl)piperazin-1-yl pyrazol-4-yl
[0189] TABLE-US-00003 TABLE 3 ##STR11##
2-[3-(Succinimid-1-yl)azetidinon-1-yl]alkanedioic acid derivatives.
n R.sup.2 R.sup.11 A A' Ar 0 H naphth-2-yl
1-benzylpiperidin-4-ylamino 4-(3-trifluorophenyl)piperazin-1-yl
pyrazol-5-yl 0 ethyl propyl N-benzyl-2-(dimethylamino)ethylamino
4-(benzyloxycarbonyl)piperazin-1-yl pyrimidin-2-yl 0 methyl
3-chloronaphth-1-yl 3-pyridylmethylamino
4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl pyrimidin-4-yl 1 ethyl
ethyl 4-(cyclohexyl)piperazin-1-yl 4-benzylpiperazin-1-yl
Pyrimidin-5-yl 1 H 6-methoxynaphth-2-
4-(2-cyclohexylethyl)piperazin-1-yl
4-(3,4-methylenedioxybenzyl)piperazin-1-yl Thiadiazol-3- yl yl 1
methyl methyl 4-[2-(morpholin-4-yl)ethyl]piperazin-1-yl
4-phenylpiperazin-1-yl Oxadiazol-3-yl 1 H 5-aminonaphth-1-yl
4-(4-tert-butylbenzyl)piperazin-1-yl
4-(3-phenylprop-2-enyl)piperazin-1-yl Quinolin-2-yl 2 methyl
ethoxycarbonyl 4-[2-(piperidin-1-yl)ethyl]piperazin-1-yl
4-ethylpiperazin-1-yl Quinolin-3-yl 2 ethyl isopropyl
4-[3-(piperidin-1-yl)propyl]piperazin-1-yl
2-(dimethylamino)ethylamino Quinolin-4-yl 2 methyl
tert-butoxycarbonyl 4-[2-(N,N-dipropylamino)ethyl]piperazin-
4-(pyrrolidin-1-ylcarbonylmethyl)piperazin- Isoquinolin-1- 1-yl
1-yl yl
[0190] TABLE-US-00004 TABLE 4 ##STR12##
2-[3-(Imidazol-2-on-1-yl)azetidinon-1-yl]alkanedioic acid
derivatives. n R.sup.2 R.sup.10 R.sup.11 R.sup.12 A A' Ar 0 H
3-nitrophenyl propyl tert-butoxycarbonyl 4-[3-(N,N-
4-(1-methylpiperidin-4- naphth- diethylamino)propyl]
yl)piperazin-1-yl 1-yl piperazin-1-yl 0 ethyl 3- naphth-1-yl
benzyloxycarbonyl 4-[2- 4-butylpiperazin-1-yl naphth-
(thiobenzyl)prop- (dimethylamino)ethyl] 2-yl 1-yl piperazin-1-yl 0
methyl Phenoxycarbonyl ethyl H 4-[3-(pyrrolidin-1-
4-isopropylpiperazin-1- 2- yl)propyl]piperazin-1-yl yl fluoro-
phenyl 1 methyl 2- naphth-2-yl 4- 4- 4-pyridylmethylamino 3-
methoxycarbonyl isopropylbenzyloxy- (cyclohexylmethyl) chloro-
ethyl carbonyl piperazin-1-yl phenyl 1 ethyl 4- methyl 3-
4-cyclopentylpiperazin-1- 3- 4- methanesulfonyl-
methoxybenzyloxycarbonyl yl (dimethylamino) bromo- phenyl
propylamino phenyl 1 H Isopropyl 2- 2- 4-[2-(pyrrolidin-1-
1-benzylpiperidin-4- 2- chloronaphth- butoxybenzyloxy-
yl)ethyl]piperazin-1-yl ylamino methyl- 1-yl carbonyl phenyl 1
ethyl 3-aminophenyl 6- 3- 4-[2-(thien-2- N-benzyl-2- 3-
methoxynaphth- chlorobenzyloxycarbonyl yl)ethyl]piperazin-1-yl
(dimethylamino)ethyl- iso- 2-yl amino propyl- phenyl 2 H
2-cyanophenyl isobutyl 3-fluoro-5- 4-(3- 3-pyridylmethylamino 2-
methoxybenzyloxycarbonyl phenylpropyl)piperazin-1-yl propoxy-
phenyl 2 methyl 3-methylthiobutyl 5- 3- 4-[2-(N,N-
4-cyclohexylpiperazin- 3- aminonaphth-1-yl cyanobenzyloxycarbonyl
diethylamino)ethyl]piperazin- 1-yl methoxy- 1-yl phenyl 2 H
4-hydroxyphenyl butyl methyl 4-benzylhomopiperazin-1-yl 4-(2- 2-
cyclohexylethyl)- ethyl- piperazin-1-yl thio- phenyl
[0191] TABLE-US-00005 TABLE 5 ##STR13##
2-[3-(Imidazol-5-on-1-yl)azetidinon-1-yl]alkanedioic acid
derivatives. n R.sup.2 R.sup.10 R.sup.12 A A' Ar 0 methyl
2-fluoro-4- 3-aminobenzyloxycarbonyl 4- 4-[2-(morpholin-4- 4-
methoxy- (bisphenylmethyl)piperazin yl)ethyl]piperazin-1-yl
methylthiophenyl phenyl 1-yl 0 ethyl 3- 2-hydroxybenzyloxycarbonyl
3-(4-methylpiperazin-1- 4-(4-tert-butylbenzyl)piperazin-
2-nitrophenyl ethoxy- yl)propylamino 1-yl phenyl 0 methyl 2- 3-
(+)-3(S)-1-benzylpyrrolidin- 4-[2-(piperidin-1- 2-carboxyphenyl
methyl- ethylaminobenzyloxycarbonyl 3-ylamino
yl)ethyl]piperazin-1-yl phenyl 1 H 2- 4- 2-pyridylmethylamino
4-[3-(piperidin-1- 3- methoxy- dimethylaminobenzyloxycarbonyl
yl)propyl]piperazin-1-yl carboxamidophenyl phenyl 1 H 3- methyl
4-ethylpiperazin-1-yl 4-[2- 2,3-difluorophenyl ethoxy-
(diisopropylamino)ethyl] phenyl piperazin-1-yl 1 H 3- benzyl 2-
4-[3- 3,5- isopropyl- (dimethylamino)ethylamino
(diethylamino)propyl]piperazin- dichlorophenyl phenyl 1-yl 1 H
4-chloro- isopropoxycarbonyl 4-(pyrrolidin-1- 4-(2- 3-chloro-4-
phenyl ylcarbonylmethyl)piperazin- dimethylaminoethyl)piperazin-
bromophenyl 1-yl 1-yl 2 ethyl 2-chloro-4- propoxycarbonyl
4-(1-methylpiperidin-4- 4-[3-(pyrrolidin-1- 5,6-dichloro-3-
bromophenyl yl)piperazin-1-yl yl)propyl]piperazin-1-yl iodophenyl 2
H 2-ethyl-3- ethoxycarbonyl 4-butylpiperazin-1-yl
4-(cyclohexylmethyl)piperazin- 2,4- bromphenyl 1-yl dimethylphenyl
2 ethyl 2-chloro-4- methoxycarbonyl 4-isopropyl)piperazin-1-yl
4-(2- 3-methyl-4- bromophenyl dimethylaminoethyl)piperazin-1-
isopropoxyphenyl yl
[0192] The compounds of the present invention are comprised of an
azetidinone nucleus, said nucleus bearing asymmetric carbons at the
3- and 4-positions as illustrated by following structures:
##STR14## The compounds of the invention may, therefore, exist as
single diastereomers, mixtures of diastereomers, or as a racemic
mixture, all of which are useful and part of the invention. It is
preferred that the azetidinone nucleus of the compounds of the
invention exist in a single diastereomeric form. It is most
preferred that the azetidinone nucleus exist as the
(3S,4R)-diastereomer.
[0193] It is appreciated that, except when A=A' and n=0, the carbon
bearing R.sup.2 is also asymmetric. Furthermore, when R.sup.3 is
4-substituted oxazolidin-2-on-3-yl, the 4-position of that ring is
asymmetric. In addition, when R.sup.3 is 2,5-disubstituted
oxazolidin-4-on-3-yl or 1,2,5-trisubstituted
imidazolidin-4-on-3-yl, the 2- and 5-carbons of those rings are
asymmetric. Finally, when R.sup.3 is succinimido and one of
R.sup.14 and R.sup.15 is hydrogen, the carbon bearing the
non-hydrogen substituent is also asymmetric. While compounds
possessing all combinations of stereochemical purity are
contemplated by the present invention, it is appreciated that in
many cases at least one of these chiral centers described above may
be present in a single absolute configuration.
[0194] The compounds of this invention are useful in methods for
antagonism of the vasopressin V.sub.1a receptor. Such antagonism is
useful in treating a variety of disorders that have been linked to
this receptor in mammals. It is preferred that the mammal to be
treated by the administration of compounds of this invention is
human.
[0195] Since certain of the compounds of this invention are amines,
they are basic in nature and accordingly react with any of a number
of inorganic and organic acids to form pharmaceutically acceptable
acid addition salts. Because some of the free amines of the
compounds of this invention are typically oils at room temperature,
it is preferable to convert the free amines to their
pharmaceutically acceptable acid addition salts for ease of
handling and administration, since the latter are routinely solid
at room temperature. Acids commonly employed to form such salts are
inorganic acids such as hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and
organic acids, such as p-toluenesulfonic acid, methanesulfonic
acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid,
succinic acid, citric acid, benzoic acid, acetic acid, and the
like. Examples of such pharmaceutically acceptable salts thus are
the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate, caprylate, acrylate, formate, isobutyrate, caproate,
heptanoate, propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,
xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,
citrate, lactate, .beta.-hydroxybutyrate, glycollate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,
naphthalene-2-sulfonate, mandelate and the like. Preferred
pharmaceutically acceptable salts are those formed with
hydrochloric acid, trifluoroacetic acid, maleic acid or fumaric
acid.
[0196] The 2-(azetidinon-1-yl)alkanedioic acid esters and amides of
formulae I and II are prepared by syntheses well known in the art.
As illustrated for compounds of formula I, the
2-(azetidinon-1-yl)alkanedioic acid esters are obtainable by the
2+2 cycloaddition of an appropriately substituted acetic acid
derivative (i), and an imine ester (ii) as described in Synthetic
Scheme I, where Z is a leaving group, and the integer n, and the
moieties A, A', R.sup.2, R.sup.3, and R.sup.4 are as previously
described. The term "leaving group" as used hereinafter refers to a
substitutent, such as halo, acyloxy, benzoyloxy and the like,
present on an activated carbon atom that may be replaced by a
nucleophile. The chemistry described in Synthetic Scheme I is
applicable to imines (ii) bearing ester, thioester, or amide
moieties. ##STR15## The preparation of the appropriate imines (ii)
and most of the required acetyl halides or anhydrides (i), as well
as the cycloaddition procedure, are generally described in U.S.
Pat. Nos. 4,665,171 and 4,751,299, hereby incorporated by
reference. The analogous synthesis of compounds of formula II may
be accomplished by this process using the appropriate
alkoxy-substituted amino acid imines.
[0197] Those compounds of formulae I and II of the invention
requiring R.sup.3 to be 4-substituted oxazolidin-2-on-3-yl or
1,4,5-trisubstituted imidazolidin-2-on-3-yl are prepared from the
corresponding (4-substituted oxazolidin-2-on-3-yl)- or
(1,4,5-trisubstituted imidazolidin-2-on-3-yl)-acetyl halide or
anhydride. The acid halide or anhydride is available from an
appropriately substituted glycine. The glycine is first converted
to the carbamate and then reduced to provide the corresponding
alcohol. The alcohol is then cyclized to the 4-substituted
oxazolidin-2-one, which is subsequently N-alkylated with a
haloacetic acid ester. The ester is hydrolyzed, and the resulting
acid is converted to the acetyl halide or anhydride (i).
[0198] Those compounds of the invention requiring R.sup.3 to be
2,5-disubstituted oxazolidin-4-on-3-yl or 1,2,5-trisubstituted
imidazolidin-4-on-3-yl are prepared from the corresponding
(2,5-disubstituted oxazolidin-4-on-3-yl)- or (1,2,5-trisubstituted
imidazolidin-4-on-3-yl)acetyl chlorides or anhydrides respectively.
The chemistry to prepare these reagents is described in U.S. Pat.
No. 4,772,694, hereby incorporated by reference. Briefly, the
required oxazolidinone or imidazolidinone is obtained from an
.alpha.-hydroxyacid or an .alpha.-aminoacid, respectively. The
imidazolones are prepared by converting the .alpha.-aminoacid,
(R.sup.11)--CH(NH.sub.2)CO.sub.2H, to an amino-protected amide and
then condensing the amide with an aldehyde, (R.sup.10)--CHO, in the
presence of an acid to form the 3-protected imidazolidin-4-one,
where R.sup.10 and R.sup.11 are as defined above. The 1-position
may be functionalized with an appropriate reagent to introduce
R.sup.12 and the 3-position deprotected, where R.sup.12 is as
defined above. The imidazolidin-4-one ring is then alkylated with a
haloacetic acid ester, the ester deesterified, and the resulting
acetic acid converted to the desired acid halide or anhydride (i).
The required oxazolidinones are prepared in an analogous manner
from the corresponding .alpha.-hydroxyacid,
(R.sup.11)--CH(OH)CO.sub.2H.
[0199] Those compounds of the invention requiring R.sup.3 to be
succinimido are prepared from the corresponding
2-(succinimido)acetyl halide or anhydride. The chemistry to prepare
these reagents is described in U.S. Pat. No. 4,734,498, hereby
incorporated by reference. Briefly, these reagents are obtained
from tartaric acid or, when one of R.sup.10 and R.sup.11 is
hydrogen, from malic acid. Tartaric acid is acylated or
O-alkylated, the corresponding diacyl or di-O-alkyl tartaric acid
is treated with an acid anhydride to form the succinic anhydride,
and reaction of this succinic anhydride with an ester of glycine to
form first the noncyclic half amide ester which is then cyclized to
the 3,4-disubstituted succinimidoacetic acid ester. The ester group
is deesterified and the resulting acid converted to the
corresponding acid halide or anhydride (i). The mono-substituted
succinimidoacetyl halide or anhydride is obtained with malic acid
via succinic anhydride formation followed by succinimide formation
as described above.
[0200] Those compounds of the invention requiring R.sup.3 to be an
N-substituted amine or an N'-substituted urea may be prepared from
the corresponding phthalimido protected 3-amino analogs. The
phthalimide protecting group may be removed using conventional
procedures, such as by treatment with hydrazine, and the like. Once
liberated, the amine may be alkylated with any one of a variety of
alkyl and cycloalkyl halides and sulfates, such as methyl iodide,
isopropylbromide, diethyl sulfate, cyclopropylmethylbromide,
cyclopentyliodide, and the like. Such amines may also be acylated
with acid halides, acid anhydrides, isocyanates, isothiocyanates,
such as acetyl chloride, propionic anhydride, methylisocyanate,
3-trifluoromethylphenylisothiocyanate, and the like.
[0201] The bases to be used in Synthetic Scheme I include, among
others, aliphatic tertiary amines, such as trimethylamine and
triethylamine, cyclic tertiary amines, such as N-methylpiperidine
and N-methylmorpholine, aromatic amines, such as pyridine and
lutidine, and other organic bases such as
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
[0202] The solvents useful for reactions described in Synthetic
Scheme I include, among others, dioxane, tetrahydrofuran, diethyl
ether, ethyl acetate, dichloromethane, chloroform, carbon
tetrachloride, benzene, toluene, acetonitrile, dimethyl sulfoxide
and N,N-dimethylformamide.
[0203] Alternatively, the compounds of formulae I and II may be
prepared via N--C(4) cyclization, as illustrated for compounds of
formula I in Synthetic Scheme II, via cyclizatoin of .beta.-hydroxy
amides iii, where R.sup.2, R.sup.3, R.sup.4, A, and A' are as
defined previously, according to the procedure of Townsend and
Nguyen in J. Am. Chem. Soc. 1981, 103, 4582, and Miller and
Mattingly in Tetra. 1983, 39, 2563, the disclosures of which are
incorporated herein by reference. The analogous synthesis of
compounds of formula II may be accomplished by cyclization of
.beta.-hydroxy amides of alkoxy-substituted amino acids.
##STR16##
[0204] The azetidinone ring may also be prepared with a deficit of
substituents R.sup.3, R.sup.4, or the R.sup.2-substituted
N-alkanedioic acid or alkoxyalkanoic acid moiety, but possessing
substituents capable of being elaborated through subsequent
chemical transformation to such groups described for compounds of
formulae I and II. In general, azetidinones may be prepared via
N--C(4) cyclization, such as the cyclization of acylhydroxamates iv
to azetidinone intermediates v, as depicted in Scheme III, where
R.sup.2, R.sup.3, R.sup.4, A, and A' are as defined above,
according to the procedure of Mattingly et al. in J. Am. Chem. Soc.
1979, 101, 3983 and Accts. Chem. Res. 1986, 19, 49, the disclosures
of which are incorporated herein by reference. It is appreciated
that other hydroxamates, such as alkylhydroxamates, aryl
hydroxamates, and the like, are suitable for carrying out the
cyclization. ##STR17## Subsequent chemical transformation of the
acyloxyazetidinone v to introduce for example an
R.sup.2-substituted alkanedioic acid moiety using conventional
procedures will illustratively provide compounds of formula I. The
analogous synthesis of compounds of formula II may be accomplished
by this process using an appropriate R.sup.2-substituted
alkoxyalkanoic acid.
[0205] An alternative cyclization to form intermediate
azetidinones, which may be further elaborated to compounds of
formulae I and II, may occur by oxidative cyclization of
acylhydroxamates vi to intermediate azetidinones vii, as
illustrated in Synthetic Scheme IV, where R.sup.3 is as defined
above, according to the procedure of Rajendra and Miller in J. Org.
Chem. 1987, 52, 4471 and Tetrahedron Lett. 1985, 26, 5385, the
disclosures of which are incorporated herein by reference. The
group R in Scheme IV represents an alkyl or aryl moiety selected to
provide R.sup.4, as defined above, upon subsequent transformation.
For example, R may be the group PhCH.sub.2--, as in vii-a, such
that oxidative elimination of HBr will provide the desired R.sup.4,
a styryl group, as in vii-b. It is appreciated that elaboration of
R to R.sup.4 is not necessarily performed immediately subsequent to
the cyclization and may be performed conveniently after other steps
in the synthesis of compounds of formulae I and II. It is further
appreciated that alternatives to the acylhydroxamates shown, such
as alkylhydroxamates, aryl hydroxamates, and the like, are suitable
for carrying out the cyclization. ##STR18##
[0206] Other useful intermediates, such as the
azetidinone-4-carboxaldehyde viii illustrated in Synthetic Scheme V
for preparing for example compounds of formula I, may be further
elaborated to 4-(R.sup.4)-substituted azetidinones via an
olefination reaction. The group R in Scheme V is selected such that
upon successful olefination of the carboxaldehyde the resulting
group R--CHCH-- corresponds to the desired alkyl or aryl moiety
R.sup.4, as defined above. Such olefination reactions may be
accomplished by any of the variety of known procedures, such as by
Wittig olefination, Peterson olefination, and the like. Synthetic
Scheme V illustrates the corresponding Wittig olefination with
phosphorane ix. The analogous synthesis of compounds of formula II
may be accomplished by this process using an appropriate
alkoxy-substituted azetidinone-4-carboxaldehyde derivative.
##STR19##
[0207] Still other useful intermediates, such as the azetidinonyl
acetic acid derivatives x, may be converted into compounds of
formulae I and II, as illustrated for the synthesis of compounds of
formula I in Synthetic Scheme VI. Introduction of an R.sup.2
moiety, and a carboxylic acid derivative
A'-C(O)--(CH.sub.2).sub.n-- for compounds of formula I, or an
alkoxyalkanoic acid derivative R.sup.6'O--(CH.sub.2).sub.n-- for
compounds of formula II, may be accomplished by alkylation of the
anion of x, where the integers n and n', and the groups R.sup.2,
R.sup.3, R.sup.4, R.sup.6', A, and A' are as defined above.
##STR20## Acetic acid derivative x is deprotonated and subsequently
alkylated with an alkyl halide corresponding to R.sup.2-Z, where Z
is a leaving group, to provide intermediate xi. Illustratively, the
anion of xi may be alkylated with a compound
Z'-(CH.sub.2).sub.nCOA', where Z' is a leaving group, to provide
compounds of formula I. It is appreciated that the order of
introduction of either the substituent R.sup.2 or the acid
derivative --(CH.sub.2).sub.nCOA', or the alkoxyalkanoic acid
derivative --(CH.sub.2).sub.n'OR.sup.6', is conveniently chosen by
the skilled artisan and such order of introduction may be different
for each compound of formula I or formula II.
[0208] A solution of the 2-(3,4-disubstituted
azetidin-2-on-1-yl)acetic acid derivative x or xi in an appropriate
solvent, such as tetrahydrofuran, dioxane, or diethyl ether, is
treated with a non-nucleophilic base to generate the anion of x or
xi, respectively. Suitable bases for this transformation include
lithium diisopropylamide, lithium
2,2,6,6-tetramethylpiperidinamide, or lithium
bis(trimethylsilyl)amide. The anion is then quenched with an
appropriate electrophile to provide the desired compounds.
Illustrative electrophiles represented by the formulae R.sup.2-Z,
R.sup.5'X'N--C(O)--(CH.sub.2).sub.n-Z, or
R.sup.6'O--C(O)--(CH.sub.2).sub.n-Z provide the corresponding
compounds xi or I, respectively. The analogous synthesis of
compounds of formula II may be accomplished by this process by
using an electrophile represented by the formula
R.sup.6'O--(CH.sub.2).sub.n-Z.
[0209] As discussed above, the compounds prepared as described in
Synthetic Schemes I, I, III, IV, V, and VI may be pure
diastereomers, mixtures of diastereomers, or racemates. The actual
stereochemical composition of the compound will be dictated by the
specific reaction conditions, combination of substituents, and
stereochemistry of the reactants employed. It is appreciated that
diasteromeric mixtures may be separated by chromatography or
fractional crystallization to provide single diastereomers if
desired. Particularly, the reactions described in Synthetic Schemes
III, IV, and VI create a new chiral center at the carbon bearing
R.sup.2, except when n=0 and A=A'.
[0210] Compounds of formula I which are 2-(3,4-disubstituted
azetidin-2-on-1-yl)alkanedioic acid half-esters, such as compounds
I-a where A' is R.sup.6'O--, while useful vasopressin V.sub.1a
agents in their own right, may also be converted to the
corresponding half-carboxylic acids xii, where the integer n and
the groups R.sup.2, R.sup.3, R.sup.4, R.sup.5', R.sup.6', A, and X'
are as previously defined, as illustrated in Synthetic Scheme VII.
These intermediates are useful for the preparation of other
compounds of the invention, such as I-b where A' is R.sup.5'X'N--.
It is appreciated that the transformation illustrated in Synthetic
Scheme VII is equally applicable for the preparation of compounds I
where A' is X'NH-- or where a different R.sup.6'O-- is desired.
##STR21##
[0211] The requisite carboxylic acid xii may be prepared from the
corresponding ester via saponification under standard conditions by
treatment with hydroxide followed by protonation of the resultant
carboxylate anion. Where R.sup.6' is tert-butyl, the ester I-a may
be dealkylated by treatment with trifluoroacetic acid. Where
R.sup.6' is benzyl, the ester I-a may be dealkylated either by
subjection to mild hydrogenolysis conditions, or by reaction with
elemental sodium or lithium in liquid ammonia. Finally, where
R.sup.6' is 2-(trimethylsilyl)ethyl, the ester I-a may be
deprotected and converted into the corresponding acid xii by
treatment with a source of fluoride ion, such as tetrabutylammonium
fluoride. The choice of conditions is dependent upon the nature of
the R.sup.6' moiety and the compatibility of other functionality in
the molecule with the reaction conditions.
[0212] The carboxylic acid xii is converted to the corresponding
amide I-b under standard conditions well recognized in the art. The
acid may be first converted to the corresponding acid halide,
preferably the chloride or fluoride, followed by treatment with an
appropriate primary or secondary amine to provide the corresponding
amide. Alternatively, the acid may be converted under standard
conditions to a mixed anhydride. This is typically accomplished by
first treating the carboxylic acid with an amine, such as
triethylamine, to provide the corresponding carboxylate anion. This
carboxylate is then reacted with a suitable haloformate, for
example benzyl chloroformate, ethyl chloroformate or
isobutylchloroformate, to provide the corresponding mixed
anhydride. This anhydride may then be treated with an appropriate
primary or secondary amine to provide the desired amide. Finally,
the carboxylic acid may be treated with a typical peptide coupling
reagent such as N,N'-carbonyldiimidazole (CDI),
N,N'-dicyclohexylcarbodiimide (DCC) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),
followed by the appropriate amine of formula R.sup.5XNH. A
polymer-supported form of EDC has been described in Tetrahedron
Letters, 34(48), 7685 (1993), the disclosure of which is
incorporated herein by reference, and is very useful for the
preparation of the compounds of the present invention. It is
appreciated that substituting an appropriate amine with an
appropriate alcohol in the synthethic scheme presented above will
provide the esters of the invention, e.g. analogs of I-a with a
different ester R.sup.6'O--.
[0213] The carboxylic acid may alternatively be converted into the
corresponding tert-butyl ester via treatment of the acid with an
acid catalyst, such as concentrated sulfuric acid, and the like,
and with isobutylene in a suitable solvent, such as dioxane, and
the like. The reaction is preferably carried out under pressure in
an appropriate vessel, such as a pressure bottle, and the like.
Reaction times of about 18 hours are not uncommon. The desired
ester may be isolated from the organic layer after partitioning the
reaction mixture between a suitable organic solvent, such as ethyl
acetate, and the like, and a basic aqueous layer, such as cold 1N
sodium hydroxide, and the like.
[0214] It is appreciated that the transformation illustrated in
Synthetic Scheme VII may also be used to convert in an analogous
fashion, the half-ester I where A is R.sup.6O-- to the
corresponding acid and subsequently into derivatives I where A is
XNH--, R.sup.5XN--, or a different R.sup.6O--. Finally, it is
appreciated that the transformation in Synthetic Scheme VII may
also be used to convert in an analogous fashion the esters of
formula II, where A is R.sup.6O--, to the corresponding acids, and
subsequently into derivatives of formula II, where A is XNH--,
R.sup.5XN--, or a different R.sup.6O--.
[0215] Compounds of formulae I and II where R.sup.4 includes an
ethenyl or ethynyl spacer, such as for example, compounds I-c and
I-d, respectively, may be converted into the corresponding
arylethyl derivatives, compounds I-e, via reduction, as illustrated
for compounds of formula I in Synthetic Scheme VIII. Conversion is
accomplished by catalytic hydrogenation, and other like reductions,
where the integer n and the groups R.sup.2, R.sup.3, A, and A' are
as previously defined. The corresponding compounds of formula II
may also be converted from ethyne and ethene precursors in an
analogous fashion. The moiety R depicted in Scheme VIII is chosen
such that the substituent R--CC--, R--CHCH--, or
R--CH.sub.2CH.sub.2-- corresponds to the desired R.sup.4 of
formulae I or II as defined above. ##STR22## The hydrogenation of
the triple or double bond proceeds readily over a precious metal
catalyst, such as palladium on carbon. The hydrogenation solvent
may consist of a lower alkanol, such as methanol or ethanol,
tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and
ethyl acetate. The hydrogenation may be performed at an initial
hydrogen pressure of about 20-80 p.s.i., preferably about 50-60
p.s.i., at a temperature of about 0-60.degree. C., preferably
within the range of from ambient temperature to about 40.degree.
C., for about 1 hour to about 3 days.
[0216] Alternatively, the ethynyl spacer of compound I-c may be
selectively reduced to the ethenyl spacer of compound I-d using
poisoned catalyts, such as Pd on BaSO.sub.4, Lindlar's catalyst,
and the like. It is appreciated that either the Z or E double bond
geometry of compound I-d may be advantageously obtained by the
appropriate choice of reaction conditions. The analogous synthesis
of compounds of formula II may be accomplished by this process.
[0217] Compounds of formula I and II where R.sup.3 is phthalimido
are conveniently treated with hydrazine or a hydrazine derivative,
for example methylhydrazine, to prepare the corresponding
2-(3-amino-4-substituted azetidin-2-on-1-yl)alkanedioic acid
derivatives xiii, as illustrated in Synthetic Scheme IX for
compounds of formula I, where the integer n, and the groups
R.sup.2, R.sup.4, R.sup.12, A, and A' are as previously defined.
This compound may then be treated with an appropriate alkylating or
acylating agent to prepare the corresponding amines or amides I-g,
or alternatively intermediates xiii may be treated with an
appropriate isocyanate to prepare the corresponding ureas I-h.
##STR23##
[0218] The ureas I-h are prepared by treating a solution of the
appropriate amine xiii in a suitable solvent, such as chloroform or
dichloromethane, with an appropriate isocyanate, R.sup.12NCO. If
necessary, an excess of the isocyanate is employed to ensure
complete reaction of the starting amine. The reactions are
performed at about ambient temperature to about 45.degree. C., for
from about three hours to about three days. Typically, the product
may be isolated by washing the reaction with water and
concentrating the remaining organic components under reduced
pressure. When an excess of isocyanate has been used, however, a
polymer bound primary or secondary amine, such as an
aminomethylated polystyrene, may be conveniently added to
facilitate removal of the excess reagent. Isolation of products
from reactions where a polymer bound reagent has been used is
greatly simplified, requiring only filtration of the reaction
mixture and then concentration of the filtrate under reduced
pressure.
[0219] The substituted amines and amides I-g are prepared by
treating a solution of the appropriate amine xiii in a suitable
solvent, such as chloroform or dichloromethane, with an appropriate
acylating or alkylating agent, R.sup.12--C(O)Z or R.sup.12
respectively. If necessary, an excess of the acylating or
alkylating agent is employed to ensure complete reaction of the
starting amine. The reactions are performed at about ambient
temperature to about 45.degree. C., for from about three hours to
about three days. Typically, the product may be isolated by washing
the reaction with water and concentrating the remaining organic
components under reduced pressure. When an excess of the acylating
or alkylating agent has been used, however, a polymer bound primary
or secondary amine, such as an aminomethylated polystyrene, may be
conveniently added to facilitate removal of the excess reagent.
Isolation of products from reactions where a polymer bound reagent
has been used is greatly simplified, requiring only filtration of
the reaction mixture and then concentration of the filtrate under
reduced pressure. The analogous synthesis of compounds of formula
II may be accomplished by this process.
[0220] The following preparations and examples further illustrate
the synthesis of the compounds of this invention and are not
intended to limit the scope of the invention in any way. Unless
otherwise indicated, all reactions were performed at ambient
temperature, and all evaporations were performed in vacuo. All of
the compounds described below were characterized by standard
analytical techniques, including nuclear magnetic resonance
spectroscopy (.sup.1H NMR) and mass spectral analysis (MS).
EXAMPLE 1
(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride
[0221] A solution of 1.0 equivalent of
(4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (Evans, U.S. Pat. No.
4,665,171) and 1.3 equivalent of oxalyl chloride in 200 mL
dichloromethane was treated with a catalytic amount of anhydrous
dimethylformamide (85 .mu.L/milliequivalent of acetic acid
derivative) resulting in vigorous gas evolution. After 45 minutes
all gas evolution had ceased and the reaction mixture was
concentrated under reduced pressure to provide the title compound
as an off-white solid after drying for 2 h under vacuum.
EXAMPLE 2
General Procedure for Amide Formation from an Activated Ester
Derivative
N-Benzyloxycarbonyl-L-aspartic acid .beta.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide
[0222] A solution of N-benzyloxycarbonyl-L-aspartic acid
.beta.-t-butyl ester .alpha.-N-hydroxysuccinimide ester (1.95 g,
4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was
treated with 0.68 mL (4.74 mmol) of 3-(trifluoromethyl)benzyl
amine. Upon completion (TLC, 60:40 hexanes/ethyl acetate), the
mixture was evaporated, and the resulting oil was partitioned
between dichloromethane and a saturated aqueous solution of sodium
bicarbonate. The organic laer was evaporated to give 2.23 g
(quantitative yield) of the title compound as a white solid;
.sup.1H NMR (CDCl.sub.3) .delta. 1.39 (s, 9H), 2.61 (dd, J=6.5 Hz,
J=17.2 Hz, 1H), 2.98 (dd, J=3.7 Hz, J=17.0 Hz, 1H), 4.41 (dd, J=5.9
Hz, J=15.3 Hz, 1H), 4.50-4.57 (m, 2H), 5.15 (s, 2H), 5.96-5.99 (m,
1H), 6.95 (s, 1H), 7.29-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52
(m, 2H).
[0223] Examples 3-5 were prepared according to the procedure of
Example 2, except that N-benzyloxycarbonyl-L-aspartic acid
.beta.-t-butyl ester .alpha.-N-hydroxysuccinimide ester was
replaced by the appropriate amino acid derivative, and
3-(trifluoromethyl)benzyl amine was replaced with the appropriate
amine.
EXAMPLE 3
N-Benzyloxycarbonyl-L-aspartic acid .beta.-t-butyl ester
.alpha.-[4-(2-phenylethyl)]piperazinamide
[0224] N-benzyloxycarbonyl-L-aspartic acid .beta.-t-butyl ester
.alpha.-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced
ChemTech) and 4-(phenylethyl)piperazine 2.27 mL (11.9 mmol) gave
5.89 g (quantitative yield) of the title compound as an off-white
oil; .sup.1H NMR (CDCl.sub.3) .delta. 1.40 (s, 9H), 2.45-2.80 (m,
10H), 3.50-3.80 (m, 4H), 4.87-4.91 (m, 1H), 5.08 (s, 2H), 5.62-5.66
(m, 1H), 7.17-7.33 (m, 10H).
EXAMPLE 4
N-Benzyloxycarbonyl-L-glutamic acid .gamma.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide
[0225] N-benzyloxycarbonyl-L-glutamic acid .beta.-t-butyl ester
.alpha.-N-hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced
ChemTech) and 3-(trifluoromethyl)benzylamine) 1.63 mL (11.4 mmol)
gave 5.41 g (98%) of the title compound as an off-white solid;
.sup.1H NMR (CDCl.sub.3) .delta. 1.40 (s, 9H), 1.88-1.99 (m, 1H),
2.03-2.13 (m, 1H), 2.23-2.33 (m, 1H), 2.38-2.47 (m, 1H), 4.19-4.25
(s, 1H), 4.46-4.48 (m, 2H), 5.05-5.08 (m, 2H), 5.67-5.72 (m, 1H),
7.27-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H).
EXAMPLE 5
N-Benzyloxycarbonyl-L-glutamic acid .gamma.-t-butyl ester
.alpha.-[4-(2-phenylethyl)]piperazinamide
[0226] N-benzyloxycarbonyl-L-glutamic acid .gamma.-t-butyl ester
.alpha.-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced
ChemTech) and 4-(phenylthyl)piperazine 2.19 mL (11.5 mmol) gave
5.87 g (quantitative yield) of the title compound as an off-white
oil; .sup.1H NMR (CDCl.sub.3) .delta. 1.43 (s, 9H); 1.64-1.73 (m,
1H); 1.93-2.01 (m, 1H); 2.23-2.40 (m, 2H); 2.42-2.68 (m, 6H);
2.75-2.85 (m, 2H); 3.61-3.74 (m, 4H); 4.66-4.73 (m, 1H); 5.03-5.12
(m, 2H); 5.69-5.72 (m, 1H); 7.16-7.34 (m, 10H).
EXAMPLE 5A
N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine t-Butyl
ester
[0227] N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine
(0.710 g, 1.70 mmole) in dichloromethane (8 mL) was treated with
t-butyl acetate (3 mL) and concentrated sulfuric acid (40 .mu.L) in
a sealed flask at 0.degree. C. Upon completion (TLC), the reaction
was quenched with of dichloromethane (10 mL) and saturated aqueous
potassium bicarbonate (15 mL). The organic layer was washed with
distilled water, and evaporated. The resulting residue was purified
by flash column chromatography (98:2 dichloromethane/methanol) to
yield the title compound as a colorless oil (0.292 g, 77%); .sup.1H
NMR (CDCl.sub.3) .delta. 1.44 (s, 9H); 3.68 (dd, J=2.9 Hz, J=9.3
Hz, 1H); 3.87 (dd, J=2.9 Hz, J=9.3 Hz, 1H); 4.22 (t, J=7.1 Hz, 1H);
4.30-4.60 (m, 5H); 5.64-5.67 (m, 1H); 7.25-7.39 (m, 9H); 7.58-7.61
(m, 2H); 7.73-7.76 (m, 2H).
EXAMPLE 5B
O-(Benzyl)-D-serine t-Butyl ester
[0228] Example 5A (0.620 g, 1.31 mmol) in dichloromethane (5 mL)
was treated with tris(2-aminoethyl)amine (2.75 mL) for 5 h. The
resulting mixture was washed twice with a phosphate buffer
(pH=5.5), once with saturated aqueous potassium bicarbonate, and
evaporated to give 0.329 g (quantitative yield) of the title
compound as an off-white solid; .sup.1H NMR (CD.sub.3OD) .delta.
1.44 (s, 9H); 3.48 (dd, J=J'=4.2 Hz, 1H); 3.61 (dd, J=4.0 Hz, J=9.2
Hz, 1H); 3.72 (dd, J=4.6 Hz, J=9.2 Hz, 1H); 4.47 (d, J=12.0 Hz,
1H); 4.55 (d, J=12.0 Hz, 1H); 7.26-7.33 (m, 5H).
EXAMPLE 6
General Procedure for Amide Formation from a Carboxylic Acid
N-Benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide
[0229] A solution of 1 g (2.93 mmol) of
N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated
by sequential addition of 0.46 mL (3.21 mmol) of
3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of
1-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride.
After at least 12 hours at ambient temperature or until complete as
determined by thin layer chromatography (95:5
dichloromethane/methanol eluent), the reaction mixture was washed
sequentially with a saturated aqueous sodium bicarbonate solution
and with distilled water. The organic layer was evaporated to give
1.41 g (quantitative yield) of the title compound as an off-white
solid; .sup.1H-NMR (CDCl.sub.3) .delta. 1.39 (s, 9H); 2.61 (dd,
J=6.5 Hz, J=17.2 Hz, 1H); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, 1H); 4.41
(dd, J=5.9 Hz, J=15.3 Hz, 1H); 4.50-4.57 (m, 2H); 5.10 (s, 2H);
5.96-6.01 (m, 1H); 6.91-7.00 (m, 1H); 7.30-7.36 (m, 5H); 7.39-7.43
(m, 2H); 7.48-7.52 (m, 2H).
[0230] Examples 7 and 7A-7E were prepared according to the
procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic
acid .beta.-t-butyl ester monohydrate was replaced by the
appropriate amino acid derivative, and 3-(trifluoromethyl)benzyl
amine was replaced with the appropriate amine.
EXAMPLE 7
N-Benzyloxycarbonyl-D-glutamic acid .gamma.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide
[0231] N-benzyloxycarbonyl-D-glutamic acid .gamma.-t-butyl ester
(1.14 g, 3.37 mmol) and 0.53 mL (3.70 mmol, Novabiochem) of
3-(trifluoromethyl)benzylamine gave 1.67 g (quantitative yield) of
Example 7 as an off-white solid.
EXAMPLE 7A
N-Benzyloxycarbonyl-L-glutamic acid .alpha.-t-butyl ester
.gamma.-(4-cyclohexyl)piperazinamide
[0232] N-benzyloxycarbonyl-L-glutamic acid .alpha.-t-butyl ester
(1.36 g, 4.03 mmol) and 0.746 g (4.43 mmol) of
1-cyclohexylpiperazine gave 1.93 g (98%) of Example 7A as an
off-white solid; .sup.1H NMR (CDCl.sub.3) .delta. 1.02-1.12 (m,
5H); 1.43 (s, 9H), 1.60-1.64 (m, 1H); 1.80-1.93 (m, 5H); 2.18-2.52
(m, 8H); 3.38-3.60 (m, 4H); 4.20-4.24 (m, 1H); 5.03-5.13 (m, 2H);
5.53-5.57 (m, 1H); 7.28-7.34 (m, 5H).
EXAMPLE 7B
N-Benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
.alpha.-(2-fluoro-3-trifluoromethyl)benzylamide
[0233] N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.12 mL of
(2-fluoro-3-trifluoromethyl)benzylamine gave 0.365 g (quantitative
yield) of Example 7B as an off-white solid; .sup.1H NMR
(CDCl.sub.3) .delta. 1.38 (s, 9H); 2.59 (dd, J=6.5 Hz, J=17.0 Hz,
1H); 2.95 (dd, J=4.3 Hz, J=17.0 Hz, 1H); 4.46-4.56 (m, 3H); 5.11
(s, 2H); 5.94-5.96 (m, 1H); 7.15 (t, J=8.0 Hz, 1H); 7.30-7.36 (m,
5H); 7.47-7.52 (m, 2H).
EXAMPLE 7C
N-Benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
.alpha.-[(S)-.alpha.-methylbenzyl]amide
[0234] N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of
(S)-.alpha.-methylbenzylamine gave 0.281 g (90%) of Example 7C as
an off-white solid; .sup.1H NMR (CDCl.sub.3) .delta. 1.41 (s, 9H);
1.44 (d, J=7.0 Hz, 3H); 2.61 (dd, J=7.0 Hz, J=17.0 Hz, 1H); 2.93
(dd, J=4.0 Hz, J=17.5 Hz, 1H); 4.50-4.54 (m, 1H); 5.04-5.14 (m,
3H); 5.94-5.96 (m, 1H); 6.76-6.80 (m, 1H); 7.21-7.37 (m, 10H).
EXAMPLE 7D
N-Benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
.alpha.-[(R)-.alpha.-methylbenzyl]amide
[0235] N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of
(R)-.alpha.-methylbenzylamine gave 0.281 g (90%) of Example 7D as
an off-white solid; .sup.1H NMR (CDCl.sub.3) .delta. 1.38 (s, 9H);
1.43 (d, J=6.9 Hz, 3H); 2.54 (dd, J=7.3 Hz, J=17.2 Hz, 1H); 2.87
(dd, J=4.1 Hz, J=17.3 Hz, 1H); 4.46-4.50 (m, 1H); 4.99-5.15 (m,
3H); 5.92-5.96 (m, 1H); 6.78-6.82 (m, 1H); 7.21-7.33 (m, 10H).
EXAMPLE 7E
N-Benzyloxycarbonyl-D-aspartic acid .gamma.-t-butyl ester
.alpha.-[N-methyl-N-(3-trifluoromethylbenzyl)]amide
[0236] N-benzyloxycarbonyl-D-aspartic acid .gamma.-t-butyl ester
(0.303 g, 0.89 mmol, Novabiochem) and 0.168 g (0.89 mmol,) of
N-methyl-N-(3-trifluoromethylbenzyl)amine gave 0.287 g (65%) of
Example 7E as an off-White solid; .sup.1H NMR (CDCl.sub.3) .delta.
1.40 (s, 9H); 2.55 (dd, J=5.8 Hz, J=15.8 Hz, 1H); 2.81 (dd, J=7.8
Hz, J=15.8 Hz, 1H); 3.10 (s, 3H); 4.25 (d, J=15.0 Hz, 1H); 4.80 (d,
J=15.5 Hz, 1H); 5.01-5.13 (m, 3H); 5.52-5.55 (m, 1H); 7.25-7.52 (m,
10H).
EXAMPLE 8
General Procedure for Hydrogenation of a Benzyloxycarbonyl
Amine
L-aspartic acid .beta.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide
[0237] A suspension of 2.23 g (4.64 mmol) of
N-benzyloxycarbonyl-L-aspartic acid .beta.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide and palladium (5% wt. on
activated carbon, 0.642 g) in 30 mL of methanol was held under an
atmosphere of hydrogen until complete conversion as determined by
thin layer chromatography (95:5 dichloromethane/methanol eluent).
The reaction was filtered to remove the palladium over carbon and
the filtrate was evaporated to give 1.52 g (96%) of the title
compound as an oil; .sup.1H NMR (CDCl.sub.3) .delta. 1.42 (s, 9H);
2.26 (brs, 2H); 2.63-2.71 (m, 1H); 2.82-2.87 (m, 1H); 3.75-3.77 (m,
1H); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.90 (brs, 1H).
[0238] Examples 9-13 and 13A-13E were prepared according to the
procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic
acid .beta.-t-butyl ester .alpha.-(3-trifluoromethyl)benzylamide
was replaced by the appropriate amino acid derivative.
EXAMPLE 9
L-aspartic acid .beta.-t-butyl ester
.alpha.-[4-(2-phenylethyl)]piperazinamide
[0239] N-benzyloxycarbonyl-L-aspartic acid .beta.-t-butyl ester
.alpha.-[4-(2-phenylethyl)]piperazinamide (5.89 g, 11.9 mmol) gave
4.24 g (98%) of Example 9 as an off-white oil; .sup.1H NMR
(CDCl.sub.3): .delta. 1.42 (s, 9H); 2.61-2.95 (m, 10H); 3.60-3.90
(m, 4H); 4.35-4.45 (m, 1H); 7.17-7.29 (m, 5H).
EXAMPLE 10
D-aspartic acid .beta.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide
[0240] N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide (1.41 g, 2.93 mmol) gave
0.973 g (96%) of Example 10 as an off-white oil; .sup.1H NMR
(CDCl.sub.3): .delta. 1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J=7.1
Hz, J=16.8 Hz, 1H); 2.84 (dd, J=3.6 Hz, J=16.7 Hz, 1H); 3.73-3.77
(m, 1H); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.83-7.87 (m,
1H).
EXAMPLE 11
L-glutamic acid .gamma.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide
[0241] N-benzyloxycarbonyl-L-glutamic acid .gamma.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide (5.41 g, 10.9 mmol) gave
3.94 g (quantitative yield) of Example 11 as an off-white oil;
.sup.1H NMR (CDCl.sub.3): .delta. 1.41 (s, 9H); 1.73-1.89 (m, 3H);
2.05-2.16 (m, 1H); 2.32-2.38 (m, 2H); 3.47 (dd, J=5.0 Hz, J=7.5 Hz,
1H); 4.47-4.49 (m, 2H); 7.36-7.54 (m, 4H); 7.69-7.77 (m, 1H).
EXAMPLE 12
L-glutamic acid .gamma.-t-butyl ester
.alpha.-[4-(2-phenylethyl)]piperazinamide
[0242] N-benzyloxycarbonyl-L-glutamic acid .gamma.-t-butyl ester
.alpha.-[4-(2-phenylethyl)]piperazinamide (5.86 g, 11.50 mmol) gave
4.28 g (99%) of Example 12 as an off-white oil; .sup.1H NMR
(CDCl.sub.3) .delta.1.39 (s, 9H); 2.00-2.08 (m, 1H); 2.38-2.46 (m,
1H); 2.55-2.90 (m, 9H); 3.61-3.82 (m, 4H); 4.48-4.56 (m, 1H);
7.17-7.26 (m, 5H).
EXAMPLE 13
D-glutamic acid .gamma.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide
[0243] N-benzyloxycarbonyl-D-glutamic acid .gamma.-t-butyl ester
.alpha.-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol) gave
1.15 g (94%) of Example 13 as an off-white oil; .sup.1H NMR
(CDCl.sub.3) .delta. 1.41 (s, 9H); 1.80-2.20 (m, 4H); 2.31-2.40 (m,
2H); 3.51-3.59 (m, 1H); 4.47-4.49 (m, 2H); 7.39-7.52 (m, 4H);
7.71-7.79 (m, 1H).
EXAMPLE 13A
L-glutamic acid .alpha.-t-butyl ester
.gamma.-(4-cyclohexyl)piperazinamide
[0244] N-Benzyloxycarbonyl-L-glutamic acid .alpha.-1-butyl ester
.gamma.-(4-cyclohexyl)piperazinamide (1.93 g, 3.96 mmol) gave 1.30
g (93%) of Example 13A as an off-white oil; .sup.1H NMR
(CDCl.sub.3) 6.1.02-1.25 (m, 5H); 1.41 (s, 9H); 1.45-1.50 (m, 1H);
1.56-1.60 (m, 1H); 1.69-1.80 (m, 6H); 3.30 (dd, J=4.8 Hz, J=8.5 Hz,
1H); 3.44 (t, J=9.9 Hz, 2H); 3.56 (t, J=9.9 Hz, 2H).
EXAMPLE 13B
D-aspartic acid .beta.-t-butyl ester
.alpha.-(2-fluoro-3-trifluoromethyl)benzylamide
[0245] N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
.alpha.-(2-fluoro-3-trifluoromethyl)benzylamide (0.36 g, 0.72 mmol)
gave 0.256 g (92%) of Example 13B as an off-white oil; .sup.1H NMR
(CDCl.sub.3) .delta. 1.39 (s, 9H); 2.50 (brs, 2H); 2.74 (dd, J=7.0
Hz, J=16.5 Hz, 1H); 2.86 (dd, J=4.8 Hz, J=16.8 Hz, 1H); 3.89 (brs,
2H); 4.47-4.57 (m, 2H); 7.16 (t, J=7.8 Hz, 1H); 7.48 (t, J=7.3 Hz,
1H); 7.56 (t, J=7.3 Hz, 1H); 7.97-8.02 (m, 1H).
EXAMPLE 13C
D-aspartic acid .beta.-t-butyl ester
.alpha.-[(S)-.alpha.-methyl]benzylamide
[0246] N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
.alpha.-[(S)-.alpha.-methylbenzyl]amide (0.275 g, 0.65 mmol) gave
0.17 g (90%) of Example 13C as an off-white oil; .sup.1H NMR
(CDCl.sub.3) .delta. 1.40 (s, 9H); 1.47 (d, J=6.9 Hz, 3H); 1.98
(brs, 2H); 2.49 (dd, J=7.9 Hz, J=17.7 Hz, 1H); 2.83 (dd, J=3.6 Hz,
J=16.7 Hz, 1H); 3.69 (brs, 1H); 4.99-5.10 (m, 1H); 7.19-7.33 (m,
5H); 7.65-7.6.8 (m, 1H).
EXAMPLE 13D
D-aspartic acid .beta.-t-butyl ester
.alpha.-[(R)-.alpha.-methylbenzyl]amide
[0247] N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
.alpha.-[(R)-.alpha.-methylbenzyl]amide (0.273 g, 0.64 mmol) gave
0.187 g (quantitative yield) of Example 13D as an off-white oil;
.sup.1H NMR (CDCl.sub.3) .delta. 1.38 (s, 9H); 1.46 (d, J=6.9 Hz,
3H); 1.79 (brs, 2H); 2.51 (dd, J=7.8 Hz, J=17.5 Hz, 1H); 2.87 (dd,
J=3.6 Hz, J=16.9 Hz, 1H); 4.19 (brs, 1H); 4.99-5.11 (m, 1H);
7.18-7.34 (m, 5H); 7.86-7.90 (m, 1H).
EXAMPLE 13E
D-aspartic acid .beta.-t-butyl ester
.alpha.-[N-methyl-N-(3-trifluoromethylbenzyl)]amide
[0248] N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
.alpha.-[N-methyl-N-(3-trifluoromethylbenzyl)]amide (0.282 g, 0.57
mmol) gave 0.195 g (95%) of Example 13E as an off-white oil.
EXAMPLE 14
General Procedure for Formation of a 2-Azetidinone from an Imine
and an Acetyl Chloride
Step, 1 General Procedure for Formation of an Imine from an Amino
Acid Derivative
[0249] A solution of 1 equivalent of an .alpha.-amino acid ester or
amide in dichloromethane is treated sequentially with 1 equivalent
of an appropriate aldehyde, and a dessicating agent, such as
magnesium sulfate or silica gel, in the amount of about 2 grams of
dessicating agent per gram of starting .alpha.-amino acid ester or
amide. The reaction is stirred at ambient temperature until all of
the reactants are consumed as measured by thin layer
chromatography. The reactions are typically complete within an
hour. The reaction mixture is then filtered, the filter cake is
washed with dichloromethane, and the filtrate concentrated under
reduced pressure to provide the desired imine that is used as is in
the subsequent step.
Step 2: General Procedure for the 2+2 Cycloaddition of an Imine and
an Acetyl Chloride
[0250] A dichloromethane solution of the imine (10 mL
dichloromethane/1 gram imine) is cooled to 0.degree. C. To this
cooled solution is added 1.5 equivalents of an appropriate amine,
typically triethylamine, followed by the dropwise addition of a
dichloromethane solution of 1.1 equivalents of an appropriate
acetyl chloride, such as that described in Example 1 (10 mL
dichloromethane/1 gm appropriate acetyl chloride). The reaction
mixture is allowed to warm to ambient temperature over 1 h and is
then quenched by the addition of a saturated aqueous solution of
ammonium chloride. The resulting mixture is partitioned between
water and dichloromethane. The layers are separated and the organic
layer is washed successively with 1N hydrochloric acid, saturated
aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
The organic layer is dried over magnesium sulfate and concentrated
under reduced pressure. The residue may be used directly for
further reactions, or purified by chromatography or by
crystallization from an appropriate solvent system if desired.
EXAMPLE 15
tert-Butyl[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin--
2-on-1-yl]acetate
[0251] Using the procedure of Example 14, the imine prepared from
4.53 g (34.5 mmol) glycine tert-butyl ester and cinnamaldehyde was
combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride
(Example 1) to give 5.5 g (30%) of Example 15 as colorless crystals
(recrystallized, n-chlorobutane); mp 194-195.degree. C.
EXAMPLE 16
General Procedure for Acylation of an
(azetidin-2-on-1-yl)acetate
[0252] A solution of (azetidin-2-on-1-yl)acetate in tetrahydrofuran
(0.22 M in azetidinone) is cooled to -78.degree. C. and is with
lithium bis(trimethylsilyl)amide (2.2 equivalents). The resulting
anion is treated with an appropriate acyl halide (1.1 equivlants).
Upon complete conversion of the azetidinone, the reaction is
quenched with saturated aqueous ammonium chloride and partitioned
between ethyl acetate and water. The organic phase is washed
sequentially with 1N hydrochloric acid, saturated aqueous sodium
bicarbonate, and saturated aqueous sodium chloride. The resulting
organic layer is dried (magnesium sulfate) and evaporated. The
residue is purified by silica gel chromatography with an
appropriate eluent, such as 3:2 hexane/ethyl acetate.
EXAMPLE 17
2,2,2-Trichloroethyl
2(RS)-(tert-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R-
)-(2-styryl)azetidin-2-on-1-yl]acetate
[0253] Using the procedure of Example 16, 9.0 g (20 mmol) of
Example 15 was acylated with 4.2 g (20 mmol) of
trichloroethylchloroformate to give 7.0 g (56%) of Example 17; mp
176-178.degree. C.
EXAMPLE 18
2(RS)-(tert-Butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-
-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0254] A solution of 0.20 g (0.32 mmol) of Example 17 and 52 .mu.L
(0.36 mmol) of (3-trifluoromethylbenzyl)amine in THF was heated at
reflux. Upon complete conversion (TLC), the solvent was evaporated
and the residue was recrystallized (chloroform/hexane) to give 0.17
g (82%) of Example 18 as a white solid; mp 182-184.degree. C.
[0255] Examples 19-25 and 25A-25H were prepared according to the
procedure of Example 14, where the appropriate amino acid
derivative and aldehyde were used in Step 1, and the appropriate
acetyl chloride was used in Step 2.
EXAMPLE 19
2(S)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-
-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0256] The imine prepared from 1.52 g (4.39 mmol) of L-aspartic
acid .beta.-t-butyl ester .alpha.-(3-trifluoromethyl)benzylamide
and cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 2.94 g of an orange-brown oil that gave, after flash column
chromatography purification (70:30 hexanes/ethyl acetate), 2.06 g
(70%) of Example 19 as a white solid; .sup.1H NMR (CDCl.sub.3)
.delta. 1.39 (s, 9H); 2.46 (dd, J=11.1 Hz, J=16.3 Hz, 1H); 3.18
(dd, J=3.8 Hz, J=16.4 Hz, 1H); 4.12-4.17 (m, 1H); 4.26 (d, J=5.0
Hz, 1H); 4.45 (dd, J=6.0 Hz, J=14.9 Hz, 1H); 4.54 (dd, J=5.3 Hz,
J=9.8 Hz, 1H); 4.58-4.66 (m, 3H); 4.69-4.75 (m, 1H); 4.81 (dd,
J=3.8 Hz, J=11.1 Hz, 1H); 6.25 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.70
(d, J=15.8 Hz, 1H); 7.14-7.17 (m, 2H); 7.28-7.46 (m, 11H); 7.62 (s,
1H); 8.27-8.32 (m, 1H).
EXAMPLE 20
2(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)--
4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0257] The imine prepared from 3.94 g (10.93 mmol) of L-glutamic
acid .gamma.-t-butyl ester x-(3-trifluoromethyl)benzylamide and
cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 5.53 g (75%) of Example 20 after flash column chromatography
purification (70:30 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.36 (s, 9H); 1.85-1.96 (m, 1H); 2.18-2.49 (m,
3H); 4.14-4.19 (m, 1H); 4.30 (d, J=4.9 Hz, 2H); 4.44 (dd, J=6.1 Hz,
J=14.9 Hz, 1H); 4.56-4.67 (m, 4H); 4.71-4.75 (m, 1H); 6.26 (dd,
J=9.6 Hz, J=15.8 Hz, 1H); 6.71 (d, J=15.8 Hz, 1H); 7.16-7.18 (m,
2H); 7.27-7.49 (m, 11H); 7.60 (s, 1H); 8.08-8.12 (m, 1H).
EXAMPLE 21
2(S)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-
-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-[4-(2-phenylethyl)]piperazinamide
[0258] The imine prepared from 4.20 g (11.6 mmol) of L-aspartic
acid .beta.-t-butyl ester .alpha.-[4-(2-phenylethyl)]piperazinamide
and cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 4.37 g (55%) of Example 21 after flash column chromatography
purification (50:50 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.34 (s, 9H); 2.26-2.32 (m, 1H); 2.46-2.63 (m,
4H); 2.75-2.89 (m, 4H); 3.24-3.32 (m, 1H); 3.49-3.76 (m, 3H);
4.07-4.13 (m, 1H); 4.30 (d, J=4.6 Hz, 1H); 4.22-4.48 (m, 1H);
4.55-4.61 (m, 1H); 4.69-4.75 (m, 1H); 5.04-5.09 (m, 1H); 6.15 (dd,
J=9.3 Hz, J=15.9 Hz, 1H); 6.63 (d, J=15.8 Hz, 1H); 7.18-7.42 (m,
15H).
EXAMPLE 22
2(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)--
4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-[4-(2-phenylethyl)]piperazinamide
[0259] The imine prepared from 2.54 g (6.75 mmol) of L-glutamic
acid .gamma.-t-butyl ester
.alpha.-[4-(2-phenylethyl)]piperazinamide and cinnamaldehyde was
combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride
(Example 1) to give 3.55 g (76%) of Example 22 after flash column
chromatography purification (50:50 hexanes/ethyl acetate); .sup.1H
NMR (CDCl.sub.3) .delta. 1.32 (s, 9H); 1.96-2.07 (m, 1H); 2.15-2.44
(m, 6H); 2.54-2.62 (m, 2H); 2.69-2.81 (m, 3H); 3.28-3.34 (m, 1H);
3.59-3.68 (1H); 4.08-4.13 (m, 1H); 4.33-4.44 (m, 2H); 4.48-4.60 (m,
2H); 4.67-4.77 (m, 1H); 6.14 (dd, J=8.9 Hz, J=16.0 Hz, 1H); 6.62
(d, J=16.0 Hz, 1H); 7.16-7.42 (m, 15H).
EXAMPLE 23
2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-
-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0260] The imine prepared from 0.973 g (2.81 mmol) of D-aspartic
acid .beta.-t-butyl ester .alpha.-(3-trifluoromethyl)benzylamide
and cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 1.53 g (82%) of Example 23 after flash column chromatography
purification (70:30 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.37 (s, 9H); 3.10 (dd, J=3.7 Hz, J=17.8 Hz,
1H); 3.20 (dd, J=10.7 Hz, J=17.8 Hz, 1H); 4.02 (dd, J=3.6 Hz,
J=10.6 Hz, 1H); 4.11-4.17 (m, 1H); 4.24 (d, J=4.9 Hz, 1H); 4.46
(dd, J=5.8 Hz, J=15.1 Hz, 1H); 4.58-4.67 (m, 3H); 4.70-4.76 (m,
1H); 6.27 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.79 (d, J=15.8 Hz, 1H);
7.25-7.50 (m, 13H); 7.63 (s, 1H); 8.50-8.54 (m, 1H).
EXAMPLE 24
2(R)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)--
4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0261] The imine prepared from 1.15 g (3.20 mmol) of D-glutamic
acid .gamma.-t-butyl ester .alpha.-(3-trifluoromethyl)benzylamide
and cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 1.84 g (85%) of Example 24 after flash column chromatography
purification (70:30 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.37 (s, 9H); 2.23-2.39 (m, 4H); 3.71-3.75 (m,
1H); 4.13-4.18 (m, 1H); 4.31 (d, J=4.9 Hz, 1H); 4.44-4.51 (m, 2H);
4.56-4.68 (m, 2H); 4.71-4.76 (m, 1H); 6.26 (dd, J=9.5 Hz, J=15.8
Hz, 1H); 6.71 (d, J=15.8 Hz, 1H); 7.25-7.52 (m, 13H); 7.63 (s, 1H);
8.25-8.30 (m, 1H).
EXAMPLE 25
2(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)--
4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-(4-cyclohexyl)piperazinamide
[0262] The imine prepared from 2.58 g (5.94 mmol) of L-glutamic
acid .gamma.-t-butyl ester .alpha.-(4-cyclohexyl)piperazinamide and
cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 3.27 g (94%) of Example 25 after flash column chromatography
purification (95:5 dichloromethane/methanol); .sup.1H NMR
(CDCl.sub.3) .delta. 1.32 (s, 9H); 1.10-1.18 (m, 1H); 1.20-1.31 (m,
2H); 1.38-1.45 (m, 2H); 1.61-1.66 (m, 1H); 1.84-1.89 (m, 2H);
1.95-2.01 (m, 1H); 2.04-2.14 (m, 3H); 2.20-2.24 (m, 1H); 2.29-2.35
(m, 1H); 2.85-2.92 (m, 1H); 3.24-3.32 (m, 1H); 3.36-3.45 (m, 2H);
3.80-3.86 (m, 1H); 4.08 (t, J=8.3 Hz, 1H); 4.27 (d, J=5.0 Hz, 1H);
4.31-4.55 (m, 4H); 4.71 (t, J=8.3 Hz, 1H); 4.83-4.90 (m, 1H); 6.18
(dd, J=9.1 Hz, J=15.9 Hz, 1H); 6.67 (d, J=15.9 Hz, 1H); 7.25-7.44
(m, 10H); 8.22 (brs, 1H).
EXAMPLE 25A
tert-Butyl
2(S)-(2-(4-cyclohexylpiperazin-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S-
)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate
[0263] The imine prepared from 1.282 g (3.63 mmol) of L-glutamic
acid .alpha.-t-butyl ester .gamma.-(4-cyclohexyl)piperazinamide and
cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 1.946 g (80%) of Example 25A after flash column chromatography
purification (50:50 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.15-1.26 (m, 6H); 1.39 (s, 9H); 1.55-1.64 (m,
2H); 1.77-1.83 (m, 3H); 2.22-2.35 (m, 2H); 2.40-2.50 (m, 6H);
2.75-2.79 (m, 1H); 3.43-3.48 (m, 1H); 3.56-3.60 (m, 2H); 3.75-3.79
(m, 1H); 4.10 (t, J=8.3 Hz, 1H); 4.31-4.35 (m, 2H); 4.58 (t, J=8.8
Hz, 1H); 4.73 (t, J=8.4 Hz, 1H); 6.17 (dd, J=8.6 Hz, J=16.0 Hz,
1H); 6.65 (d, J=16.0 Hz, 1H); 7.27-7.42 (m, 10H).
EXAMPLE 25B
2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-
-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-(2-fluoro-3-trifluoromethylbenzyl)amide
[0264] The imine prepared from 0.256 g (0.70 mmol) of D-aspartic
acid .beta.-t-butyl ester
.alpha.-(2-fluoro-3-trifluoromethyl)benzylamide and cinnamaldehyde
was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl
chloride (Example 1) to give 0.287 g (60%) of Example 25B after
flash column chromatography purification (70:30 hexanes/ethyl
acetate); .sup.1H NMR (CDCl.sub.3) .delta. 1.38 (s, 9H); 3.12 (dd,
J=4.0 Hz, J=17.8 Hz, 1H); 3.20 (dd, J=10.4 Hz, J=17.8 Hz, 1H); 4.05
(dd, J=3.9 Hz, J=10.4 Hz, 1H); 4.14 (dd, J=J'=8.2 Hz, 1H); 4.25 (d,
J=4.9 Hz, 1H); 4.59-4.67 (m, 4H); 4.74 (t, J=8.3 Hz, 1H); 6.36 (dd,
J=9.6 Hz, J=15.8 Hz, 1H); 6.83 (d, J=15.8 Hz, 1H); 7.02-7.07 (m,
1H); 7.28-7.55 (m, 12H); 8.44-8.48 (m, 1H).
EXAMPLE 25C
2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-
-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-[(S)-.alpha.-methylbenzyl]amide
[0265] The imine prepared from 0.167 g (0.57 mmol) of D-aspartic
acid .beta.-t-butyl ester [(S)-.alpha.-methylbenzyl]amide and
cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 0.219 g (63%) of Example 25C after flash column chromatography
purification (70:30 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.35 (s, 9H); 1.56 (d, J=7.0 Hz, 3H); 2.97
(dd, J=3.5 Hz, J=18.0 Hz, 1H); 3.15 (dd, J=11.0 Hz, J=17.5 Hz, 1H);
4.01 (dd, J=3.0 Hz, J=11.0 Hz, 1H); 4.14 (t, J=8.5 Hz, 1H); 4.24
(d, J=5.0 Hz, 1H); 4.57 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.64 (t,
J=8.8 Hz, 1H); 5.07 (t, J=8.5 Hz, 1H); 5.03-5.09 (m, 1H); 6.43 (dd,
J=9.5 Hz, J=16.0 Hz, 1H); 6.83 (d, J=16.0 Hz, 1H); 7.16-7.20 (m,
1H); 7.27-7.49 (m, 14H); 8.07-8.10 (m, 1H).
EXAMPLE 25D
2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-
-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-[(R)-.alpha.-methylbenzyl]amide
[0266] The imine prepared from 0.187 g (0.46 mmol) of D-aspartic
acid .beta.-t-butyl ester [(R)-.alpha.-methylbenzyl]amide and
cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 0.25 g (64%) of Example 25D after flash column chromatography
purification (70:30 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.36 (s, 9H); 1.59 (d, J=7.1 Hz, 3H); 3.10
(dd, J=3.5 Hz, J=17.8 Hz, 1H); 3.22 (dd, J=10.9 Hz, J=17.8 Hz, 1H);
3.93 (dd, J=3.5 Hz, J=10.8 Hz, 1H); 4.14 (t, J=8.1 Hz, 1H); 4.24
(d, J=5.0 Hz, 1H); 4.58 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.65 (t,
J=8.7 Hz, 1H); 4.74 (t, J=8.2 Hz, 1H); 5.06-5.14 (m, 1H); 6.32 (dd,
J=9.5 Hz, J=15.8 Hz, 1H); 6.74 (d, J=15.8 Hz, 1H); 7.19-7.43 (m,
15H); 8.15-8.18 (m, 1H).
EXAMPLE 25E
2(R)-tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)--
4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-methyl-N-(3-trifluoromethylbenzyl)amide
[0267] The imine prepared from 0.195 g (0.41 mmol) of D-aspartic
acid .beta.-t-butyl ester
.alpha.-[N-methyl-N-(3-trifluoromethylbenzyl)]amide and
cinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 0.253 g (69%) of Example 25E after flash column chromatography
purification (70:30 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.36 (s, 9H); 2.53 (dd, J=4.0 Hz, J=17.0 Hz,
1H); 3.06 (dd, J=10.8 Hz, J=16.8 Hz, 1H); 3.13 (s, 3H); 4.12 (dd,
J=8.0 Hz, J=9.0 Hz, 1H); 4.26 (d, J=5.0 Hz, 1H); 4.38 (d, J=15.0
Hz, 1H); 4.46 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.56 (t, J=6.8 Hz, 1H);
4.70-4.79 (m, 2H); 5.27 (dd, J=4.0 Hz, J=11.0 Hz, 1H); 6.22 (dd,
J=9.3 Hz, J=15.8 Hz, 1H); 6.73 (d, J=15.8 Hz, 1H); 7.33-7.45 (m,
14H).
EXAMPLE 25F
2(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)--
4(R)-(2-chlorostyr-2-yl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0268] The imine prepared from 1.62 g (4.44 mmol) of L-glutamic
acid .gamma.-t-butyl ester .alpha.-(3-trifluoromethyl)benzylamide
and .alpha.-chlorocinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 0.708 g (22%) of Example 25F after flash column chromatography
purification (70:30 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.35 (s, 9H); 1.68 (brs, 1H); 2.19-2.35 (m,
2H); 2.40-2.61 (m, 2H); 4.13 (dd, J=7.5 Hz, J=9.0 Hz, 1H); 4.22 (t,
J=7.0 Hz, 1H); 4.34 (d, J=4.5 Hz, 1H); 4.45 (dd, J=5.5 Hz, J=15.0
Hz, 1H); 4.51-4.60 (m, 3H); 4.89 (dd, J=7.5 Hz, J=8.5 Hz, 1H); 6.89
(s, 1H); 7.28-7.54 (m, 14H).
EXAMPLE 25G
2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-
-4(R)-(2'-methoxystyr-2-yl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0269] The imine prepared from 0.34 g (0.98 mmol) of D-aspartic
acid .beta.-t-butyl ester .alpha.-(3-trifluoromethylbenzyl)amide
and 2'-methoxycinnamaldehyde was combined with
2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to
give 0.402 g (59%) of Example 25G after flash column chromatography
purification (70:30 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 1.35 (s, 9H); 1.68 (brs, 1H); 2.19-2.35 (m,
2H); 2.40-2.61 (m, 2H); 4.13 (dd, J=7.5 Hz, J=9.0 Hz, 1H); 4.22 (t,
J=7.0 Hz, 1H); 4.34 (d, J=4.5 Hz, 1H); 4.45 (dd, J=5.5 Hz, J=15.0
Hz, 1H); 4.51-4.60 (m, 3H); 4.89 (dd, J=7.5 Hz, J=8.5 Hz, 1H); 6.89
(s, 1H); 7.28-7.54 (m, 14H).
EXAMPLE 25H
tert-Butyl
(2R)-(Benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl-
)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate
[0270] The imine prepared from 0.329 g (1.31 mmol) of
O-(benzyl)-D-serine t-butyl ester and cinnamaldehyde was combined
with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1)
to give 0.543 g (73%) of Example 25H after flash column
chromatography purification (90:10 hexanes/ethyl acetate); .sup.1H
NMR (CDCl.sub.3) .delta. 1.39 (s, 9H); 3.56 (dd, J=2.7 Hz, J=9.5
Hz, 1H); 3.82 (dd, J=4.8 Hz, J=9.5 Hz, 1H); 4.11 (t, J=8.3 Hz, 1H);
4.21-4.29 (m, 2H); 4.50-4.58 (m, 3H); 4.71-4.78 (m, 2H); 6.19 (dd,
J=9.1 Hz, J=16.0 Hz, 1H); 6.49 (d, J=16.0 Hz, 1H); 7.07-7.11 (m,
1H); 7.19-7.40 (m, 14H).
EXAMPLE 26
General Procedure for Hydrolysis of a Tert-Butyl Ester
[0271] A solution of tert-butyl ester derivative in formic acid,
typically 1 g in 10 mL, is stirred at ambient temperature until no
more ester is detected by thin layer chromatography
(dichloromethane 95%/methanol 5%), a typical reaction time being
around 3 hours. The formic acid is evaporated under reduced
pressure; the resulting solid residue is partitioned between
dichloromethane and saturated aqueous sodium bicarbonate. The
organic layer is evaporated to give an off-white solid that may be
used directly for further reactions, or recrystallized from an
appropriate solvent system if desired.
[0272] Examples 27-34 and 34A-34H were prepared from the
appropriate tert-butyl ester according to the procedure used in
Example 26.
EXAMPLE 27
2(R,S)-(Carboxy)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)-
azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide
[0273] Example 18 (0.30 g, 0.46 mmol) was hydrolyzed to give 0.27 g
(quantitative yield) of Example 27 as an off-white solid; .sup.1H
NMR (CDCl.sub.3) .delta. 4.17-5.28 (m, 9H); 6.21-6.29 (m, 1H),
6.68-6.82 (m, 1H); 7.05-7.75 (m, 13H); 9.12-9.18 (m, 1).
EXAMPLE 28
2(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-sty-
ryl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0274] Example 19 (1.72 g, 2.59 mmol) was hydrolyzed to give 1.57 g
(quantitative yield) of Example 28 as an off-white solid; .sup.1H
NMR (CDCl.sub.3) .delta. 2.61 (dd, J=9.3 Hz, J=16.6 Hz, 1H);
3.09-3.14 (m, 1H); 4.10-4.13 (m, 1H); 4.30 (d, J=4.5 Hz, 1H);
4.39-4.85 (m, 6H); 6.20 (dd, J=9.6 Hz, J=15.7 Hz, 1H); 6.69 (d,
J=15.8 Hz, 1H); 7.12-7.15 (m, 2H); 7.26-7.50 (m, 11H); 7.61 (s,
1H); 8.41-8.45 (m, 1H).
EXAMPLE 29
2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styr-
yl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0275] Example 20 (4.97 g, 7.34 mmol) was hydrolyzed to give 4.43 g
(97%) of Example 29 as an off-white solid; .sup.1H NMR (CDCl.sub.3)
.delta. 1.92-2.03 (m, 1H); 2.37-2.51 (m, 3H); 4.13-4.19 (m, 1H);
3.32 (d, J=4.9 Hz, 1H); 4.35-4.39 (m, 1H); 4.44 (dd, J=5.9 Hz,
J=14.9 Hz, 1H); 4.50-4.57 (m, 2H); 4.61-4.67 (m, 1H); 4.70-4.76 (m,
1H); 6.24 (dd, 3-9.6 Hz, J=15.8 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H);
7.18-7.47 (m, 14H).
EXAMPLE 30
2(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-sty-
ryl)azetidin-2-on-1-yl]acetic acid
N-[4-(2-phenylethyl)]piperazinamide
[0276] Example 21 (1.88 g, 2.78 mmol) was hydrolyzed to give 1.02 g
(60%) of Example 30 as an off-white solid; .sup.1H NMR (CDCl.sub.3)
.delta. 2.63 (dd, J=6.0 Hz, J=16.5 Hz, 1H); 2.75-2.85 (m, 1H); 3.00
(dd, J=8.2 Hz, J=16.6 Hz, 1H); 3.13-3.26 (m, 4H); 3.37-3.56 (m,
4H); 3.86-4.00 (m, 1H); 4.05-4.11 (m, 1H); 4.24 (d, J=5.0 Hz, 1H);
4.46-4.66 (m, 1H); 4.65-4.70 (m, 1H); 5.10-5.15 (m, 1H); 6.14 (dd,
J=9.3 Hz, J=15.9 Hz, 1H); 6.71 (d, J=15.9 Hz, 1H); 7.22-7.41 (m,
15H); 12.02 (s, 1H).
EXAMPLE 31
2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styr-
yl)azetidin-2-on-1-yl]acetic acid
N-[4-(2-phenylethyl)]piperazinamide
[0277] Example 22 (0.383 g, 0.55 mmol) was hydrolyzed to give 0.352
g (quantitative yield) of Example 31 as an off-white solid; .sup.1H
NMR (CDCl.sub.3) .delta. 1.93-2.01 (m, 1H); 2.07-2.36 (m, 6H);
2.82-2.90 (m, 1H); 3.00-3.20 (m, 4H); 3.36-3.54 (m, 4H); 3.74-3.82
(m, 1H); 4.06-4.11 (m, 1H); 4.29 (d, J=4.9 Hz, 1H); 4.33-4.46 (m,
2H); 4.50-4.58 (m, 2H); 4.67-4.72 (m, 1H); 4.95-5.00 (m, 1H); 6.18
(dd, J=9.2 Hz, J=16.0 Hz, 1H); 6.67 (d, J=15.9 Hz, 1H); 7.19-7.42
(m, 15H); 8.80 (brs, 1H).
EXAMPLE 32
2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-sty-
ryl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0278] Example 23 (1.51 g, 2.27 mmol) was hydrolyzed to give 1.38 g
(quantitative yield) of Example 32 as an off-white solid.
EXAMPLE 33
2(R)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styr-
yl)azetidin-2-on-L-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0279] Example 24 (0.604 g, 0.89 mmol) was hydrolyzed to give 0.554
g (quantitative yield) of Example 33 as an off-white solid.
EXAMPLE 34
2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styr-
yl)azetidin-2-on-1-yl]acetic acid
N-(4-cyclohexyl)piperazinamide
[0280] Example 25 (0.537 g, 0.80 mmol) was hydrolyzed to give 0.492
g (quantitative yield) of Example 34 as an off-white solid; .sup.1H
NMR (CDCl.sub.3) .delta. 1.09-1.17 (m, 1H); 1.22-1.33 (m, 2H);
1.40-1.47 (m, 2H); 1.63-1.67 (m, 1H); 1.85-1.90 (m, 2H); 1.95-2.00
(m, 1H); 2.05-2.15 (m, 3H); 2.20-2.24 (m, 1H); 2.30-2.36 (m, 1H);
2.85-2.93 (m, 1H); 3.25-3.33 (m, 1H); 3.36-3.46 (m, 2H); 3.81-3.87
(m, 1H); 4.08 (t, J=8.3 Hz, 1H); 4.28 (d, J=5.0 Hz, 1H); 4.33-4.56
(m, 4H); 4.70 (t, J=8.3 Hz, 1H); 4.83-4.91 (m, 1H); 6.17 (dd, J=9.1
Hz, J=15.9 Hz, 1H); 6.67 (d, J=15.9 Hz, 1H); 7.25-7.44 (m, 10H);
8.22 (brs, 1H).
EXAMPLE 34A
2(S)-(2-(4-Cyclohexylpiperazin-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxa-
zolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic
acid
[0281] Example 25A (0.787 g, 1.28 mmol) was hydrolyzed to give
0.665 g (92%) of Example 34A as an off-white solid; .sup.1H NMR
(CDCl.sub.3) .delta. 1.05-1.13 (m, 1H); 1.20-1.40 (m, 5H);
1.60-1.64 (m, 1H); 1.79-1.83 (m, 2H); 2.00-2.05 (m, 2H); 2.22-2.44
(m, 3H); 2.67-2.71 (m, 1H); 2.93-3.01 (m, 4H); 3.14-3.18 (m, 1H);
3.38-3.42 (m, 1H); 3.48-3.52 (m, 1H); 3.64-3.69 (m, 1H); 4.06-4.14
(m, 2H); 4.34-4.43 (m, 2H); 4.56 (t, J=8.8 Hz, 1H); 4.73 (t, J=8.4
Hz, 1H); 6.15 (dd, J=9.1 Hz, J=16.0 Hz, 1H); 6.65 (d, J=16.0 Hz,
1H); 7.25-7.42 (m, 10H).
EXAMPLE 34B
2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-sty-
ryl)azetidin-2-on-1-yl]acetic acid
N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide
[0282] Example 25B (0.26 g, 0.38 mmol) was hydrolyzed to give 0.238
g (quantitative yield) of Example 34B as an off-white solid;
.sup.1H NMR (CDCl.sub.3) .delta. 3.27 (d, J=7.2 Hz, 1H); 4.06 (t,
J=7.2 Hz, 1H); 4.15 (t, J=8.1 Hz, 1H); 4.27 (d, J=4.8 Hz, 1H);
4.56-4.76 (m, 5H); 6.34 (dd, J=9.5 Hz, J=15.7 Hz, 1H); 6.80 (d,
J=15.7 Hz, 1H); 7.06 (t, J=7.7 Hz, 1H); 7.31-7.54 (m, 12H); 8.58
(t, J=5.9 Hz, 1H).
EXAMPLE 34C
2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-sty-
ryl)azetidin-2-on-1-yl]acetic acid
N-[(S)-.alpha.-methylbenzyl]amide
[0283] Example 25C (0.215 g, 0.35 mmol) was hydrolyzed to give
0.195 g (quantitative yield) of Example 34C as an off-white solid;
.sup.1H NMR (CDCl.sub.3) .delta. 1.56 (d, J=7.0 Hz, 1H); 3.10 (dd,
J=4.5 Hz, J=17.9 Hz, 1H); 3.18 (dd, J=9.8 Hz, J=17.9 Hz, 1H); 4.00
(dd, J=4.5 Hz, J=9.7 Hz, 1H); 4.14 (t, J=8.2 Hz, 1H); 4.26 (d,
J=4.7 Hz, 1H); 5.02-5.09 (m, 1H); 6.41 (dd, J=9.4 Hz, J=15.8 Hz,
1H); 6.78 (d, J=15.8 Hz, 1H); 7.18 (t, J=7.3 Hz, 1H); 7.26-7.43 (m,
12H); 8.29 (d, J=8.2 Hz, 1H).
EXAMPLE 34D
2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-sty-
ryl)azetidin-2-on-1-yl]acetic acid
N-[(R)-.alpha.-methylbenzyl]amide
[0284] Example 25D (0.22 g, 0.35 mmol) was hydrolyzed to give 0.20
g (quantitative yield) of Example 34D as an off-white solid;
.sup.1H NMR (CDCl.sub.3) .delta. 1.59 (d, J=7.0 Hz, 1H); 3.25 (d,
J=7.0 Hz, 2H); 3.92 (t, J=7.3 Hz, 1H); 4.15 (t, J=8.3 Hz, 1H); 4.26
(d, J=5.0 Hz, 1H); 4.52 (dd, J=4.8 Hz, J=9.3 Hz, 1H); 4.65 (t,
J=8.8 Hz, 1H); 4.72 (t, J=8.3 Hz, 1H); 5.07-5.28 (m, 1H); 6.29 (dd,
J=9.5 Hz, J=15.6 Hz, 1H); 6.71 (d, J=16.0 Hz, 1H); 7.20-7.43 (m,
13H); 8.3.1 (d, J=8.0 Hz, 1H).
EXAMPLE 34E
2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-sty-
ryl)azetidin-2-on-1-yl]acetic acid
N-methyl-N-(3-trifluoromethylbenzyl)amide
[0285] Example 25E (0.253 g, 0.37 mmol) was hydrolyzed to give
0.232 g (quantitative yield) of Example 34E as an off-white solid;
.sup.1H NMR (CDCl.sub.3) .delta. 3.07-3.15 (m, 4H); 4.13 (t, J=8.2
Hz, 1H); 4.30 (d, J=4.9 Hz, 1H); 4.46-4.78 (m, 5H); 5.23 (dd, J=4.6
Hz, J=9.7 Hz, 1H); 6.20 (dd, J=9.4 Hz, J=15.9 Hz, 1H); 6.73 (d,
J=15.9 Hz, 1H); 7.25-7.43 (m, 15H).
EXAMPLE 34F
2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-chlo-
rostyr-2-yl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0286] Example 25F (0.707 g, 0.99 mmol) was hydrolyzed to give
0.648 g (99%) of Example 34F as an off-white solid; .sup.1H NMR
(CDCl.sub.3) .delta. 2.22-2.28 (m, 2H); 2.49-2.64 (m, 2H); 4.09 (t,
J=8.0 Hz, 1H); 4.25-4.62 (m, 6H); 4.87 (t, J=8.0 Hz, 1H); 6.88 (s,
1H); 7.25-7.66 (m, 15H).
EXAMPLE 34G
2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2'-me-
thoxystyr-2-yl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0287] Example 25G (0.268 g, 0.39 mmol) was hydrolyzed to give
0.242 g (98%) of Example 34G as an off-white solid; .sup.1H NMR
(CDCl.sub.3) .delta. 3.26, (d, J=7.1 Hz, 1H); 3.79 (s, 3H); 4.14
(t, J=8.2 Hz, 1H); 4.25 (d, J=4.5 Hz, 1H); 4.51 (dd, J=5.9 Hz,
J=15.5 Hz, 1H); 4.53-4.66 (m, 4H); 6.36 (dd, J=9.4 Hz, J=15.8 Hz,
1H); 8.88 (t, J=8.2 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.18 (d,
J=6.5 Hz, 1H); 7.25-7.48 (m, 10H); 7.48 (s, 1H); 8.66-8.69 (m,
1H).
EXAMPLE 34H
(2R)-(Benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-s-
tyryl)azetidin-2-on-1-yl]acetic acid
[0288] Example 25H (0.16 g, 0.28 mmol) was hydrolyzed to give 0.144
g (quantitative yield) of Example 34H as an off-white solid;
.sup.1H NMR (CDCl.sub.3) .delta. 3.65 (dd, J=4.0 Hz, J=9.5 Hz, 1H);
3.82 (dd, J=5.5 Hz, J=9.5 Hz, 1H); 4.11 (dd, J=7.8 Hz, J=8.8 Hz,
1H); 4.33 (s, 2H); 4.50 (d, J=5.0 Hz, 1H); 4.57 (t, J=9.0 Hz, 1H);
4.67 (dd, J=4.0 Hz, J=5.0 Hz, 1H); 4.69 (dd, J=5.0 Hz, J=9.5 Hz,
1H); 4.75 (t, J=8.0 Hz, 1H); 6.17 (dd, J=9.3 Hz, J=15.8 Hz, 1H);
6.55 (d, J=16.0 Hz, 1H); 7.09-7.12 (m, 2H); 7.19-7.42 (m, 13H).
EXAMPLE 35
2(S)-[4-(2-phenylethyl)piperazin-1-yl-carbonylethyl]-2-[3(S)-4(S)-phenylox-
azolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide
[0289] Using the procedure of Example 6, except that
N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
monohydrate was replaced with the carboxylic acid of Example 29 and
3-(trifluoromethyl)benzyl amine was replaced with
4-(2-phenylethyl)piperazine, the title compound was prepared;
.sup.1H NMR (CDCl.sub.3) .delta. 2.21-2.23 (m, 1H); 2.25-2.45 (m,
6H); 2.52-2.63 (m, 3H); 2.72-2.82 (m, 2H); 3.42-3.48 (m, 2H);
3.52-3.58 (m, 1H); 4.13-4.18 (m, 1H); 4.26 (dd, J=5.1 Hz, J=8.3 Hz,
1H); 4.29 (d, J=5.0 Hz, 1H); 4.44 (dd, J=6.0 Hz, J=15.0 Hz, 1H);
4.54 (dd, J=6.2 Hz, J=14.9 Hz, 1H); 4.61-4.68 (m, 2H); 4.70-4.75
(m, 1H); 6.27 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.73 (d, J=15.8 Hz,
1H); 7.16-7.60 (m, 19H); 8.07-8.12 (m, 1H); FAB.sup.+ (M+H).sup.+/z
794;
[0290] Elemental Analysis calculated for
C.sub.45H.sub.46F.sub.3N.sub.5O.sub.5: C, 68.08; H, 5.84; N, 8.82;
found: C, 67.94; H, 5.90; N, 8.64.
[0291] Examples 36-42 and 42A, shown in Table 6, were prepared
using the procedure of Example 6, except that
N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
monohydrate was replaced with Example 27, and
3-(trifluoromethyl)benzyl amine was replaced with the appropriate
amine; all listed Examples exhibited an .sup.1H NMR spectrum
consistent with the assigned structure. TABLE-US-00006 TABLE 6
##STR24## Example A' 36 2-(piperidin-1-yl)ethylamino 37
4-(piperidin-1-yl)piperidin-1-yl 38 4-(2-phenylethyl)piperazin-1-yl
39 1-benzylpiperidin-4-ylamino 40 4-butylpiperazin-1-yl 41
4-isopropylpiperazin-1-yl 42 4-cyclohexylpiperazin-1-yl 42A
4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl
[0292] Examples 43-86 and 86A, shown in Table 7, were prepared
using the procedure of Example 6, except that
N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
monohydrate was replaced with Example 28, and
3-(trifluoromethyl)benzyl amine was replaced with the appropriate
amine; all listed Examples exhibited an .sup.1H NMR spectrum
consistent with the assigned structure. TABLE-US-00007 TABLE 7
##STR25## Example A' 43 2-(piperidin-1-yl)ethylamino 44
4-(piperidin-1-yl)piperidin-1-yl 45 4-(phenylethyl)piperazin-1-yl
46 fur-2-ylmethylamino 47 4-(pyrrolidin-1-yl)piperazin-1-yl 48
4-(3-trifluoromethylphenyl)piperazin-1-yl 49
4-(benzyloxycarbonyl)piperazin-1-yl 50
4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl 51
4-benzylpiperazin-1-yl 52
4-(3,4-methylenedioxybenzyl)piperazin-1-yl 53
4-phenylpiperazin-1-yl 54 4-(3-phenylprop-2-enyl)piperazin-1-yl 55
4-ethylpiperazin-1-yl 56 2-(dimethylamino)ethylamino 57
4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl 58
4-(1-methylpiperidin-4-yl)piperazin-1-yl 59 4-butylpiperazin-1-yl
60 4-isopropylpiperazin-1-yl 61 4-pyridylmethylamino 62
3-(dimethylamino)propylamino 63 1-benzylpiperidin-4-ylamino 64
N-benzyl-2-(dimethylamino)ethylamino 65 3-pyridylmethylamino 66
4-(cyclohexyl)piperazin-1-yl 67 4-(2-cyclohexylethyl)piperazin-1-yl
68 4-[2-(morpholin-4-yl)ethyl]piperazin-1-yl 69
4-(4-tert-butylbenzyl)piperazin-1-yl 70
4-[2-(piperidin-1-yl)ethyl]piperazin-1-yl 71
4-[3-(piperidin-1-yl)propyl]piperazin-1-yl 72
4-[2-(N,N-dipropylamino)ethyl]piperazin-1-yl 73
4-[3-(N,N-dipropylamino)propyl]piperazin-1-yl 74
4-[2-(dimethylamino)ethyl]piperazin-1-yl 75
4-[3-(pyrrolidin-1-yl)propyl]piperazin-1-yl 76
4-(cyclohexylmethyl)piperazin-1-yl 77 4-cyclopentylpiperazin-1-yl
78 4-[2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl 79
4-[2-(thien-2-yl)ethyl]piperazin-1-yl 80
4-(3-phenylpropyl)piperazin-1-yl 81
4-[2-(N,N-diethylamino)ethyl]piperazin-1-yl 82
4-benzylhomopiperazin-1-yl 83 4-(bisphenylmethyl)piperazin-1-yl 84
3-(4-methylpiperazin-1-yl)propylamino 85
(+)-3(S)-1-benzylpyrrolidin-3-ylamino 86 2-pyridylmethylamino 86A
4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl
[0293] Examples 87-120 and 120A-120D, shown in Table 8, were
prepared using the procedure of Example 6, except that
N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
monohydrate was replaced with Example 29, and
3-(trifluoromethyl)benzyl amine was replaced with the appropriate
amine; all listed Examples exhibited an .sup.1H NMR spectrum
consistent with the assigned structure. TABLE-US-00008 TABLE 8
##STR26## Example A' 87 2-(piperidin-1-yl)ethylamino 88
4-(piperidin-1-yl)piperidin-1-yl 89 2-(pyrid-2-yl)ethylamino 90
morpholin-4-ylamino 91 4-(pyrrolidin-1-yl)piperazin-1-yl 92
4-(3-trifluorophenyl)piperazin-1-yl 93
4-(benzyloxycarboyl)piperazin-1-yl 94
4-[2-(2-hydroxylethoxy)ethyl]piperazin-1-yl 95
4-benzylpiperazin-1-yl 96
4-(3,4-methylenedioxybenzyl)piperazin-1-yl 97
4-phenylpiperazin-1-yl 98 4-(3-phenylprop-2-enyl)piperazin-1-yl 99
4-ethylpiperazin-1-yl 100 2-(dimethylamino)ethylamino 101
4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl 102
4-(1-methylpiperidin-4-yl)piperazin-1-yl 103 4-butylpiperazin-1-yl
104 4-isopropylpiperazin-1-yl 105 4-pyridylmethylamino 106
3-(dimethylamino)propylamino 107 1-benzylpiperidin-4-ylamino 108
N-benzyl-2-(dimethylamino)ethylamino 109 3-pyridylmethylamino 110
4-cyclohexylpiperazin-1-yl 111 4-(2-cyclohexylethyl)piperazin-1-yl
112 4-[2-(morpholin-4-yl)ethyl]piperazin-1-yl 113
4-(4-tert-butylbenzyl)piperazin-1-yl 114
4-[2-(piperidin-1-yl)ethyl]piperazin-1-yl 115
4-[3-(piperidin-1-yl)propyl]piperazin-1-yl 116
4-[2-(diisopropylamino)ethyl]piperazin-1-yl 117
4-[3-(diethylamino)propyl]piperazin-1-yl 118
4-(2-dimethylaminoethyl)piperazin-1-yl 119
4-[3-(pyrrolidin-1-yl)propyl]piperazin-1-yl 120
4-(cyclohexylmethyl)piperazin-1-yl 120A
4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl 120B
4-propyl-piperazin-1-yl 120C
4-[N-(isopropyl)acetamid-2-yl]piperazin-1-yl 120D
3-benzyl-hexahydro-(1 H)-1,3-diazepin-1-yl
[0294] Examples 121-132, shown in Table 9, were prepared using the
procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic
acid .beta.-t-butyl ester monohydrate was replaced with Example 30,
and 3-(trifluoromethyl)benzyl amine was replaced with the
appropriate amine; all listed Examples exhibited an .sup.1H NMR
spectrum consistent with the assigned structure. TABLE-US-00009
TABLE 9 ##STR27## Example A' 121 3-trifluoromethylbenzylamino 122
morpholin-4-ylamino 123 2-(dimethylamino)ethylamino 124
3-(dimethylamino)propylamino 125 cyclohexylamino 126 piperidin-1-yl
127 2-methoxyethylamino 128 isopropylamino 129 isobutylamino 130
ethylamino 131 dimethylamino 132 methylamino
[0295] Examples 133-134 and 134A-134F, shown in Table 10, were
prepared using the procedure of Example 6, except that
N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl ester
monohydrate was replaced with Example 32, and
3-(trifluoromethyl)benzyl amine was replaced with the appropriate
amine; all listed Examples exhibited an .sup.1H NMR spectrum
consistent with the assigned structure. TABLE-US-00010 TABLE 10
##STR28## Example A' 133 4-(piperidin-1-yl)piperidin-1-yl 134
4-(2-phenylethyl)piperazin-1-yl 134A
4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl 134B
4--(pyrrolidin-1-yl)piperazin-1-yl 134C 1-benzylpiperidin-4-ylamino
134D (pyridin-3-ylmethyl)amino 134E 3-(dimethylamino)propylamino
134F 3-(S)-(1-benzylpyrrolidin-3-yl)amino
[0296] Examples 135-140, shown in Table 11, were prepared using the
procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic
acid .beta.-t-butyl ester monohydrate was replaced with Example 33,
and 3-(trifluoromethyl)benzyl amine was replaced with the
appropriate amine; all listed Examples exhibited an .sup.1H NMR
spectrum consistent with the assigned structure. TABLE-US-00011
TABLE 11 ##STR29## Example A' 135 4(piperidin-1-yl)piperidin-1-yl
136 4-(2-phenylethyl)piperazin-1-yl 137 4-butylpiperazin-1-yl 138
4-isopropylpiperazin-1-yl 139 4-cyclohexylpiperazin-1-yl 140
4-(cyclohexylmethyl)piperazin-1-yl
[0297] Examples 141-171, shown in Table 12, were prepared using the
procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic
acid .beta.-t-butyl ester monohydrate was replaced with Example 34,
and 3-(trifluoromethyl)benzyl amine was replaced with the
appropriate amine; all listed Examples exhibited an .sup.1H NMR
spectrum consistent with the assigned structure. TABLE-US-00012
TABLE 12 ##STR30## Example A' 141 benzylamino 142
(2-methylbenzyl)amino 143 (3-methylbenzyl)amino 144
(4-methylbenzyl)amino 145 (.alpha.-methylbenzyl)amino 146
N-benzyl-N-methylamino 147 N-benzyl-N-(t-butyl)amino 148
N-benzyl-N-butylamino 149 (3,5-dimethylbenzyl)amino 150
(2-phenylethyl)amino 151 dimethylamino 152
(3-trifluoromethoxybenzyl)amino 153 (3,4-dichlorobenzyl)amino 154
(3,5-dichlorobenzyl)amino 155 (2,5-dichlorobenzyl)amino 156
(2,3-dichlorobenzyl)amino 157
(2-fluoro-5-trifluoromethylbenzyl)amino 158
(4-fluoro-3-trifluoromethylbenzyl)amino 159
(3-fluoro-5-trifluoromethylbenzyl)amino 160
(2-fluoro-3-trifluoromethylbenzyl)amino 161
(4-chloro-3-trifluoromethylbenzyl)amino 162 indan-1-ylamino 163
4-(2-hydroxybenzimidazol-1-yl)-piperidin-1-yl 164
3(S)-(tert-butylaminocarbonyl)- 1,2,3,4-tetrahydroisoquinolin-2-yl
165 (3,3-dimethylbutyl)amino 166 4-hydroxy-4-phenylpiperidin-1-yl
167 (cyclohexylmethyl)amino 168 (2-phenoxyethyl)amino 169
3,4-methylenedioxybenzylamino 170 4-benzylpiperidin-1-yl 171
(3-trifluoromethylphenyl)amino
[0298] Examples 172-221, shown in Table 13, were prepared using the
procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic
acid .beta.-t-butyl ester monohydrate was replaced with Example
34A, and 3-(trifluoromethyl)benzyl amine was replaced with the
appropriate amine; all listed Examples exhibited an .sup.1H NMR
spectrum consistent with the assigned structure. TABLE-US-00013
TABLE 13 ##STR31## Example A 172 (3-trifluoromethoxybenzyl)amino
173 (3,4-dichlorobenzyl)amino 174 (3,5-dichlorobenzyl)amino 175
(2,5-dichlorobenzyl)amino 176 (2,3-dichlorobenzyl)amino 177
(2-fluoro-5-trifluoromethylbenzyl)amino 178
(4-fluoro-3-trifluoromethylbenzyl)amino 179
(3-fluoro-5-trifluoromethylbenzyl)amino 180
(2-fluoro-3-trifluoromethylbenzyl)amino 181
(4-chloro-3-trifluoromethylbenzyl)amino 182
(2-trifluoromethylbenzyl)amino 183 (3-methoxybenzyl)amino 184
(3-fluorobenzyl)amino 185 (3,5-difluorobenzyl)amino 186
(3-chloro-4-fluorobenzyl)amino 187 (3-chlorobenzyl)amino 188
[3,5-bis(trifluoromethyl)benzyl]amino 189 (3-nitrobenzyl)amino 190
(3-bromobenzyl)amino 191 benzylamino 192 (2-methylbenzyl)amino 193
(3-methylbenzyl)amino 194 (4-methylbenzyl)amino 195
(.alpha.-methylbenzyl)amino 196 (N-methylbenzyl)amino 197
(N-tert-butylbenzyl)amino 198 (N-butylbenzyl)amino 199
(3,5-dimethylbenzyl)amino 200 (2-phenylethyl)amino 201
(3,5-dimethoxybenzyl)amino 202 (1R)-(3-methoxyphenyl)ethylamino 203
(1S)-(3-methoxyphenyl)ethylamino 204
(.alpha.,.alpha.-dimethylbenzyl)amino 205
N-methyl-N-(3-trifluoromethylbenzyl)amino 206
[(S)-.alpha.-methylbenzyl]amino 207 (1-phenylcycloprop-1-yl)amino
208 (pyridin-2-ylmethyl)amino 209 (pyridin-3-ylmethyl)amino 210
(pyridin-4-ylmethyl)amino 211 (fur-2-ylmethyl)amino 212
[(5-methylfur-2-yl)methyl]amino 213 (thien-2-ylmethyl)amino 214
[(S)-1,2,3,4-tetrahydro-1-naphth-1-yl]amino 215
[(R)-1,2,3,4-tetrahydro-1-naphth-1-yl]amino 216 (indan-1-yl)amino
217 (1-phenylcyclopent-1-yl)amino 218
(.alpha.,.alpha.-dimethyl-3,5-dimethoxybenzyl)amino 219
(2,5-dimethoxybenzyl)amino 220 (2-methoxybenzyl)amino 221
(.alpha.,.alpha.,2-trimethylbenzyl)amino
EXAMPLE 222
2(R)-[[4-(Piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-phen-
yloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic
acid N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide
[0299] Example 222 was prepared using the procedure of Example 6,
except that N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl
ester monohydrate was replaced with Example 34B, and
3-(trifluoromethyl)benzyl amine was replaced with
4-(piperidin-1-yl)piperidine; Example 222 exhibited an .sup.1H NMR
spectrum consistent with the assigned structure.
EXAMPLE 223
2(R)-[[4-(Piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-phen-
yloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic
acid N--[(S)-'-methylbenzyl]amide
[0300] Example 223 was prepared using the procedure of Example 6,
except that N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl
ester monohydrate was replaced with Example 34C, and
3-(trifluoromethyl)benzyl amine was replaced with
4-(piperidin-1-yl)piperidine; Example 223 exhibited an .sup.1H NMR
spectrum consistent with the assigned structure.
EXAMPLE 224
2(R)-[[4-(Piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-phen-
yloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic
acid N-[(R)-.alpha.-methylbenzyl]amide
[0301] Example 224 was prepared using the procedure of Example 6,
except that N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl
ester monohydrate was replaced with Example 34D, and
3-(trifluoromethyl)benzyl amine was replaced with
4-(piperidin-1-yl)piperidine; Example 223 exhibited an .sup.1H NMR
spectrum consistent with the assigned structure.
EXAMPLE 225
2(R)-[[4-piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-pheny-
loxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic
acid N-methyl-N-(3-trifluoromethylbenzyl)amide
[0302] Example 225 was prepared using the procedure of Example 6,
except that N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl
ester monohydrate was replaced with Example 34E, and
3-(trifluoromethyl)benzyl amine was replaced with
4-(piperidin-1-yl)piperidine; Example 223 exhibited an .sup.1H NMR
spectrum consistent with the assigned structure.
[0303] Examples 226-230, shown in Table 14, were prepared using the
procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic
acid .beta.-t-butyl ester monohydrate was replaced with Example
34F, and 3-(trifluoromethyl)benzyl amine was replaced with the
appropriate amine; all listed Examples exhibited an .sup.1H NMR
spectrum consistent with the assigned structure. TABLE-US-00014
TABLE 14 ##STR32## Example A' 226 4-cyclohexylpiperazin-1-yl 227
4-(pyrrolidin-1-yl)piperazin-1-yl 228 4-ethylpiperazin-1-yl 229
4-n-butylpiperazin-1-yl 230 4-isopropylpiperazin-1-yl
EXAMPLE 231
2(R)-[[4-(Piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-phen-
yloxazolidin-2-on-3-yl)-4(R)-(2'-methoxystyr-2-yl)azetidin-2-on-1-yl]aceti-
c acid N-(3-trifluoromethylbenzyl)amide
[0304] Example 231 was prepared using the procedure of Example 6,
except that N-benzyloxycarbonyl-D-aspartic acid .beta.-t-butyl
ester monohydrate was replaced with Example 34G, and
3-(trifluoromethyl)benzyl amine was replaced with
4-(piperidin-1-yl)piperidine; Example 231 exhibited an .sup.1H NMR
spectrum consistent with the assigned structure.
[0305] Examples 232-233, shown in Table 15, were prepared using the
procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic
acid .beta.-t-butyl ester monohydrate was replaced with Example
34H, and 3-(trifluoromethyl)benzyl amine was replaced with the
appropriate amine; all listed Examples exhibited an .sup.1H NMR
spectrum consistent with the assigned structure. TABLE-US-00015
TABLE 15 ##STR33## Example A' 232 4-(piperidin-1-yl)piperidin-1-yl
233 4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl
EXAMPLE 234
(2RS)-[4-piperidin-1-yl)piperidin-1-ylcarbonyl]-2-methyl-2-[3(S)-(4(S)-phe-
nyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic
acid N-(3-trifluoromethylbenzyl)amide
[0306] ##STR34##
[0307] Example 37 (50 mg, 0.067 mmol) in tetrahydrofuran (4 mL) was
treated sequentially with sodium hydride (4 mg, 0.168 mmol) and
methyl iodide (6 .mu.L, 0.094 mmol) at -78.degree. C. The resulting
mixture was slowly warmed to ambient temperature, and evaporated.
The resulting residue was partitioned between dichloromethane and
water, and the organic layer was evaporated. The resulting residue
was purified by silica gel chromatography (95:5
chloroform/methanol) to give 28 mg (55%) of the title compound as
an off-white solid; MS (ES.sup.+): m/z=757 (M.sup.+).
EXAMPLE 235
2(S)-[[(1-Benzylpiperidin-4-yl)amino]carbonylmethyl]-2-[3(S)-(4(S)-phenylo-
xazolidin-2-on-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-on-1-yl]acetic
acid N-(3-trifluoromethylbenzyl)amide
[0308] Example 235 was prepared using the procedure of Example 8,
except that N-benzyloxycarbonyl-L-aspartic acid .beta.-t-butyl
ester .alpha.-(3-trifluoromethyl)benzylamide was replaced with
Example 63 (50 mg, 0.064 mmol) to give 40 mg (80%) of Example 235
as an off-white solid; Example 235 exhibited an .sup.1H NMR
spectrum consistent with the assigned structure.
EXAMPLE 236
(2S)-[(4-cyclohexylpiperazin-1-yl)carbonylethyl]-2-[3(S)-(4(S)-phenyloxazo-
lidin-2-on-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-on-1-yl]acetic
acid N-(3-trifluoromethylbenzyl)amide
[0309] Example 236 was prepared using the procedure of Example 8,
except that N-benzyloxycarbonyl-L-aspartic acid .beta.-t-butyl
ester .alpha.-(3-trifluoromethyl)benzylamide was replaced with
Example 110 (50 mg, 0.065 mmol) to give 42 mg (84%) of Example 236
as an off-white solid; Example 236 exhibited an .sup.1H NMR
spectrum consistent with the assigned structure.
[0310] Table 16 illustrates compounds further characterized by mass
spectral analysis using FAB.sup.+ to observe the corresponding
(M+H).sup.+ parent ion. TABLE-US-00016 TABLE 16 Example (m +
H).sup.+/z 37 744 38 766 39 766 40 718 41 704 42 744 42A 772 44 758
63 780 85 766 86A 786 88 772 91 759 95 780 96 824 104 732 110 772
111 800 112 803 120 786 120A 800 120B 732 133 758 134A 786 134C 780
136 794 137 746 138 732 139 772 174 772 175 772 176 772 177 790 179
790 180 790 182 772 183 734 184 722 185 740 186 756 187 738 188 840
189 749 190 782 191 704 192 718 193 718 199 732 200 718 201 764 202
748 203 748 205 786 206 718 207 730 208 705 209 705 210 705 211 694
212 708 213 710 214 744 215 744 216 7530 217 758 218 792 219 764
220 734 221 746 222 776 224 704 225 772 226 806 227 792 228 752 229
780 230 766 231 788 232 663 233 691 234 758 235 782 236 774
METHOD EXAMPLE 1
Human Vasopression V.sub.1a Receptor Binding Assay
[0311] A cell line expressing the human V.sub.1a receptor in CHO
cells (henceforth referred to as the hV.sub.1a cell line) was
obtained from Dr. Michael Brownstein, NIMH, Bethesda, Md., USA. The
hV.sub.1a cDNA sequence is described by Thibonnier et al., Journal
of Biological Chemistry, 269, 3304-3310 (1994), and the expression
method was the same as described by Morel et al. (1992). The
hV.sub.1a cell line was grown in alpha-MEM with 10% fetal bovine
serum and 250 ug/ml G418 (Gibco, Grand Island, N.Y., USA). For
competitive binding assay, hV.sub.1a cells were plated into 6-well
culture plate at 1:10 dilution from a confluency flask, and
maintained in culture for at least two days. Culture medium was
then removed, cells were washed with 2 ml binding buffer (25 mM
Hepes, 0.25% BSA, 1.times.DMEM, PH=7.0). To each well, 990 .mu.l
binding buffer containing 1 nM 3H-AVP was added, and followed by 10
.mu.l series diluted Example compounds dissolved in DMSO. All
incubations were in triplicate, and dose-inhibition curves
consisted of total binding (DMSO) and 5 concentrations (0.1, 1.0,
10, 100, and 1000 nM) of test agents encompassing the IC.sub.50.
100 nM cold AVP (Sigma) was used to assess non-specific binding.
Cells were incubated for 45 minutes at 37.degree. C., assay mixture
was removed and each well was washed three times with PBS (pH=7.4).
1 ml 2% SDS was added per well and plates were let sit for 30
minutes. The whole content in a well was transferred to a
scintillation vial. Each well was rinsed with 0.5 ml PBS which was
then added to the corresponding vial. Scintillation fluid
(Ecoscint, National Diagnostics, Atlanta, Ga.) was then added at 3
ml per vial. Samples were counted in a liquid scintillation counter
(Beckman LS3801). IC.sub.50 values were calculated by Prism Curve
fitting software.
[0312] All of the alkanedioic esters and amides exemplified in the
foregoing examples were tested in this assay described of Example
201. Binding affinities for certain of the preferred compounds are
summarized in the Table 17. TABLE-US-00017 TABLE 17 V.sub.1a
BINDING AFFINITY Example (IC.sub.50 (nM)) 18 35 19 35 20 35 35 1.9
37 5.5 38 <25 39 23 40 11 41 <20 42 <20 44 3.1 47
.about.50 59 <100 63 1.84 66 .about.50 77 <100 78 <100 81
<100 82 <50 85 5.87 87 15 88 2.4 91 3.24 95 1.76 96 4.35 100
<100 101 .about.100 102 <100 103 0.81 104 1.85 106 .about.100
107 <50 108 .about.100 109 .about.100 110 0.49 111 1.31 112 1.34
120 0.75 133 2.43 135 .about.50 136 11 137 17 138 21 139 9.5
METHOD EXAMPLE 2
Inhibition of Phosphatidylinositol Turnover
[0313] The physiological effects of vasopressin are mediated
through specific G-protein coupled receptors. The vasopressin
V.sub.1a receptor is coupled to the G.sub.q/G.sub.11 family of G
proteins and mediates phosphatidylinositol turnover. The agonist or
antagonist character of the compounds of the invention may be
determined by their ability to inhibit vasopressin-mediated
turnover of phosphatidylinositol by the procedure described in the
following paragraphs. Representative compounds of the intention,
the compounds of Examples 35, 44, 88, 110, and 133, were tested in
this assay and found to be vasopressin V.sub.1a antagonists.
Cell Culture and Labeling of Cells
[0314] Three days prior to the assay, near-confluent cultures of
hV.sub.1a cells were dissociated and seeded in 6-well tissue
culture plates, about 100 wells being seeded from each 75 cm.sup.2
flask (equivalent to 12:1 split ratio). Each well contained 1 mL of
growth medium with 2 .mu.Ci of [.sup.3H]myo-inositol (American
Radiolabeled Chemicals, St. Louis, Mo., USA).
Incubations
[0315] All assays were in triplicate except for basal and 10 nM AVP
(both n=6). AVP ((arginine vasopressin), Peninsula Labs, Belmont,
Calif., USA (#8103)) was dissolved in 0.1N acetic acid. Test agents
were dissolved in DMSO and diluted in DMSO to 200 times the final
test concentration. Test agents and AVP (or corresponding volumes
of DMSO) were added separately as 5 mL in DMSO to 12.times.75 mm
glass tubes containing 1 mL of assay buffer (Tyrode's balanced salt
solution containing 50 mM glucose, 10 mM LiCl, 15 mM HEPES pH 7.4,
10 .mu.M phosphoramidon, and 100 .mu.M bacitracin). The order of
incubations was randomized. Incubations were initiated by removing
the prelabeling medium, washing the monolayer once with 1 mL of
0.9% NaCl, and transferring the contents of the assay tubes to
corresponding wells. The plates were incubated for 1 hour at
37.degree. C. Incubations were terminated by removing the
incubation medium and adding 500 .mu.L of ice cold 5% (w/v)
trichloroacetic acid and allowing the wells to stand for 15
min.
Measurement of [.sup.3H]Inositol Phosphates
[0316] BioRad Poly-Prep Econo-Columns were packed with 0.3 mL of AG
1 X-8 100-200 formate form resin. Resin was mixed 1:1 with water
and 0.6 mL added to each column. Columns were then washed with 10
mL water. Scintillation vials (20 mL) were placed under each
column. For each well, the contents were transferred to a
minicolumn, after which the well was washed with 0.5 mL distilled
water, which was also added to the minicolumn. The columns were
then washed twice with 5 mL of 5 mM myo-inositol to elute free
inositol. Aliquots (1 mL) were transferred to 20 mL scintillation
vials and 10 mL of Beckman Ready Protein Plus added. After the
myo-inositol wash was complete, empty scintillation vials were
placed under the columns, and [.sup.3H]inositol phosphates were
eluted with three additions of 1 mL 0.5 M ammonium formate
containing 0.1 N formic acid. Elution conditions were optimized to
recover inositol mono-, bis-, and trisphosphates, without eluting
the more metabolically inert tetrakis-, pentakis-, and
hexakis-phosphates. To each sample was added 10 mL of a high salt
capacity scintillation fluid such as Tru-Count High Salt Capacity
or Packard Hionic-Fluor. Inositol lipids were measured by adding 1
mL of 2% sodium dodecyl sulfate (SDS) to each well, allowing the
wells to stand for at least 30 min., and transferring the solution
to 20 mL scintillation vials, to which 10 mL Beckman Ready Protein
Plus scintillation fluid was then added. Samples were counted in a
Beckman LS 3801 liquid scintillation counter for 10 min. Total
inositol incorporation for each well was calculated as the sum of
free inositol, inositol phosphates, and inositol lipids.
Data Analysis: Concentration-Inhibition Experiments
[0317] Concentration-response curves for AVP and
concentration-inhibition curves for test agents versus 10 nM AVP
were analyzed by nonlinear least-squares curve-fitting to a
4-parameter logistic function. Parameters for basal and maximal
inositol phosphates, EC.sub.50 or IC.sub.50, and Hill coefficient
were varied to achieve the best fit. The curve-fitting was weighted
under the assumption that the standard deviation was proportional
to dpm of radioactivity. Full concentration-response curves for AVP
were run in each experiment, and IC.sub.50 values were converted to
K; values by application of the Cheng-Prusoff equation, based on
the EC.sub.50 for AVP in the same experiment. Inositol phosphates
were expressed as dpm per 10.sup.6 dpm of total inositol
incorporation.
Data Analysis: Competitivity Experiments
[0318] Experiments to test for competitivity of test agents
consisted of concentration-response curves for AVP in the absence
and presence of two or more concentrations of test agent. Data were
fit to a competitive logistic equation Y = B + M .times. { A / [ E
+ ( D / K ) ] } Q 1 + { A / [ E + ( D / K ) ] } Q ##EQU1## where Y
is dpm of inositol phosphates, B is concentration of basal inositol
phosphates, M is the maximal increase in concentration of inositol
phosphates, A is the concentration of agonist (AVP), E is the
EC.sub.50 for agonist, D is the concentration of antagonist (test
agent), K is the K.sub.i for antagonist, and Q is the cooperativity
(Hill coefficient).
[0319] Vasopressin V.sub.1a receptors are also known to mediate
platelet aggregation. Vasopressin V.sub.1a receptor agonists cause
platelet aggregation, while vasopressin V.sub.1a receptor
antagonists inhibit the platelet aggregation precipitated by
vasopressin or vasopressin V.sub.1a agonists. The degree of
antagonist activity of the compounds of the invention may be
determined by the assay described in the following paragraphs.
[0320] Blood from healthy, human volunteers was collected by
venipuncture and mixed with heparin (60 mL of blood added to 0.4 mL
of heparanized saline solution (4 mg heparin/mL saline)).
Platelet-rich plasma (PRP) was prepared by centrifuging whole blood
(150.times.g), and indomethacin (3 .mu.M) was added to PRP to block
the thromboxane-mediated release reaction. PRP was continuously
stirred at 37.degree. C. and change in optical density was followed
after the addition of arginine vasopressin (AVP) (30 nM) to
initiate aggregation. Compounds were dissolved in 50%
dimethylsulfoxide (DMSO) and added (10 .mu.L/415 .mu.L PRP) before
the addition of AVP. The percent inhibition of AVP-induced
aggregation was measured and an IC.sub.50 calculated.
[0321] In studies using washed platelets, 50 mL of whole blood was
mixed with 10 mL of citrate/heparin solution (85 mM sodium citrate,
64 mM citric acid, 1111 mM glucose, 5 units/mL heparin) and PRP
isolated as described above. PRP was then centrifuged (150.times.g)
and the pellet resuspended in a physiologic buffer solution (10 mM
HEPES, 135 mM sodium chloride, 5 mM potassium chloride, and 1 mM
magnesium chloride) containing 10 .mu.M indomethicin. Human
fibrinogen (0.2 mg/mL) and calcium chloride (1 mM) were added to
stirred platelets before initiating aggregation with AVP (30 nM) as
previously described.
[0322] The activity of compounds of formula I in the antagonism of
the vasopressin V.sub.1a receptor provides a method of antagonizing
the vasopressin V.sub.1a receptor comprising administering to a
subject in need of such treatment an effective amount of a compound
of that formula. It is known that numerous physiological and
therapeutic benefits are obtained through the administration of
drugs that antagonize the vasopressin V.sub.1a receptor. These
activities may be catagorized as peripheral and central. Peripheral
utilities include administration of vasopressin V.sub.1a
antagonists of formula I as adjuncts in heart failure or as
antithrombotic agents. Central effects include administration of
vasopressin V.sub.1a antagonists of formula I in the treatment of
obsessive-compulsive disorder, aggressive disorders, depression and
anxiety.
[0323] Obsessive-compulsive disease appears in a great variety of
degrees and symptoms, generally linked by the victim's
uncontrollable urge to perform heedless, ritualistic acts. Acts of
acquiring, ordering, cleansing and the like, beyond any rational
need or rationale, are the outward characteristic of the disease. A
badly afflicted subject may be unable to do anything but carry out
the rituals required by the disease. Obsessive-compulsive disease,
in all its variations, is a preferred target of treatment with the
present adjunctive therapy method and compositions. The utility of
the compounds of Formula I in the treatment of obsessive-compulsive
disorder was demonstrated as described in the following assay.
[0324] In golden hamsters, a particular stereotypy, flank marking
behavior, can be induced by microinjections of vasopressin (10-100
nL, 1-100 .mu.M) into the anterior hypothalamus (Ferris et al.,
Science, 224, 521-523 (1984); Albers and Ferris, Regulatory
Peptides, 12, 257-260 (1985); Ferris et al., European Journal of
Pharmacology, 154, 153-159 (1988)). Following the releasing
stimulus, the behavior is initiated by grooming, licking and
combing of the large sebaceous glands on the dorsolateral flanks.
Bouts of flank gland grooming may be so intense that the flank
region is left matted and soaked in saliva. After grooming, the
hamsters display flank marking behavior, a type of scent marking
involved in olfactory communication (Johnston, Physio. Behav., 51,
437-448 (1985); Ferris et al., Physio. Behav., 40, 661-664 (1987)),
by arching the back and rubbing the flank glands vigorously against
any vertical surface. Vasopressin-induced flank marking is usually
induced within a minute after the microinjection (Ferris et al.,
Science, 224, 521-523 (1984)). The behavior is specific to
vasopressin, as micro-injections of other neuropeptides, excitatory
amino acids, and catecholamines do not elicit flank marking (Ferris
et al., Science, 224, 521-523 (1984); Albers and Ferris, Regulatory
Peptides, 12, 257-260 (1985)). Furthermore, flank marking is
specific to the vasopressin V.sub.1 receptor, as the behavior is
selectively inhibited by V.sub.1 receptor antagonists and activated
by V.sub.1 receptor agonists (Ferris et al., Neuroscience Letters,
55, 239-243 (1985); Albers et al., Journal of Neuroscience, 6,
2085-2089 (1986); Ferris et al., European Journal of Pharmacology,
154, 153-159 (1988)).
[0325] All animals were adult male golden hamsters (Mesocricetus
auratus) weighing approximately 160 gm. The animals underwent
stereotaxic surgery, and were allowed to recover before behavioral
testing. The hamsters were kept on a reverse light cycle (14 hr
light, 10 hr dark, lights on at 19:00) in Plexiglas.TM. cages, and
received food and water ad libitum.
[0326] Stereotaxic surgery was performed under pentobarbital
anesthesia. The stereotaxic coordinates were: 1.1 mm anterior to
the bregma, 1.8 mm lateral to the midsagittal suture at an
8.degree. angle from the vertical line, and 4.5 mm below the dura.
The nose bar was placed at the level of the interaural line. An
unilateral 26-gauge guide cannula was lowered to the site and
secured to the skull with dental cement. The guide cannulae were
closed with a 33-gauge obturator extending 1 mm beyond the guide.
The innercanulae used for the microinjections extended 3.0 mm
beyond the guide to reach the anterior hypothalamus.
[0327] The hamsters were microinjected with 1 .mu.M vasopressin in
a volume of 150 nL. The vasopressin was given as a cocktail with
200 mM, 20 mM, 2 mM of the test compound or alone, in the vehicle,
dimethylsulfoxide. Both the vasopressin and the test compound were
dissolved in 100% dimethylsulfoxide. All injections were aimed at
the anterior hypothalamus. Animals were scored for flank marking
for a period of 10 minutes in a clean cage.
[0328] Another aspect of this invention is the use of compounds of
formula I in combination with a serotonin reuptake inhibitor for
use in the treatment of obsessive-compulsive disease, aggressive
disorder, or depression. Compounds useful as serotonin reuptake
inhibitors include but are not limited to:
[0329] Fluoxetine,
N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, is
marketed in the hydrochloride salt form, and as the racemic mixture
of its two enantiomers. U.S. Pat. No. 4,314,081 is an early
reference on the compound. Robertson et al., J. Med. Chem., 31,
1412 (1988), taught the separation of the R and S enantiomers of
fluoxetine and showed that their activity as serotonin uptake
inhibitors is similar to each other. In this document, the word
"fluoxetine" will be used to mean any acid addition salt or the
free base, and to include either the racemic mixture or either of
the R and S enantiomers;
[0330] Duloxetine,
N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, is usually
administered as the hydrochloride salt and as the (+) enantiomer.
It was first taught by U.S. Pat. No. 4,956,388, which shows its
high potency. The word "duloxetine" will be used here to refer to
any acid addition salt or the free base of the molecule;
[0331] Venlafaxine is known in the literature, and its method of
synthesis and its activity as an inhibitor of serotonin and
norepinephrine uptake are taught by U.S. Pat. No. 4,761,501.
Venlafaxine is identified as compound A in that patent;
[0332] Milnacipran
(N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide) is
taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as
its Example 4. The patent describes its compounds as
antidepressants. Moret et al., Neuropharmacology, 24, 1211-19
(1985), describe its pharmacological activities as an inhibitor of
serotonin and norepinephrine reuptake;
[0333] Citalopram,
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
ncarbonitrile, is disclosed in U.S. Pat. No. 4,136,193 as a
serotonin reuptake inhibitor. Its pharmacology was disclosed by
Christensen et al., Eur. J. Pharmacol., 41, 153 (1977), and reports
of its clinical effectiveness in depression may be found in Dufour
et al., Int. Clin. Psychopharmacol., 2, 225 (1987), and Timmerman
et al., ibid., 239;
[0334] Fluvoxamine,
5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone
O-(2-aminoethyl)oxime, is taught by U.S. Pat. No. 4,085,225.
Scientific articles about the drug have been published by Claassen
et al., Brit. J. Pharmacol., 60, 505 (1977); and De Wilde et al.,
J. Affective Disord., 4, 249 (1982); and Benfield et al., Drugs,
32, 313 (1986);
[0335] Paroxetine,
trans-(-)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidin-
e, may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Reports
of the drug's activity are in Lassen, Eur. J. Pharmacol., 47, 351
(1978); Hassan et al., Brit. J. Clin. Pharmacol., 19, 705 (1985);
Laursen et al., Acta Psychiat. Scand., 71, 249 (1985); and Battegay
et al., Neuropsychobiology, 13, 31 (1985); and
[0336] Sertraline,
(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylami-
ne hydrochloride, a serotonin reuptake inhibitor disclosed in U.S.
Pat. No. 4,536,518, is marketed as an antidepressant.
[0337] All of the above-referenced patents are hereby incorporated
by reference.
[0338] The adjunctive therapy of this aspect of the present
invention is carried out by administering a vasopressin V.sub.1a
antagonist together with a serotonin reuptake inhibitor in any
manner that provides effective levels of the compounds in the body
at the same time. All of the compounds concerned are orally
available and are normally administered orally, and so oral
administration of the adjunctive combination is preferred. They may
be administered together, in a single dosage form, or may be
administered separately.
[0339] This aspect of the present invention provides a potentiation
of the decrease in the concentration of vasopressin observed as an
effect of administration of a vasopressin V.sub.1a antagonist by
administration of a serotonin reuptake inhibitor. This aspect of
the present invention is particularly suited for use in the
treatment of depression and obsessive compulsive disorder. Such
disorders may often be resistant to treatment with a serotonin
reuptake inhibitor alone.
METHOD EXAMPLE 3
Human Oxytocin Binding and Functional Assay
[0340] Compounds of the present invention are believed to be
oxytocin agents. Oxytocin preparations and a number of oxytocin
agonists are commercially available for therapeutic use. In recent
years, oxytocin antagonists with antiuterotonic activity have been
developed and evaluated for their potential use in the treatment of
preterm labor and dysmenorrhyea (Pavo et al., J. Med. Chem., 37,
255-259 (1994); Akerlund et al., Br. J. Obstet. Gynaecol., 94,
1040-1044 (1987); Akerlund et al., Br. J. Obstet. Gynaecol., 86,
484-487 (1979)). The oxytocin antagonist atosiban has been studied
clinically and resulted in a more significant inhibition of preterm
contractions than did placebo (Goodwin et al., Am. J. Obstet.
Gynecol., 170, 474 (1994)).
[0341] The human oxytocin receptor has been cloned and expressed
(Kimura et al., Nature, 356, 526-529 (1992)), it is identified
under the accession number X64878. To demonstrate the affinity of
the compounds of the present invention for the human oxytocin
receptor, binding studies were performed using a cell line
expressing the human oxytocin receptor in 293 cells (henceforth
referred to as the OTR cell line) substantially by the procedure
described by Morel et al. (Nature, 356, 523-526 (1992)). The 293
cell line is a permanent line of primary human embryonal kidney
cells transformed by sheared human adenovirus type 5 DNA. It is
identified as ATCC CRL-1533.
[0342] The OTR cell line was grown in DMEM (Delbecco's Modified
Essential Medium, Sigma, St. Louis, Mo., USA) with 10% fetal bovine
serum, 2 mM L-glutamine, 200 .mu.g hygromycin (Sigma, St. Louis,
Mo., USA) and 250 .mu.g/ml G418 (Gibco, Grand Island, N.Y., USA).
To prepare membranes, OTR cells were grown to confluency in 20
roller bottles. Cells were dissociated with enzyme-free cell
dissociation medium (Specialty Media, Lavallette, N.J., USA) and
centrifuged at 3200 rpm for 15 minutes. The pellet was resuspended
in 40 mL of Tris-HCl (tris[hydroxymethyl]aminomethane
hydro-chloride) buffer (50 mM, pH 7.4) and homogenized for 1 minute
with a Tekmar Tissumizer (Cincinnatti, Ohio USA). The suspension
was centrifuged at 40,000.times.g for 10 minutes. The pellet was
resuspended and centrifuged as above. The final pellet was
suspended in 80 mL of Tris 7.4 buffer and stored in 4 mL aliquots
at -80.degree. C. For assay, aliquots were resuspended in assay
buffer and diluted to 375 .mu.g protein per mL. Protein
concentration was determined by BCA assay (Pierce, Rockford, Ill.,
USA).
[0343] Assay buffer was 50 mM Tris-HCl
(tris[hydroxymethyl]aminomethane hydrochloride), 5 mM MgCl.sub.2,
and 0.1% bovine serum albumin at pH 7.4. The radioligand for
binding assays was [.sup.3H]oxytocin
([tyrosyl-2,6-.sup.3H]oxytocin, 48.5 Ci/mmol, DuPont NEN, Boston,
Mass., USA). The order of additions was 195 .mu.L assay buffer, 200
.mu.L OTR membranes (75 .mu.g protein) in assay buffer, 5 .mu.L of
test agent in dimethylsulfoxide (DMSO) or DMSO alone, and 100 .mu.L
[.sup.3H]oxytocin in assay buffer (final concentration 1.0 nM).
Incubations were for one hour at room temperature. Bound
radioligand was separated from free by filtration on a Brandel cell
harvester (Gaithersburg, Md., USA) through Whatman GF/B glass-fiber
filters that had been soaked for 2 hours in 0.3% polyethylenimine.
The filters were washed with ice-cold 50 mM Tris-HCl (pH 7.7 at
25.degree. C.) and the filter circles were placed in scintillation
vials, to which were then added 5 mL Ready Protein Plus.TM.
scintillation fluid, and counted in a liquid scintillation counter.
All incubations were in triplicate, and dose-inhibition curves
consisted of total binding, nonspecific binding (100 .mu.M
oxytocin, Sigma, St. Louis, Mo., USA), and 6 or 7 concentrations of
test agent encompassing the IC.sub.50. Total binding was typically
about 1,000 cpm and nonspecific binding about 200 cpm. IC.sub.50
values were calculated by nonlinear least-squares curve-fitting to
a 4-parameter logistic model. Certain compounds of formula I have
shown affinity for the oxytocin receptor.
[0344] Several bioassays are available to determine the agonist or
antagonist character of compounds exhibiting affinity at the
oxytocin receptor. One such assay is described in U.S. Pat. No.
5,373,089, hereby incorporated by reference. Said bioassay is
derived from procedures described in a paper by Sawyer et al.
(Endocrinology, 106, 81 (1980)), which in turn was based on a
report of Holton (Brit. J. Pharmacol., 3, 328 (1948)). The assay
calculations for pA.sub.2 estimates are described by Schild (Brit.
J. Pharmacol., 2, 189 (1947)).
Assay Method
[0345] 1. Animals-a 1.5 cm piece of uterus from a virgin rat
(Holtzman) in natural estrus is used for the assay.
[0346] 2. Buffer/Assay Bath--The buffer used is Munsicks. This
buffer contains 0.5 mM Mg.sup.2+. The buffer is gassed continuously
with 95% oxygen/5% carbon dioxide giving a pH of 7.4. The
temperature of the assay bath is 37.degree. C. A 10 mL assay bath
is used that contains a water jacket for maintaining the
temperature and inlet and outlet spikets for adding and removing
buffer.
[0347] 3. Polygraph/transducer--The piece of uterine tissue used
for the assay is anchored at one end and connected to a Statham
Strain Gauge Force Transducer at the other end which in turn is
attached to a Grass Polygraph Model 79 for monitoring the
contractions.
[0348] 4. Assay Protocol:
[0349] (a) The tissue is equilibrated in the assay bath for one
hour with washing with new buffer every 15 minutes. One gram of
tension is kept on the tissue at all times.
[0350] (b) The tissue is stimulated initially with oxytocin at 10
nM to acclimate the tissue and with 4 mM potassium chloride (KCl)
to determine the maximum contractile response.
[0351] (c) A cumulative dose response curve is then done with
oxytocin and a concentration of oxytocin equivalent to
approximately 80% of the maximum is used for estimating the
pA.sub.2 of the antagonist.
[0352] (d) The tissue is exposed to oxytocin (Calbiochemical, San
Diego, Calif.) for one minute and washed out. There is a three
minute interval before addition of the next dose of agonist or
antagonist. When the antagonist is tested, it is given five minutes
before the agonist. The agonist is given for one minute. All
responses are integrated using a 7P10 Grass Integrator. A single
concentration of oxytocin, equal to 80% of the maximum response, is
used to test the antagonist. Three different concentrations of
antagonists are used, two that will reduce the response to the
agonist by less than 50% and one that will reduce the response
greater than 50% (ideally this relation would be 25%, 50% and 75%).
This is repeated three times for each dose of antagonist for a
three point assay.
[0353] (e) Calculations for pA.sub.2--The dose-response (DR) ratios
are calculated for antagonist and a Schild's Plot is performed by
plotting the Log (DR-1) vs. Log of antagonist concentration. The
line plotted is calculated by least-squares regression analysis.
The pA.sub.2 is the concentration of antagonist at the point where
the regression line crosses the 0 point of the Log (DR-1) ordinate.
The pA.sub.2 is the negative Log of the concentration of antagonist
that will reduce the response to the agonist by one-half.
[0354] Oxytocin is well known for its hormonal role in parturition
and lactation. Oxytocin agonists are useful clinically to induce
lactation; induce or augment labor; control postpartum uterine
atony and hemmorhage; cause uterine contraction after cesarean
section or during other uterine surgery; and to induce therapeutic
abortion. Oxytocin, acting as a neurotransmitter in the central
nervous system, also plays an important role in the expression of
central functions such as maternal behavior, sexual behavior
(including penile erection, lordosis and copulatory behavior),
yawning, tolerance and dependance mechanisms, feeding, grooming,
cardiovascular regulation and thermoregulation (Argiolas and Gessa,
Neuroscience and Biobehavioral Reviews, 15, 217-231 (1991)).
Oxytocin antagonists find therapeutic utility as agents for the
delay or prevention of premature labor; or to slow or arrest
delivery for brief periods in order to undertake other therapeutic
measures.
METHOD EXAMPLE 4
Tachykinin Receptor Binding Assay
[0355] Compounds of the present invention are believed to be
tachykinin agents. Tachykinins are a family of peptides which share
a common amidated carboxy terminal sequence. Substance P was the
first peptide of this family to be isolated, although its
purification and the determination of its primary sequence did not
occur until the early 1970's. Between 1983 and 1984 several groups
reported the isolation of two novel mammalian tachykinins, now
termed neurokinin A (also known as substance K, neuromedin 1, and
neurokinin .alpha.), and neurokinin B (also known as neuromedin K
and neurokinin .beta.). See, J. E. Maggio, Peptides, 6 (Supplement
3), 237-243 (1985) for a review of these discoveries.
[0356] Tachykinins are widely distributed in both the central and
peripheral nervous systems. When released from nerves, they exert a
variety of biological actions, which, in most cases, depend upon
activation of specific receptors expressed on the membrane of
target cells. Tachykinins are also produced by a number of
non-neural tissues. The mammalian tachykinins substance P,
neurokinin A, and neurokinin B act through three major receptor
subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These
receptors are present in a variety of organs.
[0357] Substance P is believed inter alia to be involved in the
neurotransmission of pain sensations, including the pain associated
with migraine headaches and with arthritis. These peptides have
also been implicated in gastrointestinal disorders and diseases of
the gastrointestinal tract such as inflammatory bowel disease.
Tachykinins have also been implicated as playing a role in numerous
other maladies, as discussed infra.
[0358] In view of the wide number of clinical maladies associated
with an excess of tachykinins, the development of tachykinin
receptor antagonists will serve to control these clinical
conditions. The earliest tachykinin receptor antagonists were
peptide derivatives. These antagonists proved to be of limited
pharmaceutical utility because of their metabolic instability.
Recent publications have described novel classes of non-peptidyl
tachykinin receptor antagonists which generally have greater oral
bioavailability and metabolic stability than the earlier classes of
tachykinin receptor antagonists. Examples of such newer
non-peptidyl tachykinin receptor antagonists are found in European
Patent Publication 591,040 A1, published Apr. 6, 1994; Patent
Cooperation Treaty publication WO 94/01402, published Jan. 20,
1994; Patent Cooperation Treaty publication WO 94/04494, published
Mar. 3, 1994; Patent Cooperation Treaty publication WO 93/011609,
published Jan. 21, 1993, Patent Cooperation Treaty publication WO
94/26735, published Nov. 24, 1994. Assays useful for evaluating
tachykinin receptor antagonists are well known in the art. See,
e.g., J. Jukic et al., Life Sciences, 49, 1463-1469 (1991); N.
Kucharczyk et al., Journal of Medicinal Chemistry, 36, 1654-1661
(1993); N. Rouissi et al., Biochemical and Biophysical Research
Communications, 176, 894-901 (1991).
METHOD EXAMPLE 5
NK-1 Receptor Binding Assay
[0359] Radioreceptor binding assays were performed using a
derivative of a previously published protocol. D. G. Payan et al.,
Journal of Immunology, 133, 3260-3265 (1984). In this assay an
aliquot of IM9 cells (1.times.10.sup.6 cells/tube in RPMI 1604
medium supplemented with 10% fetal calf serum) was incubated with
20 pM .sup.125I-labeled substance P in the presence of increasing
competitor concentrations for 45 minutes at 4.degree. C.
[0360] The IM9 cell line is a well-characterized cell line which is
readily available to the public. See, e.g., Annals of the New York
Academy of Science, 190, 221-234 (1972); Nature (London), 251,
443-444 (1974); Proceedings of the National Academy of Sciences
(USA), 71, 84-88 (1974). These cells were routinely cultured in
RPMI 1640 supplemented with 50 .mu.g/mL gentamicin sulfate and 10%
fetal calf serum.
[0361] The reaction was terminated by filtration through a glass
fiber filter harvesting system using filters previously soaked for
20 minutes in 0.1% polyethylenimine. Specific binding of labeled
substance P was determined in the presence of 20 nM unlabeled
ligand.
METHOD EXAMPLE 6
NK-2 Receptor Binding Assay
[0362] The CHO-hNK-2R cells, a CHO-derived cell line transformed
with the human NK-2 receptor, expressing about 400,000 such
receptors per cell, were grown in 75 cm.sup.2 flasks or roller
bottles in minimal essential medium (alpha modification) with 10%
fetal bovine serum. The gene sequence of the human NK-2 receptor is
given in N. P. Gerard et al., Journal of Biological Chemistry, 265,
20455-20462 (1990).
[0363] For preparation of membranes, 30 confluent roller bottle
cultures were dissociated by washing each roller bottle with 10 ml
of Dulbecco's phosphate buffered saline (PBS) without calcium and
magnesium, followed by addition of 10 ml of enzyme-free cell
dissociation solution (PBS-based, from Specialty Media, Inc.).
After an additional 15 minutes, the dissociated cells were pooled
and centrifuged at 1,000 RPM for 10 minutes in a clinical
centrifuge. Membranes were prepared by homogenization of the cell
pellets in 300 mL 50 mM Tris buffer, pH 7.4 with a Tekmnar.RTM.
homogenizer for 10-15 seconds, followed by centrifugation at 12,000
RPM (20,000.times.g) for 30 minutes using a Beckman JA-14.RTM.
rotor. The pellets were washed once using the above procedure and
the final pellets were resuspended in 100-120 mL 50 mM Tris buffer,
pH 7.4, and 4 ml aliquots stored frozen at -70.degree. C. The
protein concentration of this preparation was 2 mg/mL.
[0364] For the receptor binding assay, one 4-mL aliquot of the
CHO-hNK-2R membrane preparation was suspended in 40 mL of assay
buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride,
0.02% bovine serum albumin (BSA) and 4 .mu.g/mL chymostatin. A 200
.mu.L volume of the homogenate (40 .mu.g protein) was used per
sample. The radioactive ligand was
[.sup.125I]iodohistidyl-neurokinin A (New England Nuclear,
NEX-252), 2200 Ci/mmol. The ligand was prepared in assay buffer at
20 nCi per 100 .mu.L; the final concentration in the assay was 20
.mu.M. Non-specific binding was determined using 1 .mu.M eledoisin.
Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a
standard concentration-response curve.
[0365] All samples and standards were added to the incubation in 10
.mu.L dimethylsulfoxide (DMSO) for screening (single dose) or in 5
.mu.L DMSO for IC.sub.50 determinations. The order of additions for
incubation was 190 or 195 .mu.L assay buffer, 200 .mu.L homogenate,
10 or 5 .mu.L sample in DMSO, 100 .mu.L radioactive ligand. The
samples were incubated 1 hr at room temperature and then filtered
on a cell harvester through filters which had been presoaked for
two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The
filter was washed 3 times with approximately 3 mL of cold 50 mM
Tris buffer, pH 7.7. The filter circles were then punched into
12.times.75 mm polystyrene tubes and counted in a gamma
counter.
[0366] Tachykinin receptor antagonists are of value in the
treatment of a wide variety of clinical conditions which are
characterized by the presence of an excess of tachykinin. These
clinical conditions may include disorders of the central nervous
system such as anxiety, depression, psychosis, and schizophrenia;
neurodegenerative disorders such as dementia, including senile
dementia of the Alzheimer's type, Alzheimer's disease,
AIDS-associated dementia, and Down's syndrome; demyelinating
diseases such as multiple sclerosis and amyotrophic lateral
sclerosis and other neuropathological disorders such as peripheral
neuropathy, such as diabetic and chemotherapy-induced neuropathy,
and post-herpetic and other neuralgias; acute and chronic
obstructive airway diseases such as adult respiratory distress
syndrome, bronchopneumonia, bronchospasm, chronic bronchitis,
drivercough, and asthma; inflammatory diseases such as inflammatory
bowel disease, psoriasis, fibrositis, osteoarthritis, and
rheumatoid arthritis; disorders of the musculo-skeletal system,
such as osteoporosis; allergies such as eczema and rhinitis;
hypersensitivity disorders such as poison ivy; ophthalmic diseases
such as conjunctivitis, vernal conjunctivitis, and the like;
cutaneous diseases such as contact dermatitis, atopic dermatitis,
urticaria, and other eczematoid dermatites; addiction disorders
such as alcoholism; stress-related somatic disorders; reflex
sympathetic dystrophy such as shoulder/hand syndrome; dysthymic
disorders; adverse immunological reactions such as rejection of
transplanted tissues and disorders related to immune enhancement or
suppression such as systemic lupus erythematosis; gastrointestinal
disorders or diseases associated with the neuronal control of
viscera such as ulcerative colitis, Crohn's disease, emesis, and
irritable bowel syndrome; disorders of bladder function such as
bladder detrusor hyper-reflexia and incontinence; artherosclerosis;
fibrosing and collagen diseases such as scleroderma and
eosinophilic fascioliasis; irritative symptoms of benign prostatic
hypertrophy; disorders of blood flow caused by vasodilation and
vasospastic diseases such as angina, migraine, and Raynaud's
disease; and pain or nociception, for example, that attributable to
or associated with any of the foregoing conditions, especially the
transmission of pain in migraine.
[0367] NK-1 antagonists are useful in the treatment of pain,
especially chronic pain, such as neuropathic pain, post-operative
pain, and migraines, pain associated with arthritis,
cancer-associated pain; chronic lower back pain, cluster headaches,
herpes neuralgia, phantom limb pain, central pain, dental pain,
neuropathic pain, opioid-resistant pain, visceral pain, surgical
pain, bone injury pain, pain during labor and delivery, pain
resulting from burns, including sunburn, post partum pain, angina
pain, and genitourinary tract-related pain including cystitis.
[0368] In addition to pain, NK-1 antagonists are especially useful
in the treatment and prevention of urinary incontinence; irritative
symptoms of benign prostatic hypertrophy; motility disorders of the
gastrointestinal tract, such as irritable bowel syndrome; acute and
chronic obstructive airway diseases, such as bronchospasm,
bronchopneumonia, asthma, and adult respiratory distress syndrome;
artherosclerosis; inflammatory conditions, such as inflammatory
bowel disease, ulcerative colitis, Crohn's disease, rheumatoid
arthritis, osteoarthritis, neurogenic inflammation, allergies,
rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis,
emesis, irritation-induced miosis; tissue transplant rejection;
plasma extravasation resulting from cytokine chemotherapy and the
like; spinal cord trauma; stroke; cerebral stroke (ischemia);
Alzheimer's disease; Parkinson's disease; multiple sclerosis;
amyotrophic lateral sclerosis; schizophrenia; anxiety; and
depression.
[0369] NK-2 antagonists are useful in the treatment of urinary
incontinence, bronchospasm, asthma, adult respiratory distress
syndrome, motility disorders of the gastrointestinal tract, such as
irritable bowel syndrome, and pain.
[0370] In addition to the above indications the compounds of the
invention may be useful in the treatment of emesis, including
acute, delayed, or anticipatory emesis, such as emesis induced by
chemotherapy, radiation, toxins, pregnancy, vestibular disorders,
motion, surgery, migraine, and variations in intercranial pressure.
Most especially, the compounds of formula I are of use in the
treatment of emesis induced by antineoplastic (cytotoxic) agents
including those routinely used in cancer chemotherapy.
[0371] Examples of such chemotherapeutic agents include alkylating
agents, for example, nitrogen mustards, ethyleneimine compounds,
alkyl sulfonates, and other compounds with an alkylating action,
such as nitrosoureas, cisplatin, and dacarbazine; antimetabolites,
for example, folic acid, purine, or pyrimidine antagonists; mitotic
inhibitors, for example vinca alkaloids and derivatives of
podophyllotoxin; and cytotoxic antibiotics.
[0372] Particular examples of chemotherapeutic agents are
described, for instance, by D. J. Stewart in NAUSEA AND VOMITING:
RECENT RESEARCH AND CLINICAL ADVANCES, (J. Kucharczyk et al., eds.,
1991), at pages 177-203. Commonly used chemotherapeutic agents
include cisplatin, dacarbazine (DTIC), dactinomycin,
mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide,
carmustine (BCNU), lomustine (CCNU), doxorubicin, daunorubicin,
procarbazine, mitomycin, cytarabine, etoposide, methotrexate,
5-fluorouracil, vinblastine, vincristine, bleomycin, and
chlorambucil. R. J. Gralla et al., Cancer Treatment Reports, 68,
163-172 (1984).
[0373] The compounds of formula I may also be of use in the
treatment of emesis induced by radiation, including radiation
therapy such as in the treatment of cancer, or radiation sickness;
and in the treatment of post-operaive nausea and vomiting.
[0374] While it is possible to administer a compound employed in
the methods of this invention directly without any formulation, the
compounds are usually administered in the form of pharmaceutical
compositions comprising a pharmaceutically acceptable excipient and
at least one active ingredient. These compositions can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular, and
intranasal. Many of the compounds employed in the methods of this
invention are effective as both injectable and oral compositions.
Such compositions are prepared in a manner well known in the
pharmaceutical art and comprise at least one active compound. See,
e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
[0375] In making the compositions employed in the present invention
the active ingredient is usually mixed with an excipient, diluted
by an excipient, or enclosed within such a carrier which can be in
the form of a capsule, sachet, paper, or other container. When the
excipient serves as a diluent, it can be a solid, semi-solid, or
liquid material, which acts as a vehicle, carrier or medium for the
active ingredient. Thus, the compositions can be in the form of
tablets, pills, powders, lozenges, sachets, cachets, elixirs,
suspensions, emulsions, solutions, syrups, aerosols (as a solid or
in a liquid medium), ointments containing for example up to 10% by
weight of the active compound, soft and hard gelatin capsules,
suppositories, sterile injectable solutions, and sterile packaged
powders.
[0376] In preparing a formulation, it may be necessary to mill the
active compound to provide the appropriate particle size prior to
combining with the other ingredients. If the active compound is
substantially insoluble, it ordinarily is milled to a particle size
of less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by milling to
provide a substantially uniform distribution in the formulation,
e.g. about 40 mesh.
[0377] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxybenzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art.
[0378] The compositions are preferably formulated in a unit dosage
form, each dosage, containing from about 0.05 to about 100 mg, more
usually about 1.0 to about 30 mg, of the active ingredient. The
term "unit dosage form" refers to physically discrete units
suitable as unitary dosages for human subjects and other mammals,
each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient.
[0379] The active compounds are generally effective over a wide
dosage range. For examples, dosages per day normally fall within
the range of about 0.01 to about 30 mg/kg of body weight. In the
treatment of adult humans, the range of about 0.1 to about 15
mg/kg/day, in single or divided dose, is especially preferred.
However, it will be understood that the amount of the compound
actually administered will be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compound or
compounds administered, the age, weight, and response of the
individual patient, and the severity of the patient's symptoms, and
therefore the above dosage ranges are not intended to limit the
scope of the invention in any way. In some instances dosage levels
below the lower limit of the aforesaid range may be more than
adequate, while in other cases still larger doses may be employed
without causing any harmful side effect, provided that such larger
doses are first divided into several smaller doses for
administration throughout the day.
FORMULATION EXAMPLE 1
[0380] Hard gelatin capsules containing the following ingredients
are prepared: TABLE-US-00018 Quantity Ingredient (mg/capsule)
Compound of Example 35 30.0 Starch 305.0 Magnesium stearate 5.0
The above ingredients are mixed and filled into hard gelatin
capsules in 340 mg quantities.
FORMULATION EXAMPLE 2
[0381] A tablet formula is prepared using the ingredients below:
TABLE-US-00019 Quantity Ingredient (mg/tablet) Compound of Example
95 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide
10.0 Stearic acid 5.0
The components are blended and compressed to form tablets, each
weighing 240 mg.
FORMULATION EXAMPLE 3
[0382] A dry powder inhaler formulation is prepared containing the
following components: TABLE-US-00020 Ingredient Weight % Compound
of Example 63 5 Lactose 95
The active mixture is mixed with the lactose and the mixture is
added to a dry powder inhaling appliance.
FORMULATION EXAMPLE 4
[0383] Tablets, each containing 30 mg of active ingredient, are
prepared as follows: TABLE-US-00021 Quantity Ingredient (mg/tablet)
Compound of Example 103 30.0 mg Starch 45.0 mg Microcrystalline
cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in water)
4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg
Talc 1.0 mg Total 120 mg.sup.
The active ingredient, starch, and cellulose are passed through a
No. 20 mesh U.S. sieve and mixed thoroughly. The solution of
polyvinylpyrrolidone is mixed with the resultant powders, which are
then passed through a 16 mesh U.S. sieve. The granules so produced
are dried at 50-60.degree. C. and passed through a 16 mesh U.S.
sieve. The sodium carboxymethyl starch, magnesium stearate, and
talc, previously passed through a No. 30 mesh U.S. sieve, are then
added to the granules which, after mixing, are compressed on a
tablet machine to yield tablets each weighing 120 mg.
FORMULATION EXAMPLE 5
[0384] Capsules, each containing 40 mg of medicament are made as
follows: TABLE-US-00022 Quantity Ingredient (mg/capsule) Compound
of Example 104 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg
Total 150.0 mg
The active ingredient, cellulose, starch, and magnesium stearate
are blended, passed through a No. 20 mesh U.S. sieve, and filled
into hard gelatin capsules in 150 mg quantities.
FORMULATION EXAMPLE 6
[0385] Suppositories, each containing 25 mg of active ingredient
are made as follows: TABLE-US-00023 Ingredient Amount Compound of
Example 110 25 mg Saturated fatty acid glycerides to 2,000 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve
and suspended in the saturated fatty acid glycerides previously
melted using the minimum heat necessary. The mixture is then poured
into a suppository mold of nominal 2.0 g capacity and allowed to
cool.
FORMULATION EXAMPLE 7
[0386] Suspensions, each containing 50 mg of medicament per 5.0 ml
dose are made as follows: TABLE-US-00024 Ingredient Amount Compound
of Example 111 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl
cellulose (11%) 50.0 mg Microcrystalline cellulose (89%) Sucrose
1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water
to 5.0 ml
The medicament, sucrose, and xanthan gum are blended, passed
through a No. 10 mesh U.S. sieve, and then mixed with a previously
made solution of the microcrystalline cellulose and sodium
carboxymethyl cellulose in water. The sodium benzoate, flavor, and
color are diluted with some of the water and added with stirring.
Sufficient water is then added to produce the required volume.
FORMULATION EXAMPLE 8
[0387] Capsules, each containing 15 mg of medicament, are made as
follows: TABLE-US-00025 Quantity Ingredient (mg/capsule) Compound
of Example 112 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg
Total 425.0 mg
The active ingredient, cellulose, starch, and magnesium stearate
are blended, passed through a No. 20 mesh U.S. sieve, and filled
into hard gelatin capsules in 425 mg quantities.
FORMULATION EXAMPLE 9
[0388] An intravenous formulation may be prepared as follows:
TABLE-US-00026 Ingredient Quantity Compound of Example 120 250.0 mg
Isotonic saline 1000 ml
FORMULATION EXAMPLE 10
[0389] A topical formulation may be prepared as follows:
TABLE-US-00027 Ingredient Quantity Compound of Example 35 1-10 g
Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to
100 g
The white soft paraffin is heated until molten. The liquid paraffin
and emulsifying wax are incorporated and stirred until dissolved.
The active ingredient is added and stirring is continued until
dispersed. The mixture is then cooled until solid.
FORMULATION EXAMPLE 11
[0390] Sublingual or buccal tablets, each containing 10 mg of
active ingredient, may be prepared as follows: TABLE-US-00028
Quantity Ingredient Per Tablet Compound of Example 95 10.0 mg
Glycerol 210.5 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl
Alcohol 26.5 mg Polyvinylpyrrolidone 15.5 mg Total 410.0 mg
The glycerol, water, sodium citrate, polyvinyl alcohol, and
polyvinylpyrrolidone are admixed together by continuous stirring
and maintaining the temperature at about 90.degree. C. When the
polymers have gone into solution, the resulting solution is cooled
to about 50-55.degree. C. and the medicament is slowly admixed. The
homogenous mixture is poured into forms made of an inert material
to produce a drug-containing diffusion matrix having a thickness of
about 2-4 mm. This diffusion matrix is then cut to form individual
tablets having the appropriate size.
[0391] Another preferred formulation employed in the methods of the
present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art.
See, e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein
incorporated by reference. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[0392] Frequently, it will be desirable or necessary to introduce
the pharmaceutical composition to the brain, either directly or
indirectly. Direct techniques usually involve placement of a drug
delivery catheter into the host's ventricular system to bypass the
blood-brain barrier. One such implantable delivery system, used for
the transport of biological factors to specific anatomical regions
of the body, is described in U.S. Pat. No. 5,011,472, which is
herein incorporated by reference.
[0393] Indirect techniques, which are generally preferred, usually
involve formulating the compositions to provide for drug
latentiation by the conversion of hydrophilic drugs into
lipid-soluble drugs or prodrugs. Latentiation is generally achieved
through blocking of the hydroxy, carbonyl, sulfate, and primary
amine groups present on the drug to render the drug more lipid
soluble and amenable to transportation across the blood-brain
barrier. Alternatively, the delivery of hydrophilic drugs may be
enhanced by intra-arterial infusion of hypertonic solutions that
can transiently open the blood-brain barrier.
[0394] The type of formulation employed for the administration of
the compounds employed in the methods of the present invention may
be dictated by the particular compounds employed, the type of
pharmacokinetic profile desired from the route of administration
and the compound(s), and the state of the patient.
[0395] While the invention has been illustrated and described in
detail in the foregoing description, such an illustration and
description is to be considered as exemplary and not restrictive in
character, it being understood that only the illustrative
embodiments have been shown and described and that all changes and
modifications that come within the spirit of the invention are
desired to be protected.
* * * * *