U.S. patent application number 12/557835 was filed with the patent office on 2010-01-07 for p-38 inhibitors.
Invention is credited to Qing Dong, Fabrice Pierre, Jianqiang Wang.
Application Number | 20100004298 12/557835 |
Document ID | / |
Family ID | 33555395 |
Filed Date | 2010-01-07 |
United States Patent
Application |
20100004298 |
Kind Code |
A1 |
Dong; Qing ; et al. |
January 7, 2010 |
P-38 INHIBITORS
Abstract
Provided are 5-membered heterocycle-based p38 kinase, including
p38.alpha. and p38.beta. kinase, inhibitors. Pharmaceutical
compositions containing the compounds are also provided. Methods of
use of the compounds and compositions are also provided, including
methods of treatment, prevention, or amelioration of one or more
symptoms of p38 kinase mediated diseases and disorders, including,
but not limited to, inflammatory diseases and disorders.
Inventors: |
Dong; Qing; (San Diego,
CA) ; Pierre; Fabrice; (La Jolla, CA) ; Wang;
Jianqiang; (Woburn, MA) |
Correspondence
Address: |
NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
220 MASSACHUSETTS AVENUE
CAMBRIDGE
MA
02139
US
|
Family ID: |
33555395 |
Appl. No.: |
12/557835 |
Filed: |
September 11, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10860768 |
Jun 2, 2004 |
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12557835 |
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60531541 |
Dec 19, 2003 |
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60475662 |
Jun 3, 2003 |
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Current U.S.
Class: |
514/363 ;
435/184; 514/361; 514/364; 514/370; 514/377; 514/383; 548/128;
548/133; 548/138; 548/193; 548/234; 548/264.8 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 25/00 20180101; A61P 31/00 20180101; A61P 21/04 20180101; A61P
37/02 20180101; A61P 37/00 20180101; A61P 5/14 20180101; C07D
417/04 20130101; A61P 9/00 20180101; A61P 19/02 20180101; A61P
13/12 20180101; A61P 43/00 20180101; C07D 277/56 20130101; C07D
285/08 20130101; A61P 37/08 20180101; C07D 417/10 20130101; A61P
17/06 20180101; A61P 31/12 20180101; C07D 249/14 20130101; A61P
1/16 20180101; A61P 17/02 20180101; A61P 1/00 20180101; A61P 1/18
20180101; A61P 29/00 20180101; A61P 35/02 20180101; C07D 263/48
20130101; A61P 11/16 20180101; A61P 19/08 20180101; A61P 35/00
20180101; A61P 3/10 20180101; A61P 19/10 20180101; C07D 417/12
20130101; A61P 7/06 20180101; C07D 277/42 20130101; C07D 271/07
20130101; A61P 1/04 20180101; A61P 17/00 20180101 |
Class at
Publication: |
514/363 ;
548/193; 514/370; 435/184; 548/128; 548/138; 548/133; 548/264.8;
548/234; 514/364; 514/361; 514/377; 514/383 |
International
Class: |
A61K 31/426 20060101
A61K031/426; C07D 277/18 20060101 C07D277/18; C12N 9/99 20060101
C12N009/99; A61P 29/00 20060101 A61P029/00; A61P 37/00 20060101
A61P037/00; A61P 25/00 20060101 A61P025/00; A61P 31/12 20060101
A61P031/12; A61P 19/08 20060101 A61P019/08; C07D 285/08 20060101
C07D285/08; C07D 285/12 20060101 C07D285/12; C07D 271/06 20060101
C07D271/06; C07D 249/14 20060101 C07D249/14; C07D 263/02 20060101
C07D263/02; A61K 31/433 20060101 A61K031/433; A61K 31/4245 20060101
A61K031/4245; A61K 31/421 20060101 A61K031/421; A61K 31/4196
20060101 A61K031/4196 |
Claims
1-109. (canceled)
110. A compound of formula (I): ##STR00134## or pharmaceutically
acceptable derivatives thereof, wherein: R.sup.1 is methyl, halo,
hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl,
trifluoromethyl, methoxy, trifluoromethoxy, cyano, --NH.sub.2 or
--NR.sup.4R.sup.5; R.sup.2 is attached to any available carbon atom
of the phenyl ring A and at each occurrence is independently
selected from alkyl, substituted alkyl, lower cycloalkyl, halo,
trifluoromethyl, trifluoromethoxy, --OR.sup.4, --CN,
--NR.sup.4R.sup.5; --S(.dbd.O)alkyl, --S(.dbd.O)aryl,
--NHSO.sub.2-arylene-R.sup.4, --NHSO.sub.2alkyl, --CO.sub.2R.sup.4,
--CONH.sub.2, --SO.sub.3H, --S(O)alkyl, --S(O)aryl,
--SO.sub.2NHR.sup.4, and --NHC(.dbd.O)NHR.sup.4; n is 0, 1 or 2;
R.sup.3 is selected from hydrogen, alkyl, --OR.sup.4, substituted
alkyl, cycloalkyl, --CR.sup.4cycloalkyl, heteroaryl, substituted
heteroaryl, heterocycle and substituted heterocycle; Y is a single
bond, --C(.dbd.O)NH--, --NH(C.dbd.O)--, --NH(C.dbd.O)NH--,
--SO.sub.2NH--, --NHSO.sub.2--, --C(.dbd.O)--; Z is NR.sup.4, S or
O; B is a 5-membered heterocyclic ring system optionally
substituted with up to two R.sup.13; Q is independently selected
from a single bond, --O--, --S--, --NR.sup.4--, --S(O)--,
--SO.sub.2--, --C(O)--, --CO(O)--, --C(O)NH--(C.sub.0-4alkyl)- or
--CH.sub.2--; D is a monocyclic or bicyclic ring system optionally
containing up to four heteroatoms selected from N, O, and S, and
wherein a CH.sub.2 adjacent to any of the said N, O or S
heteroatoms is optionally substituted with oxo (.dbd.O) or D is
C.sub.1-6alkyl, and wherein D is optionally substituted by one to
four (CR.sup.9R.sup.10).sub.wE groups; w is an integer having a
value from 0-4; R.sup.10 is selected from H, C.sub.1-C.sub.4
alkylhydroxy, C.sub.1-C.sub.4alkylaryl and
C.sub.1-C.sub.4alkylheteroaryl, wherein said aryl or heteroaryl
group is unsubstituted or substituted with 1-3 groups independently
selected from halo, NO.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, haloalkyl, haloalkoxy, OH,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylcarbonyl, CN, NH.sub.2,
NR.sup.6R.sup.7, SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6,
SO.sub.3R.sup.6, SO.sub.2NR.sup.6, CO.sub.2H, CO.sub.2R.sup.6, and
CONR.sup.6R.sup.7; E is selected from H, halogen, NO.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, haloalkyl,
haloalkoxy, OH, OR.sup.6, CN, CHO, CO.sub.2R.sup.6,
CONR.sup.6R.sup.7, OCOR.sub.6, OC(.dbd.O)OR.sup.6,
OC(.dbd.O)NR.sup.6R.sup.7, OCH.sub.2CO.sub.2R.sup.6,
C(.dbd.O)R.sup.6, NH.sub.2, NHR.sup.6, NR.sup.6R.sup.7,
NR.sup.7C(.dbd.O)R.sup.6, NR.sup.7C(.dbd.O)OR.sup.6,
NR.sup.7C(.dbd.O)C(.dbd.O)OR.sup.6,
NR.sup.7C(.dbd.O)C(.dbd.O)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.O)C(.dbd.O)(C.sub.1-C.sub.6alkyl),
NR.sup.7C(.dbd.NCN)OR.sup.6, NR.sup.7C(.dbd.O)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.NCN)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.NR.sup.6)NR.sup.7R.sup.8,
NR.sup.6SO.sub.2NR.sup.6R.sup.7, NR.sup.7SO.sub.2R.sup.6, SR.sup.6,
S(.dbd.O)R.sup.6, SO.sub.2R.sup.6, SO.sub.3R.sup.7,
SO.sub.2NR.sup.6R.sup.7, NHOH, NHOR.sup.6,
NR.sup.6NR.sup.7NR.sup.8, N(COR.sup.6)OH, N(CO.sub.2R.sup.6)OH,
CONR.sup.7(CR.sup.9R.sup.10).sub.rR.sup.6,
CO(CR.sup.9R.sup.10).sub.pO(CHR.sup.9).sub.qCO.sub.2R.sup.6,
CO(CR.sup.9CR.sup.10).sub.rR.sup.6,
CO(CR.sup.9R.sup.10).sub.pO(CR.sup.9R.sup.10).sub.pO(CHR.sup.9).sub.qCO.s-
up.2R.sub.6, CO(CR.sup.9CR.sup.10).sub.rOR.sup.6,
CO(CR.sup.9R.sup.10).sub.pO(CR.sup.9R.sup.10).sub.qR.sup.6,
CO(CR.sup.6CR.sup.10).sub.rNR.sup.6R.sup.7,
OC(O)O(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
O(CO).sub.n(CR.sup.9R.sup.10)R.sup.6,
O(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7.sub.mNR.sup.7C(O)(CR.sup.9R.sup.-
10).sub.rOR.sup.6,
NR.sup.7C(.dbd.NC)(CR.sup.9R.sup.10).sub.rR.sup.6,
NR.sup.7CO(CR.sup.9R.sup.10).sub.rNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.mOR.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7, NR.sup.7,
NR.sup.3(CR.sup.9R.sup.10).sub.nSO.sub.2(CR.sup.9R.sup.10).sub.rCO.sub.2R-
.sup.6, NR.sup.7(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.nSO.sub.2(CR.sup.9R.sup.10).sub.qR.sup.6,
CONR.sup.7(CR.sup.9R.sup.10).sub.nSO.sub.2(CR.sup.9R.sup.10).sub.qR.sup.6-
, SO.sub.2NR.sup.7(CR.sup.9R.sup.10).sub.qR.sup.6,
SO.sub.2NR.sup.6(CR.sup.9R.sup.10).sub.mOR.sup.6,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylmethyl, aryl, heterocyclic optionally
substituted with one or two alkyl groups, heteroaryl optionally
substituted with one or two alkyl groups and alkylaryl, wherein
said aryl groups are unsubstituted or substituted with 1 or 2
substituents each independently selected from R.sup.12; m is an
integer having a value from 2-6; p is an integer having a value
from 1-3; q is an integer having a value from 0-3; r is an integer
having a value from 0-6; R.sup.12 at each occurrence is
independently selected from halo, NO.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, haloalkyl, haloalkoxy, OH, oxo,
C.sub.1-C.sub.4alkoxy, OR.sup.6,
O(CR.sup.9R.sup.10)CO.sub.2R.sup.6,
O(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
O(CR.sup.9R.sup.10).sub.pCN,
O(CR.sup.9R.sup.10).sub.rC(.dbd.O)NR.sup.6R.sup.7,
C.sub.1-C.sub.4alkylcarbonyl, CN, NH.sub.2, NHR.sup.6,
NR.sup.6R.sup.7, NR.sup.7(CR.sup.9R.sup.10)CO.sub.2R.sup.6,
NR.sup.7OR.sup.6, NR.sup.7(CR.sup.9R.sup.10).sub.mOR.sup.6,
NR.sup.7CH((CR.sup.9R.sup.10).sub.pOR.sup.6).sub.2,
NR.sup.7C((CR.sup.9R.sup.10).sub.pOR.sup.6).sub.3,
NR.sup.7C(.dbd.O)R.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.qR.sup.6, SR.sup.7, S(O)R.sup.7,
S.sub.2R.sup.7, SO.sub.2NR.sup.6, SO.sub.3R.sup.7, CO.sub.2H,
CO.sub.2R.sup.6, and CONR.sup.6R.sup.7; R.sup.4 is hydrogen, lower
alkyl and lower cycloalkyl; R.sup.5 is hydrogen, lower alkyl and
lower cycloalkyl; R.sup.6, R.sup.7 and R.sup.8 are independently
selected as follows: i) R.sup.6, R.sup.7 and R.sup.8 are
independently selected from H, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.7cycloalkyl(C.sub.0-C.sub.5alkyl)carbonyl,
C.sub.1-C.sub.6alkoxycarbonyl, aryl(C.sub.0-C.sub.5alkyl)carbonyl,
aryl(C.sub.1-C.sub.5alkoxy)carbonyl,
heterocyclic(C.sub.0-C.sub.5alkyl)carbonyl,
heterocyclic(C.sub.1-C.sub.5alkoxy)carbonyl,
C.sub.1-C.sub.6alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
C.sub.0-C.sub.4alkylaryl, C.sub.0-C.sub.4alkylheterocyclic, wherein
said cycloalkyl, aryl, or heterocyclic groups are unsubstituted or
substituted with 1 or 2 substituents each independently selected
from the group consisting of C.sub.1-C.sub.4alkyl, hydroxyl,
C.sub.1-C.sub.4alkoxy, F, Cl, Br, haloalkyl, NO.sub.2 and CN; or,
ii) R.sup.6 and R.sup.7, or R.sup.6 and R.sup.8, or R.sup.7 and
R.sup.8 when both substituents are on the same nitrogen atom (as in
(--NR.sup.6R.sup.7) or (--NR.sup.7R.sup.8)), can be taken together
with the nitrogen atom to which they are attached to form a
heterocycle selected from 1-aziridinyl, 1-azetidinyl,
1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl,
thiazolidinyl, 1-piperazinyl, 1-imidazolyl,
3-azabicyclo(3,2,2)nonan-3yl, and 1-tetrazolyl, the said
heterocycle being optionally substituted with 1-3 groups each
independently selected from oxo, C.sub.0-C.sub.4alkylOH,
C.sub.0-C.sub.4alkylOC.sub.1-C.sub.4alkyl,
C.sub.0-C.sub.4alkylCONH.sub.2,
C.sub.0-C.sub.4alkylCO.sub.2C.sub.0-C.sub.4alkyl,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.3-C.sub.7cycloalkyl, C.sub.0-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.7cycloalkylcarbonyl, C.sub.1-C.sub.6alkoxycarbonyl,
C.sub.3-C.sub.7cycloalkoxycarbonyl, --NHCOalkyl, aryl, heteroaryl,
arylalkoxycarbonyl, heteroarylalkoxycarbonyl,
C.sub.1-C.sub.6alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl;
R.sup.9 is hydrogen or C.sub.1-C.sub.4alkyl; and R.sup.13 is
hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxycarbonyl,
alkoxycarbonyl, cycloalkylalkylaminocarbonyl, substituted alkyl,
aryl, substituted aryl, heteroaryl, heterocyclyl, alkylthio,
alkylaminocarbonyl or lower cycloalkyl; where the substituents on
alkyl group are selected from one to four substituents selected
from halo, hydroxy, alkoxy, oxo (.dbd.O), alkanoyl, aryloxy,
alkanoyloxy, amino, alkylamino, arylamino, aralkylamino,
disubstituted amines in which the 2 amino substituents are selected
from alkyl, aryl or aralkyl; alkanoylamino, aroylamino,
aralkanoylamino, substituted alkanoylamino, substituted arylamino,
substituted aralkanoylamino, thiol, alkylthio, arylthio,
aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl,
arylsulfonyl, aralkylsulfonyl, sulfonamido, substituted
sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl,
CONHaryl, CONHaralkyl or cases where there are two substituents on
the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl,
aryl, substituted aryl, guanidino and substituted or unsubstituted
heterocycles, indolyl, imidazolyl, furyl, thienyl, thiazolyl,
pyrrolidyl, pyridyl, pyrimidyl and the substituents on aryl group
are selected from one to four substituents selected from alkyl,
substituted alkyl, haloalkyl, halo, trifluoromethoxy,
trifluoromethyl, hydroxy, hydroxyalkyl, aminoalkyl, alkoxy,
alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino,
dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro,
cyano, cyanoalkyl, heterocyclyl, carboxy, carboxyalkyl, carbamyl,
alkoxycarbonyl, aminocarbonyl, alkylthiono, arylthiono,
arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido,
aryloxy and CONR.sup.aR.sup.b, where R.sup.a and R.sup.b are
selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
alkoxycarbonylaminoalkyl and alkylamino; or R.sup.a and R.sup.b
together with the nitrogen on which they are substituted, form a
3-6 membered heterocyclic or heteroaryl ring; the substituent may
be further substituted by hydroxy, alkyl, alkoxy, aryl, substituted
aryl, substituted alkyl or aralkyl.
111. The compound of claim 110, wherein R.sup.1 is lower alkyl.
112. The compound of claim 110, wherein R.sup.3 is selected from
alkyl, --OR.sup.4, substituted alkyl, cycloalkyl,
--CR.sup.4cycloalkyl, heteroaryl, substituted heteroaryl,
heterocycle and substituted heterocycle.
113. The compound of claim 110, wherein R.sup.3 is cycloalkyl,
cycloalkylalkyl, alkoxyalkyl or heteroaryl.
114. The compound of claim 110, wherein R.sup.3 is methyl,
isopropyl, ethyl, cyclopropyl, cyclopropylmethyl, methoxymethyl,
oxazolyl or thiazolyl.
115. The compound of claim 110, wherein Y is a single bond,
--C(.dbd.O)NH-- or --SO.sub.2NH.
116. The compound of claim 110, wherein B is a thiazolyl, oxazolyl,
dithiazolyl, thiadiazolyl, oxadiazolyl or triazinyl ring optionally
substituted with one or two R.sup.13.
117. The compound of claim 110, wherein Q is a single bond,
--CO(O)--, --C(O)-- or --C(O)NH--(C.sub.0-4alkyl)-.
118. The compound of claim 110, wherein D is a monocyclic or
bicyclic ring system optionally containing up to four heteroatoms
selected from N, O, and S or D is C.sub.1-6alkyl and wherein D is
optionally substituted by one to four (CR.sup.9R.sup.10).sub.wE
groups.
119. The compound of claim 110, wherein D is substituted with one
to four substituents selected from halo, alkyl, nitro, alkoxy,
alkoxycarbonylalkoxy, alkoxyamidoalkylamido, hydroxycarbonyl,
alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, aryl,
heteroaryl containing 1 to 3 heteroatoms and optionally substituted
with one or two alkyl groups, and heterocyclyl containing 1 to 3
heteroatoms and optionally substituted with two or more alkyl or
alkoxycarbonyl groups.
120. The compound of claim 110 that has formula (I-1): ##STR00135##
where B is selected from 1,2,4-triazole, 1,2,4-oxadiazole,
1,3,4-thiadiazole, 1,2,4-thiadiazole, oxazole and thiazole.
121. The compound of claim 110 that has formula (I-2): ##STR00136##
where X.sup.1 is selected from O, S and optionally substituted N,
where the substituent on the N when present is selected from
hydrogen, alkyl, substituted alkyl, alkenyl or alkynyl and X.sup.2
is S or O.
122. The compound of claim 110 that has formula (I-3):
##STR00137##
123. The compound of claim 110 that has formula (I-5): ##STR00138##
where n.sub.1 is 0-5.
124. The compound of claim 110 that has formula (I-6): ##STR00139##
where n.sub.3 is 1-4.
125. The compound of claim 110 that has formula (I-7): ##STR00140##
where n.sub.2 is 0-4.
126. A compound of claim 110 selected from:
N-methoxy-4-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-benzamide;
N-methoxy-4-methyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylamino)-benzamide;
N-Cyclopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide;
3-[4-(4-Cyano-phenyl)-thiazol-2-ylamino]-N-cyclopropyl-4-methyl-benzamide-
;
N-Cyclopropyl-3-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-4-methyl-benzami-
de;
N-Cyclopropyl-3-[4-(4-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-benz-
amide;
N-Cyclopropyl-3-[4-(3-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-b-
enzamide;
N-Cyclopropyl-3-[4-(2-methoxy-phenyl)-thiazol-2-ylamino]-4-methy-
l-benzamide;
N-Cyclopropyl-4-methyl-3-(5-methyl-4-phenyl-thiazol-2-ylamino)-benzamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic
acid phenylamide;
N-Isopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide;
N-Ethyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide;
N-(2-Methoxy-ethyl)-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide;
[4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-phenyl]-morpholin-4-yl-methanone-
; 4-M
ethyl-3-(4-phenyl-thiazol-2-ylamino)-1-thiazol-2-yl-benzamide;
4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-N-[1,2,4]triazol-4-yl-benzamide;
4-Methyl-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-3-(4-phenyl-thiazol-2-ylamin-
o)-benzamide;
N-Cyclopropyl-4-methyl-3-(5-phenyl-oxazol-2-ylamino)-benzamide;
N-Cyclopropyl-4-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-benzamide-
;
N-Cyclopropyl-4-methyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylamino)-benzamide-
;
N-Cyclopropyl-4-methyl-3-(5-phenyl-[1,3,4]thiadiazol-2-ylamino)-benzamid-
e;
N-Cyclopropyl-4-methyl-3-(3-phenyl-[1,2,4]thiadiazol-5-ylamino)-benzami-
de;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-methyl-thiazole-5-ca-
rboxylic acid benzyl ester;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-methyl-thiazole-5-carbo-
xylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic
acid ethyl ester;
5-Bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carbox-
ylic acid ethyl ester;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-nitro-phenyl)-thiazo-
le-5-carboxylic acid ethyl ester;
N-Cyclopropyl-4-methyl-3-[4-(4-nitro-phenyl)-thiazol-2-ylamino]-benzamide-
;
3-[5-Bromo-4-(4-nitro-phenyl)-thiazol-2-ylamino]-N-cyclopropyl-4-methyl--
benzamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-morpholin--
4-yl-phenyl)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic
acid methyl ester;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic
acid;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-phenyl-thiazole-5-
-carboxylic acid cyclopropylmethyl-amide;
4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-methoxycarbonyl-t-
hiazol-4-yl]-phenyl}-piperidine-1-carboxylic acid methyl ester;
4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-(cyclopropylmethy-
l-carbamoyl)-thiazol-4-yl]-phenyl}piperidine-1-carboxylic acid
methyl ester;
4-{3-[2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-5-[1,3,4]oxa-
diazol-2-yl-thiazol-4-yl]-phenyl}-piperidinium trifluoroacetate;
N-Cyclopropyl-4-methyl-3-[4-(4-nitro-phenyl)-5-[1,3,4]oxadiazol-2-yl-thia-
zol-2-ylamino]-benzamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic
acid benzylamide;
4-Bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carbox-
ylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-fluoro-3-methyl-phen-
yl)-thiazole-5-carboxylic acid benzylamide;
4-(4-Cyanomethyl-phenyl)-2-(5-cyclo-propylcarbamoyl-2-methyl
phenylamino)-thiazole-5-carboxylic acid benzylamide;
4-(4-Cyano-phenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-4,5-d-
ihydro-thiazole-5-carboxylic acid benzylamide;
4-(2-Chloro-phenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-thia-
zole-5-carboxylic acid benzylamide;
2-(5-Cyclopropyl-carbamoyl-2-methyl-phenylamino)-4-(3-hydroxymethylphenyl-
)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-m-tolyl-thiazole-5-carb-
oxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-fluorophenyl)thiazol-
e-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-p-tolyl-thiazole-5-carb-
oxylic acid benzylamide;
4-(3-Cyanophenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazol-
e-5-carboxylic acid benzylamide;
4-(5-Acetyl-thiophen-2-yl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino-
)-thiazole-5-carboxylic acid benzylamide;
4-Benzo[1,3]dioxol-5-yl-2-(5-cyclopropylcarbamoyl-2-methylphenylamino)-th-
iazole-5-carboxylic acid benzylamide;
4-(5-Cyano-thiophen-2-yl)-2-(5-cycloprop-ylcarbamoyl-2-methylphenylamino)-
-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-methoxy-phenyl)-thia-
zole-5-carboxylic acid benzylamide;
4-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thia-
zol-4-yl]benzoic acid ethyl ester;
3-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thia-
zol-4-yl]-benzoic acid methyl ester;
2-(5-Cyclopropyl-carbamoyl-2-methyl-phenylamino)-4-(4-fluoro-phenyl)-thia-
zole-5-carboxylic acid benzylamide;
2-(5-Cyclopropyl-carbamoyl-2-methyl-phenylamino)-4-(2-methoxy-phenyl)-thi-
azole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-methoxy-phenyl)-thia-
zole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2-trifluoromethyl-phen-
yl)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-hydroxymethyl-phenyl-
)-thiazole-5-carboxylic acid benzylamide;
4-(3-Carbamoylphenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-th-
iazole-5-carboxylic acid benzylamide;
4-(4-Carbamoyl-phenyl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino)-th-
iazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2,3-dihydrobenzo[1,4]d-
ioxin-6-yl)-thiazole-5-carboxylic acid benzylamide;
4-(3-Aminomethyl-phenyl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino)--
thiazole-5-carboxylic acid benzylamide;
3-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-thi-
azol-4-yl]-benzoic acid;
4-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thia-
zol-4-yl]-benzoic acid;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-o-tolyl-thiazole-5-carb-
oxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2,4-difluoro-phenyl)-t-
hiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-methanesulfonyl-phen-
yl)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-[4-(morpholine-4-carbon-
yl)-phenyl]-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethoxy-3-fluoro-phen-
yl)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-cyclopropylcarbamoyl-
-phenyl)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-ethoxy-phenyl)-thiaz-
ole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethylsulfanyl-phenyl-
)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-fluoro-4-methoxy-phe-
nyl)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-fluoro-3-methyl-phen-
yl)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3,4-difluoro-phenyl)-t-
hiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2-fluoro-phenyl)-thiaz-
ole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethoxy-phenyl)-thiaz-
ole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(1H-indol-5-yl)-thiazol-
e-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-methoxy-3-methyl-phe-
nyl)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethylcarbamoyl-pheny-
l)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-hydroxy-phenyl)-thia-
zole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-propoxy-phenyl)-thia-
zole-5-carboxylic acid benzylamide;
4-[3-(3-Amino-propoxy)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenyla-
mino)-thiazole-5-carboxylic acid benzylamide;
4-[3-(2-Amino-ethoxy)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methylphenyl-am-
ino)-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-[3-(2-morpholin-4-yl-et-
hoxy)-phenyl]-thiazole-5-carboxylic acid benzylamide;
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-methanesulfonylamino-
-phenyl)-thiazole-5-carboxylic acid benzylamide;
4-(4-Amino-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazo-
le-5-carboxylic acid benzylamide;
4-(3-Amino-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazo-
le-5-carboxylic acid benzylamide;
({3-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-th-
iazol-4-yl]-phenylcarbamoyl}methyl)-carbamic acid tert-butyl ester;
(2-{3-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)--
thiazol-4-yl]-phenylcarbamoyl}-ethyl)-carbamic acid tert-butyl
ester;
({4-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-th-
iazol-4-yl]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl
ester;
(2-{4-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)--
thiazol-4-yl]-phenylcarbamoyl}-ethyl)-carbamic acid tert-butyl
ester;
4-[3-(2-Amino-acetylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phe-
nylamino)-thiazole-5-carboxylic acid benzylamide
ditrifluoroacetate;
4-[3-(3-Amino-propionylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl--
phenylamino)-thiazole-5-carboxylic acid benzylamide
ditrifluoroacetate;
4-[4-(2-Amino-acetylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phe-
nylamino)-thiazole-5-carboxylic acid benzylamide
ditrifluoroacetate;
2-{4-[5-benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-t-
hiazol-4-yl]-phenylcarbamoyl}-ethyl-ammonium ditrifluoroacetate;
4-(4-Cyanomethyl-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)--
thiazole-5-carboxylic acid benzylamide; and
4-[4-(2-Amino-ethyl)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylami-
no)-thiazole-5-carboxylic acid benzylamide.
127. A pharmaceutical composition, comprising a compound of claim
110 and a pharmaceutically acceptable carrier.
128. A method of inhibiting p38 kinase activity, comprising
administering a compound of claim 110.
129. The method of claim 128, wherein the disease or disorder is
selected from inflammatory disease, autoimmune disease, destructive
bone disorder, proliferative disorder, angiogenic disorder,
infectious disease, neurodegenerative disease and viral disease.
Description
FIELD
[0001] Provided herein are aminoaryl substituted 5-membered
heterocyclic compounds which have cytokine inhibitory activity.
Also provided are the uses of aminoaryl substituted 5-membered
heterocyclic compounds for treating conditions associated with
p38.alpha. and .beta. kinases and for treating p38
kinase-associated conditions.
BACKGROUND
[0002] A large number of cytokines participate in the inflammatory
response, including IL-1, IL6, IL-8 and TNF-.alpha.. Overproduction
of cytokines such as IL-1 and TNF-.alpha. are implicated in a wide
variety of diseases, including inflammatory bowel disease,
rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin
shock, osteoporosis, Alzheimer's disease, and congestive heart
failure, among others (Henry et al., Drugs Fut., 24:1345-1354
(1999); Salituro et al., Curr. Med. Chem., 6:807-823 (1999)).
Evidence in human patients indicates that protein antagonists of
cytokines are effective in treating chronic inflammatory diseases,
such as, for example, monoclonal antibody to TNF-.alpha. (Remicade)
(Rankin et al., Br. J. Rheumatol., 34:334-342 (1995)), and soluble
TNF-.alpha. receptor-Fc fusion protein (Etanercept) (Moreland et
al., 25 Ann. Intern. Med., 130:478-486 (1999)).
[0003] The biosynthesis of TNF-.alpha. occurs in many cell types in
response to an external stimulus, such as, for example, a mitogen,
an infectious organism, or trauma. Important mediators of
TNF-.alpha. production are the mitogen-activated protein (MAP)
kinases, and in particular, p38 kinases. These kinases are
activated in response to various stress stimuli, including but not
limited to proinflammatory cytokines, endotoxin, ultraviolet light,
and osmotic shock. Activation of p38 requires dual phosphorylation
by upstream MAP kinase kinases (MKK3 and MKK6) on threonine and
tyrosine within a Thr-Gly-Tyr motif characteristic of p38
isozymes.
[0004] There are four known isoforms of p38, i.e., p38.alpha.,
p38.beta., p38.gamma., and p38.delta.. The .alpha. and .beta.
isoforms are expressed in inflammatory cells and are key modulators
of TNF-.alpha. production. Inhibiting the p38.alpha. and .beta.
enzymes in cells results in reduced levels of TNF-.alpha.
expression. Also, administering inhibitors of p38.alpha. and .beta.
in animal models of inflammatory disease has proven that such
inhibitors are effective in treating those diseases. Accordingly,
the p38 enzymes serve an important role in inflammatory processes
mediated by IL-1 and TNF-.alpha.. Compounds that reportedly inhibit
p38 kinase and cytokines such as IL-1 and TNF-.alpha. for use in
treating inflammatory diseases are disclosed in U.S. Pat. Nos.
6,277,989 and 6,130,235 to Scios, Inc; U.S. Pat. Nos. 6,147,080 and
5,945,418 to Vertex Pharmaceuticals Inc; U.S. Pat. Nos. 6,251,914,
5,977,103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Pat.
Nos. 5,932,576 and 6,087,496 to G.D. Searle & Co.; WO 00/56738
and WO 01/27089 to Astra Zeneca; WO 01/34605 to Johnson &
Johnson; WO 00/12497 (quinazoline derivatives as p38 kinase
inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for
the same purpose); WO 00/12497 (discusses the relationship between
p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine
compounds useful as p38 inhibitors).
[0005] Pyrrolotriazine compounds useful as tyrosine kinase
inhibitors are disclosed in U.S. patent application Ser. No.
09/573,829 filed May 18, 2000, assigned to Bristol-Myers Squibb. In
addition, pyrrolotriazine kinase inhibitors are disclosed in WO
02/40486, assigned to Bristol-Myers Squibb. Recent applications: WO
03/032970, WO 03/033482, WO03/032971, WO03/032986, WO 03/032980, WO
03/032987, WO 03/033483, WO 03/033457 and WO 03/032972 are
incorporated into this application. A series of aminoaryl
substituted 5- and 6-membered ring heterocycles useful as
inhibitors of IMPH are disclosed in WO 00/25780. Each of the patent
applications, patents, and publications referred to herein is
incorporated herein by reference.
SUMMARY
[0006] Compounds for use in compositions and methods for modulating
the activity of cytokines are provided. In one embodiment, the
compounds are used in compositions and methods for modulating p38
kinase, including, but not limited to p38.alpha. and p38.beta.
kinase activity. In certain embodiments, the compounds are
heterocyclic compounds that are substituted with a cycloalkylamide
moiety. In certain embodiments, the compounds provided herein are
substituted aminothiazoles.
[0007] Provided herein are compounds of formula I:
##STR00001##
or pharmaceutically acceptable derivatives thereof, wherein:
[0008] R.sup.1 is hydrogen, methyl, halo, hydroxyl, lower alkyl,
lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy,
trifluoromethoxy, cyano, --NH.sub.2, --NR.sup.4R.sup.5 or
--OR.sup.4;
[0009] R.sup.2 is attached to any available carbon atom of the
phenyl ring A and at each occurrence is independently selected from
alkyl, substituted alkyl, lower cycloalkyl, halo, trifluoromethyl,
trifluoromethoxy, --OR.sup.4, --CN, --NR.sup.4R.sup.5;
--S(.dbd.O)alkyl, --S(.dbd.O)aryl, --NHSO.sub.2-arylene-R.sup.4,
--NHSO.sub.2alkyl, --CO.sub.2R.sup.4, --CONH.sub.2, --SO.sub.3H,
--S(O)alkyl, --S(O)aryl, --SO.sub.2NHR.sup.4, and
--NHC(.dbd.O)NHR.sup.4;
[0010] n is 0, 1 or 2;
[0011] R.sup.3 is selected from hydrogen, alkyl, --OR.sup.4,
substituted alkyl, cycloalkyl, --CR.sup.4cycloalkyl, heteroaryl,
substituted heteroaryl, heterocycle and substituted
heterocycle;
[0012] Y is a single bond, --C(.dbd.O)NH--, --NH(C.dbd.O)--,
--NH(C.dbd.O)NH--, --SO.sub.2NH--, --NHSO.sub.2--,
--C(.dbd.O)--;
[0013] Z is NR.sup.4, S or O;
[0014] B is a 5-membered heterocyclic ring system optionally
substituted with up to two R.sup.13;
[0015] Q is independently selected from a single bond, --O--,
--S--, --NR.sup.4--, --S(O)--, --SO.sub.2--, --C(O)--, --CO(O)--,
--C(O)NH--(C.sub.0-4alkyl)- or --CH.sub.2--;
[0016] D is a monocyclic or bicyclic ring system optionally
containing up to four heteroatoms selected from N, O, and S, and
wherein a CH.sub.2 adjacent to any of the said N, O or S
heteroatoms is optionally substituted with oxo (.dbd.O) or D is
C.sub.1-6alkyl, and wherein D is optionally substituted by one to
four (CR.sup.9R.sup.10).sub.wE groups;
[0017] w is an integer having a value from 0-4;
[0018] R.sup.10 is selected from H, C.sub.1-C.sub.4 alkylhydroxy,
C.sub.1-C.sub.4alkylaryl and C.sub.1-C.sub.4alkylheteroaryl,
wherein said aryl or heteroaryl group is unsubstituted or
substituted with 1-3 groups independently selected from halo,
NO.sub.2, C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, haloalkyl,
haloalkoxy, OH, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4alkylcarbonyl, CN, NH.sub.2, NR.sup.6R.sup.7,
SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6, SO.sub.3R.sup.6,
SO.sub.2NR.sup.6, CO.sub.2H, CO.sub.2R.sup.6, and
CONR.sup.6R.sup.7;
[0019] E is selected from H, halogen, NO.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 alkynyl, haloalkyl,
haloalkoxy, OH, OR.sup.6, CN, CHO, CO.sub.2R.sup.6,
CONR.sup.6R.sup.7, OCOR.sup.6, OC(.dbd.O)OR.sup.6,
OC(.dbd.O)NR.sup.6R.sup.7, OCH.sub.2CO.sub.2R.sup.6,
C(.dbd.O)R.sup.6, NH.sub.2, NHR.sup.6, NR.sup.6R.sup.7,
NR.sup.7C(.dbd.O)R.sup.6, NR.sup.7C(.dbd.O)OR.sup.6,
NR.sup.7C(.dbd.O)C(.dbd.O)OR.sup.6,
NR.sup.7C(.dbd.O)C(.dbd.O)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.O)C(.dbd.O)(C.sub.1-C.sub.6alkyl),
NR.sup.7C(.dbd.NCN)OR.sup.6, NR.sup.7C(.dbd.O)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.NCN)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.NR.sup.6)NR.sup.7R.sup.8,
NR.sup.6SO.sub.2NR.sup.6R.sup.7, NR.sup.7SO.sub.2R.sup.6, SR.sup.6,
S(.dbd.O)R.sup.6, SO.sub.2R.sup.6, SO.sub.3R.sup.7,
SO.sub.2NR.sup.6R.sup.7, NHOH, NHOR.sup.6,
NR.sup.6NR.sup.7NR.sup.8, N(COR.sup.6)OH, N(CO.sub.2R)OH,
CONR.sup.7(CR.sup.9R.sup.10).sub.rR.sup.6,
CO(CR.sup.9R.sup.10).sub.pO(CHR.sup.9).sub.qCO.sub.2R.sup.6,
CO(CR.sup.9CR.sup.10).sub.rR.sup.6,
CO(CR.sup.9R.sup.10).sub.pO(CR.sup.9R.sup.10).sub.pO(CHR.sup.9).sub.qCO.s-
up.2R.sub.6, CO(CR.sup.9CR.sup.10).sub.rOR.sup.6,
CO(CR.sup.9R.sup.10).sub.pO(CR.sup.9R.sup.10).sub.qR.sup.6,
CO(CR.sup.6CR.sup.10).sub.rNR.sup.6R.sup.7,
OC(O)O(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
O(CO).sub.n(CR.sup.9R.sup.10)R.sup.6,
O(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7.sub.mNR.sup.7C(O)(CR.sup.9R.sup.-
10).sub.rOR.sup.6,
NR.sup.7C(.dbd.NC)(CR.sup.9R.sup.10).sub.rR.sup.6,
NR.sup.7CO(CR.sup.9R.sup.10).sub.rNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.mOR.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7, NR.sup.7,
NR.sup.3(CR.sup.9R.sup.10).sub.nSO.sub.2(CR.sup.9R.sup.10).sub.rCO.sub.2R-
.sup.6, NR.sup.7(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.nSO.sub.2(CR.sup.9R.sup.10).sub.qR.sup.6,
CONR.sup.7(CR.sup.9R.sup.10).sub.nSO.sub.2(CR.sup.9R.sup.10).sub.qR.sup.6-
, SO.sub.2NR.sup.7(CR.sup.9R.sup.10).sub.qR.sup.6,
SO.sub.2NR.sup.6(CR.sup.9R.sup.10).sub.mOR.sup.6,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylmethyl, aryl, heterocyclic optionally
substituted with one or two alkyl groups, heteroaryl optionally
substituted with one or two alkyl groups and alkylaryl, wherein
said aryl groups are unsubstituted or substituted with 1 or 2
substituents each independently selected from R.sup.12;
[0020] m is an integer having a value from 2-6;
[0021] p is an integer having a value from 1-3;
[0022] q is an integer having a value from 0-3;
[0023] r is an integer having a value from 0-6;
[0024] R.sup.12 at each occurrence is independently selected from
halo, NO.sub.2, C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, haloalkyl,
haloalkoxy, OH, oxo, C.sub.1-C.sub.4alkoxy, OR.sup.6,
O(CR.sup.9R.sup.10)CO.sub.2R.sup.6,
O(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
O(CR.sup.9R.sup.10).sub.pCN,
O(CR.sup.9R.sup.10).sub.rC(.dbd.O)NR.sup.6R.sup.7,
C.sub.1-C.sub.4alkylcarbonyl, CN, NH.sub.2, NHR.sup.6,
NR.sup.6R.sup.7, NR.sup.7(CR.sup.9R.sup.10)CO.sub.2R.sup.6,
NR.sup.7OR.sup.6, NR.sup.7(CR.sup.9R.sup.10).sub.mOR.sup.6,
NR.sup.7CH((CR.sup.9R.sup.10).sub.pOR.sup.6).sub.2,
NR.sup.7C((CR.sup.9R.sup.10).sub.pOR.sup.6).sub.3,
NR.sup.7C(.dbd.O)R.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.qR.sup.6, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, SO.sub.2NR.sup.6, SO.sub.3R.sup.7, CO.sub.2H,
CO.sub.2R.sup.6, and CONR.sup.6R.sup.7;
[0025] R.sup.4 is hydrogen, lower alkyl and lower cycloalkyl;
[0026] R.sup.5 is hydrogen, lower alkyl and lower cycloalkyl;
[0027] R.sup.6, R.sup.7 and R.sup.8 are independently selected as
follows: [0028] i) R.sup.6, R.sup.7 and R.sup.8 are independently
selected from H, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.7cycloalkyl(C.sub.0-C.sub.5alkyl)carbonyl,
C.sub.1-C.sub.6alkoxycarbonyl, aryl(C.sub.0-C.sub.5alkyl)carbonyl,
aryl(C.sub.1-C.sub.5alkoxy)carbonyl,
heterocyclic(C.sub.0-C.sub.5alkyl)carbonyl,
heterocyclic(C.sub.1-C.sub.5alkoxy)carbonyl,
C.sub.1-C.sub.6alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
C.sub.0-C.sub.4alkylaryl, C.sub.0-C.sub.4alkylheterocyclic, wherein
said cycloalkyl, aryl, or heterocyclic groups are unsubstituted or
substituted with 1 or 2 substituents each independently selected
from the group consisting of C.sub.1-C.sub.4alkyl, hydroxyl,
C.sub.1-C.sub.4alkoxy, F, Cl, Br, haloalkyl, NO.sub.2 and CN; or,
[0029] ii) R.sup.6 and R.sup.7, or R.sup.6 and R.sup.8, or R.sup.7
and R.sup.8 when both substituents are on the same nitrogen atom
(as in (--NR.sup.6R.sup.7) or (--NR.sup.7R.sup.8)), can be taken
together with the nitrogen atom to which they are attached to form
a heterocycle selected from 1-aziridinyl, 1-azetidinyl,
1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl,
thiazolidinyl, 1-piperazinyl, 1-imidazolyl,
3-azabicyclo(3,2,2)nonan-3yl, and 1-tetrazolyl, the said
heterocycle being optionally substituted with 1-3 groups each
independently selected from oxo, C.sub.0-C.sub.4alkylOH,
C.sub.0-C.sub.4alkylOC.sub.1-C.sub.4alkyl,
C.sub.0-C.sub.4alkylCONH.sub.2,
C.sub.0-C.sub.4alkylCO.sub.2C.sub.0-C.sub.4alkyl,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.3-C.sub.7cycloalkyl, C.sub.0-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.7cycloalkylcarbonyl, C.sub.1-C.sub.6alkoxycarbonyl,
C.sub.3-C.sub.7cycloalkoxycarbonyl, --NHCOalkyl, aryl, heteroaryl,
arylalkoxycarbonyl, heteroarylalkoxycarbonyl,
C.sub.1-C.sub.6alkylsulfonyl, arylsulfonyl and
heteroarylsulfonyl;
[0030] R.sup.9 is hydrogen or C.sub.1-C.sub.4alkyl; and
[0031] R.sup.13 is hydrogen, alkyl, haloalkyl, aminocarbonyl,
hydroxycarbonyl, alkoxycarbonyl, cycloalkylalkylaminocarbonyl,
substituted alkyl, aryl, substituted aryl, heteroaryl,
heterocyclyl, alkylthio, alkylaminocarbonyl or lower cycloalkyl;
where the substituents on alkyl group are selected from one to four
substituents selected from halo, hydroxy, alkoxy, oxo (.dbd.O),
alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino,
aralkylamino, disubstituted amines in which the 2 amino
substituents are selected from alkyl, aryl or aralkyl;
alkanoylamino, aroylamino, aralkanoylamino, substituted
alkanoylamino, substituted arylamino, substituted aralkanoylamino,
thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono,
aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,
sulfonamido, e.g. SO.sub.2NH.sub.2, substituted sulfonamido, nitro,
cyano, carboxy, carbamyl, e.g. CONH.sub.2, substituted carbamyl
e.g. CONHalkyl, CONHaryl, CONHaralkyl or cases where there are two
substituents on the nitrogen selected from alkyl, aryl or aralkyl;
alkoxycarbonyl, aryl, substituted aryl, guanidino and substituted
or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl,
thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like and
the substituents on aryl group are selected from one to four
substituents selected from alkyl, substituted alkyl, haloalkyl,
halo, trifluoromethoxy, trifluoromethyl, hydroxy, hydroxyalkyl,
aminoalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino,
aralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio,
ureido, nitro, cyano, cyanoalkyl, heterocyclyl, carboxy,
carboxyalkyl, carbamyl, alkoxycarbonyl, aminocarbonyl, alkylthiono,
arylthiono, arylsulfonylamine, sulfonic acid, alkysulfonyl,
sulfonamido, aryloxy and CONR.sup.aR.sup.b, where R.sup.a and
R.sup.b are selected from hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, alkoxycarbonylaminoalkyl and alkylamino; or R.sup.a and
R.sup.b together with the nitrogen on which they are substituted,
form a 3-6 membered heterocyclic or heteroaryl ring. The
substituent may be further substituted by hydroxy, alkyl, alkoxy,
aryl, substituted aryl, substituted alkyl or aralkyl.
[0032] The groups A, Y, R.sup.1, R.sup.2, R.sup.3, B, Q and D are
selected such that the resulting compound has effect on cytokine
activity.
[0033] Also of interest are any pharmaceutically-acceptable
derivatives, including salts, esters, enol ethers, enol esters,
solvates, hydrates and prodrugs of the compounds described herein.
Pharmaceutically-acceptable salts, include, but are not limited to,
amine salts, such as but not limited to
N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia,
diethanolamine and other hydroxyalkylamines, ethylenediamine,
N-methylglucamine, procaine, N-benzylphenethylamine,
1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole,
diethylamine and other alkylamines, piperazine and
tris(hydroxymethyl)aminomethane; alkali metal salts, such as but
not limited to lithium, potassium and sodium; alkali earth metal
salts, such as but not limited to barium, calcium and magnesium;
transition metal salts, such as but not limited to zinc, aluminum,
and other metal salts, such as but not limited to sodium hydrogen
phosphate and disodium phosphate; and also including, but not
limited to, salts of mineral acids, such as but not limited to
hydrochlorides and sulfates; and salts of organic acids, such as
but not limited to acetates, lactates, malates, tartrates,
citrates, ascorbates, succinates, butyrates, valerates and
fumarates.
[0034] Pharmaceutical compositions formulated for administration by
an appropriate route and means containing effective concentrations
of one or more of the compounds provided herein, or
pharmaceutically acceptable derivatives thereof, that deliver
amounts effective for the treatment, prevention, or amelioration of
one or more symptoms of diseases or disorders that are modulated or
otherwise affected by cytokine activity, in one embodiment, p38
kinase activity, or in which cytokine activity, in one embodiment,
p38 kinase activity is implicated, are also provided. The effective
amounts and concentrations are effective for ameliorating any of
the symptoms of any of the diseases or disorders.
[0035] Methods for treatment, prevention, or amelioration of one or
more symptoms of diseases or disorders mediated by or in which
cytokine activity, in one embodiment, p38 kinase activity, is
implicated, are provided. Such methods include methods of
treatment, prevention and amelioration of one or more symptoms of
inflammatory diseases, autoimmune diseases, destructive bone
disorders, proliferative disorders, angiogenic disorders,
infectious diseases, neurodegenerative diseases, and viral
diseases, using one or more of the compounds provided herein, or
pharmaceutically acceptable derivatives thereof.
[0036] Methods of modulating the activity of cytokines, in one
embodiment, the activity of p38 kinases, using the compounds and
compositions provided herein are also provided.
[0037] Methods of reducing the expression of inducible
pro-inflammatory proteins, including, but not limited to
prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to as
cyclooxygenase-2 (COX-2), in a subject in need thereof by
administration of one or more compounds or compositions provided
herein are also provided.
[0038] In practicing the methods, effective amounts of the
compounds or compositions containing therapeutically effective
concentrations of the compounds, which are formulated for systemic
delivery, including parenteral, oral, or intravenous delivery, or
for local or topical application, for the treatment of cytokine, in
one embodiment, p38 kinase, mediated diseases or disorders, or
diseases or disorders in which cytokine activity, in one
embodiment, p38 kinase activity, is implicated, including, but not
limited to, inflammatory diseases, autoimmune diseases, destructive
bone disorders, proliferative disorders, angiogenic disorders,
infectious diseases, neurodegenerative diseases, and viral
diseases, are administered to an individual exhibiting the symptoms
of these diseases or disorders. The amounts are effective to
ameliorate or eliminate one or more symptoms of the diseases or
disorders.
[0039] Articles of manufacture containing packaging material, a
compound or composition, or pharmaceutically acceptable derivative
thereof, provided herein, which is effective for modulating the
activity cytokines, in one embodiment, p38 kinases, or for
treatment, prevention or amelioration of one or more symptoms of
cytokine, in one embodiment, p38 kinase, mediated diseases or
disorders, or diseases or disorders in which cytokine activity, in
one embodiment, p38 kinase activity, is implicated, within the
packaging material, and a label that indicates that the compound or
composition, or pharmaceutically acceptable derivative thereof, is
used for modulating the activity of cytokine, in one embodiment,
the activity of p38 kinases, or for treatment, prevention or
amelioration of one or more symptoms of cytokine, in one
embodiment, p38 kinase, mediated diseases or disorders, or diseases
or disorders in which cytokine activity, in one embodiment, p38
kinase activity, is implicated, are provided.
DETAILED DESCRIPTION OF EMBODIMENTS
A. Definitions
[0040] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art. All patents, applications, published
applications and other publications are incorporated by reference
in their entirety. In the event that there are a plurality of
definitions for a term herein, those in this section prevail unless
stated otherwise.
[0041] As used herein, p38.alpha. refers to the enzyme disclosed in
Han J, Richter B, Li Z, Kravchenko V, Ulevitch R J. Molecular
cloning of human p38 MAP kinase. Biochim Biophys Acta. 1995;
1265(2-3):224-7. As used herein, p38.beta. refers to the enzyme
disclosed in Jiang Y, Chen C, Li Z, Guo W, Gegner J A, Lin S, Han
J. Characterization of the structure and function of a new
mitogen-activated protein kinase (p38beta). J Biol Chem. 1996 Jul.
26; 271(30):17920-6. As used herein, p38.gamma. refers to the
enzyme disclosed in Li, Z.; Jiang, Y.; Ulevitch, R. J.; Han, J.:
The primary structure of p38-gamma: a new member of p38 group of
MAP kinases. Biochem. Biophys. Res. Commun. 228: 334-340, 1996. As
used herein, p38.delta. refers to the enzyme disclosed in Molecular
Cloning and Characterization of a Novel p38 Mitogen-activated
Protein Kinase, Xuhong Sunny Wang, Katrina Diener, Carl L. Manthey,
Shen-wu Wang, Bradley Rosenzweig, Jeffrey Bray, John Delaney, Craig
N. Cole, Po-Ying Chan-Hui, Nathan Mantlo, Henri S. Lichenstein,
Mark Zukowski and Zhengbin Yao.
[0042] The term "p38-associated condition", as used herein means
any disease or condition in which p38 is known to play a role. This
includes, conditions which are known to be caused by IL-1, TNF,
IL-6 or IL-8 overproduction. Such conditions include, but are not
limited to, inflammatory diseases, autoimmune diseases, destructive
bone disorders, proliferative disorders, infectious diseases, viral
disease, and neurodegenerative diseases.
[0043] As used herein, pharmaceutically acceptable derivatives of a
compound include salts, esters, enol ethers, enol esters, acetals,
ketals, orthoesters, hemiacetals, hemiketals, acids, bases,
solvates, hydrates or prodrugs thereof. Such derivatives may be
readily prepared by those of skill in this art using known methods
for such derivatization. The compounds produced may be administered
to animals or humans without substantial toxic effects and either
are pharmaceutically active or are prodrugs. Pharmaceutically
acceptable salts include, but are not limited to, amine salts, such
as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine,
choline, ammonia, diethanolamine and other hydroxyalkylamines,
ethylenediamine, N-methylglucamine, procaine,
N-benzylphenethylamine,
1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole,
diethylamine and other alkylamines, piperazine and
tris(hydroxymethyl)aminomethane; alkali metal salts, such as but
not limited to lithium, potassium and sodium; alkali earth metal
salts, such as but not limited to barium, calcium and magnesium;
transition metal salts, such as but not limited to zinc; and other
metal salts, such as but not limited to sodium hydrogen phosphate
and disodium phosphate; and also including, but not limited to,
salts of mineral acids, such as but not limited to hydrochlorides
and sulfates; and salts of organic acids, such as but not limited
to acetates, lactates, malates, tartrates, citrates, ascorbates,
succinates, butyrates, valerates and fumarates. Pharmaceutically
acceptable esters include, but are not limited to, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and
heterocyclyl esters of acidic groups, including, but not limited
to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic
acids, sulfinic acids and boronic acids. Pharmaceutically
acceptable enol ethers include, but are not limited to, derivatives
of formula C.dbd.C(OR) where R is hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl ar
heterocyclyl. Pharmaceutically acceptable enol esters include, but
are not limited to, derivatives of formula C.dbd.C(OC(O)R) where R
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,
heteroaralkyl, cycloalkyl ar heterocyclyl. Pharmaceutically
acceptable solvates and hydrates are complexes of a compound with
one or more solvent or water molecules, or 1 to about 100, or 1 to
about 10, or one to about 2, 3 or 4, solvent or water
molecules.
[0044] As used herein, the terms "treating" or "treatment"
encompass either or both responsive and prophylaxis measures, e.g.,
designed to inhibit or delay the onset of the disease or disorder,
achieve a full or partial reduction of the symptoms or disease
state, and/or to alleviate, ameliorate, lessen, or cure the disease
or disorder and/or its symptoms. Treatment also encompasses any
pharmaceutical use of the compositions herein, such as use for
treating a P-38 kinase mediated diseases or disorders.
[0045] As used herein, amelioration of the symptoms of a particular
disorder by administration of a particular compound or
pharmaceutical composition refers to any lessening, whether
permanent or temporary, lasting or transient that can be attributed
to or associated with administration of the composition.
[0046] As used herein inhibition of p-38.alpha./.beta.kinase means
either p38.alpha. and/or p38.beta. kinase are inhibited. Thus,
reference to an IC.sub.50 value for inhibiting p-38.alpha./.beta.
kinase means that the compound has such effectiveness for
inhibiting at least one of, or both of, p38.alpha. and p38.beta.
kinases.
[0047] As used herein, the IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response, such as modulation of p-38
kinase activity, in an assay that measures such response.
[0048] As used herein, EC.sub.50 refers to a dosage, concentration
or amount of a particular test compound that elicits a
dose-dependent response at 50% of maximal expression of a
particular response that is induced, provoked or potentiated by the
particular test compound.
[0049] As used herein, a prodrug is a compound that, upon in vivo
administration, is metabolized by one or more steps or processes or
otherwise converted to the biologically, pharmaceutically or
therapeutically active form of the compound. To produce a prodrug,
the pharmaceutically active compound is modified such that the
active compound will be regenerated by metabolic processes. The
prodrug may be designed to alter the metabolic stability or the
transport characteristics of a drug, to mask side effects or
toxicity, to improve the flavor of a drug or to alter other
characteristics or properties of a drug. By virtue of knowledge of
pharmacodynamic processes and drug metabolism in vivo, those of
skill in this art, once a pharmaceutically active compound is
known, can design prodrugs of the compound (see, e.g., Nogrady
(1985) Medicinal Chemistry A Biochemical Approach, Oxford
University Press, New York, pages 388-392).
[0050] It is to be understood that the compounds provided herein
may contain chiral centers. Such chiral centers may be of either
the (R) or (S) configuration, or may be a mixture thereof. Thus,
the compounds provided herein may be enantiomerically pure, or be
stereoisomeric or diastereomeric mixtures.
[0051] As used herein, substantially pure means sufficiently
homogeneous to appear free of readily detectable impurities as
determined by standard methods of analysis, such as thin layer
chromatography (TLC), gel electrophoresis, high performance liquid
chromatography (HPLC) and mass spectrometry (MS), used by those of
skill in the art to assess such purity, or sufficiently pure such
that further purification would not detectably alter the physical
and chemical properties, such as enzymatic and biological
activities, of the substance. Methods for purification of the
compounds to produce substantially chemically pure compounds are
known to those of skill in the art. A substantially chemically pure
compound may, however, be a mixture of stereoisomers. In such
instances, further purification might increase the specific
activity of the compound. The instant disclosure is meant to
include all such possible isomers, as well as, their racemic and
optically pure forms. Optically active (+) and (-), (R)- and (S)-,
or (D)- and (L)-isomers may be prepared using chiral synthons or
chiral reagents, or resolved using conventional techniques, such as
reverse phase HPLC. When the compounds described herein contain
olefinic double bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are also intended to be included.
[0052] The term "alkyl" refers to straight or branched chain
unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, in one
embodiment, 1 to 7 carbon atoms. The expression "lower alkyl"
refers to unsubstituted alkyl groups of 1 to 4 carbon atoms. When a
subscript is used with reference to an alkyl or other group, the
subscript refers to the number of carbon atoms that the group may
contain. The term "C.sub.0-4alkyl" includes a bond and alkyl groups
of 1 to 4 carbon atoms.
[0053] The term "substituted alkyl" refers to an alkyl group
substituted by one to four substituents selected from halo,
hydroxy, alkoxy, oxo (.dbd.O), alkanoyl, aryloxy, alkanoyloxy,
amino, alkylamino, arylamino, aralkylamino, disubstituted amines in
which the 2 amino substituents are selected from alkyl, aryl or
aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted
alkanoylamino, substituted arylamino, substituted aralkanoylamino,
thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono,
aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,
sulfonamido, e.g. SO.sub.2NH.sub.2, substituted sulfonamido, nitro,
cyano, carboxy, carbamyl, e.g. CONH.sub.2, substituted carbamyl
e.g. CONHalkyl, CONHaryl, CONHaralkyl or cases where there are two
substituents on the nitrogen selected from alkyl, aryl or aralkyl;
alkoxycarbonyl, aryl, substituted aryl, guanidino and substituted
or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl,
thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
Where the substituent on the alkyl is further substituted, it will
be with alkyl, alkoxy, aryl, or aralkyl.
[0054] When the term alkyl is used in connection with another
group, as in heterocycloalkyl or cycloalkylalkyl, this means the
identified group is bonded directly through an alkyl group which
may be branched or straight chain. In the case of substituents, as
in "substituted cycloalkylalkyl," the alkyl portion of the group
may, besides being branched or straight chain, be substituted as
recited above for substituted alkyl groups and/or the connected
group may be substituted as recited herein for that group.
[0055] The term "halogen" or "halo" refers to fluorine, chlorine,
bromine and iodine.
[0056] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6 to 12 carbon atoms in the ring portion,
such as phenyl, naphthyl, biphenyl and diphenyl groups. When the
aryl is substituted, each ring of the aryl may be substituted.
[0057] The term "substituted aryl" refers to an aryl group
substituted by one to four substituents selected from alkyl,
substituted alkyl, haloalkyl, halo, trifluoromethoxy,
trifluoromethyl, hydroxy, hydroxyalkyl, aminoalkyl, alkoxy,
alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino,
dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro,
cyano, cyanoalkyl, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl,
aminocarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonic
acid, alkysulfonyl, sulfonamido, aryloxy and CONR.sup.aR.sup.b,
where R.sup.a and R.sup.b are selected from hydrogen, alkyl,
alenyl, alynyl, cycloalkyl and alkylamino; or R.sup.a and R.sup.b
together with the nitrogen on which they are substituted for a 3-6
membered heterocyclic or heteroaryl ring. The substituent may be
further substituted by hydroxy, alkyl, alkoxy, aryl, substituted
aryl, substituted alkyl or aralkyl.
[0058] The term "aralkyl" refers to an aryl group bonded directly
through an alkyl group, such as benzyl, wherein the alkyl group may
be branched or straight chain. In the case of a "substituted
aralkyl," the alkyl portion of the group may, besides being
branched or straight chain, be substituted as recited above for
substituted alkyl groups and/or the aryl portion may be substituted
as recited for substituted aryl:
##STR00002##
Thus, the term "optionally substituted benzyl" refers to the group
wherein each R group may be hydrogen or may also be selected from
alkyl, halogen, cyano, nitro, amino, hydroxy, alkoxy, alkylthio,
phenyl, benzyl, phenyloxy, and benzyloxy, and other groups recited
above. At least two of these "R" groups should be hydrogen and in
one embodiment, at least five of the "R" groups are hydrogen. In
certain embodiments, the benzyl group is
##STR00003##
[0059] The term "heteroaryl" refers to an aromatic group for
example, which is a 4 to 7 membered monocyclic, 7 to 11 membered
bicyclic, or 10 to 15 membered tricyclic ring system, which has at
least one heteroatom and at least one carbon atom containing ring.
Each ring of the heteroaryl group containing a heteroatom can
contain one or two oxygen or sulfur atoms and/or from one to four
nitrogen atoms, provided that the total number of heteroatoms in
each ring is four or less and each ring has at least one carbon
atom. The fused rings completing the bicyclic and tricyclic groups
may contain only carbon atoms and may be saturated, partially
saturated, or unsaturated. The nitrogen and sulfur atoms may
optionally be oxidized and the nitrogen atoms may optionally be
quaternized. Heteroaryl groups which are bicyclic or tricyclic must
include at least one fully aromatic ring but the other fused ring
or rings may be aromatic or non-aromatic. The heteroaryl group may
be attached at any available nitrogen or carbon atom of any
ring.
[0060] A "substituted heteroaryl" has one to four substituents on
any one or more of the rings comprising the heteroaryl group. The
substituents may be selected from those 30 recited below for
heterocycle groups.
[0061] Exemplary monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, i.e.,
##STR00004##
thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
[0062] Exemplary bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl,
quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzopuranyl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the
like.
[0063] Exemplary tricyclic heteroaryl groups include carbazolyl,
benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl
and the like.
[0064] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, in certain embodiments,
2 to 15 carbon atoms, and in other embodiments, 2 to 8 carbon
atoms, having one to four double bonds.
[0065] The term "substituted alkenyl" refers to an alkenyl group
substituted by one to two substituents selected from halo, hydroxy,
alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, diallylamino,
alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl,
sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl,
guanidino, and substituted and unsubstituted heterocycles,
including indolyl, imidazolyl, furyl, thienyl, thiazolyl,
pyrrolidyl, pyridyl, pyrimidyl and the like.
[0066] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, in certain embodiments,
2 to 15 carbon atoms, and in other embodiments, 2 to 8 carbon
atoms, having one to four triple bonds.
[0067] The term "substituted alkynyl" refers to an alkynyl group
substituted by a substituent selected from halo, hydroxy, alkoxy,
alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino,
alkanoylamino, thiol, alkylthio, alkylthiono, allylsulfonyl,
sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl,
guanidino and substituted or unsubstituted heterocyclo, e.g.
imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,
pyrimidyl and the like.
[0068] The term "cycloalkyl" refers to a saturated or partially
unsaturated nonaromatic cyclic hydrocarbon ring system, in certain
embodiments, containing 1 to 3 rings and 3 to 7 carbons per ring
which may be further fused with an unsaturated C.sub.3-C.sub.7
carbocylic ring. Exemplary groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl,
cyclododecyl, and adamantyl. A "substituted cycloalkyl" is
substituted with one or more alkyl or substituted alkyl groups as
described above, or one or more groups described above as alkyl
substituents. The expression "lower cycloalkyl" refers to an
unsubstituted saturated or unsaturated nonaromatic cyclic
hydrocarbon ring system containing 3 to 5 carbon atoms.
[0069] The terms "heterocycle", "heterocyclic" and "heterocyclo"
each refer to a fully saturated or unsaturated, aromatic or
nonaromatic cyclic group, for example, which is a 4 to 7 membered
mono cyclic, 7 to 11 membered bicyclic, or 10 to 15 membered
tricyclic ring system, which has at least one heteroatom in at
least one carbon atom-containing ring. Thus, the term "heterocycle"
includes heteroaryl groups as described above. Each ring of the
heterocyclic group containing a heteroatom may have 1, 2 or 3
heteroatoms independently selected from nitrogen, oxygen or sulfur
atoms, where the nitrogen and sulfur heteroatoms may also
optionally be oxidized and the nitrogen heteroatoms may also
optionally be quaternized. The heterocyclic group may be attached
at any heteroatom or carbon atom.
[0070] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,
oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,
4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane
and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl,
thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
[0071] Exemplary bicyclic heterocyclic groups include
2,3-dihydro-2-oxo-1H-indolyl, benzothiazolyl, benzoxazolyl,
benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide,
tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl,
cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl
(such as furo (2,3-c)pyridinyl, furo (3,1-b)pyridinyl) or
furo(2,3-b)pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such
as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl,
benzotriazolyl, benzopyrazolyl, dihydrobenzofiuyl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,
isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl,
piperonyl, purinyl, pyridopyridyl, quinazolinyl,
tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl,
and the like.
[0072] Also included are smaller heterocycles, such as epoxides and
aziridines.
[0073] A "substituted heterocycle" will be substituted with one or
more alkyl or aralkyl groups as described above, and/or one or more
groups described above as alkyl substituents.
[0074] Unless otherwise indicated, when reference is made to a
specifically-named heterocyclo or heteroaryl, the reference is
intended to include those systems having the maximum number of
non-cumulative double bonds or less than that maximum number of
double bonds. Thus, for example, the term "isoquinoline" refers to
isoquinoline and tetrahydroisoquinoline. The term "diazepine"
refers to a heterocyclo ring having at least one seven atom ring
with two nitrogen atoms in the seven membered ring, including a
fully saturated or unsaturated diazepine.
[0075] The term "heteroatoms" shall include oxygen, sulfur and
nitrogen.
[0076] The term "haloalkyl" means an alkyl having one or more halo
substituents
[0077] The term "perfluoromethyl" means a methyl group substituted
by one, two, or three fluoro atoms, i.e., CH.sub.2F, CHF.sub.2 and
CF.sub.3. The term "perfluoroalkyl" means an alkyl group having
from one to five fluoro atoms, such as pentafluoroethyl.
[0078] The term "haloalkoxy" means an alkoxy group having one or
more halo substituents. For example, "haloalkoxy" includes
--OCF.sub.3.
[0079] The term "carbocyclic" means a saturated or unsaturated
monocyclic or bicyclic ring in which all atoms of all rings are
carbon. Thus, the term includes cycloalkyl and aryl rings. The
carbocyclic ring may be substituted in which case the substituents
are selected from those recited above for cycloalkyl and aryl
groups.
[0080] When the term "unsaturated" is used herein to refer to a
ring or group, the ring or group may be fully unsaturated or
partially unsaturated.
[0081] Definitions for the various other groups that are recited
above in connection with substituted alkyl, substituted alkenyl,
substituted alkynyl, substituted aryl, substituted heterocycle,
substituted cycloalkyl, and so forth, are as follows: alkoxy is
--OR.sup.a, alkanoyl is --C(.dbd.O)R.sup.a, aryloxy is --OAr,
alkanoyloxy is --OC(.dbd.O)R.sup.a, amino is --NH.sub.2, alkylamino
is NHR.sup.a, arylamino is --NHAr, aralkylamino is NH--R.sup.b-AR,
disubstituted amine or dialkylamino is NR.sup.cR.sup.d,
alkanoylamino is --NH--C(.dbd.O)R.sup.a, aroylamino is
--NH--C(.dbd.O)Ar, aralkanoylamino is NH--C(.dbd.O)R.sup.b--Ar,
thiol is --SH, alkylthio is --SR.sup.a, arylthio is --SAr,
aralkylthio is --S--R.sup.b--Ar, alkylthiono is --S(.dbd.O)R.sup.a,
arylthiono is --S(.dbd.O)Ar, aralkylthiono is
--S(.dbd.O)R.sup.b--Ar, alkylsulfonyl is --SO.sub.(q)R.sup.a,
arylsulfonyl is --SO.sub.(q)Ar, arylsulfonylamine is
--NHSO.sub.(q)Ar, alkylsulfonylamine is NHSO.sub.2R.sup.a,
aralkylsulfonyl is --SO.sub.(q)R.sup.bAr, sulfonamido is
--SO.sub.2NH.sub.2, nitro is --NO.sub.2, carboxy is --CO.sub.2H,
carbamyl is --CONH.sub.2, substituted carbamyl is
--C(.dbd.O)NHR.sup.c or --C(.dbd.O)NR.sup.cR.sup.d, alkoxycarbonyl
is --C(.dbd.O)OR.sup.a, carboxyalkyl is --R.sup.b--CO.sub.2H,
sulfonic acid is --SO.sub.3H, arylsulfonylamine is
--NHSO.sub.(q)Ar, guanidino is
##STR00005##
and ureido is
##STR00006##
wherein R.sup.a is alkyl as defined above, R.sup.b is alkylene as
defined above, R.sup.c and R.sup.d are selected from alkyl, aryl,
and aralkyl, Ar is an aryl as defined above, and q is 2 or 3.
[0082] Throughout the specification, groups and substituents
thereof may be chosen by one skilled in the field to provide stable
moieties and compounds.
[0083] As used herein, the abbreviations for any protective groups,
amino acids and other compounds, are, unless indicated otherwise,
in accord with their common usage, recognized abbreviations, or the
IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972)
Biochem. 11:942-944). Certain of the abbreviations used herein are
listed below: [0084] Ph=phenyl [0085] Bz=benzyl [0086]
t-Bu=tertiary butyl [0087] Me=methyl [0088] Et=ethyl [0089]
Pr=propyl [0090] Iso-P or iPr=isopropyl [0091] MeOH=methanol [0092]
EtOH=ethanol [0093] EtOAc=ethyl acetate [0094]
Boc=tert-butyloxycarbonyl [0095] CBZ=carbobenzyloxy or carbobenzoxy
or benzyloxycarbonyl [0096] DCM or CH.sub.2Cl.sub.2=dichloromethane
[0097] DCE=1,2-dichloroethane [0098] DMF=dimethyl formamide [0099]
DMSO=dimethyl sulfoxide [0100] TFA=trifluoroacetic acid [0101]
THF=tetrahydrofuran [0102]
HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0103] KOH=potassium hydroxide [0104]
K.sub.2CO.sub.3=potassium carbonate [0105] POCL.sub.3=phosphorous
oxychloride [0106] KOtBu=potassium t-butoxide [0107] EDC or
EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
[0108] DIPEA=diisopropylethylamine [0109]
HOBt=1-hydroxybenzotriazole hydrate [0110]
m-CPBA=m-chloroperbenzoic acid [0111] NaH=sodium hydride [0112]
NaOH=sodium hydroxide [0113] Na.sub.2SO.sub.4=sodium sulfate [0114]
Na.sub.2S.sub.2O.sub.3=sodium thiosulfate [0115] Pd=palladium
[0116] Pd/C=palladium on carbon [0117] min=minute(s) [0118] L=liter
[0119] mL=milliliter [0120] .mu.L=microliter [0121] g=gram(s)
[0122] mg=milligram(s) [0123] mol=moles [0124] mmol=millimole(s)
[0125] meq=milliequivalent [0126] RT or rt=room temperature [0127]
t.sub.r=HPLC retention time (minutes) [0128] sat or
sat'd=saturated
B. Kinase Inhibitors
[0129] In one embodiment, compounds for use in compositions and
methods for modulating p 38 kinase activity are provided. In one
embodiment, compounds for use in compositions and methods for
modulating kinases p38.alpha. and .beta., are provided.
[0130] In certain embodiments, the compounds are represented by
formula (I):
##STR00007##
or pharmaceutically acceptable derivatives thereof, wherein
[0131] R.sup.1 is hydrogen, lower alkyl, lower cycloalkyl, alkenyl
or alkynyl;
[0132] R.sup.2 is attached to any available carbon atom of the
phenyl ring A and at each occurrence is alkyl or cycloalkyl;
[0133] n is 0, 1 or 2;
[0134] R.sup.3 is selected from hydrogen, alkyl, substituted alkyl,
cycloalkyl, heterocyclyl and heteroaryl;
[0135] Y is a single bond, --C(.dbd.O)NH-- or --SO.sub.2NH--;
[0136] B is a 5-membered heterocyclic ring system optionally
substituted with up to two R.sup.13;
[0137] Q is independently selected from a single bond, --C(O)--,
--CO(O)--, --C(O)NH--(C.sub.0-4alkyl)- or --CH.sub.2--;
[0138] D is a monocyclic or bicyclic ring system optionally
containing up to four heteroatoms selected from N, O, and S or D is
C.sub.1-6alkyl, and wherein D is optionally substituted by one to
four (CR.sup.9R.sup.10).sub.wE groups;
[0139] w is an integer having a value from 0-4;
[0140] R.sup.10 is selected from H or C.sub.1-C.sub.4 alkylhydroxy,
C.sub.1-C.sub.4alkylaryl or C.sub.1-C.sub.4alkylheteroaryl, wherein
said aryl or heteroaryl group may be substituted with 0-3 groups
independently selected from H, halogen, NO.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, haloalkyl,
haloalkoxy, OH, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4alkylcarbonyl, CN, NH.sub.2, NR.sup.6R.sup.7,
SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6, SO.sub.3R.sup.6,
SO.sub.2NR.sup.6, CO.sub.2H, CO.sub.2R.sup.6, and
CONR.sup.6R.sup.7; R.sup.11 is selected from H, halogen, NO.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, haloalkyl,
haloalkoxy, OH, C.sub.1-C.sub.4alkoxy-, OR.sup.6,
O(CR.sup.9R.sup.10).sub.r, CO.sub.2R.sup.6,
O(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
O(CR.sup.9R.sup.10).sub.pCN,
O(CR.sup.9R.sup.10).sub.rC(.dbd.O)NR.sup.6R.sup.7,
C.sub.1-C.sub.4alkylcarbonyl-, CN, NH.sub.2, NHR.sup.6,
Nr.sup.6R.sup.7, NR.sup.7(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.6,
NR.sup.7OR.sup.6, NR.sup.7(CR.sup.9R.sup.10).sub.mOR.sup.6,
NR.sup.7CH((CR.sup.9R.sup.10).sub.pOR.sup.6).sub.2,
NR.sup.7C(CR.sup.9R.sup.10).sub.pOR.sup.6).sub.3,
NR.sup.7C(.dbd.O)R.sup.6, NR.sup.7(CR.sup.9R.sup.10).sub.mOR.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.mSO.sub.2(CR.sup.9R.sup.10).sub.qR.sup.6,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.2NR.sup.6,
SO.sub.3R.sup.7, CO.sub.2H, CO.sub.2R.sup.6, and
CONR.sup.6R.sup.7;
[0141] E is selected from H, halogen, NO.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.10, cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 alkynyl, haloalkyl,
haloalkoxy, OH, OR.sup.6, CN, CHO, CO.sub.2R.sup.6,
CONR.sup.6R.sup.7, OCOR.sup.6, OC(.dbd.O)OR.sup.6,
OC(.dbd.O)NR.sup.6R.sup.7, OCH.sub.2CO.sub.2R.sup.6,
C(.dbd.O)R.sup.6, NH.sub.2, NHR.sup.6, NR.sup.6R.sup.7,
NR.sup.7C(.dbd.O)R.sup.6, NR.sup.7C(.dbd.O)OR.sup.6,
NR.sup.7C(.dbd.O)C(.dbd.O)OR.sup.6,
NR.sup.7C(.dbd.O)C(.dbd.O)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.O)R.sup.6, NR.sup.7C(.dbd.O)OR.sup.6,
NR.sup.7C(.dbd.O)C(.dbd.O)OR.sup.6,
NR.sup.7C(.dbd.O)C(.dbd.O)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.O)C(.dbd.O)(C.sub.1-C.sub.6alkyl),
NR.sup.7C(+NCN)OR.sup.6, NR.sup.7C(.dbd.O)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.NCN)NR.sup.6R.sup.7,
NR.sup.7C(.dbd.NR.sup.6)NR.sup.7R.sup.8,
NR.sup.6SO.sub.2NR.sup.6R.sup.7, NR.sup.7SO.sub.2R.sup.6, SR.sup.6,
S(.dbd.O)R.sup.6, SO.sub.2R.sup.6, SO.sub.3R.sup.7,
SO.sub.2NR.sup.6R.sup.7, NHOH, HHOR.sup.6,
NR.sup.6NR.sup.7NR.sup.8, N(COR.sup.6)OH, N(CO.sub.2R.sup.6)OH,
CO.sub.2R.sup.6, CONR.sup.6R.sup.7,
CONR.sup.7(CR.sup.9R.sup.10).sub.rR.sup.6,
CO(CR.sup.9R.sup.10).sub.pO(CHR.sup.9).sub.qCO.sub.2R.sup.6,
CO(CR.sup.9CR.sup.10).sub.rR.sup.6,
CO(CR.sup.9R.sup.10).sub.pO(CR.sup.9R.sup.10).sub.pO(CHR.sup.9).sub.q,
CO.sup.2R.sub.6, CO(CR.sup.9CR.sup.10).sub.r, OR.sup.6,
CO(CR.sup.9R.sup.10).sub.pO9CR.sup.9R.sup.10.sub.qR.sup.6,
CO(CR.sup.6CR.sup.10).sub.rNR.sup.6R.sup.7,
OC(O)O(CR9R10R10).sub.mNR.sup.6R.sup.7,
O(CO).sub.N(CR.sup.9R.sup.10), R.sup.6,
O(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7.sub.mNR.sup.7C(O)(CR.su-
p.9R.sup.10).sub.rOR.sup.6, NR.sup.7C(.dbd.NC)
(CR.sup.9R.sup.10).sub.r, R.sup.6,
NR.sup.7CO(CR.sup.9R.sup.10).sub.rNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.mOR.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7, NR.sup.7,
NR.sup.3(CR.sup.9R.sup.10).sub.nSO.sub.2(CR.sup.9R.sup.10).sub.rCO.sub.2R-
.sup.6, NR.sup.7CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.nSO.sub.2(CR.sup.9R.sup.10).sub.qR.sup.6,
CONR.sup.7(CR.sup.9R.sup.10).sub.nSO.sub.2(CR.sup.9R.sup.10).sub.qR.sup.6-
, SO.sub.2NR.sup.7(CR.sup.9R.sup.10).sub.qR.sup.6,
SO.sub.2NR.sup.6(CR.sup.9R.sup.10).sub.mOR.sup.6, C.sub.2-C.sub.6
alkenyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10
cycloalkylmethyl, aryl, heterocyclic optionally substituted with
one or two alkyl groups, heteroaryl optionally substituted with one
or two alkyl groups and alkylaryl; wherein said aryl groups may be
substituted with 0-2 substituents independently selected from
R.sup.12;
[0142] R.sup.12 at each occurrence are independently selected from
H, halogen, NO.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, haloalkyl, haloalkoxy, OH, oxo,
C.sub.1-C.sub.4alkoxy-, OR.sup.6, O(CR.sup.9R.sup.10),
CO.sub.2R.sup.6, O(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
O(CR.sup.9R.sup.10).sub.pCN,
O(CR.sup.9R.sup.10).sub.rC(.dbd.O)NR.sup.6R.sup.7,
C.sub.1-C.sub.4alkylcarbonyl-, CN, NH.sub.2, NHR.sup.6,
NR.sup.6R.sup.7, NR.sup.7(CR.sup.9R.sup.10), CO.sub.2R.sup.6,
NR.sup.7OR.sup.6, NR.sup.7(CR.sup.9R.sup.10).sub.mOR.sup.6,
NR.sup.7CH((CR.sup.9R.sup.10).sub.pOR.sup.6).sub.2,
NR.sup.7C((CR.sup.9R.sup.10).sub.pOR.sup.6).sub.3,
NR.sup.7C(.dbd.O)R.sup.6, NR.sup.7(CR.sup.9R.sup.10).sub.mOR.sup.6,
NR.sup.7(CR.sup.9R.sup.10).sub.mNR.sup.6R.sup.7,
NR.sup.7(CR.sup.9R.sup.10).sub.qR.sup.6, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, SO.sub.2NR.sup.6, SO.sub.3R.sup.7, CO.sub.2H,
CO.sub.2R.sup.6, and CONR.sup.6R.sup.7;
[0143] m is an integer having a value from 2-6;
[0144] p is an integer having a value from 1-3;
[0145] q is an integer having a value from 0-3;
[0146] r is an integer having a value from 0-6;
[0147] R.sup.4 is hydrogen, lower alkyl and lower cycloalkyl;
[0148] R.sup.5 is hydrogen, lower alkyl and lower cycloalkyl;
[0149] R.sup.6, R.sup.7 and R.sup.8 are independently selected as
follows: [0150] i) R.sup.6, R.sup.7 and R.sup.8 are independently
selected from H, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.7cycloalkyl(C.sub.0-C.sub.5alkyl)carbonyl,
C.sub.1-C.sub.6alkoxycarbonyl, aryl(C.sub.0-C.sub.5 alkyl)carbonyl,
aryl(C.sub.1-C.sub.5alkoxy)carbonyl,
heterocyclic(C.sub.0-C.sub.5alkyl)carbonyl,
heterocyclic(C.sub.1-C.sub.5alkoxy)carbonyl,
C.sub.1-C.sub.6alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
C.sub.0-C.sub.4alkylaryl, C.sub.0-C.sub.4alkylheterocyclic, wherein
said cycloalkyl, aryl, or heterocyclic groups are substituted with
0-2 substituents independently selected from the group consisting
of C.sub.1-C.sub.4alkyl, hydroxyl, C.sub.1-C.sub.4 alkoxy, F, Cl,
Br, haloalkyl, NO.sub.2 and CN or, [0151] ii) R.sup.6 and R.sup.7,
or R.sup.6 and R.sup.8, or R.sup.7 and R.sup.8 when both
substituents are on the same nitrogen atom (as in
(--NR.sup.6R.sup.7) or (--NR.sup.7R.sup.8)), can be taken together
with the nitrogen atom to which they are attached to form a
heterocycle selected from 1-aziridinyl, 1-azetidinyl,
1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl,
thiazolidinyl, 1-piperazyl, 1-imidazolyl,
3-azabicyclo(3,2,2)nonan-3yl, and 1-tetrazolyl, the said
heterocycle being optionally substituted with 0.3 groups selected
from oxo, C.sub.0-C.sub.4alkylOH,
C.sub.0-C.sub.4alkylOC.sub.1-C.sub.4alkyl,
C.sub.0-C.sub.4alkylCONH.sub.2,
C.sub.0-C.sub.4alkylCO.sub.2C.sub.0-C.sub.4alkyl, C.sub.1-C alkyl,
C.sub.1-C.sub.4alkoxy, C.sub.3-C.sub.7cycloalkyl, C.sub.0-C.sub.6
alkylcarbonyl, C.sub.3-C.sub.7cycloalkylcarbonyl,
C.sub.1-C.sub.6alkoxycarbonyl, C.sub.3-C.sub.7cycloalkoxycarbonyl,
--NHCOalkyl, aryl, heteroaryl, aryl alkoxycarbonyl, heteroaryl
alkoxycarbonyl, C.sub.1-C.sub.6 alkylsulfonyl, arylsulfonyl and
heteroarylsulfonyl;
[0152] R.sup.9 is hydrogen or C.sub.1-C.sub.4alkyl;
[0153] R.sup.13 is hydrogen, alkyl, haloalkyl, aminocarbonyl,
hydroxycarbonyl, alkoxycarbonyl, cycloalkylalkylaminocarbonyl, aryl
optionally substituted with one or more R.sup.14, heteroaryl,
heterocyclyl, alkylthio, alkylaminocarbonyl or OR.sup.15;
[0154] R.sup.14 is hydrogen, halo, hydroxy, cyano, alkyl,
haloalkyl, cyanoalkyl, aminoalkyl, alkoxy, hydroxycarbonyl,
alkoxycarbonyl, aminocarbonyl, CONR.sup.aR.sup.b, where R.sup.a and
R.sup.b are each independently selected from hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, alkoxycarbonylaminoalkyl and
alkylamino; or R.sup.a and R.sup.b together with the nitrogen on
which they are substituted form a 3-6 membered heterocyclic or
heteroaryl ring;
[0155] R.sup.15 is hydrogen, alkyl, hydroxycarbonylalkyl,
alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, heterocyclyalkyl or
heteroarylalkyl.
[0156] In one embodiment, R.sup.1 is methyl, halo, hydroxyl, lower
alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy,
trifluoromethoxy, cyano, --NH.sub.2 or --NR.sup.4R.sup.5.
[0157] In another embodiment, R.sup.1 is methyl, halo, hydroxyl,
lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl,
methoxy, trifluoromethoxy, cyano, --NH.sub.2, --NR.sup.4R.sup.5 or
--OR.sup.4.
[0158] In certain embodiments, the compounds have formula (I) with
the proviso that ring B is not substituted with NH.sub.2.
[0159] In one embodiment, R.sup.1 is hydrogen or lower alkyl.
[0160] In another embodiment, R.sup.1 is hydrogen or methyl.
[0161] In another embodiment, R.sup.1 is methyl.
[0162] In one embodiment, R.sup.2 is hydrogen or alkyl.
[0163] In one embodiment, R.sup.2 is hydrogen or lower alkyl.
[0164] In one embodiment, R.sup.2 is hydrogen.
[0165] In another embodiment, R.sup.3 is selected from alkyl,
--OR.sup.4, substituted alkyl, cycloalkyl, --CR.sup.4cycloalkyl,
heteroaryl, substituted heteroaryl, heterocycle and substituted
heterocycle.
[0166] In one embodiment, R.sup.3 is cycloalkyl, cycloalkylalkyl,
alkoxyalkyl or heteroaryl.
[0167] In one embodiment, R.sup.3 is methyl, isopropyl, ethyl,
cyclopropyl, cyclopropylmethyl, methoxymethyl, oxazolyl or
thiazolyl.
[0168] In another embodiment, Y is --C(.dbd.O)NH--,
--NH(C.dbd.O)--, --NH(C.dbd.O)NH--, --SO.sub.2NH--, --NHSO.sub.2--
or --C(.dbd.O)--.
[0169] In another embodiment, Y is a single bond, --C(.dbd.O)NH--
or --SO.sub.2NH.
[0170] In another embodiment, B is a thiazolyl, oxazolyl,
dithiazolyl, thiadiazolyl, oxadiazolyl or triazinyl ring optionally
substituted with one or two R.sup.13.
[0171] In another embodiment, B is a thiazolyl ring optionally
substituted with one or two R.sup.13.
[0172] In another embodiment, B is a thiazolyl ring optionally
substituted with one R.sup.13.
[0173] In another embodiment, Q is a single bond, --CO(O)--,
--C(O)-- or --C(O)NH--(C.sub.0-4alkyl)-.
[0174] In another embodiment, Q is a single bond.
[0175] In another embodiment, Q is --C(O)--.
[0176] In another embodiment, Q is --CO(O)--.
[0177] In another embodiment, Q is --C(O)NH--(C.sub.0-4alkyl)-.
[0178] In another embodiment, Q is --C(O)NH-- or
--C(O)NHCH.sub.2CH.sub.2--.
[0179] In another embodiment, Q is --C(O)NH--.
[0180] In another embodiment, D is a monocyclic or bicyclic ring
system optionally containing up to four heteroatoms selected from
N, O, and S or D is C.sub.1-6alkyl and wherein D is optionally
substituted by one to four (CR.sup.9R.sup.10).sub.wE groups.
[0181] In another embodiment, D is C.sub.1-6alkyl, alkoxy,
cycloalkyl, aryl, arylalkyl, heterocyclyl or heteroaryl ring,
wherein the heteroatoms are selected from O, N and S and D is
optionally substituted with one or four (CR.sup.9R.sup.10).sub.wE
groups.
[0182] In another embodiment, D is selected from methyl, ethyl,
propyl, ethoxy cyclopropyl, phenyl, benzyl, benzimidazolyl,
piperazinyl, piperidinyl, diazaoxazolyl or pyrimidinyl and D is
optionally substituted with one or four (CR.sup.9R.sup.10).sub.wE
groups.
[0183] In another embodiment, D is selected from 1-piperazinyl,
4-piperidinyl, 4-pyridinyl, 1,3,4-diazaoxazolyl or 3-pyridinyl, and
D is optionally substituted with one or two
(CR.sup.9R.sup.10).sub.wE groups.
[0184] In another embodiment, D is phenyl and D is optionally
substituted with one or two (CR.sup.9R.sup.10).sub.wE groups.
[0185] In another embodiment, w is 1.
[0186] In another embodiment, w is 0.
[0187] In another embodiment, D is substituted with one to four
substituents selected from halo, alkyl, nitro, alkoxy,
alkoxycarbonylalkoxy, alkoxyamidoalkylamido, hydroxycarbonyl,
alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, aryl,
heteroaryl containing 1 to 3 heteroatoms and optionally substituted
with one or two alkyl groups, and heterocyclyl containing 1 to 3
heteroatoms and optionally substituted with two or more alkyl or
alkoxycarbonyl groups.
[0188] In another embodiment, D is substituted with one to four
substituents selected from chloro, fluoro, methyl, methoxy, ethoxy,
methylaminocarbonyl, methoxycarbonylamino,
tertbutyloxyamidoethylamido, methoxycarbonyl or phenyl.
[0189] In another embodiment, D is substituted with heterocyclyl
ring selected from morpholinyl or piperidinyl, where the
heterocyclyl ring is further substituted with one or two methyl or
methoxycarbonyl groups.
[0190] In another embodiment, D is substituted with heteroaryl ring
selected from isoxazolyl, furyl, benzimidazolyl and thiazolyl,
where the heteroaryl ring is further substituted with one or two
methyl groups.
[0191] In another embodiment, D is substituted with N-morpholinyl,
piperidin-4-yl or 1-methoxycarbonylpiperidin-4-yl.
[0192] In another embodiment, D is substituted with
2-benzimidazolyl, 3,5-dimethylisoxazol-4-yl, 5-methylisoxazol-3-yl
or 2-methylthiazol-5-yl.
[0193] In another embodiment, D is selected from methyl, ethyl,
propyl, isopropyl, hydroxycarbonylmethyl,
methylaminocarbonylmethyl, ethoxycarbonylpropyl,
ethoxycarbonylmethyl, phenyl, fluorophenyl, tolyl, methoxyphenyl,
methoxycarbonylmethoxy, ethoxy, benzimidazolyl, methylpiperazinyl,
piperidinyl, 1,3,4-diazaoxazolyl, morpholin-1-ylphenyl,
piperidin-4-ylphenyl, 1-methoxycarbonylpiperidin-4-ylphenyl,
benzyl, chlorophenyl, methylcarbonylaminophenyl, bromophenyl,
carboxymethyl, tertbutyloxyamidoethylamidophenyl,
methylaminocarbonylmethyl, N-methoxycarbonylpiperidinyl,
piperidinyl, pyridinyl, cyclopropyl, dimethylisoxazolylmethyl,
methylisoxazolylmethyl and methylthiazolylmethyl.
[0194] In another embodiment, D is selected from methyl, ethyl,
propyl, isopropyl, cyclopropylmethyl, hydroxycarbonylmethyl,
ethoxycarbonylpropyl, methylaminocarbonylmethyl,
ethoxycarbonylmethyl, phenyl, 4-fluorophenyl, p-tolyl,
4-methoxyphenyl, 4-methoxycarbonylmethoxyphenyl, ethoxy,
2-benzimidazolylmethyl, 4-methylpiperazin-1-yl,
1,3,4-diazaoxazolyl, 4-piperidinyl, benzyl, 4-chlorophenyl,
4-morpholin-1-ylphenyl, 4-(piperidin-4-yl)phenyl.
4-(1-methoxycarbonylpiperidin-4-yl)phenyl,
4-ethoxycarbonylmethoxyphenyl, 4-methylamidophenyl, and
4-tertbutyloxyamidoethylamidophenyl.
[0195] In another embodiment, R.sup.13 is selected from methyl,
trifluoromethyl, tert-butyl, amido, methoxycarbonyl, carboxyl,
ethoxycarbonyl, cyclopropylmethylaminocarbonyl, thienyl,
methylenedioxybenzyl, ethylenedioxybenzyl, pyridinyl, and phenyl;
and R.sup.13 is optionally substituted with one or more R.sup.14,
where R.sup.14 is hydrogen, chloro, fluoro, hydroxy, methyl, cyano,
amino, aminoethyl, N-morpholinyl, methylsulfonylamino,
tertbutoxyamidomethylamido, tertbutoxyamidoethylamidophenyl,
aminomethylamido, methoxycarbonylpiperazinyl, methylcarbonyl,
methoxy, ethoxy, methoxycarbonyl, trifluoromethyl, hydroxymethyl,
amido, aminomethyl, carboxy, tertbutoxyamidoethylamido,
aminoethylamido, methylsulfonyl, N-morpholinocarbonyl,
cyclopropylamido, ethylthio, carboxymethoxy, N-morpholinoethoxy,
aminoethoxy, ethylamido, n-butoxy, aminopropyloxy or
carboxymethoxy.
[0196] In another embodiment, R.sup.13 is selected from methyl,
trifluoromethyl, tert-butyl, amido, methoxycarbonyl, carboxyl,
ethoxycarbonyl, cyclopropylmethylaminocarbonyl, thienyl,
methylenedioxybenzyl, ethylenedioxybenzyl, 4-cyanomethylphenyl,
4-cyanophenyl, 2-chlorophenyl, 4-hydroxyphenyl, m-tolyl,
3-fluorophenyl, p-tolyl, 3-cyanophenyl, 5-methylcarbonylthien-2-yl,
5-cyanothien-2-yl, 4-methoxyphenyl, 4-methoxycarbonylphenyl,
4-fluorophenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl,
4-hydroxymethylphenyl, 3-aminocarbonylphenyl,
4-aminocarbonylphenyl, 3-aminomethylphenyl, 3-carboxyphenyl,
4-carboxyphenyl, o-tolyl, 2,4-difluorophenyl,
3-aminoethylaminocarbonylphenyl, 4-aminoethylaminocarbonylphenyl,
3-aminomethylaminocarbonylphenyl, 4-aminomethylaminocarbonylphenyl,
4-methylsulfonylphenyl, 4-(N-morpholino)carbonylphenyl,
4-ethoxy-3-fluorophenyl, 3-cyclopropylamidophenyl, 3-ethoxyphenyl,
4-ethylthiophenyl, 4-methoxy-3-fluorophenyl,
4-fluoro-3-methylphenyl, 3,4-difluorophenyl,
3-methyl-4-methoxyphenyl, 3-hydroxycarbonylmethoxyphenyl,
4-(N-morpholino)ethoxyphenyl, 4-hydroxyphenyl, phenyl,
3-aminoethoxyphenyl, 4-ethylaminocarbonylphenyl, 4-n-butoxyphenyl,
3-methyl-4-methoxyphenyl, 3-aminopropyloxyphenyl
4-cyanomethylphenyl, 4-aminophenyl, 3-aminophenyl,
4-aminoethylphenyl, 4-morpholin-1-ylphenyl,
4-methylsulfonylaminophenyl, 3-tertbutoxyamidomethylamidophenyl,
4-tertbutoxyamidomethylamidophenyl,
3-tertbutoxyamidoethylamidophenyl,
4-tertbutoxyamidoethylamidophenyl, 3-aminomethylamidophenyl,
4-(methoxycarbonylpiperazin-1-yl)phenyl and
2-methoxypyrimidin-3-yl.
[0197] In certain embodiments, the compounds provided herein are
represented by formula (I-1):
##STR00008##
where B is selected from 1,2,4-triazole, 1,2,4-oxadiazole,
1,3,4-thiadiazole, 1,2,4-thiadiazole, oxazole and thiazole.
[0198] In certain embodiments, the compounds provided herein are
represented by formula (I-2):
##STR00009##
where X.sup.1 is selected from O, S and optionally substituted N,
where the substituent on the N when present is selected from
hydrogen, alkyl, substituted alkyl, alkenyl or alkynyl and X.sup.2
is S or O.
[0199] In certain embodiments, the compounds provided herein are
represented by formula (I-3):
##STR00010##
[0200] In certain embodiments, the compounds have formula
(I-4):
##STR00011##
[0201] In certain embodiments, the compounds provided herein are
represented by formula (I-5):
##STR00012##
where n.sub.1 is 0-5.
[0202] In certain embodiments, the compounds provided herein are
represented by formula (I-6):
##STR00013##
where n.sub.3 is 1-4.
[0203] In certain embodiments, the compounds provided herein are
represented by formula (I-7):
##STR00014##
where n2 is 0-4.
[0204] In certain embodiments, the compounds provided herein are
represented by formula (I-8):
##STR00015##
[0205] In certain embodiments, the compounds provided herein are
represented by formula (I-9):
##STR00016##
[0206] In certain embodiments, the compounds provided herein are
selected from formula (I-10) as follows:
##STR00017##
[0207] In one embodiment, the compounds are salts of the compounds
of Formula (I). In certain embodiments, the salts are
pharmaceutically acceptable (i.e. non-toxic, physiologically
acceptable) salts, in other embodiments, the compounds are other
salts which are useful, for example, in isolating or purifying the
compounds provided herein.
[0208] In another embodiment, the compounds are selected from the
compounds listed Table 1.
[0209] The compounds of Formula (I) may form salts with alkali
metals such as sodium, potassium and lithium, with alkaline earth
metals such as calcium and magnesium, with organic bases such as
dicyclohexylamine, tributylamine, pyridine and amino acids such as
arginine, lysine and the like. Such salts can be formed as known to
those skilled in the art.
[0210] The compounds for Formula (I) may form salts with a variety
of organic and inorganic acids. Such salts include those formed
with hydrogen chloride, hydrogen bromide, methanesulfonic acid,
sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid,
maleic acid, benzenesulfonic acid, toluenesulfonic acid and various
others (e.g., nitrates, phosphates, borates, tartrates, citrates,
succinates, benzoates, ascorbates, salicylates and the like). Such
salts can be formed as known to those skilled in the art.
[0211] Salt forms of the compounds may be advantageous for
improving the compound dissolution rate and oral
bioavailability.
[0212] In addition, zwitterions ("inner salts") may be formed.
[0213] All stereoisomers of the compounds are contemplated to be
within the scope of the disclosure, either in admixture or in pure
or substantially pure form. All the possible stereoisomers and
their mixtures are contemplated to be within the scope of the
disclosure. It embraces the racemic forms and the isolated optical
isomers having the specified activity. The racemic forms can be
resolved by physical methods, such as, for example, fractional
crystallization, separation or crystallization of diastereomeric
derivatives or separation by chiral column chromatography. The
individual optical isomers can be obtained from the racemates from
the conventional methods, such as, for example, salt formation with
an optically active acid followed by crystallization.
[0214] Compounds of the Formula (I) may also have prodrug forms.
Any compound that will be converted in vivo to provide the
bioactive agent (i.e., the compound for formula I) is a prodrug and
is within the scope the disclosure.
[0215] Various forms of prodrugs are well known in the art. For
examples of such prodrug derivatives, see: [0216] a) Design of
Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.
(Academic Press, 1985); [0217] b) A Textbook of Drug Design and
Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter
5, "Design and Application of Prodrugs," by H. Bundgaard, p.
113-191 (1991); and [0218] c) H. Bundgaard, Advanced Drug Delivery
Reviews, 8, 1-38 (1992), each of which is incorporated herein by
reference.
[0219] It should further be understood that solvates (e.g.,
hydrates) of the compounds of Formula (I) are also contemplated
herein. Methods of solvation are generally known in the art.
[0220] The ability of the compounds provided herein, to inhibit the
synthesis or the activity of cytokines can be demonstrated using
the in vitro assays described in section E.
C. Preparation of the Compounds
[0221] Compounds of formula I may be generally be prepared
according to the following schemes and the knowledge of one skilled
in the art. In addition to the documents incorporated by reference
we disclose the following. Examples of methods useful for the
production of compounds provided herein are illustrated in schemes
1-18.
[0222] Appropriately substituted 1,2,4-aminotriazoles of type (II),
which are useful herein, can be made by several means, for example
as shown in scheme 1, reaction of an appropriately substituted
amine with a reagent such as 1,1'thiocarbonyldi-2(1H)-pyridone,
1,1'-thiocarbonyldiimidazole or thiophosgene in a solvent such as
methylene chloride or dioxane yields the isothiocyanate. Treatment
of the isothiocyanate with sodium salt of cyanamide yields the
sodium salt of N-cyanothiourea which is cyclized to the
aminotriazole (II) using a appropriately substituted hydrazine and
a dehydrating agent such as
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC),
or DCC. (Bioorg. Med. Chem. Letters 12: 3125-3128 (2002))
##STR00018##
[0223] 1,2,4-Aminotriazoles of type (II), which are useful herein,
may also be prepared as outlined in Scheme 2. An appropriately
substituted amine can react with diphenyl cyanocarbonimidate to
yield the N-cyano-O-phenylisourea. Cyclization of
N-cyano-O-phenylisourea to the appropriately substituted triazole
(II) is achieved using an appropriately substituted hydrazine and a
solvent such as acetonitrile.
##STR00019##
[0224] Appropriately substituted 1,2,4-triazoles of type (111),
which are useful herein, can be prepared as by several methods for
example as outlined in Scheme 3. Acylisothiocyanates are useful
intermediates in the production of some compounds provided herein
and are either commercially available or readily prepared by
reaction of an acid chloride, with either sodium or potassium
isothiocyanate in an inert solvent such as dioxane. Acid chlorides
are either commercially available or readily prepared by reaction
of a carboxylic acid and a reagent such as thionyl chloride, or
oxalyl chloride in the presence of a catalytic amount of
N,N-dimethylformamide, in an inert solvent such as chloroform or
methylene chloride. Reaction of an appropriately substituted amine
with an acylisothiocyanate yields the thiourea. The thiourea is
cyclized to (III) using hydrazine in a solvent such as ethyl
alcohol or a solvent mixture such as THF and ethyl alcohol, at a
temperature preferably between 60.degree. C. and the boiling point
of the solvents utilized. (Bioorg. Med. Chem. Letters 12: 3125-3128
(2002))
##STR00020##
[0225] Appropriately substituted 2-amino-1,3,4-oxadiazoles of type
(IV), which are useful herein, can be prepared by several methods
one of which is outlined in Scheme 4. Reaction of an appropriately
substituted amine with an activating agent such as
1,1'carbonyldiimidazole followed by treatment with a appropriately
substituted hydrazine yields the carbonylhydrazide. The
carbonylhydrazide on treatment with 1,2-dibromotetrachloroethane
and triphenylphosphine in the presence of a suitable base such as
triethylamine and an appropriate solvent such as acetonitrile
yields compound (IV). (Bioorg. Med. Chem. Letters 12: 3125-3128
(2002))
##STR00021##
[0226] Appropriately substituted 3-amino-1,2,4-oxadiazoles of type
(V), useful herein, can be prepared by several methods one of which
is outlined in Scheme 5. Reaction of an appropriately substituted
amine with an appropriately substituted acylisothiocyanate yields
the thiourea. Reaction of the thiourea with a base such as sodium
hydroxide or sodium hydride followed by a alkylating agent such as
methyl iodide gives the S-methylisothiocarbamoyl intermediate which
on treatment with hydroxylamine in the presence of a suitable
solvent such as ethyl alcohol or butyl alcohol at a temperature
preferably between 60 and 110.degree. C. results in cyclization to
the desired 3-amino-1,2,4-oxadiazole. (Bioorg. Med. Chem. Letters
12: 3125-3128 (2002))
##STR00022##
[0227] Appropriately substituted 2-amino-1,3,4-thiadiazoles of type
(VI), which are useful herein, can be prepared by several methods
one of which is illustrated in Scheme 6. Reaction of an
appropriately substituted isothiocyanate with an appropriately
substituted hydrazide yields the thiourea, which is cyclized to the
desired heterocycle using a dehydrating agent such as
methanesulphonic acid, in an inert solvent such as toluene or
xylene, at a temperature preferably between 80.degree. C. to
140.degree. C. (Bioorg. Med. Chem. Letters 12: 3125-3128
(2002))
##STR00023##
[0228] Appropriately substituted 3-amino-1,2,4-thiadiazoles of type
(VII), useful herein, can be made by several method known to one
skilled in the art of organic chemistry. One method is outlined in
scheme 7. Reaction of an appropriately substituted isothiocyanate
and an amidoxime in a solvent such as chloroform, or toluene at a
10 temperature preferably between 60.degree. C. and 110.degree. C.
results in the production of the desired heterocycle. Amidoximes
useful herein are eithercommercially available, or readily prepared
by many methods known to one skilled in the art of organic
chemistry such as reaction of a nitrile with anhydrous hydrochloric
acid in anhydrous methanol followed by reaction of resulting
imidate with hydroxylamine.
##STR00024##
[0229] Appropriately substituted 5-amino-1,2,4-thiadiazoles of type
(VII*), useful herein, can be made by several method known to one
skilled in the art of organic chemistry. One method is outlined in
scheme 7*. Reaction of an appropriately substituted isothiocyanate
and an N-hydroxy-amidinein a solvent such as DMF under microwave
radiation at a temperature of 200.degree. C. results in the
production of the desired heterocycle. N-Hydroxy-amidines useful
herein are either commercially available, or readily prepared by
many methods known to one skilled in the art of organic chemistry
such as reaction of a nitrile with hydroxylamine hydrochloride and
an appropriate base such as potassium carbonate in ethanol.
##STR00025##
[0230] 3-Aminoisoxazoles of type (VIII) that are useful herein can
be prepared by several methods including the method outlined in
scheme 8. Reaction of an appropriately substituted isocyanate with
a ketone in the presence of a base such as sodium hydride and an
alkylating agent such as methyl iodide gives a thiomethyl
intermediate which on treatment with hydroxylamine in a solvent
such as ethyl or butyl alcohol at a temperature preferably between
60-120.degree. C. yields the appropriately substituted
3-aminoisoxazoles. Ketones useful herein are either commercially
available or readily prepared by several methods such as
Friedel-Crafts acylation as described in chapter 11 of "Advanced
Organic Chemistry" 3'd edition, Part B, Carey, F. A. and Sundberg,
R. J., Plenum Press New York, 1990, hydrolysis of an enol ether, or
oxidation of an alcohol, as outlined in "Comprehensive Organic
Transformations, A Guide to Functional Group Preparations" Larock,
R. C., VCH Publishers, New York, 1989. (Bioorg. Med. Chem. Letters
12: 3125-3128 (2002))
##STR00026##
[0231] 5-Aminothiazoles of type (IX) that are useful herein can be
prepared by several methods including the method outlined in scheme
9. Reaction of an amine with an amino acid in the presence of an
activating agent such as 1,1'carbonyldiimidazole in a suitable
solvent such as tetrahydrofuran yields an amide. Amides may be
readily prepared by a number of methods including reaction of an
amine with an acid chloride, or coupling of a carboxylic acid and
the amine in the presence of a variety of coupling agents such as
EDC, DCI, in the presence of an amine base. The coupling reaction
may be enhanced by the addition of 1hydroxybenzotriazole or similar
additives. Reaction of the amide with Lawesson's reagent in the
presence of a base such as pyridine at a temperature preferably
between 80-120.degree. C. yields the appropriately substituted
5-aminothiazoles. (Bioorg. Med. Chem. Letters 12: 3125-3128
(2002))
##STR00027##
[0232] 2-Aminothiazoles of type (X) useful herein can be prepared
by several methods 20 including the method outlined in scheme 10.
Reaction of an isothiocyanate with ammonia in a solvent such as
dioxane yields the thiourea. Aryl bromides useful herein are either
commercially available or readily prepared by reaction of a
carboxylic acid with thionylbromide. Treatment of the thiourea with
an acylbromide, in the presence of a solvent such as ethyl alcohol
or dioxane, at a temperature preferably between 60.degree. C. and
110.degree. C., yields the appropriately substituted
2-amino-1,3-thiazoles. (Bioorg. Med. Chem. Letters 12: 3125-3128
(2002))
##STR00028##
[0233] 2-Aminothiazoles of type (X*) useful herein can be prepared
by several methods 20 including the method outlined in scheme 10*.
Treatment of the thiourea with an acylbromide, additionally
substituted with an electron withdrawing group such as cyano,
ester, or amide, in the presence of a solvent such as ethyl alcohol
or dioxane, at a temperature preferably between 60.degree. C. and
110.degree. C., yields the appropriately substituted
2-amino-1,3-thiazoles.
##STR00029##
[0234] Alternatively, 2-aminothiazoles of type (X**) useful herein
can be prepared by the method outlined in scheme 10**. Reaction of
2,4-dibromothiazole, obtained by treatment of 2,4-thiazolidinedione
with phosphorus oxybromide at a temperature preferably between
60.degree. C. and 110.degree. C., with lithium diisopropylamide and
an isocyanate at low temperature provides the
2,4-dibromothiazole-5-carboxamide. Treatment of this intermediate
by an aniline in the presence of a solvent such as
dimethylsulfoxide at a temperature preferably between 60.degree. C.
and 110.degree. C. yields the 4-bromo-2-anilino derivative, which
can be treated with and an appropriately substituted boronic acid,
catalytic palladium(0), and a base in the presence of a solvent
such as ethyl alcohol or dioxane, at a temperature preferably
between 60.degree. C. and 110.degree. C., to provide the
appropriately substituted 2-amino-1,3-thiazoles.
##STR00030##
[0235] 2-Aminothiazoles of type (X***) useful herein can be
prepared by several methods including the method outlined in scheme
10***. Reaction of an appropriately substituted methyl vinyl ether
such methyl trans 3-methoxyacrylate with NBS in a solvent followed
by treatment with the thiourea yields the aminothiazole.
(Tetrahedron Lett., 42: 2101-2102 (2001))
##STR00031##
[0236] Substituted acyl bromides useful herein may be prepared by
several methods, examples of which are outlined in scheme 10B.
Appropriately substituted ketones additionally substituted at the
beta carbon with an electron withdrawing group such as cyano,
ester, or amide can be treated with bromine in an appropriate
solvent such as chloroform or methylene chloride to provide acyl
bromides.
##STR00032##
[0237] Substituted .beta.-ketoamides useful herein may be prepared
by several methods, examples of which are outlined in scheme
10Ca-c. The lithium salt of an appropriately substituted methyl
ketone, generated by treatment with a base such as lithium
diisopropyl amine, in an appropriate solvent such as THF can be
reacted with an isocyanate to provide the desired
.beta.-ketoamide.
##STR00033##
[0238] Alternatively, .beta.-ketoesters can be heated with an amine
and a catalytic amount of a mild acid such as p-toluenesulfonic
acid in an appropriate solvent such as dioxane bromine to provide
the .beta.-ketoamide. Microwave heating may accelerate the
reaction.
##STR00034##
[0239] The requisite .beta.-ketoesters useful herein can be
purchased or may be prepared by several methods, examples of which
are outlined in scheme 10D. Appropriately substituted esterse can
be treated with the lithium salt of ethyl or methyl acetated to
provide .beta.-ketoesters.
##STR00035##
[0240] 2-Amino-1,3-oxazolines of type (XI) useful herein may be
prepared by several methods, an example of which is outlined in
scheme 11. An appropriately substituted isothiocyanate is reacted
with an aminoalcohol in a suitable solvent such as dioxane to yield
the thiourea. Treatment of the thiourea with
2-chloro-3-ethylbenzoxazolium tetrafluoroborate in the presence of
a base such as triethylamine in a solvent such as acetonitrile
yields the appropriately substituted 2-amino-1,3-oxazolines.
[0241] Aminoalcohols useful herein are either commercially
available or readily prepared by several methods. One convenient
method is reduction of azidoketones of the type described in
schemes 14a-14d, either by catalytic hydrogenation in the presence
of palladium on carbon in a solvent such as ethanol or ethyl
acetate, or by a hydride reagent such as lithium aluminum hydride
in a solvent such as dioxane or tetrahydrofuran. (Bioorg. Med.
Chem. Letters 12: 3125-3128 (2002))
##STR00036##
[0242] 2-Aminooxazoles of type (XII), which are useful herein, can
be prepared by several methods, including the method outlined in
Scheme 12. Reaction of an isothiocyanate with a 3-ketoamine in the
presence of a base such as triethylamine and a solvent such as
dioxane yields the thiourea. Reaction of the thiourea in the
presence of a dehydrating agent such as dicyclohexylcarbodiimide or
EDC, in a solvent such as dioxane or toluene, at a temperature
preferably between 60.degree. C. and 110.degree. C., yields the
appropriately substituted 2-aminooxazoles. .beta.-Ketoamines useful
herein are either commercially available or readily prepared by
several methods. One method is reduction of azidoketones of the
type described in schemes 14a-14d by phosphine reagents such as
triphenylphosphine in a solvent such as dioxane, followed by the
addition of water or dilute ammonium hydroxide. (Bioorg. Med. Chem.
Letters 12: 3125-3128 (2002))
##STR00037##
[0243] A second method of preparing 2-aminooxazoles of type (XII)
is outlined in scheme 13. Reaction of an appropriately substituted
isothiocyanate with an acylazide of the type described in schemes
14a-14d in the presence of a phosphine such as triphenylphosphine
in a solvent such as dichloromethane or dioxane at a temperature
from room temperature to 100.degree. C.
[0244] Caution: Appropriate safety methods, which are known to
those experienced in conducting azide reactions, such as use of a
blast shield, blast wall, or similar containment device,
particularly when the reaction involves heating the organic azide,
as well as the use of appropriate personal protection to avoid
exposure to azides which may be toxic, must be exercised during the
preparation and use of organic azides.
##STR00038##
[0245] Azides useful herein may be prepared using one of the
sequences outlined in schemes 14a-14d.
[0246] Scheme 14a outlines the treatment of the .alpha.-bromoketone
with sodium azide in a solvent such as acetone, generally at room
temperature, to yield the desired .alpha.-azidoketones useful as
intermediates herein. .alpha.-Bromoketones are either commercially
available or readily prepared by reaction of a ketone with a 10
brominating agent such as bromine in acetic acid or pyridinium
bromide per bromide and 30% hydrobromic acid.
##STR00039##
[0247] Scheme 14b outlines the treatment of the .alpha.-bromoketone
with sodium azide in acetone to give the .alpha.-azidoketone. In
this case, the .alpha.-bromoketone is prepared by reaction of a
carboxylic acid with isobutylchloroformate and N-methylmorpholine
to provide the mixed anhydride, which on treatment with
diazomethane gives the .alpha.-diazoketone. Reaction of the
.alpha.-diazoketone with either HBr gas in a solvent such as ether
or dioxane, or aqueous 48% HBr, provides the
.alpha.-bromoketone.
##STR00040##
[0248] Scheme 14c illustrated preparation of .alpha.-bromoketone by
reaction of a ketone with sulfuric acid and bromine to yield the
.alpha.,.alpha.-dibromoketone, which on treatment with
diethylphosphite and triethylamine yields the
.alpha.-(mono)bromoketone. Treatment of the .alpha.-bromoketone
with sodium azide in acetone gives the .alpha.-azidoketone.
##STR00041##
[0249] Scheme 14d illustrated preparation of .alpha.-bromoketone by
reaction of an aryl bromide with tributyl-(1-ethoxyvinyl) tin and
bis(triphenylphosphine)palladium dichloride to provide an
intermediate enol ether. Treatment of the enol ether with
N-bromosuccinamide at a temperature from 0.degree. C. to room
temperature yields the .alpha.-bromoketone. As previously described
treatment of the .alpha.-bromoketone with sodium azide in acetone
gives the .alpha.-azidoketone.
##STR00042##
[0250] Imidazoles useful herein may be prepared according to the
method outlined in scheme 15. Reaction of a guanidine with an
.alpha.-bromoketone yields 2-aminoimidazoles of type (XIV) in the
presence of a base, such as potassium carbonate, in a solvent, such
as N,N-dimethylformamide, provides the desired aminoimidazoles. It
is recognized that more than one isomeric imidazole can form during
this reaction and the desired product can be obtained by a suitable
chromatographic method or by recrystallization. (Bioorg. Med. Chem.
Letters 12: 3125-3128 (2002))
##STR00043##
[0251] Amines attached to aryl or heteroaryl ring systems are
useful as intermediates herein. There are many methods of preparing
such intermediates known to one skilled in the art of organic
chemistry. Several methods of preparing amines useful herein are
illustrated in schemes 16-18.
[0252] Substituted aniline of type (XV) can be prepared from
commercially available methyl 4-iodobenzoate as depicted in scheme
16. Nitration followed by reduction of the nitro group yields the
aniline. Palladium-catalyzed coupling with ethynyltrimethylsilane,
followed by desilylation and saponification gives the desired
ethynyl-substituted aminobenzoic acid. Coupling with methoxyamine
using coupling agent EDC affords the desired aniline (XV). (Eur. J.
Org. Chem., 4607 (2001))
##STR00044##
[0253] Alternatively, substituted aniline of type (XV) can be
prepared 4-amino-3-nitrobenzoic acid as depicted in scheme 17.
Iodide substitution of the aryldiazonium salt, followed by
esterification with methanol gives methyl 4-iodo-3-nitrobenzoate.
The nitro group can be reduced by SnCl.sub.4 to give the desired
aniline. Palladium catalyzed coupling with ethynyltrimethylsilane,
followed by desilylation and saponification yields the
ethynyl-substituted aminobenzoic acid. Coupling with methoxyamine
using coupling agent EDC affords the desired aniline (XV). (Eur. J.
Org. Chem., 4607 (2001))
##STR00045##
[0254] As depicted in scheme 18, substituted aniline of type (XVI)
can be prepared from intermediate methyl 4-iodo-3-nitrobenzoate,
which can be synthesized as shown in scheme 17. Palladium catalyzed
coupling with vinyltributyltin followed by carbene addition to the
result styrene double bond gives the cyclopropyl substituted methyl
nitrobenzoate. Reduction of the nitro group followed by Boc
protection and saponification gives the protected
3-amino-4-cyclopropylbenzoic acid. Coupling with an alkoxyamine
using coupling agent EDC affords the desired aniline (XVI).
##STR00046##
References of additional synthetic methods are as follows: [0255]
1) J. Heterocyclic Chem. 17, 631 (1980) [0256] 2) Tetrahedron
55(48), 13703 (1999) [0257] 3) EP 0 713 876 [0258] 4) Chemische
Berichte 126(10), 2317 (1993) [0259] 5) Journal of Organic Chem.
58(24), 6620 (1993) [0260] 6) Tetrahedron Letters 35, 3239 (1973)
[0261] 7) Journal of Chemical Research, Synopses 1, 2 (1997) [0262]
8) Boletin de la Sociedad Quimica del Peru 53(3), 150 (1987) [0263]
9) Journal of the Chemical Society, Chemical Communications 2, 35
(1973) [0264] 10) Comptes Rendus des Seances de l'Academie des
Sciences, Series C: Sciences Chimiques 274(20), 1703 (1972)
D. Formulation of Pharmaceutical Compositions
[0265] The pharmaceutical compositions provided herein contain
therapeutically effective amounts of one or more of the cytokine
activity modulators provided herein that are useful in the
prevention, treatment, or amelioration of one or more of the
symptoms of diseases or disorders associated with cytokine
activity, in one embodiment, p38 kinase activity. Such diseases or
disorders include, but are not limited to, inflammatory diseases,
autoimmune diseases, destructive bone disorders, proliferative
disorders, angiogenic disorders, infectious diseases,
neurodegenerative diseases, and viral diseases.
[0266] The compositions contain one or more compounds provided
herein. The compounds are formulated into suitable pharmaceutical
preparations such as solutions, suspensions, tablets, dispersible
tablets, pills, capsules, powders, sustained release formulations
or elixirs, for oral administration or in sterile solutions or
suspensions for parenteral administration, as well as transdermal
patch preparation and dry powder inhalers. Typically the compounds
described above are formulated into pharmaceutical compositions
using techniques and procedures well known in the art (see, e.g.,
Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition
1985, 126).
[0267] In the compositions, effective concentrations of one or more
compounds or pharmaceutically acceptable derivatives is (are) mixed
with a suitable pharmaceutical carrier or vehicle. The compounds
may be derivatized as the corresponding salts, esters, enol ethers
or esters, acids, bases, solvates, hydrates or prodrugs prior to
formulation, as described above. The concentrations of the
compounds in the compositions are effective for delivery of an
amount, upon administration, that treats, prevents, or ameliorates
one or more of the symptoms of diseases or disorders associated
with cytokine activity or in which cytokine activity is implicated.
Such diseases or disorders include, but are not limited to,
inflammatory diseases, autoimmune diseases, destructive bone
disorders, proliferative disorders, angiogenic disorders,
infectious diseases, neurodegenerative diseases, and viral
diseases.
[0268] Typically, the compositions are formulated for single dosage
administration. To formulate a composition, the weight fraction of
compound is dissolved, suspended, dispersed or otherwise mixed in a
selected vehicle at an effective concentration such that the
treated condition is relieved or ameliorated. Pharmaceutical
carriers or vehicles suitable for administration of the compounds
provided herein include any such carriers known to those skilled in
the art to be suitable for the particular mode of
administration.
[0269] In addition, the compounds may be formulated as the sole
pharmaceutically active ingredient in the composition or may be
combined with other active ingredients. Liposomal suspensions,
including tissue-targeted liposomes, such as tumor-targeted
liposomes, may also be suitable as pharmaceutically acceptable
carriers. These may be prepared according to methods known to those
skilled in the art. For example, liposome formulations may be
prepared as described in U.S. Pat. No. 4,522,811. Briefly,
liposomes such as multilamellar vesicles (MLV's) may be formed by
drying down egg phosphatidyl choline and brain phosphatidyl serine
(7:3 molar ratio) on the inside of a flask. A solution of a
compound provided herein in phosphate buffered saline lacking
divalent cations (PBS) is added and the flask shaken until the
lipid film is dispersed. The resulting vesicles are washed to
remove unencapsulated compound, pelleted by centrifugation, and
then resuspended in PBS.
[0270] The active compound is included in the pharmaceutically
acceptable carrier in an amount sufficient to exert a
therapeutically useful effect in the absence of undesirable side
effects on the patient treated.
[0271] The concentration of active compound in the pharmaceutical
composition will depend on absorption, inactivation and excretion
rates of the active compound, the physicochemical characteristics
of the compound, the dosage schedule, and amount administered as
well as other factors known to those of skill in the art. For
example, the amount that is delivered is sufficient to ameliorate
one or more of the symptoms of diseases or disorders associated
with cytokine activity or in which cytokine activity is implicated,
as described herein.
[0272] The effective amount of a compound of provided herein may be
determined by one of ordinary skill in the art, and includes
exemplary dosage amounts for a mammal of from about 0.05 to 100
mg/kg of body weight of active compound per day, which may be
administered in a single dose or in the form of individual divided
doses, such as from 1 to 4 times per day. It will be understood
that the specific dose level and frequency of dosage for any
particular subject may be varied and will depend upon a variety of
factors, including the activity of the specific compound employed,
the metabolic stability and length of action of that compound, the
species, age, body weight, general health, sex and diet of the
subject, the mode and time of administration, rate of excretion,
drug combination, and severity of the particular condition.
[0273] The active ingredient may be administered at once, or may be
divided into a number of smaller doses to be administered at
intervals of time. It is understood that the precise dosage and
duration of treatment is a function of the disease being treated
and may be determined empirically using known testing protocols or
by extrapolation from in vivo or in vitro test data. It is to be
noted that concentrations and dosage values may also vary with the
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
compositions.
[0274] Pharmaceutically acceptable derivatives include acids,
bases, enol ethers and esters, salts, esters, hydrates, solvates
and prodrug forms. The derivative is selected such that its
pharmacokinetic properties are superior to the corresponding
neutral compound.
[0275] Thus, effective concentrations or amounts of one or more of
the compounds described herein or pharmaceutically acceptable
derivatives thereof are mixed with a suitable pharmaceutical
carrier or vehicle for systemic, topical or local administration to
form pharmaceutical compositions. Compounds are included in an
amount effective for ameliorating one or more symptoms of, or for
treating or preventing diseases or disorders associated with
cytokine activity or in which cytokine activity is implicated, as
described herein. The concentration of active compound in the
composition will depend on absorption, inactivation, excretion
rates of the active compound, the dosage schedule, amount
administered, particular formulation as well as other factors known
to those of skill in the art.
[0276] The compositions are intended to be administered by a
suitable route, including orally in form of capsules, tablets,
granules, powders or liquid formulations including syrups;
parenterally, such as subcutaneously, intravenously,
intramiscularly, with intrasternal injection or infusion techniques
(as sterile injectable aq. or non-aq. solutions or suspensions);
nasally such as by inhalation spray; topically, such as in the form
of a cream or ointment; rectally such as in the form of
suppositories; liposomally; and locally. The compositions can be in
liquid, semi-liquid or solid form and are formulated in a manner
suitable for each route of administration. In certain embodiments,
administration of the formulation include parenteral and oral modes
of administration. In one embodiment, the compositions are
administered orally.
[0277] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include any of the
following components: a sterile diluent, such as water for
injection, saline solution, fixed oil, polyethylene glycol,
glycerine, propylene glycol or other synthetic solvent;
antimicrobial agents, such as benzyl alcohol and methyl parabens;
antioxidants, such as ascorbic acid and sodium bisulfite; chelating
agents, such as ethylenediaminetetraacetic acid (EDTA); buffers,
such as acetates, citrates and phosphates; and agents for the
adjustment of tonicity such as sodium chloride or dextrose.
Parenteral preparations can be enclosed in ampules, disposable
syringes or single or multiple dose vials made of glass, plastic or
other suitable material.
[0278] In instances in which the compounds exhibit insufficient
solubility, methods for solubilizing compounds may be used. Such
methods are known to those of skill in this art, and include, but
are not limited to, using cosolvents, such as dimethylsulfoxide
(DMSO), using surfactants, such as TWEEN.RTM., or dissolution in
aqueous sodium bicarbonate. Derivatives of the compounds, such as
prodrugs of the compounds may also be used in formulating effective
pharmaceutical compositions.
[0279] Upon mixing or addition of the compound(s), the resulting
mixture may be a solution, suspension, emulsion or the like. The
form of the resulting mixture depends upon a number of factors,
including the intended mode of administration and the solubility of
the compound in the selected carrier or vehicle. The effective
concentration is sufficient for ameliorating the symptoms of the
disease, disorder or condition treated and may be empirically
determined.
[0280] The pharmaceutical compositions are provided for
administration to humans and animals in unit dosage forms, such as
tablets, capsules, pills, powders, granules, sterile parenteral
solutions or suspensions, and oral solutions or suspensions, and
oil-water emulsions containing suitable quantities of the compounds
or pharmaceutically acceptable derivatives thereof. The
pharmaceutically therapeutically active compounds and derivatives
thereof are typically formulated and administered in unit-dosage
forms or multiple-dosage forms. Unit-dose forms as used herein
refers to physically discrete units suitable for human and animal
subjects and packaged individually as is known in the art. Each
unit-dose contains a predetermined quantity of the therapeutically
active compound sufficient to produce the desired therapeutic
effect, in association with the required pharmaceutical carrier,
vehicle or diluent. Examples of unit-dose forms include ampoules
and syringes and individually packaged tablets or capsules.
Unit-dose forms may be administered in fractions or multiples
thereof. A multiple-dose form is a plurality of identical
unit-dosage forms packaged in a single container to be administered
in segregated unit-dose form. Examples of multiple-dose forms
include vials, bottles of tablets or capsules or bottles of pints
or gallons. Hence, multiple dose form is a multiple of unit-doses
which are not segregated in packaging.
[0281] The composition can contain along with the active
ingredient: a diluent such as lactose, sucrose, dicalcium
phosphate, or carboxymethylcellulose; a lubricant, such as
magnesium stearate, calcium stearate and talc; and a binder such as
starch, natural gums, such as gum acaciagelatin, glucose, molasses,
polyinylpyrrolidine, celluloses and derivatives thereof, povidone,
crospovidones and other such binders known to those of skill in the
art. Liquid pharmaceutically administrable compositions can, for
example, be prepared by dissolving, dispersing, or otherwise mixing
an active compound as defined above and optional pharmaceutical
adjuvants in a carrier, such as, for example, water, saline,
aqueous dextrose, glycerol, glycols, ethanol, and the like, to
thereby form a solution or suspension. If desired, the
pharmaceutical composition to be administered may also contain
minor amounts of nontoxic auxiliary substances such as wetting
agents, emulsifying agents, or solubilizing agents, pH buffering
agents and the like, for example, acetate, sodium citrate,
cyclodextrine derivatives, sorbitan monolaurate, triethanolamine
sodium acetate, triethanolamine oleate, and other such agents.
Actual methods of preparing such dosage forms are known, or will be
apparent, to those skilled in this art; for example, see
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pa., 15th Edition, 1975. The composition or formulation to
be administered will, in any event, contain a quantity of the
active compound in an amount sufficient to alleviate the symptoms
of the treated subject.
[0282] Dosage forms or compositions containing active ingredient in
the range of 0.005% to 100% with the balance made up from non-toxic
carrier may be prepared. For oral administration, a
pharmaceutically acceptable non-toxic composition is formed by the
incorporation of any of the normally employed excipients, such as,
for example pharmaceutical grades of mannitol, lactose, starch,
magnesium stearate, talcum, cellulose derivatives, sodium
crosscarmellose, glucose, sucrose, magnesium carbonate or sodium
saccharin. Such compositions include solutions, suspensions,
tablets, capsules, powders and sustained release formulations, such
as, but not limited to, implants and microencapsulated delivery
systems, and biodegradable, biocompatible polymers, such as
collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic
acid, polyorthoesters, polylactic acid and others. Methods for
preparation of these compositions are known to those skilled in the
art. The contemplated compositions may contain 0.001%-100% active
ingredient, in one embodiment 0.1-85%, in another embodiment
75-95%.
[0283] The compounds may be administered in a form suitable for
immediate release or extended release. Immediate release or
extended release may be achieved with suitable pharmaceutical
compositions or, particularly in the case of extended release, with
devices such as subcutaneous implants or osmotic pumps. Exemplary
compositions for topical administration include a topical carrier
such as PLASTIBASE.RTM. (mineral oil gelled with polyethylene).
[0284] The compositions may include other active compounds to
obtain desired combinations of properties. The compounds provided
herein, or pharmaceutically acceptable derivatives thereof as
described herein, may also be advantageously administered for
therapeutic or prophylactic purposes together with another
pharmacological agent known in the general art to be of value in
treating one or more of the diseases or medical conditions referred
to hereinabove, such as diseases or disorders associated with
nuclear receptor activity or in which nuclear receptor activity is
implicated. It is to be understood that such combination therapy
constitutes a further aspect of the compositions and methods of
treatment provided herein.
[0285] 1. Compositions for Oral Administration
[0286] Oral pharmaceutical dosage forms are either solid, gel or
liquid. The solid dosage forms are tablets, capsules, granules, and
bulk powders. Types of oral tablets include compressed, chewable
lozenges and tablets which may be enteric-coated, sugar-coated or
film-coated. Capsules may be hard or soft gelatin capsules, while
granules and powders may be provided in non-effervescent or
effervescent form with the combination of other ingredients known
to those skilled in the art.
[0287] In certain embodiments, the formulations are solid dosage
forms, preferably capsules or tablets. The tablets, pills,
capsules, troches and the like can contain any of the following
ingredients, or compounds of a similar nature: a binder; a diluent;
a disintegrating agent; a lubricant; a glidant; a sweetening agent;
and a flavoring agent.
[0288] Examples of binders include microcrystalline cellulose, gum
tragacanth, glucose solution, acacia mucilage, gelatin solution,
sucrose and starch paste. Lubricants include talc, starch,
magnesium or calcium stearate, lycopodium and stearic acid.
Diluents include, for example, lactose, sucrose, starch, kaolin,
salt, mannitol and dicalcium phosphate. Glidants include, but are
not limited to, colloidal silicon dioxide. Disintegrating agents
include crosscarmellose sodium, sodium starch glycolate, alginic
acid, sodium alginate, corn starch, potato starch, bentonite,
methylcellulose, agar and carboxymethylcellulose. Coloring agents
include, for example, any of the approved certified water soluble
FD and C dyes, mixtures thereof; and water insoluble FD and C dyes
suspended on alumina hydrate. Sweetening agents include sucrose,
lactose, mannitol and artificial sweetening agents such as
saccharin, and any number of spray dried flavors. Flavoring agents
include natural flavors extracted from plants such as fruits and
synthetic blends of compounds which produce a pleasant sensation,
such as, but not limited to peppermint and methyl salicylate.
Wetting agents include propylene glycol monostearate, sorbitan
monooleate, diethylene glycol monolaurate and polyoxyethylene
laural ether. Emetic-coatings include fatty acids, fats, waxes,
shellac, ammoniated shellac and cellulose acetate phthalates. Film
coatings include hydroxyethylcellulose, sodium
carboxymethylcellulose, polyethylene glycol 4000 and cellulose
acetate phthalate.
[0289] If oral administration is desired, the compound could be
provided in a composition that protects it from the acidic
environment of the stomach. For example, the composition can be
formulated in an enteric coating that maintains its integrity in
the stomach and releases the active compound in the intestine. The
composition may also be formulated in combination with an antacid
or other such ingredient.
[0290] When the dosage unit form is a capsule, it can contain, in
addition to material of the above type, a liquid carrier such as a
fatty oil. In addition, dosage unit forms can contain various other
materials which modify the physical form of the dosage unit, for
example, coatings of sugar and other enteric agents. The compounds
can also be administered as a component of an elixir, suspension,
syrup, wafer, sprinkle, chewing gum or the like. A syrup may
contain, in addition to the active compounds, sucrose as a
sweetening agent and certain preservatives, dyes and colorings and
flavors.
[0291] The active materials can also be mixed with other active
materials which do not impair the desired action, or with materials
that supplement the desired action, such as antacids, H2 blockers,
and diuretics. The active ingredient is a compound or
pharmaceutically acceptable derivative thereof as described herein.
Higher concentrations, up to about 98% by weight of the active
ingredient may be included.
[0292] Pharmaceutically acceptable carriers included in tablets are
binders, lubricants, diluents, disintegrating agents, coloring
agents, flavoring agents, and wetting agents. Enteric-coated
tablets, because of the enteric-coating, resist the action of
stomach acid and dissolve or disintegrate in the neutral or
alkaline intestines. Sugar-coated tablets are compressed tablets to
which different layers of pharmaceutically acceptable substances
are applied. Film-coated tablets are compressed tablets which have
been coated with a polymer or other suitable coating. Multiple
compressed tablets are compressed tablets made by more than one
compression cycle utilizing the pharmaceutically acceptable
substances previously mentioned. Coloring agents may also be used
in the above dosage forms. Flavoring and sweetening agents are used
in compressed tablets, sugar-coated, multiple compressed and
chewable tablets. Flavoring and sweetening agents are especially
useful in the formation of chewable tablets and lozenges.
[0293] Liquid oral dosage forms include aqueous solutions,
emulsions, suspensions, solutions and/or suspensions reconstituted
from non-effervescent granules and effervescent preparations
reconstituted from effervescent granules. Aqueous solutions
include, for example, elixirs and syrups. Emulsions are either
oil-in-water or water-in-oil.
[0294] Elixirs are clear, sweetened, hydroalcoholic preparations.
Pharmaceutically acceptable carriers used in elixirs include
solvents. Syrups are concentrated aqueous solutions of a sugar, for
example, sucrose, and may contain a preservative. An emulsion is a
two-phase system in which one liquid is dispersed in the form of
small globules throughout another liquid. Pharmaceutically
acceptable carriers used in emulsions are non-aqueous liquids,
emulsifying agents and preservatives. Suspensions use
pharmaceutically acceptable suspending agents and preservatives.
Pharmaceutically acceptable substances used in non-effervescent
granules, to be reconstituted into a liquid oral dosage form,
include diluents, sweeteners and wetting agents. Pharmaceutically
acceptable substances used in effervescent granules, to be
reconstituted into a liquid oral dosage form, include organic acids
and a source of carbon dioxide. Coloring and flavoring agents are
used in all of the above dosage forms.
[0295] Solvents include glycerin, sorbitol, ethyl alcohol and
syrup. Examples of preservatives include glycerin, methyl and
propylparaben, benzoic add, sodium benzoate and alcohol. Examples
of non-aqueous liquids utilized in emulsions include mineral oil
and cottonseed oil. Examples of emulsifying agents include gelatin,
acacia, tragacanth, bentonite, and surfactants such as
polyoxyethylene sorbitan monooleate. Suspending agents include
sodium carboxymethylcellulose, pectin, tragacanth, Veegum and
acacia. Diluents include lactose and sucrose. Sweetening agents
include sucrose, syrups, glycerin and artificial sweetening agents
such as saccharin. Wetting agents include propylene glycol
monostearate, sorbitan monooleate, diethylene glycol monolaurate
and polyoxyethylene lauryl ether. Organic adds include citric and
tartaric acid. Sources of carbon dioxide include sodium bicarbonate
and sodium carbonate. Coloring agents include any of the approved
certified water soluble FD and C dyes, and mixtures thereof.
Flavoring agents include natural flavors extracted from plants such
fruits, and synthetic blends of compounds which produce a pleasant
taste sensation.
[0296] For a solid dosage form, the solution or suspension, in for
example propylene carbonate, vegetable oils or triglycerides, is
preferably encapsulated in a gelatin capsule. Such solutions, and
the preparation and encapsulation thereof, are disclosed in U.S.
Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage
form, the solution, e.g., for example, in a polyethylene glycol,
may be diluted with a sufficient quantity of a pharmaceutically
acceptable liquid carrier, e.g., water, to be easily measured for
administration.
[0297] Alternatively, liquid or semi-solid oral formulations may be
prepared by dissolving or dispersing the active compound or salt in
vegetable oils, glycols, triglycerides, propylene glycol esters
(e.g., propylene carbonate) and other such carriers, and
encapsulating these solutions or suspensions in hard or soft
gelatin capsule shells. Other useful formulations include those set
forth in U.S. Pat. Nos. Re 28,819 and 4,358,603. Briefly, such
formulations include, but are not limited to, those containing a
compound provided herein, a dialkylated mono- or poly-alkylene
glycol, including, but not limited to, 1,2-dimethoxymethane,
diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl
ether, polyethylene glycol-550-dimethyl ether, polyethylene
glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the
approximate average molecular weight of the polyethylene glycol,
and one or more antioxidants, such as butylated hydroxytoluene
(BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E,
hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin,
ascorbic acid, malic acid, sorbitol, phosphoric acid,
thiodipropionic acid and its esters, and dithiocarbamates.
[0298] Other formulations include, but are not limited to, aqueous
alcoholic solutions including a pharmaceutically acceptable acetal.
Alcohols used in these formulations are any pharmaceutically
acceptable water-miscible solvents having one or more hydroxyl
groups, including, but not limited to, propylene glycol and
ethanol. Acetals include, but are not limited to, di(lower
alkyl)acetals of lower alkyl aldehydes such as acetaldehyde diethyl
acetal.
[0299] In all embodiments, tablets and capsules formulations may be
coated as known by those of skill in the art in order to modify or
sustain dissolution of the active ingredient. Thus, for example,
they may be coated with a conventional enterically digestible
coating, such as phenylsalicylate, waxes and cellulose acetate
phthalate.
[0300] Exemplary compositions may include fast-dissolving diluents
such as mannitol, lactose, sucrose, and/or cyclodextrins. Also
included in such formulations may be high molecular weight
excipients such as celluloses (AVICEL.RTM.) or polyethylene glycols
(PEG); an excipient to aid mucosal adhesion such as hydroxypropyl
cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium
carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer
(e.g., GANTREZ.RTM.); and agents to control release such as
polyacrylic copolymer (e.g., CARBOPOL 934.RTM.). Lubricants,
glidants, flavors, coloring agents and stabilizers may also be
added for ease of fabrication and use.
[0301] 2. Injectables, Solutions and Emulsions
[0302] Parenteral administration, generally characterized by
injection, either subcutaneously, intramuscularly or intravenously
is also contemplated herein. Injectables can be prepared in
conventional forms, either as liquid solutions or suspensions,
solid forms suitable for solution or suspension in liquid prior to
injection, or as emulsions. Suitable excipients are, for example,
water, saline, dextrose, glycerol, mannitol, 1,3-butanediol,
Ringer's solution, an isotonic sodium chloride solution or ethanol.
In addition, if desired, the pharmaceutical compositions to be
administered may also contain minor amounts of non-toxic auxiliary
substances such as wetting or emulsifying agents, pH buffering
agents, stabilizers, solubility enhancers, and other such agents,
such as for example, mono- or diglycerides, fatty acids, such as
oleic acid, sodium acetate, sorbitan monolaurate, triethanolamine
oleate and cyclodextrins. Implantation of a slow-release or
sustained-release system, such that a constant level of dosage is
maintained (see, e.g., U.S. Pat. No. 3,710,795) is also
contemplated herein. Briefly, a compound provided herein is
dispersed in a solid inner matrix, e.g., polymethylmethacrylate,
polybutylmethacrylate, plasticized or unplasticized
polyvinylchloride, plasticized nylon, plasticized
polyethyleneterephthalate, natural rubber, polyisoprene,
polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate
copolymers, silicone rubbers, polydimethylsiloxanes, silicone
carbonate copolymers, hydrophilic polymers such as hydrogels of
esters of acrylic and methacrylic acid, collagen, cross-linked
polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl
acetate, that is surrounded by an outer polymeric membrane, e.g.,
polyethylene, polypropylene, ethylene/propylene copolymers,
ethylene/ethyl acrylate copolymers, ethylene/vinylacetate
copolymers, silicone rubbers, polydimethyl siloxanes, neoprene
rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride
copolymers with vinyl acetate, vinylidene chloride, ethylene and
propylene, ionomer polyethylene terephthalate, butyl rubber
epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,
ethylene/vinyl acetate/vinyl alcohol terpolymer, and
ethylene/vinyloxyethanol copolymer, that is insoluble in body
fluids. The compound diffuses through the outer polymeric membrane
in a release rate controlling step. The percentage of active
compound contained in such parenteral compositions is highly
dependent on the specific nature thereof, as well as the activity
of the compound and the needs of the subject.
[0303] Parenteral administration of the compositions includes
intravenous, subcutaneous and intramuscular administrations.
Preparations for parenteral administration include sterile
solutions ready for injection, sterile dry soluble products, such
as lyophilized powders, ready to be combined with a solvent just
prior to use, including hypodermic tablets, sterile suspensions
ready for injection, sterile dry insoluble products ready to be
combined with a vehicle just prior to use and sterile emulsions.
The solutions may be either aqueous or nonaqueous.
[0304] If administered intravenously, suitable carriers include
physiological saline or phosphate buffered saline (PBS), and
solutions containing thickening and solubilizing agents, such as
glucose, polyethylene glycol, and polypropylene glycol and mixtures
thereof.
[0305] Pharmaceutically acceptable carriers used in parenteral
preparations include aqueous vehicles, nonaqueous vehicles,
antimicrobial agents, isotonic agents, buffers, antioxidants, local
anesthetics, suspending and dispersing agents, emulsifying agents,
sequestering or chelating agents and other pharmaceutically
acceptable substances.
[0306] Examples of aqueous vehicles include Sodium Chloride
Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile
Water Injection, Dextrose and Lactated Ringers Injection.
Nonaqueous parenteral vehicles include fixed oils of vegetable
origin, cottonseed oil, corn oil, sesame oil and peanut oil.
Antimicrobial agents in bacteriostatic or fungistatic
concentrations must be added to parenteral preparations packaged in
multiple-dose containers which include phenols or cresols,
mercurials, benzyl alcohol, chlorobutanol, methyl and propyl
p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and
benzethonium chloride. Isotonic agents include sodium chloride and
dextrose. Buffers include phosphate and citrate. Antioxidants
include sodium bisulfate. Local anesthetics include procaine
hydrochloride. Suspending and dispersing agents include sodium
carboxymethylcelluose, hydroxypropyl methylcellulose and
polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80
(TWEEN.RTM. 80). A sequestering or chelating agent of metal ions
include EDTA. Pharmaceutical carriers also include ethyl alcohol,
polyethylene glycol and propylene glycol for water miscible
vehicles and sodium hydroxide, hydrochloric acid, citric acid or
lactic acid for pH adjustment.
[0307] The concentration of the pharmaceutically active compound is
adjusted so that an injection provides an effective amount to
produce the desired pharmacological effect. The exact dose depends
on the age, weight and condition of the patient or animal as is
known in the art.
[0308] The unit-dose parenteral preparations are packaged in an
ampoule, a vial or a syringe with a needle. All preparations for
parenteral administration must be sterile, as is known and
practiced in the art.
[0309] Illustratively, intravenous or intraarterial infusion of a
sterile aqueous solution containing an active compound is an
effective mode of administration. Another embodiment is a sterile
aqueous or oily solution or suspension containing an active
material injected as necessary to produce the desired
pharmacological effect.
[0310] Injectables are designed for local and systemic
administration. Typically a therapeutically effective dosage is
formulated to contain a concentration of at least about 0.1% w/w up
to about 90% w/w or more, preferably more than 1% w/w of the active
compound to the treated tissue(s). The active ingredient may be
administered at once, or may be divided into a number of smaller
doses to be administered at intervals of time. It is understood
that the precise dosage and duration of treatment is a function of
the tissue being treated and may be determined empirically using
known testing protocols or by extrapolation from in vivo or in
vitro test data. It is to be noted that concentrations and dosage
values may also vary with the age of the individual treated. It is
to be further understood that for any particular subject, specific
dosage regimens should be adjusted over time according to the
individual need and the professional judgment of the person
administering or supervising the administration of the
formulations, and that the concentration ranges set forth herein
are exemplary only and are not intended to limit the scope or
practice of the claimed formulations.
[0311] The compound may be suspended in micronized or other
suitable form or may be derivatized to produce a more soluble
active product or to produce a prodrug. The form of the resulting
mixture depends upon a number of factors, including the intended
mode of administration and the solubility of the compound in the
selected carrier or vehicle. The effective concentration is
sufficient for ameliorating the symptoms of the condition and may
be empirically determined.
[0312] 3. Lyophilized Powders
[0313] Of interest herein are also lyophilized powders, which can
be reconstituted for administration as solutions, emulsions and
other mixtures. They may also be reconstituted and formulated as
solids or gels.
[0314] The sterile, lyophilized powder is prepared by dissolving a
compound provided herein, or a pharmaceutically acceptable
derivative thereof, in a suitable solvent. The solvent may contain
an excipient which improves the stability or other pharmacological
component of the powder or reconstituted solution, prepared from
the powder. Excipients that may be used include, but are not
limited to, dextrose, sorbital, fructose, corn syrup, xylitol,
glycerin, glucose, sucrose or other suitable agent. The solvent may
also contain a buffer, such as citrate, sodium or potassium
phosphate or other such buffer known to those of skill in the art
at, typically, about neutral pH. Subsequent sterile filtration of
the solution followed by lyophilization under standard conditions
known to those of skill in the art provides the desired
formulation. Generally, the resulting solution will be apportioned
into vials for lyophilization. Each vial will contain a single
dosage 10-1000 mg, in one embodiment, 100-500 mg or multiple
dosages of the compound. The lyophilized powder can be stored under
appropriate conditions, such as at about 4.degree. C. to room
temperature.
[0315] Reconstitution of this lyophilized powder with water for
injection provides a formulation for use in parenteral
administration. For reconstitution, about 1-50 mg, preferably 5-35
mg, more preferably about 9-30 mg of lyophilized powder, is added
per mL of sterile water or other suitable carrier. The precise
amount depends upon the selected compound. Such amount can be
empirically determined.
[0316] 4. Topical Administration
[0317] Topical mixtures are prepared as described for the local and
systemic administration. The resulting mixture may be a solution,
suspension, emulsions or the like and are formulated as creams,
gels, ointments, emulsions, solutions, elixirs, lotions,
suspensions, tinctures, pastes, foams, aerosols, irrigations,
sprays, suppositories, bandages, dermal patches or any other
formulations suitable for topical administration.
[0318] The compounds or pharmaceutically acceptable derivatives
thereof may be formulated as aerosols for topical application, such
as by inhalation (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209,
and 4,364,923, which describe aerosols for delivery of a steroid
useful for treatment of inflammatory diseases, particularly
asthma). These formulations for administration to the respiratory
tract can be in the form of an aerosol or solution for a nebulizer,
or as a microfine powder for insufflation, alone or in combination
with an inert carrier such as lactose. In such a case, the
particles of the formulation will typically have diameters of less
than 50 microns, preferably less than 10 microns.
[0319] Exemplary compositions for nasal aerosol or inhalation
administration include solutions which may contain, for example,
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance absorption and/or bioavailability, and/or
other solubilizing or dispersing agents such as those known in the
art.
[0320] The compounds may be formulated for local or topical
application, such as for topical application to the skin and mucous
membranes, such as in the eye, in the form of gels, creams, and
lotions and for application to the eye or for intracisternal or
intraspinal application. Topical administration is contemplated for
transdermal delivery and also for administration to the eyes or
mucosa, or for inhalation therapies. Nasal solutions of the active
compound alone or in combination with other pharmaceutically
acceptable excipients can also be administered.
[0321] These solutions, particularly those intended for ophthalmic
use, may be formulated as 0.01%-10% isotonic solutions, pH about
5-7, with appropriate salts.
[0322] 5. Compositions for Other Routes of Administration
[0323] Other routes of administration, such as topical application,
transdermal patches, and rectal administration are also
contemplated herein.
[0324] For example, pharmaceutical dosage forms for rectal
administration are rectal suppositories, capsules and tablets for
systemic effect. Rectal suppositories are used herein mean solid
bodies for insertion into the rectum which melt or soften at body
temperature releasing one or more pharmacologically or
therapeutically active ingredients. Pharmaceutically acceptable
substances utilized in rectal suppositories are bases or vehicles
and agents to raise the melting point. Examples of bases include
cocoa butter (theobroma oil), glycerin-gelatin, carbowax
(polyoxyethylene glycol) and appropriate mixtures of mono-, di- and
triglycerides of fatty acids. Combinations of the various bases may
be used. Agents to raise the melting point of suppositories include
spermaceti and wax. Rectal suppositories may be prepared either by
the compressed method or by molding. The typical weight of a rectal
suppository is about 2 to 3 gm.
[0325] Tablets and capsules for rectal administration are
manufactured using the same pharmaceutically acceptable substance
and by the same methods as for formulations for oral
administration.
[0326] 6. Articles of Manufacture
[0327] The compounds or pharmaceutically acceptable derivatives may
be packaged as articles of manufacture containing packaging
material, a compound or pharmaceutically acceptable derivative
thereof provided herein, which is effective for modulating the
activity of cytokines, in one embodiment, the activity of p38
kinases, or for treatment, prevention or amelioration of one or
more symptoms of cytokine, in one embodiment, p38 kinase, mediated
diseases or disorders, or diseases or disorders in which cytokine
activity, in one embodiment, p38 kinase activity, is implicated,
within the packaging material, and a label that indicates that the
compound or composition, or pharmaceutically acceptable derivative
thereof, is used for modulating the activity of cytokines, in one
embodiment, p38 kinases, or for treatment, prevention or
amelioration of one or more symptoms of cytokine, in one
embodiment, p38 kinase, mediated diseases or disorders, or diseases
or disorders in which cytokine activity, in one embodiment, p38
kinase activity, is implicated.
[0328] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products are well known to those of skill in the
art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.
Examples of pharmaceutical packaging materials include, but are not
limited to, blister packs, bottles, tubes, inhalers, pumps, bags,
vials, containers, syringes, bottles, and any packaging material
suitable for a selected formulation and intended mode of
administration and treatment. A wide array of formulations of the
compounds and compositions provided herein are contemplated as are
a variety of treatments for any disease or disorder in which
cytokine activity, in one embodiment, p38 kinase activity, is
implicated as a mediator or contributor to the symptoms or
cause.
E. Evaluation of the Activity of the Compounds
[0329] Standard physiological, pharmacological and biochemical
procedures are available for testing the compounds to identify
those that possess biological activities that modulate the activity
of cytokines, including the p38 kinase activity.
[0330] Compound inhibitory activity was measured in a radioactive
enzyme assay. The buffer composition was adopted from Lisnock et al
(Biochemistry, 1998, vol. 37, pp 16573-16581). Peptide substrate
was selected from Chen et al (Biochemistry, 2000, vol. 39,
2079-2087). The concentrations of p38.alpha.,
[.gamma.-.sup.33P-ATP] and peptide were equal 1 nM, 85 uM and 250
uM, respectively. Incorporation of .sup.33P into peptide was
measured using absorption on filtermats with subsequent wash with
100 mM phosphoric acid followed by ethanol.
[0331] Other conditions for the p38.alpha. enzymatic assay were
also described in literature. They either differed from the assay
described in either buffer composition (Biochemistry, 2000, vol.
39, 2079-2087)), or substrate (Biochemistry, 1998, vol. 37, pp
16573-16581), or both (Protein Sci., 1998, vol. 7, pp.
2249-2255).
F. Methods of Use of the Compounds and Compositions
[0332] In certain embodiments, the compounds provided herein are
selective inhibitors of p38 kinase activity, and in one embodiment,
the compounds are inhibitors of isoforms of p38 kinase, including,
but not limited to p38.alpha. and p38.beta. kinases. Accordingly,
compounds of formula (I) have utility in treating conditions
associated with p38 kinase activity. Such conditions include
diseases in which cytokine levels are modulated as a consequence of
intracellular signaling via p38, and in particular, diseases that
are associated with an overproduction of cytokines IL-1, IL-4,
IL-8, and TNF-.alpha..
[0333] In view of their activity as inhibitors of p38.alpha./.beta.
kinase, compounds of Formula (I) are useful in treating p38
associated conditions including, but not limited to, inflammatory
diseases, autoimmune diseases, destructive bone disorders,
proliferative disorders, angiogenic disorders, infectious diseases,
neurodegenerative diseases, and viral diseases.
[0334] Inflammatory diseases related to p38-associated condition
include, but are not limited to acute pancreatitis, chronic
pancreatitis, asthma, allergies, and adult respiratory distress
syndrome.
[0335] Autoimmune diseases related to p38-associated condition
include, but are not limited to, glomeralonephritis, rheumatoid
arthritis, systemic lupus erythematosus, scleroderma, chronic
thyroiditis, Graves' disease, autoimmune gastritis,
insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic
anemia, autoimmune neutropenia, thrombocytopenia, atopic
dermatitis, chronic active hepatitis, myasthenia gravis, multiple
sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's
disease, psoriasis, or graft vs. host disease.
[0336] Destructive bone disorders related to p38-associated
condition include, but are not limited to, osteoporosis,
osteoarthritis and multiple myeloma-related bone disorder.
[0337] Proliferative diseases which are related to p38-associated
condition include, but are not limited to, acute myelogenous
leukemia, chronic myelogenous leukemia, metastatic melanoma,
Kaposi's sarcoma, and multiple myeloma.
[0338] Infectious diseases related to p38-associated condition
include, but are not limited to, sepsis, septic shock, and
Shigellosis.
[0339] Viral diseases related to p38-associated condition include,
but are not limited to, acute hepatitis infection (including
hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV
retinitis.
[0340] Degenerative or diseases related to p38-associated condition
include, but are not limited to, Alzheimer's disease, Parkinson's
disease, cerebral ischemia, and other neurodegenerative
diseases.
[0341] "p38-associated conditions" also include
ischemia/reperfusion in stroke, heart attacks, myocardial ischemia,
organ hypoxia, vascular hyperplasia, cardiac hypertrophy, and
thrombin-induced platelet aggregation.
[0342] In addition, p38 inhibitors provided herein are also capable
of inhibiting the expression of inducible pro-inflammatory proteins
such as prostaglandin endoperoxide synthase-2 (PGHS-2), also
referred to as cyclooxygenase-2 (COX-2). Therefore, other
"p38-mediated conditions" are edema, analgesia, fever and pain,
such as neuromuscular pain, headache, cancer pain, dental pain and
arthritis pain.
[0343] The diseases that may be treated or prevented by the p38
inhibitors provided herein, may also be conveniently grouped by the
cytokine (IL-1, TNF, IL-6, IL-8) that is believed to be responsible
for the disease.
[0344] Thus, an IL-1-mediated disease or condition includes
rheumatoid arthritis, osteoarthritis, stroke, endotoxemia and/or
toxic shock syndrome, inflammatory reaction induced by endotoxin,
inflammatory bowel disease, tuberculosis, atherosclerosis, muscel
degeneration, cachexia, psoriatic arthritis, Reiter's syndrome,
gout, traumatic arthritis, rubella arthritis, acute synovitis,
diabetes, pancreatic .beta.-cell disease and Alzheimer's
disease.
[0345] TNF-mediated disease or condition includes, rheumatoid
arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis
and other arthritic conditions, sepsis, septic shock, endotoxic
shock, gram negative sepsis, toxic shock syndrome, adult
respiratory distress syndrome, cerebral malaria, chronic pulmonary
inflammatory disease, silicosis, pulmonary sarcoisosis, bone
resorption diseases, reperfusion injury, graft vs. host reaction,
allograft rejections, fever and myalgias due to infection, cachexia
secondary to infection, AIDS, ARC or malignancy, keloid formation,
scar tissue formation, Crohn's disease, ulcerative colitis or
pyresis. TNF-mediated diseases also include viral infections, such
as HIV, CMV, influenza and herpes; and vetinary viral infections,
such as lentivirus infections, including, but not limited to equine
infectious anaemia virus, caprine arthritis virus, visna virus or
maedi virus; or retrovirus infections, including feline
immunodeficiency virus, bovine immunodeficiency virus, or canine
immunodeficiency virus.
[0346] IL-8 mediated disease or condition includes diseases
characterized by massive neutrophil infiltration, such as
psoriasis, inflammatory bowel disease, asthma, cardiac and renal
reperfusion injury, adult respiratory distress syndrome, thrombosis
and glomerulonephritis.
[0347] In addition, the compounds provided herein may be used
topically to treat or prevent conditions caused or exacerbated by
IL-1 or TNF. Such conditions include inflamed joints, eczema,
psoriasis, inflammatory skin conditions such as sunburn,
inflammatory eye conditions such as conjunctivitis, pyresis, pain
and other conditions associated with inflammation.
[0348] In one embodiment, the specific conditions or diseases that
may be treated with the compounds provided herein include, but are
not limited to, pancreatitis (acute or chronic), asthma, allergies,
adult respiratory distress syndrome, chronic obstructive pulmonary
disease, glomerulonephritis, rheumatoid arthritis, systemic lupus
erythematosis, scleroderma, chronic thyroiditis, Grave's disease,
autoimmune gastritis, diabetes, autoimmune hemolytic anemia,
autoimmune neutropenia, thrombocytopenia, atopic dermatitis,
chronic active hepatitis, myasthenia gravis, multiple sclerosis,
inflammatory bowel disease, ulcerative colitis, Crohn's disease,
psoriasis, graft vs. host disease, inflammatory reaction induced by
endotoxin, tuberculosis, atherosclerosis, muscle degeneration,
cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic
arthritis, rubella arthritis, acute synovitis, pancreatic
.beta.-cell disease; diseases characterized by massive neutrophil
infiltration; rheumatoid spondylitis, gouty arthritis and other
arthritic conditions, cerebral malaria, chronic pulmonary
inflammatory disease, silicosis, pulmonary sarcoisosis, bone
resorption disease, allograft rejections, fever and myalgias due to
infection, cachexia secondary to infection, meloid formation, scar
tissue formation, ulcerative colitis, pyresis, influenza,
osteoporosis, osteoarthritis and multiple myeloma-related bone
disorder, acute myelogenous leukemia, chronic myelogenous leukemia,
metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis,
septic shock, and Shigellosis; Alzheimer's disease, Parkinson's
disease, cerebral ischemias or neurodegenerative disease caused by
traumatic injury; angiogenic disorders including solid tumors,
ocular neovasculization, and infantile haemangiomas; viral diseases
including acute hepatitis infection (including hepatitis A,
hepatitis B and hepatitis C), HIV infection and CMV retinitis,
AIDS, SARS, ARC or malignancy, and herpes; stroke, myocardial
ischemia, ischemia in stroke heart attacks, organ hyposia, vascular
hyperplasia, cardiac and renal reperfusion injury, thrombosis,
cardiac hypertrophy, thrombin induced platelet aggregation,
endotoxemia and/or toxic shock syndrome, and conditions associated
with prostaglandin endoperoxidase synthase-2.
[0349] In addition, p38 inhibitors provided herein inhibit the
expression of inducible pro-inflammatory proteins such as
prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to as
cyclooxygenase-2 (COX-2). Accordingly, additional p38-associated
conditions include edema, analgesia, fever and pain, such as
neuromuscular pain, headache, pain caused by cancer, dental pain
and arthritis pain. The compounds provided herein also may be used
to treat veterinary viral infections, such as lentivirus
infections, including, but not limited to equine infectious anemia
virus; or retro virus infections, including feline immunodeficiency
virus, bovine immunodeficiency virus, and canine immunodeficiency
virus.
G. Combination Therapy
[0350] Also provided herein are methods treating p38
kinase-associated conditions by administering to a subject in need
thereof an effective amount of compounds of Formula (I) alone or in
combination with each other and/or other suitable therapeutic
agents useful in treating such conditions. Exemplary of such other
therapeutic agents include corticosteroids, rolipram, calphostin,
CSAIDs, 4-substituted imidazo (1,2-A)quinoxalines as disclosed in
U.S. Pat. No. 4,200,750 and in S. Ceccarelli et al,
"Imidazo[1,2-a]quinoxalin-4-amines: A Novel Class of Nonxanthine
A.sub.1 Adenosine Receptor Antagonists," European Journal of
Medicinal Chemistry Vol. 33, (1998), at pp. 943-955;
Interleukin-10, glucocorticoids, salicylates, nitric oxide, and
other immunosuppressants; nuclear translocation inhibitors, such as
deoxyspergualin (DSG); non-steroidal antiinflammatory drugs
(NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such
as prednisone or dexamethasone; antiviral agents such as abacavir;
antiproliferative agents such as methotrexate, leflunomide, FK506
(tacrolimus, Prograf); cytotoxic drugs such as azathioprine and
cyclophosphamide; TNF-.alpha. inhibitors such as tenidap, anti-TNF
antibodies or soluble TNF receptor, and rapamycin (sirolimus or
Rapamune) or derivatives thereof.
[0351] The above other therapeutic agents, when employed in
combination with the compounds provided herein, may be used, for
example, in those amounts indicated in the Physicians' Desk
Reference (PDR) or as otherwise determined by one of ordinary skill
in the art. In the methods provided herein, such other therapeutic
agent(s) may be administered prior to, simultaneously with, or
following the administration of the compounds provided herein.
[0352] The following Examples illustrate exemplary embodiments, and
are not intended to limit the scope of the claims. Abbreviations
employed in the Examples are defined herein. Compounds of the
Examples are identified by the example and step in which they are
prepared (for example, "1A" denotes the title compound of step A of
Example 1), or by the example only where the compound is the title
compound of the example (for example, "2" denotes the title
compound of Example 2).
[0353] General Methods. Mass spectral data were obtained on a
Thermo Finnigan LCQ Duo Ion Trap mass spectrometer. HPLC data were
obtained on a C.sub.18 Betasol column (2.1.times.50 mm) using
gradient elution 10-90% (solvent A, acetonitrile+0.025% v TFA;
solvent B, water+0.025% v TFA) over 6 minutes (flow rate 0.40
mL/min) or over 4 minutes (flow rate 0.50 mL/min). Purification by
prepatory HPLC on a Thermo Hypersi-Keystone Betasil C18 column
250.times.21.2 mm, particle size 5 .mu.m, mobile phase: A,
water+0.025% TFA; B, acetonitrile+0.025% TFA; gradient from 40 to
70% B; flow rate 15 mL/min.
EXAMPLE 1
Preparation of
N-methoxy-4-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-benzamide
##STR00047##
[0354] A. 3-(3-Benzoyl-thioureido)-N-methoxy-4-methyl-benzamide
[0355] To a stirred suspension of
3-amino-N-methoxy-4-methyl-benzamide (420 mg, 1.94 mmol,
preparation: BMS WO 02/40486 A2, P66) in CH.sub.2Cl.sub.2 (10 ml)
was added benzoyl isothiocyanate (332 mg, 2.03 mmol), followed by
the addition of N,N-diisopropylethylamine (372 ul, 2.14 mmol). The
reaction mixture was stirred at RT for one hour before it was
washed with water, dried over Na.sub.2SO.sub.4, concentrated to
give a crude. The mixture was then purified by a flash
chromatography, eluting with 1:2 EtOAc/hexanes to give the
benzamide 1A as an off-white solid (578 mg, 1.68 mmol, 87%).
.sup.1H NMR (300 MHz, DMSO-d.sup.6) .delta.2.31 (s, 3H), 3.71 (s,
3H), 7.41 (d, J=8.4 Hz, 1H), 7.53-7.70 (m, 4H), 7.94 (s, 1H), 8.01
(d, J=7.4 Hz, 2H); MS m/z 343.9 [M+H].sup.+.
B.
N-methoxy-4-methyl-3-(5-phenyl-4H-[1,2,4]-triazol-3-ylamino)-benzamide
[0356] To a mixture of benzamide 1A in THF (2 ml) and EtOH (1 ml)
was added hydrazine monohydrate. The mixture was then refluxed
(bath T=77-80.degree. C.) for 1.5 hr. It was cooled to room
temperature and purified by preparative HPLC to give the title
compound as a white solid (9.4 mg, 0.029 mmol, 9.0%). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta.2.39 (s, 3H), 3.81 (s, 3H), 7.37 (d,
J=7.9 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.51-7.53 (m, 3H), 7.94-7.97
(m, 2H), 8.08 (s, 1H); MS m/z 324.0 [M+H].sup.+.
EXAMPLE 2
Preparation of
N-methoxy-4-methyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylamino)-benzamide
##STR00048##
[0357] A.
3-(3-Benzoyl-2-methyl-isothioureido)-N-methoxy-4-methyl-benzamid-
e
[0358] To a stirred suspension of
3-(3-Benzoyl-thioureido)-N-methoxy-4-methyl-benzamide (101 mg, 0.29
mmol, see preparation 1A) in CH.sub.2Cl.sub.2 (2 ml) was added THF
(1 ml) to form a homogeneous solution. MeI (20 ul, 0.32 mmol) was
added followed by N,N-diisopropylethylamine (56 ul, 0.32 mmol). The
reaction mixture was stirred at RT for 2 hr. More MeI (40 ul, 0.64
mmol) and N,N-diisopropylethylamine (112 ul, 0.64 mmol) was added
and the reaction was left to stir at RT overnight. The mixture was
then poured into water, extracted twice with CH.sub.2Cl.sub.2. The
combined organic extracts were dried over Na.sub.2SO.sub.4,
concentrated and vacuum dried to give the title compound 2A as a
white solid (113 mg), which was used for the next reaction without
further purification. MS m/z 357.9 [M+H].sup.+.
B.
N-Methoxy-4-methyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylamino)-benzamide
[0359] Hydroxylamine (58 ul, 0.58 mmol) was added to a suspension
of compound 2A (113 mg, crude, .about.0.29 mmol) in EtOH (1 ml).
The mixture was heated at reflux for 1.5 hr. It was then cooled to
RT, and purified by preparatory HPLC to give the title compound as
a white solid (11.2 mg, 12% over two steps). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.2.41 (s, 3H), 3.82 (s, 3H), 7.31-7.40 (m, 2H),
7.59-7.66 (m, 3H), 8.13-8.18 (m, 3H); MS m/z 324.9 [M+H].sup.+.
EXAMPLE 3
Preparation of
N-Cyclopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide
##STR00049##
[0360] A. 3-Amino-N-cyclopropyl-4-methyl-benzamide
[0361] To a mixture of 3-amino-4-methyl-benzoic acid (10.2 g, 67.5
mmol) and cyclopropyl amine (9.33 mL, 135.0 mmol, 2 eq) in DMF (150
mL) was added EDCI (15.5 g, 81 mmol, 1.2 eq) followed by DMAP
(cat.) at RT. The reaction was stirred overnight at RT, then
concentrated. The residue was redissolved in water and extracted
with EtOAc. The organic layer was washed with aqueous NaCl
solution, dried over Na.sub.2SO.sub.4, and concentrated. The crude
product was purified by flash chromatography on silica gel
(gradient elution: 1:1 EtOAc/hexanes then 100% EtOAc) to provide 3A
as a solid (9.5 g, 72%).
B. N-Cyclopropyl-3-isothiocyanato-4-methyl-benzamide
[0362] To a solution of 1,1'-thiocarbonyldi-2(1H)-pyridone (10.35
g, 44.6 mmol) in 20 mL of CH.sub.2Cl.sub.2 was added
3-amino-N-cyclopropyl-4-methyl-benzamide 3A (8.5 g, 44.6 mmol, 1
eq). The mixture was stirred at RT for 3 hrs. The precipitate which
was formed was filtered, washed with CH.sub.2Cl.sub.2, and
reserved. The organic filtrate was washed with water and dried
(Na.sub.2SO.sub.4), concentrated and combined with previously
obtained solid to provide the thioisocyanate 3B as a white solid
(7.45 g) which was used without further purification.
C. N-Cyclopropyl-4-methyl-3-thioureido-benzamide
[0363] A suspension of
N-cyclopropyl-3-isothiocyanato-4-methyl-benzamide 3B (7.45 g) in a
7N solution of ammonia in methanol (40 mL) was stirred at room
temperature for 1 hr. The mixture was concentrated, then
redissolved in MeOH and reconcentrated to give the desired product
as white solid (6.1 g, 60% for two steps).
D.
N-Cyclopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide
[0364] To a stirred solution of
N-Cyclopropyl-4-methyl-3-thioureido-benzamide 3A (41 mg, 0.16 mmol)
in 5 mL of ethanol was added 2-bromoacetophenone (33 mg, 0.16 mmol)
and the reaction was heated at 75.degree. C. overnight. After 16
hours, the reaction was cooled and concentrated and the crude
product was purified by flash chromatography on silica gel loaded
with CH.sub.2Cl.sub.2 and eluted with 2:1 hexanes/ethyl acetate
followed by 1:2 hexanes/ethyl acetate to provide the title compound
as a solid (32 mg, 94%). HPLC, t.sub.R, 3.54 min. (6 minute
method); MS, m/z 350.0 [M+1].sup.+.
[0365] The following analogues were prepared by the same method,
using the appropriately substituted bromoacetophenone in step
D:
3D-2.
3-[4-(4-Cyano-phenyl)-thiazol-2-ylamino]-N-cyclopropyl-4-methyl-benz-
amide
[0366] HPLC, t.sub.R, 2.38 min. (4 minute method); MS, m/z 375.0
[M+1].sup.+.
3D-3.
N-Cyclopropyl-3-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-4-methyl-ben-
zamide
[0367] HPLC, t.sub.R, 2.38 min. (4 minute method); MS, m/z 368.0
[M+1].sup.+.
3D-4.
N-Cyclopropyl-3-[4-(4-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-be-
nzamide
[0368] HPLC, t.sub.R, 2.68 min. (4 minute method); MS, m/z 380.1
[M+1].sup.+.
3D-5.
N-Cyclopropyl-3-[4-(3-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-be-
nzamide
[0369] HPLC, t.sub.R, 2.74 min. (4 minute method); MS, m/z 380.1
[M+1].sup.+.
3D-6.
N-Cyclopropyl-3-[4-(2-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-be-
nzamide
[0370] HPLC, t.sub.R, 2.50 min. (4 minute method); MS, m/z 380.1
[M+1].sup.+.
[0371] The following analogue was prepared by the same method,
using 2-bromopropiophenone in step D:
3D-7.
N-Cyclopropyl-4-methyl-3-(5-methyl-4-phenyl-thiazol-2-ylamino)-benza-
mide
[0372] HPLC, t.sub.R, 2.38 min. (4 minute method); MS, m/z 364.1
[M+1].sup.+.
EXAMPLE 4
Preparation of
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic
acid phenylamide
##STR00050##
[0373] A.
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carbo-
xylic acid ethyl ester
[0374] To a stirred solution of
N-Cyclopropyl-4-methyl-3-thioureido-benzamide 3A (100 mg, 0.48
mmol) in 10 mL of ethanol was added ethyl bromopyruvate (89 mg,
0.48 mmol) and the reaction was heated at 75.degree. C. overnight.
After 16 hours, the reaction was cooled and concentrated and the
crude product was purified by flash chromatography on silica gel
loaded with CH.sub.2Cl.sub.2 and eluted with 1:1 hexanes/ethyl
acetate followed by 1:2 hexanes/ethyl acetate to provide the title
compound as a solid (75 mg, 45%). HPLC, t.sub.R, 2.97 min. (4
minute method); MS, m/z 346.0 [M+1].sup.+.
B.
(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic
acid phenylamide
[0375] To a stirred solution of ester 4A (60 mg, 0.17 mmol) in MeOH
(5 mL) was added 10% NaOH (3 mL). The mixture was stirred at room
temperature for 3 hrs, when the solution was acidified with conc.
HCl to pH<3.0. The mixture was extracted with EtOAc, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give a white solid.
The solid was dissolved in 10 mL of DMF and the solution was
treated with EDCI (49 mg, 0.25 mmol), and HOBt (39 mg, 0.25 mmol).
After stirring, for 15 min at room temperature, aniline (46 mL,
0.25 mmol) and DIPEA (0.18 mL, 1.03 mmol) were added and the
reaction mixture was stirred at room temperature overnight. The
reaction was quenched with water, extracted with CH.sub.2Cl.sub.2,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel eluted
with 1:2 hexane/ethyl acetate to give the title compound as a white
solid (42 mg, 62%). HPLC, t.sub.R, 2.26 min. (4 minute method); MS,
m/z 393.0 [M+1].sup.+.
EXAMPLE 5
Preparation of
N-Isopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide
##STR00051##
[0376] A. 3-Isothiocyanato-4-methyl-benzoic acid methyl ester
[0377] To a solution of 1,1'-thiocarbonyldi-2(1H)-pyridone (5.72 g,
34.6 mmol) in 20 mL of CH.sub.2Cl.sub.2 was added ethyl
3-amino-4-methyl-benzoate (8.05 g, 34.6 mmol, 1 eq). The mixture
was stirred at RT for 3 hrs. The precipitate was filtered off and
washed with CH.sub.2Cl.sub.2. The organic filtrate was washed with
water and dried (Na.sub.2SO.sub.4), concentrated and the crude
product was purified by flash chromatography on silica gel loaded
with CH.sub.2Cl.sub.2 and eluted with 9:1 hexanes/ethyl acetate to
provide 5A as a white solid (5.16 g, 72%).
B. 4-Methyl-3-thioureido-benzoic acid methyl ester
[0378] To a stirred solution of thioisocyanate 5A (5.16 g, 25 mmol)
in CH.sub.2Cl.sub.2 was added a 7N solution of ammonia in methanol
(10.6 mL, 75 mmol) was stirred at room temperature for 1 hr when
additional ammonia in methanol solution was added. The mixture was
concentrated, then redissolved in MeOH and reconcentrated to give
the desired product 5B as white solid (5.5 g, 98%).
C. 4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-benzoic acid methyl
ester
[0379] To a stirred solution of thiourea 5B (4.87 g, 21.7 mmol) in
5 mL of ethanol was added 2-bromoacetophenone (4.33 g, 21.7 mmol)
and the reaction was heated at 75.degree. C. overnight. After 16
hours, the reaction was cooled the precipitate filtered and
reserved. The filtrate was concentrated and the crude product was
purified by flash chromatography on silica gel loaded with
CH.sub.2Cl.sub.2/methanol and eluted with 10:1 hexanes/ethyl
acetate followed by 6:1 hexanes/ethyl acetate. The purified
material was combined with the previously obtained precipitate to
provide the title compound as a the hydrobromide salt (8.30 mg,
94%). MS, m/z 325.1 [M+1].sup.+.
D. 4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-benzoic acid
[0380] To a stirred solution of ester 5C (6.43 g, 19.8 mmol) in
MeOH (50 mL) was added a solution of sodium hydroxide (10% in
water, 40 mL) and the reaction was stirred at 65.degree. C. for 3
hrs. The mixture was acidified to pH<3 with conc. HCl. The white
precipitate was filtered and washed with water to give the desired
product as a white solid (4.1 g, 67%). HPLC, t.sub.R, 2.38 min. (4
minute method); MS, m/z 311.1 [M+1].sup.+.
E.
N-Isopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide
[0381] To a mixture of acid 5D (100 mg, 0.32 mmol, 1 eq) in DMF was
added EDCI (185 mg, 0.97 mmol, 3 eq), HOBt (148 mg, 0.97 mmol, 3
eq). The mixture was stirred for 15 at room temperature, when
2-propylamine (0.97 mmol, 3 eq) and DIPEA (1.93 mmol, 6 eq) were
added and the mixture was stirred at room temperature overnight.
The reaction was concentrated and water was added. The mixture was
extracted with CH.sub.2Cl.sub.2, and the extract dried with
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified by flash chromatograph on silica gel loaded in
CH.sub.2Cl.sub.2 and eluted with 3:1 hexanes/ethyl acetate to
provide the title compound as a white foamy solid (106 mg, 94%).
HPLC, t.sub.R, 2.49 min. (4 minute method); MS, m/z 352.1
[M+1].sup.+.
[0382] The following analogues were prepared by the same method,
using the appropriate amine in step E:
5E-2. N-Ethyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide
[0383] HPLC, t.sub.R, 2.33 min. (4 minute method); MS, m/z 338.1
[M+1].sup.+.
5E-3.
N-(2-Methoxy-ethyl)-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamid-
e
[0384] HPLC, t.sub.R, 2.20 min. (4 minute method); MS, m/z 368.0
[M+1].sup.+.
5E-4.
[4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-phenyl]-morpholin-4-yl-meth-
anone
[0385] HPLC, t.sub.R, 2.31 min. (4 minute method); MS, m/z 380.1
[M+1].sup.+.
5E-5.
4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-1-thiazol-2-yl-benzamide
[0386] HPLC, t.sub.R, 1.62 min. (4 minute method); MS, m/z 393.0
[M+1].sup.+.
5E-6.
4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-N-[1,2,4]triazol-4-yl-benzam-
ide
[0387] HPLC, t.sub.R, 2.00 min. (4 minute method); MS, m/z 377.7
[M+1].sup.+.
5E-7.
4-Methyl-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-3-(4-phenyl-thiazol-2-y-
lamino)-benzamide
[0388] HPLC, t.sub.R, 2.51 min. (4 minute method); MS, m/z 408.6
[M+1].sup.+.
EXAMPLE 6
Preparation of
N-Cyclopropyl-4-methyl-3-(5-phenyl-oxazol-2-ylamino)-benzamide
##STR00052##
[0389] A. 2-Azido-1-phenyl-ethanone
[0390] To a stirred solution of 2-bromoacetophenone (5.37 g, 27
mmol) in acetone (50 mL) and water (18 mL) was added sodium azide
(1.84 g, 28 mmol, 1.05 eq) and the mixture was stirred for 30
minutes. The mixture was diluted with water and extracted with
CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified by flash
chromatography on silica gel eluted with 9:1 hexanes/ethyl acetate
to provide the desired product as a yellow oil (3.23 g, 74%).
B.
N-Cyclopropyl-4-methyl-3-(5-phenyl-oxazol-2-ylamino)-benzamide
[0391] To a stirred solution of compound 6A (74 mg, 0.32 mmol) and
3B (58 mg, 0.36 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added
triphenylphosphine (94 mg, 0.36 mmol). The reaction mixture was
stirred room temperature overnight, then concentrated. The crude
product was purified by flash chromatography on silica gel loaded
in CH.sub.2Cl.sub.2/MeOH and eluted with 1:1 hexane/ethyl acetate
followed by 1:2 hexane/ethyl acetate to provide the title compound
as an off-white solid (82 mg, 77%). (TTM2003.201.A105). HPLC,
t.sub.R, 3.19 min. (4 minute method); MS, m/z 334.0
[M+H].sup.+.
EXAMPLE 7
Preparation of
N-Cyclopropyl-4-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-benzamide
##STR00053##
[0392] A.
3-(3-Benzoyl-thioureido)-N-cyclopropyl-4-methyl-benzamide
[0393] The mixture of thioisocyanate 3B (500 mg, 2.63 mmol) and
aniline 3A (429 mg, 2.63 mmol) was stirred at room temperature for
1 h. The mixture was concentrated to give the desired compound 7A
which was used without further purification. HPLC, t.sub.R, 2.78
min. (6 minute method); MS, m/z 334.0 [M+H].sup.+.
B.
N-Cyclopropyl-4-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-benzami-
de.
[0394] To the stirred solution of compound 7A (150 mg, 0.42 mmol)
in DMF was added hydrazine monohydrate (41 .mu.L, 0.84 mmol)
followed by the addition of triethylamine (0.24 mL, 1.68 mmol) and
mercury(II) chloride (0.23 g, 0.84). The reaction mixture was
stirred at room temperature for 3 hrs, then filtered through a pad
of Celite which was washed with EtOAc. The organics were
concentrated and the crude product was purified by flash
chromatography on silica gel eluent with 2:1 CH.sub.2Cl.sub.2/EtOAc
to give the title compound as a white solid (66 mg, 47%). HPLC,
t.sub.R, 2.78 min. (6 minute method); MS, m/z 334.0
[M+H].sup.+.
EXAMPLE 8
Preparation of
N-Cyclopropyl-4-methyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylamino)-benzamide
##STR00054##
[0396] To the stirred solution of compound 7A (167 mg, 0.47 mmol)
in DMF was added hydroxylamine (50% in H.sub.2O, 62 .mu.L, 0.94
mmol) followed by the addition triethylamine (0.26 mL, 1.88 mmol)
and mercury(II) chloride (0.25 g, 0.94 mmol). After 3 hrs at room
temperature, additional hydroxylamine (50% in H.sub.2O, 62 .mu.L,
0.94 mmol) and mercury(II) chloride (0.25 g, 0.94 mmol) were added
and the reaction was stirred overnight. The mixture was filtered
through a pad of Celite which was washed with EtOAc. The organics
were concentrated and the crude product was purified by flash
chromatography on silica gel eluent with 9:1 CH.sub.2Cl.sub.2/EtOAc
to give the title compound as a white solid (83 mg, 52%). HPLC,
t.sub.R, 3.61 min. (6 minute method); MS, m/z 335.9
[M+H].sup.+.
EXAMPLE 9
N-Cyclopropyl-4-methyl-3-(5-phenyl-[1,3,4]thiadiazol-2-ylamino)-benzamide
##STR00055##
[0397] A.
N-Cyclopropyl-4-methyl-3-([3-benzamido]-thioureido)-benzamide
[0398] Benzoylhydrazine (72 mg, 0.529 mmol) and the thioisocyanate
3B (123 mg, 0.529 mmol) were suspended in EtOH (3 ml) and stirred
at 80.degree. C. for 2.5 hr. After cooling down at room
temperature, the resulting precipitate was filtered off and washed
with ethanol to afford the desired compound 9A as a pure white
solid (131 mg, 0.355 mmol, 67%). HPLC (4 minutes gradient) t.sub.R
1.90 min; MS m/z 368.94 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 0.57 (m, 2H), 0.67 (m, 2H), 2.23 (s, 3H), 2.84 (m,
1H), 7.28 (d, J=7.7, 1H), 7.66-7.48 (m, 5H), 7.96 (d, J=7.3, 2H),
8.42 (d, J=3.3, 1H), 9.65 (s, 1H), 9.70 (s, 1H), 10.56 (s, 1H)
ppm.
B.
N-Cyclopropyl-4-methyl-3-(5-phenyl-[1,3,4]thiadiazol-2-ylamino)-benzami-
de
[0399] To the compound 9A (106 mg, 0.2877 mmol) was added neat
concentrated sulfuric acid (1.5 ml) and the resulting suspension
was stirred at room temperature for 50 min. The mixture was slowly
added into ice water (10 ml) and the resulting suspension was added
into an aqueous ammonia solution. The resulting solid was filtered
off and washed with water to afford a crude material (64 mg).
Purification by flash chromatography (SiO.sub.2, MeOH 1 to 2% in
CH.sub.2Cl.sub.2) afforded the pure title compound as a white
powder (32 mg, 0.091 mmol, 32%). HPLC (4 minutes gradient) t.sub.R
2.44 min; MS m/z 351.02 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 0.57 (m, 2H), 0.67 (m, 2H), 2.33 (s, 3H), 2.85 (m,
1H), 7.32 (d, J=7.8, 1H), 7.50-7.53 (m, 4H), 7.83 (m, 2H), 8.21 (s,
1H), 8.37 (d, J=3.5, 1H), 9.73 (br s, 1H) ppm.
EXAMPLE 10
N-Cyclopropyl-4-methyl-3-(3-phenyl-[1,2,4]thiadiazol-5-ylamino)-benzamide
##STR00056##
[0400] A. N-Hydroxy-benzamidine
[0401] Benzonitrile (1 ml, 9.79 mmol) was mixed with hydroxylamine
hydrochloride (1.36 g, 1.96 mmol) and K.sub.2CO.sub.3 (2.71 g, 1.96
mmol) in anhydrous ethanol (15 ml). The solution was stirred at
80.degree. C. for 16 hr. Water was added and the aqueous phase was
extracted with EtOAc (3.times.), dried over MgSO.sub.4 and the
volatiles removed in vacuo to give a viscous oil (816 mg, 5.99
mmol, 62%). The compound 10A was used for next step without any
further purification. HPLC (4 minutes gradient) t.sub.R 0.62 min;
MS m/z 137.06 [M+H].sup.+.
B.
N-Cyclopropyl-4-methyl-3-(3-phenyl-[1,2,4]thiadiazol-5-ylamino)-benzami-
de
[0402] Compound 10A (68 mg, 0.499 mmol) and thioisocyanate 3B (77
mg, 0.331 mmol) were dissolved in anhydrous DMF (1 ml). The mixture
was heated under microwave irradiation at 200.degree. C. for 10
min. Water was added and the resulting mixture was stirred at room
temperature for 1 hr. The beige solid was filtered off and washed
with water and hexanes to afford the title compound (25 mg, 0.071
mmol, 14%). HPLC (4 minutes gradient) t.sub.R 2.76 min; MS m/z
351.01 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
0.59 (m, 2H), 0.68 (m, 2H), 2.36 (s, 3H), 2.88 (m, 1H), 7.36 (d,
J=7.7, 1H), 7.49-7.65 (m, 4H), 8.15 (m, 2H), 8.39 (d, J=3.7, 1H),
8.58 (s, 1H), 10.31 (s, 1H) ppm.
EXAMPLE 11
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-methyl-thiazole-5-carbox-
ylic acid benzyl ester
##STR00057##
[0404] To a stirred solution of benzyl acetoacetate (555 mg, 2.887
mmol) in CHCl.sub.3 (5 ml) was added dropwise bromine (147 .mu.l,
2.869 mmol). After stirring at room temperature for 1 hr, the
volatiles were removed in vacuo to afford an oily residue. This
residue (200 mg, ca. 0.74 mmol) was mixed with thiourea 3C (184 mg,
0.738 mmol) in ethanol (1.5 ml) and the resulting solution was
stirred at 80.degree. C. for 3 hr. The solvent was removed in vacuo
and the crude material was purified by flash chromatography
(SiO.sub.2, MeOH 1 to 5% in CH.sub.2Cl.sub.2). Subsequent
recrystallization in ethanol afforded the title compound as a beige
solid (59 mg, 0.140 mmol, 19%). HPLC (4 minutes gradient) t.sub.R
2.99 min; MS m/z 422.02 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 0.57 (m 2H), 0.67 (m, 2H), 2.26 (s, 3H), 2.83 (m, 1H),
5.22 (s, 2H), 7.35 (m, 6H), 7.60 (d, J=7.7, 1H), 8.03 (s, 1H), 8.39
(d, J=3.4, 1H), 10.06 (s, 1H) ppm.
EXAMPLE 12
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-methyl-thiazole-5-carbox-
ylic acid benzylamide
##STR00058##
[0406] The title compound was prepared according to the procedure
for Example 10 starting from acetoacetobenzylamide. Purification by
flash chromatography (SiO.sub.2, MeOH 1 to 10% in CH.sub.2Cl.sub.2)
afforded a pale brown solid (46% yield). HPLC (4 minutes gradient)
t.sub.R 1.97 min; MS m/z 421.06 [M+H].sup.+.
EXAMPLE 13
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic
acid ethyl ester
##STR00059##
[0408] Thiourea 3C (124 mg, 0.497 mmol) and ethylbromopyruvate (69
.mu.l, 0.550 mmol) were mixed in ethanol (1.5 ml) and heated at
80.degree. C. for 45 min. After removal of the volatiles in vacuo
the crude material was purified by flash chromatography (SiO.sub.2,
MeOH 1 to 4% in CH.sub.2Cl.sub.2) to afford a white powder (105 mg,
0.304 mmol, 61% yield). HPLC (4 minutes gradient) t.sub.R 2.25 min;
MS m/z 345.97 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 0.55 (m, 2H), 0.67 (m, 2H), 1.28 (t, J=7.0, 3H), 2.28 (s,
3H), 2.83 (m, 1H), 4.24 (q, J=7.1, 2H), 7.31 (d, J=7.8, 1H), 7.51
(d, J=7.7, 1H), 7.70 (s, 1H), 8.14 (s, 1H), 8.34 (s, 1H), 9.64 (s,
1H) ppm.
EXAMPLE 14
5-Bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxy-
lic acid ethyl ester
##STR00060##
[0410] To a stirred suspension of compound 13 (23.6 mg, 0.0683
mmol) in CHCl.sub.3 (0.5 ml) was added dropwise a solution of
N-bromosuccinimide (13 mg, 0.0730 mmol) in CHCl.sub.3 (0.5 ml). The
mixture was stirred at room temperature for 30 min and the
volatiles removed in vacuo. Trituration of the crude material in
CH.sub.2Cl.sub.2/EtOAc provided an off white solid that was
filtered off and dried (18 mg, 0.042 mmol, 62% yield). HPLC (4
minutes gradient) t.sub.R 2.65 min; MS m/z 423.90, 425.88
[M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56 (m,
2H), 0.67 (m, 2H), 1.29 (t, J=7.1, 3H), 2.28 (s, 3H), 2.83 (m, 1H),
4.26 (q, J=7.0, 2H), 7.32 (d, J=7.9, 1H), 7.54 (d, J=7.4, 1H), 8.12
(s, 1H), 8.35 (d, J=3.6, 1H), 9.84 (s, 1H) ppm.
EXAMPLE 15
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-nitro-phenyl)-thiazol-
e-5-carboxylic acid ethyl ester
##STR00061##
[0412] The title compound was prepared according to the procedure
for Example 10 starting from ethyl 4-nitrobenzoyl acetate. After 30
min of heating the title compound precipitated out of the reaction
mixture to give a pure yellow solid material (67% yield). HPLC (4
minutes gradient) t.sub.R 3.03 min; MS m/z 467.02 [M+H].sup.+;
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56 (m, 2H), 0.68 (m,
2H), 1.16 (t, J=7.0, 3H), 2.32 (s, 3H), 2.84 (m, 1H), 4.14 (q,
J=6.7, 2H), 7.38 (d, J=7.9, 1H), 7.63 (d, J=7.7, 1H), 7.97 (d,
J=8.5, 2H), 8.17 (s, 1H), 8.27 (d, J=8.4, 2H), 8.42 (d, J=3.3, 1H),
10.29 (s, 1H) ppm.
EXAMPLE 16
N-Cyclopropyl-4-methyl-3-[4-(4-nitro-phenyl)-thiazol-2-ylamino]-benzamide
##STR00062##
[0414] The title compound was prepared according to the procedure
for Example 13 starting from .alpha.-bromo-4-nitroacetophenone.
After 1.5 hr of heating the compound precipitated out of the
reaction mixture to give a pure orange solid material (85% yield).
HPLC (4 minutes gradient) t.sub.R 2.90 min; MS m/z 395.00
[M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.57 (m,
2H), 0.69 (m, 2H), 2.33 (s, 3H), 2.86 (m, 1H), 7.31 (d, J=7.8, 1H),
7.50 (d, J=7.7, 1H), 7.72 (s, 1H), 8.14 (d, J=8.7, 2H), 8.27 (d,
J=8.7, 2H), 8.40 (d, J=3.6, 1H), 8.54 (s, 1H), 9.61 (s, 1H)
ppm.
EXAMPLE 17
3-[5-Bromo-4-(4-nitro-phenyl)-thiazol-2-ylamino]-N-cyclopropyl-4-methyl-be-
nzamide
##STR00063##
[0416] The title compound was prepared according to the procedure
for Example 13. After one hour the compound precipitated out of the
reaction mixture in a pure form as an orange solid (63% yield).
HPLC (4 minutes gradient) t.sub.R 3.28 min; MS m/z 472.92, 474.88
[M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.57 (m,
2H), 0.60 (m, 2H), 2.32 (s, 3H), 2.85 (m, 1H), 7.32 (d, J=7.9, 1H),
7.51 (d, J=7.6, 1H), 8.19 (d, J=8.8, 2H), 8.32 (d, J=8.7, 2H), 8.39
(d, J=3.7, 1H), 8.43 (s, 1H), 9.78 (s, 1H) ppm.
EXAMPLE 18
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-morpholin-4-yl-phenyl-
)-thiazole-5-carboxylic acid benzylamide
##STR00064##
[0417] A.
N-Benzyl-3-(4-morpholin-4-yl-phenyl)-3-oxo-propionamide
[0418] Under nitrogen atmosphere, LDA (1.8M solution in
heptane/THF/ethylbenzene, 4.1 ml, 7.38 mmol) was added through
syringe in anhydrous THF (10 ml). The mixture was cooled to
-78.degree. C. and a THF solution (5 ml) of
4-morpholinoacetophenone (1.01 g, 4.92 mmol) was added dropwise
through syringe. The mixture was allowed to warm up to 0.degree. C.
for 30 min and then cooled down to -78.degree. C. Benzylisocyanate
(0.30 ml, 2.43 mmol) was added dropwise. The mixture was stirred at
-78.degree. C. for 25 min and allowed to warm up to room
temperature overnight. The mixture was quenched by a saturated
aqueous ammonium chloride solution and the compound was extracted
with EtOAc (3.times.). The combined extracts were dried over
MgSO.sub.4 and the volatiles removed in vacuo. Addition of
CH.sub.2Cl.sub.2 to the resulting oil induces formation of an
insoluble solid. The compound was filtered off affording the
intermediate 18A as a yellow solid (202 mg, 0.597 mmol, 25% yield).
HPLC (4 minutes gradient) t.sub.R 2.30 min; MS m/z 339.07
[M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.32 (m,
4H), 3.74 (m, 4H), 3.85 (s, 2H), 4.30 (d, J=5.8, 2H), 6.99 (d,
J=8.8, 2H), 7.24-7.35 (m, 5H), 7.86 (d, J=8.7, 2H), 8.60 (t, J=5.4,
1H) ppm.
B.
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-morpholin-4-yl-phe-
nyl)-thiazole-5-carboxylic acid benzylamide
[0419] To a stirred solution of intermediate 18A (90 mg, 0.266
mmol) in CHCl.sub.3 (0.5 ml) was added dropwise bromine (42.4 mg,
0.264 mmol) as a solution in CHCl.sub.3 (0.5 ml). The mixture was
stirred at room temperature for 25 min and the volatiles removed in
vacuo to afford a yellowish solid (112 mg, 0.140 mmol, 85% crude).
This solid (111 mg, 0.223 mmol) was mixed with thiourea 3C (56 mg,
0.225 mmol) in ethanol (1.5 ml) and the resulting mixture stirred
at 80.degree. C. for 30 min. The volatiles were removed in vacuo
and the residue dissolved in CH.sub.2Cl.sub.2 containing a little
amount of methanol. The organic phase was washed with saturated
NaHCO.sub.3, dried over MgSO.sub.4 and the volatiles removed in
vacuo. Upon addition of EtOAc, the expected compound precipitated
in a very pure form and was isolated by filtration to give the
title compound as an off white solid (63 mg, 0.222 mmol, 50%
yield). HPLC (4 minutes gradient) t.sub.R 2.60 min; MS m/z 568.15
[M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56 (m,
2H), 0.68 (m, 2H), 2.31 (s, 3H), 2.84 (m, 1H), 3.15 (br s, 4H),
3.75 (br s, 4H), 4.32 (d, J=5.6, 2H), 6.87 (d, J=8.6, 2H),
7.23-7.35 (m, 6H), 7.53 (m, 3H), 8.21 (br t, 1H), 8.33 (s, 1H),
8.38 (d, J=3.8, 1H), 9.67 (s, 1H) ppm.
EXAMPLE 19
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic
acid methyl ester
##STR00065##
[0421] The compound was prepared according to a literature
procedure (Tet. Lett., 42 (2001) 2101-2102). Methyl trans
3-methoxyacrylate (0.12 ml, 1.116 mmol) was dissolved in a mixture
of water (1 ml) and 1,4-dioxane (1 ml) and cooled down to
-15.degree. C. N-bromosuccinimide (145 mg, 1.23 mmol) was added and
the solution allowed to warm to room temperature under stirring for
3 hours. The thiourea 3C (306 mg, 1.23 mmol) was added and the
mixture stirred at 80.degree. C. for 30 min. Concentrated aqueous
NH.sub.4OH was added and the compound extracted with
CH.sub.2Cl.sub.2 (2.times.). The combined extracts were dried over
MgSO.sub.4 and the solvent removed in vacuo to afford a crude
material. Purification by flash chromatography (SiO.sub.2, MeOH 1
to 4% in CH.sub.2Cl.sub.2) provided the expected compound as an off
white solid (223 mg, 0.673 mmol, 61%). HPLC (4 minutes gradient)
t.sub.R 2.11 min; MS m/z 331.95 [M+H].sup.+; .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 0.57 (m, 2H), 0.67 (m, 2H), 2.28
(s, 3H), 2.82 (m, 1H), 3.75 (s, 3H), 7.34 (d, J=7.9, 1H), 7.57 (d,
J=7.6, 1H), 7.90 (s, 1H), 8.13 (s, 1H), 8.40 (d, J=3.6, 1H), 10.10
(br s, 1H) ppm.
EXAMPLE 20
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic
acid
##STR00066##
[0423] Compound 19 (99 mg, 0.299 mmol) was suspended in a mixture
of methanol (0.5 ml), THF (0.5 ml) and water (0.5 ml) and stirred
at 60.degree. C. for 13 hr (90% conversion by HPLC). The reaction
was completed by heating at 80.degree. C. for 3 hr. The solvents
were removed in vacuo and water was added to dissolve the residue.
The title compound was precipitated in a pure form by addition of a
concentrated solution of HCl. Filtration and drying provided a
brown solid (58 mg, 61%) HPLC (4 minutes gradient) t.sub.R 1.63
min; MS m/z 318.0 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 0.56 (m, 2H), 0.67 (m, 2H), 2.28 (s, 3H), 2.84 (m, 1H),
7.33 (d, J=7.9, 1H), 7.56 (d, J=7.6, 1H), 7.80 (s, 1H), 8.14 (s,
1H), 8.40 (d, J=3.7, 1H), 10.02 (br s, 1H) ppm.
EXAMPLE 21
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-phenyl-thiazole-5-carbox-
ylic acid cyclopropylmethyl-amide
##STR00067##
[0424] A. N-Cyclopropylmethyl-3-oxo-3-phenyl-propionamide
[0425] Ethyl benzoylacetate (621 mg, 3.23 mmol) and
cyclopropylmethylamine (0.34 ml, 3.92 mmol) were dissolved in
1,4-dioxane (1 ml). Para-toluenesulfonic acid (3 crystals,
catalytic) was added and the mixture heated under microwave
irradiation at 150.degree. C. for 30 min. The crude mixture was
poured onto a SiO.sub.2 column and purified by flash chromatography
(eluted with EtOAc 10 to 35% in hexanes). The title compound was
isolated as a yellow solid (309 mg, 44%). HPLC (4 minutes gradient)
t.sub.R 2.04 min; MS m/z 218.0 [M+H].sup.+.
B.
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-phenyl-thiazole-5-car-
boxylic acid cyclopropylmethyl-amide
[0426] The title compound was prepared according to the procedure
for Example 10 starting from intermediate 21A. Purification by
flash chromatography (SiO.sub.2, MeOH 1 to 3% in CH.sub.2Cl.sub.2)
afforded a pale brown solid (33% yield). HPLC (4 minutes gradient)
t.sub.R 2.62 min; MS m/z 446.57 [M+H].sup.+; .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 0.12 (m, 2H), 0.38 (m, 2H), 0.56
(m, 2H), 0.68 (m, 2H), 0.91 (m, 1H), 2.32 (s, 3H), 2.84 (m, 1H),
2.99 (t, J=6.2, 2H), 7.32 (d, J=7.8, 1H), 7.39 (m, 3H), 7.52 (d,
J=7.7, 1H), 7.70 (d, J=6.2, 2H), 7.85 (br t, 1H), 8.35 (s, 1H),
8.40 (d, J=3.7, 1H), 9.71 (s, 1H) ppm.
EXAMPLE 22
4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-methoxycarbonyl-th-
iazol-4-yl]-phenyl}-piperidine-1-carboxylic acid methyl ester
##STR00068##
[0427] A. 4-(3-Methoxycarbonyl-phenyl)-piperidine-1-carboxylic acid
methyl ester
[0428] To a stirred solution of
4-(3-methoxycarbonylphenyl)piperidine hydrochloride (871 mg, 3.406
mmol) in anhydrous CH.sub.2Cl.sub.2 (10 ml) was added triethylamine
(1.04 ml, 7.48 mmol). The mixture was cooled down to 0.degree. C.
and methylchloroformate (0.32 ml, 4.141 mmol) was added dropwise
through syringe. The mixture was allowed to warm to room
temperature over 3 hr. After adding a 0.2 N HCl solution, the
compound was extracted with CH.sub.2Cl.sub.2, the organic phase
dried over MgSO.sub.4 and the solvent removed by evaporation.
Purification by flash chromatography (SiO.sub.2, EtOAc 20 to 30% in
hexanes), afforded the title compound 21A as a colorless viscous
oil (874 mg, 3.151 mmol, 93%). HPLC (4 minutes gradient) t.sub.R
2.83 min; MS m/z 278.0 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 1.52 (qd, J=4.0, J=12.5, 2H), 1.77 (d, J=12.3, 2H),
2.82 (m, 3H), 3.61 (s, 3H), 3.85 (s, 3H), 4.11 (m, 2H), 7.46 (t,
J=7.5, 1H), 7.56 (d, J=7.6, 1H), 7.81 (m, 2H) ppm.
B. 4-[3-(2-Methoxycarbonyl-acetyl)-phenyl]-piperidine-1-carboxylic
acid methyl ester
[0429] A LDA solution (1.8M in heptane/THF/ethylbenzene, 3.7 ml,
6.66 mmol) and THF (10 ml) were mixed in a dry flask under nitrogen
atmosphere and cooled down to -78.degree. C. Anhydrous methyl
acetate (0.24 ml, 3.026 mmol) was added dropwise through syringe
and the mixture stirred at -78.degree. C. for 40 min. A solution of
ester 21A (836 mg, 3.014 mmol) in THF (5 ml) was added dropwise and
the mixture allowed to warm to room temperature over 3 hr. The
reaction was quenched with saturated ammonium chloride, the
compound was extracted with EtOAc (2.times.) and the combined
extracts dried over MgSO.sub.4. After removal of the solvents and
purification by flash chromatography (SiO.sub.2, EtOAc 10 to 35% in
hexanes), the title compound 21B was isolated as a viscous yellow
oil (255 mg, 0.798 mmol, 27%). HPLC (4 minutes gradient) t.sub.R
2.59 min; MS m/z 319.92 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 1.52 (qd, J=4.0, J=12.5, 2H), 1.77 (d, J=12.1, 2H),
2.79 (m, 3H), 3.61 (s, 3H), 3.65 (s, 3H), 4.11 (m, 2H), 4.23 (s,
2H), 7.48 (t, J=7.6, 1H), 7.57 (d, J=7.5, 1H), 7.81 (m, 2H)
ppm.
C.
4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-methoxycarbonyl-
-thiazol-4-yl]-phenyl}-piperidine-1-carboxylic acid methyl
ester
[0430] The title compound was prepared according to the procedure
for Example 10 starting from intermediate 22B. Purification by
flash chromatography (SiO.sub.2, MeOH 1 to 3% in CH.sub.2Cl.sub.2)
provided an off white solid (58%). HPLC (4 minutes gradient)
t.sub.R 2.85 min; MS m/z 549.14 [M+H].sup.+; .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 0.56 (m, 2H), 0.68 (m, 2H), 1.54
(qd, J=3.5, J=12.2, 2H), 1.80 (d, J=12.2, 2H), 2.32 (s, 3H), 2.86
(m, 4H), 3.61 (s, 3H), 3.65 (s, 3H), 4.11 (m, 2H), 7.31-7.37 (m,
3H), 7.55-7.63 (m, 3H), 8.25 (s, 1H), 8.41 (d, J=3.8, 1H), 10.16
(s, 1H) ppm.
EXAMPLE 23
4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-(cyclopropylmethyl-
-carbamoyl)-thiazol-4-yl]-phenyl}-piperidine-1-carboxylic acid
methyl ester
##STR00069##
[0431] A.
4-{3-[2-(Cyclopropylmethyl-carbamoyl)-acetyl]-phenyl}-piperidine-
-1-carboxylic acid methyl ester
[0432] The title compound was prepared according to the procedure
used for Example 20 starting from intermediate 22B. Purification by
flash chromatography (SiO.sub.2, EtOAc 20 to 60% in hexanes)
afforded a foamy solid (36% yield). HPLC (4 minutes gradient)
t.sub.R 2.38 min; MS m/z 359.10 [M+H].sup.+.
B.
4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-(cyclopropylmet-
hyl-carbamoyl)-thiazol-4-yl]-phenyl}-piperidine-1-carboxylic acid
methyl ester
[0433] The title compound was prepared according to the procedure
used for Example 10 starting from intermediated 22A. Purification
by flash chromatography (SiO.sub.2, MeOH 1 to 4% in
CH.sub.2Cl.sub.2) provided an off white solid (41% yield). HPLC (4
minutes gradient) t.sub.R 2.74 min; MS m/z 588.09 [M+H].sup.+;
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.13 (m, 2H), 0.37 (m,
2H), 0.56 (m, 2H), 0.68 (m, 2H), 0.80 (m, 1H), 1.53 (qd, J=3.2,
J=12.0, 2H), 1.80 (d, J=11.9, 2H), 2.32 (s, 3H), 2.85 (m, 4H), 2.99
(t, J=6.0, 2H), 3.60 (s, 3H), 4.10 (m, 2H), 7.25-7.36 (m, 3H),
7.51-7.60 (m, 3H), 7.89 (br t, 1H), 8.40 (s, 2H), 9.70 (s, 1H)
ppm.
EXAMPLE 24
4-{3-[2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-5-[1,3,4]oxadiazol-2-
-yl-thiazol-4-yl]-phenyl}-piperidinium trifluoroacetate
##STR00070##
[0434] A.
4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-[1,3,4]o-
xadiazol-2-yl-thiazol-4-yl]-phenyl}-piperidine-1-carboxylic acid
methyl ester
[0435] Compound 22C (98 mg, 0.179 mmol) was dissolved in methanol
(1 ml), hydrazine hydrate (1 ml) and DMF (4 drops). The mixture was
stirred at room temperature for 8 hr. The volatiles were removed in
vacuo. The resulting yellow solid was suspended in trimethyl
orthoformate (2 ml) and heated under microwave irradiation to
120.degree. C. for 30 min. After removal of the volatiles, the
residue was dissolved in a mixture of 1,4-dioxane (2 ml) and acetic
acid (0.1 ml) and heated using microwave irradiation at 160.degree.
C. for 30 min. After removal of the volatiles in vacuo, the title
compound 24A was purified by flash chromatography (SiO.sub.2 MeOH 1
to 4% in CH.sub.2Cl.sub.2) to afford a beige solid (83 mg, 0.149
mmol, 83% yield). HPLC (4 minutes gradient) t.sub.R 2.58 min; MS
m/z 559.12 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
0.57 (m, 2H), 0.68 (m, 2H), 1.53 (qd, J=3.4, J=12.3, 2H), 1.80 (d,
J=12.2, 2H), 2.34 (s, 3H), 2.84 (m, 4H), 3.60 (s, 3H), 4.09 (m,
2H), 7.37 (m, 3H), 7.56 (m, 3H), 8.37 (s, 1H), 8.41 (d, J=3.7, 1H),
9.13 (s, 1H), 10.14 (s, 1H) ppm.
B.
4-{3-[2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-5-[1,3,4]oxadiazo-
l-2-yl-thiazol-4-yl]-phenyl}-piperidinium trifluoroacetate
[0436] Under nitrogen atmosphere, compound 24A (57 mg, 0.102 mmol)
was dissolved in a 33% HBr solution in AcOH (0.5 ml) and stirred at
room temperature for 6 hr. The reaction was quenched at 0.degree.
C. with saturated NaHCO.sub.3 and the resulting solid extracted by
CH.sub.2Cl.sub.2 (3.times.). The organic extracts were dried over
MgSO.sub.4 and the volatiles removed in vacuo to give a crude
material. Purification by preparative HPLC afforded the title
compound TFA salt as a glassy solid (3.8 mg, 0.0062 mmol, 6%
yield). HPLC (4 minutes gradient) t.sub.R 1.86 min; MS m/z 501.24
[M+H].sup.+.
EXAMPLE 25
N-Cyclopropyl-4-methyl-3-[4-(4-nitro-phenyl)-5-[1,3,4]oxadiazol-2-yl-thiaz-
ol-2-ylamino]-benzamide
##STR00071##
[0438] The title compound was prepared according to the procedure
for Example 24A starting from compound 15. Purification by flash
chromatography (SiO.sub.2, MeOH 1 to 2% in CH.sub.2Cl.sub.2)
afforded the title compound as a yellow solid (15% yield). HPLC (4
minutes gradient) t.sub.R 2.57 min; MS m/z 463.0 [M+H].sup.+;
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.57 (m, 2H), 0.69 (m,
2H), 2.27 (s, 3H), 2.84 (m, 1H), 7.37 (d, J=7.9, 1H), 7.60 (d,
J=8.1, 1H), 8.02 (d, J=8.6, 2H), 8.29 (m, 3H), 8.42 (d, J=3.7, 1H),
9.17 (s, 1H) ppm.
EXAMPLE 26
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic
acid benzylamide
##STR00072##
[0440] Compound 20 (45 mg, 0.142 mmol) and benzylamine (16 .mu.l,
0.146 mmol) were dissolved in anhydrous DMF (1 ml). To the stirred
solution were added HOBt.H.sub.2O (26 mg, 0.170 mmol) and EDCI (33
mg, 0.172 mmol) and the mixture stirred at room temperature for 1.5
hr. The mixture was poured onto a SiO.sub.2 column and the compound
eluted with 1 to 6% MeOH in CH.sub.2Cl.sub.2. The combined
CH.sub.2Cl.sub.2 phases were washed with water and dried over
MgSO.sub.4. Evaporation of the solvents afforded the title compound
as an off white solid (19 mg, 0.047 mmol, 33% yield). HPLC (4
minutes gradient) t.sub.R 2.28 min; MS m/z 407.10 [M+H].sup.+;
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56 (m, 2H), 0.67 (m,
2H), 2.28 (s, 3H), 2.83 (m, 1H), 4.40 (d, J=5.6, 2H), 7.25-7.37 (m,
6H), 7.5.3 (d, J=7.7, 1H), 7.86 (s, 1H), 8.18 (s, 1H), 8.38 (d,
J=3.4, 1H), 8.84 (br t, 1H), 9.76 (s, 1H) ppm.
EXAMPLE 27
Preparation of
4-Bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carbox-
ylic acid benzylamide
##STR00073##
[0441] A. 2,4-Dibromo-thiazole
[0442] A stirred solution of 2,4-thiazolidinedione (5 g, 42.7 mmol)
in phosphorus oxybromide (25 g, 87.2 mmol) was heated to
110.degree. C. for 3 hours. After cooling to room temperature, 250
g of crushed ice was added (CAUTION). The precipitate that is
formed was filtered and dissolved in a mixture of acetone/methylene
chloride/MeOH. The remaining aqueous phase was extracted with ether
and methylene chloride. The combined organic phases were dried over
MgSO.sub.4 and the volatiles removed in vacuo. The crude product
was purified by column chromatography on silica gel (EtOAc 20% to
100% in hexanes) to provide 2,4-dibromo-thiazole 26A as a yellow
solid (5.36 g, 55% yield).
B. 2,4-Dibromo-thiazole-5-carboxylic acid benzylamide
[0443] To a stirred solution of 2,4-dibromo-thiazole (4.95 g, 20.4
mmol) in THF at -78.degree. C. was added LDA (1.8M in THF/hexanes,
13.6 ml, 24.5 mmol) slowly. The reaction was then stirred at
-78.degree. C. for 30 min., when benzylisocyanate (3.8 ml, 30.6
mmol) was added slowly. The mixture was then stirred at -78.degree.
C. for 30 min. before it was slowly warmed up to RT. Water was then
added carefully to quench the reaction. The mixture was extracted
with EtOAc and the combined extracts were dried over sodium sulfate
and concentrated. The crude product was purified by column
chromatography on silica gel (10% EtOAc/hexanes) to give
2,4-dibromo-thiazole-5-carboxylic acid benzylamide 26B as a white
solid (5.05 g, 13.43 mmol, 66%).
C.
4-Bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carb-
oxylic acid benzylamide
[0444] To a mixture of 2,4-dibromo-thiazole-5-carboxylic acid
benzylamide 27B (3.86 g, 10.3 mmol), and
3-amino-N-cyclopropyl-4-methyl-benzamide 3A (7.81 g, 41.1 mmol) in
DMSO (10 ml, anhydrous grade) was added diisopropylethylamine (1.79
ml, 10.3 mmol) and the solution was deoxygenated and then heated at
110.degree. C. under nitrogen for 20 hours. The mixture was cooled
to RT, dissolved in methylene chloride, and washed with water. The
aqueous layer was extracted twice with methylene chloride, and the
combined organics were dried over sodium sulfate and concentrated.
The crude product was triturated with EtOAc and filtered to give
the title compound 21C as an off-white solid (2.93 g, 6.04 mmol,
59%).
EXAMPLE 28
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-fluoro-3-methyl-pheny-
l)-thiazole-5-carboxylic acid benzylamide
##STR00074##
[0446] A microwave reaction flask was charged with
4-bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carbox-
ylic acid benzylamide (10 mg, 0.02 mmol, 1.0 eq),
3-methyl-4-fluorophenylboronic acid (32 mg, 0.21 mmol, 10 eq),
tetrakistriphenylphosphine palladium (5 mg, 0.004 mmol, 0.2 eq),
200 .mu.L of dioxane, and 200 .mu.L of saturated aqueous
K.sub.2CO.sub.3. The mixture was heated with stirring in the
microwave at 120.degree. C. for 10 minutes. The layers were
separated and dioxane layer was concentrated and purified by
preparative HPLC. Fractions containing product were concentrated to
provide the title compound as a white solid (7.5 mg, 71%). HPLC (4
minutes gradient) t.sub.R 2.61 min; MS m/z 515.24 [M+H].sup.+;
.sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.53 (m, 2H), 0.66 (m,
2H), 2.16 (s, 3H), 2.29 (s, 3H), 2.82 (m, 1H), 4.29 (d, J=4.3, 2H),
7.05 (t, J=8.9, 1H), 7.20-7.30 (m, 6H), 7.44-7.51 (m, 3H),
8.30-8.36 (m, 3H), 9.72 (s, 1H) ppm.
[0447] Additional analogues were prepared by this method using the
appropriately substituted boronic acid and analyzed by HPLC and
MS.
TABLE-US-00001 TABLE 1 Example Structure Name MW m/z T.sub.r 28-2
##STR00075## 4-(4-Cyanomethyl- phenyl)-2-(5-cyclo-
propylcarbamoyl-2- methylphenylamino)- thiazole-5-carboxylic acid
benzylamide 521.643 522.1 2.72 28-3 ##STR00076##
4-(4-Cyano-phenyl)- 2-(5-cyclopropyl- carbamoyl-2-methyl-
phenylamino)-4,5- dihydro-thiazole-5- carboxylic acid benzylamide
509.632 508.06 2.75 28-4 ##STR00077## 4-(2-Chloro-phenyl)-
2-(5-cyclopropyl- carbamoyl-2-methyl- phenylamino)-
thiazole-5-carboxylic acid benzylamide 517.051 517.06 2.91 28-5
##STR00078## 2-(5-Cyclopropyl- carbamoyl-2-methyl-
phenylamino)-4-(3- hydroxymethylphen- yl)-thiazole-5-carbox- ylic
acid benzylamide 512.632 512.99 2.39 28-6 ##STR00079##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-m-
tolyl-thiazole-5- carboxylic acid benzylamide 496.633 497.14 2.97
28-7 ##STR00080## 2-(5-Cyclopropylcar- bamoyl-2-methyl-
phenylamino)-4-(3- fluorophenyl)thia- zole-5-carboxylic acid
benzylamide 500.596 501.08 2.87 28-8 ##STR00081##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-p-
tolyl-thiazole-5- carboxylic acid benzylamide 496.633 497.1 2.95
28-9 ##STR00082## 4-(3-Cyano-phenyl)- 2-(5-cyclopropyl-
carbamoyl-2-methyl- phenylamino)thia- zole-5-carboxylic acid
benzylamide 507.616 508.05 2.74 28-10 ##STR00083##
4-(5-Acetyl-thiophen- 2-yl)-2-(5-cyclo- propylcarbamoyl-2-
methylphenylamino)- thiazole-5-carboxylic acid benzylamide 530.669
530.99 2.77 28-11 ##STR00084## 4-Benzo[1,3]dioxol-
5-yl-2-(5-cycloprop- ylcarbamoyl-2- methylphenylamino)-
thiazoie-5-carboxylic acid benzylamide 526.615 527.1 2.75 28-12
##STR00085## 4-(5-Cyano-thiophen- 2-yl)-2-(5-cycloprop-
ylcarbamoyl-2- methylphenylamino)- thiazole-5-carboxylic acid
benzylamide 513.642 513.95 2.98 28-13 ##STR00086##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(4-
methoxy-phenyl)- thiazole-5-carboxylic acid benzylamide 512.632
513.14 2.76 28-14 ##STR00087## 4-[5-Benzylcarbamo-
yl-2-(5-cyclopropyl- carbamoyl-2-methyl- phenylamino)thiaz-
ol-4-yl]-benzoic acid ethyl ester 554.669 555.13 2.97 28-15
##STR00088## 3-[5-Benzylcarbamo- yl-2-(5-cyclopropyl-
carbamoyl-2-methyl- phenylamino)thiaz- ol-4-yl]-benzoic acid methyl
ester 540.642 541.06 2.76 28-16 ##STR00089## 2-(5-Cyclopropyl-
carbamoyl-2-methyl- phenylamino)-4-(4- fluoro-phenyl)-
thiazole-5-carboxylic acid benzylamide 500.596 501.1 2.87 28-17
##STR00090## 2-(5-Cyclopropyl- carbamoyl-2-methyl-
phenylamino)-4-(2- methoxy-phenyl)- thiazole-5-carboxylic acid
benzylamide 512.632 512.12 2.69 28-18 ##STR00091##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(3-
methoxy-phenyl)- thiazole-5-carboxylic acid benzylamide 512.632
513.13 2.84 28-19 ##STR00092## 2-(5-Cyclopropylcar-
bamoyl-2-methyl- phenylamino)-4-(2- trifluoromethyl-
phenyl)-thiazole-5- carboxylic acid benzylamide 550.603 551.1 2.92
28-20 ##STR00093## 2-(5-Cyclopropylcar- bamoyl-2-methyl-
phenylamino)-4-(4- hydroxymethyl- phenyl)-thiazole-5- carboxylic
acid benzylamide 512.632 513.12 2.32 28-21 ##STR00094##
4-(3-Carbamoylphen- yl)-2-(5-cyclopropyl- carbamoyl-2-methyl-
phenylamino)- thiazole-5-carboxylic acid benzylamide 525.631 526.0
2.22 28-22 ##STR00095## 4-(4-Carbamoyl- phenyl)-2-(5-cyclo-
propylcarbamoyl-2- methylphenylamino)- thiazole-5-carboxylic acid
benzylamide 525.631 256.1 2.17 28-23 ##STR00096##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(2,3-
dihydrobenzo[1,4]di- oxin-6-yl)-thiazole-5- carboxylic acid
benzylamide 540.642 541.1 2.73 28-24 ##STR00097## 4-(3-Aminomethyl-
phenyl)-2-(5-cyclo- propylcarbamoyl-2- methylphenylamino)-
thiazole-5-carboxylic acid benzylamide 511.648 512.1 1.93 28-25
##STR00098## 3-(5-Benzylcarbamo- yl-2-(5-cyclopropyl-
carbamoyl-2-methyl- phenylamino)-thiaz- ol-4-yl]-benzoic acid
526.615 527 2.41 28-26 ##STR00099## 4-[5-Benzylcarbamo-
yl-2-(5-cyclopropyl- carbamoyl-2-methyl- phenylamino)thiazol-
4-yl]-benzoic acid 526.615 257.32 1.53 28-27 ##STR00100##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-o-
tolyl-thiazole-5-car- boxylic acid benzylamide 496.633 497.22 2.41
28-28 ##STR00101## 2-(5-Cyclopropylcar- bamoyl-2-methyl-
phenylamino)-4-(2,4- difluoro-phenyl)- thiazole-5-carboxylic acid
benzylamide 518.586 519.19 2.33 28-29 ##STR00102##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(4-
methanesulfonyl- phenyl)-thiazole-5- carboxylic acid benzylamide
560.695 561.1 2.24 28-30 ##STR00103## 2-(5-Cyclopropylcar-
bamoyl-2-methyl- phenylamino)-4-(4- (morpholine-4-
carbonyl)-phenyl]- thiazole-5-carboxylic acid benzylamide 595.722
596.2 2.13 28-31 ##STR00104## 2-(5-Cyclopropylcar- bamoyl-2-methyl-
phenylamino)-4-(4- ethoxy-3-fluoro- phenyl)-thiazole-5- carboxylic
acid benzylamide 544.649 545.21 2.63 28-32 ##STR00105##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(3-
cyclopropylcarbamoyl- phenyl)-thiazole-5- carboxylic acid
benzylamide 565.696 477.12 2.19 28-33 ##STR00106##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(3-
ethoxy-phenyl)- thiazole-5-carboxylic acid benzylamide 526.659
527.1 2.6 28-34 ##STR00107## 2-(5-Cyclopropylcar- bamoyl-2-methyl-
phenylamino)-4-(4- ethylsulfanyl- phenyl)-thiazole-5- carboxylic
acid benzylamide 542.724 543.2 2.73 28-35 ##STR00108##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(3-
fluoro-4-methoxy- phenyl)-thiazole-5- carboxylic acid benzylamide
530.622 531.17 2.46 28-36 ##STR00109## 2-(5-Cyclopropylcar-
bamoyl-2-methyl- phenylamino)-4-(4- fluoro-3-methyl-
phenyl)-thiazole-5- carboxylic acid benzylamide 514.623 515.24 2.61
28-37 ##STR00110## 2-(5-Cyclopropylcar- bamoyl-2-methyl-
phenylamino)-4-(3,4- difluoro-phenyl)- thiazole-5-carboxylic acid
benzylamide 518.586 519.08 2.52 28-38 ##STR00111##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(2-
fluoro-phenyl)- thiazole-5-carboxylic acid benzylamide 500.596
501.14 2.39 28-39 ##STR00112## 2-(5-Cyclopropylcar-
bamoyl-2-methyl- phenylamino)-4-(4- ethoxy-phenyl)-
thiazole-5-carboxylic acid benzylamide 526.659 527.27 2.57 28-40
##STR00113## 2-(5-Cyclopropylcar- bamoyl-2-methyl-
phenylamino)-4-(1H- indol-5-yl)-thiazole- 5-carboxylic acid
benzylamide 521.643 522.24 2.32 28-41 ##STR00114##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(4-
methoxy-3-methyl- phenyl)-thiazole-5- carboxylic acid benzylamide
526.659 527.2 2.59 28-42 ##STR00115## 2-(5-Cyclopropylcar-
bamoyl-2-methyl- phenylamino)-4-(4- ethylcarbamoyl-
phenyl)-thiazole-5- carboxylic acid benzylamide 553.685 554.1 2.11
28-43 ##STR00116## 2-(5-Cyclopropylcar- bamoyl-2-methyl-
phenylamino)-4-(4- hydroxy-phenyl)- thiazole-5-carboxylic acid
benzylamide 498.605 499.1 2.16 28-44 ##STR00117##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-(4-
propoxy-phenyl)- thiazole-5-carboxylic acid benzylamide 540.686
541.2 2.75 28-45 ##STR00118## 4-[3-(3-Amino- propoxy)-phenyl]-2-
(5-cyclopropylcar- bamoyl-2-methyl- phenylamino)-
thiazole-5-carboxylic acid benzylamide 555.701 361.22 1.61 28-46
##STR00119## 4-[3-(2-Amino- ethoxy)-phenyl]-2-(5-
cyclopropylcarbamo- yl-2-methylphenyl- amino)-thiazole-5-
carboxylic acid benzylamide 541.674 542.16 1.63 28-47 ##STR00120##
2-(5-Cyclopropylcar- bamoyl-2-methyl- phenylamino)-4-[3-
(2-morpholin-4-yl- ethoxy)-phenyl]- thiazole-5-carboxylic acid
benzylamide 611.765 612.2 2.32
EXAMPLE 29
2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-methanesulfonylamino--
phenyl)-thiazole-5-carboxylic acid benzylamide
##STR00121##
[0449] The title compound was prepared as in Example 28 from
compound 27 and 3-(methanesulfonylamino)phenyl boronic acid.
Purification by flash chromatography on SiO.sub.2 (MeOH 1 to 5% in
CH.sub.2Cl.sub.2) afforded the title compound as an off white solid
(81% yield). HPLC (4 minutes gradient) t.sub.R 2.55 min; MS m/z
576.1 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.55
(m, 2H), 0.68 (m, 2H), 2.32 (s, 3H), 2.83 (m, 1H), 2.97 (s, 3H),
4.32 (d, J=5.5, 2H), 7.15-7.35 (m, 9H), 7.54 (m, 2H), 8.25 (s, 1H),
8.40 (m, 2H), 9.81 (s, 2H) ppm.
EXAMPLE 30
4-(4-Amino-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-
e-5-carboxylic acid benzylamide
##STR00122##
[0451] The title compound was prepared as in Example 28 from
compound 27 and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
Purification by flash chromatography (SiO.sub.2, MeOH 1 to 4% in
CH.sub.2Cl.sub.2) provided the title compound as a brown solid (83%
yield). HPLC (4 minutes gradient) t.sub.R 2.10 min; MS m/z 498.13
[M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56 (m,
2H), 0.68 (m, 2H), 2.31 (s, 3H), 2.84 (m, 1H), 4.32 (d, J=5.7, 2H),
5.37 (s, 2H), 6.50 (d, J=8.3, 2H), 7.20-7.36 (m, 8H), 7.50 (d,
J=7.5, 1H), 8.04 (br t, 1H), 8.35 (s, 1H), 8.39 (d, J=3.7, 1H),
9.62 (s, 1H) ppm.
EXAMPLE 31
4-(3-Amino-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-
e-5-carboxylic acid benzylamide
##STR00123##
[0453] The title compound was prepared as in Example 28 from
compound 27 and 3-aminophenylboronic acid hydrochloride. Flash
chromatography (SiO.sub.2, MeOH 1 to 6% in CH.sub.2Cl.sub.2)
afforded the title compound as an off white solid (59% yield). HPLC
(4 minutes gradient) t.sub.R 2.08 min; MS m/z 498.10 [M+H].sup.+;
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56 (m, 2H), 0.62 (m,
2H), 2.31 (s, 3H), 2.73 (m, 1H), 4.31 (d, J=5.5, 2H), 5.12 (s, 2H),
6.56 (d, J=7.6, 1H), 6.72 (d, J=7.4, 1H), 6.84 (s, 1H), 6.98 (t,
J=7.7, 1H), 7.18-7.33 (m, 6H), 7.53 (d, J=7.6, 1H), 7.89 (br t,
1H), 8.21 (s, 1H), 8.38 (d, J=3.5, 1H), 9.71 (s, 1H) ppm.
EXAMPLE 32
({3-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thi-
azol-4-yl]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl
ester
##STR00124##
[0455] To a stirred solution of compound 31 (29 mg, 0.058 mmol) in
anhydrous DMF (0.5 ml) was added N-Boc glycine (10 mg, 0.057 mmol),
EDCI (13 mg, 0.069 mmol), HOBt.H.sub.2O (11 mg, 0.072 mmol) and
DMAP (1 crystal, catalytic). The reaction mixture was heated at
50.degree. C. for 7 hr. After cooling to room temperature, the
crude mixture was poured on a SiO.sub.2 column and eluted with MeOH
1 to 5% in CH.sub.2Cl.sub.2. The compound was dissolved in
CH.sub.2Cl.sub.2 and filtered through a pad of celite to afford the
title compound as an off white solid (16 mg, 0.0244 mmol, 42%).
HPLC (4 minutes gradient) t.sub.R 2.78 min; MS m/z 654.88
[M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56 (m,
2H), 0.67 (m, 2H), 1.39 (s, 9H), 2.31 (s, 3H), 2.83 (m, 1H), 3.72
(d, J=5.8, 2H), 4.30 (d, J=5.5, 2H), 7.07 (t, J=5.8 1H), 7.18-7.35
(m, 8H), 7.55 (m, 2H), 7.91 (s, 1H), 8.22 (m, 2H), 8.39 (d, J=3.7,
1H), 9.80 (s, 1H), 10.00 (s, 1H) ppm.
EXAMPLE 33
(2-{3-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-t-
hiazol-4-yl]-phenylcarbamoyl}-ethyl)-carbamic acid tert-butyl
ester
##STR00125##
[0457] Prepared according to the procedure for Example 32 starting
from N-Boc .beta.-alanine. Flash chromatography (SiO.sub.2, MeOH 1
to 6% in CH.sub.2Cl.sub.2) afforded the title compound as an off
white solid (49% yield). HPLC (4 minutes gradient) t.sub.R 2.81
min; MS m/z 668.71 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. one signal overlapped by solvents signals 0.55 (m, 2H),
0.67 (m, 2H), 1.37 (s, 9H), 2.32 (s, 3H), 2.83 (m, 1H), 3.22 (m,
2H), 4.31 (d, J=5.5, 2H), 6.89 (br t, 1H), 7.18-7.35 (m, 8H), 7.55
(d, J=7.7, 1H), 7.61 (br s, 1H), 7.89 (s, 1H), 8.21 (s, 2H), 8.39
(d, J=3.6, 1H), 9.78 (s, 1H), 10.01 (s, 1H) ppm.
EXAMPLE 34
({4-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thi-
azol-4-yl]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl
ester
##STR00126##
[0459] Prepared according to the procedure for Example 32 starting
from compound 30. Flash chromatography (SiO.sub.2, MeOH 1 to 6% in
CH.sub.2Cl.sub.2) provided the title compound as a glassy solid
(72% yield). HPLC (4 minutes gradient) t.sub.R 2.49 min; MS m/z
655.01 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta.
0.55 (m, 2H), 0.67 (m, 2H), 1.39 (s, 9H), 2.30 (s, 3H), 2.83 (m,
1H), 3.72 (d, J=5.8, 2H), 4.31 (d, J=5.7, 2H), 7.06 (br t, 1H),
7.22 (d, J=7.5, 2H), 7.30 (d, J=7.8, 2H), 7.50-7.58 (m, 5H),
8.33-8.38 (m, 3H), 9.72 (s, 1H), 10.01 (s, 1H) ppm.
EXAMPLE 35
(2-{4-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-t-
hiazol-4-yl]-phenylcarbamoyl}-ethyl)-carbamic acid tert-butyl
ester
##STR00127##
[0461] Prepared according to the procedure for Example 33 starting
from compound 30. Purification by flash chromatography (SiO.sub.2,
MeOH 1 to 6% in CH.sub.2Cl.sub.2) afforded the title compound as an
off white solid (64% yield). HPLC (4 minutes gradient) t.sub.R 2.51
min; MS m/z 668.89 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 500 MHz)
.delta. one signal overlapped by solvent signals 0.55 (m, 2H), 0.67
(m, 2H), 1.36 (s, 9H), 2.30 (s, 3H), 2.83 (m, 1H), 3.20 (m, 2H),
4.30 (d, J=5.8, 2H), 6.90 (br t, 1H), 7.23 (m, 3H), 7.31 (m, 3H),
7.50 (d, J=7.1, 1H), 7.56 (s, 3H), 8.32-8.37 (m, 3H), 9.69 (s, 1H),
10.02 (s, 1H) ppm.
EXAMPLE 36
4-[3-(2-Amino-acetylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phen-
ylamino)-thiazole-5-carboxylic acid benzylamide
ditrifluoroacetate
##STR00128##
[0463] To a stirred solution of compound 32 (14 mg, 0.0214 mmol) in
CH.sub.2Cl.sub.2 (1 ml) was added trifluoroacetic acid (0.3 ml).
The mixture was stirred at room temperature for 2 hours. The
volatiles were removed in vacuo to afford the title compound
ditrifluoroacetamide salt as an off white glassy material (17 mg,
0.0217 mmol, 100%). HPLC (4 minutes gradient) t.sub.R 1.97 min; MS
m/z 555.05 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
0.57 (m, 2H), 0.67 (m, 2H), 2.32 (s, 3H), 2.83 (m, 1H), 3.78 (d,
J=5.3, 2H), 4.32 (d, J=5.4, 2H), 7.19-7.35 (m, 9H), 7.55 (d, J=7.7,
1H), 7.63 (d, J=7.1, 1H), 7.84 (s, 1H), 8.08 (br s, 3H), 8.23 (s,
1H), 8.40 (br s, 2H), 9.78 (s, 1H), 10.45 (s, 1H) ppm.
EXAMPLE 37
4-[3-(3-Amino-propionylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-p-
henylamino)-thiazole-5-carboxylic acid benzylamide
ditrifluoroacetate
##STR00129##
[0465] The title compound was prepared according to the procedure
for Example 36 starting from compound 33 as a colorless glassy
material (100%). HPLC (4 minutes gradient) t.sub.R 1.94 min; MS m/z
569.10 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 6 some
signals are overlapped by the solvents signals 0.55 (m, 2H), 0.67
(m, 2H), 2.32 (s, 3H), 2.82 (m, 1H), 3.09 (m, 2H), 4.32 (d, J=5.5,
2H), 7.19-7.35 (m, 9H), 7.54 (d, J=7.8, 1H), 7.63 (d, J=6.8, 1H),
7.72 (br s, 3H), 7.87 (s, 1H), 8.23 (s, 1H), 8.28 (t, J=5.7, 1H),
8.39 (d, J=3.8, 1H), 9.75 (s, 1H), 10.20 (s, 1H) ppm.
EXAMPLE 38
4-[4-(2-Amino-acetylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phen-
ylamino)-thiazole-5-carboxylic acid benzylamide
ditrifluoroacetate
##STR00130##
[0467] The title compound was prepared according to the procedure
for Example 36 starting from compound 34 as an off white solid
(100% yield). HPLC (4 minutes gradient) t.sub.R 1.90 min; MS m/z
555.20 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta.
0.55 (m, 2H), 0.68 (m, 2H), 2.30 (s, 3H), 2.83 (m, 1H), 3.79 (d,
J=5.6, 2H), 4.32 (d, J=5.8, 2H), 7.24 (d, J=7.5, 2H), 7.30 (d,
J=5.4, 2H), 7.50 (d, J=7.4, 1H), 7.54 (d, J=8.5, 2H), 7.62 (d,
J=8.5, 2H), 8.08 (br s, 3H), 8.38 (d, J=3.9, 2H), 8.45 (d, J=5.9,
1H), 9.69 (s, 1H), 10.48 (s, 1H) ppm.
EXAMPLE 39
2-{4-[5-benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-th-
iazol-4-yl]-phenylcarbamoyl}-ethyl-ammonium ditrifluoroacetate
##STR00131##
[0469] The title compound was prepared according to the procedure
for Example 36 starting from compound 35 as an off white solid
(100% yield). HPLC (4 minutes gradient) t.sub.R 1.89 min; MS m/z
569.13 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta.
0.55 (m, 2H), 0.68 (m, 2H), 2.30 (s, 3H), 4.51 (t, J=6.5, 2H), 2.83
(m, 1H), 3.09 (q, J=6.0, 2H), 4.32 (d, J=5.7, 2H), 7.23 (d, J=7.5,
2H), 7.30 (d, J=5.9, 2H), 7.50 (d, J=7.6, 1H), 7.56 (d, J=8.7, 2H),
7.60 (d, J=8.6, 2H), 7.70 (br s, 3H), 8.37-8.43 (m, 3H), 9.68 (s,
1H), 10.23 (s, 1H) ppm.
EXAMPLE 40
4-(4-Cyanomethyl-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-t-
hiazole-5-carboxylic acid benzylamide
##STR00132##
[0471] The title compound was prepared by the method of Example 28
from compound 27 and 4-cyanomethylphenylboronic acid. Purification
by flash chromatography (SiO.sub.2, MeOH 1 to 3% in
CH.sub.2Cl.sub.2) provided the desired compound 40 as an off white
solid (73% yield). HPLC (4 minutes gradient) t.sub.R 2.66 min; MS
m/z 522.10 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
0.56 (m, 2H), 0.68 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 4.08 (s,
2H), 4.32 (d, J=5.5, 2H), 7.22-7.33 (m, 8H), 7.53 (d, J=7.7, 1H),
7.64 (d, J=7.8, 2H), 8.36 (s, 1H), 8.40 (d, J=3.4, 1H), 8.48 (br t,
1H), 9.77 (s, 1H) ppm.
EXAMPLE 41
4-[4-(2-Amino-ethyl)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamin-
o)-thiazole-5-carboxylic acid benzylamide
##STR00133##
[0473] Prepared using chemistry described in J. Med. Chem., 2003,
46, 345-348. To a stirred suspension of compound 40 (45 mg, 0.0862
mmol) in MeOH (1.5 ml) was added cobalt chloride hexahydrate (0.172
mmol). Upon addition of NaBH.sub.4 (33 mg, 0.872 mmol) the solution
turned black instantly. After stirring at room temperature for 1
hour, 1N HCl was added (5 ml) and the mixture filtered through a
pad of celite. The solution was alkalinized by adding concentrated
NH.sub.4OH and the compound extracted with CH.sub.2Cl.sub.2
(3.times.). After drying of the extracts over MgSO.sub.4 and
removal of the solvents, the crude product was purified by flash
chromatography on silica gel eluted with 1 to 10% MeOH in
CH.sub.2Cl.sub.2 to remove impurities, then 10:1:89
MeOH/NEt.sub.3/CH.sub.2Cl.sub.2 to elute the title compound as an
off white solid (34% yield). HPLC (4 minutes gradient) t.sub.R
1.93; MS m/z 526.13 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 0.56 (m 2H), 0.68 (m, 2H), 2.32 (s, 3H), 2.76 (m, 2H),
2.89 (m, 3H), 4.32 (d, J=5.6, 2H), 7.16-7.33 (m, 9H), 7.50-7.58 (m,
3H), 8.39 (m, 3H) ppm.
EXAMPLE 42
[0474] The ability of the compounds provided herein to inhibit the
synthesis or the activity of cytokines can be demonstrated using
the following in vitro assays.
[0475] Generation of p38 Kinases
[0476] cDNAs of human p38.alpha. and .beta. were cloned by PCR. The
.alpha. and .beta. cDNAs were subcloned into DEST2 plasmid
(Gateway, InVitrogen). His.sub.6-p38 fusion protein was expressed
in E. coli and purified from bacterial lysates by affinity
chromatography using Ni.sup.+2-NTA-agarose. His.sub.6-p38 protein
was activated by incubating with constitutively active MKK6. Active
p38 was separated from MKK6 by affinity chromatography.
Constitutively active MKK6 was generated in a manner similar to
Raingeaud et al. (Mol. Cell. Biol., 1247-1255 (1996)).
[0477] TNF-.alpha. Production by LPS-Stimulated PBMCs
[0478] Heparinized human whole blood was obtained from healthy
volunteers. Peripheral blood mononuclear cells (PBMCs) were
purified from human whole blood by Accu-paque density gradient
centrifugation and resuspended at a concentration of
5.times.10.sup.6/ml in assay medium (RPMI medium containing 10%
fetal bovine serum). 175 uL of cell suspension was incubated with
10 uL of test compound (in 4% DMSO) in 96-well tissue culture
plates for 30 minutes at RT. 15 uL of LPS (13.33 ug/ml stock) was
then added to the cell suspension and the plate was incubated for
18 hours at 37.degree. C. in a humidified atmosphere containing 5%
CO.sub.2. Following incubation, the culture medium was collected
and stored at -20.degree. C.
[0479] THP-1 cells (TIB-202, ATCC) were washed and resuspended at a
concentration of 1.times.10.sup.5/ml in assay medium (RPMI medium
containing 3% fetal bovine serum). 175 uL of cell suspension was
incubated with 10 uL of test compound (in 4% DMSO) in 96-well
tissue culture plates for 30 minutes at RT. 15 uL of LPS (13.33
ug/ml stock) was then added to the cell suspension and the plate
was incubated for 18 hours at 37.degree. C. in a humidified
atmosphere containing 5% CO.sub.2. Following incubation, the
culture medium was collected and stored at -20.degree. C.
[0480] TNF-.alpha. concentration in the medium was quantified using
a standard ELISA kit (BioSource International, Camarillo, Calif.).
Concentrations of TNF-.alpha. and IC.sub.50 values for test
compounds (concentration of compound that inhibited LPS-stimulated
TNF-.alpha. production by 50%) were calculated by four parameter
logistic curve (SigmaPlot, SPSS, Inc.).
[0481] p38.alpha. Assay
[0482] The p38.alpha. assay employed is based on measurement of ADP
released in the reaction of interest through NADH oxidation
obtained by coupling with pyruvate kinase and lactate dehydrogenase
reactions. The assays were performed in 384-well UV-plates. The
final volume was 25 uL prepared from the addition of 2.5 uL
compound dissolved in 10% DMSO, 17.5 uL of assay buffer and 5 uL of
ATP. Assay buffer contains the following reagents to give final
concentration in the assay: 25 mM HEPES, 20 mM 2-glycerophosphate,
pH 7.6, 10 mM MgCl.sub.2, 0.1 mM sodium orthovanadate, 0.5 mM
phosphoenolpyruvate, 0.12 mM NADH, 3.1 mg/ml LDH, 6.67 mg/ml
pyruvate kinase, 0.25 mM peptide substrate, 2 mM DTT, 0.005% Tween
80 and 20 nM p38.alpha. kinase from Upstate. Test compounds are
preincubated with p38.alpha. kinase for 60 min and the reaction
started by addition of ATP to 0.15 mM final concentration. Reaction
rates were measured at 340 nm using SpectraMax plate-reading
spectrophotometer for 10 min at 37.degree. C. Inhibition data were
analyzed by non-linear least-squares regression using
SigmaPlot.
[0483] TNF-.alpha. Production by LPS-Stimulated Mice
[0484] Mice (Balb/c female, 6-8 weeks of age, Taconic Labs;
n=8/treatment group) were injected intraperitoneally with
lipopolysaccharide (LPS) (50 ug/kg of E. coli strain 0111:B4,
Sigma) suspended in sterile saline. Ninety minutes later, mice were
sedated by CO.sub.2:O.sub.2 inhalation and a blood sample was
obtained. Serum was separated and analyzed for TNF-.alpha.
concentrations by commercial ELISA assay per the manufacturer's
instructions (BioSource International). Test compounds were
administered orally at various times before LPS injection. The
compounds were dosed either as suspensions or as solutions in
various vehicles or solubilizing agents.
Results
[0485] IC.sub.50 data were obtained for the compounds provided
herein. Most of the compounds exhibited p38.alpha. kinase IC.sub.50
values of less than 10 .mu.M, many less than 1 .mu.M. Data for
selected compounds is shown in the Table below.
TABLE-US-00002 Compound p38.alpha. kinase IC.sub.50 (nM)* 1 +++ 2
+++ 3 + 26 +++ 28-6 ++ 28-9 ++ 28-24 +++ 28-40 + *+ refers to
>100 nM ++ refers to 50-100 nM +++ refers to <50 nM
[0486] Since modifications will be apparent to those of skill in
this art, it is intended that the subject matter claimed herein be
limited only by the scope of the appended claims.
* * * * *