U.S. patent application number 12/545671 was filed with the patent office on 2009-12-31 for tyrosine derivative.
This patent application is currently assigned to Genentech, Inc.. Invention is credited to David Y. Jackson, Frederick C. Sailes, Daniel P. Sutherlin.
Application Number | 20090325962 12/545671 |
Document ID | / |
Family ID | 22557944 |
Filed Date | 2009-12-31 |
United States Patent
Application |
20090325962 |
Kind Code |
A1 |
Jackson; David Y. ; et
al. |
December 31, 2009 |
TYROSINE DERIVATIVE
Abstract
The compounds of the invention are inhibitors of alpha4
containing integrin-mediated binding to ligands such as VCAM-1 and
MAdCAM.
Inventors: |
Jackson; David Y.; (Belmont,
CA) ; Sailes; Frederick C.; (Norcross, GA) ;
Sutherlin; Daniel P.; (San Carlos, CA) |
Correspondence
Address: |
GENENTECH, INC.
1 DNA WAY
SOUTH SAN FRANCISCO
CA
94080
US
|
Assignee: |
Genentech, Inc.
South San Francisco
CA
|
Family ID: |
22557944 |
Appl. No.: |
12/545671 |
Filed: |
August 21, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10772678 |
Feb 4, 2004 |
7595399 |
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12545671 |
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10198328 |
Jul 16, 2002 |
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10772678 |
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09669779 |
Sep 25, 2000 |
6469047 |
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10198328 |
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60156062 |
Sep 24, 1999 |
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Current U.S.
Class: |
514/237.5 ;
514/255.01; 514/307; 514/312; 514/375; 514/490; 514/563; 544/169;
544/389; 546/147; 546/153; 548/221; 560/115; 562/449 |
Current CPC
Class: |
C07D 295/205 20130101;
C07D 217/06 20130101; A61P 25/00 20180101; C07D 211/46 20130101;
C07D 333/62 20130101; A61P 1/00 20180101; A61P 1/04 20180101; A61P
17/00 20180101; C07C 271/58 20130101; C07D 277/56 20130101; C07D
333/34 20130101; C07D 235/26 20130101; C07C 323/59 20130101; A61P
15/14 20180101; C07C 271/48 20130101; C07D 235/06 20130101; C07D
207/16 20130101; C07D 207/22 20130101; C07D 217/14 20130101; A61P
1/18 20180101; C07D 231/16 20130101; C07D 249/18 20130101; A61P
1/16 20180101; A61P 29/00 20180101; C07D 471/10 20130101; A61P 5/50
20180101; A61P 11/00 20180101; A61P 11/02 20180101; C07D 207/28
20130101; C07D 211/60 20130101; C07D 211/62 20130101; C07D 317/58
20130101; A61P 11/06 20180101; C07C 233/87 20130101; C07D 333/38
20130101; A61P 37/02 20180101; C07C 271/44 20130101; C07D 215/36
20130101; C07C 271/56 20130101; C07C 311/06 20130101; C07C 323/43
20130101; C07D 217/22 20130101; C07D 333/72 20130101; A61P 3/10
20180101; C07C 311/58 20130101; A61P 43/00 20180101; C07D 213/75
20130101; C07C 271/54 20130101; C07C 311/09 20130101; C07D 277/12
20130101; A61P 17/06 20180101; A61P 37/06 20180101; C07C 271/22
20130101; C07D 333/20 20130101; A61P 19/02 20180101 |
Class at
Publication: |
514/237.5 ;
560/115; 514/490; 548/221; 514/375; 546/147; 514/307; 546/153;
514/312; 544/169; 544/389; 514/255.01; 562/449; 514/563 |
International
Class: |
A61K 31/5375 20060101
A61K031/5375; C07C 271/40 20060101 C07C271/40; A61K 31/27 20060101
A61K031/27; C07D 263/58 20060101 C07D263/58; A61K 31/421 20060101
A61K031/421; C07D 217/00 20060101 C07D217/00; A61K 31/47 20060101
A61K031/47; C07D 215/00 20060101 C07D215/00; C07D 265/30 20060101
C07D265/30; C07D 241/04 20060101 C07D241/04; A61K 31/495 20060101
A61K031/495; C07C 229/00 20060101 C07C229/00; A61K 31/195 20060101
A61K031/195; A61P 19/02 20060101 A61P019/02; A61P 11/06 20060101
A61P011/06; A61P 17/00 20060101 A61P017/00; A61P 1/00 20060101
A61P001/00 |
Claims
1. A compound of the formula I, II or III: ##STR00724## wherein Z
is H or lower alkyl; A has the structure: ##STR00725## in which B
is cyanoalkyl, a carbocycle or a heterocycle optionally substituted
with one or more R.sub.1 substituents; q is 0-3; R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 independently are hydrogen,
alkyl, amino, alkylamino, dialkylamino, nitro, urea, cyano, thio,
alkylthio, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylamino, aryloxycarbonylamino, alkylsulfinyl, sulfonyl,
alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
alkanoyl, alkanoylamino, cycloalkanoylamino, aryl, arylalkyl,
halogen, or alkylphosphonyl, and R.sub.1, R.sub.2, R.sub.3, R.sub.4
and R.sub.5 are substituted with 0-3 substituents selected from the
group consisting of hydroxy, carboxyl, lower alkoxycarbonyl, lower
alkyl, nitro, oxo, cyano, carbocyclyl, heterocyclyl, heteroaryl,
lower alkylthio, lower alkoxy, lower alkylamino, lower
alkanoylamino, lower alkylsulfinyl, lower sulfonyl, lower
alkylsulfonyl, lower alkanoyl, aryl, aroyl, heterocyclylcarbonyl,
halogen and lower alkylphosphonyl; or two of R.sub.1 to R.sub.5
together form a carbocycle or heterocyclic ring; Y is H, alkoxy,
alkoxyalkoxy, aryloxy, alkylaminoalkoxy, dialkylaminoalkoxy,
alkylamino, arylamino, heterocyclyl or heteroarylalkyl, where each
of the forgoing may be substituted or unsubstituted; X.sub.1 is H,
C(O)OR, C(O)NRaRb, C(O)R, or C(O)SR, wherein R, Ra and Rb,
individually, is hydrogen or alkyl, alkoxy, aryl, heterocyclyl,
heteroaryl, substituted with 0-4 substituents selected from the
group consisting of halogen, hydroxy, amino, carboxyl, nitro,
cyano, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, aralkyl,
aralkyloxy, aryloxycarbonyl, aralkyloxycarbonyl, alkylenedioxy,
lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl,
lower alkylthio, lower alkoxy, lower alkylamino, lower
alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl,
lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower
alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl,
alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy
lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, and
alkoxy lower alkyl; wherein said heterocyclyl, heteroaryl, aryl,
aroyl, aryloxy, aralkyl, aralkyloxy, aryloxycarbonyl and
aralkyloxycarbonyl is optionally substituted with halogen,
hydroxyl, amino, carboxyl, nitro, cyano, alkyl and alkoxy; and
wherein Ra and Rb together with the nitrogen to which they are
attached may form a heterocyclyl or heteroaryl group substituted
with 0-5 substituents R or Rd; wherein Rd has the structure
##STR00726## wherein X' is a divalent linker selected from the
group consisting of C(O)NRa, C(O) or a bond; X.sub.2 and X.sub.3
are each independently hydrogen, halogen, hydroxy, amino, carboxyl,
nitro, cyano, or substituted or unsubstituted alkyl, aryl,
heterocylyl, heteroaryl, aryl, aroyl, aryloxy, alkylenedioxy, lower
alkyl carbonylamino, lower alkenyl carbonylamino, aryl
carbonylamino, arylalkyl carbonylamino, lower alkoxy carbonylamino,
lower alkylamino carbonylamino, arylamino carbonylamino, lower
alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower
alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl,
lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower
alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl,
alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio
lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl,
heteroarylamino lower alkyl, halo lower alkyl, alkoxy lower alkyl;
and wherein X.sub.1 and X.sub.2 or X.sub.3 may be bonded together
to form a heterocylic or heteroaryl ring(s); or X.sub.3 and Z
together form a heterobicyclic ring; X.sub.1', X.sub.2', X.sub.3',
and X.sub.4', are each independently hydrogen, halogen, hydroxy,
amino, carboxyl, nitro, cyano, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, arylalkyl, heterocylyl, heteroaryl, aryl,
aroyl, aryloxy, alkylenedioxy, lower alkyl carbonylamino, lower
alkenyl carbonylamino, aryl carbonylamino, arylalkyl carbonylamino,
lower alkoxy carbonylamino, lower alkylamino carbonylamino,
arylamino carbonylamino, lower alkoxycarbonyl, lower alkyl, lower
alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower
alkylamino, lower alkylsulfinyl, lower sulfonyl, lower
alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl
lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl,
alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio
lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower
alkyl, halo lower alkyl, alkoxy lower alkyl; or a pharmaceutically
acceptable salt thereof.
2. A compound according to claim 1, having the formula:
##STR00727## wherein Z is H or lower alkyl; A has the structure:
##STR00728## in which R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5, independently are hydrogen, alkyl, amino, alkylamino,
dialkylamino, nitro, cyano, thio, alkylthio, hydroxy, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkylsulfinyl, sulfonyl,
alkylsulfonyl, alkanoyl, aryl, arylalkyl, halogen, or
alkylphosphonyl, and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5
are substituted with 0-3 substituents selected from the group
consisting of hydroxy, carboxyl, lower alkoxycarbonyl, lower alkyl,
nitro, cyano, heterocylyl, heteroaryl, lower alkylthio, lower
alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl,
lower alkylsulfonyl, lower alkanoyl, aryl, halogen and lower
alkylphosphonyl; Y is H, alkoxy, alkoxyalkoxy, aryloxy,
aminoalkylalkoxy, diaminoalkylalkoxy, alkylamino, arylamino,
heterocyclyl or heteroarylalkyl, where each of the forgoing may be
substituted or unsubstituted; X.sub.1 is H, C(O)OR, C(O)NRaRb,
C(O)R, or C(O)SR, wherein R, Ra and Rb, individually, is hydrogen
or alkyl, aryl, heterocyclyl, heteroaryl, substituted with 0-4
substituents selected from the group consisting of halogen,
hydroxy, amino, carboxyl, nitro, cyano, heterocylyl, heteroaryl,
aryl, aroyl, aryloxy, alkylenedioxy, lower alkoxycarbonyl, lower
alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy,
lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower
alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl
lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl,
alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio
lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower
alkyl, halo lower alkyl, alkoxy lower alkyl; and wherein Ra and Rb
together with the nitrogen to which they are attached may form a
heterocyclyl or heteroaryl group substituted with 0-4 substituents
R; X.sub.2 and X.sub.3 are each independently hydrogen, halogen,
hydroxy, amino, carboxyl, nitro, cyano, or substituted or
unsubstituted alkyl, aryl, heterocylyl, heteroaryl, aryl, aroyl,
aryloxy, alkylenedioxy, lower alkyl carbonylamino, lower alkenyl
carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower
alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino
carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl,
lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino,
lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower
alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy
lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl,
alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy
lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy
lower alkyl; and wherein X.sub.1 and X.sub.2 or X.sub.3 may be
bonded together to form a heterocylic or heteroaryl ring(s); or
##STR00729## wherein Z is H or lower alkyl; A has the structure:
##STR00730## in which R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5, independently are hydrogen, alkyl, amino, alkylamino,
dialkylamino, nitro, cyano, thio, alkylthio, hydroxy, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkylsulfinyl, sulfonyl,
alkylsulfonyl, alkanoyl, aryl, arylalkyl, halogen, or
alkylphosphonyl, and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5
are substituted with 0-3 substituents selected from the group
consisting of hydroxy, carboxyl, lower alkoxycarbonyl, lower alkyl,
nitro, cyano, heterocylyl, heteroaryl, lower alkylthio, lower
alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl,
lower alkylsulfonyl, lower alkanoyl, aryl, halogen and lower
alkylphosphonyl; Y is H, alkoxy, alkoxyalkoxy, aryloxy,
aminoalkylalkoxy, diaminoalkylalkoxy, alkylamino, arylamino,
heterocyclyl or heteroarylalkyl, where each of the forgoing may be
substituted or unsubstituted; X.sub.1, X.sub.2 and X.sub.3 are each
independently hydrogen, halogen, hydroxy, amino, carboxyl, nitro,
cyano, or substituted or unsubstituted alkyl, alkenyl, alkynyl,
arylalkyl, heterocylyl, heteroaryl, aryl, aroyl, aryloxy,
alkylenedioxy, lower alkyl carbonylamino, lower alkenyl
carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower
alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino
carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl,
lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino,
lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower
alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy
lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl,
alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy
lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy
lower alkyl; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 having structure I.
4. The compound of claim 2, having structure II.
5. The compound of one of claims 2, wherein X.sub.1 X.sub.2,
X.sub.3 are each independently H, alkyl, alkenyl, alkynyl, aryl,
arylalkyl, heterocylyl, or heteroaryl.
6. The compound of claim 5, wherein X.sub.1 is C(O)OR, C(O)R, or
C(O)SR.
7. The compound of claim 5, wherein X.sub.1 is C(O)NRaRb.
8. The compound of claim 5, wherein X.sub.1 is C(O)NRaRb and
wherein Ra and Rb together with the nitrogen to which they are
attached form a 5-membered or 6-membered heterocyclyl or heteroaryl
group substituted with 0-4 substituents R.
9. The compound of claim 7, wherein X.sub.1 is a member selected
from the group consisting of ##STR00731##
10. The compound of claim 9, wherein X.sub.1 is ##STR00732##
11. The compound of claim 7, wherein X.sub.1 is C(O)NRaRb and
wherein Ra and Rb are independently hydrogen, substituted or
unsubstituted alkyl, aryl, heterocyclyl, or heteroaryl.
12. The compound of claim 11, wherein X.sub.1 is a member selected
from the group consisting of ##STR00733## ##STR00734##
13. The compound of claim 11, wherein R.sub.1, R.sub.5 or both are
not hydrogen.
14. The compound of claim 1, wherein X.sub.2, X.sub.3, Z or a
combination thereof are hydrogen.
15. The compound of claim 1, wherein A is selected from the group
consisting of ##STR00735## ##STR00736##
16. The compound of claim 1, wherein A is ##STR00737##
17. The compound of claim 1, wherein X.sub.2 is a member selected
from the group consisting of ##STR00738##
18. The compound of claim 1, wherein the compound has S
stereochemical configuration.
19. A composition, comprising the compound of claim 1 and a carrier
or excipient.
20. A medicament, comprising the compound of claim 1 and a
therapeutically inert carrier or excipient.
21. A medicament for treating a disease or condition associated
with binding of alpha4beta7 to MAdCAM-1 or alpha4beta1 to VCAM-1,
comprising the compound of claim 1 and a therapeutically inert
carrier or excipient.
22. A medicament for treating rheumatoid arthritis, asthma,
psoriasis, multiple sclerosis, inflammatory bowel disease,
ulcerative colitis, pouchitis, Crohn's disease, Celiac disease,
nontropical Sprue, graft-versus-host disease, pancreatitis,
insulin-dependent diabetes mellitus, mastitis, cholecystitis,
pericholangitis, chronic sinusitis, chronic bronchitis,
pneumonitis, collagen disease, eczema or systemic lupus
erythematosis, comprising the compound of claim 1 and a
therapeutically inert carrier or excipient.
23. A method for treating a disease or condition associated with
binding of alpha4beta7 to or alpha4beta1 to VCAM-1, comprising
administering an effective amount of the compound of claim 1 to a
mammal in need thereof.
24. A method for treating rheumatoid arthritis, asthma, psoriasis,
multiple sclerosis, inflammatory bowel disease, ulcerative colitis,
pouchitis, Crohn's disease, Celiac disease, nontropical Sprue,
graft-versus-host disease, pancreatitis, insulin-dependent diabetes
mellitus, mastitis, cholecystitis, pericholangitis, chronic
sinusitis, chronic bronchitis, pneumonitis, collagen disease,
eczema or systemic lupus erythematosis, comprising administering an
effective amount of the compound of claim 1 to a mammal in need
thereof.
Description
RELATED APPLICATIONS
[0001] This application is a continuation application of pending
U.S. application Ser. No. 10/772,678 filed Feb. 4, 2004, which is a
continuation of application Ser. No. 10/198,328, filed Jul. 16,
2002, now abandoned, which is a continuation of application U.S.
Ser. No. 09/669,779, filed Sep. 25, 2000, now U.S. Pat. No.
6,469,047 B1, which claims priority under 35 U.S.C. .sctn. 119 to
U.S. provisional application Ser. No. 60/156,062, filed Sep. 24,
1999, the entire disclosures of which are hereby incorporated by
reference.
BACKGROUND OF THE INVENTION
[0002] The integrins are .alpha./.beta. heterodimeric cell surface
receptors involved in numerous cellular processes from cell
adhesion to gene regulation. Hynes, R. O., Cell, 1992, 69:11-25;
Hemler, M. E., Annu. Rev. Immunol., 1990, 8:365-368. Several
integrins have been implicated in disease processes and have
generated widespread interest as potential targets for drug
discovery. Sharar, S. R. et al., Springer Semin. Immunopathol.,
1995, 16:359-378. In the immune system integrins are involved in
leukocyte trafficking, adhesion and infiltration during
inflammatory processes. Nakajima, H. et al., J. Exp. Med., 1994,
179:1145-1154. Differential expression of integrins regulates the
adhesive properties of cells and different integrins are involved
in different inflammatory responses. Butcher, E. C. et al.,
Science, 1996, 272:60-66. The alpha4 integrins (i.e. alpha4beta1
(.alpha.4.beta.1) and alpha4beta7 (.alpha.4.beta.7)) are expressed
primarily on monocytes, lymphocytes, eosinophils, basophils, and
macrophages but not on neutrophils. Elices, M. J. et al., Cell,
1990, 60:577-584. The primary ligands for .alpha.4 integrins are
the endothelial surface proteins mucosal addressin cell adhesion
molecule (MAdCAM) and vascular cell adhesion molecule (VCAM) with
lower affinity. Makarem, R. et al., J. Biol. Chem., 1994,
269:4005-4011. The binding of the .alpha.4.beta.7 or
.alpha.4.beta.1 to MAdCAM and/or VCAM expressed on high endothelial
venules (HEVs) at sites of inflammation results in firm adhesion of
the leukocyte to the endothelium followed by extravasation into the
inflamed tissue. Chuluyan, H. E. et al., Springer Semin.
Immunopathol., 1995, 16:391-404. Monoclonal antibodies directed
against .alpha.4.beta.1, .alpha.4.beta.7, MAdCAM or VCAM have been
shown to be effective modulators in animal models of chronic
inflammatory diseases such as asthma (Laberge, S. et al., Am. J.
Respir. Crit. Care Med., 1995, 151:822-829.), rheumatoid arthritis
(RA; Barbadillo, C. et al., Springer Semin. Immunopathol., 1995,
16:375-379), colitis (Viney et al, J. Immunol., 1996, 157:
2488-2497) and inflammatory bowel diseases (IBD; Podalski, D. K.,
N. Eng. J. Med., 1991, 325:928-937; Powrie, F. et al., Ther.
Immunol., 1995, 2:115-123).
[0003] A need exists for non-protein small molecule compounds which
inhibit the interaction between the .alpha.4.beta.7 integrin and
its ligands MAdCAM and/or VCAM. These compounds are useful for
treatment of chronic inflammatory diseases such as arthritis,
asthma, multiple sclerosis, Crone's disease, ulcerative colitis,
and Hepatitis C.
SUMMARY OF THE INVENTION
[0004] Accordingly, the present invention relates to new compounds
of the formula I, II or III:
##STR00001##
wherein
[0005] Z is H or lower alkyl;
[0006] A has the structure:
##STR00002##
in which
[0007] B is cyanoalkyl, a carbocycle or a heterocycle optionally
substituted with one or more R.sub.1 substituents;
[0008] q is 0-3;
[0009] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6
independently are hydrogen, alkyl, amino, alkylamino, dialkylamino,
nitro, urea, cyano, thio, alkylthio, hydroxy, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylamino, aryloxycarbonylamino,
alkylsulfinyl, sulfonyl, alkylsulfonyl, aralkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkanoyl, alkanoylamino,
cycloalkanoylamino, aryl, arylalkyl, halogen, or alkylphosphonyl,
and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are substituted
with 0-3 substituents selected from the group consisting of
hydroxy, carboxyl, lower alkoxycarbonyl, lower alkyl, nitro, oxo,
cyano, carbocyclyl, heterocyclyl, heteroaryl, lower alkylthio,
lower alkoxy, lower alkylamino, lower alkanoylamino, lower
alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl,
aryl, aroyl, heterocyclylcarbonyl, halogen and lower
alkylphosphonyl; or two of R.sub.1 to R.sub.5 together form a
carbocycle or heterocyclic ring;
[0010] Y is H, alkoxy, alkoxyalkoxy, aryloxy, alkylaminoalkoxy,
dialkylaminoalkoxy, alkylamino, arylamino, heterocyclyl or
heteroarylalkyl, where each of the forgoing may be substituted or
unsubstituted;
[0011] X.sub.1 is H, C(O)OR, C(O)NRaRb, C(O)R, or C(O)SR, wherein
R, Ra and Rb, individually, is hydrogen or alkyl, alkoxy, aryl,
heterocyclyl, heteroaryl, substituted with 0-4 substituents
selected from the group consisting of halogen, hydroxy, amino,
carboxyl, nitro, cyano, heterocylyl, heteroaryl, aryl, aroyl,
aryloxy, aralkyl, aralkyloxy, aryloxycarbonyl, aralkyloxycarbonyl,
alkylenedioxy, lower alkoxycarbonyl, lower alkyl, lower alkenyl,
lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino,
lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower
alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy
lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl,
alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy
lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, and
alkoxy lower alkyl; wherein said heterocyclyl, heteroaryl, aryl,
aroyl, aryloxy, aralkyl, aralkyloxy, aryloxycarbonyl and
aralkyloxycarbonyl is optionally substituted with halogen,
hydroxyl, amino, carboxyl, nitro, cyano, alkyl and alkoxy; and
wherein Ra and Rb together with the nitrogen to which they are
attached may form a heterocyclyl or heteroaryl group substituted
with 0-5 substituents R or d; wherein Rd has the structure
##STR00003##
wherein X' is a divalent linker selected from the group consisting
of C(O)NRa, C(O) or a bond;
[0012] X.sub.2 and X.sub.3 are each independently hydrogen,
halogen, hydroxy, amino, carboxyl, nitro, cyano, or substituted or
unsubstituted alkyl, aryl, heterocylyl, heteroaryl, aryl, aroyl,
aryloxy, alkylenedioxy, lower alkyl carbonylamino, lower alkenyl
carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower
alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino
carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl,
lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino,
lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower
alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy
lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl,
alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy
lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy
lower alkyl; and wherein X.sub.1 and X.sub.2 or X.sub.3 may be
bonded together to form a heterocylic or heteroaryl ring(s); or
X.sub.3 and Z together form a heterobicyclic ring;
[0013] X.sub.1', X.sub.2', X.sub.3', and X.sub.4', are each
independently hydrogen, halogen, hydroxy, amino, carboxyl, nitro,
cyano, or substituted or unsubstituted alkyl, alkenyl, alkynyl,
arylalkyl, heterocylyl, heteroaryl, aryl, aroyl, aryloxy,
alkylenedioxy, lower alkyl carbonylamino, lower alkenyl
carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower
alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino
carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl,
lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino,
lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower
alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy
lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl,
alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy
lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy
lower alkyl;
or a pharmaceutically acceptable salt thereof.
[0014] These compounds inhibit the binding of .alpha.4.beta.7 or
.alpha.4.beta.1 to MAdCAM and/or VCAM. The invention also relates
to methods of making such compounds, compositions and medicaments
containing the compounds and to methods of inhibiting the binding
of .alpha.4.beta.7 or .alpha.4.beta.1 to MAdCAM and/or VCAM and to
treating diseases associated with this binding.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A. Definitions
[0015] The term "alkyl", used alone or as part of another term, for
example alkylamino, alkylsulfonyl, alkylthio, etc., means a
branched or unbranched, saturated or unsaturated aliphatic
hydrocarbon group, having the number of carbon atoms specified, or
if no number is specified, having up to and including 12 carbon
atoms. "Alkyl" when used alone or as part of another term
preferably means a saturated hydrocarbon chain, however also
includes unsaturated hydrocarbon carbon chains such as "alkenyl"
and "alkynyl". Examples of alkyl groups include methyl, ethyl,
n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl,
2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl,
2-methylhexyl, and the like. The terms "lower alkyl"
"C.sub.1-C.sub.6 alkyl" and "alkyl of 1 to 6 carbon atoms" are
synonymous and used interchangeably. Preferred "C.sub.1-C.sub.6
alkyl" groups are methyl, ethyl, 1-propyl, isopropyl, 1-butyl or
sec-butyl.
[0016] The terms "substituted alkyl" or "substituted
C.sub.n-C.sub.m alkyl" where m and n are integers identifying the
range of carbon atoms contained in the alkyl group, denotes the
above alkyl groups that are substituted by one, two, three or four
halogen, trifluoromethyl, hydroxy, unsubstituted and substituted
C.sub.1-C.sub.7 alkoxy, protected hydroxy, amino (including alkyl
and dialkyl amino), protected amino, unsubstituted and substituted
C.sub.1-C.sub.7 acyloxy, unsubstituted and substituted
C.sub.3-C.sub.7 heterocyclyl, unsubstituted and substituted
phenoxy, nitro, carboxy, protected carboxy, unsubstituted and
substituted carboalkoxy, unsubstituted and substituted acyl,
carbamoyl, carbamoyloxy, cyano, methylsulfonylamino, unsubstituted
and substituted benzyloxy, unsubstituted and substituted
C.sub.3-C.sub.6 carbocyclyl or C.sub.1-C.sub.4 alkoxy groups. The
substituted alkyl groups may be substituted once (preferably),
twice or three times with the same or with different
substituents.
[0017] Examples of the above substituted alkyl groups include, but
are not limited to; cyanomethyl, nitromethyl, hydroxymethyl,
trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl,
carboxyethyl, carboxypropyl, alkyloxycarbonylmethyl,
allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl,
ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl,
bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl,
2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2-carbamoyloxyethyl and
the like. The alkyl group may also be substituted with a
carbocyclyl group. Examples include cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl groups,
as well as the corresponding -ethyl, -propyl, -butyl, -pentyl,
-hexyl groups, etc. A preferred group of examples within the above
group includes the substituted methyl group, e.g. a methyl group
substituted by the same substituents as the "substituted
C.sub.n-C.sub.m alkyl" group. Examples of the substituted methyl
group include groups such as hydroxymethyl, protected hydroxymethyl
(e.g. tetrahydropyranyloxymethyl), acetoxymethyl,
carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl,
bromomethyl and iodomethyl.
[0018] The term "alkoxy" denotes groups having the number of carbon
atoms specified such as methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, t-butoxy and like groups. The term "substituted alkoxy"
means these alkoxy groups substituted by the same substituents as
the "substituted alkyl" group.
[0019] The term "acyloxy" denotes carboacyloxy groups having the
specified number of carbon atoms such as formyloxy, acetoxy,
propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy,
and the like. The term "substituted acyloxy" means these acyloxy
groups substituted by the same substituents as the "substituted
alkyl" group.
[0020] The term "alkylcarbonyl", "alkanoyl" and "acyl" are used
interchangeably herein encompass groups having the specified number
of carbon atoms such as formyl, acetyl, propionyl, butyryl,
pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.
[0021] The term "alkylsulfonyl" denotes the groups
--NH--SO.sub.2-alkyl, --SO.sub.2--NH-alkyl,
--N--(SO.sub.2-alkyl).sub.2 and --SO.sub.2--N(alkyl).sub.2.
Preferred alkylsulfonyl groups are --NH--SO.sub.2-Me,
--NH--SO.sub.2-Et, --NH--SO.sub.2--Pr, --NH--SO.sub.2-iPr,
--N--(SO.sub.2-Me).sub.2 and --N--(SO.sub.2-Bu).sub.2.
[0022] The term "amino" denotes primary (i.e. --NH.sub.2),
secondary (i.e. --NRH) and tertiary (i.e. --NRR) amines. Preferred
secondary and tertiary amines are alkylamine and dialkyl amines
such as methylamine, ethylamine, propylamine, isopropylamine,
dimethylamine, diethylamine, dipropylamine and disopropylamine.
[0023] The terms "carbocyclyl", "carbocyclylic" and "carbocyclo"
alone and when used as a moiety in a complex group such as a
carbocycloalkyl group, refers to a mono-, bi-, or tricyclic
aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7
carbon atoms. Preferred carbocyclic groups include cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl groups. The terms
"substituted carbocyclyl" and "carbocyclo" mean these groups
substituted by the same substituents as the "substituted alkyl"
group.
[0024] A "carbocycloalkyl" group is a carbocyclo group as defined
above covalently bonded to an alkyl group as defined above.
[0025] The term "alkenyl" means a branched or unbranched
hydrocarbon group having the number of carbon atoms designated
containing one or more carbon-carbon double bonds, each double bond
being independently cis, trans, or a nongeometric isomer. The term
"substituted alkenyl" means these alkenyl groups substituted by the
same substituents as the "substituted alkyl" group.
[0026] The term "alkynyl" means a branched or unbranched
hydrocarbon group having the number of carbon atoms designated
containing one or more carbon-carbon triple bonds. The term
"substituted alkynyl" means these alkynyl groups substituted by the
same substituents as the "substituted alkyl" group.
[0027] The terms "alkylthio" and "C.sub.1-C.sub.12 substituted
alkylthio" denote C.sub.1-C.sub.12 alkyl and C.sub.1-C.sub.12
substituted alkyl groups, respectively, attached to a sulfur which
is in turn the point of attachment for the alkylthio or substituted
alkylthio group to the group or substituent designated.
[0028] An "alkylenedioxy" group is a --O-alkyl-O-- group, where
alkyl is as defined above. Preferred alkylenedioxy groups are
methylenedioxy and ethylenedioxy.
[0029] The term "aryl" when used alone or as part of another term
means a homocyclic aromatic group whether or not fused having the
number of carbon atoms designated or if no number is designated, up
to 14 carbon atoms. Preferred aryl groups include phenyl, naphthyl,
biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g.
Lang's Handbook of Chemistry (Dean, J. A., ed)13.sup.th ed. Table
7-2 [1985]).
[0030] The term "aroyl" means an aryl group bonded to a carbonyl,
such as benzoyl, etc.
[0031] The term "substituted phenyl" or "substituted aryl" denotes
a phenyl group or aryl group substituted with one, two, three, four
or five, preferably 1-2, 1-3 or 1-4 substituents chosen from
halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro,
alkyl (preferably C.sub.1-C.sub.6 alkyl), alkoxy (preferably
C.sub.1-C.sub.6 alkoxy), benzyloxy, carboxy, protected carboxy,
carboxymethyl, protected carboxymethyl, hydroxymethyl, protected
hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl,
alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino,
heterocyclyl, aryl, or other groups specified. One or methyne (CH)
and/or methylene (CH.sub.2) groups in these substituents may in
tern be substituted with a similar group as those denoted above.
Examples of the term "substituted phenyl" includes but is not
limited to a mono- or di(halo)phenyl group such as 2-chlorophenyl,
2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,
2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl,
3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl,
3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or
di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl,
2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and
the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a
cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower
alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl,
2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl,
3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group,
for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl,
3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl,
4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl
and the like; 3- or 4-trifluoromethylphenyl; a mono- or
dicarboxyphenyl or (protected carboxy)phenyl group such
4-carboxyphenyl; a mono- or di(hydroxymethyl)phenyl or (protected
hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or
3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or
(protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or
2,4-(protected aminomethyl)phenyl; or a mono- or
di(N-(methylsulfonylamino))phenyl such as
3-(N-methylsulfonylamino))phenyl. Also, the term "substituted
phenyl" represents disubstituted phenyl groups where the
substituents are different, for example, 3-methyl-4-hydroxyphenyl,
3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,
4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,
2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted
phenyl groups where the substituents are different, for example
3-methoxy-4-benzyloxy-6-methyl sulfonylamino,
3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted
phenyl groups where the substituents are different such as
3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Preferred
substituted phenyl groups include the 2-chlorophenyl,
2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl,
4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl,
3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl,
3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl,
3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenyl
groups. Also, the term "substituted phenyl" represents phenyl
groups having an aryl, phenyl or heteroaryl group fused thereto.
The fused ring may also be substituted with any, preferably 1, 2 or
3, of the substituents identified above for "substituted alkyl"
groups.
[0032] The term "arylalkyl" means one, two, or three aryl groups
having the number of carbon atoms designated, appended to an alkyl
group having the number of carbon atoms designated including but
not limited to; benzyl, napthylmethyl, phenethyl, benzhydryl
(diphenylmethyl), trityl, and the like. A preferred arylalkyl group
is the benzyl group.
[0033] The term "substituted arylalkyl" denotes an alkyl group,
preferably a C.sub.1-C.sub.8alkyl group, substituted at any carbon
with an aryl group, preferably a C.sub.6-C.sub.10aryl group, bonded
to the alkyl group through any aryl ring position and substituted
on the alkyl portion with one, two or three groups chosen from
halogen (F, Cl, Br, I), hydroxy, protected hydroxy, amino,
protected amino, C.sub.1-C.sub.7acyloxy, nitro, carboxy, protected
carboxy, carbamoyl, carbamoyloxy, cyano, C.sub.1-C.sub.6alkylthio,
N-(methylsulfonylamino) or C.sub.1-C.sub.4alkoxy. Optionally the
aryl group may be substituted with one, two, three, four or five
groups chosen from halogen, hydroxy, protected hydroxy, nitro,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, carboxy, protected
carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl,
protected hydroxymethyl, aminomethyl, protected aminomethyl, or an
N-(methylsulfonylamino) group. As before, when either the
C.sub.1-C.sub.8 alkyl portion or the aryl portion or both are
disubstituted, the substituents can be the same or different. This
group may also appear as the substituted aralkyl moiety of a
substituted aralkoxy group.
[0034] Examples of the term "substituted aralkyl" and this group
when it occurs in a "substituted aralkoxy" group include groups
such as 2-phenyl-1-chloroethyl, 1-phenyl-1-chloromethyl,
1-phenyl-1-bromomethyl, 2-(4-methoxyphenyl)ethyl,
2,6-dihydroxy-4-phenyl(n-hexyl),
5-cyano-3-methoxy-2-phenyl(n-pentyl),
3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl,
6-(4-methoxyphenyl)-3-carboxy(n-hexyl), 5-(4-aminomethyl
phenyl)-3-(aminomethyl)(n-pentyl), and the like.
[0035] The term "carboxy-protecting group" as used herein refers to
one of the ester derivatives of the carboxylic acid group commonly
employed to block or protect the carboxylic acid group while
reactions are carried out on other functional groups on the
compound. Examples of such carboxylic acid protecting groups
include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl,
2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl,
pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl,
4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl
such as t-butyl or t-amyl, trityl, 4-methoxytrityl,
4,4'-dimethoxytrityl, 4,4',4''-trimethoxytrityl, 2-phenylprop-2-yl,
trimethylsilyl, t-butyldimethylsilyl, phenacyl,
2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl,
beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,
4-nitrobenzylsulfonylethyl, allyl, cinnamyl,
1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The
species of carboxy-protecting group employed is not critical so
long as the derivatized carboxylic acid is stable to the condition
of subsequent reaction(s) on other positions of the molecule and
can be removed at the appropriate point without disrupting the
remainder of the molecule. In particular, it is important not to
subject a carboxy-protected molecule to strong nucleophilic bases
or reductive conditions employing highly activated metal catalysts
such as Raney nickel. (Such harsh removal conditions are also to be
avoided when removing amino-protecting groups and
hydroxy-protecting groups, discussed below.) Preferred carboxylic
acid protecting groups are the allyl and p-nitrobenzyl groups.
Similar carboxy-protecting groups used in the cephalosporin,
penicillin and peptide arts can also be used to protect a carboxy
group substituents. Further examples of these groups are found in
T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic
Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, N.Y.,
1991, chapter 5; E. Haslam, "Protective Groups in Organic
Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,
1973, Chapter 5, and T. W. Greene, "Protective Groups in Organic
Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 5.
The term "protected carboxy" refers to a carboxy group substituted
with one of the above carboxy-protecting groups.
[0036] The term "hydroxy-protecting group" as used herein refers to
a derivative of the hydroxy group commonly employed to block or
protect the hydroxy group while reactions are carried out on other
functional groups on the compound. Examples of such protecting
groups include tetrahydropyranyloxy, acetoxy, carbamoyloxy,
trifluoro, chloro, carboxy, bromo and iodo groups. Further examples
of these groups are found in T. W. Greene and P. G. M. Wuts,
"Protective Groups in Organic Synthesis", 2nd ed., John Wiley &
Sons, Inc., New York, N.Y., 1991, chapters 2-3; E. Haslam,
"Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed.,
Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene,
"Protective Groups in Organic Synthesis", John Wiley and Sons, New
York, N.Y., 1981. The term "protected hydroxy" refers to a hydroxy
group substituted with one of the above hydroxy-protecting
groups.
[0037] The term "amino-protecting group" as used herein refers to a
derivative of the groups commonly employed to block or protect an
amino group while reactions are carried out on other functional
groups on the compound. Examples of such protecting groups include
carbamates, amides, alkyl and aryl groups, imines, as well as many
N-heteroatom derivatives which can be removed to regenerate the
desired amine group. Further examples of these groups are found in
T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic
Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, N.Y.,
1991, chapter 7; E. Haslam, "Protective Groups in Organic
Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,
1973, Chapter 5, and T. W. Greene, "Protective Groups in Organic
Synthesis", John Wiley and Sons, New York, N.Y., 1981. The term
"protected amino" refers to an amino group substituted with one of
the above amino-protecting groups.
[0038] The term "inhibitor" means a compound which reduces or
prevents the binding of an alpha4beta1 integrin to a VCAM-1 ligand
or reduces or prevents the binding of an alpha4beta7 integrin to a
MAdCAM-1 ligand or which reduces or prevents the initiation of a
cellular response mediated by the ligand. An "effective amount" is
an amount is an amount sufficient to at least partially inhibit the
binding and may be an inhibitory amount.
[0039] The terms "heterocyclic group", "heterocyclic",
"heterocyclyl", or "heterocyclo" alone and when used as a moiety in
a complex group such as a heterocycloalkyl group, are used
interchangeably and refer to any mono-, bi-, or tricyclic saturated
or non-aromatically unsaturated ring having the number of atoms
designated, generally from 3 to about 10 ring atoms, where the ring
atoms are carbon and 1,2, 3 or 4 nitrogen, sulfur or oxygen atoms.
Typically, a 5-membered ring has 0 to 2 double bonds and 6- or
7-membered ring has 0 to 3 double bonds and the nitrogen or sulfur
heteroatoms may optionally be oxidized, and any nitrogen heteroatom
may optionally be quaternized. Examples include morpholinyl,
pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,
2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl,
thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl,
1-methyl-2-pyrrolyl, piperidinyl, and
3,4,5,6-tetrahydropiperidinyl. A preferred group is the morpholinyl
group.
[0040] A "heterocycloalkyl" or a "heterocycloalkenyl" group is a
heterocyclo group as defined above covalently bonded to an alkyl or
alkenyl group as defined above.
[0041] Unless otherwise specified, "heteroaryl" alone and when used
as a moiety in a complex group such as a heteroaralkyl group,
refers to any mono-, bi-, or tricyclic aromatic ring system having
the number of atoms designated where at least one ring is a 5-, 6-
or 7-membered ring containing from one to four heteroatoms selected
from the group nitrogen, oxygen, and sulfur, and preferably at
least one heteroatom is nitrogen (Lang's Handbook of Chemistry,
supra). Included in the definition are any bicyclic groups where
any of the above heteroaryl rings are fused to a benzene ring.
Heteroaryls in which nitrogen or oxygen is the heteroatom are
preferred.
[0042] The following ring systems are examples of the heteroaryl
(whether substituted or unsubstituted) groups denoted by the term
"heteroaryl": thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,
oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl,
thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,
tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl,
imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl,
tetrazolo[1,5-b]pyridazinyl and purinyl, as well as benzo-fused
derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl,
benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.
[0043] Heterocyclic 5-membered ring systems containing a sulfur or
oxygen atom and one to three nitrogen atoms are also suitable for
use in the instant invention. Examples of such preferred groups
include thiazolyl, in particular thiazol-2-yl and thiazol-2-yl
N-oxide, thiadiazolyl, in particular 1,3,4-thiadiazol-5-yl and
1,2,4-thiadiazol-5-yl, oxazolyl, preferably oxazol-2-yl, and
oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and
1,2,4-oxadiazol-5-yl. A group of further preferred examples of
5-membered ring systems with 2 to 4 nitrogen atoms include
imidazolyl, preferably imidazol-2-yl; triazolyl, preferably
1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and
tetrazolyl, preferably 1H-tetrazol-5-yl. A preferred group of
examples of benzo-fused derivatives are benzoxazol-2-yl,
benzthiazol-2-yl and benzimidazol-2-yl.
[0044] Further suitable specific examples of the above heterocylic
ring systems are 6-membered ring systems containing one to three
nitrogen atoms and optionally a sulfur or oxygen atom. Such
examples include pyridyl, such as pyrid-2-yl, pyrid-3-yl, and
pyrid-4-yl; pyrimidyl, preferably pyrimid-2-yl and pyrimid-4-yl;
triazinyl, preferably 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl;
pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The
pyridine N-oxides and pyridazine N-oxides and the pyridyl,
pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl
groups, are a preferred group. The substituents for the optionally
substituted heterocyclic ring systems, and further examples of the
5- and 6-membered ring systems discussed above can be found in W.
Druckheimer et al, U.S. Pat. No. 4,278,793.
[0045] A particularly preferred group of "heteroaryl" include;
1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,
4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,
1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl,
1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl,
2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl
sodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl,
1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl,
2-methyl-1,3,4-oxadiazol-5-yl,
2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl,
1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl,
2-(methylthio)-1,3,4-thiadiazol-5-yl,
2-amino-1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl,
1-methyl-1H-tetrazol-5-yl,
1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,
1-(carboxymethyl)-1H-tetrazol-5-yl,
1-(carboxymethyl)-1H-tetrazol-5-yl sodium salt, 1-(methylsulfonic
acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl
sodium salt, 2-methyl-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl,
1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl,
4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide,
6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl,
1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl,
1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,
1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl,
2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl,
2,5-dihydro-5-oxo-6-hydroxy-as-triazin-yl sodium salt,
2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl sodium salt,
2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,
2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl,
2,5-dihydro-5-oxo-as-triazin-3-yl,
2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl,
2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl,
tetrazolo[1,5-b]pyridazin-6-yl and
8-aminotetrazolo[1,5-b]-pyridazin-6-yl.
[0046] An alternative group of "heteroaryl" includes;
4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,
4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,
1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl,
1-methyl-1H-tetrazol-5-yl,
1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,
1-(carboxymethyl)-1H-tetrazol-5-yl,
1-(carboxymethyl)-1H-tetrazol-5-yl sodium salt, 1-(methylsulfonic
acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl
sodium salt, 1,2,3-triazol-5-yl,
1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,
1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl,
2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt,
2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,
tetrazolo[1,5-b]pyridazin-6-yl, and
8-aminotetrazolo[1,5-b]pyridazin-6-yl.
[0047] The term "lower" when used with a term such as alkyl to form
"lower alkyl", for example, means containing from 1 to 6 carbon
atoms.
[0048] "Pharmaceutically acceptable salts" include both acid and
base addition salts. "Pharmaceutically acceptable acid addition
salt" refers to those salts which retain the biological
effectiveness and properties of the free bases and which are not
biologically or otherwise undesirable, formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, carbonic acid, phosphoric acid and the like, and organic
acids may be selected from aliphatic, cycloaliphatic, aromatic,
araliphatic, heterocyclic, carboxylic, and sulfonic classes of
organic acids such as formic acid, acetic acid, propionic acid,
glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic
acid, malic acid, maleic acid, maloneic acid, succinic acid,
fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic
acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid,
mandelic acid, embonic acid, phenylacetic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid
and the like.
[0049] "Pharmaceutically acceptable base addition salts" include
those derived from inorganic bases such as sodium, potassium,
lithium, ammonium, calcium, magnesium, iron, zinc, copper,
manganese, aluminum salts and the like. Particularly preferred are
the ammonium, potassium, sodium, calcium and magnesium salts. Salts
derived from pharmaceutically acceptable organic nontoxic bases
includes salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
isopropylamine, trimethylamine, diethylamine, triethylamine,
tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, ethylenediamine, glucosamine,
methylglucamine, theobromine, purines, piperizine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Particularly
preferred organic non-toxic bases are isopropylamine, diethylamine,
ethanolamine, trimethamine, dicyclohexylamine, choline, and
caffeine.
[0050] The term "prodrug" as used herein means a derivative of a
parent drug molecule that enhances pharmaceutically desirable
characteristics or properties (e.g. transport, bioavailablity,
pharmacodynamics, etc.) and that requires biotransformation, either
spontaneous or enzymatic, within the organism to release the active
parent drug.
[0051] The following definitions are used herein:
[0052] DIPC: diisopropylcarbodiimide
[0053] DMAP: dimethylaminopyridine
[0054] FMOC: fluorenylmethoxycarbonyl
[0055] DMA: dimethylacetamide
[0056] HBTU: 2-(H-benzotriazole)-1-yl-1,1,3,3-tetramethyluronium
hexafluorophosphate
[0057] HOBT: N-hydroxy benzotriazole
[0058] TFA: trifluoracetic acid
[0059] HPLC: high pressure liquid chromatography
[0060] NMM: N-methylmorpholine
[0061] DIPEA: diisopropyethylamine
[0062] DCM: dichloromethane
[0063] THF: tetrahydrofuran
[0064] NMP: N-methylpyrolidone
[0065] CDI: carbonyldiimidazole
B. Preferred Embodiments
[0066] The compounds of the invention have the general structures
I, II and III shown below.
##STR00004##
where A, Z, Y, X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are as defined
above, both generally and preferably.
[0067] The compounds of the invention contain one or more
asymmetric carbon atoms. Accordingly, the compounds may exist as
diasteriomers, enantiomers or mixtures thereof. The syntheses
described above may employ racemates, diasteriomers or enantiomers
as starting materials or as intermediates. Diasteriomeric compounds
may be separated by chromatographic or crystallization methods.
Similarly, enantiomeric mixtures may be separated using the same
techniques or others known in the art. Each of the asymmetric
carbon atoms may be in the R or S configuration and both of these
configurations are within the scope of the invention. Compounds
having the S configuration are preferred.
[0068] In one preferred embodiment, X.sub.1 in structure I is
C(O)OR, C(O)R, or C(O)SR, more preferably C(O)NRaRb, with the
remaining variables A, Z, Y, X.sub.2, X.sub.3 and X.sub.4 having
any of the definitions given above. The X.sub.1 group is preferably
in the para position relative to the point of ring attachment, but
may also be preferably in the meta position. Ra and Rb together
with the nitrogen to which they are attached may preferably form a
5-membered or 6-membered heterocyclyl or heteroaryl group
substituted with 0-5 substituents R. The heterocyclyl or heteroaryl
ring system will preferably contain one nitrogen atom, but may also
preferably contain another nitrogen or an oxygen atom in the ring
system. The hetero ring systems may contain fused heterocyclyl or
heteroaryl rings or a combination of both and the rings may be
substituted or unsubstitued. Representative examples of suitable
specific heterocyclyl and heteroaryl groups are:
##STR00005##
[0069] In a particular embodiment, X.sub.1 is any one of the groups
shown in table 2 below which is designated as substituent R when
combined with the carbonyl from which it depends.
[0070] R, Ra and Rb may also be non-cyclic, for example an hydrogen
or alkyl, aryl, heterocyclyl, heteroaryl, substituted with 0-4
substituents selected from the group consisting of halogen,
hydroxy, amino, carboxyl, nitro, cyano, heterocylyl, heteroaryl,
aryl, aroyl, aryloxy, alkylenedioxy, lower alkoxycarbonyl, lower
alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy,
lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower
alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl
lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl,
alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio
lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower
alkyl, halo lower alkyl, alkoxy lower alkyl; optionally substituted
as described above. Preferred groups are substituted and
unsubstituted lower alkyl, lower alkenyl, aryl, and aryl lower
alkyl. Some representative examples of such R, Ra and Rb groups are
shown below:
##STR00006## ##STR00007##
[0071] In a particular embodiment, A has the structure:
##STR00008##
in which
[0072] B is cyanoalkyl, a carbocycle or a heterocycle optionally
substituted with one or more R.sub.1 substituents;
[0073] q is 0-3;
[0074] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6
independently are hydrogen, alkyl, amino, alkylamino, dialkylamino,
nitro, urea, cyano, thio, alkylthio, hydroxy, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylamino, aryloxycarbonylamino,
alkylsulfinyl, sulfonyl, alkylsulfonyl, aralkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkanoyl, alkanoylamino,
cycloalkanoylamino, aryl, arylalkyl, halogen, or alkylphosphonyl,
and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are substituted
with 0-3 substituents selected from the group consisting of
hydroxy, carboxyl, lower alkoxycarbonyl, lower alkyl, nitro, oxo,
cyano, carbocyclyl, heterocyclyl, heteroaryl, lower alkylthio,
lower alkoxy, lower alkylamino, lower alkanoylamino, lower
alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl,
aryl, aroyl, heterocyclylcarbonyl, halogen and lower
alkylphosphonyl; or two of R.sub.1 to R.sub.5 together form a
carbocycle or heterocyclic ring. In a preferred embodiment, A is
the group
##STR00009##
where preferably R.sub.1, R.sub.5 or both R.sub.1 and R.sub.5 are
not hydrogen. That is, preferred A groups are ortho-substituted
benzoyl groups. Particularly preferred ortho substituents are
chloro, bromo, amino and hydroxy. In addition to R.sub.1 and/or
R.sub.5, the phenyl ring of the benzoyl may preferably have one or
two additional substituents at R.sub.2, R.sub.3 or R.sub.4.
Preferred R.sub.1, R.sub.2, R.sub.3 R.sub.4, and R.sub.5 include
nitro, halogen (Cl, Br, F, I), amino, aryl, lower alkyl, lower
alkylthio, lower alkoxy, lower alkylamino, lower alkyl sulfinyl,
lower alkylsulfonyl, lower alkanoyl, and lower alkylphosphonyl,
which may each be substituted or unsubstituted. Some representative
examples include:
##STR00010## ##STR00011##
[0075] In a particular embodiment, A is any one of the groups shown
in table 2 which is designated as substituent R'.
[0076] Y is preferably OH or an ester or pharmaceutically
acceptable carboxylic acid salt thereof. Preferred esters are
substituted or unsubstituted alkyl, alkenyl, aryl, and aryl alkyl
esters.
[0077] Z is preferably hydrogen.
[0078] Preferred X.sub.2, X.sub.3 and X.sub.4 include halogen,
alkyl, amino, alkylamino, and alkyl carbonylamino, the alkyl group
of which may be substituted or unsubstituted. For compounds having
structure I, X.sub.2 and X.sub.3 are more preferably hydrogen. For
compounds having structure II, X.sub.2, X.sub.3 and X.sub.4 are
more preferably hydrogen.
[0079] In another embodiment, preferred compounds have structure I,
the S configuration, the OX.sub.1 group is in the 4-position on the
phenyl ring, Z is hydrogen, X.sub.1 is C(O)NRaRb, and Y is OH or a
salt or prodrug thereof.
[0080] In another embodiment, preferred compounds have structure I,
the S configuration, the OX.sub.1 group is in the 4-position on the
phenyl ring, Z is hydrogen, X.sub.1 is C(O)NRaRb, Y is OH, and
R.sub.3, R.sub.5, X.sub.2, and X.sub.3 are all hydrogen or a salt
or prodrug thereof.
[0081] In another embodiment, preferred compounds have structure I,
the S configuration, the OX.sub.1 group is in the 4-position on the
phenyl ring, Z is hydrogen, X.sub.1 is C(O)NRaRb, Y is OH, Ra and
Rb together with the nitrogen atom to which they are attached form
a substituted or unsubstituted 5-membered or 6-membered
heterocyclic or heteroaromatic ring; R.sub.3, R.sub.5, X.sub.2, and
X.sub.3 are all hydrogen, or a salt or prodrug thereof.
[0082] In another embodiment, preferred compounds have structure I,
the S configuration, the OX.sub.1 group is in the 4-position on the
phenyl ring, Z is hydrogen, X.sub.1 is C(O)NRaRb, Y is OH, Ra and
Rb together with the nitrogen atom to which they are attached form
a substituted or unsubstituted 5-membered or 6-membered
heterocyclic ring containing up to 2 additional nitrogen atoms,
oxygen atoms or a combination thereof, R.sub.2, R.sub.3 R.sub.4,
R.sub.5, X.sub.2, and X.sub.3 are all hydrogen, or a salt or
prodrug thereof.
[0083] In another embodiment, preferred compounds have structure I,
the S configuration, the OX.sub.1 group is in the 4-position on the
phenyl ring, Z is hydrogen, X.sub.1 is C(O)NRaRb, Y is OH, Ra and
Rb together with the nitrogen atom to which they are attached form
an unsubstituted 5-membered or 6-membered heterocyclic ring or such
a ring substituted with 1-3 lower alkoxy, lower alkylamino, lower
alkyl, lower alkoxycarbonyl, lower alkylenedioxy, lower alkylthio,
lower alkenyl, lower cyanoalkyl, phenyl, phenoxy or halo groups;
R.sub.2, R.sub.3 R.sub.4, R.sub.5, X.sub.2, and X.sub.3 are all
hydrogen, or a salt or prodrug thereof.
[0084] In another embodiment, preferred compounds have structure I,
the S configuration, the OX, group is in the 4-position on the
phenyl ring, Z is hydrogen, X.sub.1 is C(O)NRaRb, Y is OH, Ra and
Rb, are independently, substituted or unsubstituted alkyl, aryl,
arylalkyl, heterocylyl, heteroaryl, heterocyclylalkyl,
heteroarylalkyl or cycloalkylalkyl; R.sub.3, R.sub.5, X.sub.2, and
X.sub.3 are all hydrogen, or a salt or prodrug thereof.
[0085] In another embodiment, preferred compounds have structure I,
the S configuration, the OX.sub.1 group is in the 4-position on the
phenyl ring, Z is hydrogen, X.sub.1 is C(O)NRaRb, Y is OH, Ra and
Rb, are independently, substituted or unsubstituted alkyl, aryl,
arylalkyl, heterocylyl, heteroaryl, heterocyclylalkyl,
heteroarylalkyl or cycloalkylalkyl; R.sub.2, R.sub.3 R.sub.4,
R.sub.5, X.sub.2, and X.sub.3 are all hydrogen, or a salt or
prodrug thereof.
C. Uses
[0086] The compounds of the invention inhibit the binding of
alpha4beta1 and alpha4beta7 on lymphocytes, eosinophiles,
basophiles and monocytes to a cell expressing VCAM-1 and/or MAdCAM
on the cell surface. The inhibitory compounds of the invention are
useful to prevent the interaction of an epithelial cell bearing
VCAM-1 and/or MAdCAM on the cell surface with a leukocyte cell
bearing alpha4beta1 and/or alpha4beta7 on the surface by contacting
the epithelial cell or the leukocyte with an inhibitory amount of
the compound of the invention. The compounds are useful in assays
to determine the inhibitory effect of a compound which antagonizes
the binding of alpha4beta1 and/or alpha4beta7 integrin to VCAM-1
ligand and/or MAdCAM ligand. The inhibitory compound may be a small
molecule, a protein or peptide or an antibody. In an in vitro
assay, the ligand or the integrin may be directly or indirectly
bound to a surface, such as microtiter plate, using known methods
described for example in WO 9820110, WO 9413312, WO 9624673, WO
9806248, WO 9936393, and WO 9910312. The other member of the
binding pair, e.g. the integrin or the ligand, respectively, (or a
cell expressing the same on its surface) is then added to the
surface bound member and the inhibitory effect of a test molecule
is determined. The inhibitory activity of the compounds of the
invention can also be determined with this type of assay.
[0087] The binding of the integrins to their respective ligands is
known to be involved in inflammatory conditions associated with
leukocyte infiltration of tissues lined with epithelial cells
expressing VCAM-1 or MAdCAM. Such tissues include the
gastrointestinal tract, skin, urinary tract, respiratory airways
and joint synovial tissues. The compounds of the invention are
useful in treating diseases in which such binding is implicated as
a cause of the disease or symptoms of the disease. Undesired
disease symptoms may arise from cell adhesin and/or cell activation
which releases proinflammatory mediators, typically when there is
an increase or upregulation in the expression of VCAM-1 and/or
MAdCAM on the surface of endothelial cells. Various disease states
which can be treated and for which the inflammatory symptoms can be
reduced upon administration of the compounds of the invention
include rheumatoid arthritis, asthma, psoriasis, multiple
sclerosis, inflammatory bowel disease including ulcerative colitis,
pouchitis and Crohn's disease, Celiac disease, nontropical Sprue,
graft-versus-host disease, pancreatitis, insulin-dependent diabetes
mellitus, mastitis, cholecystitis, pericholangitis, chronic
sinusitis, chronic bronchitis, pneumonitis, collagen disease,
eczema, and systemic lupus erythematosis. The compounds of the
invention are useful in treating these diseases and conditions by
inhibiting the integrin/ligand binding.
[0088] The compounds of the invention can be assayed for ability to
block the alpha4beta7/MAdCAM-1 or alpha4beta1/VCAM-1 binding
interaction by addition of serial dilutions of the samples to
plates with the receptors as follows. 96-well plates are coated
with mouse anti-human alpha4 (31470D, PharMingen, San Diego,
Calif.). The plates are decanted and blocked with 0.5% BSA. After
washing alpha.sub.4beta.sub.7 or alpha.sub.4beta1 is added,
followed by incubation for 2 h at room temperature. The plates are
washed and samples of the small molecule antagonists are added to
the plates with MAdCAM-1-Ig-HRP or VCAM-1-Ig-HRP for 2 h at room
temperature. After an additional wash, the bound MAdCAM-1-Ig-HRP or
VCAM-1-Ig-HRP is detected by addition of tetramethylbenzidine (TMB,
Kirkegaard & Perry, Gaithersberg, Md.), followed by detection
of the absorbance of the product.
[0089] Alternatively, the compounds can be assayed using any known
protein-protein or cell-based assay method, such as those
described, for example, in WO 99/10312 (examples 179-180) and WO
99/36393 (RPMI-CS-1 cell adhesion assay); Cardarelli et al., 1994,
J. Biol. Chem., 269:18668-18673; and Viney et al, J. Immunol.,
1996, 157: 2488-2497 (cell adhesion assay).
[0090] For example, 96-well ELISA plates are coated overnight at
4.degree. C. with 2 .mu.g/ml with anti-human CD49d, (31470D,
PharMingen, San Diego, Calif.) in phosphate buffered saline. The
plates are decanted and blocked with assay buffer (50 mM Tris-HCl,
pH 7.5, 150 mM NaCl, 1 mM MnCl.sub.2, 0.05% Tween-20 and 0.5% BSA)
at room temperature for one hour, with gentle shaking. The plates
are washed three times (in 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1
mM MnCl.sub.2, 0.05% Tween-20) and 2 .mu.g/ml of the desired
integrin (Genentech, Inc.) in assay buffer is added, followed by
incubation at room temperature for two hours, with gentle shaking.
After washing three times, 50 .mu.l of samples of the small
molecule antagonists (serial dilutions from 10 mM stocks in 100%
DMSO) are added to the plates with 50 .mu.l of 1 .mu.g/ml
MAdCAM-1-Ig-HRP or VCAM-1-Ig-HRP (Genentech, Inc) in assay buffer.
The plates are incubated two hours at room temperature, with gentle
shaking, followed by washing six times. The bound MAdCAM-1-Ig-HRP
or VCAM-1-Ig-HRP is detected by addition of the peroxidase
substrate, 3, 3', 5, 5', tetramethylbenzidine (TMB, Kirkegaard
& Perry, Gaithersberg, Md.), for 10 minutes, followed by
addition of 1M phosphoric acid to stop the reaction. The absorbance
of the solutions are read at 450 nm on a plate reader.
[0091] Suitable animal models exist for many diseases and
conditions which can be treated with the compounds of the
invention. Additional confirmation of the efficacy of these
compounds in specific diseases and at desired doses can be assayed
using these established models. For example, animal models of
chronic inflammatory diseases such as asthma (Laberge, S. et al.,
Am. J. Respir. Crit. Care Med., 1995, 151:822-829.), rheumatoid
arthritis (RA; Barbadillo, C. et al., Springer Semin.
Immunopathol., 1995, 16:375-379), colitis (Viney et al, J.
Immunol., 1996, 157: 2488-2497) and inflammatory bowel diseases
(IBD; Podalski, D. K., N. Eng. J. Med., 1991, 325:928-937; Powrie,
F. et al., Ther. Immunol., 1995, 2:115-123) may be used to
demonstrate the activity of the compounds of the invention and to
conduct dose and efficacy studies.
[0092] The invention also includes pharmaceutical compositions or
medicaments containing the compounds of the invention and a
therapeutically inert carrier or excipient, as well as methods of
using the compounds of the invention to prepare such compositions
and medicaments. Typically, the inhibitors used in the method of
this invention are formulated by mixing at ambient temperature at
the appropriate pH, and at the desired degree of purity, with
physiologically acceptable carriers, i.e., carriers that are
non-toxic to recipients at the dosages and concentrations employed
into a galenical administration form. The pH of the formulation
depends mainly on the particular use and the concentration of
compound, but preferably ranges anywhere from about 3 to about 8.
Formulation in an acetate buffer at pH 5 is a suitable
embodiment.
[0093] The inhibitory compound for use herein is preferably
sterile. The compound ordinarily will be stored as a solid
composition, although lyophilized formulations or aqueous solutions
are acceptable.
[0094] The composition of the invention will be formulated, dosed,
and administered in a fashion consistent with good medical
practice. Factors for consideration in this context include the
particular disorder being treated, the particular mammal being
treated, the clinical condition of the individual patient, the
cause of the disorder, the site of delivery of the agent, the
method of administration, the scheduling of administration, and
other factors known to medical practitioners. The "effective
amount" of the compound to be administered will be governed by such
considerations, and is the minimum amount necessary to prevent,
ameliorate, or treat the alpha4 mediated disorder. Such amount is
preferably below the amount that is toxic to the host or renders
the host significantly more susceptible to severe infection.
[0095] As a general proposition, the initial pharmaceutically
effective amount of the inhibitor administered parenterally per
dose will be in the range of about 0.01-100 mg/kg, preferably about
0.1 to 20 mg/kg of patient body weight per day, with the typical
initial range of compound used being 0.3 to 15 mg/kg/day. Oral unit
dosage forms, such as tablets and capsules, preferably contain from
about 25 to about 1000 mg of the compound of the invention.
[0096] The compound of the invention may be administered by any
suitable means, including oral, topical, transdermal, parenteral,
subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and,
if desired for local immunosuppressive treatment, intralesional
administration. Parenteral infusions include intramuscular,
intravenous, intraarterial, intraperitoneal, or subcutaneous
administration.
[0097] An example of a suitable oral dosage form is a tablet
containing 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg of the compound
of the invention compounded with about 90-30 mg anhydrous lactose,
about 5-40 mg sodium croscarmellose, about 5-30 mg
polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium
stearate. The powdered ingredients are first mixed together and
then mixed with a solution of the PVP. The resulting composition
can be dried, granulated, mixed with the magnesium stearate and
compressed to tablet form using conventional equipment. An aerosol
formulation can be prepared by dissolving the compound, for example
5-400 mg, of the invention in a suitable buffer solution, e.g. a
phosphate buffer, adding a tonicifier, e.g. a salt such sodium
chloride, if desired. The solution is typically filtered, e.g.
using a 0.2 micron filter, to remove impurities and
contaminants.
D. Methods of Making
Synthesis of Acyltyrosine Compounds (I)
[0098] I. Solid Phase Synthesis:
[0099] The compounds of invention are prepared from tyrosine and
tyrosine derivatives using known chemical reactions and according
to the method shown below.
##STR00012##
[0100] In this method, the amino group of tyrosine or a derivative
thereof is reacted with an acyl halide of the formula ZC(O)Hal,
where Hal is a halogen, preferably Cl or Br, or an acyl anhydride
of the formula ZC(O)OC(O)Z to acylate the amino nitrogen atom.
Typically, the reaction conditions are dilute base in a suitable
solvent, for example bicarbonate in water/THF. Other suitable mild
bases and solvents/solvent mixtures will be readily apparent to
those having ordinary skill in organic synthesis. Numerous starting
tyrosine derivatives are commercially available or can be readily
synthesized using standard chemical reactions. An example of the
synthesis of a compound within the scope of the invention is shown
below.
##STR00013##
In this scheme, R may be any suitable group which is non-reactive
under the reaction conditions. Examples of suitable R groups
include substituted and unsubstituted alkyl, alkenyl, aryl,
arylalkyl, etc. Additional compounds of the invention can then be
prepared by acylating the phenyl hydroxy group with an activated
carbonyl followed by the formation of a carbamate, carbonate or
thiocarbamate as described below.
[0101] Solid phase reaction chemistry provides a convenient method
for synthesizing the compounds of the invention. FMOC- or
BOC-protected amino acids and derivatives thereof are readily
available and can be used as starting materials in the synthesis of
the compounds of the invention. The protected amino acid is
initially attached to a synthetic resin having an available
coupling group, such as an available hydroxy (e.g. benzyloxy resin
beads). Coupling is achieved using known chemical reactions, e.g.
condensation reactions using for example DIPC or DMAP, to attach
the amino acid to the solid support. Any known coupling reactions
and resin surfaces may be used. The amino nitrogen is then
deprotected using, for example, a weak base such as piperidine or
other suitable base. The free amino group can then be reacted with
an activated ester such a HBTU or HOBT ester of a suitable benzoic
acid to form the desired A group. The resulting hydroxy compounds
are within the scope of the invention.
[0102] Additional compounds can be prepared by further reacting the
hydroxy group to form esters, carbamates, carbonates, etc. using
known chemistry. For example, the hydroxy compounds can be reacted
with a carbonyl synthon such as phosgene, carbonyldiimidazole or
p-nitrophenylformate followed by a primary or secondary amine,
including cyclic amines, to form carbamates as shown in the
reaction scheme below.
##STR00014##
In this scheme, a=DIPC cat./DMAP; b=20% piperidine/DMA or DMF; c=a
substituted benzoic acid/HBTU or other amide coupling agent/TEA or
other weak base; d=primary or secondary amine;
e=TFA/triethylsilane, for example.
[0103] Compounds of structure I were typically synthesized manually
via solid phase synthesis on p-alkoxybenzyl alcohol resin (Advanced
Chemtech, USA) as shown above. Commercially available FMOC
protected tyrosine or other tyrosine analogs (X2/X3) were purchased
from BACHEM Ca., Advanced ChemTech U.S.A., or Calbiochem Corp.
(Ca.). Typically 1 mmol of FMOC-tyrosine (or tyrosine analog) was
added to 1 g of p-alkoxybenzylalcohol resin in 50 mL
dichloromethane. Diisopropylcarbodiimide (DIPC, 1 mmol) was added
followed by catalytic dimethylaminopyridine (DMAP, 0.1 mmol) and
the resulting mixture was stirred under nitrogen at 20 C. for 4
hours. The resin was then washed with dichloromethane and
dimethylacetamide (DMA) and the FMOC group was removed via mixing
with 20% piperidine in DMA for fifteen minutes. The resin was then
washed three times with DMA to remove excess piperidine.
[0104] Ortho-Chlorobenzoic acid (2 mmol) or other substituted
benzoic acid was mixed with HBTU (2 mmol) or other suitable
activating agent in 20 mL of DMA and added the previously washed
resin. N-methylmorpholine or triethylamine (4 mmol) was added and
the mixture was sparged with nitrogen for 30 minutes. The resin was
washed with dichloromethane and treated with 2 mmol of
p-nitrophenylchloroformate (phosgene or carbonyldiimidazole can
also be used) and 0.05 mmol DMAP in 20 mL of DMA for 1 h. Excess
reagents were washed away and 2 mmol of morpholine or other
substituted amine RaRb--NH in 20 mL dichloromethane was added. The
mixture was sparged overnight at room temperature and washed with
dichlormethane.
[0105] Treatment with TFA containing 5% triethylsilane for 1 hour
afforded the crude product. The crude material was extracted from
the resin by stirring with 100 mL of 2:1 H.sub.2O/CH.sub.3CN for 5
minutes followed by filtration to remove the resin. The crude
filtrate was lyophilized and purified by preparative reverse phase
C.sub.18 HPLC(CH.sub.3CN/H.sub.2O gradient, 0.1% TFA) to afford
purified material. Pure fractions (>98% pure by analytical HPLC)
were characterized by electrospray ionization mass spectrometry
(Sciex API100) and proton NMR, lyophilized to dryness and
resuspended in DMSO at 10 mM just prior to biological assay. Serial
dilutions of
peptide starting at 0.5 mM were titrated into an ELISA format assay
and the IC.sub.50 for each compound was determined.
[0106] II. Solution Phase Synthesis:
[0107] Alternatively, inhibitors with general structure I can be
synthesized in three steps via solution phase chemistry starting
with commercially available (L)-tyrosine or tyrosine analogs having
substituents at X2/X3 and/or Y. A general synthesis of type I
Analogs is depicted below. This type of synthesis is amenable to
scale up and for introducing ester prodrugs.
[0108] Typically, 100 mmols of (L)-tyrosine or similar tyrosine
analog is dissolved in 500 mL THF/H.sub.2O (1:1) and 300 mmols of
sodium bicarbonate is added followed by 110 mmols (1.1 eq.) of a
suitable benzoyl chloride or anhydride of general structure Z-COCl.
The solution is stirred at room temperature for 1 h. The mixture is
concentrated via rotary evaporation and acidified to pH<3 with
1N HCL. The acidified solution is extracted with ethyl acetate and
the organic layer is washed with satd. NaCl and evaporated to
dryness. Crystallization of the crude material from
ethylacetate/hexane affords pure compound as determined by
analytical HPLC (average yield; 75 mmol or 75%).
[0109] If a suitable benzoyl chloride or anhydride is not available
then the corresponding substituted benzoic acid (100 mmols) is used
in combination with HBTU or other amide coupling reagent. If this
route is employed, 100 mmols of (L)-tyrosine or similar tyrosine
analog is dissolved in 250 mL of dimethylformamide. In a separate
vessel, the appropriate benzoic acid (110 mmols) in DMF is mixed
with 110 mmols of HBTU or other amide coupling agent and 300 mmols
of triethylamine or other weak base (NMM, DIPEA etc.). The mixture
is allowed to stand for 10 minutes and then added to the tyrosine
in one portion. After stirring for 1 hour at room temperature, the
reaction mixture is concentrated under high vacuum and resuspended
in ethyl acetate. The suspension is washed with 1N HCL, water and
satd. NaCl and evaporated to dryness. Crystallization affords pure
compound (average yield; 66 mmol or 66%).
[0110] Purified 2 (50 mmols) is dissolved in 400 mL of THF and 100
mmols of TEA (or other base) is added followed by 50 mmol of
p-nitrophenylchloroformate (phosgene or carbonyldiimidazole can
also be used). The reaction is stirred for 1 hour at room temp,
filtered and the filtrate is concentrated to dryness to afford
crude compound which can be isolated via crystallization from
ethyacetate/hexane or used directly in the next step. If phosgene
or CDI is used instead of p-nitrophenylchloroformate then isolation
at this stage is not an option and an appropriate amine RaRb--NH is
added to the above reaction 30 minutes after the addition of
p-nitrophenylchloroformate.
[0111] The p-nitrophenylcarbonate (10 mmol is dissolved in 100 ml
of THF, 15 mmol of an appropriate amine RaRb--NH is added, and the
reaction is stirred overnight at room temp. The solvent is
evaporated and the resulting residue is tritrated with hexane to
remove byproducts. Crystallization affords the desired
O-carbamoyl-N-acyltyrosine inhibitor.
##STR00015##
Synthesis of Biphenylalanine Compounds (II).
[0112] The biphenyl compounds of structure II can be synthesized
starting from substituted or unsubstituted halo phenylalanine
compounds as shown below. The protected amino acid starting
material can be coupled to a resin as described above or using any
known resin/coupling reaction system known in the art. The biphenyl
ring system can then be prepared by reacting the halo amino acid
with a substituted or unsubstituted phenyl boronic acid. If
desired, a substituent on one of the phenyl rings may then be
further elaborated using known chemical reactions. For example, a
substituent containing a nitrogen atom can be further modified to
provide amides, carbamates, etc. A substituent having a hydroxy or
carboxy group can be converted to an ester, carbonate, etc.
##STR00016##
[0113] A representative synthetic procedure for preparing the
compounds of the invention is set forth below and refers to the
scheme shown above.
[0114] Halo-N-FMOC-Phe 1 (10 mmol) is suspended in 80 mL of DCM
along with Wang resin (8 mmol) in a peptide synthesis flask with
bubbling N.sub.2 gas providing agitation. DIPC is added to a 0.25 M
concentration followed by DMAP (1 mmol) and the reaction bubbled
for 16 h. After washing the resin (3.times.80 mL with alternating
DMF, methanol, and DCM) the resin is treated with 80 mL of 25%
piperidine in NMP for 1 h followed by another wash cycle. A
solution of 0.25 M 2-Chlorobenzoic acid, HOBT, HBTU, and DIPEA in
NMP is stirred for 0.5 h prior to addition to the resin 2. The
reaction bubbled for 16 h and is washed as before. 100 mg portions
of the resin can then be transferred to reaction vessels on the
Argonaut Quest 210 parallel synthesis instrument and suspended with
0.25 M boronic acid and DIPEA in 3 mL of degassed NMP that
contained Pd(PPh.sub.3).sub.2Cl.sub.2 catalyst. The reactions were
stirred magnetically and heated to 80 degrees C. for 16 h. The
resin 3 was washed (3.times.5 mL with alternating DMF, methanol,
and DCM). When in the previous step a formyl substituted boronic
acid was used, the resin was swelled with 0.5 M amine in 2 mL of 2%
AcOH/NMP. After 1 h of stirring a 2 mL portion of 0.5 M
Na(OAc).sub.3BH in NMP was added, followed by agitation for 16 h.
After washing the resin 3 or 4 as before, 2 mL of TFA that
contained 5% DCM and 2% triethylsilane was added followed by 1 h of
agitation and filtration. The resin was washed with 1 mL of DCM and
combined with the original filtrate. The reductive amination and
TFA deblocking were also performed in polypropylene 48 well
reaction blocks. The TFA was evaporated either by a vacuum
centrifuge or via a stream of nitrogen gas to yield 20 mg of crude
oil containing products 5 that were purified on HPLC and confirmed
by Electrospray mass spectroscopy.
[0115] In cases where primary amines were used, compounds 4 can be
further elaborated using standard methods to prepare sulfonamides
6, amides and carbamates 7, and disubstituted amines 8 as shown
below.
##STR00017##
[0116] The free alpha carboxylic acid may be converted to an ester
or to an amide using reactions well known in the art. For example,
a free carboxyl group can be reacted with a suitable alcohol in the
presence of an acid to esterify the carboxyl group using well known
reactions and reagents. Similarly, amides are formed by reacting
the carboxylic acid with an amine with removal of the water
produced by the condensation using known methods. A example of a
reaction for esterification is shown below.
##STR00018##
[0117] Also included in the scope of this invention are prodrugs of
the compounds described above. Suitable prodrugs include known
amino-protecting and carboxy-protecting groups which are released,
for example hydrolyzed, to yield the parent compound under
physiologic conditions. A preferred class of prodrugs are compounds
in which a nitrogen atom in an amino, amidino, aminoalkyleneamino,
iminoalkyleneamino or guanidino group is substituted with a hydroxy
(OH) group, an alkylcarbonyl (--CO--W) group, an alkoxycarbonyl
(--CO--OW), an acyloxyalkyl-alkoxycarbonyl (--CO--O--W--O--CO--W)
group where W is a monovalent or divalent group and as defined
above or a group having the formula --C(O)--O--CP1P2-haloalkyl,
where P1 and P2 are the same or different and are H, lower alkyl,
lower alkoxy, cyano, halo lower alkyl or aryl. Preferably the
nitrogen atom is one of the nitrogen atoms of the amidino group of
the compounds of the invention. These prodrug compounds are
prepared reacting the compounds of the invention described above
with an activated acyl compound to bond a nitrogen atom in the
compound of the invention to the carbonyl of the activated acyl
compound. Suitable activated carbonyl compounds contain a good
leaving group bonded to the carbonyl carbon and include acyl
halides, acyl amines, acyl pyridinium salts, acyl alkoxides, in
particular acyl phenoxides such as p-nitrophenoxy acyl,
dinitrophenoxy acyl, fluorophenoxy acyl, and defluorophenoxy acyl.
The reactions are generally exothermic and are carried out in inert
solvents at reduced temperatures such as -78 to about 50 C. The
reactions are usually also carried out in the presence of an
inorganic base such as potassium carbonate or sodium bicarbonate,
or an organic base such as an amine, including pyridine,
triethylamine, etc. One manner of preparing prodrugs is described
in U.S. Ser. No. 08/843,369 filed Apr. 15, 1997 the contents of
which are incorporated herein by reference in their entirety.
EXAMPLES
[0118] The invention will be more fully understood by reference to
the following examples. They should not, however, be construed as
limiting the scope of the invention. All patent and literature
citations are herein incorporated by reference in their
entirety.
[0119] Specific and representative compounds have been prepared and
assayed for inhibitory binding activity using the methods described
above and are shown in table 1 below. In the assay results, A
represents an IC.sub.50 value greater than 1.0 micromolar and B
represents an IC.sub.50 value less than 1.0 micromolar.
TABLE-US-00001 TABLE 1 Compound Assay Structure number Result
##STR00019## 001 B ##STR00020## 002 B ##STR00021## 003 B
##STR00022## 004 B ##STR00023## 005 B ##STR00024## 006 B
##STR00025## 007 B ##STR00026## 008 B ##STR00027## 009 B
##STR00028## 010 B ##STR00029## 011 B ##STR00030## 012 B
##STR00031## 013 B ##STR00032## 014 B ##STR00033## 015 B
##STR00034## 016 B ##STR00035## 017 B ##STR00036## 018 B
##STR00037## 019 B ##STR00038## 020 B ##STR00039## 021 B
##STR00040## 022 B ##STR00041## 023 B ##STR00042## 024 B
##STR00043## 025 B ##STR00044## 026 B ##STR00045## 027 B
##STR00046## 028 B ##STR00047## 029 B ##STR00048## 030 B
##STR00049## 031 B ##STR00050## 032 B ##STR00051## 033 B
##STR00052## 034 B ##STR00053## 035 B ##STR00054## 036 B
##STR00055## 037 B ##STR00056## 038 B ##STR00057## 039 B
##STR00058## 040 B ##STR00059## 041 B ##STR00060## 042 B
##STR00061## 043 A ##STR00062## 044 A ##STR00063## 045 A
##STR00064## 046 A ##STR00065## 047 A ##STR00066## 048 A
##STR00067## 049 A ##STR00068## 050 A ##STR00069## 051 A
##STR00070## 052 A ##STR00071## 053 A ##STR00072## 054 A
##STR00073## 055 A ##STR00074## 056 A ##STR00075## 057 A
##STR00076## 058 B ##STR00077## 059 B ##STR00078## 060 B
##STR00079## 061 B ##STR00080## 062 B ##STR00081## 063 B
##STR00082## 064 B ##STR00083## 065 B ##STR00084## 066 B
##STR00085## 067 B ##STR00086## 068 B ##STR00087## 069 B
##STR00088## 070 B ##STR00089## 071 B ##STR00090## 072 B
##STR00091## 073 B ##STR00092## 074 B ##STR00093## 075 B
##STR00094## 076 B ##STR00095## 077 B ##STR00096## 078 B
##STR00097## 079 B ##STR00098## 080 B ##STR00099## 081 B
##STR00100## 082 B ##STR00101## 083 B ##STR00102## 084 B
##STR00103## 085 B ##STR00104## 086 B ##STR00105## 087 B
##STR00106## 088 B ##STR00107## 089 B ##STR00108## 090 B
##STR00109## 091 B ##STR00110## 092 B ##STR00111## 093 B
##STR00112## 094 B ##STR00113## 095 B ##STR00114## 096 B
##STR00115## 097 B ##STR00116## 098 B ##STR00117## 099 B
##STR00118## 100 B ##STR00119## 101 B ##STR00120## 102 B
##STR00121## 103 B ##STR00122## 104 A ##STR00123## 105 A
##STR00124## 106 A ##STR00125## 107 A ##STR00126## 108 A
##STR00127## 109 A ##STR00128## 111 B ##STR00129## 112 B
##STR00130## 113 B ##STR00131## 114 B ##STR00132## 115 B
##STR00133## 116 A ##STR00134## 117 B ##STR00135## 118 B
##STR00136## 119 B ##STR00137## 120 B ##STR00138## 121 B
##STR00139## 122 B ##STR00140## 123 B ##STR00141## 124 B
##STR00142## 125 B ##STR00143## 126 B ##STR00144## 127 B
##STR00145## 128 B
[0120] The following table 2 illustrates further compounds prepared
and assayed, each of which was found to inhibit binding activity
exhibiting an IC.sub.50 value less than 1.0 micromolar using the
methods described above.
TABLE-US-00002 TABLE 2 ##STR00146## R R'- compd no. ##STR00147##
##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152##
##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157##
##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162##
##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167##
##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172##
##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177##
##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182##
##STR00183## ##STR00184## ##STR00185## ##STR00186## ##STR00187##
##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192##
##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197##
##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202##
##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207##
##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212##
##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217##
##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222##
##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227##
##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232##
##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237##
##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242##
##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247##
##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252##
##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257##
##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262##
##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267##
##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272##
##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277##
##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282##
##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287##
##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292##
##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297##
##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302##
##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307##
##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312##
##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317##
##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322##
##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327##
##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332##
##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337##
##STR00338## ##STR00339## ##STR00340## ##STR00341## ##STR00342##
##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347##
##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352##
##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357##
##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362##
##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367##
##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372##
##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377##
##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382##
##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387##
##STR00388## ##STR00389## ##STR00390##
##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395##
##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400##
##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405##
##STR00406## ##STR00407## ##STR00408## ##STR00409## ##STR00410##
##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415##
##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420##
##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425##
##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430##
##STR00431## ##STR00432## ##STR00433## ##STR00434## ##STR00435##
##STR00436## ##STR00437## ##STR00438## ##STR00439## ##STR00440##
##STR00441## ##STR00442## ##STR00443## ##STR00444## ##STR00445##
##STR00446## ##STR00447## ##STR00448## ##STR00449## ##STR00450##
##STR00451## ##STR00452## ##STR00453## ##STR00454## ##STR00455##
##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460##
##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465##
##STR00466## ##STR00467## ##STR00468## ##STR00469## ##STR00470##
##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475##
##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480##
##STR00481## ##STR00482## ##STR00483## ##STR00484## ##STR00485##
##STR00486## ##STR00487## ##STR00488## ##STR00489## ##STR00490##
##STR00491## ##STR00492## ##STR00493## ##STR00494## ##STR00495##
##STR00496## ##STR00497## ##STR00498## ##STR00499## ##STR00500##
##STR00501## ##STR00502## ##STR00503## ##STR00504## ##STR00505##
##STR00506## ##STR00507## ##STR00508## ##STR00509## ##STR00510##
##STR00511## ##STR00512## ##STR00513## ##STR00514## ##STR00515##
##STR00516## ##STR00517## ##STR00518## ##STR00519## ##STR00520##
##STR00521## ##STR00522## ##STR00523## ##STR00524## ##STR00525##
##STR00526## ##STR00527## ##STR00528## ##STR00529## ##STR00530##
##STR00531## ##STR00532## ##STR00533## ##STR00534## ##STR00535##
##STR00536## ##STR00537## ##STR00538## ##STR00539## ##STR00540##
##STR00541## ##STR00542## ##STR00543## ##STR00544## ##STR00545##
##STR00546## ##STR00547## ##STR00548## ##STR00549## ##STR00550##
##STR00551## ##STR00552## ##STR00553## ##STR00554## ##STR00555##
##STR00556## ##STR00557## ##STR00558## ##STR00559## ##STR00560##
##STR00561## ##STR00562## ##STR00563## ##STR00564## ##STR00565##
##STR00566## ##STR00567## ##STR00568## ##STR00569## ##STR00570##
##STR00571## ##STR00572## ##STR00573## ##STR00574## ##STR00575##
##STR00576## ##STR00577## ##STR00578## ##STR00579## ##STR00580##
##STR00581## ##STR00582## ##STR00583## ##STR00584## ##STR00585##
##STR00586## ##STR00587## ##STR00588## ##STR00589## ##STR00590##
##STR00591## ##STR00592## ##STR00593## ##STR00594## ##STR00595##
##STR00596## ##STR00597## ##STR00598## ##STR00599## ##STR00600##
##STR00601## ##STR00602## ##STR00603## ##STR00604## ##STR00605##
##STR00606## ##STR00607## ##STR00608## ##STR00609## ##STR00610##
##STR00611## ##STR00612## ##STR00613## ##STR00614## ##STR00615##
##STR00616## ##STR00617## ##STR00618## ##STR00619## ##STR00620##
##STR00621## ##STR00622## ##STR00623## ##STR00624## ##STR00625##
##STR00626## ##STR00627## ##STR00628## ##STR00629## ##STR00630##
##STR00631## ##STR00632## ##STR00633## ##STR00634## ##STR00635##
##STR00636## ##STR00637## ##STR00638## ##STR00639## ##STR00640##
##STR00641## ##STR00642##
##STR00643## ##STR00644## ##STR00645## ##STR00646## ##STR00647##
##STR00648## ##STR00649## ##STR00650## ##STR00651## ##STR00652##
##STR00653## ##STR00654## ##STR00655## ##STR00656## ##STR00657##
##STR00658## ##STR00659## ##STR00660## ##STR00661## ##STR00662##
##STR00663## ##STR00664## ##STR00665## ##STR00666## ##STR00667##
##STR00668## ##STR00669## ##STR00670## ##STR00671## ##STR00672##
##STR00673## ##STR00674##
[0121] The following table illustrates further compounds prepared
and assayed, each of which was found to inhibit binding activity
exhibiting an IC.sub.50 value greater than 1.0 micromolar using the
methods described above.
TABLE-US-00003 ##STR00675## R R' ##STR00676## ##STR00677##
##STR00678## ##STR00679## ##STR00680## ##STR00681## ##STR00682##
##STR00683## ##STR00684## ##STR00685## ##STR00686## ##STR00687##
##STR00688## ##STR00689## ##STR00690## ##STR00691## ##STR00692##
##STR00693## ##STR00694## ##STR00695## ##STR00696## ##STR00697##
##STR00698## ##STR00699## ##STR00700## ##STR00701## ##STR00702##
##STR00703## ##STR00704## ##STR00705## ##STR00706## ##STR00707##
##STR00708## ##STR00709## ##STR00710## ##STR00711## ##STR00712##
##STR00713## ##STR00714## ##STR00715## ##STR00716## ##STR00717##
##STR00718## ##STR00719## ##STR00720## ##STR00721## ##STR00722##
##STR00723##
* * * * *