U.S. patent application number 09/747246 was filed with the patent office on 2002-04-25 for non-peptidyl inhibitors of vla-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases.
Invention is credited to Chupak, Louis S., Duplantier, Allen J., Lau, Wan F., Milici, Anthony J..
Application Number | 20020049236 09/747246 |
Document ID | / |
Family ID | 22631221 |
Filed Date | 2002-04-25 |
United States Patent
Application |
20020049236 |
Kind Code |
A1 |
Duplantier, Allen J. ; et
al. |
April 25, 2002 |
Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in
treating inflammatory, autoimmune, and respiratory diseases
Abstract
There is disclosed a genus of non-peptidyl compounds, wherein
said compounds are VLA-4 inhibitors useful in treating
inflammatory, autoimmune, and respiratory diseases, and wherein
said compounds comprise a compound of Formula (1.0.0): 1 and
pharmaceutically acceptable salts and other prodrug derivatives
thereof, wherein: A is (C.sub.1-C.sub.6) alkyl, cycloalkyl, aryl,
heteroaryl or heterocyclyl optionally substituted with 0 to 3
R.sup.9; or is a member selected from the group consisting of the
following radicals: A.sup.1-NHC(.dbd.O)NH-A.s- up.2-,
A.sup.1-NHC(.dbd.O)O-A.sup.2-, A.sup.1-OC(.dbd.O)NH-A.sup.2-,
A.sup.1-NHSO.sub.2NH-A.sup.2-, A.sup.1-NHC(.dbd.O)-A.sup.2-,
A.sup.1-C(.dbd.O)NH-A.sup.2-, A.sup.1-NHSO.sub.2-A.sup.2-,
A.sup.1-SO.sub.2NH-A.sup.2-, A.sup.1-(CH.sub.2).sub.r-A.sup.2-,
where A.sup.1 and A.sup.2 are each independently selected from the
group consisting of hydrogen, aryl, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, cycloalkyl,
heteroaryl, and heterocyclyl substituted with 0 to 3 R.sup.9; B is
a member independently selected from the group consisting of the
following: 2 E is a single bond; --O--; --NR.sup.10--;
--CH.dbd.CH--; --CC--; --S(.dbd.).sub.q;
--CR.sup.11R.sup.12NR.sup.10--; or --CR.sup.11R.sup.12; X is --O--;
--C(.dbd.O)--; --S(.dbd.O).sub.q--; or --NR.sup.10--; X.sup.1,
X.sup.2 and X.sup.3 are each independently selected from the group
consisting of CH, CR.sup.9 or N; Y is a single bond; --C(.dbd.O)--;
--C(.dbd.S)--; or --S(.dbd.O).sub.2--; R.sup.7 is (C.sub.1-C.sub.6)
alkyl; (CH.sub.2).sub.kOR.sup.5;
(CH.sub.2).sub.kNR.sup.6C(.dbd.O)R.sup.5- ;
(CH.sub.2).sub.kNR.sup.6C(.dbd.O)OR.sup.5;
(CH.sub.2).sub.kNR.sup.6SO.su- b.2R.sup.5;
(CH.sub.2).sub.kNR.sup.6R.sup.5; F; CF.sub.3; OCF.sub.3; aryl,
substituted with 0 to 3 R.sup.9; heterocyclyl, substituted with 0
to 3 R.sup.9; heteroaryl, substituted with 0 to 3 R.sup.9;
cycloalkyl, substituted with 0 to 3 R.sup.9; or R.sup.7 may be
taken together with R.sup.8 to form a cycloalkyl or heterocyclyl
ring; or R.sup.7 may be taken together with R.sup.11 to form a
cycloalkyl or heterocyclyl ring; and R.sup.8 is hydrogen; F;
(C.sub.1-C.sub.6) alkyl or (C.sub.1-C.sub.6) alkoxy.
Inventors: |
Duplantier, Allen J.;
(Ledyard, CT) ; Chupak, Louis S.; (Old Saybrook,
CT) ; Milici, Anthony J.; (Branford, CT) ;
Lau, Wan F.; (Noank, CT) |
Correspondence
Address: |
Paul H. Ginsburg
Pfizer Inc
20th Floor
235 East 42nd Street
New York
NY
10017-5755
US
|
Family ID: |
22631221 |
Appl. No.: |
09/747246 |
Filed: |
December 21, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60173260 |
Dec 28, 1999 |
|
|
|
Current U.S.
Class: |
514/343 ;
514/374; 514/397; 514/403; 514/408; 546/276.4; 548/215; 548/311.1;
548/364.1 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
11/08 20180101; A61P 3/00 20180101; A61P 17/06 20180101; C07C
233/47 20130101; C07D 413/04 20130101; C07C 229/34 20130101; C07D
261/08 20130101; A61P 37/04 20180101; A61P 19/02 20180101; A61P
11/06 20180101; A61P 3/10 20180101; A61P 19/00 20180101; A61P 29/00
20180101; A61P 25/28 20180101; C07D 235/14 20130101; A61P 25/00
20180101; A61P 37/00 20180101; A61P 37/06 20180101; A61P 19/10
20180101; A61P 1/00 20180101; C07C 311/06 20130101 |
Class at
Publication: |
514/343 ;
514/374; 514/397; 514/408; 546/276.4; 548/215; 548/311.1; 514/403;
548/364.1 |
International
Class: |
A61K 031/4439; A61K
031/422; A61K 031/4155; A61K 031/4178 |
Claims
What is claimed is:
1. A compound of Formula (1.0.0): 236and pharmaceutically
acceptable salts and other prodrug derivatives thereof, wherein: A
is (C.sub.1-C.sub.6) alkyl, cycloalkyl, aryl, heteroaryl or
heterocyclyl as defined herein; where said alkyl, cycloalkyl, aryl,
heteroaryl or heterocyclyl is optionally substituted with 0 to 3
R.sup.9; or is a member selected from the group consisting of the
following radicals: A.sup.1-NHC(.dbd.O)NH-A.sup.2-,
A.sup.1-NHC(.dbd.O)O-A.sup.2-, A.sup.1-OC(.dbd.O)NH-A.sup.2-,
A.sup.1-NHSO.sub.2NH-A.sup.2-, A.sup.1-NHC(.dbd.O)-A.sup.2-,
A.sup.1-C(.dbd.O)NH-A.sup.2-, A.sup.1-NHSO.sub.2-A.sup.2-,
A.sup.1-SO.sub.2NH-A.sup.2-, A.sup.1-(CH.sub.2).sub.rO-A.sup.2,
A.sup.1-O(CH.sub.2).sub.rA.sup.2-,
A.sup.1-(CH.sub.2).sub.r-A.sup.2-, where A.sup.1 and A.sup.2 are
each independently selected from the group consisting of hydrogen,
aryl, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, cycloalkyl, heteroaryl, and
heterocyclyl; where said aryl, alkyl, cycloalkyl, heteroaryl, or
heterocyclyl group is substituted with 0 to 3 R.sup.9; B is a
member independently selected from the group consisting of the
following: 237where the symbol "*" indicates the point of
attachment of the moiety represented by each partial Formula
(1.1.0) through (1.1.22) to the moiety "CR.sup.2R.sup.3" in Formula
(1.0.0); and the symbol ".fwdarw." indicates the point of
attachment of the moiety represented by each partial Formula
(1.1.0) through (1.1.22) to the moiety "E" in Formula (1.0.0); Each
of Formula (1.1.0) through (1.1.22), with the exception of formulas
(1.1.10) and (1.1.22), may be optionally substituted with R.sup.9;
E is a single bond; --O--; --NR.sup.10--; --CH.dbd.CH--;
--C.ident.C--; --S(.dbd.O).sub.q; --CR.sup.11R.sup.12NR.su- p.10--;
or --CR.sup.11R.sup.12--; X is --O--; --C(.dbd.O)--;
--S(.dbd.O).sub.q--; or --NR.sup.10--; X.sup.1, X.sup.2 and X.sup.3
are each independently selected from the group consisting of CH,
CR.sup.9 or N; Y is a single bond; --C(.dbd.O)--; --C(.dbd.S)--; or
--S(.dbd.O).sub.2--; k is an integer independently selected from 0,
1 and 2; m is an integer independently selected from 0 and 1; n is
an integer independently selected from 0, 1 and 2; p is an integer
independently selected from 0 and 1, provided that p must be
selected as 1 where B is selected as partial formula (1.1.0)
through (1.1.11); q is an integer independently selected from 0, 1
and 2; r is an integer independently selected from 0, 1 and 2;
R.sup.2and R.sup.3 are each independently selected from the group
consisting of hydrogen; (C.sub.1-C.sub.6) alkyl substituted with 0
to 3 R.sup.13; (C.sub.2-C.sub.6) alkenyl substituted with 0 to 3
R.sup.13; a (C.sub.3-C.sub.14) carbocyclic ring system substituted
with 0 to 3 R.sup.13; a heterocyclyl ring as defined herein,
substituted with 0 to 3 R.sup.13; (C.sub.1-C.sub.6) alkyl-OR.sup.5
substituted with 0 to 3 R.sup.13; (C.sub.1-C.sub.6) alkyl-SR.sup.5
substituted with 0 to 3 R.sup.13; (C.sub.1-C.sub.6)
alkyl-SO.sub.2R.sup.5 substituted with 0 to 3 R.sup.13; a
heteroaryl ring as defined herein, substituted with 0 to 3
R.sup.13; an aryl ring as defined herein, substituted with 0 to 3
R.sup.13; provided that R.sup.2 and R.sup.3 are each defined as
above; or they are taken together as defined below; or one of them
is taken together with R.sup.4 as defined below, in which case the
other has the meaning of hydrogen or methyl; R.sup.2 and R.sup.3
are taken together to form either a cycloalkyl or heterocyclyl ring
substituted with 0 to 3 R.sup.13; or R.sup.2 or R.sup.3 is taken
together with R.sup.4 and the carbon and nitrogen atoms to which
they are respectively attached to form a heteroaryl or heterocyclyl
group as defined herein, substituted with 0 to 3 R.sup.13; R.sup.4
is hydrogen; or (C.sub.1-C.sub.6) alkyl optionally substituted with
R.sup.13; or R.sup.4 may be taken together with either R.sup.2 or
R.sup.3 to form a carbocyclic or heterocyclic ring; R.sup.5 and
R.sup.6 are independently hydrogen; (C.sub.1-C.sub.6) alkyl;
(C.sub.2-C.sub.6) alkenyl; (C.sub.2-C.sub.6) alkynyl; CF.sub.3;
aryl; cycloalkyl; heteroaryl; or heterocyclyl; wherein said alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl is
substituted by 0 to 3 R.sup.13; R.sup.7 is (C.sub.1-C.sub.6) alkyl;
(CH.sub.2).sub.kOR.sup.5; (CH.sub.2).sub.kNR.sup.6C(.dbd.O)R.sup.5;
(CH.sub.2).sub.kNR.sup.6C(.dbd.- O)OR.sup.5;
(CH.sub.2).sub.kNR.sup.6SO.sub.2R.sup.5;
(CH.sub.2).sub.kNR.sup.6R.sup.5; F; CF.sub.3; OCF.sub.3; aryl,
substituted with 0 to 3 R.sup.9; heterocyclyl, substituted with 0
to 3 R.sup.9; heteroaryl, substituted with 0 to 3 R.sup.9;
cycloalkyl, substituted with 0 to 3 R.sup.9; or R.sup.7 may be
taken together with R.sup.8 to form a cycloalkyl or heterocyclyl
ring; or R.sup.7 may be taken together with R.sup.11 to form a
cycloalkyl or heterocyclyl ring; R.sup.8 is hydrogen; F;
(C.sub.1-C.sub.6) alkyl or (C.sub.1-C.sub.6) alkoxy; R.sup.9 is
halogen; (C.sub.1-C.sub.6) alkyl; (C.sub.1-C.sub.6) alkoxy;
(C.sub.3-C.sub.6) cycloalkyl; (C.sub.3-C.sub.6) cycloalkoxy; cyano;
(CH.sub.2).sub.kOH; C(.dbd.O)R.sup.5; (CH.sub.2).sub.kC(O)NR.sup.5-
R.sup.6; (CH.sub.2).sub.kNR.sup.5R.sup.6;
(CH.sub.2).sub.kNR.sup.5SO.sub.2- R.sup.6; CF.sub.3; OCF.sub.3;
SO.sub.2NR.sup.5R.sup.6; (CH.sub.2).sub.mC(.dbd.O)OR.sup.5; when
R.sup.9 is attached to a saturated carbon atom R.sup.9 may be
.dbd.O or .dbd.S; when R.sup.9 is attached to a sulphur atom
R.sup.9 may be .dbd.O; R.sup.10 is hydrogen; C(.dbd.O)R.sup.5;
C(.dbd.O)OR.sup.5; (C.sub.1-C.sub.6) alkyl; aryl; heterocyclyl;
heteroaryl; cycloalkyl; or SO.sub.2R.sup.5; R.sup.11 and R.sup.12
are independently --H; (C.sub.1-C.sub.6) alkyl; -OH; --CN;
(C.sub.1-C.sub.6) alkoxy; NR.sup.6C(.dbd.O)R.sup.5;
NR.sup.6SO.sub.2R.sup.5; NR.sup.6R.sup.5; CF.sub.3; F; aryl;
heterocyclyl; heteroaryl; cycloalkyl; cycloalkoxy; or R.sup.11 may
be taken together with R.sup.12 to form a cycloalkyl or
heterocyclyl ring; and R.sup.13 is independently selected from the
group consisting of halogen; CF.sub.3; (C.sub.1-C.sub.6) alkyl;
aryl; heteroaryl; heterocyclyl; hydroxy; cyano; (C.sub.1-C.sub.6)
alkoxy; (C.sub.3-C.sub.6) cycloalkyl; (C.sub.3-C.sub.6)
cycloalkoxy; (C.sub.2-C.sub.6) alkynyl; (C.sub.2-C.sub.6) alkenyl;
--NR.sup.6R.sup.5; --C(.dbd.O)NR.sup.5R.sup.6; SO.sub.2R.sup.5;
C(.dbd.O)R.sup.5; NR.sup.5SO.sub.2R.sup.6;
NR.sup.5C(.dbd.O)R.sup.6; C(.dbd.O)NR.sup.5SO.sub.2R.sup.6;
NR.sup.5C(.dbd.O)OR.sup.6; and SO.sub.2NR.sup.6R.sup.5.
2. A compound according to claim 1 wherein when A is heteroaryl it
is a member selected from the group consisting of furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl,
thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl,
pyrimidinyl, triazinyl, pyranyl, parathiazinyl, indolyl,
isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl,
2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl,
benzimidazolyl, benzoxazolyl; benzthiazolyl, purinyl, quinolinyl,
isoquinolinyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl,
carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
and pyrazolo[1,5-c]triazinyl.
3. A compound according to claim 2 wherein A is furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl,
pyrimidinyl, indolyl, benzo[b]furanyl, benzimidazolyl, or
quinolinyl.
4. A compound according to claim 3 wherein A is pyridyl.
5. A compound according to claim 1 wherein when A is heterocyclyl
it is a member selected from the group consisting of oxiranyl,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl,
piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
benzodioxolane, and 1,3-benzodioxol-5-yl.
6. A compound according to claim 5 wherein A is pyrrolidinyl,
piperidinyl, piperazinyl, or morpholinyl.
7. A compound according to claim 1 wherein A is a radical selected
from the group consisting of radicals:
A.sup.1-NHC(.dbd.O)NH-A.sup.2-, A.sup.1-NHC(.dbd.O)O-A.sup.2-,
A.sup.1-OC(.dbd.O)NH-A.sup.2-, A.sup.1-NHSO.sub.2NH-A.sup.2-,
A.sup.1-NHC(.dbd.O)-A.sup.2-, A.sup.1-C(-O)NH-A.sup.2-,
A.sup.1-NHSO.sub.2-A.sup.2-, A.sup.1-SO.sub.2NH-A.sup.2-,
Al-(CH.sub.2).sub.rO-A.sup.2-, A.sup.1-O(CH.sub.2).sub.r-A.sup.2-,
A.sup.1-(CH.sub.2).sub.r-A.sup.2-, where A.sup.1 and A.sup.2 are
each independently selected from the group consisting of hydrogen,
aryl, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, cycloalkyl, heteroaryl, and
heterocyclyl; where said aryl, alkyl, cycloalkyl, heteroaryl, or
heterocyclyl group is substituted with 0 to 3 R.sup.9.
8. A compound according to claim 7 wherein A.sup.1 and A.sup.2 are
both aryl or heteroaryl.
9. A compound according to claim 8 wherein said aryl is phenyl and
said heteroaryl is pyridyl, each of which is independently
substituted by 0 or 1 substituent R.sup.9 which is a member
selected from the group consisting of F; Cl; F.sub.3C--; methyl;
methoxy; hydroxy; isopropyl; cyclopropyloxy; and cyclopentyl.
10. A compound according to claim 9 wherein n is the integer 1
resulting in a methylene bridge.
11. A compound according to claim 10 wherein said component A and
said methylene bridge attached thereto comprise a member selected
from the group consisting of 4-hydroxyphenyl-;
3-methoxy-4-(N'-phenylurea)-phenylm- ethyl-;
4-(N'-phenylurea)-phenylmethyl-; 4-(N'-(2-methylphenyl)urea)-pheny-
lmethyl-; 4-(N'-(2-methoxyphenyl)urea)-phenylmethyl-;
3-methoxy-4-(N'-(2-methylphenyl)urea)-phenylmethyl-;
4-(N'-(2-pyridyl)urea)-phenylmethyl-;
6-methoxy-5-(N'-(2-methylphenyl)ure- a-2-pyridylmethyl-;
4-(N'-(3-methyl-2-pyridyl)urea)-phenylmethyl-;
3-methoxy-4-(N'-(3-methyl-2-pyridyl)urea-phenylmethyl-;
3-methoxy-4-(N'-(2-pyridylurea)-phenylmethyl-;
4-(N'-(2-pyridyl)urea)-phe- nylmethyl-;
4-(N'-(2-fluorophenyl)urea)-phenylmethyl-;
4-(N'-(2-chlorophenyl)urea)-phenylmethyl-;
4-(N'-(2-chlorophenyl)urea)-3-- methoxyphenylmethyl-;
4-(N'-(4-iso-propylphenyl)urea)-phenylmethyl-;
6-methoxy-5-(N'-(o-toluyl)urea-2-pyridylmethyl-;
4-(N'-(3-cyclopropyloxy-- 2-pyridyl)urea)-phenylmethyl-; and
4-(N'-(o-toluyl)urea)-pyrid-5-ylmethyl-- .
12. A compound according to claim 9 wherein Y is --C(.dbd.O)--.
13. A compound according to claim 12 wherein for the component of
Formula (1.0.0) which is --NR.sup.4CR.sup.2CR.sup.3--, R.sup.4 is
hydrogen, R.sup.2 is hydrogen, and R.sup.3 is hydrogen.
14. A compound according to claim 12 wherein for the component of
Formula (1.0.0) which is --NR.sup.4CR.sup.2CR.sup.3--, R.sup.4 is
hydrogen, R.sup.2 is hydrogen, and R is iso-butyl.
15. A compound according to claim 12 wherein for the component of
Formula (1.0.0) which is --NR.sup.4CR.sup.2CR.sup.3--, R.sup.2 is
hydrogen, R.sup.3 is hydrogen.
16. A compound according to claim 12 wherein for the component of
Formula (1.0.0) which is --NR.sup.4CR.sup.2CR.sup.3--, R.sup.2 is
hydrogen, R.sup.3 is hydrogen and R is methyl.
17. A compound according to claim 12 wherein for the component of
Formula (1.0.0) which is --NRCR.sup.2CR.sup.3--, R.sup.4 is taken
together with R.sup.2 or R.sup.3 to form pyrrolidinyl, whereby
R.sup.4 is methylene or ethylene, one of R.sup.2 or R.sup.3 is
hydrogen, and the other of R.sup.2 or R.sup.3 is ethylene or
methylene.
18. A compound according to claim 12 wherein B is a member selected
from the group consisting of partial Formulas (1.1.2) (1.1.6),
(1.1.17), (1.1.18), (1.1.19), and (1.1.22): 238where the symbol "*"
and the symbol ".fwdarw." are as previously defined; X is oxygen,
S(.dbd.O).sub.q or nitrogen; and X.sup.1, X.sup.2 and X.sup.3 are
each independently selected from the group consisting of --CH--;
--CR.sup.9--; and --N--.
19. A compound according to claim 18 where B is partial Formula
(1.1.6).
20. A compound according to claim 19 wherein in partial Formula
(1.1.6), X is --O--.
21. A compound according to claim 18 where B is partial Formula
(1.1.22).
22. A compound according to claim 21 wherein in partial Formula
(1.1.22), where X is --NR.sup.10-- where R.sup.10 is --H; and
X.sup.1, X.sup.2 and X.sup.3 are each --CH--.
23. A compound according to claim 12 wherein p is 1; m is 0 or 1;
and E is --CR.sup.11R.sup.12--.
24. A compound according to claim 23 where p is 1; m is 0; R.sup.11
is --H; and R.sup.12 is --H.
25. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.0):
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino)-3-methyl--
butyl)-4,5-dihydro-oxazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylam-
ino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-
-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionic
acid
2,2-Difluoro-3-{2-[1-(methyl-[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl-a-
mino)-ethyl]-4,5-dihydro-oxazol-5-yl}-propionic acid
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolid-
in-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-3-
-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methy-
l]-4,5-dihydro-oxazol-5-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(2-
-1[methyl-(4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-am-
ino]-methyl}-4,5-dihydro-oxazol-5-yl)-propionic acid
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl-
)-4,5-dihydro-oxazol-5-yl]-propionic acid
2-Formylamino-3-{2-[1-(biphenyl--
4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-thiazol-5-yl}-propionic
acid
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihy-
dro-oxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxy-
methyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-5-yl)-propionic
acid
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phen-
yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic
acid
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic
acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-4-methyl-4,5-dihydro-oxazol-5-yl}-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-4,5-dihydro-thiazol-5-yl}-propionic acid
3-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-4,5-dihydro-3H-imidazol-4-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phen-
yl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-5-yl}-propionic
acid.
26. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.1):
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-4,5-dihydro-oxazol-4-yl]-2-methyl-propionic acid
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylam-
ino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-
-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-propionic
acid
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-
-amino)-ethyl]-4,5-dihydro-oxazol-4-yl}-propionic acid
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolid-
in-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic acid
2-Allyloxycarbonylamino-3-
-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methy-
l]-4,5-dihydro-oxazol-4-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(2-
-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-a-
mino]-methyl}-4,5-dihydro-oxazol-4-yl)-propionic acid
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl-
)-4,5-dihydro-oxazol-4-yl]-propionic acid
2-Acetylamino-3-{2-[1-(biphenyl--
4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-thiazol-4-yl}-propionic
acid
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihy-
dro-oxazol-4-yl)-propionic acid
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxy-
methyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-4-yl)-propionic
acid
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phen-
yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic
acid
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic
acid 2-Acetyl
amino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-me-
thyl-amino)-methyl]-5-methyl-4,5-dihydro-oxazol-4-yl}-propionic
acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-4,5-dihydro-thiazol-4-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-4-yl}-propionic
acid
27. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.2):
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-oxazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[2-(1-(2-[.sup-
.3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazo-
l-5-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(1-{2-[.sup.3-methoxy-4-
-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-prop-
ionic acid
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-y-
l]-acetyl}-amino)-ethyl]-oxazol-5-yl}-propionic acid
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolid-
in-2-yl)-oxazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-3-{2-[([3-met-
hoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-5-y-
l}-propionic acid
2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methy-
l-pyridin-2-y)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-5-yl)-
-propionic acid
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}--
pyrrolidin-2-y)-oxazol-5-yl]-propionic acid
2-Acetylamino-3-{2-[1-(bipheny-
l-4-yl-acetyl)-pyrrolidin-2-yl]-thiazol-5-yl}-propionic acid
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-5-
-yl)-propionic acid
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-pheny-
l)-acetyl]-pyrrolidin-2-yl}-oxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-4-methyl-oxazol-5-yl}-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-thiazol-5-yl}-propionic acid
3-Acetylamino-3-{2-[({[3-m-
ethoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-3H-imida-
zol-4-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy--
4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-5-yl}-pr-
opionic acid
28. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.3):
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-oxazol-4-yl]-2-methyl-propionic acid
2-Acetylamino-3-[2-(1-{2-[.sup-
.3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazo-
l-4-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-
-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-propionic
acid
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-ac-
etyl}-amino)-ethyl]-oxazol-4-yl}-propionic acid
2,2-Dimethyl-3-[2-(1-{[6-(- 3-phenyl-ureido)-pyrid i
n-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-pro- pionic acid
2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido-
)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-4-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-u-
reido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-4-yl)-propionic
acid
2-Methyl-3-[2-(1-[4-(2-methyl-benzyloxy)-phenyl]-acetyl-pyrrolidin-2-yl)--
oxazol-4-yl]-propionic acid
2-Formylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-p-
yrrolidin-2-yl]-thiazol-4-yl}-propionic acid
2-Methyl-3-(2-{1-[(4-o-tolylo-
xy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-4-yl)-propionic acid
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolid-
in-2-yl}-oxazol-4-yl)-propionic acid
2-Benzenesulfonylamino-3-[2-(1-{[3-me-
thoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-p-
ropionic acid
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureid-
o)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionic
acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-5-methyl-oxazol-4-yl}-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-thiazol-4-yl}-propionic acid
2-(2,6-Dichloro-benzoylami-
no)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)--
methyl]-oxazol-4-yl}-propionic acid
29. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.4):
3-[3-(1-12-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino)-3-methyl--
butyl)-4,5-dihydro-isooxazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylam-
ino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-
-acetylamino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionic
acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-
-amino)-ethyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolid-
in-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-
-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-10
amino)-methyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-u-
reido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-isoxazol-5-yl)-p-
ropionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl-pyr-
rolidin-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionic acid
2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-
-isothiazol-5-yl-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-ac-
etyl]-pyrrolidin-2-yl}-4,5-dihydro-isoxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolid-
in-2-yl}-4,5-dihydro-isoxazol-5-yl)-propionic acid
2-Benzenesulfonylamino--
3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)--
4,5-dihydro-isoxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-m-
ethyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5--
dihydro-isoxazol-5-yl]-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(-
3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-4,5-dihyd-
ro-isoxazol-5-yl}-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-t-
olyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isothiazol--
5-yl}-propionic acid
3-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-
-phenyl]-acetyl}-methyl-amino)-methyl]-3,4-dihydro-2H-pyrazol-3-yl}-propio-
nic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ure-
ido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isoxazol-5-yl}-prop-
ionic acid
30. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.5):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino)-3-methyl--
butyl)-4,5-dihydro-pyrazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylam-
ino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-
-acetylamino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic
acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-
-amino)-ethyl]-4,5-dihydro-pyrazol-1-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolid-
in-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
2-(Butane-1-sulfonylamin-
o)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-ac-
etyl)-amino]-methyl}-4,5-dihydro-pyrazol-1-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl-
)-4,5-dihydro-pyrazol-1-yl]-propionic acid
2-Acetylamino-3-{3-[1-(biphenyl-
-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-pyrazol-1-yl}-propionic
acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihy-
dro-pyrazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenox-
ymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-pyrazol-1-yl)-propion-
ic acid
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-ph-
enyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic
acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic
acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-5-methyl-4,5-dihydro-pyrazol-1-yl}-propionic
acid
2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-4,5-dihydro-pyrazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-pyrazol-1-yl}-propionic
acid
31. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.6):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-isooxazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-
-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazo-
l-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-
-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propion-
ic acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]--
acetyl}-amino)-ethyl]-isoxazol-5-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolid-
in-2-yl)-isoxazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-3-{3-[({[3--
methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazo-
l-5-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3--
methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-isoxaz-
ol-5-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]--
acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-isothiazol--
5-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrro-
lidin-2-yl}-isoxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[-
(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic
acid
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phen-
yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-4-methyl-isoxazol-5-yl}-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-isothiazol-5-yl}-propionic acid
3-Acetylamino-3-{5-[({[-
3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2H-py-
razol-3-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methox-
y-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-5-yl-
}-propionic acid
32. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.7):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-pyrazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-m-
ethoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-
-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-to-
lyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionic
acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-ac-
etyl}-amino)-ethyl]-pyrazol-1-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6--
(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-pro-
pionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyri-
din-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrazol-1-yl)-pro-
pionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrr-
olidin-2-yl)-pyrazol-1-yl]-propionic acid 2-
Formylamino-3-{3-[1-(biphenyl-
-4-yl-acetyl)-pyrrolidin-2-yl]-pyrazol-1-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol--
1-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phen-
yl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-5-methyl-pyrazol-1-yl}-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-pyrazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylami-
no)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl-methyl-amino)-m-
ethyl]-pyrazol-1-yl}-propionic acid
33. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.8):
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-oxazol-2-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3-me-
thoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-y-
l]-propionic acid
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-toly-
l-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionic
acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl--
amino)-ethyl]-oxazol-2-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-{[6-(3-phen-
yl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic
acid
2-Allyloxycarbonylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phen-
yl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-u-
reido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-2-yl)-propionic
acid
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl-
)-oxazol-2-yl]-propionic acid
2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-
-pyrrolidin-2-yl]-thiazol-2-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o-toly-
loxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolid-
in-2-yl}-oxazol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-me-
thoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-p-
ropionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureid-
o)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic
acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-5-methyl-oxazol-2-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-thiazol-2-yl}-propionic acid 2-(2,
6-Dichloro-benzoylamino)-3-4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-1H-imidazol-2-yl}-propionic acid
34. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.9):
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-imidazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3--
methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-imidazol-
-1-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o--
tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-imidazol-1-yl]-propioni-
c acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-imidazol-1-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-{[-
6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]--
propionic acid
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-p-
yridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-imidazol-1-yl)-
-propionic acid
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl-p-
yrrolidin-2-y)-imidazol-1-yl]-propionic acid
2-Formylamino-3-{4-[1-(biphen-
yl-4-yl-acetyl)-pyrrolidin-2-yl]-imidazol-1-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-imidazol-
-1-yl)-propionic acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phe-
nyl)-acetyl]-pyrrolidin-2-yl}-imidazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-5-methyl-imidazol-1-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-imidazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylam-
ino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-
-methyl]-imidazol-1-yl}-propionic acid
35. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.10):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylam-
ino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-
-acetylamino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-
-amino)-ethyl]-[1,2,4]oxadiazol-5-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolid-
in-2-yl)-[1,2,4]oxadiazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-3-{-
3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-
-[1,2,4]oxadiazol-5-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[m-
ethyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino-
]-methyl}-[1,2,4]oxadiazol-5-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-me-
thyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-pr-
opionic acid
2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-
-[1,2,4]thiadiazol-5-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-ph-
enyl)-acetyl]-pyrrolidin-2-yl}-[1,2,4]oxadiazol-5-yl)-propionic
acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolid-
in-2-yl}-[1,2,4]oxadiazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-[3-
-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2-
,4]oxadiazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1--
{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadi-
azol-5-yl]-propionic acid
2-Acetylamino-3-{3-[({(3-methoxy-4-(3-o-tolyl-ur-
eido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propion-
ic acid
2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acet-
yl}-methyl-amino)-methyl]-[1,2 ,4]thiadiazol-5-yl}-propionic acid
3-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-2H-[1,2,4]triazol-3-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionic
acid.
36. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.11):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino-3-methyl-b-
utyl)-[1,2,4]triazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-(-
2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,-
2,4]triazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-meth-
oxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]triaz-
ol-1-yl]-propionic acid 2,2-Difluoro-3-{3-[l
-(methyl-{[6-(3-o-tolyl-ureid-
o)-pyridin-3-yl]-acetyl}-amino)-ethyl]-[1,2,4]triazol-1-yl}-propionic
acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolid-
in-2-yl)-[1,2,4]triazol-1-yl]-propionic acid
2-Allyloxycarbonylamino-3-{3--
[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[-
1,2,4]triazol-1-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methy-
l-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-me-
thyl}-[1,2,4]triazol-1-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-b-
enzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionic
acid
2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-[1,2,4-
]triazol-1-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acet-
yl]-pyrrolidin-2-yl}-[1,2,4]triazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolid-
in-2-yl}-[1,2,4]triazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[3-(-
1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4-
]triazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5--
(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-
-yl]-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)--
phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-[1,2,4]triazol-1-yl}-propio-
nic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ace-
tyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionic
acid
37. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.12):
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino-3-methyl-b-
utyl)-thiophen-2-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3-m-
ethoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-furan-2-y-
l]-propionic acid
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-toly-
l-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-propionic
acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-ac-
etyl}-amino)-ethyl]-1H-pyrrol-2-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-[6-
-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-p-
ropionic acid
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-py-
ridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-2-yl)-pro-
pionic acid
2-Methyl-3-[4-(1-([4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrr-
olidin-2-yl)-1H-pyrrol-2-yl]-propionic acid
2-Formylamino-3-{4-[1-(bipheny-
l-4-yl-acetyl)-pyrrolidin-2-yl]-thiophen-2-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-pyrro-
l-2-yl)-propionic acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-ph-
enyl)-acetyl]-pyrrolidin-2-yl}-furan-2-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-5-methyl-1H-pyrrol-2-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-thiophen-2-yl}-propionic acid
2-(2,6-Dichloro-benzoylam-
ino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-
-methyl]-furan-2-yl}-propionic acid.
38. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.13):
3-[5-(1-2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-b-
utyl)-thiophen-3-yl]-2-methyl-propionic acid
2-Acetylamino-3-[5-(1-{2-[3-m-
ethoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-furan-3-y-
l]-propionic acid
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-toly-
l-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-3-yl]-propionic
acid
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-ac-
etyl}-amino)-ethyl]-1H-pyrrol-3-yl}-propionic acid
2,2-Dimethyl-3-[5-(1-[6-
-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-thiophen-3-yl]-p-
ropionic acid
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-py-
ridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-3-yl)-pro-
pionic acid
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrr-
olidin-2-yl)-1H-pyrrol-3-yl]-propionic acid
2-Formylamino-3-{5-[1-(bipheny-
l-4-yl-acetyl)-pyrrolidin-2-yl]-thiophen-3-yl}-propionic acid
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-pyrro-
l-3-yl)-propionic acid
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-ph-
enyl)-acetyl]-pyrrolidin-2-yl}-furan-3-yl)-propionic acid
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-pyrrolidin-2-yl)-thiophen-3-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-3-yl]-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-2-methyl-1H-pyrrol-3-yl}-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-thiophen-3-yl}-propionic acid
2-(2,6-Dichloro-benzoylam-
ino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]acetyl}-methyl-amino)--
methyl]-furan-3-yl}-propionic acid
39. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.14):
3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-thiophen-2-yl]-2-methyl-propionic acid
2-Acetylamino-3-[5-(1-{2-[3--
methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-furan-2--
yl]-propionic acid
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tol-
yl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-propionic
acid
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-ac-
etyl}-amino)-ethyl]-1H-pyrrol-2-yl}-propionic acid
2,2-Dimethyl-3-[5-(1-[6-
-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-p-
ropionic acid
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-py-
ridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-2-yl)-pro-
pionic acid
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrr-
olidin-2-yl)-1H-pyrrol-2-yl]-propionic acid
2-Formylamino-3-{5-[1-(bipheny-
l-4-yl-acetyl)-pyrrolidin-2-yl]-thiophen-2-yl}-propionic acid
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-l
H-pyrrol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxym-
ethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-furan-2-yl)-propionic acid
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-2-methyl-1H-pyrrol-2-yl}-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-thiophen-2-yl}-propionic acid
2-(2,6-Dichloro-benzoylam-
ino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-
-methyl]-furan-2-yl}-propionic acid
40. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.15):
3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-isooxazol-3-yl]-2-methyl-propionic acid
2-Acetylamino-3-[5-(1-{2-[3-
-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazo-
l-3-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-
-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-3-yl]-propion-
ic acid
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]--
acetyl}-amino)-ethyl]-isoxazol-3-yl}-propionic acid
2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolid-
in-2-yl)-isoxazol-3-yl]-propionic acid
2-Allyloxycarbonylamino-3-{5-[({[3--
methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazo-
l-3-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3--
methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-isoxaz-
ol-3-yl)-propionic acid
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]--
acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionic acid
2-Acetylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-isothiazol--
3-yl}-propionic acid
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrro-
lidin-2-yl}-isoxazol-3-yl)-propionic acid
2-Benzenesulfonylamino-3-(5-{1-[-
(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-3-yl)-propionic
acid
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phen-
yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionic acid
2-Formylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-4-methyl-isoxazol-3-yl}-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-isothiazol-3-yl}-propionic acid
3-Acetylamino-3-{3-[({[-
3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl)-methyl-amino)-methyl]-2H-py-
razol-5-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methox-
y-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-3-yl-
}-propionic acid
41. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.16):
3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-oxazol-2-yl]-2-methyl-propionic acid
2-Acetylamino-3-[5-(1-{2-[3-me-
thoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylaminol-3-methyl-butyl)-oxazol-2-y-
l]-propionic acid
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-toly-
l-ureido)-phenyl]-acetylaminol-3-methyl-butyl)-oxazol-2-yl]-propionic
acid
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-
-amino)-ethyl]-oxazol-2-yl}-propionic acid
2,2-Dimethyl-3-[5-(1-{[6-(3-phe-
nyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic
acid
2-Allyloxycarbonylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phen-
yl -acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-u-
reido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-2-yl)-propionic
acid
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl)-pyrrolidin-2-yl-
)-oxazol-2-yl]-propionic acid
2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-
-pyrrolidin-2-yl]-thiazol-2-yl}-propionic acid
2-Methyl-3-(5-{1-[(4-o-toly-
loxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolid-
in-2-yl}-oxazol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-[5-(1-{[3-me-
thoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-p-
ropionic acid
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureid-
o)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic
acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-5-methyl-oxazol-2-yl}-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-thiazol-2-yl}-propionic acid
2-(2,6-Dichloro-benzoylami-
no)-3-(5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)--
methyl]-oxazol-2-yl}-propionic acid 2-Acetylamino
3-[5-({2-[4-(3-o-tolyl-u-
reido)-phenyl]-acetylamino}-methyl)-1H-imidazol-2-yl]-propionic
acid
42. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formulas (1.1.17),
(1.1.18) and (1.1.19):
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-methyl-amino)-methyl]-phenyl}-propionic acid
2-Formylamino-3-{6-[1-({3-methoxy-4-[3-(3-methyl-pyridin-2-yl)-ureido]-ph-
enyl}-acetyl)-pyrrolidin-2-yl]-pyridin-2-yl}-propionic acid
3-{4-[1-({3-Ethyl-4-[3-(3-methyl-pyridin-2-yl)-ureido]-phenyl}-acetyl)-py-
rrolidin-2-yl]-pyrimidin-2-yl}-propionic acid
2-Acetylamino-3-[3-(1-{[3-me-
thoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl)-pyrrolidin-2-yl)-phenyl]-propio-
nic acid
2-Acetylamino-3-[3-({2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-methyl)-phenyl]-propionic acid
2-{2-[{[3-Methoxy-4-(3-o-tolyl-u-
reido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyridin-4-ylmethyl]-4-methyl--
pentanoic acid
3-(2-[(Methyl-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-
-methyl]-pyridin-4-yl}-propionic acid
2-Methanesulfonylamino-3-{4-[({[3-me-
thoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,3,5]tr-
iazin-2-yl}-propionic acid
1-[4-(1-{[6-(3-Pyridin-2-yl-ureido)-pyridin-3-y-
l]-acetyl}-pyrrolidin-2-yl)-pyridin-2-ylmethyl]-cyclopropanecarboxylic
acid
3-[3-(1-{[6-(3-Pyridin-2-yl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-
-2-yl)-phenyl]-butyric acid
2-Butane-1-sulfonylamino)-3-{3-[({[3-methoxy-4-
-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-phenyl}-propioni-
c acid
2-Benzenesulfonylamino-3-[3-({[(2-methoxy-2'-methyl-biphenyl-4-yl)--
acetyl]-methyl-amino}-methyl)-phenyl]-propionic acid
43. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.20):
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-pyrrol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3-me-
thoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrrol-1-y-
l]-propionic acid
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-toly-
l-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrrol-1-yl]-propionic
acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-
-amino)-ethyl]-pyrrol-1-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-{[6-(3-phe-
nyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionic
acid
2-(Butane-1-sulfonylamino)-3-(4-[methyl-({4-[3-(3-methyl-pyridin-2-y-
l)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrrol-1-yl)-propionic
acid
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-
-2-yl)-pyrrol-1-yl]-propionic acid
2-Formylamino-3-{4-[1-(biphenyl-4-yl-ac-
etyl)-pyrrolidin-2-yl]-pyrrol-1-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o--
tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrrol-1-yl)-propionic
acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolid-
in-2-yl}-pyrrol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-me-
thoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-p-
ropionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureid-
o)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionic
acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-5-methyl-pyrrol-1-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-pyrrol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamin-
o)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-m-
ethyl]-pyrrol-1-yl}-propionic acid.
44. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.21):
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl--
butyl)-pyrazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3-m-
ethoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-
-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(1-(2-[3-methoxy-4-(3-o-to-
lyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionic
acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-ac-
etyl}-amino)-ethyl]-pyrazol-1-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-{[6--
(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-pro-
pionic acid
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyri-
din-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrazol-1-yl)-pro-
pionic acid
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrr-
olidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Formylamino-3-{4-[1-(biphenyl--
4-yl-acetyl)-pyrrolidin-2-yl]-pyrazol-1-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol--
1-yl)-propionic acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phen-
yl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2--
yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-met-
hyl-amino)-methyl]-5-methyl-pyrazol-1-yl}-propionic acid
2-Acetylamino-3-4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-meth-
yl-amino)-methyl]-pyrazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamin- o)-3-{4-[({[3-methoxy-4-(3-o-tolyl
-ureido)-phenyl]-acetyl}-methyl-amino)--
methyl]-pyrazol-1-yl}-propionic acid.
45. A compound according to claim 1 wherein said compound is:
Compounds which include the moiety of partial Formula (1.1.22):
2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl-
]-benzooxazole-6-carboxylic acid
2-[1-(2-3-Methoxy-4-[3-(3-methyl-pyridin--
2-yl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-3H-benzoimidazole-5-car-
boxylic acid
2-(1-{[4-(3-Pyridin-2-yl-ureido)-phenyl]-acetyl}-pyrrolidin-2-
-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid
2-(1-{[3-Ethoxy-4-(3-pyri-
din-2-yl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-benzothiazole-6-carboxyl-
ic acid
2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-
-methyl]-benzothiazole-6-carboxylic acid
2-({[(4-Benzyloxy-phenyl)-acetyl]-
-methyl-amino}-methyl)-oxazolo[5,4-b] pyridine-5-carboxylic acid
3-Methyl-2-{1-[(4-phenoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-benzoimidaz-
ole-5-carboxylic acid.
46. A pharmaceutical composition comprising a compound of Formula
(1.0.0) as defined in claim 1 together with a pharmaceutically
acceptable carrier for said compound, wherein the amount of said
compound present is effective for preventing, inhibiting,
suppressing or reducing cell adhesion and consequent or associated
pathogenic processes subsequently mediated by VLA-4.
47. A pharmaceutical composition according to claim 46 additionally
comprising one or more therapeutic agents.
48. A pharmaceutical composition according to claim 47 wherein said
one or more therapeutic agent or agents is or are selected from the
group consisting essentially of anti-inflammatory corticosteroids;
nonsteroidal anti-inflammatory agents; bronchodilators;
anti-asthmatic agents; immunosuppressant agents; immunostimulants;
antimetabolites; antipsoriatics; and antidiabetics.
49. A pharmaceutical composition according to claim 48 wherein said
therapeutic agent is a member selected from the group consisting
essentially of theophylline, salbutamol, salmeterol, mometasone,
fluticasone, ariflo, montelukast, sulfasalazine, aminosalicylates;
cyclosporin, FK-506, rapamycin, clophosphamide, methotrexate, and
the interferons.
50. A method of treating or preventing an inflammatory, autoimmune
or respiratory diseases by inhibiting cell adhesion and consequent
or associated pathogenic processes subsequently mediated by VLA-4,
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of Formula (1.0.0)
as defined in claim 1 or a pharmaceutical composition as defined in
claim 46.
51. A method according to claim 50 wherein said inflammatory,
autoimmune or respiratory disease is a member selected from the
group consisting essentially of asthma, multiple sclerosis,
rheumatoid arthritis, osteoarthritis, inflammatory bowel disease,
psoriasis, host rejection following organ transplantation,
atherosclerosis, and other diseases mediated by or associated with
VLA-4.
52. A compound that is converted in vivo to a compound of claim 1.
Description
REFERENCE TO CO-PENDING APPLICATIONS
[0001] Reference is made herein to co-pending application U.S. Ser.
No. 09/403846 (Attorney Docket No. PC10112B), filed Oct. 26, 1999;
which is a continuation-in-part of U.S. Ser. No. 09/338832
(Attorney Docket No. PC101121A), filed Jun. 23, 1999; which is a
continuation of provisional application U.S. Ser. No. 60/091180
(Attorney Docket No. PC10112), filed Jun. 30, 1998, and now
abandoned; and reference is further made to corresponding
International Application PCT/IB99/00973 (Attorney Docket No.
PC10112A PCT), filed May 31, 1999, and published as WO 00/00477 on
Jan. 6, 2000.
[0002] The present invention relates to compounds which are
non-peptidyl in structure and active as potent inhibitors of the
binding of very late antigen-4 (VLA-4; .alpha..sub.4.beta..sub.1;
CD49d/CD29) to proteins such as vascular cell adhesion molecule-1
(VCAM-1), the HepII/IIICS domain (CS-1 region) of fibronectin and
osteopontin. As such they are useful in the inhibition of cell
adhesion and consequent or associated pathogenic processes
subsequently mediated by VLA-4. The compounds and pharmaceutical
compositions of this invention may be used in the treatment of many
inflammatory, autoimmune and respiratory diseases, especially
asthma.
BACKGROUND OF THE INVENTION
[0003] One of the most fundamental processes necessary for normal
host defence is the regulated trafficking of leukocytes out of the
vasculature. This system is designed to allow normal recirculation
of leukocytes, yet because it enables the rapid extravasation of
leukocytes at sites of injury it is one of the central pathogenic
mechanisms of inflammatory, respiratory and autoimmune diseases in
mammals. Cell adhesion is a key factor in this process, and it is
particularly relevant to the present invention regarding the
cell/cell and cell/matrix binding of hematopoietic cells containing
VLA-4.
[0004] VLA-4 is a member of a superfamily of cell surface
macromolecular receptors called integrins, which are non-covalent
heterodimeric complexes consisting of an .alpha. subunit and a
.beta. subunit (Hemler, Ann. Rev. Immunol., 8, p. 365, 1990).
Eighteen different a subunits have been identified and labeled
.alpha..sub.1-.alpha..sub.10, .alpha..sub.L, .alpha..sub.M,
.alpha..sub.X, .alpha..sub.D, .alpha..sub.LRI, .alpha..sub.IIB,
.alpha..sub.V and .alpha..sub.E; while eight different .beta.
subunits have been identified and labeled .beta..sub.1-.beta..sub.-
8. Each integrin molecule can be categorized into a subfamily based
on the type of its .alpha. and .beta. subunits.
[0005] The .alpha..sub.4.beta..sub.1 integrin, VLA-4, is an
integrin constitutively expressed by all leukocytes (e.g.,
monocytes, lymphocytes, basophils, eosinophils, mast cells and
macrophages) except polymorphonuclear leukocytes. The binding of
this integrin to one of its ligands has a number of known cell
adhesion and activation functions (Hemler, Ann. Rev. Immunol., 8,
p. 365, 1990; Walsh et al., Clin. and Exp. Allergy, 25, p. 1128,
1995; Huhtala et al., J. Cell Biol., 129, p. 867, 1995). In
particular, it is a receptor for the cytokine-inducible endothelial
cell surface protein known as vascular cell adhesion molecule-1
(VCAM-1), for the alternatively spliced forms of the extracellular
matrix protein fibronectin (FN) containing the CS-1 domain (Ruegg
et al., J. Cell Biol., 177, p. 179, 1991; Wayner et al., J. Cell
Biol., 105, p. 1873, 1987; Kramer et al., J. Biol. Chem., 264,
p.4684, 1989; Gehlsen et al., Science, 24, p. 1228, 1988) and for
the extracellular matrix protein osteopontin (Bayless, K. I. et al.
J. Cell Science, 111, p. 1165-1174, 1998). The importance of VLA-4
cell adhesion interactions has been established by the use of
specific monoclonal antibody (mAb) antagonists of the .alpha.
subunit of VLA-4, which have demonstrated that inhibitors of VLA-4
dependent cell adhesion prevent or inhibit numerous inflammatory,
respiratory and autoimmune pathological conditions (Chisholm et
al., Eur. J. Immunol., 23, p. 682, 1993; Lobb et al., J. Clin.
Invest., 94, p. 1722, 1994; Richards et al., Am. J. Respir. Cell
Mol. Biol., 15, p. 172, 1996; Soiluhanninen et al., J.
Neuroimmunol., 72, p. 95, 1997; Sagara et al., Int. Arch. Allergy
Immunol., 112, p. 287, 1997; Fryer et al., J. Clin. Invest., 99, p.
2036, 1997). In addition, confirmation that this pathological
processes can be inhibited with agents other than antibodies has
been observed in animal models following treatment with a synthetic
CS-1 peptide or a small molecule peptide inhibitor of VLA-4
(Ferguson et al., Proc. Natl. Acad. Sci., 88, p. 8072, 1991; Wahl
et al., J. Clin. Invest., 94, p. 655, 1994; Molossi et al., J.
Clin. Invest., 95, p. 2601, 1995; Abraham et al., Am. J. Respir.
Crit. Care Med., 156, p. 696, 1997; Jackson et al., J. Med. Chem.,
40, p. 3359, 1997).
DESCRIPTION OF THE STATE OF THE ART
[0006] The investigation of mAb and peptide VLA-4 antagonists in
the art has already been noted above. In defining the binding site
for .alpha..sub.4.beta..sub.1 it has been observed that lymphoid
cells can bind to two different sites on fibronectin (Bernardi et
al., J. Cell Biol., 105, p. 489, 1987). One component of this cell
binding activity has previously been identified as the tripeptide
Arg-Gly-Asp (RGD) that binds to the integrin
.alpha..sub.5.beta..sub.1 (VLA5). Subsequently, the minimum amino
acid sequence required to bind and antagonize the activity of VLA-4
on leukocytes to the alternatively spliced site in fibronectin was
determined (Humphries et al., J. Biol. Chem., 266, p. 6886, 1987;
Garcia-Pardo et al., J. Immunol., 144, p. 3361, 1990; Komoriya et
al., J. Biol. Chem., 266, p. 15075, 1991). It has been discovered
that the VLA-4 binding domain in the CS-1 region of fibronectin
(FN) comprises the octapeptide: Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr, as
well as two overlapping pentapeptides: Glu-Ile-Leu-Asp-Val and
Leu-Asp-Val-Pro-Ser. All of these peptides inhibit FN-dependent
cell adhesion, leading to the early conclusion that the minimal
amino acid sequence required for inhibition would be Leu-Asp-Val
(LDV). In fact the LDV minimal inhibitory sequence has been
observed to be equally effective as the full length CS-1 fragment
in binding the activated form of VLA-4 (Wayner et al., J. Cell
Biol., 116, p. 489, 1992).
[0007] Various integrins are believed to bind to extracellular
matrix proteins at an Arg-Gly Asp (RGD) recognition site. RGD based
cyclic peptides have been made that are said to be able to inhibit
both .alpha..sub.4.beta..sub.1 and .alpha..sub.5.beta..sub.1
binding to FN (Nowlin et al., J. Biol. Chem., 268, p. 20352, 1993;
PCT/US91/04862) even though the primary recognition on FN for
.alpha.4.beta.1 is LDV. The cyclic peptide may be represented by
Formula (0.0.1): 3
[0008] where TPro denotes 4-thioproline.
[0009] Other peptidyl inhibitors of VLA-4 are those referred to in
Arrhenius et al., "CS-1 Peptidomimetics," WO 95/15973, which is
assigned to the Cytel Corporation and is related to the two U.S.
patents noted below. A representative compound of the type
described is the peptide of Formula (0.0.2):
N-Phenylacetyl-Leu-Asp-Phe-NCy.sup.3 (0.0.2)
[0010] wherein NCy.sup.3 is selected from, inter alia,
morpholinamido; thiomorpholinamido; 4-(thiadioxo)piperidinamido;
and D-2-(carboxamide)-pyrrolidinamido; piperidinamido; and
substituted piperidinamido.
[0011] WO 95/15973 . . . U.S. Pat. No. 5,821,231 . . . U.S. Pat.
No. 5,936,065 . . . Cytel Corporation
[0012] Further work by Arrhenius et al. involving cyclic CS-1
peptidomimetics is described in WO 96/06108 assigned to the Cytel
Corporation, which is related to the U.S. patent noted below.
[0013] WO 96/06108 . . . U.S. Pat. No. 5,869,448 . . . Cytel
Corporation
[0014] The Arrhenius group has also discovered non-peptidal
inhibitors of VLA-4 dependent cell binding as described in He et
al. WO 98/42656. The inhibitors therein described are of the
general Formula (0.0.3): 4
[0015] A typical inhibitor is that represented by Formula (0.0.4):
5
[0016] WO 98/42656 . . . Cytel Corporation
[0017] The Leu-Asp-Val tripeptide has been used as the core of a
group of inhibitors of VLA-4 dependent cell adhesion described in
Adams et al. WO 96/22966, which is assigned to Biogen, Inc. These
inhibitors may be represented by Formula (0.0.5): 6
[0018] where R.sup.1 may be
4-(N'-(2-methylphenyl)urea)phenylmethyl; Y may be C.dbd.O; R.sup.2
may be H; R.sup.3 may be iso-butyl; and R.sup.14 may be
1,3-benzodioxol-5-yl. An example of a typical inhibitor of this
type is that of Formula (0.0.6): 7
[0019] WO 96/22966 . . . Biogen, Inc.
[0020] The Adams group has also discovered semi-peptidic cell
adhesion inhibitors for the treatment of inflammation and
autoimmune disease, described in Lin et al., WO 97/03094. These
inhibitors may be represented by Formula (0.0.7):
Z-(Y.sup.1)-(Y.sup.2)--(Y.sup.3).sub.n-X (0.0.7)
[0021] where Z may be 4-(N'-(2-methylphenyl)urea)phenylacetyl;
(Y.sup.1)--(Y.sup.2)--(Y.sup.3).sub.n represents a series of amino
acids forming a peptide chain; and X may be OH. A typical inhibitor
of this type is shown in Formula (0.0.8): 8
[0022] WO 97/03094 . . . Biogen, Inc.
[0023] The Adams group has also asserted, in Zheng et al., WO
98/04247, the discovery that existing IIb/IIIa integrin inhibitory
compounds may be converted into VLA-4 inhibitory compounds, and
that IIb/IIIa inhibitory compounds can be made by combining a
unique VLA-4 integrin scaffold with a IIb/IIIa specificity
determinant. These cell adhesion inhibitors may be viewed as
comprising a compound of the formula: A-B, where A comprises a
VLA-4 specificity determinant which does not impart significant
IIb/IIIa integrin inhibitory activity, and B is an integrin
scaffold derived from a IIb/IIIa inhibitor. A three dimensional
pharmacophore model of a compound having VLA-4 inhibitory activity
is also described. Representative of the inhibitors thus derived
are the compounds of Formulas (0.0.9) and (0.0.10): 9
[0024] WO 98/04247 . . . Biogen, Inc.
[0025] See also Singh et al., WO 98/04913, which refers to a three
dimensional pharmacophore model of a compound having VLA-4
inhibitory activity, comprising features defined by a table of
tolerances and three dimensional coordinates x, y, and z. The
following compound, representative of those referred to, may be
represented by Formula (0.0.11): 10
[0026] WO 98/04913 . . . Biogen, Inc.
[0027] Another type of VLA-4 dependent cell adhesion inhibitor is
that described in Head et al., "Anti-inflammatory Tyrosine
Derivatives", WO 98/54207, which may be represented by general
Formula (0.0.12): 11
[0028] where R.sup.1 is an optionally substituted alkyl or aromatic
group; X.sup.2 is --C(.dbd.O)--; --C(.dbd.O)O--; --C(.dbd.O)NH--;
or --S(.dbd.O).sub.2--; and R.sup.7 is an optionally substituted
alkyl or aryl group. A compound typical of this type of inhibitor
may be represented by Formula (0.0.13): 12
[0029] WO 98/54207 . . . Celltech Therapeutics Ltd.
[0030] The Head group has also discovered a related group of VLA-4
dependent cell adhesion inhibitors, described in Head et al.,
"Phenylalanine Derivatives Useful As Pharmaceutical Agents," WO
99/37618, which are of the general Formula (0.0.14): 13
[0031] where L.sup.1 is a linker atom or group; A is a chain
--[C(R.sup.7)(R.sup.8)].sub.p--Y--[C(R.sup.9)(R.sup.10)].sub.q--;
and L.sup.2 is a linker group selected from --C(.dbd.O)--;
--C(.dbd.O)O--; --C(.dbd.S)--; --S(.dbd.O).sub.2, or
--C(.dbd.O)N(R.sup.11)--. An example of this type of inhibitor is
that of a compound of Formula (0.0.15): 14
[0032] WO 99/35163 . . . Celltech Therapeutics, Ltd.
[0033] Another closely related group of VLA-4 inhibitors discovered
by the Head group is described in Head et al., "Novel Phenylalanine
Derivatives Useful as Integrin Antagonists," WO 99/37618, which is
characterized by general Formula (0.0.16): 15
[0034] A representative example of these inhibitory compounds is
that of Formula (0.0.17): 16
[0035] WO 99/37618 . . . Celltech Therapeutics, Ltd.
[0036] A still further related group of compounds discovered by the
Head group to be inhibitors of VLA-4 dependent cell adhesion is
described in Head et al., "Phenylalanine Derivatives As Inhibitors
of Alpha4 Integrins," WO 99/43642, and may be characterized by
general Formula (0.0.18): 17
[0037] Inhibitors of the type described are illustrated in Formula
(0.0.19): 18
[0038] WO 99/43642 . . . Celltech Therapeutics, Ltd.
[0039] Early work in the discovery of inhibitors of VLA-4 dependent
cell adhesion has also been done by Pleiss and Thorsett and their
co-workers, e.g., as described in Thorsett et al., "Inhibitors of
Leukocyte Adhesion," WO 96/01544 assigned to Athena Neurosciences,
Inc. These inhibitors comprise inhibitors that block cellular
adhesion mediated by VLA-4 and they are used to treat a number of
inflammatory diseases, especially inflammatory brain disorders.
[0040] Non-peptide, i.e., small molecule inhibitors of VLA-4 have
also been discovered by the Pleiss and Thorsett group, e.g., as
described in Thorsett, "Carbamoyloxy Compounds Which Inhibit
Leukocyte Adhesion Mediated by VLA-4," WO 99/06390 assigned to
Athena Neurosciences, Inc. Inhibitors of this type may be
represented by general Formula (0.0.20): 19
[0041] where R.sup.1 is alkyl, aryl, cycloalkyl, heterocyclic, or
heteroaryl, all of which are optionally substituted; R.sup.2 is
defined similarly to R.sup.1 and may be combined with it and the
--S(.dbd.O).sub.2-- moiety to form an optionally substituted
heterocyclic group; R.sup.3 is defined similarly to R.sup.1 and is
optionally taken together with the nitrogen atom bound to R.sup.2
and the carbon atom bound to R.sup.3 to form an optionally
substituted heterocyclic group; R.sup.7 is --H or alkyl; Ar is
optionally substituted aryl or heteroaryl; and R.sup.5' is
--O--Z--NR.sup.8R.sup.8' or --O--Z--R.sup.12 where Z is --C(.dbd.O)
or --S(.dbd.O).sub.2, R.sup.8 and R.sup.8' are --H, or optionally
substituted alkyl, cycloalkyl or hetercyclic, or R.sup.8 and
R.sup.8' may be joined to form an optionally substituted
heterocycle, and R.sup.12 is optionally substituted
heterocycle.
[0042] A representative example of the above-described VLA-4
inhibitors is the compound of Formula (0.0.21): 20
[0043] WO 99/06390 . . . Athena Neurosciences, Inc.
[0044] In Yednock and Pleiss "Alpha-9 Integrin Antagonists and
Anti-inflammatory Compositions thereof," WO 99/06391 assigned to
Athena Neurosciences, Inc., there is described the use of the
inhibitory compounds of above-mentioned WO 99/06390 in methods of
treating disorders that involve binding of .alpha.-9 integrin,
particularly adhesion macrophages or neutrophils. Disorders said to
be susceptible to treatment include airway hyper-responsiveness and
occlusion that occur in conjunction with chronic asthma, smooth
muscle cell proliferation in atherosclerosis, vascular occlusion
following angioplasty, fibrosis and glomerular scarring as a result
of renal disease, aortic stenosis, hypertrophy of synovial
membranes in rheumatoid arthritis, and inflammation and scarring
that occur with the progression of ulcerative colitis, and Crohn's
disease.
[0045] The Thorsett and Pleiss group has discovered a group of
inhibitors of VLA-4 which is described in Thorsett et al.
"Substituted Phenylalanine Type Compounds Which Inhibit Leukocyte
Adhesion Mediated by VLA-4," WO 99/06431 assigned to Athena
Neurosciences, Inc. and American Home Products Corporation, which
may be represented by general Formula (0.0.22): 21
[0046] where R.sup.1, R.sup.2, R.sup.3, R.sup.7, and Ar have
substantially the same meaning as described above with respect to
WO 99/06390; and R.sup.5 is an optionally substituted member
selected from the group consisting of --NHC(.dbd.O)R; alkoxyaryl;
aryl; heteroaryl; --NRR'; alkoxy-NRR'; alkenyl; alkynyl; aryloxy;
heteroaryloxy; alkoxy-heterocyclic; O-heterocyclic; tetrazolyl;
--NRS(.dbd.O).sub.2-alky- l; alkenylsulfonylamino;
alkynylsulfonylamino; alkoxy; amidine; --C(.dbd.O)NRR';
--NRC(.dbd.O)R'; --S(.dbd.O).sub.2-aryl;
S(.dbd.O).sub.2-heteroaryl; --NRC(.dbd.O)NRR'; --N RC(.dbd.O)OR';
aminocarbonyl-(N-formylheterocyclyl); and
alkyl-C(.dbd.O)NH-heterocyclyl.
[0047] A compound which illustrates the type of VLA-4 inhibitors
disclosed is that of Formula (0.0.23): 22
[0048] WO 99/06431 . . . Athena Neurosciences, Inc.
[0049] A related group of inhibitory compounds which has also been
discovered by the Thorsett and Pleiss group is described in
Thorsett et al, "Dipeptide and Related Compounds Which Inhibit
Leukocyte Adhesion Mediated by VLA-4," WO 99/06432 assigned to
Athena Neurosciences, Inc. and American Home Products Corporation.
Inhibitory compounds of this type are characterized by general
Formula (0.0.24): 23
[0050] where R.sup.1, R.sup.2, R.sup.3, and R.sup.7 have
substantially the same meaning as described above with respect to
WO 99/06390 and WO 99/06431; and R.sup.5 is -ALK-X or .dbd.CH--Y
where X and Y are defined to mean a wide variety of groups, all of
which are optionally substituted.
[0051] An example of this type of VLA-4 inhibitor is the compound
of Formula (0.0.25): 24
[0052] WO 99/06432 . . . Athena Neurosciences, Inc.
[0053] A further related group of VLA-4 inhibitory compounds which
has also been discovered by the Thorsett and Pleiss group is
described in Dappen et al., "Compounds Which Inhibit Leukocyte
Adhesion Mediated by VLA-4," WO 99/06433 assigned to Athena
Neurosciences, Inc. and American Home Products Corporation.
Inhibitory compounds of this type are characterized by general
Formula (0.0.26): 25
[0054] where R.sup.1, R.sup.2, R.sup.3, and R.sup.7 have
substantially the same meaning as described above with respect to
WO 99/06390, WO 99/06431, and WO 99/06432; and X is --H; --OH;
acylamino; --C(.dbd.O)OH; and optionally substituted alkyl; alkoxy;
aryl; aryloxy; aryloxyaryl; carboxy-alkyl; carboxy-cycloalkyl;
carboxy-aryl; carboxy-heteroaryl; carboxy-heterocyclic; and
cycloalkyl.
[0055] The type of VLA-4 inhibitor described in the paragraph
immediately above may be represented by the compound of Formula
(0.0.27): 26
[0056] WO 99/06433 . . . Athena Neurosciences, Inc.
[0057] A still further group of VLA-4 inhibitory compounds which
has been discovered by the Thorsett and Pleiss group is described
in Ashwell et al., "4-Amino-Phenylalanine Type Compounds Which
Inhibit Leukocyte Adhesion Mediated by VLA-4," WO 99/06434 assigned
to Athena Neurosciences, Inc. and American Home Products
Corporation. Inhibitory compounds of this type are characterized by
general Formula (0.0.28): 27
[0058] where R.sup.1, R.sup.2, R.sup.3, and R.sup.7 have
substantially the same meaning as described above with respect to
WO 99/06390, WO 99/06431, WO 99/06432, and WO 99/06433; and R is
--H, alkyl, or aryl; X is O, S, or NR; and Y is NRR' or
heterocycle, all of which are optionally substituted by a wide
variety of groups.
[0059] This further type of VLA-4 inhibitor may be illustrated by
the compound of Formula (0.0.29): 28
[0060] WO 99/06434 . . . Athena Neurosciences, Inc.
[0061] Another group of VLA-4 inhibitors structurally related to
those groups of VLA-4 inhibitors described above, which has been
discovered by the Thorsett and Pleiss group is described in
Thorsett et al., "Dipeptide Compounds Which Inhibit Leukocyte
Adhesion Mediated by VLA-4," WO 99/06435 assigned to Athena
Neurosciences, Inc. and American Home Products Corporation.
Inhibitory compounds of this type are characterized by general
Formula (0.0.30): 29
[0062] where R.sup.1, R.sup.2, R.sup.3, and R.sup.7 have
substantially the same meaning as described above with respect to
WO 99/06390, WO 99/06431, WO 99/06432, WO 99/06433, and WO
99/06434; R.sup.5 has substantially the same meaning as described
above with respect to WO 99/06432; and R.sup.4is --H; and
optionally substituted alkyl; cycloalkyl; aryl; heteroaryl;
heterocyclic; and R.sup.1 and R.sup.2 may be taken together, or
R.sup.2 and R.sup.3 may be taken together, or R.sup.3 and R.sup.4
may be taken together to form cycloalkyl or heterocyclic
groups.
[0063] This type of VLA-4 inhibitor may be illustrated by the
compound of Formula (0.0.31): 30
[0064] WO 99/06435 . . . Athena Neurosciences, Inc.
[0065] A still further group of structurally related inhibitors of
VLA-4 dependent cell adhesion which has been discovered by the
Thorsett and Pleiss group is described in Thorsett et al., "Benzyl
Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4," WO
99/06436 assigned to Athena Neurosciences, Inc. and American Home
Products Corporation. Inhibitory compounds of this type are
characterized by general Formula (0.0.32): 31
[0066] where R.sup.1, R.sup.2, R.sup.3, and R.sup.7 have
substantially the same meaning as described above with respect to
WO 99/06390, WO 99/06431, WO 99/06432, WO 99/06433, and WO
99/06434; and Ar is aryl or heteroaryl. This type of VLA-4
inhibitor may be illustrated by the compound of Formula (0.0.33):
32
[0067] WO 99/06436 . . . Athena Neurosciences, Inc.
[0068] There is a further description of compounds related
structurally to those described above in WO 99/06390, WO 99/06431,
WO 99/06432, WO 99/06433, WO 99/06434, WO 99/06435, and WO
99/06436, but distinguished from them by means of extensive
provisos, that is set out in Thorsett et al., "Sulfonylated
Dipeptide Compounds Which Inhibit Leukocyte Adhesion Mediated by
VLA-4," WO 99/06437. Three such inhibitory compounds are those of
Formulas (0.0.34) through (0.0.36): 33
[0069] WO 99/06437 . . . Athena Neurosciences, Inc.
[0070] The Stilz and Wehner group has discovered a different class
of compounds which possess inhibitory activity with regard to VLA-4
mediated cell adhesion. These inhibitory compounds are described,
e.g., in Stilz et al., "5-Ring Heterocycles As Inhibitors of
Leukocyte Adhesion and As VLA-4 Antagonists," EP 842 943 assigned
to Hoechst AG., which may be characterized by general Formula
(0.0.37): 34
[0071] where R is 4-amido-phenyl, 4-guanidino-phenyl,
4-aminomethyl-phenyl, 3-amino-propyl, or 3-guanidino-propyl;
R.sup.1 is methyl or benzyl; R.sup.2 is --H, methyl, ethyl,
optionally substituted benzyl, or naphthylmethyl; R.sup.3 is a
mono-, di-, or tri-peptide; R.sup.4 is --H, methyl, or butyl; and
R.sup.5 is --H, alkyl, cycloalkyl, or optionally substituted aryl.
A representative compound falling within the scope of the
above-described class of VLA-4 inhibitors is that of Formula
(0.0.38): 35
[0072] EP 842 943 . . . Hoechst AG.
[0073] The Stilz and Wehner group has also discovered inhibitory
compounds which are structurally close to those in above-described
EP 842 943, and which are described in Stilz et al., "Heterocycles
As Inhibitors of Leukocyte Adhesion and As Antagonists of VLA-4,"
EP 842 944. These compounds may be characterized by general Formula
(0.0.39): 36
[0074] where R.sup.4 is methyl or 4-R.sup.3-phenyl where R.sup.3 is
4,5-dihydroimidazol-2-yl or --C(.dbd.O)NH.sub.2; R.sup.2 is
optionally substituted phenyl, pyridyl, or naphthyl; and R.sup.4 is
--H, ethyl, n-butyl, or iso-butyl. A representative example of this
type of inhibitory compound is that of Formula (0.0.40): 37
[0075] EP 842 944 . . . Hoechst AG.
[0076] Further inhibitory compounds structurally close to those in
above-described EP 842 944 are described in Stilz et al., EP 842
945, which may be characterized by general Formula (0.0.41): 38
[0077] where R is 4-R.sup.2-phenyl where R.sup.2 is --CN,
--NO.sub.2, optionally substituted --NH.sub.2C(.dbd.O)NH, or
--NH.sub.2C(.dbd.O)NHCH.- sub.2; and R.sup.2 is optionally
substituted phenyl. A representative example of this type of
inhibitory compound is that of Formula (0.0.42): 39
[0078] EP 842 945 . . . Hoechst AG.
[0079] The Stilz and Wehner group has also further discovered
inhibitors of VLA-4 dependent cell adhesion which are described in
Wehner et al., "Imidazolidine Derivatives with VLA-4 Antagonist
Activity Useful for the Treatment of Diseases Mediated by Leukocyte
Adhesion," EP 903 353 assigned to Hoechst Marion Roussel
Deutschland GmBH. Compounds of this type are characterized by
general Formula (0.0.43): 40
[0080] where A is optionally substituted alkylene, alkenylene,
phenylene, -phenyl-alkylene, or alkylene-phenyl-; L and M are a
bond or --CH.sub.2--; X is optionally substituted --CH(R.sup.7)--
or --C(.dbd.CHR.sup.7)-- where R.sup.7 is optionally substituted
alkyl, phenyl, furyl, thienyl, pyrrolyl, indazolyl, or pyridinyl;
R.sup.1 is --H, cycloalkyl, optionally substituted alkyl, aryl,
heterocyclyl; --C(.dbd.O)R.sup.6, or --SO.sub.2R.sup.6 where
R.sup.6 is --H, cycloalkyl, optionally substituted alkyl, aryl, or
heterocyclyl; R.sup.2 is --NH.sub.2, --C(.dbd.O)NH.sub.2, or
--C(.dbd.O)OH; R.sup.3 is --H, alkyl, optionally substituted aryl,
or heterocyclyl; and R.sup.5 is --C(.dbd.O)OH, tetrazolyl,
--SO.sub.3H, or --SO.sub.2NH.sub.2.
[0081] A typical VLA-4 inhibitor falling within the above-described
class of compounds is illustrated by Formula (0.0.44): 41
[0082] EP 903 353 . . . Hoechst Marion Roussel Deutschland GmBH
[0083] Another group of inhibitory compounds closely related in
structure to those above-described has been discovered by the Stilz
and Wehner group and is described in Wehner et al., "Substituted
Imidazoline Derivatives with VLA-4 Antagonist Activity," EP 918
059. Said group may be illustrated by general Formula (0.0.45):
42
[0084] where R is methyl or phenyl; R.sup.1 is tert-butyl, propyl,
iso-propyl, benzyl, cyclohexyl, or optionally substituted phenyl;
R.sup.3 is adamantyl, --CH(CH.sub.3)CH.sub.2C(.dbd.O)OH, optionally
substituted --CH(phenyl)CH.sub.2C(.dbd.O)OH or
--CH(phenyl)C(.dbd.O)OH; and R.sup.4 is --H or iso-butyl. An
example of a compound which illustrates this class of VLA-4
inhibitors is that of Formula (0.0.46): 43
[0085] EP 918 059 . . . Hoechst Marion Roussel Deutschland GmBH
[0086] Yet another class of VLA-4 inhibitors has been discovered by
the Chen group, e.g., as described in Chen et al., "Novel
N-Aroylphenylalanine Derivatives As Integrin Antagonists," WO
99/10312 assigned to F. Hoffmann-La Roche AG. This class of
inhibitors may be illustrated by general Formulas (0.0.47) and
(0.0.48): 44
[0087] where there are two sub-classes of compounds based on
different A rings as shown above. Further, the A and B rings may be
replaced with various heterocycles, although an ortho-substituted B
ring is preferred. A representative example of a compound falling
within this class of inhibitors is that of Formula (0.0.49): 45
[0088] WO 99/10312 . . . F. Hoffmann-La Roche AG.
[0089] A closely related group of inhibitors discovered by the Chen
group is described in Chen et al., WO 99/10313 assigned to F.
Hoffmann-La Roche AG., which may be illustrated by general Formulas
(0.0.50) and (0.0.51): 46
[0090] where there are two sub-classes of compounds as described
above in the case of those of Formulas (0.0.47) and (0.0.48).
Further, the three R groups attached to the amide linker combine to
form a quaternary center. A typical compound representative of the
VLA-4 inhibitors in this class is that of Formula (0.0.52): 47
[0091] WO 99/10313 . . . F. Hoffmann-La Roche AG.
[0092] A still further class of inhibitors of VLA-4 dependent cell
adhesion is that discovered by Hagmann and his co-workers, e.g., as
described in Durette and Hagmann, "Heterocyclic Amide Compounds As
Cell Adhesion Inhibitors," WO 98/53814 which is assigned to Merck
& Co., Inc. This class of compounds may be illustrated by
general Formula (0.0.53): 48
[0093] where X is --C(.dbd.O)OH or acid isostere; Y is --C(.dbd.O)
or --S(.dbd.O).sub.2; R.sup.1 through R.sup.8 are selected from a
wide variety of well known substituents; and A, B, and Z are
selected so as to afford heterocycles of different types and ring
sizes. An example of an inhibitory compound which is representative
of this class is that of Formula (0.0.54): 49
[0094] WO 98/53814 . . . Merck & Co., Inc.
[0095] Another class of structurally related inhibitory compounds
discovered by the Hagmann group is described in Durette et al.,
"Biarylalkanoic Acids As Cell Adhesion Inhibitors," WO 98/53817
assigned to Merck & Co., Inc., which may be illustrated by
general Formulas (0.0.55) and (0.0.56): 50
[0096] where X, Y, and R.sup.1 through R.sup.7 have substantially
the same meaning as defined above for Formula (0.0.53), except that
R.sup.2 and R.sup.3 may be taken together with the atoms to which
they are attached to form a ring of 4 to 7 members containing 0-2
additional heteroatoms selected from O, S, and N; and R.sup.b is
optionally substituted alkyl, alkenyl, alkynyl, arylalkyl, or
heteroarylalkyl. A representative example of a compound falling
within the scope of this class of VLA-4 inhibitors is that of
Formula (0.0.57): 51
[0097] WO 98/53817 . . . Merck & Co., Inc.
[0098] A further class of inhibitory compounds discovered by the
Hagmann group and closely related in structure to those described
immediately above, is disclosed in Durette et al., "Sulfonamides As
Cell Adhesion Inhibitors," WO 98/53818 assigned to Merck & Co.,
Inc. These compounds may be illustrated by general Formulas
(0.0.57) and (0.0.58): 52
[0099] where R.sup.b and R.sup.1 through R.sup.7 have the same
meaning as defined above for Formulas (0.0.55) and (0.0.56). A
representative inhibitory compound falling within the
above-described class is that of Formula (0.0.59): 53
[0100] WO 98/53818 . . . Merck & Co., Inc.
[0101] A still further class of VLA-4 inhibitory compounds related
in structure to those described above has been discovered by the
Hagmann group and is disclosed in Delaszlo, "Azapeptide Acids As
Cell Adhesion Inhibitors," WO 99/20272. This class of inhibitors
may be illustrated by general Formula (0.0.60): 54
[0102] where m and n are 0 to 2; and X, Y, and R.sup.1 through
R.sup.6 have the same meaning as defined above for Formulas
(0.0.55) and (0.0.56). Representative inhibitory compounds falling
within the above-described class are those of Formulas (0.0.61) and
(0.0.62): 55
[0103] WO 99/20272 . . . Merck & Co., Inc.
[0104] Another class of VLA-4 dependent cell adhesion inhibitors
discovered by the Hagmann group is described in Delaszlo and
Hagmann, "4-Substituted-4-Piperidine Carboxamide Derivatives Useful
in the Treatment of Asthma, Inflammation and Multiple Sclerosis."
WO 99/25685 assigned to Merck & Co., Inc. Compounds of this
class may be illustrated by general Formula (0.0.63): 56
[0105] where X is a bond or substituted carbon atom; Z is
--C(.dbd.O)OH or acid isostere; L is --C(.dbd.O)--,
--S(.dbd.O).sub.2--; and R.sup.1 through R.sup.5 have the
substantially the same meaning as defined above for Formulas
(0.0.55) and (0.0.56). A typical VLA-4 inhibitory compound in this
class is that of Formula (0.0.64): 57
[0106] WO 99/25685 . . . Merck & Co., Inc.
[0107] Another class of VLA-4 inhibitors closely related in
structure to those described above is disclosed in Chang et al.,
"Cyclic Amino Acids As Cell Adhesion Inhibitors," WO 99/26615
assigned to Merck & Co., Inc. Inhibitory compounds of this
class are illustrated by general Formula (0.0.65): 58
[0108] where R indicates the ring size, and X, Y, and R.sup.1
through R.sup.7 have the same meaning as defined above for Formulas
(0.0.55) and (0.0.56). A representative example of an inhibitory
compound within this class is that of Formula (0.0.66): 59
[0109] WO 99/26615 . . . Merck & Co., Inc.
[0110] A class of VLA-4 dependent cell adhesion inhibitors has been
discovered which differs from those disclosed in WO 98153814
described above only with respect to the terminal amino acid, which
is a .beta.-amino acid. Accordingly, reference may be made to
general Formula (0.0.53) above. These .beta.-amino acids are
disclosed in Durette et al., "Substituted .beta.-Alanine
Derivatives As Cell Adhesion Inhibitors," WO 99/26921 assigned to
Merck & Co., Inc. Typical inhibitors of this type are
illustrated in Formulas (0.0.67) and (0.0.68): 60
[0111] WO 99/26921 . . . Merck & Co., Inc.
[0112] A further class of VLA-4 dependent cell adhesion inhibitors
related in structure to those described above has been discovered
by the Hagmann group and is disclosed in Chang et al., "Substituted
Pyrrole Derivates As Cell Adhesion Inhibitors," WO 99/26922
assigned to Merck & Co., Inc. This class of inhibitors is
illustrated by general Formula (0.0.69): 61
[0113] where Y and R.sup.1 through R.sup.7 have the same meaning as
defined above for Formulas (0.0.55) and (0.0.56), and X and Z have
the same meaning as defined above for Formula (0.0.63), except that
the meanings are reversed because -X-Z- in (0.0.63) has been
changed to -Z- X- in (0.0.69). An example of inhibitory compounds
falling within this class is illustrated by Formula (0.0.70):
62
[0114] WO 99/26922 . . . Merck & Co., Inc.
[0115] Another class of VLA-4 inhibitory compounds discovered by
the Hagmann group and closely related to those above is that
described in Delaszlo and Hagmann, "Para-Aminomethylaryl
Carboxamide Derivatives," WO 99/26923 assigned to Merck & Co.,
Inc., and which may be represent by general Formula (0.0.71):
63
[0116] where L, X, Z, and R.sup.1 through R.sup.6 have
substantially the same meaning as defined above under Formulas
(0.0.55) and (0.0.56). Ar is a 1,4 substituted aryl or heteroaryl
moiety. A typical compound falling within the scope of this class
of VLA-4 inhibitors is illustrated as Formula (0.0.72): 64
[0117] WO 99/26923 . . . Merck & Co., Inc.
[0118] A different group has discovered a new class of VLA-4
antagonists which is described in Wattanasin and Von Matt, "VLA-4
Antagonists," WO 99/37605 assigned to Novartis. The inhibitory
compounds in this new class may be represented by general Formula
(0.0.73): 65
[0119] where Y is --C(.dbd.O)--, --S(.dbd.O).sub.2--, or
--P(.dbd.O).sub.2--; Z is --(CH.sub.2).sub.n--, --CHR--, or --NR--;
W is --CH-- or --N--; X is --C(.dbd.O)OH or acid isostere; and
R.sup.1 through R.sup.4 are a wide variety of common substituents.
A representative example of a VLA-4 inhibitor from this class is
illustrated by Formula (0.0.74): 66
[0120] WO 99/37605 . . . Novartis
[0121] Another different group has discovered a further new class
of compounds which inhibit VLA-4 dependent cell adhesion, which is
described in Astles et al., "Substituted Anilides and Their Use in
the Treatment of Various Disease States including Inflammation,
arthritis, and atherosclerosis," WO 99/23063 assigned to
Rhone-Poulenc Rorer Ltd. This class of VLA-4 inhibitors may be
represented by general Formula (0.0.75): 67
[0122] where X.sup.1, X.sup.2, and X.sup.3 are --N-- or --CR--;
Ar.sup.1 is aryl or heteroaryl; L.sup.2 is an optionally
substituted alkylene linkage; Y is carboxy, an acid bioisostere, or
--C(.dbd.O)NRR; and R.sup.1 is --H, halo, --OH, lower alkyl or
lower alkoxy. A representative example of an inhibitory compound
which fits into this class is illustrated by Formula (0.0.76):
68
[0123] WO 99/23063 . . . Rhone-Poulenc Rorer Ltd.
[0124] Another class of VLA-4 inhibitors which is closely related
in structure to those described immediately above is described in
Artles et al. "Biaryl .beta.-Alanine Derivatives Useful As VLA-4
Antagonists," WO 99/33789 assigned to Rhone-Poulenc Rorer Ltd.
Members of this class of inhibitors may be represented by general
Formula (0.0.77): 69
[0125] where X.sup.1, X.sup.2, and Y have the same meaning as
defined above under Formula (0.0.75). R.sup.4 is aryl or heteroaryl
or is optionally substituted alkyl, alkenyl or alkynyl. A
representative example of an inhibitory compound within this class
is illustrated by Formula (0.0.78): 70
[0126] WO 99/33789 . . . Rhone-Poulenc Rorer Ltd.
[0127] A further different group has also discovered a new class of
VLA-4 dependent cell adhesion inhibitors, which is described in
Lobl et al. "Cyclic Peptide Inhibitors of .beta..sub.1 and
.beta..sub.2 Integrin-Mediated Adhesion," WO 96/40781 assigned to
Tanabe Seiyaku Co., Ltd. The inhibitors are cyclic peptides which
contain a free acid.
[0128] WO 96/40781 . . . Tanabe Seiyaku Co., Ltd.
[0129] Another class of VLA-4 inhibitors discovered by the same
group is described in Lobl et al. "Inhibitors of
.alpha..sub.1.beta..sub.4 Mediated Cell Adhesion," WO 98/58902
assigned to Tanabe Seiyaku Co., Ltd. and Pharmacia & Upjohn
Company. Members of this further class of VLA-4 inhibitors may be
represented by general Formula (0.0.79): 71
[0130] where R.sup.1 is acid or amide; X is phenyl; and Z is amide
or methylene ether. A representative example of an inhibitory
compound from this class is that of Formula (0.0.80): 72
[0131] WO 98/58902 . . . Tanabe Seiyaku Co., Ltd.
[0132] Another class of VLA-4 inhibitors discovered by the same
group is described in Sircar et al. "Inhibitors of .alpha.4
Mediated Cell Adhesion," WO 99/36393 assigned to Tanabe Seiyaku
Co., Ltd. Members of this class of VLA-4 inhibitors may be
characterized by general Formula (0.0.81): 73
[0133] where R.sup.1 through R.sup.6, except R.sup.4, are selected
from a wide variety of common substituent groups; R.sup.4 is acid,
acid isostere, or amide; A is aryl or heteroaryl; Q is a bond,
--C(.dbd.O)--, or substituted alkylene; n is 0 to 2; and W is
--O--, --S--, --CH.dbd.CH--, or --N.dbd.CH--. A representative
member of this class of VLA-4 inhibitors is illustrated by Formula
(0.0.82): 74
[0134] WO 99/36393 . . . Tanabe Seiyaku Co., Ltd.
[0135] A still further different group has also discovered a new
class of VLA-4 dependent cell adhesion inhibitors, which is
described in Kogan et al. "Process to Inhibit Binding of the
Integrin alpha 4 beta 1 to VCAM-1 or Fibronectin," WO 96/00581
assigned to Texas Biotechnology Corporation. This class of VLA-4
antagonists comprises cyclic peptides of from 5 to 13 residues
modeled after a portion of the CS1 peptide, that also contain a
free acid.
[0136] WO 96/00581 . . . Texas Biotechnology Corporation
[0137] A yet still further different group has also discovered a
new class of VLA-4 antagonists, which is described in Dutta,
"Fibronectin Adhesion Inhibitors," WO 96/20216 assigned to Zeneca
Limited. This class of VLA-4 antagonists comprises cyclic peptides
that contain a free acid.
[0138] WO 96/00581 . . . Zeneca Limited
[0139] A related class of VLA-4 antagonists discovered by the same
group is described in Dutta, "Cyclic Tetrapeptide Dimers Useful As
Fibronectin Inhibitors," WO 97/02289 assigned to Zeneca Limited.
This class of VLA-4 antagonists comprises cyclic dimeric peptides
in which a peptide 1 and peptide 2 independently representing a
tetrapeptide, are juxtaposed in parallel or antiparallel
orientation by means of two linking moieties L1 and L2.
[0140] WO 97/02289 . . . Zeneca Limited
[0141] Another related class of VLA-4 antagonists discovered by the
same group is described in Dutta, "Cyclic Octapeptide Derivatives
That Are Integrin Antagonists," WO 97/49731 assigned to Zeneca
Limited. This class of VLA-4 antagonists comprises a variety of
cyclic octapeptides containing a free acid.
[0142] WO 97/49731 . . . Zeneca Limited
[0143] The same group has also discovered a non-peptidal class of
VLA-4 antagonists which is described in Brittain and Johnstone,
"Chemical Compounds," WO 99/24398 assigned to Zeneca Limited.
Members of this class may be represented by general Formula
(0.0.83): 75
[0144] where Y is --O--, --S--, or --S(.dbd.O).sub.2--; R.sup.11 is
urea; R.sup.11 is acid or acid isostere; and m is 0 or 1 and when m
is 0 then n is 1 to 4, and when m is 1 then n is 0. A
representative member of this class of VLA-4 antagonists is
illustrated by Formula (0.0.84): 76
[0145] WO 99/24398 . . . Zeneca Limited
[0146] None of the references discussed above discloses or suggests
the compounds of the present invention.
[0147] Despite the above-described advances in the art with regard
to inhibitors of VLA-4 mediated cell adhesion, the artisan will
quickly recognize that the peptidyl inhibitors are prone to poor
absorption, poor solubility and are subject to metabolism in vivo
(both systemically and locally when administered directly into the
lung) diminishing their opportunity to appreciably affect the
course of an inflammatory, respiratory or autoimmune disease.
[0148] Those of the above-described VLA-4 antagonists that are
non-peptidal, i.e., that may be regarded as small molecules, are
thereby able to avoid the liabilities of peptidal agents as
discussed above. However, the small molecule VLA-4 antagonists
known in the art, as described in detail above, have not yet been
established to possess sufficiently high levels of the desired
potency with low levels of acceptable side effects, together with
adequately workable pharmacokinetic and adsorption profiles, such
as would enable such compounds to become suitable therapeutic
agents for use in treating the diseases and conditions discussed
herein. Accordingly, there still exists in the art a need for
non-peptidyl or semi-peptidyl therapeutic agents which can
effectively treat or prevent such pathological conditions.
SUMMARY OF THE INVENTION
[0149] The present invention is concerned with compositions which
inhibit VLA-4 dependent cell adhesion in a mammal. The present
invention thus relates to a compound of Formula (1.0.0): 77
[0150] and pharmaceutically acceptable salts and other prodrug
derivatives thereof, wherein:
[0151] A is (C.sub.1-C.sub.6) alkyl, cycloalkyl, aryl, heteroaryl
or heterocyclyl as defined herein; where said alkyl, cycloalkyl,
aryl, heteroaryl or heterocyclyl is optionally substituted with 0
to 3 R.sup.9; or is a member selected from the group consisting of
the following radicals: A.sup.1-NHCNHC(.dbd.O)NH-A.sup.2-;
A.sup.1-NHC(.dbd.O)O-A.sup.2- -; A.sup.1-OC(.dbd.O)NH-A.sup.2-;
A.sup.1-NHSO.sub.2NH-A.sup.2-; A.sup.1-NHC(.dbd.O)-A.sup.2-;
A.sup.1-C(.dbd.O)NH-A.sup.2-; A.sup.1-NHSO.sub.2-A.sup.2-;
A.sup.1-SO.sub.2NH-A.sup.2-; A.sup.1-(CH.sub.2).sub.r-A.sup.2-;
A.sup.1-CH(R.sup.1)--O-A.sup.2-; A.sup.1-(CH.sub.2).sub.r-A.sup.2;
A.sup.1-O(CH.sub.2).sub.r-A.sup.2-;
A.sup.1-(CH.sub.2).sub.rNH-A.sup.2-;
A.sup.1-NH(CH.sub.2).sub.r-A.sup.2-; and
A.sup.1-(CH.sub.2).sub.rS(.dbd.O).sub.q-A.sup.2-; where A.sup.1 and
A.sup.2 are each independently selected from the group consisting
of hydrogen, aryl, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, cycloalkyl, heteroaryl, and
heterocyclyl; where said aryl, alkyl, cycloalkyl, heteroaryl, or
heterocyclyl group is substituted with 0 to 3 R.sup.9;
[0152] B is a member independently selected from the group
consisting of the following: 78
[0153] where the symbol "*" indicates the point of attachment of
the moiety represented by each partial Formula (1.1.0) through
(1.1.23) to the moiety "CR.sup.2R.sup.3" in Formula (1.0.0); and
the symbol ".fwdarw." indicates the point of attachment of the
moiety represented by each partial Formula (1.1.0) through (1.1.23)
to the moiety "E" in Formula (1.0.0); and each of Formula (1.1.0)
through (1.1.23), with the exception of Formulas (1.1.10),
(1.1.17), and (1.1.23), may be optionally substituted with
R.sup.9;
[0154] E is a single bond; --O--; --NR.sup.10--; --CH.dbd.CH--;
--C.ident.--C--; --S(.dbd.O).sub.q; --CR.sup.11R.sup.12NR.sup.10--;
or --CR.sup.11R.sup.12--;
[0155] X is --O--; --C(.dbd.O)--; --S(.dbd.O).sub.q--; or
--NR.sup.10--;
[0156] X.sup.1, X.sup.2 and X.sup.3 are each independently selected
from the group consisting of CH, CR.sup.9 or N;
[0157] Y is a single bond; --C(.dbd.O)--; --C(.dbd.S)--; or
--S(.dbd.O).sub.2--;
[0158] k is an integer independently selected from 0, 1 and 2;
[0159] m is an integer independently selected from 0 and 1;
[0160] n is an integer independently selected from 0, 1 and 2;
[0161] p is an integer independently selected from 0 and 1,
provided that p must be selected as 1 where B is selected as
partial formula (1.1.0) through (1.1.11);
[0162] q is an integer independently selected from 0, 1 and 2;
[0163] r is an integer independently selected from 0, 1 and 2;
[0164] R.sup.1 is (C.sub.1-C.sub.3) alkyl substituted with 0 or 1
of F; CF.sub.3; OCF.sub.3; or cyano;
[0165] R.sup.2and R.sup.3 are each independently selected from the
group consisting of hydrogen; (C.sub.1-C.sub.6) alkyl substituted
with 0 to 3 R.sup.13; (C.sub.2-C.sub.6) alkenyl substituted with 0
to 3 R.sup.13; a (C.sub.3-C.sub.14) carbocyclic ring system
substituted with 0 to 3 R.sup.13; a heterocyclyl ring as defined
herein, substituted with 0 to 3 R.sup.13; (C.sub.1-C.sub.6)
alkyl-OR.sup.5 substituted with 0 to 3 R.sup.13; (C.sub.1-C.sub.6)
alkyl-SR.sup.5 substituted with 0 to 3 R.sup.13; (C.sub.1-C.sub.6)
alkyl-SO.sub.2R.sup.5 substituted with 0 to 3 R.sup.13; a
heteroaryl ring as defined herein, substituted with 0 to 3
R.sup.13; an aryl ring as defined herein, substituted with 0 to 3
R.sup.13;
[0166] provided that
[0167] R.sup.2 and R.sup.3 are each defined as above; or they are
taken together as defined below; or one of them is taken together
with R.sup.4 as defined below, in which case the other has the
meaning of hydrogen or methyl;
[0168] R.sup.2 and R.sup.3 are taken together to form either a
cycloalkyl or heterocyclyl ring substituted with 0 to 3 R.sup.13;
or
[0169] R.sup.2 or R.sup.3 is taken together with R.sup.4 and the
carbon and nitrogen atoms to which they are respectively attached
to form a heteroaryl or heterocyclyl group as defined herein,
substituted with 0 to 3 R.sup.13;
[0170] R.sup.4 is hydrogen; or (C.sub.1-C.sub.6) alkyl optionally
substituted with R.sup.13; or R.sup.4 may be taken together with
either R.sup.2 or R.sup.3 to form a carbocyclic or heterocyclic
ring;
[0171] R.sup.5 and R.sup.6 are independently hydrogen;
(C.sub.1-C.sub.6) alkyl; (C.sub.2-C.sub.6) alkenyl;
(C.sub.2-C.sub.6) alkynyl; CF.sub.3; aryl; cycloalkyl; heteroaryl;
or heterocyclyl; wherein said alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heteroaryl, or heterocyclyl is substituted by 0 to 3
R.sup.13;
[0172] R.sup.7 is (C.sub.1-C.sub.6) alkyl;
(CH.sub.2).sub.kOR.sup.5; (CH.sub.2).sub.kC(.dbd.O)R.sup.5;
(CH.sub.2).sub.kC(.dbd.O)NR.sup.6R.sup.- 5;
(CH.sub.2).sub.kNR.sup.6C(.dbd.O)R.sup.5;
(CH.sub.2).sub.kNR.sup.6C(.db- d.O)OR.sup.5;
(CH.sub.2).sub.kNR.sup.6SO.sub.2R.sup.5;
(CH.sub.2).sub.kNR.sup.6R.sup.5; F; CF.sub.3; OCF.sub.3; aryl,
substituted with 0 to 3 R.sup.9; heterocyclyl, substituted with 0-3
R.sup.9; heteroaryl, substituted with 0-3 R.sup.9; cycloalkyl,
substituted with 0 to 3 R.sup.9; or R.sup.7 may be taken together
with R.sup.8 to form a cycloalkyl or heterocyclyl ring; or R.sup.7
may be taken together with R.sup.11 to form a cycloalkyl or
heterocyclyl ring;
[0173] R.sup.8 is hydrogen; F; CN; (C.sub.1-C.sub.6) alkyl or
(C.sub.1-C.sub.6) alkoxy;
[0174] R.sup.9 is halogen; (C.sub.1-C.sub.6) alkyl;
(C.sub.1-C.sub.6) alkoxy; (C.sub.3-C.sub.6) cycloalkyl;
(C.sub.3-C.sub.6) cycloalkoxy; cyano; (CH.sub.2).sub.kOH;
C(.dbd.O)R.sup.5; (CH.sub.2).sub.kC(O)NR.sup.5- R.sup.6;
(CH.sub.2).sub.kNR.sup.5R.sup.6; (CH.sub.2).sub.kNR.sup.5SO.sub.2-
R.sup.6; CF.sub.3; OCF.sub.3; SO.sub.2NR.sup.5R.sup.6;
(CH.sub.2).sub.mC(.dbd.O)OR.sup.5; when R.sup.9 is attached to a
saturated carbon atom R.sup.9 may be .dbd.O or .dbd.S; when R.sup.9
is attached to a sulphur atom R.sup.9 may be .dbd.O;
[0175] R.sup.10 is hydrogen; C(.alpha.O)R.sup.5; C(.dbd.O)OR.sup.5;
(C.sub.1-C.sub.6) alkyl; aryl; heterocyclyl; heteroaryl;
cycloalkyl; or SO.sub.2R.sup.5;
[0176] R.sup.11 and R.sup.12 are independently hydrogen;
(C.sub.1-C.sub.6) alkyl; hydroxy; cyano; (C.sub.1-C.sub.6) alkoxy;
NR.sup.6C(.dbd.O)R.sup.5- ; NR.sup.6SO.sub.2R.sup.5;
NR.sup.6R.sup.5; CF.sub.3; F; aryl; heterocyclyl; heteroaryl;
cycloalkyl; cycloalkoxy; or R.sup.11 may be taken together with
R.sup.12 to form a cycloalkyl or heterocyclyl ring;
[0177] R.sup.13 is independently selected from the group consisting
of halogen; CF.sub.3; (C.sub.1-C.sub.6) alkyl; aryl; heteroaryl;
heterocyclyl; hydroxy; cyano; (C.sub.1-C.sub.6) alkoxy;
(C.sub.3-C.sub.6) cycloalkyl; (C.sub.3-C.sub.6) cycloalkoxy;
(C.sub.2-C.sub.6) alkynyl; (C.sub.2-C.sub.6) alkenyl;
--NR.sup.6R.sup.5; --C(.dbd.O)NR.sup.5R.sup.6; SO.sub.2R.sup.5;
C(.dbd.O)R.sup.5; NR.sup.5SO.sub.2R.sup.6;
NR.sup.5C(.dbd.O)R.sup.6; C(.dbd.O)NR.sup.5SO.sub.2R.sup.6;
NR.sup.5C(.dbd.O)OR.sup.6; and SO.sub.2NR.sup.6R.sup.5.
[0178] The present invention is also concerned with pharmaceutical
compositions comprising one or more of the compounds of the present
invention as described above together with a pharmaceutically
acceptable carrier for said compound(s), wherein the amount of said
compound(s) present is effective for preventing, inhibiting,
suppressing or reducing cell adhesion and consequent or associated
pathogenic processes subsequently mediated by VLA-4. The present
invention is further concerned with pharmaceutical compositions
which in addition to containing a compound of the present
invention, additionally comprise one or more therapeutic agents
selected from the group consisting essentially of anti-inflammatory
corticosteroids, nonsteroidal anti-inflammatory agents,
bronchodilators, anti-asthmatic agents, and immunosuppressant
agents.
[0179] The present invention is still further concerned with a
method of treating or preventing an inflammatory, autoimmune or
respiratory diseases by inhibiting cell adhesion and consequent or
associated pathogenic processes subsequently mediated by VLA-4,
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of a pharmaceutical composition of
the present invention. The pharmaceutical compositions of the
present invention may be used in the treatment of many
inflammatory, autoimmune and respiratory diseases, including but
not limited to asthma, multiple sclerosis, rheumatoid arthritis,
osteoarthritis, inflammatory bowel disease, psoriasis, host
rejection following organ transplantation, atherosclerosis, and
other diseases mediated by or associated with VLA-4.
DETAILED DESCRIPTION OF THE INVENTION
[0180] The present invention relates to compounds which inhibit
cell adhesion and subsequent pathogenic processes mediated by
VLA-4. These compounds, which are thus useful in the treatment of
many inflammatory, autoimmune and respiratory diseases, may be
illustrated by Formula (1.0.0): 79
[0181] For compounds of Formula (1.0.0), the terminal group
identified as A has the meaning alkyl, cycloalkyl, aryl, heteroaryl
or heterocyclyl substituted with 0 to 3 R.sup.9; or is a member
selected from the group consisting of the following radicals:
A.sup.1-NHC(.dbd.O)NH-A.sup.2-, A.sup.1-NHC(.dbd.O)O-A.sup.2-,
A.sup.1-OC(.dbd.O)NH-A.sup.2-, A.sup.1-NHSO.sub.2NH-A.sup.2-,
A.sup.1-NHC(.dbd.O)-A.sup.2-, A.sup.1-C(.dbd.O)NH-A.sup.2-,
A.sup.1-NHSO.sub.2-A.sup.2-, A.sup.1-SO.sub.2NH-A.sup.2-,
A.sup.1-(CH.sub.2).sub.rO-A.sup.2-,
A.sup.1-O(CH.sub.2).sub.r-A.sup.2-,
A.sup.1-(CH.sub.2).sub.r-A.sup.2-, where A.sup.1 and A.sup.2 is
each independently selected from the group consisting of hydrogen,
aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and
heterocyclyl; where said aryl, alkyl, alkenyl, cycloalkyl,
heteroaryl, or heterocyclyl group is substituted with 0 to 3
R.sup.9.
[0182] The term "alkyl" as used with reference to "A", as well as
in other contexts throughout the instant specification, and whether
used alone or in combination, refers to a straight-chain or
branched chain alkyl radical containing the indicated number of
carbon atoms, usually from 1 to 6 but often from 1 to 4, carbon
atoms. Examples of such radicals include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, pentyl, iso-amyl, and hexyl.
[0183] The term "cycloalkyl" as used with reference to "A", as well
as in other contexts throughout the instant specification, and
whether used alone or in combination, refers to a cyclic alkyl
radical containing from 3 to 6 carbon atoms. Examples of such
cycloalkyl radicals include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl.
[0184] The term "aryl" as used with reference to "A", as well as in
other contexts throughout the instant specification, is intended to
refer to a carbocyclic aromatic group which is a member selected
from the group consisting essentially of phenyl, naphthyl, indenyl,
indanyl, and fluorenyl. It is preferred, however, that where "A" is
"aryl", that it is phenyl.
[0185] The term "heteroaryl" as used with reference to "A", as well
as in other contexts throughout the instant specification, is
intended to refer to a heterocyclic aromatic group which is a
member selected from the group consisting essentially of furyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl,
thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl,
pyrimidinyl, triazinyl, pyranyl, parathiazinyl, indolyl,
isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl,
2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl,
benzimidazolyl, benzoxazolyl, benzthiazolyl, purinyl, quinolinyl,
isoquinolinyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl,
carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
and pyrazolo[1,5-c]triazinyl.
[0186] It is preferred, however, that where "A" is "heteroaryl"
that it is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,
thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl,
benzo[b]furanyl, benzimidazolyl, or quinolinyl. More preferably,
"A" is pyridyl.
[0187] The terms "heterocylic" and "heterocyclyl" as used with
reference to "A", as well as in other contexts throughout the
instant specification, are both intended to refer to a non-aromatic
3- to 10-membered carbocyclic ring in which at least one of the
carbon atoms of the ring has been replaced by a heteroatom selected
from N, O or S. Preferably two, and more preferably one heteroatom
is present, except that in the case of nitrogen, as many as four N
heteroatoms may be present. The heterocyclyl group may comprise one
or two fused rings, and further may include an aryl-fused ring. In
a preferred meaning, "heterocyclyl" refers to a member selected
from the group consisting essentially of oxiranyl, pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, tetrazolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, and benzodioxolane,
especially 1,3-benzodioxol-5-yl.
[0188] It is preferred, however, that where "A" is "heterocyclyl"
that it is pyrrolidinyl, piperidinyl, piperazinyl, or
morpholinyl.
[0189] Where "A" is defined as a moiety selected from the
above-defined alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl
groups, said moiety may be substituted with 0 to 3 R.sup.9. The
choice of "0" merely denotes that there are no substituents,
substitution being optional. Where substitution occurs, preferably
there are two substituents, and more preferably there is only one
substituent.
[0190] Where a substituent R.sup.9 is used, it will be
independently selected from the group consisting essentially of
halogen; (C.sub.1-C.sub.6) alkyl; (C.sub.1-C.sub.6) alkoxy;
(C.sub.3-C.sub.6) cycloalkyl; (C.sub.3-C.sub.6) cycloalkoxy; cyano;
hydroxy; C(.dbd.O)R.sup.5; C(O)NR.sup.5R.sup.6; NR.sup.5R.sup.6;
NR.sup.5SO.sub.2R.sup.6; CF.sub.3; OCF.sub.3;
SO.sub.2NR.sup.5R.sup.6; C(.dbd.O)OR.sup.5; when R.sup.9 is
attached to a saturated carbon atom R.sup.9 may be .dbd.O or
.dbd.S; when R.sup.9 is attached to a sulfur atom R.sup.9 may be
.dbd.O; where R.sup.5 and R.sup.6 are as further defined herein.
Preferably, however, there is a single substituent and it is F, Cl,
OH, methyl, methoxy, cyclohexyl, acetyl, cyclopropyloxy, or
F.sub.3C--.
[0191] The term "alkoxy" as used with reference to the substituents
"R.sup.9" on the group "A", as well as in other contexts throughout
the instant specification, and whether used alone or in
combination, refers to an alkyl ether radical, wherein the term
"alkyl" is as defined above. Examples of suitable alkyl ether
radicals include, but are not limited to, methoxy, ethoxy,
n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and
tert-butoxy.
[0192] The term "cycloalkoxy" as used with reference to the
substituents "R.sup.9" on the group "A", as well as in other
contexts throughout the instant specification, and whether used
alone or in combination, refers to an cycloalkyl ether radical,
wherein the term "cycloalkyl" is as defined above. Examples of
suitable cycloalkoxy radicals include, but are not limited to,
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and
cyclohexyloxy.
[0193] A preferred meaning of "A" is that of a divalent radical
which is a member selected from the group consisting of the
following radicals: A1-NHC(.dbd.O)NH-A2-, A1-NHC(.dbd.O)O-A2-,
A1-OC(.dbd.O)NH-A2-, A1-NHSO2NH-A2-, A1-NHC(.dbd.O)-A2-,
A1-C(.dbd.O)NH-A2-, A1-NHSO2-A2-, A1-SO2NH-A.sup.2-,
A1-(CH2).sub.rO-A2-, A1-O (CH2)r-A2-, A1-(CH2)r-A2-, where A.sup.1
and A.sup.2 is each independently selected from the group
consisting of hydrogen, aryl, (C.sub.1-C.sub.6) alkyl, cycloalkyl,
heteroaryl, and heterocyclyl; where said aryl, alkyl, cycloalkyl,
heteroaryl, or heterocyclyl group is substituted with 0 to 3
R.sup.9. The alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl
group which is bonded to one or both sides of the ureido radical is
selected in accordance with the definitions set out above, as are
the 0 to 3 substituents R.sup.9. It is preferred that an aryl group
be covalently bonded to the both sides of the ureido radical, and
it is further preferred that this aryl group be phenyl. It is most
preferred that said phenyl group have a single substituent which is
preferably F, Cl, methyl, methoxy, or F.sub.3C--. Examples of the
preferred meanings of "A" are shown in partial Formulas (4.0.0)
though (4.0.11): 80
[0194] The component of the compounds of Formula (1.0.0) which is
immediately adjacent to the "A" component, is a single bond, or a
methylene or ethylene bridging element where n =0, 1 or 2,
respectively. It is preferred that n=1 and that there be a
methylene bridge. Accordingly, within the context of the
above-stated preferences for the meaning of the "A" component, and
adding the methylene bridge, the following most preferred termini
which include the component "A", may be represented by the
following partial Formulas (4.1.0) through (4.1.23):
1 4-hydroxyphenyl- 81 (4.1.0) 3-methoxy-4-(N'-phenylurea)-
phenylmethyl- 82 (4.1.1) 4-(N'-phenylurea)-phenylmethyl- 83 (4.1.2)
4-[N'-(2-methylphenyl)-urea]- phenylmethyl- 84 (4.1.3)
4-[N'-(2-methoxyphenyl)-urea]- phenylmethyl- 85 (4.1.4)
3-methoxy-4-[N'-(2-methylphenyl)-urea]- phenylmethyl- 86 (4.1.5)
4-[N'-(2-pyridyl)-urea]-phenylmethyl- 87 (4.1.6)
6-methoxy-5-[N'-(2-methylphenyl)-urea]- 2-pyridylmethyl- 88 (4.1.7)
4-[N'-(3-methyl-2-pyridyl)-urea]- phenylmethyl- 89 (4.1.8)
3-methoxy-4-[N'-(3-methyl-2-pyridyl)- urea]-phenylmethyl- 90
(4.9.9) 3-methoxy-4-[N'-(2-pyridyl)-urea]- phenylmethyl- 91
(4.1.10) 4-[N'-(2-pyridyl)-urea]-phenylmethyl- 92 (4.1.11)
4-[N'-(2-fluorophenyl)-urea]- phenylmethyl- 93 (4.1.12)
4-[N'-(2-chlorophenyl)-urea]- phenylmethyl- 94 (4.1.13)
4-[N'-(2-chlorophenyl)-urea]-3- methoxyphenylmethyl- 95 (4.1.14)
4-[N'-(4-iso-propylpheny- l)-urea]- phenylmethyl- 96 (4.1.15)
6-methoxy-5-[N'-(o-toluyl)-urea]-2- pyridylmethyl- 97 (4.1.16)
4-[N'-(3-cyclopentyl-2-pyridyl)-urea]- phenylmethyl- 98 (4.1.17)
4-[N'-(2-cyclopentyl)-urea]- phenylmethyl- 99 (4.1.18)
4-[N'-(3-cyclopropyloxy-2-pyridyl)-urea]- phenylmethyl- 100
(4.1.19) 4-[N'-(o-toluyl)-urea]-pyrid-5-ylmethyl- 101 (4.1.20)
4-[3-(4-methyl-pyridin-3-yl)-ureido]- phenylmethyl- 102 (4.1.21)
4-[3-(2,6-dichloro-phenyl)-ure- ido]- phenylmethyl- 103 (4.1.22)
4-[3-(2,6-dimethyl-phenyl- )-ureido]- phenylmethyl- 104
(4.1.23)
[0195] It will be further noted partial structural formulas that
the preferred methylene bridge is also preferably attached to the
N,N'-diphenylureido group in a para relationship to the point of
attachment of the divalent ureido group to the phenyl group
involved.
[0196] The "Y" component of Formula (1.0.0) may be --C(.dbd.O)--;
--C(.dbd.S)--; or --S(.dbd.O).sub.2--. Overall, however, it is most
preferred that "Y" be a carbonyl moiety, i.e., that "Y" is the
moiety --C(.dbd.O)--.
[0197] The next component of the compounds of Formula (1.0.0) is
--NR.sup.4CR.sup.2R.sup.3--. In this component R.sup.2 and R.sup.3
are each independently selected from the group consisting of
hydrogen; (C.sub.1-C.sub.6) alkyl substituted with 0 to 3 R.sup.13;
(C.sub.2-C.sub.6) alkenyl substituted with 0 to 3 R.sup.13; a
(C.sub.3-C.sub.14) carbocyclic ring system substituted with 0 to 3
R.sup.13; a heterocyclyl ring as defined herein, substituted with 0
to 3 R.sup.13; (C.sub.1-C.sub.6) alkyl-OR.sup.5 substituted with 0
to 3 R.sup.13; (C.sub.1-C.sub.6) alkyl-SR.sup.5 substituted with 0
to 3 R.sup.13; (C.sub.1-C.sub.6) alkyl-SO.sub.2R.sup.5 substituted
with 0 to 3 R.sup.13; a heteroaryl ring as defined herein,
substituted with 0 to 3 R.sup.13; and an aryl ring as defined
herein, substituted with 0 to 3 R.sup.13. R.sup.2 and R.sup.3 may
also be taken together in accordance with an optional definition of
R.sup.2 and R.sup.3, in which case they form a cycloalkyl or
heterocyclyl ring substituted with 0 to 3 R.sup.13. For example,
where R.sup.2 and R.sup.3 are taken together to form a spirocyclic
cyclopropyl, cyclobutyl, or cyclopentyl group, the resulting
compounds of the present invention will include moieties such as
those of partial Formulas (1.2.0) through (1.2.2): 105
[0198] Another preferred sub-group of compounds of the present
invention is that formed when either R.sup.2 or R.sup.3 is taken
together with R.sup.4 and the carbon and nitrogen atoms to which
they are respectively attached to form a heteroaryl or heterocyclyl
group as defined herein. Said heteroaryl or heterocyclycl group
may, in turn, be substituted with 0 to 3 R.sup.13. In accordance
with the above-mentioned proviso, when either R.sup.2 or R.sup.3 is
taken together with R.sup.4, the other must be hydrogen or methyl.
The sub-group may be represented by partial Formula (1.3.0) as
follows: 106
[0199] where the symbol "*" indicates the point of attachment of
the moiety represented by partial Formula (1.3.0) to the moiety "Y"
in Formula (1.0.0); and the symbol ".fwdarw." indicates the point
of attachment of the moiety represented by partial Formula (1.3.0)
to "B" in Formula (1.0.0), defined by partial Formulas (1.1.0)
through (1.1.22). The substituent "R.sup.2/3" indicates the
presence of either the R.sup.2 substituent or the R.sup.3
substituent. They both may not be present, since one or the other
has already been selected to be taken together with R.sup.4 to form
the heteroaryl or heterocyclyl group of partial Formula (1.3.0),
represented as follows: 107
[0200] It will be understood that whether R.sup.2 or R.sup.3 is
present, it will have the meaning of hydrogen, alkyl or methyl.
[0201] Accordingly, this sub-group of the group
"--NR.sup.4CR.sup.2R.sup.3- B--" represented by partial Formula
(1.3.0) includes, but is not limited to, the embodiments which are
represented by partial Formulas (1.3.1) through (1.3.20): 108
[0202] where the symbol "*" indicates the point of attachment of
the moiety represented by each partial Formula (1.3.1) through
(1.3.20) to the moiety "Y" in Formula (1.0.0); and the symbol
".fwdarw." indicates the point of attachment of the moiety
represented by each partial Formula (1.3.1) through (1.3.20) to the
moiety "E" in Formula (1.0.0).
[0203] With reference to the optional substituent R.sup.13 which
may be present on the R.sup.2 and R.sup.3 substituents of the B
component, R.sup.13 is absent when "0" is selected. It is preferred
that R.sup.13 either be absent or be present as a single
substituent selected from halogen; CF.sub.3; (C.sub.1-C.sub.6)
alkyl; aryl; heteroaryl; heterocyclyl; hydroxy; cyano;
(C.sub.1-C.sub.6) alkoxy; (C.sub.3-C.sub.14) carbocyclic ring
system; (C.sub.3-C.sub.6) cycloalkoxy; (C.sub.2-C.sub.6) alkynyl;
(C.sub.2-C.sub.6) alkenyl; --NR.sup.6R.sup.5;
--C(.dbd.O)NR.sup.5R.sup.6; SO.sub.2R.sup.5; C(.dbd.O)R.sup.5;
NR.sup.5SO.sub.2R.sup.6; NR.sup.5C(.dbd.O)R.sup.6;
C(.dbd.O)NR.sup.5SO.sub.2R.sup.6; NR.sup.5C(.dbd.O)OR.sup.6; and
SO.sub.2NR.sup.5. With reference to the optional substituent
R.sup.13, but also with reference to the remainder of the instant
specification, the term "alkynyl" alone or in combination, refers
to a straight-chain or branched-chain alkynyl radical containing
from 2 to 6, preferably 2 to 4 carbon atoms. Examples of such
radicals include, but are not limited to, ethynyl (acetylenyl),
propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
[0204] With reference to the definition of R.sup.13, the term
"alkenyl" alone or in combination, refers to a straight-chain or
branched-chain alkenyl radical containing from 2 to 6, preferably 2
to 4 carbon atoms. Examples of such radicals include, but are not
limited to, ethenyl, E- and Z-propenyl, iso-propenyl, E- and
Z-butenyl, E- and Z-iso-butenyl, and E- and Z-pentenyl.
[0205] The term "(C.sub.3 -C.sub.14)carbocyclic ring system" as
used with reference to R.sup.2 and R.sup.3, as well as in other
contexts throughout the instant specification, used alone or in
combination, is intended to refer to cycloalkyl and cycloalkenyl
groups consisting of one, two or three fused rings containing a
total of from three to fourteen carbon atoms. The term "cycloalkyl"
in turn, means a cyclic alkyl radical containing from 3 to 8,
preferably from 3 to 6, carbon atoms. Examples of such cycloalkyl
radicals include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and the like. The term "cycloalkenyl" on
the other hand, refers to a cyclic carbocycle containing from 4 to
8, preferably 5 or 6, carbon atoms and one or more double bonds.
Examples of such cycloalkenyl radicals include, but are not limited
to, cyclopentenyl, cyclohexenyl, and cyclopentadienyl.
[0206] Where two or three fused rings are present, one of the rings
may be a cycloalkyl ring system while the other one or two rings
may be cycloalkenyl ring systems.
[0207] It is preferred that when one of R.sup.2 and R.sup.3 is
hydrogen that the other be selected from the group consisting
essentially of hydrogen, methyl, ethyl, propyl, butyl, and
iso-butyl; hydroxymethyl, methoxymethyl; allyl, propenyl, E- and
Z-iso-butenyl, and E- and Z-pentenyl; cyclopropylmethyl,
cyclopentylmethyl and cyclohexylmethyl; cyclohexenylmethyl, benzyl,
benzyloxymethyl and phenoxymethyl; 2-(methylthio)ethyl;
3-(hydroxypropylthio)methyl; 2-(methylsulfonyl)ethyl- ;
4-(acetylamino)butyl; 4-(methylsulfonylamino)butyl; and
4-ethoxycarbonylamino)butyl.
[0208] The next component, the "B" group of the compounds of
Formula (1.0.0) is one of the more important portions of the
molecule and is a key element in providing the unexpectedly good
biological properties possessed by the compounds of the present
invention. The "B" group comprises a member selected from the group
consisting of partial Formulas (1.1.0) through (1.1.22): 109
[0209] where the symbol "*" indicates the point of attachment of
the moiety represented by each partial Formula (1.1.0) through
(1.1.22) to the moiety "CR.sup.2R.sup.3" in Formula (1.0.0); and
the symbol ".fwdarw." indicates the point of attachment of the
moiety represented by each partial Formula (1.1.0) through (1.1.22)
to the moiety "E" in Formula (1.0.0).
[0210] All of the above partial Formulas (1.1.0) through (1.1.22)
inclusive are illustrated as fragments in the manner
above-described, wherein the points of attachment at either end of
a particular fragment are indicated by the symbols "*" and
".fwdarw.".
[0211] In the above partial formulas defining the B component of
the compounds of Formula (1.0.0), the moiety "X" may be oxygen;
sulfur (q=0) and sulfur to which two oxygen atoms is attached
(q=2), i.e., sulfonyl; or NH (R.sup.10=hydrogen) or nitrogen which
is substituted (R.sup.10=(C.sub.1-C.sub.6)alkyl;
(C.sub.3-C.sub.6)cycloalkyl; heterocyclyl; heteroaryl; or aryl). It
is preferred, however, that "X" be simply oxygen, sulfur or NH.
[0212] Attached to component B in the compounds of Formula (1.0.0)
are the remaining structural elements which may be represented by
partial Formula (1.4.0): 110
[0213] It will be noted first that the moiety represented by
partial Formula (1.4.0) is directly attached to component B in the
overall compound of Formula (1.0.0). E is a single bond; oxygen;
--NR.sup.10--; --CH.dbd.CH--; or --CR.sup.11R.sup.12--.
[0214] Where a substituent R.sup.10 is used, it will be
independently selected from the group consisting essentially of
hydrogen, C(.dbd.O)R.sup.5; (C.sub.1-C.sub.6) alkyl; aryl;
heterocyclyl; heteroaryl; cycloalkyl; or SO.sub.2R.sup.5.
[0215] Where substituents R.sup.11 and R.sup.12 are used, they will
be independently selected from the group consisting essentially of
hydrogen; (C.sub.1-C.sub.6) alkyl; hydroxy; (C.sub.1-C.sub.6)
alkoxy; NR.sup.6COR.sup.5; NR.sup.6SO.sub.2R.sup.5;
NR.sup.5R.sup.5; CF.sub.3; F; aryl; heterocyclyl; heteroaryl;
cycloalkyl; and cycloalkoxy. R.sup.11 may be taken together with
R.sup.12 to form a cycloalkyl or heterocyclyl ring. R.sup.5 and
R.sup.6 are independently hydrogen; (C.sub.1-C.sub.6) alkyl;
CF.sub.3; aryl; cycloalkyl; heteroaryl; or heterocyclyl.
[0216] The groups (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
aryl, heterocyclyl, heteroaryl, cycloalkyl and cycloalkoxy have
already been defined in detail above. Within the meaning of these
groups it is preferred that R.sup.11 and R.sup.12 be independently
selected from the group consisting of methyl, ethyl, propyl, butyl,
iso-butyl, methoxy, cyclopropoxy, cyclopropyl, phenyl, morpholinyl,
piperidinyl and pyridyl.
[0217] In the portions of the compounds of the present invention
represented by partial Formula (1.4.0) above, the moiety E is
followed by an optional methylene bridge: (--CH.sub.2--).sub.m
where m is an integer independently selected from 0 and 1.
[0218] The next component of Formula (1.0.0) is represented by
"--(CR.sup.7R.sup.8).sub.p--" in which "p" is selected from the
integers 0 and 1, provided that "p" must be selected as 1 where "B"
is selected as partial formula (1.1.0) through (1.1.11).
[0219] The substituent R.sup.7 is selected from the group
consisting of (C.sub.1-C.sub.6) alkyl; hydroxy; (C.sub.1-C.sub.6)
alkoxy; NHC(.dbd.O)R.sup.5; NHSO.sub.2R.sup.5; NR.sup.6R.sup.5; F;
CF.sub.3; OCF.sub.3; aryl; heterocyclyl; heteroaryl; cycloalkyl; or
R.sup.7 may be taken together with R.sup.8 to form a cycloalkyl or
heterocyclyl ring. The substituent R.sup.8 is selected from
hydrogen; F; (C.sub.1-C.sub.6) alkyl or (C.sub.1-C.sub.6)
alkoxy.
[0220] The final component of Formula (1.0.0) is the
"--C(.dbd.O)OR.sup.1" group wherein R.sup.1 is hydrogen.
[0221] The component represented by partial Formula (1.4.0)
includes, but is not limited to, the embodiments which are
represented by partial Formulas (1.4.1) through (1.4.20): 111
[0222] Included within the scope of the present invention are the
pharmaceutically acceptable derivatives of the compounds of Formula
(1.0.0). The expression "pharmaceutically acceptable derivative" as
used in the instant specification denotes any pharmaceutically
acceptable salt of a compound of Formula (1.0.0). Further included
within the scope of the present invention is any other compound
which, upon administration to a patient, is capable of directly or
indirectly providing a compound of Formula (1.0.0). Such compounds
are recognized as prodrugs, and a number of established procedures
are available for preparing such prodrug forms of the compounds of
Formula (1.0.0).
[0223] The term "patient" as used above and throughout the instant
specification, refers to mammals, including humans. And where the
term "cell" is used it refers to mammalian cells, including human
cells, unless otherwise specified.
[0224] Further included within the scope of the present invention
are metabolites or residues of the compounds of Formula (1.0.0)
which possess biological activity such that they are able to
inhibit cell adhesion and consequent or associated pathogenic
processes subsequently mediated by VLA-4. Once synthesized, the
inhibitory activities and VLA-4 specificities of the compounds of
Formula (1.0.0) according to this invention may be determined using
in vitro and in vivo assays which are described in detail further
below.
[0225] The desirable biological activity of the compounds of
Formula (1.0.0) may also be improved by appending thereto
appropriate functionalities which will function to enhance existing
biological properties of the compound, improve the selectivity of
the compound for the existing biological activities, or add to the
existing biological activities further desirable biological
activities. Such modifications are known in the art and include
those which increase biological penetration into a given biological
system, e.g., blood, the lymphatic system, and central nervous
system; increase oral availability; increase solubility to allow
administration by injection; alter metabolism; and alter the rate
of excretion of the compound of Formula (1.0.0).
[0226] In view of the above definitions and others throughout the
instant specification, other chemical and biological terms used
herein can be easily understood by those of skill in the art. The
defined terms may be used alone or in any combination thereof. The
preferred and more preferred chain lengths of the radicals which
have been specified herein apply to all such combinations.
[0227] Further pursuant to the descriptions above of certain
preferred subgeneric and more preferred subgeneric definitions of
the compounds of Formula (1.0.0), there follows an enumeration of
preferred and more preferred species in order to provide a further
illustration of the present invention.
[0228] Compounds which include the moiety of partial Formula
(1.1.0):
[0229]
3-[2-(1-2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino)-3-me-
thyl-butyl)-4,5-dihydro-oxazol-5-yl]-2-methyl-propionic acid
[0230]
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionic
acid
[0231]
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionic
acid
[0232]
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl-4,5-dihydro-oxazol-5-yl}-propionic acid
[0233]
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl-pyr-
rolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic acid
[0234]
2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-5-yl}-propionic
acid
[0235]
2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-oxazol-5-y-
l)-propionic acid
[0236]
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic acid
[0237]
2-Formylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-d-
ihydro-thiazol-5-yl}-propionic acid
[0238]
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,-
5-dihydro-oxazol-5-yl)-propionic acid
[0239]
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-4,5-dihydro-oxazol-5-yl)-propionic acid
[0240]
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic
acid
[0241]
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic
acid
[0242]
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4-methyl-4,5-dihydro-oxazol-5-yl}-propionic
acid
[0243]
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4,5-dihydro-thiazol-5-yl}-propionic
acid
[0244]
3-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4,5-dihydro-3H-imidazol-4-yl}-propionic
acid
[0245]
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-5-yl}-propioni-
c acid
[0246] Compounds which include the moiety of partial Formula
(1.1.1):
[0247]
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-4,5-dihydro-oxazol-4-yl]-2-methyl-propionic acid
[0248]
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-4,5-dihydro-oxazol4-yl]-propionic
acid
[0249]
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-propionic
acid
[0250]
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-4,5-dihydro-oxazol-4-yl}-propionic acid
[0251]
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic acid
[0252]
2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-4-yl}-propionic
acid
[0253]
2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-oxazol-4-y-
l)-propionic acid
[0254]
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic acid
[0255]
2-Acetylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-d-
ihydro-thiazol-4-yl}-propionic acid
[0256]
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,-
5-dihydro-oxazol-4-yl)-propionic acid
[0257]
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-4,5-dihydro-oxazol-4-yl)-propionic acid
[0258]
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic
acid
[0259]
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic
acid
[0260]
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-5-methyl-4,5-dihydro-oxazol-4-yl}-propionic
acid
[0261]
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4,5-dihydro-thiazol-4-yl}-propionic
acid
[0262]
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-4-yl}-propioni-
c acid
[0263] Compounds which include the moiety of partial Formula
(1.1.2):
[0264]
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-oxazo-5-yl]-2-methyl-propionic acid
[0265]
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-oxazol-5-yl]-propionic acid
[0266]
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-propionic acid
[0267]
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl-amino)-ethyl]-oxazol-5-yl}-propionic acid
[0268]
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-oxazol-5-yl]-propionic acid
[0269]
2-Allyloxycarbonylamino-3-{2-[{[3-methoxy-4-(3-o-tolyl-ureido)-phen-
yl]-acetyl}-methyl-amino)-methyl]-oxazol-5-yl}-propionic acid
[0270]
2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-5-yl)-propionic
acid
[0271]
2-Methyl-3-[2-(1-[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-
-2-yl)-oxazol-5-yl]-propionic acid
[0272]
2-Acetylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiaz-
ol-5-yl}-propionic acid
[0273]
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-ox-
azol-5-yl)-propionic acid
[0274]
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-oxazol-5-yl)-propionic acid
[0275]
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid
[0276]
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid
[0277]
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4-methyl-oxazol-5-yl}-propionic acid
[0278]
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-thiazol-5-yl}-propionic acid
[0279]
3-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-3H-imidazol-4-yl}-propionic acid
[0280]
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-5-yl}-propionic
acid
[0281] Compounds which include the moiety of partial Formula
(1.1.3):
[0282]
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-oxazol-4-yl]-2-methyl-propionic acid
[0283]
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-oxazol-4-yl]-propionic acid
[0284]
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-propionic acid
[0285]
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl-amino)-ethyl]-oxazol-4-yl}-propionic acid
[0286]
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-oxazol-4-yl]-propionic acid
[0287]
2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-oxazol-4-yl}-propionic acid
[0288]
2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-4-yl)-propionic
acid
[0289]
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl-pyrrolidin-
-2-yl)-oxazol-4-yl]-propionic acid
[0290]
2-Formylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiaz-
ol-4-yl}-propionic acid
[0291]
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl2-ox-
azo1-4-yl)-propionic acid
[0292]
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-oxazol-4-yl)-propionic acid
[0293]
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionic acid
[0294]
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionic acid
[0295]
2-Acetylamino-3-2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl-
}-methyl-amino)-methyl]-5-methyl-oxazol-4-yl}-propionic acid
[0296]
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-thiazol-4-yl}-propionic acid
[0297]
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-4-yl}-propionic
acid
[0298] Compounds which include the moiety of partial Formula
(1.1.4):
[0299]
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-4,5-dihydro-isooxazol-5-yl]-2-methyl-propionic
acid
[0300]
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionic
acid
[0301]
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionic
acid
[0302]
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid
[0303]
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionic acid
[0304]
2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isoxazol-5-yl}-propionic
acid
[0305]
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-isoxazol-5-
-yl)-propionic acid
[0306]
2-Methyl-3-[3-(1-[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-
-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionic acid
[0307]
2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-d-
ihydro-isothiazol-5-yl}-propionic acid
[0308]
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,-
5-dihydro-isoxazol-5-yl)-propionic acid
[0309]
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-4,5-dihydro-isoxazol-5-yl)-propionic acid
[0310]
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionic
acid
[0311] 2-Methanesulfonylamino-3-[3-(3-methyl- I
-{[5-(3-o-tolyl-ureido)-py-
ridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionic
acid
[0312]
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4-methyl-4,5-dihydro-isoxazol-5-yl}-propionic
acid
[0313]
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4,5-dihydro-isothiazol-5-yl}-propionic
acid
[0314]
3-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-3,4-dihydro-2H-pyrazol-3-yl}-propionic
acid
[0315]
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isoxazol-5-yl}-propio-
nic acid
[0316] Compounds which include the moiety of partial Formula
(1.1.5):
[0317]
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-4,5-dihydro-pyrazol-1-yl]-2-methyl-propionic acid
[0318]
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic
acid
[0319]
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic
acid
[0320]
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl-amino)-ethyl]-4,5-dihydro-pyrazol-1-yl}-propionic acid
[0321]
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
[0322]
2-(Butane-1-sulfonylamino)-3-(3-[methyl-({4-[3-(3-methyl-pyridin-2--
yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-pyrazol-1-y-
l)-propionic acid
[0323]
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
[0324]
2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-d-
ihydro-pyrazol-1-yl}-propionic acid
[0325]
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,-
5-dihydro-pyrazol-1-yl)-propionic acid
[0326]
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-4,5-dihydro-pyrazol-1-yl)-propionic acid
[0327]
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic
acid
[0328]
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic
acid
[0329]
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-5-methyl-4,5-dihydro-pyrazol-1-yl}-propionic
acid
[0330]
2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4,5-dihydro-pyrazol-1-yl}-propionic
acid
[0331]
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-pyrazol-1-yl}-propion-
ic acid
[0332] Compounds which include the moiety of partial Formula
(1.1.6):
[0333]
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino-3-me-
thyl-butyl)-isooxazol-5-yl]-2-methyl-propionic acid
[0334]
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic acid
[0335]
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic
acid
[0336]
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-isoxazol-5-yl}-propionic acid
[0337]
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl-pyr-
rolidin-2-yl)-isoxazol-5-yl]-propionic acid
[0338]
2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl)-methyl-amino)-methyl]-isoxazol-5-yl}-propionic
acid
[0339]
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-isoxazol-5-yl)-propion-
ic acid
[0340]
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-isoxazol-5-y]-propionic acid
[0341]
2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-isoth-
iazol-5-yl-propionic acid
[0342]
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-is-
oxazol-5-yl)-propionic acid
[0343]
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-isoxazol-5-yl)-propionic acid
[0344]
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
[0345]
2-Methanesulfonylamino-3-[3-(3-methyl-1-([5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic
acid
[0346]
2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4-methyl-isoxazol-5-yl}-propionic acid
[0347]
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-isothiazol-5-yl}-propionic acid
[0348]
3-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-2H-pyrazol-3-yl}-propionic acid
[0349]
2-(2,6-Dichloro-benzoylamino)-3-{3-[([3-methoxy-4-(3-o-tolyl-ureido-
)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-5-yl}-propionic
acid
[0350] Compounds which include the moiety of partial Formula
(1.1.7):
[0351]
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-pyrazol-1-yl]-2-methyl-propionic acid
[0352]
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionic acid
[0353]
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionic
acid
[0354]
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-pyrazol-1-yl}-propionic acid
[0355]
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-pyrazol-1-yl]-propionic acid
[0356]
2-(Butane-1-sulfonylamino)-3-(3-[methyl-({4-[3-(3-methyl-pyridin-2--
yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrazol-1-yl)-propionic
acid
[0357]
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-pyrazol-1-yl]-propionic acid
[0358]
2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-pyraz-
ol-1-yl}-propionic acid
[0359]
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-py-
razol-1-yl)-propionic acid
[0360]
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-pyrazol-1-yl)-propionic acid
[0361]
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
[0362]
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
[0363]
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-5-methyl-pyrazol-1-yl}-propionic acid
[0364]
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-pyrazol-1-yl}-propionic acid
[0365]
2-(2,6-Dichloro-benzoylamino)-3-{3-[([3-methoxy-4-(3-o-tolyl-ureido-
)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionic
acid
[0366] Compounds which include the moiety of partial Formula
(1.1.8):
[0367]
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-oxazo-2-yl]-2-methyl-propionic acid
[0368]
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-oxazol-2-yl]-propionic acid
[0369]
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionic acid
[0370]
2,2-Difluoro-3-(4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-oxazol-2-yl}-propionic acid
[0371]
2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-oxazol-2-yl]-propionic acid
[0372]
2-Allyloxycarbonylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid
[0373]
2-(Butane-1-sulfonylamino)-3-(4-{methyl-({4-[3-(3-methyl-pyridin-2--
yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-2-yl)-propionic
acid
[0374]
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-oxazol-2-yl]-propionic acid
[0375]
2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiaz-
ol-2-yl}-propionic acid
[0376]
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-ox-
azol-2-yl)-propionic acid
[0377]
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-oxazol-2-yl)-propionic acid
[0378]
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
[0379]
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
[0380]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-5-methyl-oxazol-2-yl}-propionic acid
[0381]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l)-methyl-amino)-methyl]-thiazol-2-yl}-propionic acid
[0382]
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic
acid
[0383]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l-methyl-amino)-methyl]-1H-imidazol-2-yl}-propionic acid
[0384] Compounds which include the moiety of partial Formula
(1.1.9):
[0385]
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-imidazol-1-yl]-2-methyl-propionic acid
[0386]
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-imidazol-1-yl]-propionic acid
[0387]
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-imidazol-1-yl]-propionic
acid
[0388]
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-imidazol-1-yl}-propionic acid
[0389]
2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-imidazol-1-yl]-propionic acid
[0390]
2-(Butane-1-sulfonylamino)-3-(4-[methyl-({4-[3-(3-methyl-pyridin-2--
yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-imidazol-1-yl)-propioni-
c acid
[0391]
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-imidazol-1-yl]-propionic acid
[0392]
2-Formylamino-3-(4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-imida-
zol-1-yl}-propionic acid
[0393]
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-im-
idazol-1-yl)-propionic acid
[0394]
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-imidazol-1-yl)-propionic acid
[0395]
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionic acid
[0396]
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionic
acid
[0397]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-5-methyl-imidazol-1-yl}-propionic acid
[0398]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-imidazol-1-yl}-propionic acid
[0399]
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-imidazol-1-yl}-propionic
acid
[0400] Compounds which include the moiety of partial Formula
(1.1.10):
[0401]
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}3-me-
thyl-butyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-propionic acid
[0402]
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-propionic
acid
[0403]
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-propionic
acid
[0404]
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-[1,2,4]oxadiazol-5-yl}-propionic acid
[0405]
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionic acid
[0406]
2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionic
acid
[0407]
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-[1,2,4]oxadiazol-5-yl)-
-propionic acid
[0408]
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-[1,2,4]oxadiazol-5-yl]-propionic acid
[0409]
2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-[1,2,-
4]thiadiazol-5-yl}-propionic acid
[0410]
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-[1-
,2,4]oxadiazol-5-yl)-propionic acid
[0411]
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-[1,2,4]oxadiazol-5-yl)-propionic acid
[0412]
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionic
acid
[0413]
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionic
acid
[0414]
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionic acid
[0415]
2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-[1,2,4]thiadiazol-5-yl}-propionic acid
[0416]
3-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-2H-[1,2,4]triazol-3-yl}-propionic acid
[0417]
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl)-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionic
acid
[0418] Compounds which include the moiety of partial Formula
(1.1.11):
[0419]
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-[1,2,4]triazol-1-yl]-2-methyl-propionic acid
[0420]
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-[1,2,4]triazol-1-yl]-propionic acid
[0421]
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-[1,2,4]triazol-1-yl]-propionic
acid
[0422]
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-[1,2,4]triazol-1-yl}-propionic acid
[0423]
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionic acid
[0424]
2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionic
acid
[0425]
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-[1,2,4]triazol-1-yl)-p-
ropionic acid
[0426]
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-[1,2,4]triazol-1-yl]-propionic acid
[0427]
2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-[1,2,-
4]triazol-1-yl}-propionic acid
[0428]
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-[1-
,2,4]triazol-1-yl)-propionic acid
[0429]
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-[1,2,4]triazol-1-yl)-propionic acid
[0430]
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionic
acid
[0431]
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionic
acid
[0432]
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4-methyl-[1,2,4]triazol-1-yl}-propionic
acid
[0433]
2-Acetylamino-3-(3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l)-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionic acid
[0434]
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionic
acid
[0435] Compounds which include the moiety of partial Formula
(1.1.12
[0436]
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino-3-me-
thyl-butyl)-thiophen-2-yl]-2-methyl-propionic acid
[0437]
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-furan-2-yl]-propionic acid
[0438]
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-propionic
acid
[0439]
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-1H-pyrrol-2-yl}-propionic acid
[0440]
2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-thiophen-2-yl]-propionic acid
[0441]
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-2-yl)-propionic
acid
[0442]
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-1H-pyrrol-2-yl]-propionic acid
[0443]
2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiop-
hen-2-yl}-propionic acid
[0444]
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-
-pyrrol-2-yl)-propionic acid
[0445]
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-furan-2-yl)-propionic acid
[0446]
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionic acid
[0447]
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionic
acid
[0448]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-5-methyl-1H-pyrrol-2-yl}-propionic
acid
[0449]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-thiophen-2-yl}-propionic acid
[0450]
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-furan-2-yl}-propionic
acid
[0451] Compounds which include the moiety of partial Formula
(1.1.13):
[0452]
3-[5-(1-2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-me-
thyl-butyl)-thiophen-3-yl]-2-methyl-propionic acid
[0453]
2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-furan-3-yl]-propionic acid
[0454]
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-thiophen-3-yl]-propionic
acid
[0455]
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-1H-pyrrol-3-yl}-propionic acid
[0456]
2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-thiophen-3-yl]-propionic acid
[0457]
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-(4-[3-(3-methyl-pyridin-2--
yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-3-yl)-propionic
acid
[0458]
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-1H-pyrrol-3-yl]-propionic acid
[0459]
2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiop-
hen-3-yl}-propionic acid
[0460]
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-
-pyrrol-3-yl)-propionic acid
[0461]
2-Benzenesulfonylamino-3-(5-{-[(4-phenoxymethyl-phenyl)-acetyl]-pyr-
rolidin-2-yl}-furan-3-yl)-propionic acid
[0462]
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-thiophen-3-yl]-propionic acid
[0463]
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-3-yl]-propionic
acid
[0464]
2-Acetylamino-3-{5-[(([3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l)-methyl-amino)-methyl]-2-methyl-1H-pyrrol-3-yl}-propionic
acid
[0465]
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-thiophen-3-yl}-propionic acid
[0466]
2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-furan-3-yl}-propionic
acid
[0467] Compounds which include the moiety of partial Formula
(1.1.14):
[0468]
3-[5-(1-2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-me-
thyl-butyl)-thiophen-2-yl]-2-methyl-propionic acid
[0469]
2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-furan-2-yl]-propionic acid
[0470]
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-propionic
acid
[0471]
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-1H-pyrrol-2-yl}-propionic acid
[0472]
2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-thiophen-2-yl]-propionic acid
[0473]
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-2-yl)-propionic
acid
[0474]
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)- H-pyrrol-2-yl]-propionic acid
[0475]
2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiop-
hen-2-yl-propionic acid
[0476]
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-
-pyrrol-2-yl)-propionic acid
[0477]
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-furan-2-yl)-propionic acid
[0478]
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionic acid
[0479] 2-Methanesulfonylamino-3-[5-(3-methyl-
-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionic
acid
[0480]
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-2-methyl-1H-pyrrol-2-yl}-propionic
acid
[0481]
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l)-methyl-amino)-methyl]-thiophen-2-yl}-propionic acid
[0482] 2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-m
ethoxy-4-(3-o-tolyl-urei-
do)-phenyl]-acetyl}-methyl-amino)-methyl]-furan-2-yl}-propionic
acid
[0483] Compounds which include the moiety of partial Formula
(1.1.15):
[0484]
3-[5-(1-2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-me-
thyl-butyl)-isooxazol-3-yl]-2-methyl-propionic acid
[0485]
2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-isoxazol-3-yl]-propionic acid
[0486]
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-isoxazol-3-yl]-propionic
acid
[0487]
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-isoxazol-3-yl}-propionic acid
[0488]
2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-y]-acetyl}-pyr-
rolidin-2-yl)-isoxazol-3-yl]-propionic acid
[0489]
2-Allyloxycarbonylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-isoxazol-3-yl}-propionic
acid
[0490]
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-(4-[3-(3-methyl-pyridin-2--
yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-isoxazol-3-yl)-propioni-
c acid
[0491]
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-isoxazol-3-yl]-propionic acid
[0492]
2-Acetylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-isoth-
iazol-3-yl}-propionic acid
[0493]
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-is-
oxazol-3-yl)-propionic acid
[0494]
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-isoxazol-3-yl)-propionic acid
[0495]
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionic acid
[0496]
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionic
acid
[0497]
2-Formylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-4-methyl-isoxazol-3-yl}-propionic acid
[0498]
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-isothiazol-3-yl}-propionic acid
[0499]
3-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-2H-pyrazol-5-yl}-propionic acid
[0500]
2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-3-yl}-propionic
acid
[0501] Compounds which include the moiety of partial Formula
(1.1.16):
[0502]
3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-oxazo-2-yl]-2-methyl-propionic acid
[0503]
2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-oxazol-2-yl]-propionic acid
[0504]
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionic acid
[0505]
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-oxazol-2-yl}-propionic acid
[0506]
2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-oxazol-2-yl]-propionic acid
[0507]
2-Allyloxycarbonylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid
[0508]
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-2-yl)-propionic
acid
[0509]
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-oxazol-2-yl]-propionic acid
[0510]
2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiaz-
ol-2-yl}-propionic acid
[0511]
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-ox-
azol-2-yl)-propionic acid
[0512]
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-oxazol-2-yl)-propionic acid
[0513]
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
[0514]
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
[0515]
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-5-methyl-oxazol-2-yl}-propionic acid
[0516]
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-thiazol-2-yl}-propionic acid
[0517]
2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic
acid
[0518] 2-Acetylamino
3-[5-({2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-m-
ethyl)-1H-imidazol-2-yl]-propionic acid
[0519] Compounds which include the moiety of partial Formulas
(1.1.17), (1.1.18) and (1.1.19):
[0520]
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-phenyl}-propionic acid
[0521]
2-Formylamino-3-{6-[1-({3-methoxy-4-[3-(3-methyl-pyridin-2-yl)-urei-
do]-phenyl}-acetyl)-pyrrolidin-2-yl]-pyridin-2-yl}-propionic
acid
[0522]
3-{4-[1-({3-Ethyl-4-[3-(3-methyl-pyridin-2-yl)-ureido]-phenyl}-acet-
yl)-pyrrolidin-2-yl]-pyrimidin-2-yl}-propionic acid
[0523]
2-Acetylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acet-
yl}-pyrrolidin-2-yl)-phenyl]-propionic acid
[0524]
2-Acetylamino-3-[3-({2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acet-
ylamino}-methyl)-phenyl]-propionic acid
[0525]
2-{2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amin-
o)-methyl]-pyridin-4-ylmethyl}-4-methyl-pentanoic acid
[0526]
3-{2-[(Methyl-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-methyl]-
-pyridin-4-yl)-propionic acid
[0527]
2-Methanesulfonylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phen-
yl]-acetyl}-methyl-amino)-methyl]-[1,3,5]triazin-2-yl}-propionic
acid
[0528]
1-[4-(1-{[6-(3-Pyridin-2-yl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidi-
n-2-yl)-pyridin-2-ylmethyl]cyclopropanecarboxylic acid
[0529]
3-[3-(1-{[6-(3-Pyridin-2-yl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidi-
n-2-yl)-phenyl]-butyric acid
[0530]
2-(Butane-1-sulfonylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)--
phenyl]-acetyl}-methyl-amino)-methyl]-phenyl}-propionic acid
[0531]
2-Benzenesulfonylamino-3-[3-({[(2-methoxy-2'-methyl-biphenyl-4-yl)--
acetyl]-methyl-amino}-methyl)-phenyl]-propionic acid
[0532] Compounds which include the moiety of partial Formula
(1.1.20):
[0533]
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-m-
ethyl-butyl)-pyrrol-1-yl]-2-methyl-propionic acid
[0534]
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-pyrrol-1-yl]-propionic acid
[0535]
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-pyrrol-1-yl]-propionic acid
[0536] 2,2-Difluoro-3-{4-[1-(methyl-[6-
(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-pyrrol-1-yl}-propionic acid
[0537]
2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-py-
rrolidin-2-yl)-pyrrol-1-yl]-propionic acid
[0538]
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrrol-1-yl)-propionic
acid
[0539]
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-pyrrol-1-yl]-propionic acid
[0540]
2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-pyrro-
l-1-yl}-propionic acid
[0541]
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-py-
rrol-1-yl)-propionic acid
[0542]
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-pyrrol-1-yl)-propionic acid
[0543]
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionic acid
[0544]
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionic acid
[0545]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-5-methyl-pyrrol-1-yl}-propionic acid
[0546]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-pyrrol-1-yl}-propionic acid
[0547]
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrrol-1-yl}-propionic
acid
[0548] Compounds which include the moiety of partial Formula
(1.1.21):
[0549]
3-[4-(1-2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-me-
thyl-butyl)-pyrazol-1-yl]-2-methyl-propionic acid
[0550]
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionic acid
[0551]
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-p-
henyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionic
acid
[0552]
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-a-
cetyl}-amino)-ethyl]-pyrazol-1-yl}-propionic acid
[0553]
2,2-Dimethyl-3-[4-(1-[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl1-pyr-
rolidin-2-yl)-pyrazol-1-yl]-propionic acid
[0554]
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-
-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrazol-1-yl)-propioni-
c acid
[0555]
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-pyrazol-1-yl]-propionic acid
[0556]
2-Formylamino-3-(4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-pyraz-
ol-1-yl}-propionic acid
[0557]
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-py-
razol-1-yl)-propionic acid
[0558]
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-py-
rrolidin-2-yl}-pyrazol-1-yl)-propionic acid
[0559]
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
[0560]
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyri-
din-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
[0561]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-5-methyl-pyrazol-1-yl}-propionic acid
[0562]
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acety-
l}-methyl-amino)-methyl]-pyrazol-1-yl}-propionic acid
[0563]
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureid-
o)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionic
acid
[0564] Compounds which include the moiety of partial Formula
(1.1.22):
[0565]
2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)--
methyl]-benzooxazole-6-carboxylic acid
[0566]
2-[1-(2-{3-Methoxy-4-[3-(3-methyl-pyridin-2-yl)-ureido]-phenyl)-ace-
tylamino)-3-methyl-butyl]-3H-benzoimidazole-5-carboxylic acid
[0567]
2-(1-{[4-(3-Pyridin-2-yl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-1-
H-imidazo[4,5-c]pyridine-6-carboxylic acid
[0568]
2-(1-{[3-Ethoxy-4-(3-pyridin-2-yl-ureido)-phenyl]-acetyl}-pyrrolidi-
n-2-yl)-benzothiazole-6-carboxylic acid
[0569]
2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)--
methyl]-benzothiazole-6-carboxylic acid
[0570]
2-({[(4-Benzyloxy-phenyl)-acetyl]-methyl-amino)-methyl)-oxazolo[5,4-
-b]pyridine-5-carboxylic acid
[0571]
3-Methyl-2-{1-[(4-phenoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-benzo-
imidazole-5-carboxylic acid
[0572] The above-described compounds of the present invention may
be utilized in the form of acids, esters, or other chemical classes
of compounds to which the compounds described belong. It is also
within the scope of the present invention to utilize those
compounds in the form of pharmaceutically acceptable salts derived
from various organic and inorganic acids and bases in accordance
with procedures well known in the art. Such well-known
pharmaceutically acceptable salts include, but are not limited to
acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,
besylate, bisulfate, butyrate, citrate, camphorate,
camphorsulfonate, cyclopentanepropionate, digluconate,
dodecysulfate, ethanesulfonate, fumarate, glucoheptanoate,
gluconate, glycerophosphate, hemisuccinate, hemisulfate,
heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, isethionate, lactate,
lactobionate, maleate, mandelate, methanesulfonate,
2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate,
pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate,
picrate, pivalate, propionate, salicylate, sodium phosphate,
stearate, succinate, sulfate, sulfosalicylate, tartrate,
thiocyanate, thiomalate, tosylate, and undecanoate.
[0573] Base salts of the compounds of the present invention
include, but are not limited to ammonium salts; alkali metal salts
such as sodium and potassium; alkaline earth metal salts such as
calcium and magnesium; salts with organic bases such as
dicyclohexylamine, meglumine, N-methyl-D-glucamine,
tris-(hydroxymethyl)-methylamine (tromethamine), and salts with
amino acids such as arginine, lysine, etc. Compounds of the present
invention which comprise basic nitrogen-containing groups may be
quaternized with such agents as (C.sub.1-C.sub.4)alkyl halides,
e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides
and iodides; di(C.sub.1-C.sub.4) alkyl sulfate, e.g., dimethyl,
diethyl and diamyl sulfates; (C.sub.10-C.sub.18) alkyl halides,
e.g., decyl, dodecyl, lauryl, myristyl and stearyl chlorides,
bromides and iodides; and aryl-(C.sub.1-C.sub.4) alkyl halides,
e.g., benzyl chloride and phenethyl bromide. Such salts permit the
preparation of both water-soluble and oil-soluble compounds of the
present invention.
[0574] Among the above-recited pharmaceutical salts those which are
preferred include, but are not limited to acetate, mesylate,
citrate, fumarate, gluconate, hemisuccinate, hippurate,
hydrochloride, hydrobromide, isothionate, mandelate, meglumine,
nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate,
sulfate, sulfosalicylate, tartrate, thiomalate, tosylate, and
trimethylamine.
[0575] Multiple salts forms are included within the scope of the
present invention where a compound of the present invention
contains more than one group capable of forming such
pharmaceutically acceptable salts. Examples of typical multiple
salt forms include, but are not limited to bitartrate, diacetate,
difumarate, dimeglumine, diphosphate, disodium, and
trihydrochloride.
[0576] The pharmaceutical compositions of the present invention
comprise any one or more of the above-described inhibitory
compounds of the present invention, or a pharmaceutically
acceptable salt thereof as also above-described, together with a
pharmaceutically acceptable carrier in accordance with the
properties and expected performance of such carriers which are
well-known in the pertinent art.
[0577] The term "carrier" as used herein includes acceptable
diluents, excipient, adjuvants and vehicles. Pharmaceutically
acceptable carriers that may be used in the pharmaceutical
compositions of this invention include but are not limited to, ion
exchange compositions; alumina; aluminum stearate; lecithin; serum
proteins, e.g., human serum albumin; phosphates; glycine; sorbic
acid; potassium sorbate; partial glyceride mixtures of saturated
vegetable fatty acids; water; salts or electrolytes, e.g.,
prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, and zinc salts; colloidal silica;
magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based
substances; e.g., sodium carboxymethylcellulose; polyethylene
glycol; polyacrylates; waxes; polyethylene-polyoxypropylene-block
polymers; and wool fat.
[0578] More particularly, the diluents, excipient, adjuvants and
vehicles used in the pharmaceutical compositions of the present
invention comprise members selected from the groups consisting
essentially of the following: acidifying and alkalizing agents
added to obtain a desired or predetermined pH comprise acidifying
agents, e.g., acetic acid, glacial acetic acid, malic acid, and
propionic acid, and alkalizing agents, e.g., edetol, potassium
carbonate, potassium hydroxide, sodium borate, sodium carbonate,
and sodium hydroxide; aerosol propellants required where the
pharmaceutical composition is to be delivered as an aerosol under
significant pressure, e.g., acceptable halogenated hydrocarbons;
nitrogen; or a volatile hydrocarbon such as butane, propane,
isobutane or mixtures thereof; antimicrobial agents including
antibacterial, antifungal and antiprotozoal agents added where the
pharmaceutical composition is topically applied, e.g.,
antimicrobial agents such as benzyl alcohol, chlorobutanol,
phenylethyl alcohol, phenylmercuric acetate, potassium sorbate, and
sorbic acid, and antifungal agents such as benzoic acid,
butylparaben, ethylparaben, methylparaben, propylparaben, and
sodium benzoate; antimicrobial preservatives added to the
pharmaceutical compositions in order to protect them against the
growth of potentially harmful microorganisms, e.g., alkyl esters of
p-hydroxybenzoic acid, propionate salts, phenoxyethanol,
methylparaben sodium, propylparaben sodium, sodium dehydroacetate,
benzalkonium chloride, benzethonium chloride, and benzyl alcohol;
antioxidants added to protect all of the ingredients of the
pharmaceutical composition from damage or degradation by oxidizing
agents present in the composition itself or the use environment,
e.g., anoxomer, ascorbyl palmitate, butylated hydroxyanisole,
butylated hydroxytoluene, hypophosphorous acid, potassium
metabisulfite, propyl octyl and dodecyl gallate, sodium
metabisulfite, sulfur dioxide, and tocopherols; buffering agents
used to maintain a desired pH of a composition once established,
e.g., calcium acetate, potassium metaphosphate, potassium phosphate
monobasic, and tartaric acid; and chelating agents used to help
maintain the ionic strength of the pharmaceutical composition and
bind to and effectively remove destructive compounds and metals,
e.g., edetate dipotassium, edetate disodium, and edetic acid.
[0579] Dermatologically active agents are added to the
pharmaceutical compositions of the present invention to be applied
topically, e.g., wound healing agents such as peptide derivatives,
yeast, panthenol, hexylresorcinol, phenol, tetracycline
hydrochloride, lamin and kinetin, glucocorticosteroids for treating
inflammation, e.g., hydrocortisone, dexamethasone, betamethasone,
triamcinolone, fluocinolone and methylprednisolone, retinoids for
treating acne, psoriasis, cutaneous aging, and skin cancer, e.g.,
retinol, tretinoin, isotretinoin, etretinate, acitretin, and
arotinoid, immunosuppressive agents for treating inflammation,
e.g., dapsone and sulfasalazine; mild antibacterial agents, e.g.,
resorcinol, salicylic acid, benzoyl peroxide, erythromycin-benzoyl
peroxide, erythromycin, clindamycin, and mupirocin, antifungal
agents, e.g., griseofulvin, azoles such as miconazole, econazole,
itraconazole, fluconazole, and ketoconazole, and allylamines such
as naftifine and terfinafine, antiviral agents, e.g., acyclovir,
famciclovir, and valacyclovir, antihistamines, e.g.,
diphenhydramine, terfenadine, astemizole, loratadine, cetirizine,
acrivastine, and temelastine, topical anesthetics, e.g.,
benzocaine, lidocaine, dibucaine, and pramoxine hydrochloride,
topical analgesics, e.g., methyl salicylate, camphor, menthol, and
resorcinol; topical antiseptics for preventing infection, e.g.,
benzalkonium chloride and povidone-iodine; vitamins and derivatives
thereof such as tocopherol, tocopherol acetate, retinoic acid and
retinol.
[0580] Further examples of diluents, excipient, adjuvants and
vehicles used in the pharmaceutical compositions of the present
invention comprise members selected from the groups consisting
essentially of the following: dispersing and suspending agents,
e.g., poligeenan, povidone, and silicon dioxide; emollients, e.g.,
hydrocarbon oils and waxes, triglyceride esters, acetylated
monoglycerides, methyl and other alkyl esters of C.sub.10-C.sub.20
fatty acids, C.sub.10-C.sub.20 fatty acids, C.sub.10-C.sub.20 fatty
alcohols, lanolin and derivatives, polyhydric alcohol esters such
as polyethylene glycol (200-600), polyoxyethylene sorbitan fatty
acid esters, wax esters, phospholipids, and sterols; emulsifying
agents used for preparing oil-in-water emulsions; excipients, e.g.,
laurocapram and polyethylene glycol monomethyl ether; humectants,
e.g., sorbitol, glycerin and hyaluronic acid; ointment bases, e.g.,
petrolatum, polyethylene glycol, lanolin, and poloxamer;
penetration enhancers, e.g., dimethyl isosorbide,
diethyl-glycol-monoethylether, 1-dodecylazacycloheptan-2-one, and
dimethylsulfoxide (DMSO); preservatives, e.g., benzalkonium
chloride, benzethonium chloride, alkyl esters of p-hydroxybenzoic
acid, hydantoin derivatives, cetylpyridinium chloride,
propylparaben, quaternary ammonium compounds such as potassium
benzoate, and thimerosal; sequestering agents comprising
cyclodextrins; solvents, e.g., acetone, alcohol, amylene hydrate,
butyl alcohol, corn oil, cottonseed oil, ethyl acetate, glycerin,
hexylene glycol, isopropyl alcohol, isostearyl alcohol, methyl
alcohol, methylene chloride, mineral oil, peanut oil, phosphoric
acid, polyethylene glycol, polyoxypropylene 15 stearyl ether,
propylene glycol, propylene glycol diacetate, sesame oil, and
purified water; stabilizers, e.g., calcium saccharate and thymol;
surfactants, e.g., lapyrium chloride; laureth 4, i.e.,
.alpha.-dodecyl-.omega.-hydroxy-poly(oxy-1,2-ethanediyl) or
polyethylene glycol monododecyl ether.
[0581] According to this invention, the pharmaceutical compositions
may be in the form of a sterile injectable preparation, for example
a sterile injectable aqueous or oleaginous suspension. This
suspension may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose, any bland fixed oil may be employed including
synthetic mono- or di-glycerides. Fatty acids, such as oleic acid
and its glyceride derivatives are useful in the preparation of
injectables, as do natural pharmaceutically-acceptable oils, such
as olive oil or castor oil, especially in their polyoxyethylated
versions. These oil solutions or suspensions may also contain a
long-chain alcohol diluent or dispersant, such as Rh, HCIX or
similar alcohol.
[0582] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, aqueous suspensions or
solutions. In the case of tablets for oral use, carriers which are
commonly used include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added. For oral
administration in a capsule form, useful diluents include lactose
and dried corn starch. When aqueous suspensions are required for
oral use, the active ingredient is combined with emulsifying and
suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added. Alternatively, the
pharmaceutical compositions of this invention may be administered
in the form of suppositories for rectal administration. These can
be prepared by mixing the agent with a suitable non-irritating
excipient which is solid at room temperature but liquid at the
rectal temperature and therefore will melt in the rectum to release
the drug. Such materials include cocoa butter, beeswax and
polyethylene glycols.
[0583] The pharmaceutical compositions of this invention may also
be administered topically, especially when the target of treatment
includes areas or organs readily accessible by topical application,
including diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily prepared for each
of these areas or organs.
[0584] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation, as described above,
or in a suitable enema formulation. Topically active transdermal
patches may also be used.
[0585] For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions can be formulated in
a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited to,
mineral oil, sorbitan monostearate, polysorbate, cetyl esters wax,
cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
[0586] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspension in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with our without a preservative
such as benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated in an
ointment such as petrolatum.
[0587] The pharmaceutical compositions of this invention may also
be administered by nasal aerosol or inhalation through the use of a
nebulizer, a dry powder inhaler or a metered dose inhaler. Such
compositions are prepared according to techniques well-known in the
art of pharmaceutical formulation and may be prepared as solutions
in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
hydrofluorocarbons, and/or other conventional solubilizing or
dispersing agents.
[0588] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated, and the particular mode of
administration. It should be understood, however, that a specific
dosage and treatment regimen for any particular patient will depend
upon a variety of factors, including the activity of the specific
compound employed, the age, body weight, general health, sex, diet,
time of administration, rate of excretion, drug combination, and
the judgment of the treating physician and the severity of the
particular disease being treated. The amount of active ingredient
may also depend upon the therapeutic or prophylactic agent, if any,
with which the ingredient is co-administered.
[0589] The dosage and dose rate of the compounds of this invention
effective for preventing, inhibiting, suppressing or reducing cell
adhesion and consequent or associated pathogenic processes
subsequently mediated by VLA-4 will depend on a variety of factors,
such as the nature of the inhibitor, the size of the patient, the
goal of the treatment, the nature of the pathology to be treated,
the specific pharmaceutical composition used, and the observations
and conclusions of the treating physician.
[0590] For example, where the dosage form is oral, e.g., a tablet
or capsule, suitable dosage levels of the compounds of Formula
(1.0.0) will be between about 1.0 .mu.g and about 10.0 mg/kg body
weight per day, preferably between about 5.0 .mu.g and about 5.0
mg/kg body weight per day, more preferably between about 10.0 .mu.g
and about 1.0 mg/kg of body weight per day, and most preferably
between about 20.0 .mu.g and about 0.5 mg/kg of body weight per day
of the active ingredient.
[0591] Where the dosage form is topically administered to the
bronchia and lungs, e.g., by means of a powder inhaler or
nebulizer, suitable dosage levels of the compounds of Formula
(1.0.0) will be between about 0.1 .mu.g and about 1.0 mg/kg body
weight per day, preferably between about 0.5 .mu.g and about 0.5
mg/kg body weight per day, more preferably between about 1.0 .mu.g
and about 0.1 mg/kg of body weight per day, and most preferably
between about 2.0 .mu.g and about 0.05 mg/kg of body weight per day
of the active ingredient.
[0592] Using representative body weights of 10 kg and 100 kg in
order to illustrate the range of daily topical dosages which might
be used as described above, suitable dosage levels of the compounds
of Formula (1.0.0) will be between about 1.0-10.0 .mu.g and
10.0-100.0 mg per day, preferably between about 5.0-50.0 .mu.g and
5.0-50.0 mg per day, more preferably between about 10.0-100.0 .mu.g
and 1.0-10.0 mg per day, and most preferably between about
20.0-200.0 .mu.g and about 0.5-5.0 mg per day of the active
ingredient comprising a compound of Formula (1.0.0). These ranges
of dosage amounts represent total dosage amounts of the active
ingredient per day for a given patient. The number of times per day
that a dose is administered will depend upon such pharmacological
and pharmacokinetic factors as the half-life of the active
ingredient, which reflects its rate of catabolism and clearance, as
well as the minimal and optimal blood plasma or other body fluid
levels of said active ingredient attained in the patient which are
required for therapeutic efficacy
[0593] Numerous other factors must also be considered in deciding
upon the number of doses per day and the amount of active
ingredient per dose which will be administered. Not the least
important of such other factors is the individual response of the
patient being treated. Thus, for example, where the active
ingredient is used to treat or prevent asthma, and is administered
topically via aerosol inhalation into the lungs, from one to four
doses consisting of actuations of a dispensing device, i.e.,
"puffs" of an inhaler, will be administered each day, each dose
containing from about 50.0 .mu.g to about 10.0 mg of active
ingredient.
[0594] Included within the scope of the present invention are
embodiments comprising compositions which contain, in addition to a
compound of the present invention as active ingredient, additional
therapeutic agent active ingredients selected from the group
consisting essentially of anti-inflammatory corticosteroids;
bronchodilators; antiasthmatics; non-steroidal anti-inflammatories;
immunosuppressants; immunostimulants; antimetabolites;
antipsoriatics and antidiabetics. Specific compounds within each of
these classes may be selected from those listed under the
appropriate headings in Comprehensive Medicinal Chemistry, Pergamon
Press, Oxford, England, pp. 970-986 (1990); and Goodman and
Gilman's The Pharmacological Basis of Therapeutics, 9th ed.,
Hardman, J. G. and Limbird, L. E., eds., McGraw-Hill, 1996, the
disclosure of which are incorporated herein by reference in their
entireties. Especially preferred active ingredients to be included
for use in combination with the compounds of Formula (1.0.0) are
anti-inflammatory compounds such as theophylline, sulfasalazine and
aminosalicylates; immunosuppressants such as cyclosporin, FK-506,
and rapamycin; antimetabolites such as cyclophosphamide and
methotrexate; and immunomodulators such as the interferons.
[0595] Still further embodiments of the present invention relate to
a method of treating or preventing an inflammatory, autoimmune or
respiratory disease by inhibiting cell adhesion and consequent or
associated pathogenic processes subsequently mediated by VLA-4. As
already mentioned,. VLA-4-associated cell adhesion plays a central
role in a variety of inflammatory, immune and autoimmune diseases.
Thus, inhibition of cell adhesion by the compounds of this
invention may be utilized in methods of treating or preventing
inflammatory, immune and autoimmune diseases. Preferably the
diseases to be treated with the methods of this invention are
selected from asthma, arthritis, psoriasis, transplantation
rejection, multiple sclerosis, diabetes and inflammatory bowel
disease.
[0596] The above-described methods of treatment of the present
invention may employ the compounds of Formula (1.0.0) in the form
of monotherapy, but said methods may also be used in the form of
multiple therapy in which one or more compounds of Formula (1.0.0)
are coadministered in combination with a known anti-inflammatory,
immunomodulating, immunostimulating or immunosuppressive agent. The
terms "coadministered" or "coadministration" as used herein are
intended to mean therapeutic utilization of one or more compounds
of Formula (1.0.0) in combination with one or more additional
therapeutic agents, including but not limited to, administration of
the combination of therapeutic active agents in a single dosage
form or in multiple dosage forms representing the same or different
routes of administration, said multiple dosage forms being
administered at substantially the same time or at different
times.
[0597] Subsequent to synthesis of any of the above-recited
preferred species of the present invention or any other compounds
falling within the scope of the present invention, the biological
activities relating to the VLA-4 specificities of said compounds
may be determined using one or more of the numerous in vitro and in
vivo assays which have been described heretofore in the technical
literature pertinent to the art. For example, some of the now
very-well established assay methods and models concern measurement
of VLA-4 activity by determining the concentration of a test
candidate inhibitor required to block the binding of
VLA-4-expressing cells to fibronectin- or CS-1 coated plates. In
this assay microtiter wells are coated with either fibronectin
(containing the CS-1 sequence), CS-1 peptide or soluble VCAM-1.
Once the wells are coated, varying concentrations of the test
compound are then added together with appropriately labelled,
VLA-4-expressing cells. Alternatively, the test compound may be
added first and allowed to incubate with the coated wells prior to
the addition of the cells. The cells are allowed to incubate in the
wells for at least 30 minutes. Following incubation, the wells are
emptied and washed. Inhibition of binding is measured by
quantitating the fluorescence or radioactivity bound to the plate
for each of the various concentrations of test compound, as well as
for controls containing no test compound. However, the assay just
described is less preferred than other assays mentioned further
below in determining the VLA-4 activity of the compounds of Formula
(1.0.0).
[0598] VLA-4-expressing cells that may be utilized in this assay
include Ramos cells, Jurkat cells, A375 melanoma cells, as well as
human peripheral blood lymphocytes (PBL). The cells used in this
assay may be fluorescently or radioactively labelled.
[0599] In order to assess the VLA-4 inhibitory specificity of test
compounds, assays for other major groups of integrins, i.e.,
.beta..sub.2 and .beta..sub.3, as well as other .beta..sub.1
integrins, such as VLA-5, VLA-6 and .alpha..sub.4.beta..sub.7 may
be performed. These assays may be similar to the adhesion
inhibition and direct binding assays described above, substituting
the appropriate integrin-expressing cell and corresponding ligand.
For example, polymorphonuclear cells (PMNs) express .beta..sub.2
integrins on their surface and bind to ICAM; while .beta..sub.3
integrins are involved in platelet aggregation and inhibition may
be measured in a standard platelet aggregation assay. VLA-5 binds
specifically to Arg-Gly-Asp sequences, while VLA-6 binds to
laminin. Further, .alpha..sub.4.beta..sub.7 is a recently
discovered homologue of VLA-4, which also binds fibronectin and
VCAM as well as MAdCAM-1. Specificity with respect to
.alpha..sub.4.beta..sub.7 is determined in a binding assay that
utilizes CS-1, VCAM or MAdCAM-1 and a cell line that expresses
.alpha..sub.4.beta..sub.7, but not VLA-4, such as RPMI-8866
cells.
[0600] Once VLA-4-specific inhibitors are identified, they may be
further characterized in in vivo assays. One such assay tests the
inhibition of allergen induced airway hyperresponsiveness and cell
influx, such as described by Henderson et al., "Blockade of CD49d
(.alpha..sub.4 integrin) on intrapulmonary but not circulating
leukocytes inhibits airway inflammation and hyperresponsiveness in
a mouse model of asthma", J. Clin. Invest., 100(12), pp. 3083-92
(1997). In this assay, mice are sensitized by ip exposure to an
irritant, such as ovalbumin. Following a recovery period, the mice
are challenged by aerosol exposure to the allergen. Before aerosol
exposure, the mice are given various doses of the VLA-4 inhibitor
by intratracheal injection. In vivo inhibition of cell adhesion
associated inflammation is assessed by measuring the number of
cells and cytokines in the bronchial alveolar lavage fluid. In this
manner, one may identify those inhibitors of this invention which
are best suited for inhibiting inflammation.
[0601] Another in vivo assay that may be employed is the primate
asthma assay. This assay is performed essentially as described in
Turner, C. R., et al., "Characterization of a primate model of
asthma using anti-allergy/anti-asthma agents", Inflammation
Research, 45(5), pp. 239-45 (1996), the disclosure of which is
incorporated herein by reference in its entirety. This assay
measures inhibition of Ascaris antigen-induced late phase airway
responses and airway hyperresponsiveness in allergic primates
following administration of anti-allergy/anti-asthma agents.
[0602] The compounds of the present invention may be formulated
into pharmaceutical compositions that may be administered orally,
parenterally, by inhalation (metered dose inhaler, dry powder
inhaler or nebulizer), topically, rectally, nasally, intraocularly,
buccally, vaginally or via an implanted reservoir. The term
"parenteral" as used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial, intrasternal,
intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques.
[0603] The compounds of Formula (1.0.0) may be prepared in
accordance with well-known procedures for carrying out the
synthesis of organic compounds which are non-peptidyl or
semi-peptidyl in nature. A number of different procedures are
available which are fully disclosed in the technical literature and
with which the skilled artisan will be familiar. The description
which follows of several such synthesis schemes is merely
representative and not intended to be in any way limiting. A number
of abbreviations are used in said description in order to conserve
space. Although these abbreviations are also well known to the
artisan, they are set out immediately below for clarity and
convenience:
2 BOP benzotriazol-1-yloxy- EDCI 1-(3-dimethylaminopropyl)-
tris(dimethylamino) 3-ethylcarbodiimide phosphonium hexafluoro-
hydrochloride phosphate DAST diethylaminosulfur HOBT
1-hydroxybenzotriazole trifluoride DIEA diisoproylethyl amine THF
tetrahydrofuran DMF Dimethylformamide
[0604] 112
[0605] The synthesis of compounds of the Formula 1.0.0 in which the
"B" component is an isoxazole ring and the "Y" component is
--SO.sub.2-- is illustrated in Scheme 1, steps A through G. In
Scheme 1, step A, the starting material , diethyl amino malonate,
is commercially available, e.g., from Aldrich Chemical Company,
Milwaukee, Wis. 53233. The amide product (2.0.1), where R.sup.5 is
hydrogen, methyl or phenyl, is also commercially available. Other
amides, where R.sup.5 is alkyl, aryl, heterocyclyl or heteroaryl
are made readily available by the reaction of the appropriate acid
chloride with the amine (2.0.0) using the conditions that are well
described in the literature (e.g. March, J. "Advanced Organic
Chemistry", 3.sup.rd edition, 1985). Under similar conditions, the
amine (2.0.0) may be converted to its corresponding sulfonamide by
the reaction of 2.0.0 with an alkyl or aryl sulfonyl chloride. The
carbamate product (2.0.1), where R.sup.5 is alkoxy or aryloxy is
prepared from amine 2.0.0 in accordance with procedures described
by Paik, Yi Hyon; Dowd, Paul; J. Org. Chem. 1986, 51(15),
2910-2913; and Kawai, Masao; Nyfeler, Rolf; Berman, Judd M.;
Goodman, Murray; J. Med. Chem., 1982 25(4), 397-402. 113
[0606] In Scheme 1, Step B, the intermediate 2.0.3 is prepared from
the oxime 2.0.2. Oxime 2.0.2 is prepared from its corresponding
aldehyde by procedures well known to those skilled in the art (e.g.
Chung, Yong Jun; Ryu, Eun Jung; Keum, Gyochang; Kim, Byeang Hyean;
Bioorg. Med. Chem.; 1996, 4(2) 209-226; and Kim, Byeang Hyean;
Chung, Yong Jun; Keum, Gyochang; Kim, Jaheon; Kim, Kimoon;
Tetrahedron Lett.; 1992, 33(45); 6811-6814). Oxime 2.0.2 is
converted to the isoxazole 2.0.3 by oxidation with a suitable
oxidant such as sodium hypochlorite, tert-butyl hypochlorite, or
N-chlorosuccinimide in a suitable solvent such as THF, chloroform
or methylene chloride; and reacting the resulting nitrile N-oxide
in situ with propargyl bromide. This [2+3] cycloaddition reaction
is well known in the literature as a method for preparing the
isoxazole ring structure. See, e.g., Synthesis, 508-9, 1982.
114
[0607] In Scheme 1, Step C, the bromide intermediate 2.0.3 is
converted to the isoxazole containing component 2.0.4. The bromide
2.0.3 is reacted with an optionally substituted malonate (2.0.1) in
a suitable solvent such as DMF, DMSO or methylene chloride, in the
presence of a base such as triethlyamine or cesium carbonate. DMF
is the preferred solvent and cesium carbonate is the preferred
base. The reaction is performed at a temperature between 0 and
30.degree. C. for a period of 1 to 16 hours. The reaction of
bromide 2.0.3 with malonate 2.0.1 in Scheme 1, step C, is not
limited to 2-amino malonates, but can be expanded to include
malonates of the formula [EtOC(.dbd.O)CHR.sup.7C(.dbd.O)OEt], where
R.sup.7 is defined above in the definition of Formula 1.0.0.
115
[0608] The synthesis of the mono ester intermediate 2.0.5 is
illustrated in Scheme 1, Step D. The diethyl malonate 2.0.4 is
converted to its half-ester intermediate by reaction with one
equivalent of a suitable base such as aqueous sodium hydroxide or
lithium hydroxide in a solvent such as THF, methanol, tert-butanol
or dioxane. The use of aqueous sodium hydroxide in dioxane is
preferred. The reaction is conducted at a temperature between 0 and
50.degree. C. for a time period of between 1 and 16 hours. Three
hours at ambient temperature is preferred. This half-ester
intermediate is subsequently transformed to mono ester 2.0.5 in
situ by heating it in a suitable solvent such as benzene, toduene
or dioxane at a temperature between 0 and 200.degree. C. for a time
period of between 1 and 16 hours. Heating at 125.degree. C. for 3
hours in dioxane is preferred. 116
[0609] The synthesis of the amine intermediate 2.0.6 is illustrated
in Scheme 1, Step E. The tert-butyloxycarbamate intermediate 2.0.5
is reacted with an acid such as neat trifluoroacetic acid, or a
solution hydrochloric acid in a suitable non-aqueous solvent such
as dioxane. The reaction is conducted at a temperature between 0
and 50.degree. C. for a time period of between 1 and 16 hours.
Hydrochloric acid in dioxane at ambient temperature for 1 hour is
the preferred conditions. It will be recognized by those skilled in
the art that the tert-butyloxycarbonyl group serves as a protecting
group for the amine and that other suitable protecting groups can
be employed. It will be further recognized that methods for removal
of these protecting groups must be compatible with all the
functionality present in R.sup.5. These methods are well-known in
the technical literature of the relevant art. For example, see
Greene, T. W., Wuts, P. G. M. Protective Group in Organic
Synthesis; John Wiley & Sons: New York, 1991. 117
[0610] The synthesis of the sulfonamide intermediate 2.0.7 is
described in scheme 1 step F. The amine 2.0.6 is reacted with a
sulfonyl chloride [A(CH.sub.2).sub.n--SO.sub.2Cl, where "A" and "n"
are defined above in the definition of formula 1.0.0] in a solvent
such as dichloromethane, water, or pyridine with or without a base
such as sodium carbonate or diisopropylethylamine. The reaction is
conducted at a temperature between 0 and 50.degree. C. for a period
of between 1 and 16 hours. The preferred conditions are sodium
carbonate in water at ambient temperature for 16 hours. 118
[0611] The carboxylic acid product is prepared from ester
intermediate 2.0.7 as illustrated in scheme 1, step G. The ester
intermediate 2.0.7 is reacted with a suitable aqueous base, such as
lithium hydroxide, potassium hydroxide or sodium hydroxide in a
solvent such as tert-butanol, methanol, and / or THF. The reaction
is conducted at a temperature between 0 and 50.degree. C. for a
time period between 0.5 and 24 hours. Aqueous lithium hydroxide in
a mixture of THF and methanol at ambient temperature for 1 hour are
the preferred conditions.
[0612] The above-described synthesis is broadly applicable to the
compounds of Formula (1.0.0). In order to make said synthesis even
more clear, there is set out below Synthesis Scheme 1-.alpha.,
Steps A through G with reference to a particular compound of the
present invention: 119
[0613] The following schematic synthesis diagram illustrates a
generalized preparation process for the compounds of Formula 1.0.0
in which the "Y" component is C.dbd.O: 120
[0614] The starting material A.sup.1-NCO is an isocyanate in which
"A.sup.1" has the same definition as the A component of Formula
(1.0.0) regarding the aryl, heteroaryl and heterocyclyl moieties
substituted with 0 to 3 R.sup.9. Isocyanate starting materials for
making component A, such as phenyl isocyanate, otolyl isocyanate,
2-fluorophenyl isocyanate and 2-chlorophenyl isocyanate are
commercially available, e.g., from Aldrich Chemical Company,
Milwaukee, Wis. 53233. Alternatively, isocyanate starting materials
can be readily prepared from their corresponding amines using the
methods described in the literature (e.g. March, J. "Advanced
Organic Chemistry", 3.sup.rd edition, 1985). Pyridyl analogues of
the above phenyl isocyanates can be used to prepare the
corresponding compounds of Formula (1.0.0) where the A component
contains a pyridyl group.
[0615] One of the above-described isocyantes is reacted with an
amine of formula 2.0.10. The addition of amines to isocyanates is a
well-known reaction which provides substituted ureas in a facile
manner. The reaction can be carried out in a solvent such as
methylene chloride with triethylamine at slightly elevated
temperatures. The disubstituted urea (2.0.11) prepared as in the
above-indicated reaction scheme, which forms the reactant
eventually resulting in component A of the compounds of Formula
(1.0.0), is next reacted with an amine of the formula
"--NR.sup.4CR.sup.2R.sup.3--B", in which "B" is defined as one of
the partial Formulas (1.1.0)-(1.1.22). 121
[0616] The reaction between the component A forming reactant
(2.0.11) and the amine 2.0.6 will be recognized by the artisan as
one involving the acylation of an amine by a carboxylic acid which
can be made to proceed in good yield at room temperature or
slightly above by the use of coupling agents such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
and 1-hydroxybenzotriazole (HOBT); dicyclohexylcarbodiimide (DCCI);
N,N'-carbonyldiimidazole; N,N,N',N'-tetramethyl(succinimido)uronium
tetrafluoroborate; and benzotriazol-1-yloxy-tris(dimethylamino)
phosphonium hexafluorophosphate (BOP). The amine component (2.0.6)
is available as described in Scheme 1. This reaction may be
illustrated in the above schematic synthesis diagram which provides
a generalized preparation process for the compounds of Formulas
(1.0.0).
[0617] To prepare the final product of Formula (1.0.0) in the form
of the acid, an additional step is required, as is shown in the
following reaction scheme: 122
[0618] The final acid product (2.0.13) is prepared from ester
2.0.12 as illustrated in the above scheme. The intermediate is
reacted with a suitable aqueous hydroxide base, such as lithium
hydroxide, potassium hydroxide or sodium hydroxide in a solvent
system comprised of tert-butanol, methanol or THF and methanol. The
reaction is conducted at a temperature between 0 and 50.degree. C.
for 0.5 to 16 hours. Lithium hydroxide in THF, methanol, and water
at ambient temperature for 1 hour are the preferred conditions.
[0619] The above-described synthesis is broadly applicable to the
compounds of Formula (1.0.0). In order to make said synthesis even
more clear, there is set out below Synthesis Scheme 2-.alpha.,
Steps A through C with reference to a particular compound of the
present invention: 123
[0620] An alternative synthesis of compounds of the Formula (1.0.0)
is illustrated in Synthesis Scheme 3, steps A through C. The
synthesis of the amine intermediate 2.0.14 is illustrated in scheme
3, step A. Tert-butyloxycarbamate intermediate 2.0.4 is reacted
with an acid such as neat trifluoroacetic acid, or a solution
hydrochloric acid in a suitable non-aqueous solvent such as
dioxane. The reaction is conducted at a temperature between 0 and
50.degree. C. for a time period of between 1 and 16 hours.
Hydrochloric acid in dioxane at ambient temperature for 1 hour are
the preferred conditions. It will be recognized by those skilled in
the art that the tert-butyloxycarbonyl group serves as a protecting
group for the amine and that other suitable protecting groups can
be employed. It will be further recognized that methods for removal
of these protecting groups must be compatible with all of the
functionality present in R.sup.5. These methods are well-known in
the technical literature of the relevant art. For example, see
Greene, T. W., Wuts, P. G. M. Protective Group in Organic
Synthesis; John Wiley & Sons: New York, 1991. 124
[0621] In scheme 3, step B, the amine 2.0.14 is reacted with acid
2.0.15 under the same conditions as synthesis Scheme 2, step B.
[0622] To prepare the final product of Formula (1.0.0) in the form
of the acid, an additional step is required, as is shown in the
following reaction scheme: 125
[0623] The final acid product (2.0.17) is prepared from ester
2.0.16 as illustrated in the above scheme. The intermediate is
reacted with a suitable aqueous hydroxide base, such as lithium
hydroxide, potassium hydroxide or sodium hydroxide in a solvent
system comprised of tert-butanol, methanol or THF and methanol. The
reaction is conducted at a temperature between 0 and 50.degree. C.
for 0.5 to 16 hours. Lithium hydroxide in THF, methanol, and water
at ambient temperature for 1 hour are the preferred conditions.
[0624] The above-described synthesis is broadly applicable to the
compounds of Formula (1.0.0). In order to make said synthesis even
more clear, there is set out below Synthesis Scheme 3-.alpha.,
Steps A through C with reference to a particular compound of the
present invention: 126
[0625] An alternative mode for the synthesis of compounds of the
Formula (1.0.0) is illustrated in Synthesis Scheme 4, Steps A
through D. 127
[0626] In Scheme 4, Step A, the oxime 2.0.2 is converted to the
isoxazole 2.0.18 by oxidation with a suitable oxidant such as
sodium hypochlorite, tert-butyl hypochlorite, or
N-chlorosuccinimide in a suitable solvent such as THF, chloroform
or methylene chloride; and reacting the resulting nitrile N-oxide
in situ with a 2,2-disubstituted methyl pent-4-ynoate. This [2+3]
cycloaddition reaction is well known in the literature as a method
for preparing the isoxazole ring structure. See, e.g., Synthesis,
508-9, 1982. 128
[0627] The synthesis of the amine intermediate 2.0.19 is
illustrated in the above reaction scheme using the same conditions
as Scheme 3, step A. The starting material is the
tert-butyloxycarbamate intermediate 2.0.18. 129
[0628] In scheme 4, step C, the amine 2.0.19 is reacted with acid
2.0.15 under the same conditions as synthesis Scheme 2, step B.
This reaction may be illustrated in the above schematic synthesis
diagram which provides a generalized preparation process for the
compounds of Formulas (1.0.0).
[0629] To prepare the final product of Formula (1.0.0) in the form
of the acid, an additional step is required, as is shown in the
following reaction scheme: 130
[0630] The final acid product 2.0.21 was prepared from ester 2.0.20
as illustrated in the above scheme using the method of Scheme 3,
step C.
[0631] The above-described synthesis is broadly applicable to the
compounds of Formula (1.0.0). In order to make said synthesis even
more clear, there is set out below Synthesis Scheme 4-.alpha.,
Steps A through C with reference to a particular compound of the
present invention: 131
[0632] An alternative mode for the synthesis of compounds of the
Formula (1.0.0) is illustrated in Synthesis Scheme 5 Steps A
through D. 132
[0633] The bromide 2.0.22 is available commercially from, for
example, from Aldrich Chemical Company, Milwaukee, Wis. 53233.
Bromide 2.0.22 is converted into the desired diester containing
component 2.0.23, as shown in the above scheme. The bromide is
reacted with an amino malonate under the conditions described in
scheme 1, step C. 133
[0634] The nitrile 2.0.23 is converted to the desired amine 2.0.24
as illustrated in the above reaction scheme. The nitrile 2.0.23 is
reduced to the corresponding amine 2.0.24 by hydrogenation as
described in the literature (e.g. March, J. "Advanced Organic
Chemistry", 3.sup.rd edition, 1985).
[0635] The above-described synthesis is broadly applicable to the
compounds of Formula (1.0.0). In order to make said synthesis even
more clear, there is set out below Synthesis Scheme 5-.alpha.:
134
[0636] The synthesis of bicyclic compounds of the Formula (1.0.0)
is illustrated in Synthesis Scheme 6 Steps A through D. Starting
materials are acids and amines available from commercial sources,
eg., Aldrich Chemical Company, Milwaukee, Wis. 53233. 135
[0637] The reaction illustrated in the above scheme will be
recognized by the artisan as one involving the acylation of an
amine 2.0.22 by a carboxylic acid 2.0.23 which can be made to
proceed in good yield at room temperature or slightly above by the
use of coupling agents such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
and 1-hydroxybenzotriazole (HOBT); dicyclohexylcarbodiimide (DCCI);
N,N'-carbonyldiimidazole; POCl.sub.3; TiCl.sub.4; SO.sub.2ClF;
Ti(OBu).sub.4; P.sub.2I.sub.4; Bu.sub.3N; benzotriazol-1-yl diethyl
phosphate; N,N,N',N'-tetramethyl(succinimido)uronium
tetrafluoroborate; and preferably di-iso-propylethyl amine (DIEA)
and benzotriazol-1-yloxy-tris(dimethylamino) phosphonium
hexafluorophosphate (BOP). 136
[0638] The synthesis of the amine intermediate 2.0.26 is
illustrated in the above reaction scheme. The starting material is
a mixture of the tert-butyloxycarbamate intermediates 2.0.24 and
2.0.25. Intermediates 2.0.24 and 2.0.25 are reacted with an acid
such as hydrochloric acid or acetic acid with or without a suitable
solvent such as dioxane. The reaction is conducted at a temperature
between 0 and 100.degree. C. for 1 to 16 hours. Acetic acid in the
absence of additional solvent at 800 for 1.5 hours is preferred. It
will be recognized by those skilled in the art that these
conditions accomplish both the cyclization to form the desired
bicyclic ring system and removal of the tert-butyloxycarbonyl
group. It will also be recognized by those skilled in the art that
the tert-butyloxycarbonyl group serves as a protecting group for
the amine and that other suitable protecting groups can be
employed. It will be further recognized that methods for removal of
these protecting groups must be compatible with all the
functionality present in intermediate 2.0.26. These methods are
well-known in the technical literature of the relevant art. For
example, see Greene, T. W., Wuts, P. G. M. Protective Group in
Organic Synthesis; John Wiley & Sons: New York, 1991.
[0639] The above-described synthesis is broadly applicable to the
compounds of Formula (1.0.0). In order to make said synthesis even
more clear, there is set out below Synthesis Scheme 6-.alpha., with
reference to a particular compound of the present invention:
137
[0640] An alternative mode for the synthesis of compounds of the
Formula (1.0.0) is illustrated in Synthesis Scheme 7 Steps A
through C. These steps describe an alternative route to the B
component used in the coupling reaction as describes in Synthesis
Scheme 2 Step B. 138
[0641] The preparation of bromide intermediate 2.0.29 was described
in Synthesis Scheme 1 Step A. The intermediate bromide 2.0.29 was
reacted with the commercially available imine 2.0.30 in a suitable
solvent such as toluene, methylene chloride or DMF with a base such
as cesium carbonate, cesium hydroxide or potassium hydroxide in the
presence of an additive such as tertabutyl ammonium bromide,
tetrabutyl ammonium chloride, or tetraphenylammonium bromide. The
reaction was performed at a temperature between -78 and 50.degree.
C. for a period of 1 to 16 hours. The reaction of the bromide
intermediate 2.0.29 with the imine 2.0.30 in toluene at ambient
temperature in the presence of tetrabutylammonium bromide for 1
hour was preferred. 139
[0642] The synthesis of the amine intermediate 2.0.32 is
illustrated in the above reaction scheme. The imine intermediate
2.0.31 can be transformed to the amine 2.0.32 by a variety of
methods well known to those skilled in the art and described in the
literature. For examples, Wolfe, John P.; Ahman, Jens; Sadighi,
Joseph P.; Singer, Robert A.; Buchwald, Stephen L.; Tetrahedron
Lett.; 1997, 38(36); 6367-6370; and Corey, E.J.; Xu, Feng,; Noe,
Mark C.; J. Am. Chem, Soc., 1997, 119, 12414-12415. In the
preferred method, intermediate imine 2.0.31 is treated with a
mixture of ethyl acetate and hydrochloric acid for three hours at
ambient temperature. 140
[0643] The synthesis of the amide intermediate 2.0.33 is
illustrated in the above reaction scheme. The amine with or without
a solvent, such as dicloromethane, chloroform, benzene, water or
pyridine is reacted with an acid anhydride or acid chloride with or
without the addition of a base such as sodium carbonate, pyridine
or diisopropyl ethyl amine. The reaction is performed between 0 and
50.degree. C. for a period of 1 to 16 hours. The preferred
conditions employ dichloromethane and pyridine at ambient
temperature for 16 hours.
[0644] The above-described synthesis is broadly applicable to the
compounds of Formula (1.0.0). In order to make said synthesis even
more clear, there is set out below Synthesis Scheme 7-.alpha.:
141
EXEMPLIFICATION OF PREFERRED EMBODIMENTS
[0645] The examples which follow further illustrate the compounds,
compositions and methods of treatment of the present invention, but
are not intended to thereby limit the scope of the present
invention. A number abbreviations are used in the following
examples in order to conserve space. Although these abbreviations
are well known to the artisan, they are set out immediately below
for clarity and convenience of the reader:
[0646] BOP benzotriazol-1-yloxy-tris(dimethylamino) phosphonium
hexafluorophosphate
[0647] DAST diethylaminosulfur trifluoride
[0648] DIEA diisopropylethyl amine
[0649] DMF dimethylformamide
[0650] EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
[0651] HOBT 1-hydroxybenzotriazole
[0652] THF tetrahydrofuran
EXAMPLE 1
[0653] A.
2-Allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-p-
yrrolidin-2-yl]-isoxazol-5-yl}-propionic acid 142
[0654] A tetrahydrofuran (1.0 mL) and methanol (0.5 mL) solution of
2-allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidin-
-2-yl]-isoxazol-5-yl)-propionic acid ethyl ester (59 mg, 0.108
mmol) was stirred with 2M aqueous lithium hydroxide (0.5 mL) at
room temperature for 40 minutes. The reaction was acidified to pH 1
with 1M hydrochloric acid and extracted twice with ethyl acetate.
The combined extracts were dried over magnesium sulfate and
concentrated in vacuo to give the title compound as a white solid
(51 mg, 91%). MS (Cl) m/z 518 (M+1).
[0655] B.
2-Allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-p-
yrrolidin-2-yl]-isoxazol-5-yl}-propionic acid ethyl ester 143
[0656]
2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propion-
ic acid ethyl ester hydrochloride (110 mg, 0.294 mmol) and sodium
carbonate (93.5 mg, 0.882 mmol) were dissolved in water (1.5 mL)
and 3,5-dichlorobenzenesulfonylchloride (86.7 mg, 0.353 mmol) was
added. This mixture was stirred overnight. The reaction was
extracted twice with dichloromethane. The combined organic portion
was washed with brine, dried over magnesium sulfate and
concentrated in vacuo to yield the title compound (59 mg, 37%). MS
(Cl) m/z 545.7 (M+1)
[0657] C.
2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-prop-
ionic acid ethyl ester hydrochloride 144
[0658]
2-[5-(2-Allyloxycarbonylamino-2-ethoxycarbonyl-ethyl)-isoxazol-3-yl-
]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.44 g, 7.86
mmol) was dissolved in 4M hydrochloric acid in dioxane (10 mL) and
stirred at room temperature for 2 hours. The reaction was then
concentrated in vacuo and co-evaporated with dichloromethane to
give the desired product as a brown waxy solid. MS (Cl) m/z 509.9
(M+1)
[0659] D.
2-[5-(2-Allyloxycarbonylamino-2-ethoxycarbonyl-ethyl)-isoxazol-3-
-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester 145
[0660] A mixture of
2-allyloxycarbonylamino-2-[3-(1-tert-butyloxycarbonyl--
pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonic acid monoethyl ester
and
2-allyloxycarbonylamino-2-[3-(1-tert-butyloxycarbonyl-pyrrolidin-2-yl)-is-
oxazol-5-ylmethyl]-malonic acid diethyl ester (10.4 g, 21.5 mmol)
was dissolved in dioxane (130 mL) and heated in an oil bath to
125.degree. C. for 3 hours. The dioxane was then removed in vacuo.
The residue was dissolved in ethyl acetate, washed with saturated
sodium carbonate and brine, dried over magnesium sulfate and
concentrated. The crude material was chromatographed on a Biotage
Flash 40M column eluting with ethyl acetate/hexanes (1:4) to give
the title compound as a clear oil (5.12 g, 56% 2 steps). MS (Cl)
m/z 338.0 (M-99). 2-Allyloxycarbonylamino-2-[3-(1-t-
ert-butyloxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonic
acid diethyl ester was recovered (2.96 g, 27%). MS (Cl) m/z 509.9
(M+1), 409.9 (M-99)
[0661] E.
2-Allyloxycarbonylamino-2-[3-(1-tert-butyloxycarbonyl-pyrrolidin-
-2-yl)-isoxazol-5-ylmethyl]-malonic acid monoethyl ester 146
[0662] Sodium hydroxide, 1M, (21.5 mL, 21.5 mmol) was added in
portions over 30 minutes to a dioxane (22 mL) solution of
2-allyloxycarbonylamino--
2-[3-(1-tert-butyloxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-maloni-
c acid diethyl ester (10.95 g, 21.5 mmol). After stirring
overnight, the reaction had not gone to completion. An additional
0.2 equivalents of 1M sodium hydroxide (4.2 mL, 4.2 mmol) was added
and stirring continued for 3 hours. The reaction was diluted with
ethyl acetate (50 mL) and 1M sulfuric acid (23 mL) was added
dropwise at 0.degree. C. The aqueous portion was extracted twice
with ethyl acetate. The combined organic portions were dried over
magnesium sulfate and concentrated in vacuo to give a the title
compound. The crude product was used directly in the next step
without separation of the unreacted diester. MS (Cl) m/z 382.2
(M-99).
[0663] F.
2-Allyloxycarbonylamino-2-[3-(1-tert-butyloxycarbonyl-pyrrolidin-
-2-yl)-isoxazol-5-ylmethyl]-malonic acid diethyl ester 147
[0664] A dimethyl formamide (260 mL) solution of
2-(5-Bromomethyl-isoxazol- -3-yl)-pyrrolidine-1-carboxylic acid
tert-butyl ester (7.29 g, 56 mmol) and
2-allyloxycarbonylamino-malonic acid diethyl ester (8.25 g, 32
mmol) was cooled to 0.degree. C. and cesium carbonate (25.41 g, 78
mmol) was added. The reaction was allowed to warm to room
temperature and stirred for 3 hours. The reaction mixture was then
poured into diethyl ether (2 L) and washed with water (5.times.200
mL) and brine. The organic portion was dried over magnesium sulfate
and concentrated in vacuo. The crude residue was chromatographed on
silica gel eluting with ethyl acetate:hexane (3:7) to afford the
title compound as a clear colorless oil (10.95 g; 83%). MS (Cl) m/z
260.1 (M-99).
[0665] G. 2-Allyloxycarbonylamino-malonic acid diethyl ester
148
[0666] A methylene chloride (1.0 L) solution of diethylamino
malonate hydrochloride (47.0 g, 226 mmol) was cooled to 0.degree.
C. and pyridine (45 mL, 564 mmol) was added. Previously insoluble
solid dissolved upon addition of the pyridine. Allyl chloroformate
(20 mL, 188 mmol) was slowly added dropwise to maintain the
temperature of the reaction below 50.degree. C. After the addition
was complete, the reaction was stirred at 0.degree. C. for 15
minutes. The reaction was washed with 1M hydrochloric acid
(6.times.100 mL), dried over magnesium sulfate and concentrated in
vacuo to give the title compound as a white solid (46.78 g, 80%).
The crude product was used without further purification. MS (Cl)
m/z 260.1 (M+1)
[0667] H. 2-(5-Bromomethyl-isoxazol-3-yl)-pyrrolidine-1-carboxylic
acid tert-butyl ester 149
[0668] The title compound was prepared in the manner described for
examples 7H and 7I, utilizing
2-(hydroxyimino-methyl)-pyrrolidine-1-carba- mic acid tert-butyl
ester in step 7I.
EXAMPLE 2
[0669] A.
2-Allyloxycarbonylamino-3-(3-{1-[(4-nitro-phenyl)-acetyl]-pyrrol-
idin-2-yl}-isoxazol-5-yl)-propionic acid 150
[0670] The hydrolysis of
2-allyloxycarbonylamino-3-(3-{1-[(4-nitro-phenyl)-
-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic acid ethyl ester
was carried out according to the same protocol as in Example 1A to
afford the title compound. MS (Cl) m/z 472.6 (M+1), 471.7
(M-1).
[0671] B.
2-Allyloxycarbonylamino-3-(3-{1-[(4-nitro-phenyl)-acetyl]-pyrrol-
idin-2-yl}-isoxazol-5-yl)-propionic acid ethyl ester 151
[0672] A dimethyl formamide (82 mL) solution of 4-nitrophenylacetic
acid (1.61 g, 8.87 mmol) in dimethyl formamide (82 mL) was stirred
with 4-hydroxybenzotriazole monohydrate (1.40 g, 10.4 mmol) for 10
minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride
(1.86 g, 9.72 mmol) was added and the mixture was stirred until all
1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride had
dissolved. To this solution,
2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-
-yl)-propionic acid ethyl ester hydrochloride from Example 1C (3.16
g, 8.25 mmol) was added and the mixture stirred 30 minutes followed
by addition of triethyl amine (1.26 mL, 9.04 mmol). After the
reaction had stirred at room temperature over night it was poured
into water and extracted with ethyl acetate three times. The
combined extracts were washed with a saturated solution of sodium
bicarbonate, water (2.times.) and brine. The organic portion was
dried over magnesium sulfate and concentrated. The resulting
residue was chromatographed on a Biotage Flash 40S column eluting
with ethyl acetate/hexanes (5:1) to yield the title compound as a
yellow oil (674 mg, 15%). MS (Cl) m/z 501.3 (M+1). Additionally,
starting material 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-
-yl-isoxazol-5-yl)-propionic acid ethyl ester was recovered (2.15
g, 75%). MS (Cl) m/z 338.1 (M+1)
EXAMPLE 3
[0673] A.
2-Allyloxycarbonylamino-3-[3-(1-{[4-(2,6-dichloro-benzoylamino)--
phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
152
[0674] The hydrolysis of
2-allyloxycarbonylamino-3-[3-(1-{[4-(2,6-dichloro-
-benzoylamino)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic
acid ethyl ester was carried out according to the same protocol as
in example 1A to afford the title compound (77 mg, 75%). MS (Cl)
m/z 616.7 (M+1), 612.5 (M-1).
[0675] B.
2-Allyloxycarbonylamino-3-[3-(1-{[4-(2,6-dichloro-benzoylamino)--
phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
ethyl ester 153
[0676] A dichloromethane (1 mL) solution
2-allyloxycarbonylamino-3-(3-{1-[-
(4-amino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic
acid ethyl ester (80 mg, 0.170 mmol) was cooled to 0.degree. C. and
2,6-dichlorobenzoylchloride (39 mg, 0.187 mmol) was added. The
mixture was stirred for 15 minutes then pyridine (28 .mu.L, 0.34
mmol) was added. The reaction was slowly warmed to room temperature
and stirred overnight. The reaction was diluted with ethyl acetate
and washed with water, 1M sodium hydroxide and brine. The organic
portion was dried over magnesium sulfate and concentrated to give
the title compound (84 mg, 78%). MS (Cl) m/z 635.3 (M+1), 632.5
(M-1)
[0677] C. 2-Allyloxycarbonylamino-3-(3-{l
-[(4-amino-phenyl)-acetyl]-pyrro-
lidin-2-yl}-isoxazol-5-yl)-propionic acid ethyl ester 154
[0678] A solution of
2-allyloxycarbonylamino-3-(3-{1-[(4-nitro-phenyl)-ace-
tyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic acid ethyl ester
(2B) (565 mg, 1.13 mmol) and iron(0) powder (384 mg, 6.98 mmol) in
ethanol/water (5 mL, 1:1) was heated to reflux. Hydrochloric acid,
1M, (0.29 mL, 0.29 mmol) was added drop wise and the reaction was
heated at reflux for 45 minutes. It was then neutralized with 1M
sodium hydroxide and filtered through celite. The filtrate was
diluted with ethyl acetate and washed with water and brine. The
organic portion was dried over magnesium sulfate and concentrated
in vacuo. The crude residue was chromatographed on a Biotage Flash
403 column eluting with ethyl acetate/hexanes (6:1) to provide the
title compound as a yellow oil (240 mg, 51%). MS (Cl) m/z 471.0
(M+1)
EXAMPLE 4
[0679] A.
2-Allyloxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid 155
[0680] The hydrolysis of
2-allyloxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ur-
eido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic
acid ethyl ester was carried out according to the same protocol as
in example 1A to afford the title compound. MS (Cl) m/z 576.0
(M+1), 573.9 (M-1)
[0681] B.
2-Allyloxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-a-
cetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid ethyl ester
156
[0682] The title compound was prepared in the manner described in
example 2B using [4-(3-o-tolyl-ureido)-phenyl]-acetic acid MS (Cl)
m/z 604.0 (M+1).
EXAMPLE 5
[0683] A.
3-(3-{1-[(4-Acetylamino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazo-
l-5-yl)-2-allyloxycarbonylamino-propionic acid 157
[0684] The hydrolysis of
3-(3-{1-[(4-acetylamino-phenyl)-acetyl]-pyrrolidi-
n-2-yl}-isoxazol-5-yl)-2-allyloxycarbonylamino-propionic acid ethyl
ester was carried out according to the same protocol as in example
1A to afford the title compound. MS (Cl) m/z 485.3 (M+1), 483.0
(M-1)
[0685] B.
3-(3-{1-[(4-Acetylamino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazo-
l-5-yl)-2-allyloxycarbonylamino-propionic acid ethyl ester 158
[0686] The title compound was prepared in the manner described in
Example 3B using acetyl chloride in place of
2,6-dichlorobenzoylchloride. MS (Cl) m/z 513.0 (M+1).
EXAMPLE 6
[0687] A.
2-tert-Butoxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl-
]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid 159
[0688] The hydrolysis of
2-tert-butoxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-
-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic
acid methyl ester was carried out according to the protocol in
example 1A to afford the title compound. MS (Cl) m/z 590.2 (M-1),
492.2 (M-99)
[0689] B.
2-tert-Butoxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl-
]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid methyl
ester 160
[0690] A solution of
1-(4-{2-[2-(hydroxyimino-methyl)-pyrrolidin-1-yl]-2-o-
xo-ethyl}-phenyl)-3-o-tolyl-urea (300 mg, 0.789 mmol),
2-tert-butoxycarbonylamino-pent-4-ynoic acid methyl ester (359 mg,
1.182 mmol, crude mixture) and triethyl amine (12.9 [L) in
dichloromethane (2 mL) was stirred 5 minutes. A sodium hypochlorite
solution (5.25%, 2 mL) was added. The reaction was stirred at room
temperature overnight. The aqueous portion was extracted 4 times
with dichloromethane. The combined organic portions were washed
with brine, dried over magnesium sulfate and concentrated.
Chromatography of the crude mixture on a Biotage Flash 40S column
eluting with ethyl acetate/hexane 1:5 gave the title compound (66
mg, 14%). MS (Cl) m/z 604.5 (M-1), 505.9 (M-99)
[0691] C. 2-tert-Butoxycarbonylamino-pent-4-ynoic acid methyl ester
161
[0692] Potassium carbonate (1.687 g, 12.2 mmol) was added to an
anhydrous methanol (91.5 mL) solution of
2-tert-butoxycarbonylamino-4-oxo-butyric acid benzyl ester (1.875
g, 6.10 mmol) and the reaction stirred 10 minutes.
(1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (1.407 g,
7.32 mmol) was added and the reaction was stirred at room temp
temperature 1 hour. The reaction was poured into diethyl ether and
washed 4 times with 5% sodium bicarbonate, dried over magnesium
sulfate and concentrated (1.05 g, crude product mixture). The crude
product was used directly in the next step. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.39-5.31 (m, 1H), 4.49-4.41 (m, 1H), 3.77 (s,
3H), 2.79-2.65 (m, 2H), 2.03 (s, 1H), 1.59 and 1.44 (2 singlets,
rotamers, 3H).
[0693] D. 2-tert-Butoxycarbonylamino-4-oxo-butyric acid benzyl
ester 162
[0694] A dimethyl sulfoxide (10 mL) solution of
2-tert-butoxycarbonylamino- -4-hydroxy-butyric acid benzyl ester
(13.58 g, 43.9 mmol) and triethyl amine (18.35 mL, 131.7 mmol) was
cooled to 0.degree. C. Pyridine sulfur trioxide (21.0 g. 131.7
mmol) in dimethyl sulfoxide (80 mL) was added in a steady stream.
The cooling bath was removed and the reaction stirred 1.5 hours.
The reaction was poured into 130 mL ice water and extracted with
diethyl ether (2.times.180 mL and 100 mL). The combined organic
portion was washed sequentially with saturated sodium bicarbonate,
water, brine and dried over magnesium sulfate. The solvent was
removed in vacuo and the crude product was chromatographed on
silica gel (900 mL) eluting with ethyl acetate/hexanes (1:4), to
give the title compound as a clear, colorless oil (9.20 g, 70%). MS
(Cl) m/z 208.0 (M-99).
EXAMPLE 7
[0695] A.
2-Acetylamino-4-(3-(1-[2-(4-benzyloxy-phenyl)-acetylamino]-3-met-
hyl-butyl}- isoxazol-5-yl)-propionic acid 163
[0696] A 1:2 methanol/tetrahydrofuran (9 mL) solution of
2-acetylamino-4-(3-{1-[2-(4-benzyloxy-phenyl)-acetylamino]-3-methyl-butyl-
}-isoxazol-5-yl)-propionic acid ethyl ester (92 mg, 0.17 mmol) was
combined with 2M aqueous lithium hydroxide (3 mL) at room
temperature stirred for 3 hours. After the reaction was acidified
to pH=1 with 1N hydrochloric acid, the aqueous portion was
extracted with ethyl acetate (2.times.50 mL). The combined organic
portions were dried over sodium sulfate, and concentrated to give
2-acetylamino-4-(3-{1-[2-(4-benzyloxy-p-
henyl)-acetylamino]-3-methyl-butyl}-isoxazol-5-yl)-propionic acid
as a white crystalline solid (83 mg, 95%). MS (Cl) m/z 508.1 (M+1),
506.1 (M-1).
[0697] B. 2-Acetylamino-4-(3-{1-[2-(4-benzyloxy-phenyl)-
acetylamino]-3-methyl-butyl}-isoxazol-5-yl)-propionic acid ethyl
ester 164
[0698] A solution of (4-benzyloxy-phenyl)-acetic acid (125 mg, 0.29
mmol, 1.00 equivalents) and 1-hydroxybenzotriazole hydrate (48 mg,
0.36 mmol, 1.23 equivalents) in dimethyl formamide (5 mL) was
stirred at room temperature for 15 minutes.
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (64 mg, 0.33 mmol,
1.15 equivalents) was added and the reaction was stirred for 15
minutes. 2-Acetylamino-3-[3-(1-amino-3-methyl-butyl)-isoxa-
zol-5-yl]-propionic acid ethyl ester hydrochloride (100 mg, 0.29
mmol, 1.00 equivalents) was added and the reaction was stirred for
25 minutes Triethylamine (43 .mu.l, 0.31 mmol, 1.07 equivalents)
was added. The reaction was stirred at room temperature overnight
then diluted with ethyl acetate (30 mL) and extracted with 1N
hydrochloric acid (2.times.30 mL), saturated sodium bicarbonate
(2.times.30 mL) and brine (30 mL). The organic portion was dried
over sodium sulfate and the solvent was removed in vacuo. The
residue was chromatographed on a 40S Biotage column (ethyl acetate)
to give the title compound as a clear colorless oil (94 mg, 61%).
MS (Cl) m/z 536.2 (M+1).
[0699] C.
2-Acetylamino-3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-propi-
onic acid ethyl ester hydrochloride 165
[0700]
2-Acetylamino-3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isox-
azol-5-yl]-propionic acid ethyl ester (7F) (5.95 g, 14.5 mmol) was
stirred in 4N hydrochloric acid in dioxane (25 mL) at room
temperature overnight. The product was concentrated and dried under
high vacuum to give the title compound as a white solid (5.38 g,
100%). MS (Cl) m/z 312.2 (M+1 for the free base).
[0701] D. (4-Benzyloxy-phenyl)-acetic acid 166
[0702] A 1:2 methanol/tetrahydrofuran (60 mL) solution of
(4-benzyloxy-phenyl)-acetic acid methyl ester (1.35 g, 5.27 mmol)
was combined with 2M aqueous lithium hydroxide (20 mL) at room
temperature and the reaction was stirred overnight. The reaction
was acidified to pH 1 with 1N hydrochloric acid and extracted with
ethyl acetate (2.times.50 mL). The organic portions were dried over
sodium sulfate and the solvent removed in vacuo to give the title
compound as a white crystalline solid (1.25 g, 98%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 3.63 (s, 2H), 5.09 (s, 2H), 6.96-6.99
(d, 2H), 7.22-7.25 (d, 2H), 7.3-7.5 (m, 5H).
[0703] E. (4-Benzyloxy-phenyl)-acetic acid methyl ester 167
[0704] Cesium carbonate (5.35 g, 16.4 mmol, 3.00 equivalents) was
added to a solution of methyl 4-hydroxyphenylacetate (1.00 g, 6.02
mmol, 1.10 equivalents) and benzyl bromide (0.65 mL, 5.47 mmol,
1.00 equivalents) in dichloromethane (40 mL) at 0.degree. C. The
mixture was allowed to warm to room temperature and stirred
vigorously overnight. The reaction was extracted with 1N
hydrochloric acid (2.times.100 mL) and brine (100 mL). The organic
portion was dried over sodium sulfate and the solvent removed in
vacuo. The resulting oily solid was chromatographed on a 40S
Biotage column (20% ethyl acetate/Hexanes) to give the title ester
as a clear colorless oil (1.35 g, 96%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.56 (s, 2H), 3.67 (s, 3H), 5.04 (s, 2H),
6.91-6.94 (d, 2H), 7.17-7.19 (d, 2H), 7.3-7.4 (m, 5H).
[0705] F. 2-Acetylamino-3-[3-(1-tert-butoxycarbonylamino-3-methyl
-butyl)-isoxazol-5-yl]-propionic acid ethyl ester 168
[0706] Sodium hydroxide, 1N, (20.5 mL, 20.5 mmol, 1.10 equivalents)
was added to a dioxane solution of
2-acetylamino-2-[3-(1-tert-butoxycarbonyla-
mino-3-methyl-butyl)-isoxazol-5-ylmethyl]-malonic acid diethyl
ester (8.99 g, 18.6 mmol, 1.0 equivalents) at room temperature over
30 minutes and the reaction was stirred overnight. The reaction was
diluted with ethyl acetate (200 mL) and acidified to pH=1-1.5 with
1N hydrochloric acid. The organic portion was washed with brine
(200 mL) and dried over sodium sulfate. The solvent was removed in
vacuo to give 8.58 g of a 1:1 mixture (by .sup.1H NMR) of
2-Acetylamino-2-[3-(1-tert-butoxycarbonylamino-3-meth-
yl-butyl)-isoxazol-5-ylmethyl]-malonic acid monoethyl ester [MS
(Cl) m/z 356.3 (M-99)] and the decarboxylated title compound [MS
(Cl) m/z 412.3 (M+1), 312.2 (M-99), 410.3(M-1)].
[0707] The mixture was refluxed in dioxane (150 mL) overnight and
concentrated to yield an orange oil that was chromatographed using
a Biotage column (40M, 50% ethyl acetate/hexanes) to give the title
compound as a thick orange solid (6.72 g, 88%). MS (Cl) m/z 412.3
(M+1), 312.2 (M-99).
[0708] G.
2-Acetylamino-2-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-i-
soxazol-5-ylmethyl]-malonic acid diethyl ester 169
[0709] Cesium carbonate (18.28 g, 56.1 mmol, 3.0 equivalents)was
added to a dimethyl formamide (300 mL) solution of
[1-(5-bromomethyl-isoxazol-3-yl- )-3-methyl-butyl]-carbamic acid
tert-butyl ester (6.48 g, 18.7 mmol, 1.00 equivalents) and
diethylacetamidomalonate (4.86 g, 22.4 mmol, 1.20 equivalents) at
0.degree. C. The mixture was stirred at room temperature for 5
hours. The reaction was poured into diethyl ether (200 mL) and
extracted with water (5.times.200 mL) and brine (200 mL). The
organic portion was dried over sodium sulfate and the solvent was
removed in vacuo to give the title compound as a viscous oil (8.99
g, 99.4%). MS (Cl) m/z 484.0 (M+1), 384.1 (M-99).
[0710] H. [1-(5-Bromomethyl-isoxazol-3-yl)-3-methyl-butyl]-carbamic
acid t-butyl ester 170
[0711] N-Chlorosuccinimide (5.80 g, 43.4 mmol, 1.00 equivalents),
[1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid tert-butyl
ester (10.00 g, 43.4 mmol, 1.00 equivalents) and pyridine (0.70 mL)
were stirred in chloroform (70 mL) at room temperature for 1 hour.
Propargyl bromide (4.83 mL, 54.3 mmol, 1.25 equivalents) was added
and the reaction was heated to 45.degree. C. Triethylamine (6.35
mL, 45.6 mmol, 1.05 equivalents) was added dropwise over 20 minutes
at 45.degree. C. The reaction was stirred for an additional 1 hour,
then it was diluted with water (200 mL) and extracted with
dichloromethane (2.times.200 mL). The combined organic extracts
were washed with saturated sodium bicarbonate (2.times.200 mL) and
brine (200 mL). The organic portion was dried over sodium sulfate.
Evaporation of the solvent gave a brown residue that was
chromatographed by flash chromatography on silica gel to give the
title compound as a white solid (6.48 g, 43%). MS (Cl) m/z 247.0
(M-99)
[0712] I. 1-(Hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid
tert-butyl ester 171
[0713] A mixture of (1-formyl-3-methyl-butyl)-carbamic acid
tert-butyl ester (2.13 g), hydroxylamine hydrochloride (0.71 g,
10.2 mmol) and NaOAc (2 g, 24.4 mmol) in MeOH (20 mL) and water (20
mL) was stirred vigorously. After 24 h the mixture was diluted with
water (60 mL) and extracted with EtOAc (50 mL.times.3). The
combined organics were washed with water and brine; dried over
MgSO4; filtered and concentrated under reduced pressure.
Purification by Flash 40 chromatography using a silica gel column
and eluting with 15-25% EtOAc/hexane gave 1.5 g of the title
compound as a white solid. MP 156-157.degree. C.
EXAMPLE 8
[0714] A.
2-Allyloxycarbonylamino-3-[3-(1-benzoyl-pyrrolidin-2-yl)-isoxazo-
l-5-yl]-propionic acid 172
[0715] The hydrolysis of 8B was carried out according to the
protocol in example 1A to afford the title compound. MS (Cl) m/z
414.2 (M+1), 412.2 (M-1).
[0716] B.
2-Allyloxycarbonylamino-3-[3-(1-benzoyl-pyrrolidin-2-yl)-isoxazo-
l-5-yl]-propionic acid ethyl ester 173
[0717] Benzoyl chloride (21 .mu.l, 0.18 mmol, 1.0 equivalents) was
added in one portion to a solution of
2-allyloxycarbonylamino-3-(3-pyrrolidin-2-
-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride (1C)
(74 mg, 0.20 mmol, 1.1 equivalents) in pyridine (29 .mu.l, 0.36
mmol, 2.0 equivalents) and dichloromethane (2 mL) at 0.degree. C.
The reaction was stirred at room temperature for 4 hours then
diluted with ethyl acetate (30 mL). The reaction was extracted with
1N hydrochloric acid (30 mL) and brine (30 mL). The organic portion
was dried over sodium sulfate and concentrated in vacuo to give the
title compound (66 mg, 84%). MS (Cl) m/z 442.3 (M+1).
EXAMPLE 9
[0718] A.
2-Allyloxycarbonylamino-3-{3-[1-(biphenyl-4-carbonyl)-pyrrolidin-
-2-yl]-isoxazol-5-yl}-propionic acid 174
[0719] The hydrolysis of 9B was carried out using the protocol in
example 1A to afford the title compound MS (Cl) m/z 490.0 (M+1),
487.8 (M-1).
[0720] B.
2-Allyloxycarbonylamino-3-{3-[1-(biphenyl-4-carbonyl)-pyrrolidin-
-2-yl]-isoxazol-5-yl}-propionic acid ethyl ester 175
[0721] Prepared using the same method described in example 8B. MS
(Cl) m/z 518.0 (M+1).
EXAMPLE 10
[0722] A.
2-Acetylamino-3-(3-{3-methyl-1-[2-(4-naphthalen-2-yl-phenyl)-ace-
tylamino]-butyl}-isoxazol-5-yl)-propionic acid 176
[0723] The hydrolysis of 10B was carried out using the protocol in
example 1A to afford the title compound MS (Cl) m/z 528.0 (M+1),
525.8 (M-1).
[0724] B.
2-Acetylamino-3-(3-{3-methyl-1-[2-(4-naphthalen-2-yl-phenyl)-ace-
tylamnino]-butyl)-isoxazol-5-yl)-propionic acid 177
[0725] Prepared from (4-Naphthalen-2-yl-phenyl)-acetic acid in the
manner described for example 7B.
[0726] C. (4-Naphthalen-2-yl-phenyl)-acetic acid 178
[0727] Lithium hydroxide, 2M, (3.0 mL) was added to a 2:1
tetrahydrofuran:methanol (9.0 mL) solution of
(4-Naphthalen-2-yl-phenyl)-- acetic acid methyl ester (270 mg,
0.977 mmol). The resulting mixture was stirred at room temperature
for 1 hour. The reaction was acidified to pH=1 with 1M hydrochloric
acid and extracted twice with ethyl acetate. The combined organic
portions were washed with brine, dried over magnesium sulfate and
concentrated in vacuo to give the title compound as a white solid
(233 mg, 91%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.01-7.39
(m, 11H), 3.72 (s, 2H)
[0728] D. (4-Naphthalen-2-yl-phenyl)-acetic acid methyl ester
179
[0729] Tetrakis triphenyphosphine palladium (65 mg, 7.4 mol %) was
added to a dimethoxyethane (5.4 mL) solution of
(4-Trifluoromethanesulfonyloxy-- phenyl)-acetic acid methyl ester
(447 mg, 1.5 mmol), 2-naphthaleneboronic acid (286 mg, 1.67 mmol)
and cesium fluoride (505 mg, 3.33 mmol). The reaction was flushed
with nitrogen and heated in an oil bath to 100.degree. C. while
stirring for 3 hours. The reaction was then diluted with ethyl
acetate and extracted with water, 1M sodium hydroxide, water and
brine. The organic portion was dried over magnesium sulfate and
concentrated in vacuo. The resulting residue was chromatographed on
a Biotage Flash 40S column eluting with 5% ethyl acetate in hexanes
to give the title compound as a clear oil (273 mg, 66%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.01-7.38 (m, 11H), 3.72 (s, 3H),
3.69 (2H)
[0730] E. (4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl
ester 180
[0731] Trifluoromethane sulfonic anhydride (32.2 mmol) was added
dropwise over 5 minutes to a -40.degree. C. pyridine (70 mL)
solution of (4-hydroxy-phenyl)-acetic acid methyl ester (5.35 g,
32.2 mmol). The reaction was stirred at -40.degree. C. for 10
minutes and then at 0.degree. C. for 2 hours. The reaction was
diluted with diethyl ether and washed with water and 2N
hydrochloric acid. The organic portion was dried over magnesium
sulfate and concentrated in vacuo. The crude residue was
chromatographed on a Biotage Flash 40M column eluting with ethyl
acetate/hexanes (1:4) to provide the title compound as a clear,
colorless oil, which crystallized upon standing 9.27 g, 97%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.37-7.34 (m, 2H),
7.24-7.21 (m, 2H), 3.70 (3H), 3.64 (2H).
EXAMPLE 11
[0732] A.
2,2-Dimethyl-3-[3-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-a-
cetylamino}-butyl)-isoxazol-5-yl]-propionic acid 181
[0733] The hydrolysis of 11B was carried out using the protocol in
example 1A to afford the title compound MS (Cl) m/z: 521.2 (M+1),
519.1 (M-1)
[0734] B.
2,2-Dimethyl-3-[3-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-a-
cetylamino}-butyl)-isoxazol-5-yl]-propionic acid methyl ester
182
[0735] Prepared from
3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isox-
azol-5-yl]-2,2-dimethyl-propionic acid methyl ester in two steps by
following the procedure outlined in examples 1C and 2B. MS (Cl) m/z
535.1 (M+1), 535.1 (M-1)
[0736] C.
3-[3-(1-tert-Butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]--
2,2-dimethyl-propionic acid methyl ester 183
[0737] Prepared from
[1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid tert-butyl
ester (7I) and 2,2-dimethyl-pent-4-ynoic acid methyl ester
according to the procedure outlined in example 6A. MS (Cl) m/z:
313.2 (M-tBu), 269.3 (M-99)
EXAMPLE 12
[0738] A.
3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-b-
utyl)-isoxazol-5-yl]-2-phenyl-propionic acid 184
[0739] The hydrolysis of 12B was carried out using the protocol in
example 1A to afford the title compound.
[0740] B.
3-[3-(3-Methyl-1-{2-[4-(o-tolyl-ureido)-phenyl]-acetylamino}-but-
yl)-isoxazol-5=yl]-2-phenyl-propionic acid methyl ester 185
[0741] The title compound was prepared from
3-[3-(1-tertbutoxycarbonylamin-
o-3-methyl-butyl)-isoxazol-5-yl]-2-phenyl-propionic acid methyl
ester in the manner described in example 11B.
[0742] C.
3-[3-(1-tert-Butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]--
2-phenyl-propionic acid methyl ester 186
[0743] The title compound was prepared from 2-phenyl-pent-4-ynoic
acid methyl ester in the manner described in example 6A.
[0744] D. 2-Phenyl-pent-4-ynoic acid methyl ester 187
[0745] Diisopropyl ethyl amine (5.9 mL, 42 mmol) was dissolved in
tetrahydrofuran (30 mL). Butyllithium, 2.5 M in hexanes, (16.8 mL,
42 mmol) was added slowly at A solution of phenyl acetic acid (2.72
g, 20 mmol) in tetrahydrofuran (20 mL) was added slowly via a
dropping funnel over 20 minutes. The reaction was stirred for 25
minutes. Propargyl bromide was added as an 80% weight solution in
toluene (2.3 mL, 21.0 mmol). The reaction was stirred for 1.5 hours
and 4N hydrochloric acid (15 mL) was added. The mixture was diluted
with ethyl acetate (50 mL). The organic portion was concentrated in
vacuo. The residue was dissolved in diethyl ether and extracted
with water (3.times.) and 1N hydrochloric acid (3.times.). The
organic portion was dried over magnesium sulfate and the solvent
removed in vacuo. The resulting yellow solid (1.7 g) was dissolved
in methanol (50 mL) and cooled to 0.degree. C. Acetylchloride (2
mL) was added and the reaction was allowed to warm to room
temperature. After the reaction stirred for 18 hours, the solvent
was removed in vacuo. The residue was dissolved in diethyl ether.
The solution was extracted with saturated sodium bicarbonate,
water, and brine. The organic portion was dried over magnesium
sulfate and the solvent removed in vacuo. The residue was
chromatographed on silica gel with 10% ethyl acetate in hexanes to
give the title compound as an oil (0.58 g, 15%)
EXAMPLE 13
[0746] A.
2-Acetylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyr-
rolidin-2-yl)-isoxazol-5-yl]-propionic acid 188
[0747] The hydrolysis of 13B was carried out using the protocol in
example 1A to afford the title compound. MS (Cl) m/z 534.2 (M+1),
532.4 (M-1).
[0748] B.
2-Acetylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyr-
rolidin-2-yl)-isoxazol-5-yl]-propionic acid ethyl ester 189
[0749] The title compound was prepared from
2-[5-(2-acetylamino-2-methoxyc-
arbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylic acid
tert-butyl ester as described in example 11B. MS (Cl) m/z 562.1
(M+1).
[0750] C.
2-[5-(2-Acetylamino-2-methoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrr-
olidine-1-carboxylic acid tert-butyl ester 190
[0751] The title compound was prepared from the
2-(hydroxyimino-methyl)-py- rrolidine-1-carbamic acid tert-butyl
ester and the 2-acetylamino-pent-4-yn- oic acid methyl ester as
described in example 6B. MS (Cl) m/z 296.0 (M-99)
EXAMPLE 14
[0752] A.
2-(2,6-Dichloro-benzoylamino)-3-[3(1-{[4-(3-o-tolyl-ureido)-phen-
yl]-acetyl-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid 191
[0753] The hydrolysis of 14B was carried out using the protocol in
example 1A to afford the title compound. MS (Cl) m/z 663.8
(M+1).
[0754] B.
2-(2,6-Dichloro-benzoylamino)-3-[3-(1-{[4-(3-o-tolyl-ureido)-phe-
nyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid ethyl
ester 192
[0755] The title compound was prepared from
2-{5-[2-(2,6-dichloro-benzoyla-
mino)-2-ethoxycarbonyl-ethyl]-isoxazol-3-yl}-pyrrolidine-1-carboxylic
acid tert-butyl ester in a manner similar to that described in 11B.
MS (Cl) m/z 691.8 (M+1), 689.7 (M-1).
[0756] C. 2-{5-[2-(2,
6-Dichloro-benzoylamino)-2-ethyoxycarbonyl-ethyl]-is-
oxazol-3-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester 193
[0757] The title compound was prepared from
2-[5-(2-amino-2-ethoxycarbonyl-
-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylic acid tert-butyl
ester hydrocloride and 2,6-dichlorobenzoylchloride in the manner
described in example 3B. MS (Cl) m/z 525.9 (M+1), 425.9 (M-99).
[0758] D.
2-[5-(2-Amino-2-ethoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-
-1-carboxylic acid tert-butyl ester hydrocloride 194
[0759]
2-{5-[2-(Benzhydrylidene-amino)-2-ethoxycarbonyl-ethyl]-isoxazol-3--
yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 1.35
mmol) was stirred in a mixture of ethyl acetate (20 mL) and 1N
hydrochloric acid (100 mL) for 3 hours. The reaction was
neutralized by the addition of saturated sodium bicarbonate. The
aqueous portion was extracted with diethyl ether. The combined
organics were dried over magnesium sulfate and the solvent removed
in vacuo. The resulting oil (200 mg) was used directly in example
14C.
[0760] E.
2-{5-[2-(Benzhydrylidene-amino)-2-ethoxycarbonyl-ethyl]-isoxazol-
-3-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester 195
[0761] 2-(5-Bromomethyl-isoxazol-3-yl)-pyrrolidine-1-carboxylic
acid tert-butyl ester (1.0 g, 3 mmol) and
N-(diphenylmethylene)glycine glycine ethyl ester (1.0 g, 3.74 mmol)
were dissolved in toluene (10 mL). Aqueous potassium hydroxide,
18M, (0.25 mL, 4.5 mmol) and tetrabutylammonium bromide (97 mg,
0.30 mmol) were added. After the reaction was stirred at room
temperature for 1 hour, 1N hydrochloric acid was added (4.5 mL).
The organic phase was extracted with 1N hydrochloric acid,
saturated sodium bicarbonate, and brine. The organic portion was
dried over magnesium sulfate and the solvent removed in vacuo. The
residue was chromatographed with 15% ethyl acetate in hexanes on a
Biotage 40S column to give the title compound (700 mg, 45%). MS
(Cl) m/z 518.0 (M+1).
EXAMPLE 15
[0762] A.
2-Allyloxycarbonylamino-3-{3-[1-(toluene-4-sulfonyl)-pyrrolidin--
2-yl]-isoxazol-5-yl}-propionic acid 196
[0763] The hydrolysis of 15B was carried out using the protocol in
example 1A to afford the title compound. MS (Cl) m/z 464.0 (M+1),
461.9 (M-1).
[0764] B.
2-Allyloxycarbonylamino-3-{3-[1-(toluene-4-sulfonyl)-pyrrolidin--
2-yl]-isoxazol-5-yl}-propionic acid ethyl ester 197
[0765] The title compound was prepared according to the method
described in example 1B. MS (Cl) m/z 492.0 (M+1).
EXAMPLE 16
[0766] A.
2-Allyloxycarbonylamino-3-[3-(1-([4-(2,6-dimethoxy-benzoylamino)-
-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
198
[0767] The hydrolysis of 16B was carried out using the protocol in
example 1A to afford the title compound. MS (Cl) m/z 606.7 (M+1),
605.1 (M-1).
[0768] B.
2-Allyloxycarbonylamino-3-[3-(1-{[4-(2,6-dimethoxy-benzoylamino)-
-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
ethyl ester 199
[0769] The title compound was prepared according to the procedure
described in example 3B, using 2,6-dimethoxybenzoylchloride in
place of 2,6-dichlorobenzoylchloride. MS (Cl) m/z 635.3 (M+1),
632.5 (M-1)
EXAMPLE 17
[0770] A.
2-Allyloxycarbonylamino-3-{3-[1-(3,4-dimethoxy-benzenesulfonyl)--
pyrrolidin-2-yl]-isoxazol-5-yl}-propionic acid 200
[0771] The hydrolysis of 17B was carried out using the protocol in
example 1A to afford the title compound. MS (Cl) m/z 507.6
(M-1).
[0772] B.
2-Allyloxycarbonylamino-3-{3-[1-(3,4-dimethoxy-benzenesulfonyl)--
pyrrolidin-2-yl]-isoxazol-5-yl}-propionic acid ethyl ester 201
[0773] The title compound was prepared according to the method
described in example 1B, using
3,4-dimethoxybenzenesulfonylchloride. MS (Cl) m/z 537.8 (M+1).
EXAMPLE 18
[0774] A.
2-Allyloxycarbonylamino-3-[3-(1-cyclopropanecarbonyl-pyrrolidin--
2-yl)-isoxazol-5-yl]-propionic acid 202
[0775] The hydrolysis of 18B was carried out using the protocol in
example 1A to afford the title compound. MS (Cl) m/z 378.2 (M+1),
376.2 (M-1).
[0776] B.
2-Allyloxycarbonylamino-3-[3-(1-cyclopropanecarbonyl-pyrrolidin--
2-yl)-isoxazol-5-yl]-propionic acid ethyl ester 203
[0777] The title compound was prepared according to the method
described in example 3B using the appropriate reagents. MS (Cl) m/z
406.1 (M+1).
EXAMPLE 19
[0778] A.
2-Acetylamino-3-[3-(3-methyl-1-{2-[4-(2-methyl-benzyloxy)-phenyl-
]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid 204
[0779] The hydrolysis of 19B was carried out using the protocol in
example 1A to afford the title compound. MS (Cl) m/z 508.1 (M+1),
506.1 (M-1).
[0780] B.
2-Acetylamino-3-[3-(3-methyl-1-{2-[4-(2-methyl-benzyloxy)-phenyl-
]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid ethyl ester
205
[0781] The title compound was prepared according to the method
described in example 7B, using
[4-(2-methyl-benzyloxy)-phenyl]-acetic acid. MS (Cl) m/z 550.2
(M+1).
[0782] B. [4-(2-Methyl-benzyloxy)-phenyl]-acetic acid 206
[0783] The title compound was prepared according to the method
described in example 7D. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
2.40 (s, 3H), 3.65 (s, 2H), 5.05 (s, 2H), 6.98-7.01 (d, 2H),
7.02-7.30 (m, 5H), 7.42-7.44 (d, 1H).
[0784] D. [4-(2-Methyl-benzyloxy)-phenyl]-acetic acid methyl ester
207
[0785] The title compound was prepared according to the method
described in example 7E. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
2.35 (s, 3H), 3.56 (s, 2H), 3.67 (s, 3H), 5.00 (s, 2H), 6.92-6.94
(d, 2H), 7.18-7.26 (m, 5H), 7.37-7.39 (d, 1H).
EXAMPLE 20
[0786] A.
2-Acetylamino-3-(3-{1-[2-(4'-ethyl-biphenyl-4-yl)-acetylamino]-3-
-methyl-butyl}-isoxazol-5-yl)-propionic acid 208
[0787] The hydrolysis of 20B was carried out using the protocol in
example 1A to afford the title compound. MS (Cl) m/z 506.1 (M+1),
504.0 (M-1).
[0788] B.
2-Acetylamino-3-(3-{1-[2-(4'-ethyl-biphenyl4-yl)-acetylamino]-3--
methyl-butyl}-isoxazol-5-yl)-propionic acid ethyl ester 209
[0789] The title compound was prepared according to the method
described in example 7B, using (4'-ethyl-biphenyl-4-yl)-acetic
acid. MS (Cl) m/z 534.2 (M+1).
[0790] C. (4'-Ethyl-biphenyl-4-yl)-acetic acid 210
[0791] The title compound was prepared according to the method
described in example 10B MS (Cl) m/z 239.0 (M-1).
[0792] D. (4'-Ethyl-biphenyl-4-yl)-acetic acid methyl ester 211
[0793] The title compound was prepared according to the method
described in example 1C. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.63(d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz,
2H), 7.36 (d, J=8.1 Hz, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 2.78 (q,
J=7.5 Hz, 2H), 1.37 (t, J=7.5 Hz, 3H).
EXAMPLE 21
[0794] A.
2-Acetylamino-3-(3-{1-[(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-
-yl}-isoxazol-5-yl)-propionic acid 212
[0795] The title compound was prepared from
2-acetylamino-2-(3-{1-[(4-benz-
yloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-ylmethyl)-malonic
acid diethyl ester using the method of example 1D. MS (Cl) m/z
492.2 (M+1), 490.3 (M-1)
[0796] B.
2-Acetylamino-2-(3-{1-[(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-
-yl}-isoxazol-5-ylmethyl)-malonic acid diethyl ester 213
[0797] MS (Cl) m/z 602.0 (M+1)
EXAMPLE 22
[0798] A.
2-Acetylamino-3-[3-(1-{[4-(4-chloro-benzyloxy)-phenyl]-acetyl}-p-
yrrolidin-2-yl)-isoxazol-5-yl]-propionic acid 214
[0799] The title compound was prepared from 22B according to the
method described in example 21A. MS (Cl) m/z 526.2 (M+1), 524.2
(M-1).
[0800] B.
2-Acetylamino-3-[3-(1-{[4-(4-chloro-benzyloxy)-phenyl]-acetyl}-p-
yrrolidin-2-yl)-isoxazol-5-ylmethyl)-malonic acid diethyl ester
215
[0801] The title compound was prepared according to the method
described in example 21B, using
[4-(4-chloro-benzyloxy)-phenyl]-acetic acid. MS (Cl) m/z 626.0
(M+1).
[0802] C. [4-(4-Chloro-benzyloxy)-phenyl]-acetic acid 216
[0803] The title compound was prepared according to the method
described in example 7D. .sup.1H NMR (400 MHz, dimethyl sulfoxide)
.delta. 3.44 (s, 2H), 5.05 (s, 2H), 6.88-6.92 (m, 2H), 7.11-7.14
(m, 2H), 7.42 (s, 4H), 12.20 (s, 1H). .sup.13C NMR (100 MHz,
dimethyl sulfoxide) .delta. 68.9, 115.2, 128.1, 129.1, 130.1 (2
overlapping peaks), 131.1, 133.0, 136.9, 157.5, 173.6.
[0804] D. [4-(4-Chloro-benzyloxy)-phenyl]-acetic acid methyl ester
217
[0805] The title compound was prepared according to the method
described in example 7E. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.55 (s, 2H), 3.67 (s, 3H), 5.00 (s, 2H), 6.88-6.90 (d, 2H),
7.17-7.19 (d, 2H), 7.34 (s, 4H).
EXAMPLE 23
[0806] A.
2-Acetylamino-3-[3-(1-{[4-(3-phenyl-allyl)-phenyl]-acetyl}-pyrro-
lidin-2-yl)-isoxazol-5-yl]-propionic acid 218
[0807] The title compound was prepared from 23B according to the
method described in example 22A. MS (Cl) m/z 502.2 (M+1), 500.2
(M-1)
[0808] B.
2-Acetylamino-3-[3-(1-{[4-(3-phenyl-allyl)-phenyl]-acetyl}-pyrro-
lidin-2-yl)-isoxazol-5-ylmethyl)-malonic acid diethyl ester 219
[0809] The title compound was prepared from
[4-(3-phenyl-allyl)-phenyl]-ac- etic acid according to the method
described in example 22B. MS (Cl) m/z 602.0 (M+1).
[0810] C. [4-(3-Phenyl-allyl)-phenyl]-acetic acid 220
[0811] The title compound was prepared from
[4-(3-phenyl-allyl)-phenyl]-ac- etic acid according to the method
described in example 10B. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.51 (d, 2H, J=7 Hz), 3.62 (s, 2H), 6.28-6.46 (m, 2H), 7.18-7.37
(m, 9H).
[0812] D. [4-(3-Phenyl-allyl)-phenyl]-acetic acid 221
[0813] (4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl
ester (500 mg, 1.68 mmol, 1.00 equivalents), palladium (II)
chloride (15 mg, 5 mol %), bis-diphenylphosphinoethane (50 mg, 5
mol %), bis(pinacolato)diboron (469 mg, 1.85 mmol, 1.10
equivalents), and potassium acetate (495 mg, 5.04 mmol, 3.00
equivalents) were heated in dimethyl formamide (10 mL) at
80.degree. C. for 3 hours. The black reaction mixture was cooled to
room temperature. Palladium (II) chloride (15 mg, 5 mol %),
bis-diphenylphosphinoethane (50 mg, 5 mol %), cinnamyl bromide (660
mg, 3.35 mmol, 2.00 equivalents), sodium carbonate (890 mg, 8.40
mmol, 5.00 equivalents), and water (4 mL) were added. The reaction
mixture was heated to 80.degree. C. overnight. The reaction was
cooled to room temperature and diluted with ethyl acetate (50 mL).
This mixture was extracted with saturated sodium bicarbonate
(2.times.50 mL), water (2.times.50 mL) and brine (50 mL). The
organic portion was dried over sodium sulfate. Evaporation of the
solvent gave a black oily residue that was chromatographed on
Biotage (5% ethyl acetate/hexanes) to give a 9:1 mixture of the
title compound and acetic acid 3-phenyl-allyl ester (200 mg, 45%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.52 (dd, 2H, J=7, 1.2
Hz), 3.60 (s, 2H), 3.68 (s, 3H), 6.24-6.38 (m, 1H), 6.43-6.47 (d,
1H), 7.1-7.4 (m, 9H). This material was used in example 23C without
further purification.
EXAMPLE 24
[0814] A.
2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-buty-
l)-1H-benzoimidazole-4-carboxylic acid 222
[0815] The title compound was prepared from 24B according to the
method described in example 1A. MS (Cl) m/z 514.1 (M+1), 512.2
(M-1)
[0816] B.
2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-buty-
l)-1H-benzoimidazole-4-carboxylic acid methyl ester 223
[0817] The title compound was prepared from 24C according to the
method described in example 2B. MS (Cl) m/z 528.0 (M+1), 526.2
(M-1)
[0818] C. 2-(1-Amino-3-methyl-butyl)-1H-benzoimidazole-5-carboxylic
acid methyl ester hydrochloride 224
[0819] A solution of
4-Amino-3-(2-tert-butoxycarbonylamino-4-methyl-pentan-
oylamino)-benzoic acid methyl ester (690 mg, 1.82 mmol) in acetic
acid (9 mL) was heated to 70.degree. C. with stirring for 1.5
hours. The acetic acid was removed in vacuo and the crude mixture
was dissolved up in 4M hydrochloric acid in dioxane (9 mL) and
stirred at room temperature for 30 minutes. The reaction was
concentrated in vacuo to give the title compound. MS (Cl) m/z 262.0
(M+1), 260.1 (M-1)
[0820] E.
4-Amino-3-(2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-b-
enzoic acid methyl ester 225
[0821] Hydroxybenzotriazole monohydrate (760 mg, 5.62 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (973 mg,
5.07 mmol) were added to a dimethyl formamide (30 mL) solution of
N-tert-butyloxycarbonyl-L-leucine (1.06 g, 4.57 mmol). The mixture
was stirred until all 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde
hydrochloride had dissolved. Methyl 3,4-diaminobenzoate (759 mg,
4.57 mmol) in dimethyl formamide (10 mL) and triethyl amine (0.68
mL, 4.89 mmol) were added sequentially. The reaction was stirred at
room temperature over night and poured into water. This mixture was
extracted with ethyl acetate three times. The organic portion was
extracted with a saturated solution of sodium bicarbonate, water
(2.times.) and brine. The organic portion was dried over magnesium
sulfate and the solvent removed in vacuo. The resulting residue was
chromatographed on a Biotage Flash 40S column eluting with ethyl
acetate/hexanes (2:3) which yielded the title compound (690 mg,
40%). MS (Cl) m/z 380.0 (M+1), 378.2 (M-1).
EXAMPLE 25
[0822] A.
2-(2,6-Dichloro-benzoylamino)-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-
-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic
acid 226
[0823] A mixture of 25B (56 mg, 0.13 mmol) in tert-butanol (1 mL)
and 1N sodium hydroxide (0.27 mL) was stirred at reflux. After 30
minutes the mixture was concentrated under reduced pressure, and
the resulting residue was dissolved in water and washed with ethyl
acetate. The aqueous layer was acidified to pH 1 with 1N HCl and
extracted into ethyl acetate. The combined organic layers were
washed with water and brine, dried over sodium sulfate and
concentrated under reduced pressure to give an off-white solid. MP
102-4.degree. C.; MS (m/z) 710.3 and 713.3 (M+1).
[0824] B.
2-(2,6-Dichloro-benzoylamino)-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-
-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic
acid methyl ester 227
[0825] The title compound was prepared in the manner described in
example 2B using 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic acid
and
3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-benzoylamino-
)-propionic acid methyl ester hydrochloride. 51% yield; white
solid. MS (m/z) 724.2 and 726.2 (M+1).
[0826] C.
3-[3-(1-Amino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-ben-
zoylamino)-propionic acid methyl ester hydrochloride 228
[0827] The title compound was prepared from 25Din the same manner
as example 1C. MS (m/z) 428.3 and 430.3 (M+1).
[0828] D.
3-[3-(1-tert-Butoxyarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-2-
-(2,6-dichloro-benzoylamino)-propionic acid methyl ester 229
[0829] The title compound was prepared from 25E and 7I in the same
manner as example 7H. MS (m/z) 526.2 and 528.0 (M-1).
[0830] E. 2-(2,6-Dichloro-benzoylamino)-pent-4-ynoic acid methyl
ester 230
[0831] The title compound was prepared from 2-amino-pent-4-ynoic
acid methyl ester and 2,5-dichlorobenzoyl chloride in the same
manner as example 3B. MS (m/z) 300.2 and 302.2 (M+1).
EXAMPLE 26
[0832] A.
2-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}--
3-methyl-butyl)-isoxazol-5-ylmethyl]-4-methyl-pentanoic acid
231
[0833] The title compound was prepared in the same manner as
Example 25, steps A-D, using 4-methyl-2-propargyl pentanoic acid
methyl ester in step D. MS (m/z) 577.3 (M-1).
EXAMPLE 27
[0834] A.
2-acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-
-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic acid 232
[0835] The title compound was prepared in the same manner as
Example 7A and B, using 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic
acid in part B. White solid; MP 123-5.degree. C.; MS (m/z) 578.1
(M-1).
EXAMPLE 28
[0836] A.
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-ac-
etyl}-amino)-methyl]-phenyl}-propionic acid 233
[0837] The title compound was prepared in the same manner as
example 25, steps A and B, using 28B in step 25B. MS (m/z) 633
(M+1).
[0838] B. 2-Acetylamino-2-[(3-aminomethyl-phenyl)-methyl]-malonic
acid diethyl ester 234
[0839] A mixture of 28C (1.15 g, 3.5 mmol), 10% Pd on carbon (0.15
g) and concentrated HCl (0.3 mL) in ethanol (50 mL) was placed on a
Parr shaker apparatus under 45 p.s.i. hydrogen for 6 hours. The
mixture was filtered through celite and concentrated under reduced
pressure to give 1.2 g of the title compound as a white solid. MS
(m/z) 337.3 (M+1).
[0840] C. 2-Acetylamino-2-[(3-cyanophenyl)-methyl]-malonic acid
diethyl ester 235
[0841] The title compound was prepared from
alpha-bromo-meta-tolunitrile in the same manner as example 7G. MS
(m/z) 333 (M+1).
EXAMPLE 29
[0842] Binding of Biotinylated CS-1 to Isolated VLA-4
[0843] The VLA-4/bCS-1 receptor ligand binding assay described
herein tests the ability of a compound to specifically inhibit
VLA-4 dependent binding.
[0844] A. Preparation of VLA-4 coated plates
[0845] VLA-4 coated plates were prepared the day before the assay
was carried out. The VLA-4-expressing stock was isolated from
Jurkat cells according to the protocol of Makarem et al., J. Biol.
Chem., 269, 4005-4011 (1994) and was diluted in 50 mM NaHCO.sub.3
(pH 8.8) to a final concentration of 0.4 mg/ml. Aliquots of 100 ml
of this stock solution were then added to each well of a 96 well
Microfluor "B" U-bottom plate (Dynatech No. 0010107205) and
incubated overnight at 4.degree. C. The coating solution was
removed by aspiration and the wells were quenched for 0.5 hour with
PBS plus 1 mM MnCl containing 1% non-fat dry milk (200 ml/well,
37.degree. C.). The dry milk was removed by aspiration immediately
before addition of the biotinylated CS-1.
[0846] B. Binding of biotinylated CS-1 to isolated VLA-4
[0847] The biotinylated CS-1 peptide (bCS-1) was prepared. This
peptide was diluted with PBS plus 1 mM MnCl containing 0.1% non-fat
dry milk (PBSB) to a final concentration of 5 mg/ml. Aliquots of
200 ml are added to the wells of a 96 well polypropylene transfer
plate containing compounds (32, 10, 3.2, 1, 0.32 and 0.1 mM),
vehicle or antibodies (0.5 mg/ml) in PBSB containing 0.1% DMSO for
60 min (37.degree. C.). The plate is washed three times with 200
ml/well of PBSB to remove unbound bCS-1. Following this, 100 ml of
a 1:5000 dilution of streptavidin poly-HRP in PBSB was added to
each well for 60 min (37.degree. C.). Unbound streptavidin poly-HRP
was removed by aspiration and the plate was washed three times with
PBSB (200 ml/well). Following the final wash, 100 ml of TMB
substrate was added to each well to react with the bound
streptavidin poly-HRP and the OD of each well on the plate was
determined on the Emax plate reader (650). The results were based
on the mean of duplicate determinations.
EXAMPLE 30
[0848] VLA-4 Dependent THP1 Cell Binding to Baculovirus sVCAM
[0849] The THP1 baculovirus sVCAM cell binding assay tests the
ability of a compound to inhibit VLA-4 dependent binding to
sVCAM.
[0850] A. Preparation of sVCAM coated plates
[0851] The baculovirus sVCAM coated plates were prepared the day
before the experiment was carried out. The baculovirus sVCAM stock
from PanVera was diluted in 50 mM NaHCO.sub.3 (pH 8.8) to a final
concentration of 5 mg/ml. Aliquots of 50 ml of this stock solution
were then added to each well of a 96 well Microfluor "B" U bottom
plate (Dynatech No. 0010107205) and incubated overnight (4.degree.
C.). The coating solution was removed by aspiration and the wells
were quenched for 1 hour with PBS containing 5% non-fat dry milk
(150 ml/well, 4.degree. C.). The dry milk is removed by shock
dumping immediately before addition of the biotinylated CS-1.
[0852] B. Labeling and binding of THP1 cells
[0853] THP1 cells were obtained from the American Type Culture
Collection (ATCC, Rockville, Md.) and grown in RPMI 1640 media
containing 10% 1 mM MnCl.sub.2 for 20 min (37.degree. C.).
Following MnCl.sub.2 activation, the cells were spun down
(approximately 500 g for 5 min) and resuspended twice in serum free
basal media (EBM, 37.degree. C.). The cells in serum free media
(2.times.10.sup.6/ml) were then incubated with 5 mM Calcein AM for
30 min at 37.degree. C. Following labeling, all cells are spun down
(approximately 500 g for 5 min) and resuspended twice in RPMI 1640
containing 10% FBS to cleave any free calcein AM. The cells were
then resuspended twice in DPBS (+1 mM CaCl.sub.2 and 1 mM
MgCl.sub.2) containing 1 mg/ml BSA (DPBSB) and diluted to 667,000
cells/ml. Aliquots Of 200 ml were added to the wells of a 96 well
polypropylene transfer plate containing test compounds (10, 5, 1
and 0.1 mM), vehicle or antibodies (0.5 mg/ml) in DPBSB containing
0.1% DMSO for 30 min (37.degree. C.). The next 150 ml (100,000
cells) were removed from each well and transferred into appropriate
wells of a quenched baculovirus sVCAM coated plate for 45 min
(37.degree. C.). Unbound cells were removed by aspiration and the
plate was washed three times with DPBSB (100 ml/well). Following
the final wash, 100 ml of DPBSB was added to each well and the
plate was read on a Cytoflour II fluorescent plate reader. Three
readings were taken per well at an excitation of 480 and emission
of 530. The results were based on the mean of duplicate
determinations. The average background fluorescence of blank wells
was subtracted from each sample to give a corrected fluorescence
intensity value for each sample.
* * * * *