U.S. patent application number 11/085347 was filed with the patent office on 2005-08-04 for modulators of the glucocorticoid receptor and method.
Invention is credited to Chen, Xiao-Tao, Doweyko, Arthur M., Doweyko, Lidia, Huynh, Tram, Kim, Soong-Hoon, Leavitt, Kenneth J., Li, Wenying, Tortolani, David R., Vaccaro, Wayne, Yang, Bingwei Vera.
Application Number | 20050171136 11/085347 |
Document ID | / |
Family ID | 30770955 |
Filed Date | 2005-08-04 |
United States Patent
Application |
20050171136 |
Kind Code |
A1 |
Vaccaro, Wayne ; et
al. |
August 4, 2005 |
Modulators of the glucocorticoid receptor and method
Abstract
Novel non-steroidal compounds are provided which are
glucocorticoid receptor modulators which are useful in treating
diseases requiring glucocorticoid receptor agonist or antagonist
therapy such as obesity, diabetes, inflammatory and immune
disorders, and have the structure 1 where Z is CONR.sup.1R.sup.2 or
CH.sup.2NR.sup.1R.sup.2 and where R, R.sup.a, R.sup.b, R.sup.c,
R.sup.d, Z, A and B are defined herein.
Inventors: |
Vaccaro, Wayne; (Yardley,
PA) ; Yang, Bingwei Vera; (Belle Mead, NJ) ;
Kim, Soong-Hoon; (Titusville, NJ) ; Huynh, Tram;
(Pennington, NJ) ; Tortolani, David R.; (Skillman,
NJ) ; Leavitt, Kenneth J.; (Lawrenceville, NJ)
; Li, Wenying; (Middletown, CT) ; Doweyko, Arthur
M.; (Long Valley, NJ) ; Chen, Xiao-Tao;
(Newark, DE) ; Doweyko, Lidia; (Long Valley,
NJ) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
30770955 |
Appl. No.: |
11/085347 |
Filed: |
March 21, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11085347 |
Mar 21, 2005 |
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10621909 |
Jul 17, 2003 |
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60396877 |
Jul 18, 2002 |
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Current U.S.
Class: |
514/284 ;
514/520; 514/617; 546/63; 558/418; 564/172 |
Current CPC
Class: |
C07D 471/08 20130101;
A61K 31/473 20130101; A61P 11/02 20180101; C07D 213/75 20130101;
A61P 17/00 20180101; A61P 17/06 20180101; A61P 19/02 20180101; A61P
19/08 20180101; C07D 213/40 20130101; C07D 215/38 20130101; C07D
235/14 20130101; C07D 277/46 20130101; A61P 3/00 20180101; A61P
7/00 20180101; C07D 333/34 20130101; C07D 417/12 20130101; A61P
1/16 20180101; A61P 11/16 20180101; A61P 3/04 20180101; C07D 471/04
20130101; A61P 1/02 20180101; C07D 307/58 20130101; C07D 333/20
20130101; A61P 1/04 20180101; A61K 45/06 20130101; A61P 35/00
20180101; C07D 417/04 20130101; C07D 263/48 20130101; A61P 27/14
20180101; A61P 11/00 20180101; A61P 5/00 20180101; C07D 277/64
20130101; C07D 495/04 20130101; A61P 9/10 20180101; A61P 7/06
20180101; C07D 239/94 20130101; C07D 261/14 20130101; A61P 31/04
20180101; A61P 3/10 20180101; C07D 261/12 20130101; C07D 487/04
20130101; A61K 31/473 20130101; C07D 231/16 20130101; C07D 235/30
20130101; A61P 21/04 20180101; A61P 19/00 20180101; A61P 1/18
20180101; A61P 37/08 20180101; C07D 209/48 20130101; C07D 213/82
20130101; A61P 27/02 20180101; C07D 317/58 20130101; A61P 1/00
20180101; A61P 13/12 20180101; A61P 19/06 20180101; A61P 37/00
20180101; C07D 207/34 20130101; A61K 31/403 20130101; A61P 43/00
20180101; C07D 405/04 20130101; A61P 37/06 20180101; C07D 239/42
20130101; A61K 31/403 20130101; A61P 11/06 20180101; A61P 25/00
20180101; C07D 285/06 20130101; A61P 29/00 20180101; C07D 401/04
20130101; C07D 417/10 20130101; C07D 241/20 20130101; A61P 17/02
20180101; C07D 233/88 20130101; A61P 17/14 20180101; A61P 35/02
20180101; A61P 37/02 20180101; C07D 217/22 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/284 ;
514/617; 514/520; 546/063; 558/418; 564/172 |
International
Class: |
C07D 471/02; A61K
031/4745; A61K 031/277; A61K 031/165; C07C 255/60 |
Claims
1-34. (canceled)
35. A method for preventing, inhibiting onset of or treating an
inflammatory or immune associated disease or disorder which is an
endocrine disorder, rheumatic disorder, collagen disease,
dermatologic disease, allergic disease, ophthalmic disease,
respiratory disease, hematologic disease, gastrointestinal disease,
inflammatory disease, autoimmune disease, neoplastic disease and
metabolic disease which is associated with the expression product
of a gene whose transcription is stimulated or repressed by
glucocorticoid receptors, or a method for preventing, inhibiting
onset of or treating a disease associated with AP-1- and/or
NF-.kappa.B-induced transcription, or a method for preventing,
inhibiting onset of or treating a disease associated with AP-1
and/or NF-.kappa.B dependent gene expression, wherein the disease
is associated with the expression of a gene under the regulatory
control of AP-1 and/or NF-.kappa.B, the method comprises
administering to a patient in need of treatment a therapeutically
effective amount of a compound having below structure: 783including
all stereoisomers thereof, or a prodrug ester thereof, or a
pharmaceutically acceptable salt thereof, wherein R is hydrogen,
alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy,
heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl,
aminoalkyl, hydroxyalkyl, aryloxyalkyl, or hydroxyaryl; R.sup.a is
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy,
heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarboyl,
cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl,
hydroxyalkyl, hydroxyaryl, aryloxyalkyl, nitro, amino, CHO,
CO.sub.2 alkyl, CONR.sup.eR.sup.f, CH.sub.2NR.sup.gR.sup.h,
CO.sub.2H, CH.sub.2OH, CH.sub.2NHR.sup.g, NHCH.sub.2R.sup.g,
NHCHR.sup.gR.sup.h, NHCOR.sup.e, NHCONR.sup.eR.sup.f or
NHSO.sub.2R.sup.e; R.sup.b is hydrogen, alkyl, alkenyl, alkynyl,
alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl,
heteroarylalkyl, cycloheteroalkylalkyl, cyano, halogen,
heteroarylaminocarbonyl, cycloheteroalkylcarbonyl, cyanoalkyl,
alkylaminoalkyl, hydroxyalkyl, nitro, amino, CHO, CO.sub.2 alkyl,
hydroxyaryl, aryloxyalkyl, CONR.sup.iR.sup.j,
CH.sub.2NR.sup.kR.sup.l, CO.sub.2H, CH.sub.2OH, CH.sub.2NHR.sup.k,
NHCH.sub.2R.sup.k, NHCHR.sup.kR.sup.l, NHCOR.sup.i,
NHCONR.sup.iR.sup.j or NHSO.sub.2R.sup.i; where R.sup.e and R.sup.f
are the same or different and are independently selected from
hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino,
alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,
cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,
cycloalkyl, and cycloalkylalkyl, and R.sup.e and R.sup.f can be
taken together with the nitrogen to which they are attached to form
a 5-, 6- or 7-membered heteroaryl or cycloheteroalkyl ring which
contains 1, 2 or 3 hetero atoms which can be N, O or S; R.sup.g and
R.sup.h are the same or different and are independently selected
from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino,
alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,
cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,
cycloalkyl, and cycloalkylalkyl, and R.sup.g and R.sup.h can be
taken together with the nitrogen to which they are attached to form
a 5-, 6- or 7-membered heteroaryl ring or cycloheteroalkyl ring
which contains 1, 2 or 3 hetero atoms which can be N, O or S;
R.sup.i and R.sup.j are the same or different and are independently
selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy,
amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,
cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,
cycloalkyl, and cycloalkylalkyl, and R.sup.i and R.sup.j can be
taken together with the nitrogen to which they are attached to form
a 5-, 6- or 7-membered heteroaryl ring or cycloheteroalkyl ring
which contains 1, 2 or 3 hetero atoms which can be N, O or S;
R.sup.k and R.sup.l are the same or different and are independently
selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy,
amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,
cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,
cycloalkyl, and cycloalkylalkyl, and R.sup.k and R.sup.l can be
taken together with the nitrogen to which they are attached to form
a 5-, 6- or 7-membered heteroaryl ring or cycloheteroalkyl ring
which contains 1, 2 or 3 hetero atoms which can be N, O or S;
R.sup.c and R.sup.d are the same or different and are independently
selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,
hydroxy, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, hydroxyaryl, and aryloxyalkyl; R.sup.c and
R.sup.d may optionally be taken together with the carbon to which
they are attached to form a 3- to 7-membered ring which may
optionally include an O atom or an N atom; Z is CONR.sup.1R.sup.2
or CH.sub.2NR.sup.1R.sup.2 wherein R.sup.1 and R.sup.2 are the same
or different and are independently selected from hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl,
heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloalkenyl,
monoalkylaminoalkyl, dialkylaminoalkyl, cycloheteroalkylalkyl,
hydroxyaryl, aryloxyalkyl, alkoxyalkyl and hydroxyalkyl; the A ring
represents a saturated, partially saturated or unsaturated
6-membered carbocyclic or heterocyclic ring; and the B ring
represents a saturated, partially saturated or unsaturated
6-membered carbocyclic or heterocyclic ring; with the following
provisos: I. provided that where Z is CONR.sup.1R.sup.2 and (a) R
is CH.sub.3 or H and R.sup.a, R.sup.b, R.sup.c and R.sup.d are each
hydrogen, or (b) R.sup.a and R.sup.b are each hydrogen and one of
R.sup.c and R.sup.d is alkyl, then (1) at least one of R.sup.1 and
R.sup.2 is heteroaryl, heteroarylalkyl, cycloheteroalkyl or
cycloheteroalkylalkyl, but where the heteroaryl is unsubstituted
784or unsubstituted 785or the heteroarylalkyl is unsubstituted
786or unsubstituted 787then the other of R.sup.1 and R.sup.2 is
other than hydrogen, and/or the A ring includes a hetero atom
and/or the B ring includes a hetero atom; or (2) where one of
R.sup.1 and R.sup.2 is phenyl which is substituted with alkyl,
hydroxy, halo, C.sub.1-C.sub.2-alkoxycarbonyl or nitro, then (a)
the phenyl must be substituted with at least one other group other
than hydrogen, alkyl, hydroxy, halo,
C.sub.1,-C.sub.2-alkoxycarbonyl or nitro, except that the phenyl
may be substituted with two or more halo atoms, and/or two or more
hydroxy groups and/or (b) the other of R.sup.1 and R.sup.2 is other
than hydrogen and/or (c) the A ring includes a hetero atom and/or
the B ring includes a hetero atom; (3) where one of R.sup.1 and
R.sup.2 is phenyl substituted with C.sub.1-C.sub.2 alkoxy, the
phenyl cannot be substituted with a second C.sub.1-C.sub.2 alkoxy
or the other of R.sup.1 and R.sup.2 is other than hydrogen; or (4)
where at least one of R.sup.1 and R.sup.2 is hydrogen,
unsubstituted alkyl, alkenyl, cycloalkyl, alkylcycloalkyl,
cycloalkenyl, alkylcycloalkenyl, alkylphenyl, monoalkylaminoalkyl,
dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl or hydroxyalkyl
then (a) the other of R.sup.1 and R.sup.2 is other than hydrogen,
unsubstituted alkyl, alkenyl, cycloaklyl, alkylcycloalkyl,
cycloalkenyl, alkylcycloalkenyl, alkylphenyl, monoalkylaminoalkyl,
dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl or hydroxyalkyl
and/or (b) at least one of R.sup.a, R.sup.b, R.sup.c and/or R.sup.d
is other than hydrogen and/or (c) R is other than hydrogen or
C.sub.1-C.sub.2 alkyl and/or (d) the A ring includes a hetero atom
and/or the B ring includes a hetero atom; and II. provided that
where Z is CH.sub.2NR.sup.1R.sup.2 and/or where at least one of
R.sup.1 and R.sup.2 is hydrogen, alkyl, alkenyl, cycloalkyl,
alkylcycloalkyl, phenyl, alkylphenyl, phenylalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl,
alkoxyalkyl, hydroxyalkyl, heteroaryl which is pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl or imidazolinyl, or
cycloheteroalkyl which is 4,5-dihydro-imidazol-2-yl, piperidinyl or
piperazinyl, then (a) the other of R.sup.1 and R.sup.2 is other
than hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, phenyl,
alkylphenyl, phenylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,
arylalkyl, aryl, alkoxyalkyl, or hydroxyalkyl, and/or (b) at least
one of R.sup.a, R.sup.b, R.sup.c and/or R.sup.d is other than
hydrogen or C.sub.1-2 alkyl, and/or (c) R is other than hydrogen or
C.sub.1-C.sub.2 alkyl and/or (d) the A ring includes a hetero atom
and/or the B ring includes a hetero atom, and/or (e) one of R.sup.c
and R.sup.d is other than hydroxyalkyl.
36. The method as defined in claim 35 wherein the A ring of the
compound has the structure 788and the B ring has the structure
789wherein X.sub.1, X.sub.2, X.sub.3 and X.sub.4, are the same or
different and are independently selected from CH, CH.sub.2,
CHR.sup.15, CR.sup.16, CR.sup.16R.sup.17, N, NH, NR.sup.18, O and
S, and X.sub.5, X.sub.6, X.sub.7 and X.sub.8 are the same or
different and are independently selected from CH, CH.sub.2,
CHR.sup.19, CR.sup.20, CR.sup.20R.sup.21, N, NH, NR.sup.22, O and
S, wherein R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.20, R.sup.21 and R.sup.22 are the same or different and are
independently selected from hydrogen, alkyl, aryl, cycloalkyl,
heteroaryl, and cycloheteroalkyl, wherein each of said A ring and
said B ring contains at most two nitrogen ring atoms, at most two
oxygen ring atom and at most one sulfur ring atom.
37. The method as defined in claim 35 wherein the compound has the
structure 790
38. The method as defined in claim 35 wherein the compound has the
structure 791where R is H or alkyl; R.sup.a is selected from H, CN,
NO.sub.2, NH.sub.2, CHO, CO.sub.2 alkyl, CONR.sup.eR.sup.f or
CH.sub.2NR.sup.gR.sup.h; and R.sup.b is selected from H, CN,
NO.sub.2, NH.sub.2, CHO, CO.sub.2 alkyl, CONR.sup.iR.sup.j or
CH.sub.2NR.sup.kR.sup.l.
39. The method as defined in claim 35 wherein the compound has the
structure 792where R is H, CH.sub.3 or C.sub.2H.sub.5 and R.sup.c
is H or OH, and one of R.sup.1 and R.sup.2 is heteroaryl.
40. The method as defined in claim 39 wherein one of R.sup.1 and
R.sup.2 of the compound is 793where R.sup.m is selected from H,
alkyl, aryl, heteroaryl, halo, and alkoxy and R.sup.o is H or
alkyl.
41. A method for preventing, inhibiting onset of or treating an
inflammatory or immune associated disease or disorder which is an
endocrine disorder, rheumatic disorder, collagen disease,
dermatologic disease, allergic disease, ophthalmic disease,
respiratory disease, hematologic disease, gastrointestinal disease,
inflammatory disease, autoimmune disease, neoplastic disease and
metabolic disease which is associated with the expression product
of a gene whose transcription is stimulated or repressed by
glucocorticoid receptors, or a method for preventing inhibiting
onset of or treating a disease associated with AP-1- and/or
NF-.kappa.B-induced transcription, or a method for preventing,
inhibiting onset of or treating a disease associated with AP-1
and/or NF-.kappa.B dependent gene expression, wherein the disease
is associated with the expression of a gene under the regulatory
control of AP-1 and/or NF-.kappa.B, the method comprises
administering to a patient in need of treatment a therapeutically
effective amount of a compound having below structure 794where X is
aryl or alkyl; 795where X is aryl; 796where X is aryl; 797where X
is aryl, alkyl, heteroaryl or halo and R is alkyl; 798where X.sub.a
is aryl, heteroaryl or heteroarylalkyl, 799where R.sup.a is
alkoxycarbonyl (CO.sub.2 alkyl), nitro, cyano, or hydrogen; R.sup.b
is hydrogen, CO.sub.2 alkyl, nitro, cyano, formyl,
cycloheteroalkylcarbonyl, alkylaminoalkyl or amino, X is hydrogen,
alkyl or halo; 800
42. The method as defined in claim 41 wherein the compound has the
structure 801where X is 1-naphthyl, 1-(4-methyl)naphthyl,
1-(4-fluoro)naphthyl, 1-(6-methoxy)naphthyl, phenyl, or t-butyl,
802where X is 1-naphthyl, 803where X=1-naphthyl, 804where R is
CH.sub.3 or C.sub.2H.sub.5 and X is phenyl, t-butyl, 1-naphthyl,
1-(4-fluoro)naphthyl, benzthiophen-3-yl, 1-(4-methyl)naphthyl,
1-(2-methoxy)naphthyl, 1-(6-methoxy)naphthyl, 3-fluorophenyl,
4-fluorophenyl, 3-methylphenyl, 2-chlorophenyl,
1-(4-methoxy)naphthyl, 1-(4-bromo)naphthyl, 1-(4-iodo)naphthyl,
5-anthracenyl, 1-anthracenyl, 4-quinolin-1-yl, 2-quinolin-1-yl,
1-(4-cyano)naphthyl, 5-iodo, 4-benzthiophenyl,
1-(2-hydroxy)naphthyl, 1-(6-hydroxy)naphthyl, or
1-(4-hydroxy)naphthyl, 805where X.sub.a is phenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl,
3-pyridyl, 2-(4-pridyl)ethyl, 2-(4-imidazolyl)ethyl,
3-chloro-4-methoxyphenyl, 3-hydroxy-4-methoxyphenyl,
3-fluoro-4-methoxyphenyl, 3,4,5-trimethoxyphenyl,
3,4-dimethoxyphenyl, 4-methyl-3-methoxyphenyl, 3-methoxyphenyl,
3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 4-chlorophenyl,
2-naphthyl, 3-chlorophenyl, 3,4-dichlorophenyl, 4-azidophenyl,
2,4-dimethoxyphenyl, 3-ethoxyphenyl, 3-(methylthio)phenyl,
4-(methylthio)phenyl, 3-(acetylenyl)phenyl, 4-methoxy-3-pyridyl,
3-cyanophenyl, 2-methyl-4-methoxyphenyl, 3-azidophenyl,
3-methyl-isothiazolyl, 1-methyl-pyrazol-5-yl, or
5-trifluoromethyl-1,3,4-- thiadiazol-2-yl,
23 R.sup.a R.sup.b X 806 CH.sub.3OOC-- H H Nitro H H Cyano H H
CH.sub.3OOC-- H Methyl Nitro H Methyl Cyano H Methyl H
CH.sub.3OOC-- H H Nitro H H Cyano H H formyl H H CO--(N-morpholine)
H H --CH2--NH-Ethyl H H --CH2--(N-morpholine) H H Nitro Methyl H
Cyano Methyl H NH2 Methyl H Nitro F H Cyano F H Cl H H Cl F H Cl
Methyl H Br F H Br Methyl H CH3 H H CH3 F H CH3 Methyl 807
CH.sub.3OOC-- H H Nitro H H Cyano H H CH.sub.3OOC-- H Methyl Nitro
H Methyl Cyano H Methyl H CH.sub.3OOC-- H H Nitro H H Cyano H H
formyl H H CO--(N-morpholine) H H --CH2--NH-Ethyl H H
--CH2--(N-morpholine) H H Nitro Methyl H Cyano Methyl H NH2 Methyl
H Nitro F H Cyano F H Cl H H Cl F H Cl Methyl H Br F H Br Methyl H
CH3 H H CH3 F H CH3 Methyl, 808 H H 809 H nitro 810 H H 811 H nitro
812 H H 813 H nitro 814 H H 815 H nitro 816 817 Q.dbd.N, Y.dbd.CH
or Q.dbd.CH, and Y.dbd.N.
43. A method for preventing, inhibiting onset of or treating an
inflammatory or immune associated disease or disorder which is an
endocrine disorder, rheumatic disorder, collagen disease,
dermatologic disease, allergic disease, ophthalmic disease,
respiratory disease, hematologic disease, gastrointestinal disease,
inflammatory disease, autoimmune disease, neoplastic disease and
metabolic disease which is associated with the expression product
of a gene whose transcription is stimulated or repressed by
glucocorticoid receptors, or a method for preventing inhibiting
onset of or treating a disease associated with AP-1- and/or
NF-.kappa.B-induced transcription, or a method for preventing,
inhibiting onset of or treating a disease associated with AP-1
and/or NF-.kappa.B dependent gene expression, wherein the disease
is associated with the expression of a gene under the regulatory
control of AP-1 and/or NF-.kappa.B, the method comprises
administering to a patient in need of treatment a therapeutically
effective amount of a compound having below structure 818where R is
CH.sub.3, C.sub.2H.sub.5 or 2-hydroxyethyl, and one of R.sup.1 and
R.sup.2 is H and the other of R.sup.1 and R.sup.2 is
benzothiazol-2-yl, alkylbenzothiazol-2-yl, alkoxybenzothiazol-2-yl,
halobenzothiazol-2-yl, thiazol-2-yl, 4-(1-naphthyl)thiazol-2-yl,
2-quinolin-1-yl, or a thiazole which is optionally substituted with
heteroarylthio, heteroaryl, dialkyl, alkyl, or aryl, where the aryl
may be optionally substituted with halo, alkyl, nitro, hydroxy,
alkoxy, dialkoxy, carboxy, alkylaminocarbonyl, arylaminocarbonyl,
hydroxyalkylaminocarbonyl, cycloheteroalkylcarbonyl,
alkoxyalkylaminocarbonyl or heteroarylaminocarbonyl; with the
proviso that where one of R.sup.1 and R.sup.2 is thiazol-2-yl, then
R is C.sub.2H.sub.5 or 2-hydroxyethyl.
44. The method as defined in claim 43 wherein the compound has the
structure 819where X is H, 6-CH.sub.3, 4-CH.sub.3O, 6-Cl or 6-F; or
820where X is 4,5-dimethyl, 5-chloro, 4-methyl, 5-methyl, 4-phenyl,
4-(1-naphthyl), 4-(2-naphthyl), 4-(4-fluoronaphth-1-yl),
4-(4-methylnaphth-1-yl), 4-(3-nitrophenyl),
4-(6-hydroxynaphth-1-yl), 4-[(1,2,4-triazol-5-yl)thio]methyl,
4-benzoic acid, 4-(4-bromonaphth-1-yl), 4-(N-ethyl)benzamide,
4-(N-2-methoxyphenyl)benzam- ide,
4-(N-methyl-N-2-hydroxyethyl)benzamide,
4-(N-(pyrrolidinyl)benzamide, 4-(N-mopholinyl)benzamide,
4-(N-phenyl-N-methyl)benzamide, 3-(N-ethyl)benzamide,
3-(N-2-methoxyphenyl)benzamide, 3-(N-2-methoxyethyl)benzamide,
3-(N-methyl-N-2-hydroxyethyl)benzamide,
3-(N-methyl-N-phenyl)benzamide,
3-(N-4-acetylpiperaziny-1-yl)benzamide,
3-(N-3-methoxypropyl)benzamide, 2-(6-carboxy)pyridine,
3-(N-3-hydroxy-4-methoxyphenyl)benzamide,
3-(N-3-fluoro-4-methoxyphenyl)b- enzamide,
3-(N-2,3-dimethoxyphenyl)benzamide, 3-(N-3-dimethoxyphenyl)benza-
mide, 3-(N-5-trifluormethyl-1,3,4-thiadiazol-2-yl)benzamide,
3-(N-5-methyl-1,3,4-thiadiazol-2-yl)benzamide,
3-(N-5-chlorobenzoxazol-2-- yl)benzamide,
3-(N-3-benzonitrile)benzamide, 3-(N-4-methoxypyrid-3-yl)benz-
amide, 5-(1,4-benzodioxane), or 4-(1,3-benzodioxole).
45. The method as defined in claim 35 wherein the compound has the
structure:
24 821 822 823 Chi- ral (S) 824 Chi- ral (S) 825 826 Chi- ral (S)
827 Chi- ral (S) 828 Chi- ral (S) 829 830 Chi- ral (S) 831 Chi- ral
(S) 832 Chi- ral (S) 833 Chi- ral (S) 834 Chi- ral (S) 835 836 837
838 839 840 841 842 843 Chi- ral (S) 844 Chi- ral (S) 845 846 847
848 849 850 851 852 Chi- ral (R) 853 Chi- ral (R) 854 Chi- ral (R)
855 Chi- ral (R) 856 Chi- ral (R) 857 Chi- ral (R) 858 Chi- ral (R)
859 860 861 862 863 864 865 866
46. The method as defined in claim 35 wherein the compound has the
structure:
25 867 868 869 870 871 872 873 874 875 876 877 Chi- ral (R) 878 879
880 881 882 Chi- ral (R) 883 884 885 Chi- ral (R) 886 887 888 889
890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906
907 908 909 910 Chi- ral (R) 911 Chi- ral (R) 912 Chi- ral (R) 913
914 915 916 917
47. A method for preventing, inhibiting onset of or treating an
inflammatory or immune associated disease or disorder which is an
endocrine disorder, rheumatic disorder, collagen disease,
dermatologic disease, allergic disease, ophthalmic disease,
respiratory disease, hematologic disease, gastrointestinal disease,
inflammatory disease, autoimmune disease, neoplastic disease and
metabolic disease which is associated with the expression product
of a gene whose transcription is stimulated or repressed by
glucocorticoid receptors, or a method for preventing inhibiting
onset of or treating a disease associated with AP-1- and/or
NF-B-induced transcription, or a method for preventing, inhibiting
onset of or treating a disease associated with AP-1 and/or
NF-.kappa.B dependent gene expression, wherein the disease is
associated with the expression of a gene under the regulatory
control of AP-1 and/or NF-.kappa.B, the method comprises
administering to a patient in need of treatment a therapeutically
effective amount of a compound having the structure: 918or an alkyl
ester thereof, where R is CH.sub.3, C.sub.2H.sub.5; R.sup.a is
nitro, cyano, Cl, Br, CH.sub.3, --COOCH.sub.3, or formyl, and
R.sup.b is H, R.sup.b is nitro, cyano, Cl, Br, CH.sub.3,
--COOCH.sub.3, or formyl, and R.sup.a is H; or a compound having
the structure: 919where X.sub.9 is S or NH; and X is: 920
48. The method as defined in claim 35 wherein the compound has the
structure 921where R is CH.sub.3, C.sub.2H.sub.5 or 2-hydroxyethyl;
R.sup.b is H, CN, NO.sub.2, halogen, alkyl or amino; and Xb is H,
arylalkoxycarbonyl, arylalkylaminocarbonyl,
alkoxyalkylaminocarbonyl, heteroarylcarbonyl, aryl,
alkoxyalkylamidocarbonyl, arylaminocarbonyl,
heteroarylaminocarbonyl, arylaminocarbonylaryl or heteroaryl;
provided that where Xb is H, then R is C.sub.2H.sub.5 or
2-hydroxymethyl or R.sup.b is CN or NO.sub.2.
49. The compound as defined in claim 48 wherein the compound has
the structure 922923924925
50. The method as defined in claim 35 wherein the compound has the
structure 926where R is CH.sub.3, C.sub.2H.sub.5 or 2-hydroxyethyl;
R.sup.b is H, CN, NO.sub.2, halogen, alkyl or amino; and Xc is
aryl, quinolinyl or isoquinolinyl.
51. The method as defined in claim 50 wherein the compound has the
structure 927928929930931
52. The method as defined in claim 35 wherein the inflammatory or
immune associated disease or disorder is transplant rejection of
kidney, liver, heart, lung, pancreas, bone marrow, cornea, small
bowel, skin allografts, skin homografts, heart valve xenograft,
serum sickness, and graft vs. host disease, rheumatoid arthritis,
psoriatic arthritis, multiple sclerosis, Type I and Type II
diabetes, juvenile diabetes, obesity, asthma, inflammatory bowel
disease, Crohn's disease, ulcerative colitis, pyoderma gangrenum,
systemic lupus erythematosis, myasthenia gravis, psoriasis,
dermatitis, dermatomyositis; eczema, seborrhoea, pulmonary
inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's
thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's
syndrome, pernicious or immunohaemolytic anaemia, atherosclerosis,
Addison's disease, idiopathic adrenal insufficiency, autoimmune
polyglandular disease, glomerulonephritis, scleroderma, morphea,
lichen planus, viteligo, alopecia areata, autoimmune alopecia,
autoimmune hypopituatarism, Guillain-Barre syndrome, and
alveolitis; contact hypersensitivity, delayed-type
hypersensitivity, contact dermatitis, uticaria, skin allergies,
respiratory allergies, hayfever, allergic rhinitis and
gluten-sensitive enteropathy, osteoarthritis, acute pancreatis,
chronic pancreatitis, acute respiratory distress syndrome, Sezary's
syndrome, restenosis, stenosis and artherosclerosis, congenital
adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia
associated with cancer, juvenile rheumatoid arthritis, Ankylosing
spondylitis, acute and subacute bursitis, acute nonspecific
tenosynovitis, acute gouty arthritis, post-traumatic
osteroarthritis, synovitis of osteoarthritis, epicondylitis, acute
rheumatic carditis, pemphigus, bullous dermatitis herpetitformis,
severe erythema multiforme, exfoliative dermatitis, psoriasis,
seborrheic dermatitis, seasonal or perennial allergic rhinitis,
bronchial asthma, contact dermatitis, atopic dermatitis, drug
hypersensitivity reactions, allergic conjuncivitis, keratitis,
herpes zoster ophthalmicus, iritis and iridocyclitis,
chorioretinitis, optic neuritis, symptomatic sarcoidosis,
fulminating or disseminated pulmonary tuberculosis chemotherapy,
idiopathic thrombocytopenic purpura in adults, secondary
thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia,
leukemias and lymphomas in adults, acute leukemia of childhood,
ulcerative colitis, regional enteritis, Crohn's disease, Sjogren's
syndrome, autoimmune vasculitis, multiple sclerosis, myasthenia
gravis, sepsis, and chronic obstructive pulmonary disease.
53. The method as defined in claim 52 wherein inflammatory or
immune associated disease or disorder is selected from transplant
rejection, rheumatoid arthritis, psoriatic arthritis, multiple
sclerosis, Type I diabetes, asthma, inflammatory bowel disease,
systemic lupus erythematosis, psoriasis and chronic pulmonary
disease.
Description
[0001] This application claims priority from U.S. Provisional
Application 60/396,877 filed Jul. 18, 2002 which is incorporated
herein by reference.
[0002] The present invention relates to new non-steroidal compounds
which are glucocorticoid receptor (GR) modulators (that is agonists
and antagonists) and thus are useful in treating diseases requiring
glucocorticoid receptor agonist or antagonist therapy such as
obesity, diabetes and inflammatory or immune associated diseases,
and to a method for using such compounds to treat these and related
diseases.
BACKGROUND OF THE INVENTION
[0003] The nuclear hormone receptor (NHR) family of transcription
factors bind low molecular weight ligands and either stimulate or
repress transcription (The Nuclear Receptor Facts Book, V. Laudet
and H. Gronemeyer, Academic Press, p 345, 2002). NHRs stimulate
transcription by binding to DNA and inducing transcription of
specific genes. NHRs may also stimulate transcription by not
binding to DNA itself, rather they may modulate the activity of
other DNA binding proteins (Stocklin, E., et al., Nature (1996)
383: 726-8). The process of stimulation of transcription is called
transactivation. NHRs repress transcription by interacting with
other transcription factors or coactivators and inhibiting the
ability of these other transcription factors or coactivators from
inducing transcription of specific genes. This repression is called
transrepression. (for a review see The Nuclear Receptor Factsbook,
V. Laudet and H. Gronemeyer, Academic Press, p 42, 2002).
[0004] The glucocorticoid receptor (GR) is a member of the nuclear
hormone receptor family of transcription factors, and a member of
the steroid hormone family of transcription factors. Affinity
labeling of the glucocorticoid receptor protein allowed the
production of antibodies against the receptor which facilitated
cloning the human (Weinberger, et al. Science 228, p 640-742, 1985,
Weinberger, et al. Nature, 318, p 670-672, 1986) and rat (Miesfeld,
R. Nature, 312, p 779-781, 1985) glucocorticoid receptors.
[0005] Glucocorticoids which interact with GR have been used for
over 50 years to treat inflammatory diseases. It has been clearly
shown that glucocorticoids exert their anti-inflammatory activity
via the inhibition by GR of the transcription factors NF-kappaB and
AP-1. This inhibition is termed transrepression. It has been shown
that the primary mechanism for inhibition of these transcription
factors by GR is via a direct physical interaction. This
interaction alters the transcription factor complex and inhibits
the ability of NF-kappaB and AP-1 to stimulate transcription
(Jonat, C., et al. Cell, 62, p 1189, 1990, Yang-Yen, H. F., et al.
Cell 62, p 1205, 1990, Diamond, M. I. et al. Science 249, p 1266,
1990, Caldenhoven, E. et al., Mol. Endocrinol. 9, p 401, 1995).
Other mechanisms such as sequestration of co-activators by GR have
also been proposed (Kamer Y, et al., Cell 85, p 403, 1996,
Chakravarti, D. et al., Nature 383, p 99, 1996). NF-kappaB and AP-1
play key roles in the initiation and perpetuation of inflammatory
and immunological disorders (Baldwin, A S, Journal of Clin.
Investigation 107, p 3, 2001, Firestein, G. S., and Manning, A. M.
Arthritis and Rheumatism, 42, p 609, 1999, Peltz, G., Curr. Opin,
in Biotech. 8, p 467, 1997). NF-kappaB and AP-1 are involved in
regulating the expression of a number of important inflammatory and
immunomodulatory genes including: TNF-alpha, IL-1, IL-2, IL-5,
adhesion molecules (such as E-selectin), chemokines (such as
Eoxtaxin and Rantes), Cox-2, and others.
[0006] In addition to causing transrepression, the interaction of a
glucocorticoid with GR can cause GR to induce transcription of
certain genes. This induction of transcription is termed
transactivation. Transactivation requires dimerization of GR and
binding to a glucocorticoid response element (GRE).
[0007] Recent studies using a transgenic GR dimerization defective
mouse which cannot bind DNA have shown that the transactivation
(DNA binding) activities of GR could be separated from the
transrepressive (non-DNA binding) effect of GR. These studies also
indicate that many of the side effects of glucocorticoid therapy
are due to the ability of GR to induce transcription of various
genes involved in metabolism, whereas, transrepression, which does
not require DNA binding leads to suppression of inflammation
(Tuckermann, J. et al. Cell 93, p 531, 1998; Reichardt, H M. EMBO
J., 20, p 7168, 2001).
[0008] The art is in need of modulators of NHRs. A modulator of an
NHR may be useful in treating NHR-associated diseases, that is
diseases associated with the expression products of genes whose
transcription is stimulated or repressed by NHRs. For instance, the
art is in need of modulators of NHRs that inhibit AP-1 and
NF.kappa.B, as such compounds would be useful in the treatment of
inflammatory and immune diseases and disorders such as
osteoarthritis, rheumatoid arthritis, multiple sclerosis, asthma,
inflammatory bowel disease, transplant rejection and graft vs. host
disease.
[0009] Particularly concerning GR, although glucocorticoids are
potent anti-inflammatory agents, their systemic use is limited by
side effects. A compound that retained the anti-inflammatory
efficacy of glucocorticoids while minimizing the side effects such
as diabetes, osteoporosis and glaucoma would be of great benefit to
a very large number of patients with inflammatory diseases.
[0010] Additionally concerning GR, the art is in need of compounds
that antagonize transactivation. Such compounds may be useful in
treating metabolic diseases associated with increased levels of
glucocorticoid, such as diabetes, osteoporosis and glaucoma.
[0011] Additionally concerning GR, the art is in need of compounds
that cause transactivation. Such compounds may be useful in
treating metabolic diseases associated with a deficiency in
glucocorticoid. Such diseases include Addison's disease.
[0012] It is believed that the compounds of the present invention
as described below fill the above needs.
DESCRIPTION OF THE INVENTION
[0013] In accordance with the present invention, compounds are
provided having the structure 2
[0014] including all stereoisomers thereof, or a prodrug ester
thereof, or a pharmaceutically acceptable salt thereof, wherein
[0015] R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,
arylalkyl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl,
aminoalkyl, hydroxyalkyl, aryloxyalkyl, or hydroxyaryl;
[0016] R.sup.a is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,
aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarbonyl,
cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl,
hydroxyalkyl, hydroxyaryl, aryloxyalkyl, nitro, amino, CHO,
CO.sub.2 alkyl, CONR.sup.eR.sup.f, CH.sub.2NR.sup.gR.sup.h,
CO.sub.2H, CH.sub.2OH, CH.sub.2NHR.sup.g, NHCH.sub.2R.sup.g,
NHCHR.sup.gR.sup.h, NHCOR.sup.e, NHCONR.sup.eR.sup.f or
NHSO.sub.2R.sup.e;
[0017] R.sup.b is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,
aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarbonyl,
cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl,
hydroxyalkyl, nitro, amino, CHO, CO.sub.2 alkyl, hydroxyaryl,
aryloxyalkyl, CONR.sup.iR.sup.j, CH.sub.2NR.sup.kR.sup.l,
CO.sub.2H, CH.sub.2OH, CH.sub.2NHR.sup.k, NHCH.sub.2R.sup.k,
NHCHR.sup.kR.sup.l, NHCOR.sup.i, NHCONR.sup.iR.sup.j or
NHSO.sub.2R.sup.i;
[0018] where R.sup.e and R.sup.f are the same or different and are
independently selected from hydrogen, aryl, alkyl, alkenyl,
alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,
dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R.sup.e
and R.sup.f can be taken together with the nitrogen to which they
are attached to form a 5-, 6- or 7-membered heteroaryl ring or
cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which
can be N, O or S;
[0019] R.sup.g and R.sup.h are the same or different and are
independently selected from hydrogen, aryl, alkyl, alkenyl,
alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,
dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R.sup.g
and R.sup.h can be taken together with the nitrogen to which they
are attached to form a 5-, 6- or 7-membered heteroaryl ring or
cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which
can be N, O or S;
[0020] R.sup.i and R.sup.j are the same or different and are
independently selected from hydrogen, aryl, alkyl, alkenyl,
alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,
dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R.sup.i
and R.sup.j can be taken together with the nitrogen to which they
are attached to form a 5-, 6- or 7-membered heteroaryl ring or
cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which
can be N, O or S;
[0021] R.sup.k and R.sup.l are the same or different and are
independently selected from hydrogen, aryl, alkyl, alkenyl,
alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,
dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,
cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R.sup.k
and R.sup.l can be taken together with the nitrogen to which they
are attached to form a 5-, 6- or 7-membered heteroaryl ring or
cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which
can be N, O or S;
[0022] R.sup.c and R.sup.d are the same or different and are
independently selected from hydrogen, alkyl, alkenyl, alkynyl,
alkoxy, aryl, hydroxy, aryloxy, heteroaryl, cycloheteroalkyl,
heteroarylalkyl, cycloheteroalkylalkyl, hydroxyaryl, or
aryloxyalkyl;
[0023] R.sup.c and R.sup.d can be taken together with the carbon to
which they are attached to form a 3- to 7-membered ring which may
include an O or N atom in the ring;
[0024] Z is CONR.sup.1R.sup.2 or CH.sub.2NR.sup.1R.sup.2 wherein
R.sup.1 and R.sup.2 are the same or different and are independently
selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl,
cycloheteroalkyl, cycloalkenyl, mono- or di-alkylaminoalkyl,
cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl or
hydroxyalkyl;
[0025] the A ring represents a saturated, partially saturated or
unsaturated 6-membered carbocyclic or heterocyclic ring; and
[0026] the B ring represents a saturated, partially saturated or
unsaturated 6-membered carbocyclic or heterocyclic ring;
[0027] with the following provisos;
[0028] I. provided that where Z is CONR.sup.1R.sup.2 and (a) R is
CH.sub.3 or H and R.sup.a, R.sup.b, R.sup.c and R.sup.d are each
hydrogen, or (b) R.sup.a and R.sup.b are each hydrogen and one of
R.sup.c and R.sup.d is alkyl, then
[0029] (1) at least one of R.sup.1 and R.sup.2 is heteroaryl,
heteroarylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl, but
where the heteroaryl is 3
[0030] or the heteroarylalkyl is 4
[0031] then the other of R.sup.1 and R.sup.2 is other than
hydrogen, and/or the A ring and/or the B ring includes a hetero
atom; or
[0032] (2) where one of R.sup.1 and R.sup.2 is phenyl which is
substituted with alkyl, hydroxy, halo,
C.sub.1-C.sub.2-alkoxycarbonyl or nitro, then (a) the phenyl must
be substituted with at least one other group other than hydrogen,
alkyl, hydroxy, halo, C.sub.1,-C.sub.2-alkoxycarbonyl or nitro,
except that the phenyl may be substituted with two or more halo
atoms, and/or two or more hydroxy groups, and/or (b) the other of
R.sup.1 and R.sup.2 is other than hydrogen and/or (c) the A ring
and/or the B ring includes a hetero atom;
[0033] (3) where one of R.sup.1 and R.sup.2 is phenyl substituted
with C.sub.1-C.sub.2 alkoxy, the phenyl cannot be substituted with
a second C.sub.1-C.sub.2 alkoxy or the other of R.sup.1 and R.sup.2
is other than hydrogen, or
[0034] (4) where at least one of R.sup.1 and R.sup.2 is hydrogen,
unsubstituted alkyl, alkenyl, cycloalkyl, alkylcycloalkyl,
cycloalkenyl, alkylcycloalkenyl, alkylphenyl, monoalkylaminoalkyl,
dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl or hydroxyalkyl
then (a) the other of R.sup.1 and R.sup.2 is other than hydrogen,
unsubstituted alkyl, alkenyl, cycloaklyl, alkylcycloalkyl,
cycloalkenyl, alkylcycloalkenyl, alkylphenyl, monoalkylaminoalkyl,
dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl or hydroxyalkyl;
and/or (b) at least one of R.sup.a, R.sup.b, R.sup.c and/or R.sup.d
is other than hydrogen and/or (c) R is other than hydrogen or
C.sub.1-C.sub.2 alkyl and/or (d) the A ring and/or the B ring
includes a hetero atom; and
[0035] II. provided that where Z is CH.sub.2NR.sup.1R.sup.2 and/or
where at least one of R.sup.1 and R.sup.2 is hydrogen, alkyl,
alkenyl, cycloalkyl, alkylcycloalkyl, phenyl, alkylphenyl,
phenylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl,
aryl, alkoxyalkyl, hydroxyalkyl, heteroaryl which is pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl or imidazolinyl, or
cycloheteroalkyl which is 4,5-dihydro-imidazol-2-yl, piperidinyl or
piperazinyl, then (a) the other of R.sup.1 and R.sup.2 is other
than hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, phenyl,
alkylphenyl, phenylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,
arylalkyl, aryl, alkoxyalkyl or hydroxyalkyl and/or (b) at least
one of R.sup.a, R.sup.b, R.sup.c and/or R.sup.d is other than
hydrogen or C.sub.1-2 alkyl and/or (c) R is other than hydrogen or
C.sub.1-C.sub.2 alkyl and/or (d) the A ring and/or the B ring
includes a hetero atom and/or (e) one of R.sup.c or R.sup.d cannot
be hydroxyalkyl.
[0036] In the compounds of formula I the A ring has the structure
5
[0037] and the B ring has the structure 6
[0038] wherein X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are the same
or different and are independently selected from CH, CH.sub.2,
CHR.sup.15, CR.sup.16, CR.sup.16R.sup.17, N, NH, NR.sup.18, O or S,
and X.sub.5, X.sub.6, X.sub.7 and X.sub.8 are the same or different
and are independently selected from CH, CH.sub.2, CHR.sup.19,
CR.sup.20, CR.sup.20R.sup.21, N, NH, NR.sup.22, O or S, wherein
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21 and R.sup.22 are the same or different and are
independently selected from hydrogen, alkyl, aryl, cycloalkyl,
heteroaryl, and cycloheteroalkyl, wherein each of said A ring and
said B ring contains at most two nitrogen ring atoms, at most two
oxygen ring atoms and at most one sulfur ring atom.
[0039] It is preferred that the A ring and B ring are each
6-membered rings which are aromatic carbocyclic rings, namely benzo
rings, or are heterocyclic rings each of which includes one hetero
atom, which is nitrogen, namely pyridyl rings preferably 7
[0040] Preferred compounds of formula I of the invention which have
glucocorticoid receptor (GR)/Dexamethasone (Dex) inhibition
activity (>95% at 10 .mu.M) are set out below:
[0041] 1. compounds of formula I of the invention where A and B are
fused phenyl rings, R is CH.sup.3, R.sup.a, R.sup.b, R.sup.c and
R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of R.sup.1
and R.sup.2 is H and the other is heteroaryl, preferably
imidazol-2-yl, that is 8
[0042] 2. compounds of formula I of the invention where A and B are
fused phenyl rings, R is CH.sub.3, R.sup.a, R.sup.b, R.sup.c and
R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of R.sup.1
and R.sup.2 is H and the other is heteroaryl, other than
benzothiazol-2-yl, and preferably heteroaryl is
alkylbenzothiazol-2-yl, alkoxybenzothiazol-2-yl, and
halobenzothiazol-2-yl, such as
[0043] 6-methylbenzothiazol-2-yl
[0044] 4-methoxybenzothiazol-2-yl
[0045] 6-fluorobenzothiazol-2-yl
[0046] 6-chlorobenzothiazol-2-yl
[0047] for example, compounds of the structure 9
[0048] where X is 6-CH.sub.3, 4-CH.sub.3O, 6-Cl or 6-F.
[0049] 3. compounds of formula I of the invention where A and B are
fused phenyl rings, R is CH.sub.3, R.sup.a, R.sup.b, R.sup.c and
R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of R.sup.1
and R.sup.2 is H and the other is a thiazole which preferably is
substituted with dialkyl, alkyl, 10
[0050] alkyl, aryl such as phenyl or naphthyl (where the aryl may
be optionally substituted with halo, alkyl, nitro, hydroxy, alkoxy,
dialkoxy, carboxy, alkylaminocarbonyl, arylaminocarbonyl,
hydroxyalkylaminocarbonyl, cycloheteroalkylcarbonyl,
alkoxyalkylaminocarbonyl, heteroarylaminocarbonyl), heteroarylthio
or heteroaryl such as
[0051] 4,5-dimethylthiazol-2-yl
[0052] 5-chlorothiazol-2-yl
[0053] 4-methylthiazol-2-yl
[0054] 5-methylthiazol-2-yl
[0055] 4-phenylthiazol-2-yl
[0056] 4-(1-naphthyl)thiazol-2-yl
[0057] 5-(1-naphthyl)thiazol-2-yl
[0058] 4-[1-(4-fluoro)naphthyl]thiazol-2-yl
[0059] 4-[1-(4-methyl)naphthyl]thiazol-2-yl
[0060] 4-(3-nitrophenyl)thiazol-2-yl
[0061] 4-[1-(6-hydroxy)naphthyl]thiazol-2-yl
[0062] 4-[(1,2,4-triazol-5-yl)thio]methylthiazol-2-yl
[0063] 4-(4-benzoic acid)thiazol-2-yl
[0064] 4-[1-(4-bromo)naphthyl]thiazol-2-yl
[0065] 4-[4-N-ethylbenzamide]thiazol-2-yl
[0066] 4-[4-N-(2-methoxyphenyl)benzamide]thiazol-2-yl
[0067] 4-[4-N-methy-N-(2-hydroxyethyl)benzamide]thiazol-2-yl
[0068] 4-[4-N-(pyrrolidinyl)benzamide]thiazol-2-yl
[0069] 4-[4-N-(mopholinyl)benzamide]thiazol-2-yl
[0070] 4-[4-N-phenyl-N-methylbenzamide]thiazol-2-yl
[0071] 4-[3-N-ethylbenzamide]thiazol-2-yl
[0072] 4-[3-N-(2-methoxyphenyl)benzamide]thiazol-2-yl
[0073] 4-[3-N-(2-methoxyethyl)benzamide]thiazol-2-yl
[0074] 4-[3-N-methyl-N-2-hydroxyethyl)benzamide]thiazol-2-yl
[0075] 4-[3-N-methyl-N-phenylbenzamide]thiazol-2-yl
[0076] 4-[3-N-(4-acetylpiperaziny-1-yl)benzamide]thiazol-2-yl
[0077] 4-[3-N-(3-methoxypropyl)benzamide]thiazol-2-yl
[0078] 4-(6-carboxypyrid-2-yl)thiazol-2-yl
[0079] 4-[3-N-(3-hydroxy-4-methoxyphenyl)benzamide]thiazol-2-yl
[0080] 4-[3-N-(3-fluoro-4-methoxyphenyl)benzamide]thiazol-2-yl
[0081] 4-[3-N-(2,3-dimethoxyphenyl)benzamide]thiazol-2-yl
[0082] 4-[3-N-(3-dimethoxyphenyl)benzamide]thiazol-2-yl
[0083]
4-[3-N-(5-trifluormethyl-1,3,4-thiadiazol-2-yl)benzamide]thiazol-2--
yl
[0084]
4-[3-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide]thiazol-2-yl
[0085] 4-[3-N-(5-chlorobenzoxazol-2-yl)benzamide]thiazol-2-yl
[0086] 4-[3-N-(3-benzonitrile)benzamide]thiazol-2-yl
[0087] 4-[3-N-(4-methoxypyrid-3-yl)benzamide]thiazol-2-yl
[0088] 4-[5-(1,4-benzodioxane)]thiazol-2-yl
[0089] 4-[4-(1,3-benzodioxole)]thiazol-2-yl,
[0090] for example, compounds of the structure 11
[0091] X=4,5-dimethyl, 5-chloro, 4-methyl, 5-methyl, 4-phenyl,
4-(1-naphthyl), 4-(2-naphthyl), 4-(4-fluoronaphth-1-yl),
4-(4-methylnaphth-1-yl), 4-(3-nitrophenyl),
4-(6-hydroxynaphth-1-yl), 4-[(1,2,4-triazol-5-yl)thio]methyl,
4-benzoic acid, 4-(4-bromonaphth-1-yl), 4-(N-ethyl)benzamide,
4-(N-2-methoxyphenyl)benzam- ide, 4-(N-deoxyspergualin
methyl-N-2-hydroxyethyl)benzamide, 4-(N-(pyrrolidinyl)benzamide,
4-(N-morpholinyl)benzamide, 4-(N-phenyl-N-methyl)benzamide,
3-(N-ethyl)benzamide, 3-(N-2-methoxyphenyl)benzamide,
3-(N-2-methoxyethyl)benzamide,
3-(N-methyl-N-2-hydroxyethyl)benzamide,
3-(N-methyl-N-phenyl)benzamide,
3-(N-4-acetylpiperaziny-1-yl)benzamide,
3-(N-3-methoxypropyl)benzamide, 2-(6-carboxy)pyridine,
3-(N-3-hydroxy-4-methoxyphenyl)benzamide,
3-(N-3-fluoro-4-methoxyphenyl)benzamide,
3-(N-2,3-dimethoxyphenyl)benzami- de,
3-(N-3-dimethoxyphenyl)benzamide,
3-(N-5-trifluormethyl-1,3,4-thiadiaz- ol-2-yl)benzamide,
3-(N-5-methyl-1,3,4-thiadiazol-2-yl)benzamide,
3-(N-5-chlorobenzoxazol-2-yl)benzamide,
3-(N-3-benzonitrile)benzamide, 3-(N-4-methoxypyrid-3-yl)benzamide,
5-(1,4-benzodioxane), 4-(1,3-benzodioxole).
[0092] 4. compounds of formula I of the invention where A and B are
fused phenyl rings, R is C.sub.2H.sub.5, R.sup.a, R.sup.b, R.sup.c
and R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of
R.sup.1 and R.sup.2 is H and the other is heteroaryl, preferably
thiazol-2-yl or 4-(1-naphthyl)thiazol-2-yl.
[0093] 5. compounds of formula I of the invention where A and B are
fused phenyl rings, R is 2-hydroxyethyl, R.sup.a, R.sup.b, R.sup.c
and R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of
R.sup.1 and R.sup.2 is H and the other is heteroaryl, preferably
thiazol-2-yl.
[0094] 6. compounds of the formula I of the invention where A and B
are fused phenyl rings, R is CH.sub.3, R.sup.a, R.sup.b, R.sup.c
and R.sup.d are H, and Z is CONR.sup.1R.sup.2 where one of R.sup.1
and R.sup.2 is H and the other is a heteroaryl, preferably
2-quinolin-1-yl.
[0095] Preferred compounds of formula I of the invention which have
AP-1 inhibitory activity (IC50<15 .mu.M) are set out below:
[0096] 1(a). compounds of formula I of the invention where A and B
are fused phenyl rings, R is CH.sub.3, R.sup.a, R.sup.b, R.sup.c
and R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of
R.sup.1 and R.sup.2 is H and the other is heteroaryl, preferably
imidazole which is preferably substituted with an aryl group, which
preferably is naphthyl preferably substituted with alkyl, halo or
alkoxy, such as
[0097] 4-(1-naphthyl)imidazol-2-yl
[0098] 4-[1-(4-methyl)naphthyl]imidazol-2-yl
[0099] 4-[1-(4-fluoro)naphthyl]imidazol-2-yl
[0100] 4-[1-(6-methoxynaphthyl)]imidazol-2-yl
[0101] 4-phenylimidazol-2-yl
[0102] 4-t-butylimidazol-2-yl
[0103] for example, compounds of the structure 12
[0104] X is aryl or alkyl, such as 1-naphthyl,
1-[(4-methyl)naphthyl, 1-(4-fluoro)naphthyl, 1-(6-methoxynaphthyl),
phenyl, t-butyl, or quinolinyl optionally substituted with alkyl
such as methyl and/or alkoxy such as methoxy, or isoquinolinyl
optionally substituted with alkyl such as methyl and/or alkoxy such
as methoxy.
[0105] 1(b). compounds of the structure
1 13 R.sup.a R.sup.b X H H 14 H nitro 15 H H 16 H nitro 17 H H 18 H
nitro 19 H H 20 H nitro 21
[0106] 2. compounds of formula I of the invention where A and B are
fused phenyl rings, R is CH.sub.3, R.sup.a, R.sup.b, R.sup.c and
R.sup.d are each H, and Z is CONR.sup.1R.sup.2
[0107] where one of R.sup.1 and R.sup.2 is H and the other is
heteroaryl, preferably an oxazole which is preferably substituted
with an aryl group which preferably is naphthyl such as
4-(1-naphthyl)oxazol-2-yl,
[0108] that is, a compound of the structure 22
[0109] where X is aryl such as 1-naphthyl.
[0110] 3. compounds of formula I of the invention where A and B are
fused phenyl rings, R is CH.sub.3, R.sup.a, R.sup.b, R.sup.c and
R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of R.sup.1
and R.sup.2 is H and the other is a pyridyl which is preferably
substituted with an aryl group which preferably is naphthyl, such
as 4-(1-naphthyl)pyrid-2-yl, that is a compound of the structure
23
[0111] where X is aryl such as 1-naphthyl.
[0112] 4. compounds of formula I of the invention where A and B are
fused phenyl rings, R is CH.sub.3, R.sup.a, R.sup.b, R.sup.c and
R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of R.sup.1
and R.sup.2 is H and the other is a heteroaryl, preferably a
thiazole substituted with alkyl, aryl, heteroaryl or alkoxy, and
where the aryl is phenyl, naphthyl or anthracenyl, which preferably
is substituted with halo, alkyl, alkoxy, aryl, or hydroxy, such
as
[0113] 4-(phenyl)thiazol-2-yl
[0114] 4-(t-butyl)thiazol-2-yl
[0115] 4-(1-naphthyl)thiazol-2-yl
[0116] 4-[1-(4-fluoro)naphthyl]thiazol-2-yl
[0117] 4-(benzthiophen-3-yl)thiazol-2-yl
[0118] 4-[1-(4-methyl)naphthyl]thiazol-2-yl
[0119] 4-[1-(2-methoxynaphthyl)]thiazol-2-yl
[0120] 4-[1-(6-methoxynaphthyl)]thiazol-2-yl
[0121] 4-(3-fluorophenyl)thiazol-2-yl
[0122] 4-(4-fluorophenyl)thiazol-2-yl
[0123] 4-(3-methylphenyl)thiazol-2-yl
[0124] 4-(2-chlorophenyl)thiazol-2-yl
[0125] 4-[1-(4-methoxynaphthyl)]thiazol-2-yl
[0126] 4-[1-(4-bromonaphthyl)]thiazol-2-yl
[0127] 4-[1-(4-iodonaphthyl)]thiazol-2-yl
[0128] 4-[anthracen-5-yl)]thiazol-2-yl
[0129] 4-[anthracen-1-yl)]thiazol-2-yl
[0130] 4-[4-quinolin-1-yl)]thiazol-2-yl
[0131] 4-[2-quinolin-1-yl)]thiazol-2-yl
[0132] 4-[1-(4-cyano-naphthyl)]thiazol-2-yl
[0133] 5-iodothiazol-2-yl
[0134] 4-(benzthiophen-4-yl)thiazol-2-yl
[0135] 4-[1-(2-hydroxynaphthyl)]thiazol-2-yl
[0136] 4-[1-(6-hydroxynaphthyl)]thiazol-2-yl
[0137] 4-[1-(4-hydroxynaphthyl)]thiazol-2-yl
[0138] for example, compounds of the structure 24
[0139] where X is aryl, alkyl, heteroaryl or halo, such as phenyl,
t-butyl, 1-naphthyl, 1-(4-fluoro)naphthyl, benzthiophen-3-yl,
1-(4-methyl)naphthyl, 1-(2-methoxy)naphthyl, 1-(6-methoxy)naphthyl,
3-fluorophenyl, 4-fluorophenyl, 3-methylphenyl, 2chlorophenyl,
1-(4-methoxy)naphthyl, 1-(4-bromo)naphthyl, 1-(4-iodo)naphthyl,
5-anthracenyl, 1-anthracenyl, 4-quinolin-1-yl, 2-quinolin-1-yl,
1-(4-cyano)naphthyl, 5-iodo, 4-benzthiophenyl,
1-(2-hydroxy)naphthyl, 1-(6-hydroxy)naphthyl,
1-(4-hydroxy)naphthyl.
[0140] 5. compounds of formula I of the invention where A and B are
fused phenyl rings, R is C.sub.2H.sub.5, R.sup.a, R.sup.b, R.sup.c
and R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of
R.sup.1 and R.sup.2 is H and the other is a heteroaryl, preferably
thiazole which is substituted with aryl, preferably naphthyl, such
as 4-(1-naphthyl)thiazol-2-yl, that is 25
[0141] 6. compounds of formula I of the invention where A and B are
fused phenyl rings, R is CH.sub.3, R.sup.a, R.sup.b, R.sup.c and
R.sup.d are each H, and Z is CONR.sup.1R.sup.2 where one of R.sup.1
and R.sup.2 is H and the other is 26
[0142] that is 27
[0143] where X is aryl, alkoxyaryl, dialkoxyaryl, heteroaryl,
heteroarylalkyl, halo(alkoxy)aryl, hydroxy(alkoxy)aryl,
trialkoxyaryl, alkyl(alkoxy)aryl, haloaryl, dihaloaryl,
heteroarylaryl, alkylthioaryl, alkenylaryl, alkoxyheteroaryl,
cyanoaryl, where aryl is phenyl or naphthyl and heteroaryl by
itself or part of another group is pyridyl, imidazolyl, azido,
isothiazolyl, pyrazolyl or thiadiazolyl;
[0144] preferred examples of X include
[0145] phenyl, 3-methoxyphenyl, 4-methoxyphenyl,
2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3-pyridyl,
2-(4-pyridyl)ethyl, 2-(4-imidazolyl)ethyl,
3-chloro-4-methoxyphenyl, 3-hydroxy-4-methoxypheny- l,
3-fluoro-4-methoxyphenyl, 3,4,5-trimethoxyphenyl,
3,4-dimethoxyphenyl, 4-methyl-3-methoxyphenyl, 3-methoxyphenyl,
3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 4-chlorophenyl,
2-naphthyl, 3-chlorophenyl, 3,4-dichlorophenyl, 4-azidophenyl,
2,4-dimethoxyphenyl, 3-ethoxyphenyl, 3-(methylthio)phenyl,
4-(methylthio)phenyl, 3-(acetylenyl)phenyl, 4-methoxy-3-pyridyl,
3-cyanophenyl, 2-methyl-4-methoxyphenyl, 3-azidophenyl,
3-methyl-isothiazolyl, 1-methyl-pyrazol-5-yl or
5-trifluormethyl-1,3,4-thiadiazol-2-yl.
[0146] 7. compounds of formula I of the invention of the
structure
2 (a) Ih 28 R.sup.a R.sup.b X carboxymethyl H H nitro H H cyano H H
carboxymethyl H methyl nitro H methyl cyano H meethyl H
carboxymethyl H H nitro H H cyano H H formyl H H CO-(N-morpholine)
H H CH.sub.2--NH-ethyl H H CH.sub.2-(N-morpholine) H H nitro methyl
H cyano methyl H NH.sub.2 methyl H nitro F H cyano F H Cl H H Cl F
H Cl Methyl H Br F H Br Methyl H CH3 H H CH3 F H CH3 Methyl
[0147] 29
[0148] Q=N, Y=CH or Q=CH, Y=N
[0149] Z=CONR.sup.1R.sup.1R.sup.2
[0150] R=CH.sub.3
[0151] R.sup.a, R.sup.b, R.sup.c, R.sup.d are H
[0152] R.sup.2=4-(4-fluoronaphthyl)thiazol-2-yl
[0153] R.sup.1=H.
3 (d) 30 R.sup.a R.sup.b X CH.sub.3OOC-- H H Nitro H H Cyano H H
CH.sub.3OOC-- H Methyl Nitro H Methyl Cyano H Methyl H
CH.sub.3OOC-- H H Nitro H H Cyano H H formyl H H CO-(N-morpholine)
H H --CH2-NH-Ethyl H H --CH2-(N-morpholine) H H Nitro Methyl H
Cyano Methyl H NH2 Methyl H Nitro F H Cyano F H Cl H H Cl F H Cl
Methyl H Br F H Br Methyl H CH3 H H CH3 F H CH3 Methyl
[0154] 8. compounds of formula I of the structure 31
[0155] wherein one of R.sup.1 and R.sup.2 is heteroaryl, preferably
wherein one of R.sup.1 and R.sup.2 is 32
[0156] where R.sup.m is selected from H, alkyl, aryl, heteroaryl,
halo, or alkoxy and R.sup.o is H or alkyl, and more preferably
where one of R.sup.1 and R.sup.2 is 33
[0157] Other preferred compounds of the invention have the
structure 34
[0158] where R is CH.sub.3, C.sub.2H.sub.5 or 2-hydroxyethyl,
R.sup.b is H, CN, NO.sub.2, halogen, alkyl or amino, and
[0159] Xb is H, arylalkoxycarbonyl, arylalkylaminocarbonyl,
alkoxyalkylaminocarbonyl, heteroarylcarbonyl, aryl,
alkoxyalkylamidocarbonyl, arylaminocarbonyl,
heteroarylaminocarbonyl, arylaminocarbonylaryl or heteroaryl;
[0160] provided that where Xb is H, then R is C.sub.2H.sub.5 or
2-hydroxymethyl or R.sup.b is CN or NO.sub.2.
[0161] Examples of the above preferred compounds include the
following: 35363738
[0162] Still other preferred compounds of the invention have the
structure 39
[0163] where R is CH.sub.3, C.sub.2H.sub.5 or 2-hydroxyethyl,
R.sup.b is H, CN, NO.sub.2, halogen, alkyl or amino, and Xc is
aryl, quinolinyl or isoquinolinyl.
[0164] Examples of the above preferred compounds include the
following: 4041424344
[0165] In another aspect of the present invention, there is
provided pharmaceutical compositions useful in treating endocrine
disorders, rheumatic disorders, collagen diseases, dermatologic
disease, allergic disease, ophthalmic disease, respiratory disease,
hematologic disease, gastrointestinal disease, inflammatory
disease, autoimmune disease, diabetes, obesity, and neoplastic
disease, as well as other uses as described herein, which includes
a therapeutically effective amount (depending upon use) of a
compound of formula I of the invention and a pharmaceutically
acceptable carrier.
[0166] In still another aspect, the present invention provides a
method of preventing, inhibiting onset of or treating endocrine
disorders, rheumatic disorders, collagen diseases, dermatologic
disease, allergic disease, ophthalmic disease, respiratory disease,
hematologic disease, gastrointestinal disease, inflammatory
disease, autoimmune disease, diabetes, obesity, and neoplastic
disease, GR-associated diseases, that is a disease associated with
the expression product of a gene whose transcription is stimulated
or repressed by GR or a disease associated with GR transactivation,
including inflammatory and immune diseases and disorders as
described hereinafter, which includes the step of administering a
therapeutically effective amount of a compound of formula I of the
invention to a patient in need of treatment.
[0167] Another aspect of the present involves a method for
preventing, inhibiting onset of or treating a disease associated
with AP-1-dependent gene expression, that is a disease associated
with the expression of a gene under the regulatory control of AP-1,
such as inflammatory and immune disorders, cancer and tumor
disorders, such as solid tumors, lymphomas and leukemia, and fungal
infections such as mycosis fungoides.
[0168] The term "disease associated with GR transactivation," as
used herein, refers to a disease associated with the transcription
product of a gene whose transcription is transactivated by a GR.
Such diseases include, but are not limited to: osteoporosis,
diabetes, glaucoma, muscle loss, facial swelling, personality
changes, hypertension, obesity, depression, and AIDS, the condition
of wound healing, primary or secondary andrenocortical
insufficiency, and Addison's disease.
[0169] The term "treat", "treating", or "treatment," in all
grammatical forms, as used herein refers to the prevention,
reduction, or amelioration, partial or complete alleviation, or
cure of a disease, disorder, or condition.
[0170] The terms "glucocorticoid receptor" and "GR," as used
herein, refer either to a member of the nuclear hormone receptor
family of transcription factors which bind glucocorticoids and
either stimulate or repress transcription, or to GR-beta. These
terms, as used herein, refer to glucocorticoid receptor from any
source, including but not limited to: human glucocorticoid receptor
as disclosed in Weinberger, et al. Science 228, p 640-742, 1985,
and in Weinberger, et al. Nature, 318, p 670-672, 1986; rat
glucocorticoid receptor as disclosed in Miesfeld, R. Nature, 312, p
779-781, 1985; mouse glucocortoid receptor as disclosed in
Danielson, M. et al. EMBO J., 5, 2513; sheep glucocorticoid
receptor as disclosed in Yang, K., et al. J. Mol. Endocrinol. 8, p
173-180, 1992; marmoset glucocortoid receptor as disclosed in
Brandon, D. D., et al, J. Mol. Endocrinol. 7, p 89-96, 1991; and
human GR-beta as disclosed in Hollenberg, S M. et al. Nature, 318,
p 635, 1985, Bamberger, C. M. et al. J. Clin Invest. 95, p 2435,
1995.
[0171] The term, "disease associated with AP-1-dependent gene
expression," as used herein, refers to a disease associated with
the expression product of a gene under the regulatory control of
AP-1. Such diseases include, but are not limited to: inflammatory
and immune diseases and disorders; cancer and tumor disorders, such
as solid tumors, lymphomas and leukemia; and fungal infections such
as mycosis fungoides.
[0172] The term "inflammatory or immune associated diseases or
disorders" is used herein to encompass any condition, disease, or
disorder that has an inflammatory or immune component, including,
but not limited to, each of the following conditions: transplant
rejection (e.g., kidney, liver, heart, lung, pancreas (e.g., islet
cells), bone marrow, cornea, small bowel, skin allografts, skin
homografts (such as employed in burn treatment), heart valve
xenografts, serum sickness, and graft vs. host disease, autoimmune
diseases, such as rheumatoid arthritis, psoriatic arthritis,
multiple sclerosis, Type I and Type II diabetes, juvenile diabetes,
obesity, asthma, inflammatory bowel disease (such as Crohn's
disease and ulcerative colitis), pyoderma gangrenum, lupus
(systemic lupus erythematosis), myasthenia gravis, psoriasis,
dermatitis, dermatomyositis; eczema, seborrhoea, pulmonary
inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's
thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome
(dry eyes/mouth), pernicious or immunohaemolytic anaemia,
atherosclerosis, Addison's disease (autoimmune disease of the
adrenal glands), idiopathic adrenal insufficiency, autoimmune
polyglandular disease (also known as autoimmune polyglandular
syndrome), glomerulonephritis, scleroderma, morphea, lichen planus,
viteligo (depigmentation of the skin), alopecia areata, autoimmune
alopecia, autoimmune hypopituatarism, Guillain-Barre syndrome, and
alveolitis; T-cell mediated hypersensitivity diseases, including
contact hypersensitivity, delayed-type hypersensitivity, contact
dermatitis (including that due to poison ivy), uticaria, skin
allergies, respiratory allergies (hayfever, allergic rhinitis) and
gluten-sensitive enteropathy (Celiac disease); inflammatory
diseases such as osteoarthritis, acute pancreatitis, chronic
pancreatitis, acute respiratory distress syndrome, Sezary's
syndrome and vascular diseases which have an inflammatory and or a
proliferatory component such as restenosis, stenosis and
artherosclerosis. Inflammatory or immune associated diseases or
disorders also includes, but is not limited to: endocrine
disorders, rheumatic disorders, collagen diseases, dermatologic
disease, allergic disease, ophthalmic disease, respiratory disease,
hematologic disease, gastrointestinal disease, inflammatory
disease, autoimmune disease, congenital adrenal hyperplasia,
nonsuppurative thyroiditis, hypercalcemia associated with cancer,
juvenile rheumatoid arthritis, Ankylosing spondylitis, acute and
subacute bursitis, acute nonspecific tenosynovitis, acute gouty
arthritis, post-traumatic osteoarthritis, synovitis of
osteoarthritis, epicondylitis, acute rheumatic carditis, pemphigus,
bullous dermatitis herpetiformis, severe erythema multiforme,
exfoliative dermatitis, seborrheic dermatitis, seasonal or
perennial allergic rhinitis, bronchial asthma, contact dermatitis,
atopic dermatitis, drug hypersensitivity reactions, allergic
conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and
iridocyclitis, chorioretinitis, optic neuritis, symptomatic
sarcoidosis, fulminating or disseminated pulmonary tuberculosis
chemotherapy, idiopathic thrombocytopenic purpura in adults,
secondary thrombocytopenia in adults, acquired (autoimmune)
hemolytic anemia, leukemias and lymphomas in adults, acute leukemia
of childhood, regional enteritis, autoimmune vasculitis, multiple
sclerosis, chronic obstructive pulmonary disease, solid organ
transplant rejection, sepsis.
[0173] In addition, in accordance with the present invention a
method of treating a disease associated with AP-1-induced or
NF.kappa.B-induced transcription is provided wherein a compound of
formula I of the invention is administered to a patient in need of
treatment in a therapeutically effective amount to induce NHR
transrepression of the AP-1-induced or NF.kappa.B-induced
transcription, thereby treating the disease.
[0174] Other therapeutic agents, such as those described hereafter,
may be employed with the compounds of the invention in the present
methods. In the methods of the present invention, such other
therapeutic agent(s) may be administered prior to, simultaneously
with or following the administration of the compound(s) of the
present invention.
[0175] In a particular embodiment, the compounds of the present
invention are useful for the treatment of the aforementioned
exemplary disorders irrespective of their etiology, for example,
for the treatment of transplant rejection, rheumatoid arthritis,
inflammatory bowel disease, and viral infections.
Methods of Preparation
[0176] The compounds of the present invention may be synthesized by
many methods available to those skilled in the art of organic
chemistry. General synthetic schemes, in accordance with the
present invention, for preparing compounds of the present invention
are described below. These schemes are illustrative and are not
meant to limit the possible techniques one skilled in the art may
use to prepare the compounds disclosed herein. Different methods to
prepare the compounds of the present invention will be evident to
those skilled in the art. Additionally, the various steps in the
synthesis may be performed in an alternate sequence in order to
give the desired compound or compounds. Examples of compounds of
the present invention prepared by methods described in the general
schemes are given in the preparations and examples section set out
hereinafter.
Compounds of Formula 1
[0177] Compounds of formula I of the invention are prepared as
described in the Schemes and examples below. In the schemes the
various groups A, B, Z, R, R.sup.a, R.sup.b, R.sup.c, and R.sup.d
correspond to those described above. 45
Scheme A
[0178] General methods for the synthesis of compounds of the
invention of structure IA of the invention where A and B are each
fused phenyl or pyridyl, and Z is 46
[0179] are well known in the literature. Compound IA is constructed
by the cycloaddition of a compound of formula 1 with an unsaturated
compound of formula 2 neat or in an appropriate solvent such as
xylenes or benzene, at temperatures ranging from 50 to 200.degree.
C. to form compound 3 (which is a novel intermediate). It is well
known that the cycloaddition may be facilitated by the use of a
catalysts such diethylaluminium chloride or boron trifluoride
diethyl etherate. The cycloaddition may also be carried out at
higher pressures as when the reactions are performed in sealed
vessels. 47
[0180] Compound 3 is reacted with an amine of formula 4 by one of
the many methods of amidation well known to those skilled in the
art (preferably treatment of 3 in a suitable solvent such as
acetonitrile with diethylaminoethyl chloride hydrochloride (DEC),
1-hydroxy-7-azabenzotriaz- ole, triethylamine and amine 4) to
provide compounds of the invention of structure IA.
[0181] The starting compound 1 is known in the art and may be
commercially available or prepared employing procedures known in
the art.
Scheme B
[0182] Compounds of formula I of the invention where R is other
than H and Z is 48
[0183] (that is IA) may be prepared preferably starting with
compound 3 where R is H which is treated with a suitable base such
as lithium diisopropylamide (LDA) in a suitable solvent such as
tetrahydrofuran or dethyl ether and at a temperature ranging from
-100.degree. C. to 100.degree. C. and with a compound 5
(R.sup.x-LG, where LG is a leaving group, such as methyl iodide and
R.sup.x is R other than H) affords compounds of structure 6.
Compound 6 may be subjected to amidation as described in Scheme A
to form compounds of the invention IA (where R is other than H).
49
Scheme C
[0184] Compounds of formula I of the invention where Z is 50
[0185] where each of R.sup.1 and R.sup.2 is other than H may be
prepared starting with compound of formula IA where R.sup.1a is
R.sup.1 other than H and R.sup.2 is H which is treated with base
such as sodium hydride and compound 5a R.sup.2a-LG, where LG is a
leaving group, such as methyl iodide, and R.sup.2a is R.sup.2 other
than H, to provide compounds of structure IB of the invention where
R.sup.1 and R.sup.2 are other than H. 51
Scheme D
[0186] Compounds of formula I of the invention where Z is
--CH.sub.2NR.sup.1R.sup.2 (that is IC) may be prepared starting
with compounds of formula IA which when treated with a reducing
agent such as lithium aluminum hydride (LAH) provides compounds IC
of the invention. 52
Scheme E
[0187] Compounds of formula I of the invention where one or more of
A, B, Z, R, R.sup.a, R.sup.b, R.sup.c and R.sup.d includes a
hydroxyaryl group may be prepared as follows.
[0188] A compound of formula IA of the invention that contains one
or more aryloxyalkyl groups located in A, B, Z, R, R.sup.a,
R.sup.b, R.sup.c, and R.sup.d when treated with dealkylating agent
such as boron tribromide, sodium methyl sulfide or other known
dealkylating agents provides phenols of formula ID of the
invention. 53
Scheme F
[0189] A compound of formula IE where R.sup.a or R.sup.b is a
functional group such as CHO, NH.sub.2, CO.sub.2H or NO.sub.2 may
be further elaborated by various methods well known to those
skilled in the art to give compounds of structure IF. A few
illustrative examples are shown below. The newly introduced groups
may also be further elaborated,
4 54 R.sup.a or R.sup.b = R.sup.a or R.sup.b = CHO 55 CH.sub.2OH,
CH.sub.2NHR.sup.g, CH.sub.2NH.sup.gR.sup.h, CH.sub.2NHR.sup.k or
CH.sub.2NR.sup.kR.sup.l NH.sub.2 56 NHCH.sub.2R.sup.g,
NHCHR.sup.gR.sup.h, NHCH.sub.2R.sup.k or NHCHR.sup.kR.sup.l
CO.sub.2H 57 CONR.sup.eR.sup.f, CONR.sup.i R.sup.j NO.sub.2 58
NH.sub.2
[0190] The following compounds are new intermediates and may be
prepared employing procedures set out hereinbefore and/or known in
the art: 59
[0191] or an alkyl ester thereof,
[0192] where R is CH.sub.3, C.sub.2H.sub.5; R.sup.a is nitro,
cyano, Cl, Br, CH.sub.3, --COOCH3, formyl and R.sup.b is H; R.sup.b
is nitro, cyano, Cl, Br, CH.sub.3, --COOCH3, formyl and R.sup.a is
H; and 60
[0193] where X.sub.9 is S or NH; X is: 61
Definition of Terms
[0194] Unless otherwise indicated, the term "lower alkyl", "alkyl"
or "alk" as employed herein alone or as part of another group
includes both straight and branched chain hydrocarbons, containing
1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8
carbons, in the normal chain, and may optionally include an oxygen
or nitrogen in the normal chain, such as methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl,
heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl,
decyl, undecyl, dodecyl, the various branched chain isomers
thereof, and the like as well as such groups including 1 to 4
substituents such as halo, for example F, Br, Cl or I or CF.sub.3,
alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,
arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,
cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl,
heteroaryloxy, HO--N.dbd., cycloheteroalkyl, alkyloxycarbonyl,
alkoxyoximyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl,
heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido,
alkanoylamino, hydroxyalkyl (alkyl)amino carbonyl,
arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl
and/or alkylthio and/or any of the substituents for aryl.
[0195] Unless otherwise indicated, the term "cycloalkyl" as
employed herein alone or as part of another group includes
saturated or partially unsaturated (containing 1 or 2 double bonds)
cyclic hydrocarbon groups containing 1 to 3 rings, including
monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a
total of 3 to 20 carbons forming the rings, preferably 3 to 10
carbons, forming the ring and which may be fused to 1 or 2 aromatic
rings as described for aryl, which include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and
cyclododecyl, cyclohexenyl, 62
[0196] any of which groups may be optionally substituted with 1 to
4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl,
aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo,
acyl, arylcarbonylamino, amino, nitro, cyano, thiol and/or
alkylthio and/or any of the substituents for alkyl.
[0197] The term "cycloalkenyl" as employed herein alone or as part
of another group refers to cyclic hydrocarbons containing 3 to 12
carbons, preferably 5 to 10 carbons and 1 or 2 double bonds.
Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl,
which may be optionally substituted as defined for cycloalkyl.
[0198] The term "cycloalkylene" as employed herein refers to a
"cycloalkyl" group which includes free bonds and thus is a linking
group such as 63
[0199] and the like, and may optionally be substituted as defined
above for "cycloalkyl".
[0200] The term "alkanoyl" as used herein alone or as part of
another group refers to alkyl linked to a carbonyl group.
[0201] Unless otherwise indicated, the term "lower alkenyl" or
"alkenyl" as used herein by itself or as part of another group
refers to straight or branched chain radicals of 2 to 20 carbons,
preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in
the normal chain, which include one to six double bonds in the
normal chain, and may optionally include an oxygen or nitrogen in
the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl,
4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2heptenyl,
3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,
3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like,
and which may be optionally substituted with 1 to 4 substituents,
namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl,
arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl,
cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino,
nitro, cyano, thiol, alkylthio and/or any of the substituents for
alkyl set out herein.
[0202] Unless otherwise indicated, the term "lower alkynyl" or
"alkynyl" as used herein by itself or as part of another group
refers to straight or branched chain radicals of 2 to 20 carbons,
preferably 2 to 12 carbons and more preferably 2 to 8 carbons in
the normal chain, which include one triple bond in the normal
chain, and may optionally include an oxygen or nitrogen in the
normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl,
3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl,
4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl,
4-dodecynyl and the like, and which may be optionally substituted
with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino,
heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,
arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or
any of the substituents for alkyl set out herein.
[0203] The terms "arylalkenyl" and "arylalkynyl" as used alone or
as part of another group refer to alkenyl and alkynyl groups as
described above having an aryl substituent.
[0204] Where alkyl groups as defined above have single bonds for
attachment to other groups at two different carbon atoms, they are
termed "alkylene" groups and may optionally be substituted as
defined above for "alkyl".
[0205] Where alkenyl groups as defined above and alkynyl groups as
defined above, respectively, have single bonds for attachment at
two different carbon atoms, they are termed "alkenylene groups" and
"alkynylene groups", respectively, and may optionally be
substituted as defined above for "alkenyl" and "alkynyl".
[0206] (CH.sub.2).sub.p and (CH.sub.2).sub.q, includes alkylene,
allenyl, alkenylene or alkynylene groups, as defined herein, each
of which may optionally include an oxygen or nitrogen in the normal
chain, which may optionally include 1, 2, or 3 substituents which
include alkyl, alkenyl, halogen, cyano, hydroxy, alkoxy, amino,
thioalkyl, keto, C.sub.3-C.sub.6 cycloalkyl, alkylcarbonylamino or
alkylcarbonyloxy; the alkyl substituent may be an alkylene moiety
of 1 to 4 carbons which may be attached to one or two carbons in
the (CH.sub.2).sub.p or (CH.sub.2).sub.q group to form a cycloalkyl
group therewith.
[0207] Examples of (CH.sub.2).sub.p, (CH.sub.2).sub.q, alkylene,
alkenylene and alkynylene include 6465
[0208] The term "halogen" or "halo" as used herein alone or as part
of another group refers to chlorine, bromine, fluorine, and iodine
as well as CF.sub.3, with chlorine or fluorine being preferred.
[0209] The term "metal ion" refers to alkali metal ions such as
sodium, potassium or lithium and alkaline earth metal ions such as
magnesium and calcium, as well as zinc and aluminum.
[0210] Unless otherwise indicated, the term "aryl", as employed
herein alone or as part of another group refers to monocyclic and
bicyclic aromatic groups containing 6 to 10 carbons in the ring
portion (such as phenyl or naphthyl including 1-naphthyl and
2-naphthyl) and may optionally include one to three additional
rings fused to a carbocyclic ring or a heterocyclic ring (such as
aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings for example
66
[0211] and may be optionally substituted through available carbon
atoms with 1, 2, or 3 groups selected from hydrogen, halo,
haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl,
cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl,
arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl,
arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio,
arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl,
heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino,
substituted amino wherein the amino includes 1 or 2 substituents
(which are alkyl, aryl or any of the other aryl compounds mentioned
in the definitions), thiol, alkylthio, arylthio, heteroarylthio,
arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl,
alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,
arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl,
carboxy, cycloalkyl, arylalkoxy, aryloxycarbonyl,
cycloalkylaminocarbonyl, cycloalkylalkylaminocarbonyl,
alkoxycarbonylalkyl, alkoxyalkylaminocarbonyl,
heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl,
arylalkylaminocarbonyl, N-hydroxyalkyl(N-alkyl)aminocarbonyl,
cycloheteroalkylaminocarbonyl, cycloheteroalkylalkylaminocarbonyl,
N-aryl(N-alkyl)aminocarbonyl,
N-arylalkyl(N-cyanoalkyl)aminocarbonyl,
dialkylaminoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl-,
arylalkyl- or arylcycloheteroalkylaminocarb- onyl,
N-dialkylaminoalkyl(N-alkyl or N-arylalkyl)aminocarbonyl,
N-heteroarylalkyl(N-alkyl)aminocarbonyl,
N-arylalkyl(N-alkyl)aminocarbony- l,
N-dialkylamino(N-arylalkyl)aminocarbonyl,
N-hydroxyalkyl(N-arylalkyl)am- inocarbonyl, aminoalkyloxycarbonyl,
cycloheteroalkylcarbonyl, N.dbd.N.dbd.N, alkylsulfonyl,
aminosulfonyl, heteroarylaminosulfonyl, and/or any of the
substituents for alkyl set out herein.
[0212] Unless otherwise indicated, the term "lower alkoxy",
"alkoxy", "aryloxy" or "aralkoxy" as employed herein alone or as
part of another group includes any of the above alkyl, aralkyl or
aryl groups linked to an oxygen atom.
[0213] Unless otherwise indicated, the term "substituted amino" as
employed herein alone or as part of another group refers to amino
substituted with one or two substituents, which may be the same or
different, such as alkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl
or thioalkyl. These substituents may be further substituted with a
carboxylic acid and/or any of the substituents for alkyl as set out
above. In addition, the amino substituents may be taken together
with the nitrogen atom to which they are attached to form
1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,
4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,
4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl,
1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally
substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or
hydroxy.
[0214] Unless otherwise indicated, the term "lower alkylthio",
alkylthio", "arylthio" or "aralkylthio" as employed herein alone or
as part of another group includes any of the above alkyl, aralkyl
or aryl groups linked to a sulfur atom.
[0215] Unless otherwise indicated, the term "lower alkylamino",
"alkylamino", "arylamino", or "arylalkylamino" as employed herein
alone or as part of another group includes any of the above alkyl,
aryl or arylalkyl groups linked to a nitrogen atom.
[0216] Unless otherwise indicated, the term "acyl" as employed
herein by itself or part of another group, as defined herein,
refers to an organic radical linked to a carbonyl 67
[0217] group; examples of acyl groups include any of the R groups
attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl,
aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the
like.
[0218] Unless otherwise indicated, the term "cycloheteroalkyl" as
used herein alone or as part of another group refers to a 5-, 6- or
7-membered saturated or partially unsaturated ring which includes 1
to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked
through a carbon atom or a heteroatom, where possible, optionally
via the linker (CH.sub.2).sub.p (where p is 0, 1, 2 or 3), such as
68
[0219] and the like. The above groups may include 1 to 4
substituents such as alkyl, halo, oxo and/or any of of the
substituents for alkyl or aryl set out herein. In addition, any of
the cycloheteroalkyl rings can be fused to a cycloalkyl, aryl,
heteroaryl or cycloheteroalkyl ring.
[0220] Unless otherwise indicated, the term "heteroaryl" as used
herein alone or as part of another group refers to a 5-, 6- or
7-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms
such as nitrogen, oxygen or sulfur, and such rings fused to an
aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g.
benzothiophenyl, indolyl), and includes possible N-oxides, linked
through a carbon atom or a heteroatom, where possible, optionally
via the linker (CH.sub.2).sub.q (where q is 0, 1, 2 or 3). The
heteroaryl group may optionally include 1 to 4 substituents such as
any of the substituents for alkyl or aryl set out above. Examples
of heteroaryl groups include the following: 6970
[0221] and the like.
[0222] Examples of A rings and B rings include, but are not limited
to any of the 6-membered heteroaryl groups as defined above,
6-membered cycloheteroalkyl groups as defined above, and 6-membered
aryl groups as defined above.
[0223] The term "cycloheteroalkylalkyl" as used herein alone or as
part of another group refers to cycloheteroalkyl groups as defined
above linked through a C atom or heteroatom to a (CH.sub.2).sub.p
chain.
[0224] The term "heteroarylalkyl" or "heteroarylalkenyl" as used
herein alone or as part of another group refers to a heteroaryl
group as defined above linked through a C atom or heteroatom to a
--(CH.sub.2).sub.q-- chain, alkylene or alkenylene as defined
above.
[0225] The term "polyhaloalkyl" as used herein refers to an "alkyl"
group as defined above which includes from 2 to 9, preferably from
2 to 5, halo substituents, such as F or Cl, preferably F, such as
CF.sub.3CH.sub.2, CF.sub.3 or CF.sub.3CF.sub.2CH.sub.2.
[0226] The term "polyhaloalkyloxy" as used herein refers to an
"alkoxy" or "alkyloxy" group as defined above which includes from 2
to 9, preferably from 2 to 5, halo substituents, such as F or Cl,
preferably F, such as CF.sub.3CH.sub.2O, CF.sub.3O or
CF.sub.3CF.sub.2CH.sub.2O.
[0227] The term "prodrug esters" as employed herein includes
prodrug esters which are known in the art for carboxylic and
phosphorus acid esters such as methyl, ethyl, benzyl and the like.
Other prodrug ester examples include the following groups:
(1-alkanoyloxy)alkyl such as, 71
[0228] wherein R.sup.z, R.sup.t and R.sup.y are H, alkyl, aryl or
arylalkyl; however, R.sup.zO cannot be HO.
[0229] Examples of such prodrug esters include 72
[0230] Other examples of suitable prodrug esters include 73
[0231] wherein R.sup.z can be H, alkyl (such as methyl or t-butyl),
arylalkyl (such as benzyl) or aryl (such as phenyl); R.sup.v is H,
alkyl, halogen or alkoxy, R.sup.u is alkyl, aryl, arylalkyl or
alkoxyl, and n.sub.1 is 0, 1 or 2.
[0232] The terms pharmaceutically acceptable "salt" and "salts"
refer to basic salts formed with inorganic and organic bases. Such
salts include ammonium salts; alkali metal salts, such as lithium,
sodium and potassium salts (which are preferred); alkaline earth
metal salts, such as calcium and magnesium salts; salts with
organic bases, such as amine like salts (e.g., dicyclohexylamine
salt, benzathine, N-methyl-D-glucamine, and hydrabamine salts); and
salts with amino acids like arginine, lysine and the like; and
zwitterions, the so-called "inner salts". Nontoxic,
pharmaceutically acceptable salts are preferred, although other
salts are also useful, e.g., in isolating or purifying the
product.
[0233] The term pharmaceutically acceptable "salt" and "salts" also
includes acid addition salts. These are formed, for example, with
strong inorganic acids, such as mineral acids, for example sulfuric
acid, phosphoric acid or a hydrohalic acid such as HCl or HBr, with
strong organic carboxylic acids, such as alkanecarboxylic acids of
1 to 4 carbon atoms which are unsubstituted or substituted, for
example, by halogen, for example acetic acid, such as saturated or
unsaturated dicarboxylic acids, for example oxalic, malonic,
succinic, maleic, fumaric, phthalic or terephthalic acid, such as
hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,
malic, tartaric or citric acid, such as amino acids, (for example
aspartic or glutamic acid or lysine or arginine), or benzoic acid,
or with organic sulfonic acids, such as (C1-C4) alkyl or
arylsulfonic acids which are unsubstituted or substituted, for
example by halogen, for example methanesulfonic acid or
p-toluenesulfonic acid.
[0234] All stereoisomers of the compounds of the instant invention
are contemplated, either in admixture or in pure or substantially
pure form. The compounds of the present invention can have
asymmetric centers at any of the carbon atoms including any one or
the R substituents. Consequently, compounds of formula I can exist
in enantiomeric or diastereomeric forms or in mixtures thereof. The
processes for preparation can utilize racemates, enantiomers or
diastereomers as starting materials. When diastereomeric or
enantiomeric products are prepared, they can be separated by
conventional methods for example, chromatographic or fractional
crystallization.
Combinations
[0235] Where desired, the compounds of structure I may be used in
combination with one or more other types of therapeutic agents such
as immunosuppressants, anticancer agents, anti-viral agents,
anti-inflammatory agents, anti-fungal agents, antibiotics,
anti-vascular hyperproliferation agents, anti-depressive agents,
hypolipidemic agents or lipid-lowering agents or lipid modulating
agents, antidiabetic agents, anti-obesity agents, antihypertensive
agents, platelet aggregation inhibitors, and/or anti-osteoporosis
agents, which may be administered orally in the same dosage form,
in a separate oral dosage form or by injection.
[0236] The immunosuppressants which may be optionally employed in
combination with compounds of formula I of the invention include
cyclosporins, for example cyclosporin A, mycophenolate,
interferon-beta, deoxyspergolin, FK-506 or Ant.-IL-2.
[0237] The anti-cancer agents which may be optionally employed in
combination with compounds of formula I of the invention include
azathiprine, 5-fluorouracil, cyclophosphamide, cisplatin,
methotrexate, thiotepa, carboplatin, and the like.
[0238] The anti-viral agents which may be optionally employed in
combination with compounds of formula I of the invention include
abacavir, aciclovir, ganciclovir, zidanocin, vidarabine, and the
like.
[0239] The anti-inflammatory agents which may be optionally
employed in combination with compounds of formula I of the
invention include non-steroidal anti-inflammatory drugs (NSAIDs)
such as ibuprofen, cox-2 inhibitors such as celecoxib, rofecoxib,
aspirin, naproxen, ketoprofen, diclofenac sodium, indomethacin,
piroxicam, steroids such as prednisone, dexamethasone,
hydrocortisone, triamcinolone diacetate, gold compounds, such as
gold sodium thiomalate, TNF-.alpha. inhibitors such as tenidap,
anti-TNF antibodies or soluble TNF receptor, and rapamycin
(sirolimus or Rapamune) or derivatives thereof, infliximab
(Remicade.RTM. Centocor, Inc.). CTLA-4Ig, LEA29Y, antibodies such
as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB,
anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86,
monoclonal antibody OKT3, agents blocking the interaction between
CD40 and CD154 (a.k.a. "gp39"), such as antibodies specific for
CD40 and/or CD154, fusion proteins such as etanercept, fusion
proteins constructed from CD40 and/or CD154gp39 (e.g. CD40Ig and
CD8gp39), inhibitors, such as nuclear translocation inhibitors, of
NF-kappa B function, such as deoxyspergualin (DSG).
[0240] The anti-fungal agents which may be optionally employed in
combination with compounds of formula I of the invention include
fluconazole, miconazole, amphotericin B, and the like.
[0241] The antibiotics which may be optionally employed in
combination with compounds of formula I of the invention include
penicillin, tetracycline, amoxicillin, ampicillin, erythromycin,
doxycycline, vancomycin, minocycline, clindamycin or cefalexin.
[0242] The anti-vascular hyperproliferation agents which may be
optionally employed with compounds of formula I of the invention
include methotrexate, leflunomide, FK506 (tacrolimus, Prograf).
[0243] The hypolipidemic agent or lipid-lowering agent or lipid
modulating agents which may be optionally employed in combination
with the compounds of formula I of the invention may include 1, 2,
3 or more MTP inhibitors, HMG CoA reductase inhibitors, squalene
synthetase inhibitors, fibric acid derivatives, ACAT inhibitors,
lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal
Na.sup.+/bile acid cotransporter inhibitors, upregulators of LDL
receptor activity, bile acid sequestrants, and/or nicotinic acid
and derivatives thereof.
[0244] MTP inhibitors employed herein include MTP inhibitors
disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S.
Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No.
5,827,875, U.S. Pat. No. 5,885,983 and U.S. application Ser. No.
09/175,180 filed Oct. 20, 1998, now U.S. Pat. No. 5,962,440.
Preferred are each of the preferred MTP inhibitors disclosed in
each of the above patents and applications.
[0245] All of the above U.S. patents and applications are
incorporated herein by reference.
[0246] Most preferred MTP inhibitors to be employed in accordance
with the present invention include preferred MTP inhibitors as set
out in U.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No.
5,760,246.
[0247] The most preferred MTP inhibitor is
9-[4-[4-[[2-(2,2,2-trifluoroeth-
oxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluore-
ne-9-carboxamide 74
[0248] The hypolipidemic agent may be an HMG CoA reductase
inhibitor which includes, but is not limited to, mevastatin and
related compounds as disclosed in U.S. Pat. No. 3,983,140,
lovastatin (mevinolin) and related compounds as disclosed in U.S.
Pat. No. 4,231,938, pravastatin and related compounds such as
disclosed in U.S. Pat. No. 4,346,227, simvastatin and related
compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171.
Other HMG CoA reductase inhibitors which may be employed herein
include, but are not limited to, fluvastatin, disclosed in U.S.
Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.
5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.
4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin
(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.
5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in
U.S. Pat. No. 5,260,440, and related statin compounds disclosed in
U.S. Pat. No. 5,753,675, pyrazole analogs of mevalonolactone
derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs
of mevalonolactone derivatives as disclosed in PCT application WO
86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and
derivatives thereof as disclosed in U.S. Pat. No. 4,647,576,
Searle's SC-45355 (a 3-substituted pentanedioic acid derivative)
dichloroacetate, imidazole analogs of mevalonolactone as disclosed
in PCT application WO 86/07054,
3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as
disclosed in French Patent No. 2,596,393, 2,3-disubstituted
pyrrole, furan and thiophene derivatives as disclosed in European
Patent Application No. 0221025, naphthyl analogs of mevalonolactone
as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such
as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin
(lovastatin) as disclosed in European Patent Application No.
0,142,146 A2, and quinoline and pyridine derivatives disclosed in
U.S. Pat. Nos. 5,506,219 and 5,691,322.
[0249] In addition, phosphinic acid compounds useful in inhibiting
HMG CoA reductase suitable for use herein are disclosed in GB
2205837.
[0250] The squalene synthetase inhibitors suitable for use herein
include, but are not limited to, .alpha.-phosphono-sulfonates
disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et
al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including
isoprenoid (phosphinyl-methyl)phosphonates as well as other known
squalene synthetase inhibitors, for example, as disclosed in U.S.
Pat. Nos. 4,871,721 and 4,924,024 and in Biller, S. A.,
Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current
Pharmaceutical Design, 2, 1-40 (1996).
[0251] In addition, other squalene synthetase inhibitors suitable
for use herein include the terpenoid pyrophosphates disclosed by P.
Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the
farnesyl diphosphate analog A and presqualene pyrophosphate
(PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem.
Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by
McClard, R. W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes
reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med.
Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43,
48-51, Summary.
[0252] Other hypolipidemic agents suitable for use herein include,
but are not limited to, fibric acid derivatives, such as
fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate,
clinofibrate and the like, probucol, and related compounds as
disclosed in U.S. Pat. No. 3,674,836, probucol and gemfibrozil
being preferred, bile acid sequestrants such as cholestyramine,
colestipol and DEAE-Sephadex (Secholex.RTM., Policexide.RTM.) and
cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),
Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil
(HOE-402), tetrahydrolipstatin (THL),
istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin
(Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide
(Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and
CL-283,546 (disubstituted urea derivatives), nicotinic acid
(niacin), acipimox, acifran, neomycin, p-aminosalicylic acid,
aspirin, poly(diallylmethylamine) derivatives such as disclosed in
U.S. Pat. No. 4,759,923, quaternary amine
poly(diallyldimethylammonium chloride) and ionenes such as
disclosed in U.S. Pat. No. 4,027,009, and other known serum
cholesterol lowering agents.
[0253] The hypolipidemic agent may be an ACAT inhibitor such as
disclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe);
"The ACAT inhibitor, Cl-1011 is effective in the prevention and
regression of aortic fatty streak area in hamsters", Nicolosi et
al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; "The
pharmacological profile of FCE 27677: a novel ACAT inhibitor with
potent hypolipidemic activity mediated by selective suppression of
the hepatic secretion of ApoB100-containing lipoprotein", Ghiselli,
Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; "RP73163: a
bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor",
Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50;
"ACAT inhibitors: physiologic mechanisms for hypolipidemic and
anti-atherosclerotic activities in experimental animals", Krause et
al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,
Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC,
Boca Raton, Fla.; "ACAT inhibitors: potential anti-atherosclerotic
agents", Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25;
"Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as
hypocholesterolemic agents. 6. The first water-soluble ACAT
inhibitor with lipid-regulating activity. Inhibitors of
acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a
series of substituted
N-phenyl-N'-[(1-phenylcyclopentyl)methyl]ureas with enhanced
hypocholesterolemic activity", Stout et al, Chemtracts: Org. Chem.
(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co.
Ltd).
[0254] The hypolipidemic agent may be an upregulator of LD2
receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd)
and LY295427 (Eli Lilly).
[0255] The hypolipidemic agent may be a cholesterol absorption
inhibitor preferably Schering-Plough's ezetimibe (SCH58235) and
SCH48461 as well as those disclosed in Atherosclerosis 115, 45-63
(1995) and J. Med. Chem. 41, 973 (1998).
[0256] The hypolipidemic agent may be an ileal Na.sup.+/bile acid
cotransporter inhibitor such as disclosed in Drugs of the Future,
24, 425-430 (1999).
[0257] The lipid-modulating agent may be a cholesteryl ester
transfer protein (CETP) inhibitor such as Pfizer's CP 529,414
(WO/0038722 and EP 818448) and Pharmacia's SC-744 and SC-795.
[0258] The ATP citrate lyase inhibitor which may be employed in the
combination of the invention may include, for example, those
disclosed in U.S. Pat. No. 5,447,954.
[0259] Preferred hypolipidemic agents are pravastatin, lovastatin,
simvastatin, atorvastatin, fluvastatin, cerivastatin, itavastatin
and visastatin and ZD-4522.
[0260] The above-mentioned U.S. patents are incorporated herein by
reference. The amounts and dosages employed will be as indicated in
the Physician's Desk Reference and/or in the patents set out
above.
[0261] The compounds of formula I of the invention will be employed
in a weight ratio to the hypolipidemic agent (were present), within
the range from about 500:1 to about 1:500, preferably from about
100:1 to about 1:100.
[0262] The dose administered must be carefully adjusted according
to age, weight and condition of the patient, as well as the route
of administration, dosage form and regimen and the desired
result.
[0263] The dosages and formulations for the hypolipidemic agent
will be as disclosed in the various patents and applications
discussed above.
[0264] The dosages and formulations for the other hypolipidemic
agent to be employed, where applicable, will be as set out in the
latest edition of the Physicians' Desk Reference.
[0265] For oral administration, a satisfactory result may be
obtained employing the MTP inhibitor in an amount within the range
of from about 0.01 mg to about 500 mg and preferably from about 0.1
mg to about 100 mg, one to four times daily.
[0266] A preferred oral dosage form, such as tablets or capsules,
will contain the MTP inhibitor in an amount of from about 1 to
about 500 mg, preferably from about 2 to about 400 mg, and more
preferably from about 5 to about 250 mg, one to four times
daily.
[0267] For oral administration, a satisfactory result may be
obtained employing an HMG CoA reductase inhibitor, for example,
pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or
cerivastatin in dosages employed as indicated in the Physician's
Desk Reference, such as in an amount within the range of from about
1 to 2000 mg, and preferably from about 4 to about 200 mg.
[0268] The squalene synthetase inhibitor may be employed in dosages
in an amount within the range of from about 10 mg to about 2000 mg
and preferably from about 25 mg to about 200 mg.
[0269] A preferred oral dosage form, such as tablets or capsules,
will contain the HMG CoA reductase inhibitor in an amount from
about 0.1 to about 100 mg, preferably from about 0.5 to about 80
mg, and more preferably from about 1 to about 40 mg.
[0270] A preferred oral dosage form, such as tablets or capsules
will contain the squalene synthetase inhibitor in an amount of from
about 10 to about 500 mg, preferably from about 25 to about 200
mg.
[0271] The hypolipidemic agent may also be a lipoxygenase inhibitor
including a 15-lipoxygenase (15-LO) inhibitor such as benzimidazole
derivatives as disclosed in WO 97/12615, 15-LO inhibitors as
disclosed in WO 97/12613, isothiazolones as disclosed in WO
96/38144, and 15-LO inhibitors as disclosed by Sendobry et al
"Attenuation of diet-induced atherosclerosis in rabbits with a
highly selective 15-lipoxygenase inhibitor lacking significant
antioxidant properties", Brit. J. Pharmacology (1997) 120,
1199-1206, and Comicelli et al, "15-Lipoxygenase and its
Inhibition: A Novel Therapeutic Target for Vascular Disease",
Current Pharmaceutical Design, 1999, 5, 11-20.
[0272] The compounds of formula I and the hypolipidemic agent may
be employed together in the same oral dosage form or in separate
oral dosage forms taken at the same time.
[0273] The compositions described above may be administered in the
dosage forms as described above in single or divided doses of one
to four times daily. It may be advisable to start a patient on a
low dose combination and work up gradually to a high dose
combination.
[0274] The preferred hypolipidemic agent is pravastatin,
simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin
as well as niacin and/or cholestagel.
[0275] The other antidiabetic agent which may be optionally
employed in combination with the compound of formula I may be 1, 2,
3 or more antidiabetic agents or antihyperglycemic agents including
insulin secretagogues or insulin sensitizers, or other antidiabetic
agents preferably having a mechanism of action different from the
compounds of formula I of the invention, which may include
biguanides, sulfonyl ureas, glucosidase inhibitors, PPAR .gamma.
agonists, such as thiazolidinediones, aP2 inhibitors, dipeptidyl
peptidase IV (DP4) inhibitors, SGLT2 inhibitors, and/or
meglitinides, as well as insulin, and/or glucagon-like peptide-1
(GLP-1).
[0276] The other antidiabetic agent may be an oral
antihyperglycemic agent preferably a biguanide such as metformin or
phenformin or salts thereof, preferably metformin HCl.
[0277] Where the antidiabetic agent is a biguanide, the compounds
of structure I will be employed in a weight ratio to biguanide
within the range from about 0.001:1 to about 10:1, preferably from
about 0.01:1 to about 5:1.
[0278] The other antidiabetic agent may also preferably be a
sulfonyl urea such as glyburide (also known as glibenclamide),
glimepiride (disclosed in U.S. Pat. No. 4,379,785), glipizide,
gliclazide or chlorpropamide, other known sulfonylureas or other
antihyperglycemic agents which act on the ATP-dependent channel of
the .quadrature.-cells, with glyburide and glipizide being
preferred, which may be administered in the same or in separate
oral dosage forms.
[0279] The compounds of structure I will be employed in a weight
ratio to the sulfonyl urea in the range from about 0.01:1 to about
100:1, preferably from about 0.02:1 to about 5:1.
[0280] The oral antidiabetic agent may also be a glucosidase
inhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769)
or miglitol (disclosed in U.S. Pat. No. 4,639,436), which may be
administered in the same or in a separate oral dosage forms.
[0281] The compounds of structure I will be employed in a weight
ratio to the glucosidase inhibitor within the range from about
0.01:1 to about 100:1, preferably from about 0.05:1 to about
10:1.
[0282] The compounds of structure I may be employed in combination
with a PPAR .gamma. agonist such as a thiazolidinedione oral
anti-diabetic agent or other insulin sensitizers (which has an
insulin sensitivity effect in NIDDM patients) such as troglitazone
(Warner-Lambert's Rezulin.RTM., disclosed in U.S. Pat. No.
4,572,912), rosiglitazone (SKB), pioglitazone (Takeda),
Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),
Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) or
darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501
(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344
(Dr. Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone
and pioglitazone.
[0283] The compounds of structure I will be employed in a weight
ratio to the thiazolidinedione in an amount within the range from
about 0.01:1 to about 100:1, preferably from about 0.05 to about
10:1.
[0284] The sulfonyl urea and thiazolidinedione in amounts of less
than about 150 mg oral antidiabetic agent may be incorporated in a
single tablet with the compounds of structure I.
[0285] The compounds of structure I may also be employed in
combination with a antihyperglycemic agent such as insulin or with
glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide,
GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No.
5,614,492 to Habener, the disclosure of which is incorporated
herein by reference), as well as AC2993 (Amylin) and LY-315902
(Lilly), which may be administered via injection, intranasal,
inhalation or by transdermal or buccal devices.
[0286] Where present, metformin, the sulfonyl ureas, such as
glyburide, glimepiride, glipyride, glipizide, chlorpropamide and
gliclazide and the glucosidase inhibitors acarbose or miglitol or
insulin (injectable, pulmonary, buccal, or oral) may be employed in
formulations as described above and in amounts and dosing as
indicated in the Physician's Desk Reference (PDR).
[0287] Where present, metformin or salt thereof may be employed in
amounts within the range from about 500 to about 2000 mg per day
which may be administered in single or divided doses one to four
times daily.
[0288] Where present, the thiazolidinedione anti-diabetic agent may
be employed in amounts within the range from about 0.01 to about
2000 mg/day which may be administered in single or divided doses
one to four times per day.
[0289] Where present insulin may be employed in formulations,
amounts and dosing as indicated by the Physician's Desk
Reference.
[0290] Where present GLP-1 peptides may be administered in oral
buccal formulations, by nasal administration or parenterally as
described in U.S. Pat. No. 5,346,701 (TheraTech), U.S. Pat. Nos.
5,614,492 and 5,631,224 which are incorporated herein by
reference.
[0291] The other antidiabetic agent may also be a PPAR
.alpha./.gamma. dual agonist such as AR-HO39242 (Astra/Zeneca),
GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) as well as those
disclosed by Murakami et al, "A Novel Insulin Sensitizer Acts As a
Coligand for Peroxisome Proliferation-Activated Receptor Alpha
(PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on
Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats", Diabetes
47, 1841-1847 (1998).
[0292] The antidiabetic agent may be an SGLT2 inhibitor such as
disclosed in U.S. application Ser. No. 09/679,027, filed Oct. 4,
2000 (attorney file LA49 NP), employing dosages as set out therein.
Preferred are the compounds designated as preferred in the above
application.
[0293] The antidiabetic agent may be an aP2 inhibitor such as
disclosed in U.S. application Ser. No. 09/391,053, filed Sep. 7,
1999, and in U.S. application Ser. No. 09/519,079, filed Mar. 6,
2000 (attorney file LA27 NP), employing dosages as set out herein.
Preferred are the compounds designated as preferred in the above
application.
[0294] The antidiabetic agent may be a DP4 inhibitor such as
disclosed in U.S. application Ser. No. 09/788,173 filed Feb. 16,
2001 (attorney file LA50), WO99/38501, WO99/46272, WO99/67279
(PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431 (PROBIODRUG),
NVP-DPP728A
(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrro-
lidine) (Novartis) (preferred) as disclosed by Hughes et al,
Biochemistry, 38(36), 11597-11603, 1999, TSL-225
(tryptophyl-1,2,3,4-tetrahydro-isoquin- oline-3-carboxylic acid
(disclosed by Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998)
1537-1540, 2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed
by Ashworth et al, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22,
pp 1163-1166 and 2745-2748 (1996) employing dosages as set out in
the above references.
[0295] The meglitinide which may optionally be employed in
combination with the compound of formula I of the invention may be
repaglinide, nateglinide (Novartis) or KAD1229 (PF/Kissei), with
repaglinide being preferred.
[0296] The compound of formula I will be employed in a weight ratio
to the meglitinide, PPAR .gamma. agonist, PPAR .alpha./.gamma. dual
agonist, aP2 inhibitor, DP4 inhibitor or SGLT2 inhibitor within the
range from about 0.01:1 to about 100:1, preferably from about 0.05
to about 10:1.
[0297] The other type of therapeutic agent which may be optionally
employed with a compound of formula I may be 1, 2, 3 or more of an
anti-obesity agent including a beta 3 adrenergic agonist, a lipase
inhibitor, a serotonin (and dopamine) reuptake inhibitor, an aP2
inhibitor, a thyroid receptor agonist and/or an anorectic
agent.
[0298] The beta 3 adrenergic agonist which may be optionally
employed in combination with a compound of formula I may be AJ9677
(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other
known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204,
5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677,
L750,355 and CP331648 being preferred.
[0299] The lipase inhibitor which may be optionally employed in
combination with a compound of formula I may be orlistat or ATL-962
(Alizyme), with orlistat being preferred.
[0300] The serotonin (and dopoamine) reuptake inhibitor which may
be optionally employed in combination with a compound of formula I
may be sibutramine, topiramate (Johnson & Johnson) or axokine
(Regeneron), with sibutramine and topiramate being preferred.
[0301] The thyroid receptor agonist which may be optionally
employed in combination with a compound of formula I may be a
thyroid receptor ligand as disclosed in WO97/21993 (U. Cal SF),
WO99/00353 (KaroBio), GB98/284425 (KaroBio), and U.S. Provisional
Application 60/183,223 filed Feb. 17, 2000, with compounds of the
KaroBio applications and the above U.S. provisional application
being preferred.
[0302] The anorectic agent which may be optionally employed in
combination with a compound of formula I may be dexamphetamine,
phentermine, phenylpropanolamine or mazindol, with dexamphetamine
being preferred.
[0303] The various anti-obesity agents described above may be
employed in the same dosage form with the compound of formula I or
in different dosage forms, in dosages and regimens as generally
known in the art or in the PDR.
[0304] The antihypertensive agents which may be employed in
combination with the compound of formula I of the invention include
ACE inhibitors, angiotensin II receptor antagonists, NEP/ACE
inhibitors, as well as calcium channel blockers, .beta.-adrenergic
blockers and other types of antihypertensive agents including
diuretics.
[0305] The angiotensin converting enzyme inhibitor which may be
employed herein includes those containing a mercapto (--S--) moiety
such as substituted proline derivatives, such as any of those
disclosed in U.S. Pat. No. 4,046,889 to Ondetti et al mentioned
above, with captopril, that is,
1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred,
and mercaptoacyl derivatives of substituted prolines such as any of
those disclosed in U.S. Pat. No. 4,316,906 with zofenopril being
preferred.
[0306] Other examples of mercapto containing ACE inhibitors that
may be employed herein include rentiapril (fentiapril, Santen)
disclosed in Clin. Exp. Pharmacol. Physiol. 10: 131 (1983); as well
as pivopril and YS980.
[0307] Other examples of angiotensin converting enzyme inhibitors
which may be employed herein include any of those disclosed in U.S.
Pat. No. 4,374,829 mentioned above, with
N-(1-ethoxycarbonyl-3-phenylpropyl)-L-ala- nyl-L-proline, that is,
enalapril, being preferred, any of the phosphonate substituted
amino or imino acids or salts disclosed in U.S. Pat. No. 4,452,790
with (S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]--
1-oxohexyl]-L-proline or (ceronapril) being preferred,
phosphinylalkanoyl prolines disclosed in U.S. Pat. No. 4,168,267
mentioned above with fosinopril being preferred, any of the
phosphinylalkanoyl substituted prolines disclosed in U.S. Pat. No.
4,337,201, and the phosphonamidates disclosed in U.S. Pat. No.
4,432,971 discussed above.
[0308] Other examples of ACE inhibitors that may be employed herein
include Beecham's BRL 36,378 as disclosed in European Patent
Application Nos. 80822 and 60668; Chugai's MC-838 disclosed in C.A.
102:72588v and Jap. J. Pharmacol. 40: 373 (1986); Ciba-Geigy's CGS
14824
(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-ox-
o-1-(3S)-benzazepine-1 acetic acid HCl) disclosed in U.K. Patent
No. 2103614 and CGS 16,617
(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,-
5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoic acid) disclosed in
U.S. Pat. No. 4,473,575; cetapril (alacepril, Dainippon) disclosed
in Eur. Therap. Res. 39: 671 (1986); 40: 543 (1986); ramipril
(Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.
Res. 40: 74 (1986); Ru 44570 (Hoechst) disclosed in
Arzneimittelforschung 34: 1254 (1985), cilazapril (Hoffman-LaRoche)
disclosed in J. Cardiovasc. Pharmacol. 9: 39 (1987); R 31-2201
(Hoffman-LaRoche) disclosed in FEBS Lett. 165: 201 (1984);
lisinopril (Merck), indalapril (delapril) disclosed in U.S. Pat.
No. 4,385,051; indolapril (Schering) disclosed in J. Cardiovasc.
Pharmacol. 5: 643, 655 (1983), spirapril (Schering) disclosed in
Acta. Pharmacol. Toxicol. 59 (Supp. 5): 173 (1986); perindopril
(Servier) disclosed in Eur. J. clin. Pharmacol. 31: 519 (1987);
quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949 and
CI925 (Warner-Lambert)
([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-ph-
enylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquino-
linecarboxylic acid HCl) disclosed in Pharmacologist 26: 243, 266
(1984), WY-44221 (Wyeth) disclosed in J. Med. Chem. 26: 394
(1983).
[0309] Preferred ACE inhibitors are captopril, fosinopril,
enalapril, lisinopril, quinapril, benazepril, fentiapril, ramipril
and moexipril.
[0310] NEP/ACE inhibitors may also be employed herein in that they
possess neutral endopeptidase (NEP) inhibitory activity and
angiotensin converting enzyme (ACE) inhibitory activity. Examples
of NEP/ACE inhibitors suitable for use herein include those
disclosed in U.S. Pat. Nos. 5,362,727, 5,366,973, 5,225,401,
4,722,810, 5,223,516, 4,749,688, U.S. Pat. No. 5,552,397, U.S. Pat.
No. 5,504,080, U.S. Pat. No. 5,612,359,U.S. Pat. No. 5,525,723,
European Patent Application 0599,444, 0481,522, 0599,444, 0595,610,
European Patent Application 0534363A2, 534,396 and 534,492, and
European Patent Application 0629627A2.
[0311] Preferred are those NEP/ACE inhibitors and dosages thereof
which are designated as preferred in the above patents/applications
which U.S. patents are incorporated herein by reference; most
preferred are omapatrilat, BMS 189,921
([S--(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-p-
henylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-acetic acid
(gemopatrilat)) and CGS 30440.
[0312] The angiotensin II receptor antagonist (also referred to
herein as angiotensin II antagonist or AII antagonist) suitable for
use herein includes, but is not limited to, irbesartan, losartan,
valsartan, candesartan, telmisartan, tasosartan or eprosartan, with
irbesartan, losartan or valsartan being preferred.
[0313] A preferred oral dosage form, such as tablets or capsules,
will contain the ACE inhibitor or AII antagonist in an amount
within the range from abut 0.1 to about 500 mg, preferably from
about 5 to about 200 mg and more preferably from about 10 to about
150 mg.
[0314] For parenteral administration, the ACE inhibitor,
angiotensin II antagonist or NEP/ACE inhibitor will be employed in
an amount within the range from about 0.005 mg/kg to about 10 mg/kg
and preferably from about 0.01 mg/kg to about 1 mg/kg.
[0315] Where a drug is to be administered intravenously, it will be
formulated in conventional vehicles, such as distilled water,
saline, Ringer's solution or other conventional carriers.
[0316] It will be appreciated that preferred dosages of ACE
inhibitor and AII antagonist as well as other antihypertensives
disclosed herein will be as set out in the latest edition of the
Physician's Desk Reference (PDR).
[0317] Other examples of preferred antihypertensive agents suitable
for use herein include omapatrilat (Vanlev.RTM.) amlodipine
besylate (Norvasc.RTM.), prazosin HCl (Minipress.RTM.), verapamil,
nifedipine, nadolol, diltiazem, felodipine, nisoldipine,
isradipine, nicardipine, atenolol, carvedilol, sotalol, terazosin,
doxazosin, propranolol, and clonidine HCl (Catapres.RTM.).
[0318] Diuretics which may be employed in combination with
compounds of formula I include hydrochlorothiazide, torasemide,
furosemide, spironolactono, and indapamide.
[0319] Antiplatelet agents which may be employed in combination
with compounds of formula I of the invention include aspirin,
clopidogrel, ticlopidine, dipyridamole, abciximab, tirofiban,
eptifibatide, anagrelide, and ifetroban, with clopidogrel and
aspirin being preferred.
[0320] The antiplatelet drugs may be employed in amounts as
indicated in the PDR. Ifetroban may be employed in amounts as set
out in U.S. Pat. No. 5,100,889.
[0321] Antiosteoporosis agents suitable for use herein in
combination with the compounds of formula I of the invention
include parathyroid hormone or bisphosphonates, such as MK-217
(alendronate) (Fosamax.RTM.).
[0322] Dosages employed for the above drugs will be as set out in
the Physician's Desk Reference.
Pharmaceutical Formulations
[0323] The pharmaceutical composition of the invention includes a
pharmaceutically acceptable carrier, adjuvant or vehicle that may
be administered to a subject, together with a compound of the
present invention, and which does not destroy the pharmacological
activity thereof. Pharmaceutically acceptable carriers, adjuvants
and vehicles that may be used in the pharmaceutical compositions of
the present invention include, but are not limited to, the
following: ion exchangers, alumina, aluminum stearate, lecithin,
self-emulsifying drug delivery systems ("SEDDS") such as
d(-tocopherol polyethyleneglycol 1000 succinate), surfactants used
in pharmaceutical dosage forms such as Tweens or other similar
polymeric delivery matrices, serum proteins such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat. Cyclodextrins such as .alpha.-, .beta.- and
.gamma.-cyclodextrin, or chemically modified derivatives such as
hydroxyalkylcyclodextrins, including 2- and
3-hydroxypropyl-.beta.-cyclod- extrins, or other solubilized
derivatives may also be used to enhance delivery of the modulators
of the present invention.
[0324] The compositions of the present invention may contain other
therapeutic agents as described below, and may be formulated, for
example, by employing conventional solid or liquid vehicles or
diluents, as well as pharmaceutical additives of a type appropriate
to the mode of desired administration (for example, excipients,
binders, preservatives, stabilizers, flavors, etc.) according to
techniques such as those well known in the art of pharmaceutical
formulation.
[0325] The compounds of the invention may be administered by any
suitable means, for example, orally, such as in the form of
tablets, capsules, granules or powders; sublingually; buccally;
parenterally, such as by subcutaneous, intravenous, intramuscular,
or intrasternal injection or infusion techniques (e.g., as sterile
injectable aqueous or non-aqueous solutions or suspensions);
nasally such as by inhalation spray; topically, such as in the form
of a cream or ointment; or rectally such as in the form of
suppositories; in dosage unit formulations containing non-toxic,
pharmaceutically acceptable vehicles or diluents. The compounds of
the invention may, for example, be administered in a form suitable
for immediate release or extended release. Immediate release or
extended release may be achieved by the use of suitable
pharmaceutical compositions including the compounds of the
invention, or, particularly in the case of extended release, by the
use of devices such as subcutaneous implants or osmotic pumps. The
compounds of the invention may also be administered
liposomally.
[0326] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The present compunds may also be delivered
through the oral cavity by sublingual and/or buccal administration.
Molded tablets, compressed tablets or freeze-dried tablets are
exemplary forms which may be used. Exemplary compositions include
those formulating the compound(s) of the invention with 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) or
polyethylene glycols (PEG). Such formulations may also include an
excipient to aid mucosal adhesion such as hydroxy propyl cellulose
(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy
methyl cellulose (SCMC), maleic anhydride copolymer (e.g.,
Gantrez), and agents to control release such as polyacrylic
copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors,
coloring agents and stabilizers may also be added for ease of
fabrication and use.
[0327] Exemplary compositions for nasal aerosol or inhalation
administration include solutions in saline which may contain, for
example, benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, and/or other solubilizing or
dispersing agents such as those known in the art.
[0328] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid. The term
"parenteral" as used herein includes subcutaneous, intracutaneous,
intravenous, intramuscular, intraarticular, intraarterial,
intrasynovial, intrasternal, intrathecal, intralesional and
intracranial injection or infusion techniques.
[0329] Exemplary compositions for rectal administration include
suppositories which may contain, for example, a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride
esters or polyethylene glycols, which are solid at ordinary
temperatures, but liquify and/or dissolve in the rectal cavity to
release the drug.
[0330] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0331] The effective amount of a compound of the present invention
may be determined by one of ordinary skill in the art, and includes
exemplary dosage amounts for an adult human of from about 0.1 to
500 mg/kg of body weight of active compound per day, or between 5
and 2000 mg per day which may be administered in a single dose or
in the form of individual divided doses, such as from 1 to 5 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. Preferred subjects for treatment
include animals, most preferably mammalian species such as humans,
and domestic animals such as dogs, cats and the like.
[0332] A typical capsule for oral administration contains compounds
of structure I (250 mg), lactose (75 mg) and magnesium stearate (15
mg). The mixture is passed through a 60 mesh sieve and packed into
a No. 1 gelatin capsule.
[0333] A typical injectable preparation is produced by aseptically
placing 250 mg of compounds of structure I into a vial, aseptically
freeze-drying and sealing. For use, the contents of the vial are
mixed with 2 mL of physiological saline, to produce an injectable
preparation.
[0334] The compounds of formula I of the invention are
glucocorticoid receptor modulators as shown by their ability to
bind glucocorticoid receptors in GR binding assays.
[0335] Compounds of formula I of the invention may also inhibit
AP-1 activity as indicated in cellular transrespressional assays,
and cause none to minimal transactivation as indicated in cellular
transscriptional assays.
[0336] The GR binding assay, cellular transrespressional assay and
cellular transcriptional assay employed are described in copending
provisional application No. 60/396,907, filed Jul. 18, 2002
(attorney docket D0250 PSP) which is incorporated herein by
reference.
[0337] The following abbreviations are employed in the
Examples:
[0338] Ph=phenyl
[0339] Bn=benzyl
[0340] t-Bu=tertiary butyl
[0341] Me=methyl
[0342] Et=ethyl
[0343] TMS=trimethylsilyl
[0344] TMSN.sub.3=trimethylsilyl azide
[0345] TBS=tert-butyldimethylsilyl
[0346] FMOC=fluorenylmethoxycarbonyl
[0347] Boc=tert-butoxycarbonyl
[0348] Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl
[0349] THF=tetrahydrofuran
[0350] Et.sub.2O=diethyl ether
[0351] hex=hexanes
[0352] EtOAc=ethyl acetate
[0353] DMF=dimethyl formamide
[0354] MeOH=methanol
[0355] EtOH=ethanol
[0356] i-PrOH=isopropanol
[0357] DMSO=dimethyl sulfoxide
[0358] DME=1,2 dimethoxyethane
[0359] DCE=1,2 dichloroethane
[0360] HMPA=hexamethyl phosphoric triamide
[0361] HOAc or AcOH=acetic acid
[0362] TFA=trifluoroacetic acid
[0363] TFAA=trifluoroacetic anhydride
[0364] i-Pr.sub.2NEt=diisopropylethylamine
[0365] Et.sub.3N=triethylamine
[0366] NMM=N-methyl morpholine
[0367] DMAP=4-dimethylaminopyridine
[0368] NaBH.sub.4=sodium borohydride
[0369] NaBH(OAc).sub.3=sodium triacetoxyborohydride
[0370] DIBALH=diisobutyl aluminum hydride
[0371] LAH or LiAlH.sub.4=lithium aluminum hydride
[0372] n-BuLi=n-butyllithium
[0373] LDA=lithium diisopropylamide
[0374] Pd/C=palladium on carbon
[0375] PtO.sub.2=platinum oxide
[0376] KOH=potassium hydroxide
[0377] NaOH=sodium hydroxide
[0378] LiOH=lithium hydroxide
[0379] K.sub.2CO.sub.3=potassium carbonate
[0380] NaHCO.sub.3=sodium bicarbonate
[0381] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene
[0382] EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or
EDAC=3-ethyl-3'-(dimethyl- amino)propyl-carbodiimide hydrochloride
(or 1-(3-dimethylaminopropyl)-3-et- hylcarbodiimide
hydrochloride)
[0383] HOBT or HOBT.H.sub.2O=1-hydroxybenzotriazole hydrate
[0384] HOAT=1-Hydroxy-7-azabenzotriazole
[0385] BOP
reagent=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate
[0386] NaN(TMS).sub.2=sodium hexamethyldisilazide or sodium
bis(trimethylsilyl)amide
[0387] Ph.sub.3P=triphenylphosphine
[0388] Pd(OAc).sub.2=Palladium acetate
[0389] (Ph.sub.3P).sub.4Pd.sup.o=tetrakis triphenylphosphine
palladium
[0390] DEAD=diethyl azodicarboxylate
[0391] DIAD=diisopropyl azodicarboxylate
[0392] Cbz-Cl=benzyl chloroformate
[0393] CAN=ceric ammonium nitrate
[0394] SAX=Strong Anion Exchanger
[0395] SCX=Strong Cation Exchanger
[0396] Ar=argon
[0397] N.sub.2=nitrogen
[0398] min=minute(s)
[0399] h or hr=hour(s)
[0400] L=liter
[0401] mL=milliliter
[0402] L=microliter
[0403] g=gram(s)
[0404] mg=milligram(s)
[0405] mol=moles
[0406] mmol=millimole(s)
[0407] meq=milliequivalent
[0408] RT=room temperature
[0409] sat or sat'd=saturated
[0410] aq.=aqueous
[0411] TLC=thin layer chromatography
[0412] HPLC=high performance liquid chromatography
[0413] LC/MS=high performance liquid chromatography/mass
spectrometry
[0414] MS or Mass Spec=mass spectrometry
[0415] NMR=nuclear magnetic resonance
[0416] NMR spectral data: s=singlet; d=doublet; m=multiplet;
br=broad; t=triplet
[0417] mp=melting point
Preparations
[0418] The preparations set out below are for the synthesis of
reagents that were not obtained from commercial sources and were
employed for the preparation of compounds of formula I of the
invention. All chemical structures in the tables and schemes are
racemic unless specified otherwise.
Preparation 1
2-Amino-4-[1-(4-fluoro)naphthyl]thiazole 1a
[0419] 75
[0420] Step 1
[0421] To a solution of 4'-fluoro-1'-acetonaphthone (28.69 mmol,
5.4 g) in 1,4-dioxane (18.0 mL) at 0.degree. C. was added bromine
(35.13 mmol, 5.61 g). After 3 hours at room temperature the
reaction mixture was concentrated in vacuo to give 7.66 g (Y:
.delta. 100%) of the product of step 1.
[0422] Step 2
[0423] To a solution of the product of step 1 (28.69 mmol, 7.66 g)
in ethyl alcohol (20 mL) at room temperature was added thiourea
(36.13 mmol, 2.75 g). After 1 hour at room temperature a
precipitate formed. To the reaction mixture was added water (100
mL) and the solid was collected by vacuum filtration. The solid was
then washed with water (3.times.100 mL) and dichloromethane
(3.times.100 mL). The solid was then dried in vacuo to give 5.5 g
(Y: 75%) of the title compound 1a. MS (E+) m/z: 245 (MH.sup.+).
[0424] In a similar manner the following compounds were prepared
from the corresponding ketone.
5 Preparation Structure 1b 76 1c 77 1d 78 1e 79 1f 80 1g 81 1h 82
1i 83 1j 84 1k 85 1l 86 1m 87 1n 88 1o 89 1p 90 1q 91 1r 92 1s 93
1t 94 1u 95 1v 96 1w 97
Preparation 2
2-Amino-4-[1-(4-fluoro)naphthyl]imidazole 2a
[0425] 98
[0426] Step 1
[0427] To a solution of the product of preparation 1a, step 1
(18.73 mmol, 5.0 g) in DMF (15 mL) at room temperature was added
1-acetylguanidine (57.43 mmol, 5.80 g). After 5 hours at room
temperature, the reaction mixture was diluted with water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). The organic
phases were concentrated in vacuo and the residue chromatographed
on silica gel (eluted with 5% methanol in dichloromethane) to give
2.0 g (Y: 39%) of the product of step 1. MS (E+) m/z: 270
(MH.sup.+).
[0428] Step 2
[0429] To a solution of the product of step 1 (7.43 mmol, 2.0 g) in
methanol (17 mL) was added water (8.5 mL) and 12 N HCl (12.0 mL).
After 1 hour at reflux the reaction mixture was concentrated in
vacuo to approximately 15 mL. The resulting solution was then
purified and neutralized by cation exchange SPE to give 1.66 g (Y:
99%) of the title compound 2a. MS (E+) m/z: 228 (MH.sup.+).
[0430] In a similar manner the following compounds were prepared
from the corresponding ketones.
6 Preparation Structure 2b 99 2c 100 2d 101 2e 102
Preparation 3
2-Amino-4-(1-naphthyl)oxazole 3a
[0431] 103
[0432] Step 1
[0433] To a solution of 1-acetonaphthone (29.38 mmol, 5.0 g) in
glacial acetic acid (10.0 mL) at RT was added bromine (30.06 mmol,
4.80 g) in glacial acetic acid (5.0 mL). After 5 minutes the
reaction mixture was poured onto crushed ice and extracted with
dichloromethane to give 7.31 g (Y: 100%) of the product of step 1.
MS (E+) m/z: 250 (MH.sup.+).
[0434] Step 2
[0435] To a solution of the product of step 1 (5.50 mmol, 1.37 g)
in ethyl alcohol (10 mL) was added urea (27.50 mmol, 1.65 g). After
2 hours at reflux the reaction mixture was concentrated in vacuo
and the residue chromatographed on silica gel (eluted with 30%
ethyl acetate in hexane) to give 100 mg (Y: 9%) of the title
compound 3a. MS (E+) m/z: 211 (MH.sup.+).
Preparation 4
5-(1-Naphthyl)-3-aminoisoxazole 4a
[0436] 104
[0437] Step 1
[0438] To a solution of acetonitrile (12.18 mmol, 0.50 g) in THF
(10.0 mL) was added 60% sodium hydride (24.36 mmol, 0.975 g),
followed by 1-naphthoic acid methyl ester (12.18 mmol, 2.27 g).
After 2 hours at 70.degree. C. the reaction mixture was quenched
with an excess of 1N HCl and extracted with dichloromethane
(3.times.30 mL). The organic phases were concentrated in vacuo and
the residue was chromatographed on silica gel (eluted with 33%
ethyl acetate in hexane) to give 1.80 g (Y: 76%) of the product of
step 1. MS (E+) m/z: 196 (MH.sup.+).
[0439] Step 2
[0440] Hydroxylamine sulfate (1.61 mmol, 264 mg) was added to a
stirred solution of the product of step 1 (2.94 mmol, 573 mg) and
NaOH (3.53 mmol, 141 mg) in 50% aq. EtOH (6.0 mL). The mixture was
heated at 80.degree. C. for 5 hours and then stirred at RT for 14
hours. The reaction mixture was quenched with an excess of 1N HCl,
washed with dichloromethane (3.times.50 mL), neutralized with
saturated sodium bicarbonate solution and extracted with
dichloromethane (3.times.50 mL). The organic extracts were
combined, dried over Na.sub.2SO.sub.4 and concentrated under vacuo
to give 237 mg (Y: 38%) of the title compound 4a. MS (E+) m/z: 211
(MH.sup.+).
Preparation 5
3-(1-Naphthyl)-5-aminopyrazole 5a
[0441] 105
[0442] To a solution of the product of preparation 4, step 1 (2.70
mmol, 527 mg) in EtOH (5.0 mL) was added hydrazine (2.70 mmol, 85
mg). The resulting mixture was refluxed for 2 h, cooled, diluted
with 1N HCl, washed with dichloromethane (3.times.50 mL),
neutralized with saturated sodium bicarbonate solution and
extracted with dichloromethane (3.times.50 mL). The organic
extracts were combined, dried over Na.sub.2SO.sub.4 and
concentrated under vacuum to give 280 mg (Y: 51%) of the title
compound 5a. MS (E+) m/z: 210 (MH.sup.+).
Preparation 6
4-[1-(6-Methoxy)naphthyl]-2-aminothiazole 6a
[0443] 106
[0444] Step 1
[0445] To a solution of 6-methoxy-1-naphthoic acid (0.5 g, 2.47
mmol, 1.0 equi.) in dichloromethane (10 mL) at room temperature was
added a solution of oxalyl chloride (2M in dichloromethane, 2.5 mL,
5.0 mmol, 2 equi.). The solution was stirred at room temperature
for 2 hours, and the excess oxalyl chloride removed in vacuo. The
residue was dissolved in methanol and stirred at room temperature
for 18 hours. The solvent was removed in vacuo, yielding 0.45 g
(84%) of the product of step 1: LC/MS (m/z 217, (M-H).sup.+);
.sup.1H NMR (CDCl.sub.3) .delta. 8.82 (d, 1H), 8.03 (dd, 1H), 7.90
(d, 1H), 7.44 (t, 1H), 7.26 (dd, 1H), 7.16 (s, 1H), 4.02 (s, 3H),
3.95 (s, 3H).
[0446] Step 2
[0447] Reference: P. Chen, P. T. Cheng, S. H. Spergel, R. Zahler,
X. Wang, J. Thottathil, J. C. Barrish, R. P. Polniaszek,
Tetrahedron Letters, 38, 3175 (1997).
[0448] To a solution of the product of step 1 (0.238 g, 1.1 mmol,
1.0 equi.) and chloroiodomethane (0.32 mL, 4.4 mmol, 4 equi.) in
THF (5 mL) was added a solution of LDA (2M, 2.2 mL, 4.0 equi.) in
THF (10 mL) dropwise in 30 minutes, while keeping the solution
temperature at -78.degree. C. The reaction solution was stirred at
-78.degree. C. for 10 minutes. A solution of acetic acid (1.5 mL)
in THF (10 mL) was added in dropwise in 10 minutes. After stirring
for an additional 10 minutes at -78.degree. C., the solution was
quenched with ethyl acetate and saturated sodium chloride solution.
The organic phase was washed with saturated sodium bisulfite,
saturated sodium chloride, dried with sodium sulfate and
concentrated in vacuo. The residue was purified by flash
chromatography (10% ethyl acetate in hexane) to yield 0.23 g (90%)
of the product of step 2: LC/MS (m/z 235, (M+H).sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 8.82 (d, 1H), 8.03 (dd, 1H), 7.90 (d, 1H),
7.44 (t, 1H), 7.26 (dd, 1H), 7.16 (s, 1H), 4.80 (s, 2H), 3.95 (s,
3H).
[0449] Step 3
[0450] To a solution of the product of step 2 (0.23 g, 1.0 mmol,
1.0 equi.) in ethanol (5 mL) at room temperature was added thiourea
(90 mg, 1.2 mmol, 1.2 equi.). The reaction solution was stirred at
room temperature for 2 hours, after which a yellow precipitate was
formed. The reaction was quenched by addition of water and ethyl
acetate. The aqueous phase was extracted with ethyl acetate
(3.times.). The combined organic phases were dried with sodium
sulfate and concentrated in vacuo to yield 200 mg (78%) of the
title compound 6a: LC/MS (m/z 235, (M+H).sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 8.1 (d, 1H), 7.9 (m, 1H), 7.43 (m, 2H), 7.25
(m, 1H), 7.10 (dd, 1H), 6.65 (s, 1H), 3.95 (s, 3H).
[0451] In a similar manner the following compounds were
prepared.
7 Preparation Structure 6b 107 6c 108
Preparation 7
4-[1-(6-Methoxy)naphthyl]-2-aminoimidazole 7a
[0452] 109
[0453] Step 1
[0454] To a solution of the product of preparation 6, step 2 (0.5
g, 2.14 mmol, 1.0 equi.), in ethanol (5 mL) at room temperature was
added 1-acetylguanidine (650 mg, 6.42 mmol, 3.0 equi.). The
reaction solution was stirred at room temperature for 24 hours. The
reaction was quenched by addition of water and ethyl acetate. The
aqueous phase was extracted with ethyl acetate (3.times.). The
combined organic phases were dried with sodium sulfate and
concentrated in vacuo to yield 0.2 g (35%) of the product of step
1: LC/MS (m/z 282, (M+H).sup.+).
[0455] Step 2
[0456] To a solution of the product of step 1 (0.2 g, 0.7 mmol, 1.0
equi.) in methanol (5 mL) was added water (1.0 mL) and hydrochloric
acid (12N, 1.0 mL). The reaction solution was heated to reflux for
1 hour, after which the solvent was removed in vacuo. The crude
mixture was purified by cation exchange SPE to give 0.12 g (70%) of
the title compound 7a: LC/MS (m/z 240, (M+H).sup.+).
Preparation 8
4-(3-Pyridyl)-2-aminothiazole 8a
[0457] 110
[0458] Step 1
[0459] To a solution of 3-acetylpyridine (20.0 mmol, 2.42 g) in 48%
HBr (10.0 mL) was added bromine (20.0 mmol, 3.2 g) in 48% HBr (4.0
mL). The reaction mixture was heated to 65.degree. C. for one hour
and stirred at RT for an additional hour. The reaction mixture was
quenched with ice and filtered. The solid was washed with acetone
(2.times.10 mL) and diethyl ether (2.times.10 mL). The solid was
then dried in vacuo to give 3.70 g (Y: 83%) of the product of step
1.
[0460] Step 2
[0461] To a solution of the product of step 1 (6.10 mmol, 1.22 g)
in ethyl alcohol (10 mL) at room temperature was added thiourea
(7.32 mmol, 560 mg). After 1 hour at room temperature the reaction
mixture was quenched with water (30 mL) and washed with
dichloromethane (3.times.100 mL). The aqueous layer was then
purified by cation exchange chromatography to give 600 mg (Y: 56%)
of the title compound 8a. MS (E+) m/z: 178 (MH.sup.+).
[0462] In a similar manner the following compounds were
prepared.
8 Preparation Structure 8b 111 8c 112 8d 113
Preparation 9
4-(1-Isoquinolinyl)-2-aminothiazole 9a
[0463] 114
[0464] Step 1
[0465] To a solution of 1-isoquinolinecarboxylic acid (11.55 mmol,
2.0 g) in THF (20.0 mL) and methanol (10.0 mL) is added
trimethylsilyldiazometha- ne (69.3 mmol, 32.0 mL of a 2 M solution
in hexanes). After 2 h at RT the reaction mixture was concentrated
in vacuo to give 1.17 g (Y: 99%) of the product of step 1. MS (E+)
m/z: 188 (MH.sup.+).
[0466] Step 2
[0467] To a solution of the product of step 1 (10.69 mmol, 2.0 g)
in dichloromethane (100.0 mL) was added trimethylaluminum (32.88
mmol, 16.44 mL of a 2.0 M solution in toluene) at -78.degree. C.
After the addition was complete the reaction was allowed to warm to
0.degree. C. The reaction mixture was then quenched with water (30
mL) and extracted with dichloromethane (3.times.30 mL). The organic
phases were concentrated in vacuo and the residue chromatographed
on silica gel (eluted with 10% ethyl acetate in hexanes) to give
930 mg (Y: 51%) of the product of step 2. MS (E+) m/z: 172
(MH.sup.+).
[0468] Step 3
[0469] The product of step 2 was converted to the title compound 9a
as described in preparation 8, step 2. MS (E+) m/z: 228
(MH.sup.+).
Preparation 10
5-(1-naphthyl)-2-aminopyridine 10a
[0470] 115
[0471] Potassium carbonate (5.19 mmol, 717 mg) in water (2.5 mL)
and tetrakis(triphenylphosphine)palladium(0) (0.04 mol %, 80 mg) in
ethyl alcohol (2.5 mL) were added to 2-amino-5-bromopyridine (1.73
mmol, 299 mg) and 1-naphthaleneboronic acid (2.60 mmol, 446 mg) in
benzene (10.0 mL). After 2 hours at 90.degree. C. the reaction
mixture was quenched with water (30 mL) and extracted with
dichloromethane (3.times.30 mL). The organic phases were
concentrated in vacuo and the residue chromatographed on silica gel
(eluted with 50% ethyl acetate in hexanes) to give 260 mg (Y: 68%)
of the title compound 10a. MS (E+) m/z: 381 (MH.sup.+).
[0472] In a similar manner the following compounds were
prepared.
9 Preparation Structure 10b 116 10c 117
Preparation 11a
4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-thiazol-2-ylamine
[0473] 118
[0474] Step 1
[0475] A suspension of 2,3-dihydroxy-benzoic acid methyl ester (336
mg, 2 mmol) and cesium carbonate (1.56 g, 4.8 mmol) in DMF was
stirred at room temperature for 0.5 h. 1,2-Dibromoethane (0.224 ml,
2.6 mmol) was added to the DMF solution. The mixture was stirred at
80 C for 4 h, and then diluted with ethyl acetate. The organic
layer was washed with water and brine, dried over anhydrous MgSO4,
filtered and concentrated in vacuo to give the crude product. It
was chromatographed on silica gel with EtOAc/hexane (20%-40%) as
eluent to afford 2,3-dihydro-benzo[1,4]dioxine-- 5-carboxylic acid
methyl ester as a white solid. (223 mg, 1.14 mmol, 57.4%
yield).
[0476] Step 2
[0477] Reference: Tetrahedron Lett, 1997, 3173-78
[0478] To a mixture of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic
acid methyl ester (100 mg, 0.515 mmol) and chloroiodomethane (0.075
ml, 1.03 mmol) in 1 ml of THF was added a solution of LDA in THF
(2M, 0.57 ml, 1.13 mmol) dropwise at -78 C over 15 min. The
reaction mixture was stirred at -78 C for 10 min. A solution of
acetic acid (0.75 ml) in THF (5 ml) was added dropwise over 5 min
at -78 C. The resulting solution was stirred at the same
temperature for additional 10 min. and was then partitioned between
ethyl acetate and water. The organic layer was washed with aqueous
sodium bicarbonate, brine, dried over MgSO4 and concentrated in
vacuo to give the crude
2-chloro-1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)- -ethanone as a
light brown liquid.
[0479] Step 3
[0480] The crude product of step 2 was dissolved in EtOH (1.5 ml).
Thiourea (76 mg, 1 mmol) was added followed by addition of TEA
(0.14 ml, 1 mmol). The solution was heated at 80 C for 6 h. After
removal of ethanol, the reaction mixture was taken into ethyl
acetate and aqueous sodium bicarbonate. The organic layer was
washed with 0.5 N HCl. After separation, the aqueous layer was
adjusted to pH 9 with sodium carbonate, and extracted with ethyl
acetate. The ethyl acetate solution was washed with brine, dried
over MgSO4 and concentrated to give
4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-thiazol-2-ylamine 11a as a
brown solid, 37 mg (0.16 mmol, 31% yield). .sup.1H NMR (CDCl.sub.3)
.delta. 7.46 (dd, 1H), 7.04 (s, 1H), 6.75-6.83 (m, 2H), 5.33 (br s,
2H), 4.23-4.34 (m, 4H); LC/MS m/z 235 (M+H).sup.+.
Preparation 11b
4-Benzo[1,3]dioxol-4-yl-thiazol-2-ylamine
[0481] Preparation 11b was prepared in a similar manner to
preparation 11a.
10 Compound Structure 11b 119
Preparation 12a
[0482] 120
[0483] Step 1
[0484] To 1,3-dimethyl-4,6-dinitrobenzene (5.0 g, 25.489 mmol)
under nitrogen in 50.0 mL DMF was added 10.16 mL
N,N-dimethylformamide dimethyl acetal (76.468 mmol, 9.112 g, 3.0
eq). The mixture was stirred under nitrogen at 140.degree. C. for 5
h, allowed to cool to room temperature and the solvent was removed
under vacuum to afford a dark, black solid. To this solid was added
330 mL of 50% aqueous THF, followed by sodium periodate (32.7 g,
152.9 mmol, 6 eq). The solution turned red and produced a slight
exotherm. The mixture was allowed to stir at room temperature for 5
h. This mixture was then filtered through a scintered glass funnel
to remove excess solid material and rinsed with ethyl acetate until
colorless. (Total volume of eluent was 750 mL after rinsing). The
filtrate was washed with 100 mL saturated NaHCO.sub.3(aq). The
aqueous was extracted again with 200 mL ethyl acetate. The organic
layers were combined and dried over sodium sulfate. The solution
was concentrated under vacuum. The remaining crude oil was
chromatographed using silica gel eluted with 30% ethyl acetate in
hexanes to yield 2.77 g of the product of step 1 as a yellow solid
(48%).
[0485] Step 2
[0486] The product of step 1 (1.93 g, 8.62 mmol) and powdered iron
(3.85 g, 68.93 mmol, 8 eq) were placed into a flask containing 100
mL of a 2:2:1 mixture of ethanol/acetic acid/water, respectively.
The flask was placed into a 0.degree. C. ice bath and allowed to
equilibrate for 20 minutes. 8 drops of concentrated HCl were added.
The reaction began to change color (yellow to green to red/brown).
After 1 hour, the cooling bath was removed and allowed to warm to
room temperature. After stirring for an additional 1 hour at room
temperature, the mixture was filtered through a thin pad of celite.
The filtrate was concentrated under vacuum to afford a yellow/green
solid. This crude material was chromatographed using silica gel
eluted with 30% hexanes in ethyl acetate. Removal of the solvent
under vacuum yielded 1.165 g of the product of step 2 as a
yellow/orange solid (82%).
[0487] Step 3
[0488] To the product of step 2 (901 mg, 5.49 mmol) under nitrogen
in 30.0 mL ethanol was added 0.92 mL pyruvic acid (1.160 g, 13.173
mmol) followed by 13.0 mL of 2N aqueous sodium hydroxide. The
mixture was stirred at 80.degree. C. for 5 hours. 0.6 N Aqueous
ammonia (.about.100 mL) was added and the mixture was gently heated
to 74.degree. C. A 0.6N HCl/0.3N AcOH solution was added until pH
was .about.4 to precipitate the product. The mixture was filtered
to collect solid which was dried under vacuum to obtain 1.303 g of
the product of step 3 as a yellow solid (88%).
[0489] Step 4
[0490] The product of step 3 (99 mg, 0.369 mmol) and .about.3 mg
Cu.sub.2O (.about.0.018 mmol, 0.05 eq) were placed under nitrogen
in 3.0 mL di(ethylene glycol)methyl ether. The mixture was stirred
at 165.degree. C. for 6 h and .about.30 mL concentrated aqueous
ammonia was added. The mixture was extracted with 2.times.100 mL
methylene chloride and dried over sodium sulfate, concentrated
under vacuum and chromatographed using silica gel eluted with 1%
triethylamine, 7% methanol in chloroform. The eluent was removed
under vacuum to obtain 44 mg of the product of step 4 as a brown
crystalline solid (67%) M+H=181.28.
[0491] Step 5
[0492] The product of step 4 (21 mg, 0.117 mmol), 49 .mu.L methyl
acrylic acid (50 mg, 0.583 mmol, 5 eq), and .about.3 mg
hydroquinone were placed in a tube under nitrogen in 1.0 mL
xylenes. The tube was sealed with a teflon lined cap and heated at
140.degree. C. for 3 days. LC/MS shows reaction is complete. The
solvent was removed under vacuum and the crude material was
chromatographed using silica gel eluted with 1% triethylamine, 10%
methanol in chloroform to afford 21 mg of the title compound 12a as
a clear oil (68%). M+H=267.14.
Preparation 13
[0493] 121
[0494] Step 1 The product of preparation 12a, step 4 (128 mg, 0.710
mmol), ethyl methacrylate (442 .mu.L, 3.551 mmol, 5 eq), and
.about.20 mg hydroquinone into 5.0 mL xylenes were placed in a tube
under nitrogen. The tube was sealed with a teflon lined cap and
stirred at 140.degree. C. for 3 days. Solvent was removed under
vacuum and the crude material was directly purified on prep HPLC.
The retention times on the HPLC (both analytical and prep) for the
two isomeric products are very similar. 24 mgs of the pure minor
isomer and 28 mg of a mixture of both the major and minor isomers
was isolated.
[0495] Step 2
[0496] The minor product of step 1 (24 mg, 0.082 mmol) was placed
under nitrogen in 1.5 mL methanol. 0.3 mL of 1N NaOH were added and
the mixture stirred at 60.degree. C. for 2 hours. An additional 0.1
mL of saturated aqueous NaOH were added and the mixture stirred an
additional 5 h at 60.degree. C. The mixture was allowed to cool,
then 50 .mu.L TFA were added. The mixture was purified directly on
prep HPLC. Solvent was removed under vacuum to afford 21 mg of the
title compound 13 as a clear oil (.about.95%). M+H=267.
Preparation 14
[0497] 122
[0498] Step 1
[0499] Reference: B. Bacle and G. Levesque, Polymer Communications,
28, 36 (1987).
[0500] A 1 L flask was charged with anthracene (14 g, 0.078 mol,
1.0 equi.), hydroquinone (0.8 g, 0.008 mol, 0.1 equi.), methacrylic
acid (14 mL, 0.156 mol, 2.0 equi.) and xylene (500 mL). The
solution was heated to reflux for 1 day. The solution was cooled
and concentrated in vacuo. The residue was dissolved in ethyl
acetate and extracted with 1N NaOH (3.times.). The aqueous phase
was acidified with 1N HCl, and the product was extracted with ethyl
acetate (3.times.). The combined organic phases were concentrated
in vacuo to give the crude product mixture. Recrystallization with
hexane and ethyl acetate to yield 8 g (40%) of the product of step
1, 14: LC/MS (m/z 263 (M-H).sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 7.08-7.25 (m, 8H), 4.37 (s, 1H), 4.25(t, 1H), 2.61 (dd,
1H), 1.39 (dd, 1H), 1.07 (s, 3H).
[0501] Step 2
[0502] The product of step 1, 14 was resolved into its
corresponding enantiomers, 14(R) and 14(S) by chiral preparative
HPLC with the following conditions, Column: Chiracel.RTM.-OJ,
5.times.50 cm, Mobile phase: trifluroacetic acid/acetonitrile:
1/1000 (vol/vol), Temperature: ambient, Flowrate: 70 mL/min,
Injection: 1.5 grams in 50 mL solvent, Detection: UV (250 nm).
Retention times for R-enantiomer, 30 min, S-enantiomer, 52 min.
Analytical HPLC conditions, Column: Chiracel.RTM.-OJ, 4.6.times.250
cm, Mobile phase: trifluroacetic acid/acetonitrile: 1/1000
(vol/vol), Temperature: ambient, Flowrate: 1.5 mL/min, Detection:
UV (250 nm). Retention times: R-enantiomer, 6.5 min, S-enantiomer,
15 min.
Preparation 15
[0503] 123
[0504] Acrylic acid and anthracene were reacted as described in
preparation 14 to provide compound 15.
Preparation 16a
[0505] 124
[0506] To a solution of the product of step 1 preparation 14 (5.0
g, 18.9 mmol, 1.0 equi.) in dichloromethane (20 mL) was added an
oxalyl chloride solution in dichloromethane (2M, 11.4 mL, 22.8
mmol, 1.2 equi.) dropwise. The solution was stirred at RT for 2
hours, after which the solvent was removed in vacuo. The residue
was dissolved in acetonitrile (20 mL) and added dropwise to a
solution of ethylene glycol (1.27 mL, 22.8 mmol, 1.2 equi.) in
acetonitrile (20 mL). The reaction solution was stirred at RT for 4
hours and then the solution was concentrated in vacuo. Purification
by flash chromatography (10% ethyl acetate in hexane) yielded 2.0 g
(34%) of compound 16a: .sup.1H NMR (CDCl.sub.3) .delta. 7.52 (d,
1H), 7.09-7.27 (m, 8H), 4.40 (s, 1H), 4.31 (t, 1H), 4.11(m, 1H),
4.0 (m, 1H), 3.63 (m, 2H), 2.72 (dd, 1H), 1.42 (dd, 1H), 1.16(s,
3H).
[0507] In a similar manner the following compounds were prepared
from the corresponding acids and alcohols.
11 Chiral Preparation Number Compounds Structure 16b 125 16c 126
16d 127 16e Chiral (S) 128 16f Chiral (R) 129 16g Chiral (S) 130
16h Chiral (R) 131
Preparation 17
[0508] 132
[0509] Reference: P. V. Alston, R. M. Ottenbrite, J. Newby, J. Org.
Chem., 44, 4939 (1979).
[0510] 9-Anthracenecarboxylic acid (4 g, 0.017 mol, 1.0 equi.) was
added to a mixture of methacrylic acid (20 mL, 0.23 mol, 14.0
equi.), benzene (20 mL) and hydroquinone (0.2 g, 0.0017 mol, 0.1
equi.). The solution was heated to reflux for 7 days. The solution
was cooled and the precipitate formed was filtered and washed with
benzene. The precipitate was recrystallized with hexane and ethyl
acetate to yield 0.4 g (7.2%) of the ortho product 17a: MS (m/z
321(M-H).sup.+); .sup.1H NMR (CDCl.sub.3) .delta. 7.1-7.28 (m, 8H),
4.25 (t, 1H), 4.06 (s, 3H), 2.25 (dd, 1H), 1.69 (dd, 1H), 1.08 (s,
3H). The filtrate was extracted with 1N NaOH (3.times.). The
aqueous phase was acidified with 1N HCl, and the product was
extracted with ethyl acetate (3.times.). The organic phases were
concentrated in vacuo. Recrystallization of the residue with hexane
and ethyl acetate yielded 0.2 g (4%) of the meta product 17b MS
(m/z 321 (M-H).sup.+); .sup.1H NMR (CDCl.sub.3) .delta. 7.16-7.27
(m, 8H), 4.36 (s, 1H), 4.08 (s, 3H), 2.90 (d, 1H), 1.67 (d, 1H),
1.06 (s, 3H).
[0511] In a similar manner the following compounds were prepared
from methacrylic acid and the appropriate anthracene.
12 Preparation Number Structure 17C 133 17D 134 17E 135 17F 136 17G
137 17H 138 17I 139 17J 140
EXAMPLES
[0512] The following Examples represent preferred embodiments of
the invention.
Example 1
[0513] 141
[0514] To a solution of the product of Preparation 14, step 1 (20
mg, 0.075 mmol, 1.0 equi.) in acetonitrile (2 mL) was added
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (DEC)
(17 mg, 0.09 mmol, 1.2 equi.), 1-hydroxy-7-azabenzotriazole (HOAt)
(12 mg. 0.09 mmol, 1.2 equi.), triethyl amine (0.025 mL, 0.18 mmol,
2.5 equi.), and 2-amino-4,5-dimethylthiazole hydrochloride salt
(14.8 mg, 0.09 mmol, 1.2 equi.). The reaction solution was heated
to 80.degree. C. for 18 hours. The reaction was then concentrated
in vacuo. The product mixture was purified by flash chromatography
(20% ethyl acetate in hexane) to yield 19.8 mg (70%) of Example 1.
LC/MS (m/z 375, (M+H).sup.+).
Examples 2 to 339
[0515] In a similar manner Examples 2-339 were prepared from the
coupling of the appropriate acids and amines. Preparations of
amines or acids not commercially available are described in the
preceding preparations section of this document. All examples in
the tables are racemic unless specified otherwise. Examples in the
table where one enantiomer predominates or is the sole component,
are designated as either R or S.
13 Chiral MS: (M + H = Example Compounds Structure MW + 1) 2 142
513.6 3 143 409.5 4 144 414.5 5 145 475.5 6 146 364.5 7 147 482.6 8
148 443.6 9 149 382.5 10 150 524.6 11 151 422.5 12 152 410.5 13 153
395.5 14 154 446.6 15 155 426.5 16 156 393.5 17 157 499.6 18 158
482.6 19 159 400.4 20 160 379.5 21 161 461.5 22 162 350.4 23 163
429.5 24 164 367.5 25 165 368.4 26 166 408.5 27 167 396.5 28 168
381.5 29 169 403.5 30 170 412.5 31 171 418.4 32 172 409.5 33 173
484.4 34 174 395.46 35 175 359.5 36 176 396.5 37 177 426.5 38 178
354.5 39 179 374.9 40-41 180 354.5 42 181 354.5 43 182 475.6 44 183
393.5 45 184 372.4 46 185 390.5 47 186 393.5 48 187 395.5 49 188
380.9 50 189 415.5 51 190 425.5 52 191 402.5 53 192 374.4 54 193
400.5 55 194 368.5 56 195 393.5 57 196 357.5 58 197 59 198 369.5 60
199 369.5 61 200 383.5 62 201 399.5 63 202 399.5 64 203 422.4 65
204 422.4 66 205 413.5 67 206 409.5 68 207 329.4 69 208 360.5 70
209 432.5 71 210 397.5 72 211 370.5 73 212 446.6 74 213 368.5 75
214 383.5 76 215 354.5 77-78 216 354.5 79 217 390.5 80 218 357.5 81
219 390.5 82 220 446.6 83 221 373.5 84 222 383.5 85 223 343.4 86
224 360.5 87 225 437.6 88 226 390.5 89 227 374.4 90 228 369.5 91
229 422.4 92 230 383.5 93 231 383.5 94 232 427.5 95 233 399.5 96
234 399.5 97 235 396.5 98 236 413.5 99 237 413.5 100 238 399.5 101
239 379.47 102 240 329.41 103 241 461.5 104 242 422.6 105 243 457
106 244 402.6 107 245 481.5 108 246 458.5 109 247 432.5 110 248
436.6 111 249 485 112 250 472.6 113 251 481.6 114 252 410.5 115 253
424.6 116 254 431 117 255 426.5 118 256 410.5 119 257 341.4 120 258
414.5 121 259 396.5 122 260 450.6 123-124 261 341.4 125 262 385.4
126 263 354.5 127 264 431 128 265 486.52 129 266 441.51 130 267
402.56 131 Chiral (R) 268 472.61 132 Chiral (S) 269 472.61 133 270
344.4 134 271 345.4 135 272 354.5 136 273 357.5 137 274 358.4 138
275 381.4 139 276 385.4 140 277 386.5 141 278 395.5 142 279 401.5
143 280 403.5 144 281 403.5 145 282 405.5 146 283 405.5 147 284
409.5 148 285 469.6 149 286 472.6 150 287 497.5 151 288 422.55 152
289 458.59 153 290 472.61 154 291 466.59 155 292 490.6 156 293
456.55 157 294 478.64 158 295 386.5 159 296 389.5 160 297 389.5 161
298 417.6 162 299 403.5 163 300 417.6 164 301 432.57 165 302 417.6
166 303 417.6 167 304 391.5 168 305 423.5 169 306 431.6 170 307
390.5 171 308 397.5 172 309 486.64 173 310 455.56 174 311 466.59
175 312 452.58 176 313 502.64 177 314 462.57 178 315 502.64 179 316
440.5 180 317 440.5 181 318 467.6 182 319 436.6 183 320 455.6 184
321 440.5 185 322 457 186 323 457 187 324 467.6 188 Chiral (R) 325
486.64 189 Chiral (S) 326 486.64 190 327 467.58 191 328 526.7 192
329 498.7 193 330 510.7 194 331 490.6 195 332 541.7 196 333 436.6
197 334 466.6 198 335 541.7 199 336 454.6 200 337 476.6 201 338
534.7 202 339 459.6 203 340 462.6 204 341 469.59 205 342 405.5 206
343 502.64 207 Chiral (R) 344 490.6 208 Chiral (S) 345 490.6 209
346 464.63 210 347 385.51 211 348 493.68 212 349 551.51 213 Chiral
(S) 350 502.64 214 Chiral (R) 351 502.64 215 352 473.55 216 Chiral
(S) 353 455.56 217 Chiral (R) 354 455.56 218 Chiral (S) 355 469.59
219 Chiral (R) 356 469.59 220 357 423.54 221 358 548.45 222 359
423.54 223 360 548.45 224 361 423.54 225 362 598.51 226 363 485.59
227 Chiral (S) 364 485.59 228 Chiral (R) 365 485.59 229 Chiral (S)
366 473.55 230 Chiral (R) 367 473.55 231 368 522.67 232 Chiral (S)
369 522.67 233 Chiral (R) 370 551.51 234 Chiral (S) 371 551.51 235
Chiral (S) 372 598.51 236 Chiral (R) 373 598.51 237 374 473.6 238
375 473.6 239 Chiral (S) 376 417.56 240 377 500.62 241 378 530.65
242 379 522.67 243 Chiral (S) 380 522.67 244 381 530.65 245 382
517.61 246 383 517.61 247 384 497.62 248 385 500.62 249 386 544.68
250 387 511.65 251 388 531.64 252 389 531.64 253 390 514.65 254 391
492.58 255 392 480.59 256 393 478.64 257 394 466.56 258 395 348.43
259 396 492.58 260 397 511.65 261 398 497.62 262 399 535.6 263 400
515.61 264 Chiral (S) 401 396.5 265 Chiral (S) 402 426.5 266 Chiral
(S) 403 354.5 267 Chiral (S) 404 374.5 268 Chiral (S) 405 380.9 269
Chiral (S) 406 329.4 270 Chiral (S) 407 343.4 271 Chiral (S) 408
360.5 272 Chiral (S) 409 329.4 273 Chiral (S) 410 422.6 274 Chiral
(S) 411 457 275 Chiral (S) 412 458.5 276 Chiral (S) 413 432.5 277
Chiral (S) 414 436.6 278 Chiral (S) 415 410.5 279 Chiral (S) 416
424.6 280 Chiral (S) 417 431 281 Chiral (S) 418 426.5 282 Chiral
(S) 419 410.5 283 Chiral (S) 420 414.5 284 Chiral (S) 421 396.5 285
Chiral (S) 422 431 286 Chiral (S) 423 441.5 287 Chiral (S) 424
472.6 288 Chiral (S) 425 417.6 289 Chiral (S) 426 440.5 290 Chiral
(S) 427 436.6 291 Chiral (S) 428 440.5 292 Chiral (S) 429 457 293
Chiral (S) 430 467.6 294 Chiral (S) 431 454.6 295 Chiral (S) 432
476.6 296 Chiral (S) 433 459.6 297 Chiral (S) 434 427.5 298 Chiral
(S) 435 423.5 299-300 Chiral (S) 436 462.6 301 Chiral (S) 437 359.5
302 Chiral (S) 438 422.4 303 Chiral (R) 439 396.5 304 Chiral (R)
440 426.5 305 Chiral (R) 441 354.5 306 Chiral (R) 442 374.5 307
Chiral (R) 443 380.9 308 Chiral (R) 444 329.4 309 Chiral (R) 445
343.4 310 Chiral (R) 446 360.5 311 Chiral (R) 447 329.4 312 Chiral
(R) 448 422.6 313 Chiral (R) 449 457 314 Chiral (R) 450 458.5 315
Chiral (R) 451 432.5 316 Chiral (R) 452 436.6 317 Chiral (R) 453
410.5 318 Chiral (R) 454 424.6 319 Chiral (R) 455 431 320 Chiral
(R) 456 426.5 321 Chiral (R) 457 410.5 322 Chiral (R) 458 414.5 323
Chiral (R) 459 396.5 324 Chiral (R) 460 431 325 Chiral (R) 461
441.5 326 Chiral (R) 462 472.6 327 Chiral (R) 463 417.6 328 Chiral
(R) 464 440.5 329 Chiral (R) 465 436.6 330 Chiral (R) 466 440.5 331
Chiral (R) 467 457 332 Chiral (R) 468 467.6 333 Chiral (R) 469
454.6 334 Chiral (R) 470 476.6 335 Chiral (R) 471 459.6 336 Chiral
(R) 472 427.5 337 Chiral (R) 473 423.5 338 Chiral (R) 474 359.5 339
Chiral (R) 475 422.4
Example 340
[0516] 476
[0517] Step 1
[0518] To a solution of the product of preparation 14 (100 mg, 0.38
mmol, 1.0 equi.) in acetonitrile (5 mL) was added
1-[3-(dimethylamino)propyl]-3- -ethylcarbodiimide hydrochloride
(DEC) (87 mg, 0.45 mmol, 1.2 equi.), 1-hydroxy-7-azabenzotriazole
(HOAt) (62 mg. 0.45 mmol, 1.2 equi.), triethyl amine (0.13 mL, 0.94
mmol, 2.5 equi.), and 2-aminothiazole (45.5 mg, 0.45 mmol, 1.2
equi.). The reaction solution was heated to 80.degree. C. for 18
hours. The reaction was then concentrated in vacuo. The product
mixture was purified by flash chromatography (20% ethyl acetate in
hexane) to yield 112.4 mg (86%) of the product of step 1: LC/MS
(m/z 347, (M+H).sup.+); .sup.1H NMR (CDCl.sub.3) .delta. 7.52 (d,
1H), 6.98-7.27 (m, 9H), 4.42 (s, 1H), 4.32 (t, 1H), 2.69 (dd, 1H),
1.52 (dd, 1H), 1.16(s, 3H).
[0519] Step 2
[0520] To a solution of the product of step 1 (175 mg, 0.5 mmol,
1.0 equi.) in THF (5 mL) was added sodium hydride (18 mg, 0.75
mmol, 1.5 equi.) and the solution stirred at RT for 1 hour. A
solution of methyl iodide (0.047 mL, 0.75 mmol, 1.5 equi.) in THF
(1 mL) was added and the reaction solution was stirred at RT for 3
hours. The solution was quenched with ethyl acetate. The organic
layer was washed with water, saturated sodium chloride, dried with
magnesium sulfate and concentrated in vacuo. Purification of the
crude product mixture by flash chromatography (10% ethyl acetate in
hexane) yielded 141.7 mg (78%) of Example 340: LC/MS (m/z 361
(M+H).sup.+); .sup.1H NMR (CDCl3) .delta. 6.41-7.12 (m, 8H), 4.67
(s, 1H), 4.3 (t, 1H), 3.63 (s, 3H), 3.0 (dd, 1H), 1.49 (dd, 1H),
1.07 (s, 3H).
Examples 341 to 343
[0521] In a similar manner the following compounds were
prepared.
14 MS: (M + H = Example Structure MW + 1) 341 477 436.58 342 478
486.64 343 479 562.74
Examples 344 to 346
[0522] 480
[0523] Step 1
[0524] To a solution of the product of Preparation 14, (4.72 mmol,
1.25 g) in acetonitrile (20 .mu.L) was added
1-[3-(dimethylamino)propyl-3-ethylca- rbodiimide hydrochloride
(EDCI), (5.66 mmol, 1.09 g), 1-hydroxy-7-azabenzotriazole (HOAt),
(5.66 mmol, 0.77 g), triethylamine (11.8 mmol, 1.20 g) and the
product of preparation 11 (5.66 mmol, 1.41 g). The resulting
mixture was heated to 80.degree. C. for 20 h, cooled and
concentrated in vacuo. The residue was chromatographed on silica
gel (eluted with 15% ethyl acetate in hexane) to give 1.80 g (Y:
77%) of Example 344. MS (E+) m/z: 494 (MH.sup.+).
[0525] Step 2
[0526] To a solution of Example 344 (3.44 mmol, 1.70 g) in EtOH (30
mL) was added 10 N NaOH (2.0 mL). The resulting mixture was heated
to 75.degree. C. for 2.5 h, cooled and diluted with an excess of 1
N HCl. The mixture was then extracted with dichloromethane
(3.times.100 mL), dried over Na.sub.2SO.sub.4 and concentrated
under vacuo to give 1.40 g (Y: 88%) of Example 345. MS (E+) m/z:
467 (MH.sup.+).
[0527] Step 3
[0528] To a solution of Example 345 (0.038 mmol, 18.0 mg) in
tetrahydrofuran (1.0 mL) was added
1-[3-(dimethylamino)propyl-3-ethylcarb- odiimide hydrochloride
(EDCI), (0.046 mmol, 8.9 mg), 1-hydroxy-7-azabenzotriazole (HOAt),
(0.046 mmol, 6.3 mg), triethylamine (0.046 mmol, 5.6 mg) and
aniline (0.046 mmol, 4.3 mg). After 20 h at room temperature the
product was purified using solid phase extraction cartridges (500
mg 1/1 high load, SCX strong cation exchanger/SAX strong anion
exchanger) from United Chemical Technologies, Inc. After
conditioning the cartridge with MeOH (2.times.1.5 mL) the crude
reaction mixture was loaded on to the cartridge. The cartridge was
then washed with MeOH (2.times.1.5 mL) to afford two fractions of
the title compound. These fractions were combined &
concentrated and then purified a second time using solid phase
extraction cartridges (500 mg SAX strong anion exchanger) to remove
any HOAt that was still present. After conditioning the cartridge
with MeOH (2.times.1.5 mL) the crude product was loaded on to the
cartridge. The cartridge was then washed with MeOH (1.times.1.5 mL)
and the eluent was collected. The resultant eluent was evaporated
in vacuo to afford 7.70 mg (37%) of Example 346. MS (E+) m/z: 542
(MH.sup.+).
Examples 347 to 563
[0529] In a similar manner the Examples 347-563 were prepared.
15 Chiral MS: (M + H = Example Compounds Structure MW + 1) 347 481
555.7 348 482 555.7 349 483 569.73 350 484 493.6 351 485 547.7 352
486 561.8 353 487 571.7 354 488 571.7 355 489 571.7 356 490 590.2
357 491 585.7 358 492 585.7 359 493 590.2 360 494 585.7 361 495
523.7 362 496 569.7 363 497 604.2 364 498 599.8 365 499 599.8 366
500 604.2 367 501 599.8 368 502 590.2 369 503 604.2 370 504 617.8
371 505 583.8 372 506 523.7 373 507 519.7 374 508 535.7 375 509
535.7 376 510 581.7 377 511 555.7 378 512 576.7 379 513 599.8 380
514 626.8 381 515 583.8 382 516 638.6 383 517 629.8 384 518 559.7
385 519 652.6 386 520 551.7 387 521 613.8 388 522 597.8 389 523
597.8 390 524 627.8 391 525 601.7 392 526 533.7 393 527 575.8 394
528 561.8 395 529 561.8 396 530 545.7 397 531 591.7 398 532 549.7
399 533 561.7 400 534 570.7 401 535 542.7 402 536 542.7 403 537
556.7 404 538 536.7 405 539 570.7 406 540 610.8 407 541 548.7 408
542 624.8 409 543 550.7 410 544 570.7 411 545 584.7 412 546 562.7
413 547 559.7 414 548 493.6 415 549 547.7 416 550 561.8 417 551
541.7 418 552 571.7 419 553 571.7 420 554 571.7 421 555 590.2 422
556 585.7 423 557 585.7 424 558 590.2 425 559 585.7 426 560 523.7
427 561 569.7 428 562 604.2 429 563 599.8 430 564 599.8 431 565
604.2 432 566 599.8 433 567 590.2 434 568 604.2 435 569 617.8 436
570 583.8 437 571 523.7 438 572 535.7 439 573 581.7 440 574 555.7
441 575 576.7 442 576 608.8 443 577 599.8 444 578 569.7 445 579
561.7 446 580 583.8 447 581 638.6 448 582 629.8 449 583 559.7 450
584 652.6 451 585 652.6 452 586 551.7 453 587 601.7 454 588 597.8
455 589 597.8 456 590 627.8 457 591 601.7 458 592 533.7 459 593
575.8 460 594 561.8 461 595 561.8 462 596 545.7 463 597 549.7 464
598 626.8 465 599 570.7 466 600 542.7 467 601 556.7 468 602 556.7
469 603 536.7 470 604 570.7 471 605 610.8 472 606 548.7 473 607
624.8 474 608 550.7 475 609 562.7 476 610 559.7 477 611 481.58 478
612 467.55 479 613 572.69 480 614 572.69 481 615 602.72 482 616
606.1 483 617 587.7 484 618 589.7 485 619 631.8 486 620 601.7 487
621 601.7 488 622 585.7 489 623 541.68 490 624 571.7 491 625 571.7
492 626 601.73 493 Chiral (S) 627 571.7 494 Chiral (S) 628 606.1
495 Chiral (S) 629 587.7 496 Chiral (S) 630 589.7 497 Chiral (S)
631 631.8 498 Chiral (S) 632 601.7 499 Chiral (S) 633 601.7 500
Chiral (S) 634 585.7 501 635 576.1 502 636 591.7 503 637 576.1 504
638 576.1 505 639 610.6 506 640 610.6 507 641 617.8 508 642 610.6
509 643 610.6 510 644 581.7 511 645 548.7 512 646 677.7 513 647
549.7 514 648 542.7 515 649 582.7 516 650 617.7 517 651 563.7 518
652 562.7 519 653 617.1 520 654 598.8 521 655 577.7 522 656 587.8
523 657 585.7 524 658 573.7 525 659 585.7 526 660 587.8 527 661
609.7 528 662 555.7 529 663 569.7 530 664 587.8 531 665 562.7 532
666 565.7 533 667 606.1 534 668 545.7 535 669 572.7 536 Chiral (S)
670 466.56 537 Chiral (S) 671 480.59 538 Chiral (S) 672 572.7 539
Chiral (S) 673 587.8 540 Chiral (S) 674 585.7 541 Chiral (S) 675
573.7 542 Chiral (S) 676 585.7 543 Chiral (S) 677 582.7 544 Chiral
(S) 678 576.1 545 Chiral (S) 679 571.7 546 Chiral (S) 680 533.7 547
Chiral (S) 681 542.7 548 Chiral (S) 682 582.7 549 Chiral (S) 683
562.72 550 Chiral (R) 684 606.15 551 Chiral (R) 685 566.7 552
Chiral (R) 686 572.7 553 Chiral (R) 687 562.7 554 Chiral (R) 688
587.8 555 Chiral (R) 689 585.7 556 Chiral (R) 690 573.7 557 Chiral
(R) 691 585.7 558 Chiral (R) 692 582.7 559 Chiral (R) 693 576.1 560
Chiral (R) 694 571.7 561 Chiral (R) 695 533.7 562 Chiral (R) 696
542.7 563 Chiral (R) 697 582.7
Example 564
[0530] 698
[0531] Step 1 From the frozen vegetative stock culture of
Streptomyces griseus ATCC 10137, 2 ml was used to inoculate 100 ml
of F7 medium contained the following per liter of deionized water:
dextrose, 10 g; yeast extract, 10 g; malt extract, 10 g; peptone, 1
g, in a 500 ml flask (pH was adjusted to 7 before sterilization at
120.degree. C. for 30 minutes). The culture was incubated for 3
days at 28.degree. C. on a rotary shaker operating at 250 rpm. Two
ml of this culture was used to inoculate each of twelve 500-ml
flasks containing 100 ml of F7 medium. The flasks were incubated at
28.degree. C. on a rotary shaker operating at 250 rpm for 17 hours.
Eight mg of Preparation 16g S-isomer (97.9% ee) in 0.32 ml DMF was
added to each flask. The flasks were then returned to the shaker
and incubated for additional 9.5 hours at 28.degree. C. and 250
rpm. The culture was pooled and subjected to sonication for total
of 5 min. with a High Intensity Ultrasonic Processor (Model:
VCX600, Sonics & Material Inc.) equipped with a microtip, at
40% out put. The resulting mixture was extracted with 600 ml ethyl
acetate and the ethyl acetate extract was evaporated to dryness.
The residue was dissolved in 2 ml of acetoniltrile and subjected to
preparative HPLC with a YMC ODS-A column (30 mm ID.times.100 mm
length, 5 .mu.l particle size). Elution flow rate was 30 ml/min. In
each run, sample (0.5 to 1 ml) was loaded onto the column at water
(solvent A)-acetonitrile (solvent B) 90/10 v/v and separated using
the following gradient program: 10% B, 3 min; 10% to 35% B linear
gradient, 1 min; 35% B, 9 min; 35% to 60% B linear gradient, 1 min;
60% B, 4 min; 60% to 90% B linear gradient, 1 min; 90% B, 4 min.
Detection (UV) was at 210 nm. The fractions containing BMS-585157
was eluted between 18 to 19 minutes. The BMS-585157 fractions were
pooled and evaporated in vacuo to a small volume, then was
lyophilized. A total of 60 mg of BMS-585751 was obtained as light
yellow solid (yield, 62.5%). The reaction and purification were
monitored by analytical HPLC with a Hewlett Packard 1100 Series
Liquid Chromatograph using an YMC Packed ODS-AQ column, 4.6 mm
i.d..times.15 cm 1. A gradient system of 1 mM HCl in water (solvent
A) and acetonitrile (solvent B) was used: 70% to 90% B linear
gradient, 5 min; 90% B, 1.5 min; 90% to 70% linear gradient, 0.5
min. The flow rate was 1.2 ml/min and UV detection was at 210 nm.
Retention time for starting compound and product was 5.16 and 2.76
min, respectively. .sup.1H-NMR Observed Chemical Shifts (relative
to CD.sub.3CN signal .delta. 1.94): .delta. 7.33 (3H, m), 7.21 (1H,
m), 7.15 (2H, m), 7.09 (2H, m), 4.61 (1H, dd, J.sub.1=5.8 Hz,
J.sub.2=3.2 Hz, CH-3), 4.40 (1H, s, CH-11), 4.32 (1H, d, J=3.5 Hz,
CH-4), 3.51 (3H, s, CH.sub.3-19), 2.90 (1H, d, J=6.0 Hz, OH), 0.93
(1H, s, CH.sub.3-18). .sup.1H-.sup.1H NOE Observed NOE: CH-4 and OH
(when CH-3 was irradiated); CH-11 and OH (when CH.sub.3-18 was
irradiated). MS: +c APCI (m/z): 312 ([M+H.sub.2O]+), 294, 277.
[0532] Step 2
[0533] To a solution of the product of step 1 (0.079 mmol, 23 mg)
in MeOH (2 mL) was added sodium hydroxide (400 .mu.L of 1 N NaOH,
0.4 mmol). After 4 hours at 75.degree. C. and 16 hours at RT the
reaction mixture was quenched with 1N HCl (3 mL) and extracted with
dichloromethane (3.times.30 mL). The organic phases were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to give 19.6 g (Y: 89%)
of the product of step 2.
[0534] Step 3
[0535] To a solution of the product of step 2 (0.070 mmol, 19.6 mg)
in acetonitrile (1.0 mL) was added
1-[3-(dimethylamino)propyl-3-ethylcarbodi- imide hydrochloride
(EDCI), (0.084 mmol, 16 mg), 1-hydroxy-7-azabenzotriaz- ole (HOAt),
(0.084 mmol, 11.5 mg), triethylamine (0.175 mmol, 17.7 mg) and
Preparation 1a (0.086 mmol, 21 mg). The resulting mixture was
heated to 80.degree. C. for 20 h, cooled and diluted with MeOH (1.0
mL). The diluted reaction mixture was then purified by preparative
HPLC to afford the TFA salt of the title compound. The product was
then neutralized using a solid phase extraction cartridge (500 mg
high load, SCX strong cation exchanger from United Chemical
Technologies, Inc). After conditioning the cartridge with MeOH
(2.times.1.5 mL) the product was loaded on to the cartridge. The
cartridge was then washed with MeOH (2.times.1.5 mL), followed by a
2N NH.sub.3 in MeOH solution to afford 18.8 mg (55%) of Example
564. MS (E+) m/z: 507 (MH.sup.+).
Example 565
[0536] 699
[0537] To a solution of Example 178 (20.0 mg, 0.04 mmol, 1.0 equi.)
in dichloromethane (5 mL) at 0.degree. C., was added a solution of
boron tribromide in dichloromethane (1M, 0.20 mL, 0.20 mmol, 5
equi.). The reaction solution was stirred at 0.degree. C. for 3
hours, and let warmed up to room temperature and let stirred at
room temperature overnight. The next day, the reaction solution was
quenched with methanol in an ice bath. The crude product mixture
was purified by reversed phased PREP HPLC, followed by
neutralization with cation exchange SPE, to yield 5.4 mg (28%
yield) of Example 565: LC/MS (m/z 489, (M+H).sup.+).
Examples 566 to 567
[0538] Examples 566 to 567 in the table below were prepared in a
similar manner from the corresponding methyl ethers.
16 MS: (M + H = Example Structure MW + 1) 566 700 488.61 567 701
488.61
Examples 568 to 569
[0539] 702
[0540] Step 1
[0541] To a solution of the product of preparation 16d (2.45 mmol,
650 mg) in THF (10.0 mL) at -78.degree. C. was added lithium
diisopropylamide (2.94 mmol, 1.47 ml of a 2 M solution in
heptane/THF/ethyl benzene) dropwise. After 1 hour,
bromoacetonitrile (3.68 mmol, 440 mg) in THF (0.70 mL) was added
dropwise. The mixture was allowed to warm to RT. After 16 hours the
reaction mixture was quenched with 1N HCl (30 mL) and extracted
with dichloromethane (3.times.30 mL). The organic phases were
concentrated in vacuo and the residue chromatographed on silica gel
(eluted with 20% ethyl acetate in hexane) to give 510 mg (Y: 69%)
of the product of step 1.
[0542] Step 2
[0543] To a solution of the product of step 1 (1.68 mmol, 510 mg)
in THF (3.4 mL) was added lithium hydroxide (1.7 mL of 5N LiOH).
After 20 hours at 70.degree. C. the reaction mixture was quenched
with 1N HCl (30 mL) and extracted with dichloromethane (3.times.30
mL). The organic phases were dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to give 410 mg (Y: 84%) the product of step
2.
[0544] Step 3
[0545] To a solution of the product of step 2 (0.45 mmol, 130 mg)
in dichloromethane (2.0 mL) was added oxalyl chloride (0.54 mmol,
0.28 mL of a 2 N solution in dichloromethane) and DMF (2 drops).
After 1 hour at RT the reaction mixture is concentrated in vacuo
and then redissolved in dichloromethane (1.0 mL). To the resulting
mixture is then added triethylamine (0.54 mmol, 0.075 mL) and
methylamine (0.90 mmol, 0.45 mL of a 2 M solution in THF). After 2
hours the reaction mixture was quenched with saturated sodium
bicarbonate solution, extracted by dichloromethane (3.times.30 mL),
dried over Na.sub.2SO.sub.4 and concentrated under vacuo to give 53
mg (Y: 39%) of Example 568.
[0546] Step 4
[0547] To a solution of the product of step 3 (0.132 mmol, 40 mg)
in methanolic ammonia (7.0 mL) was added 5% rhodium on alumina (100
mg). The reaction mixture was then allowed to hydrogenate at 55 psi
of H.sub.2 in a Parr apparatus. After 20 hours the reaction mixture
was filtered through celite and concentrated in vacuo to give 40 mg
(Y: 99%) of Example 569.
Examples 570 to 572
[0548] In a similar manner the Examples 570 to 572 were
prepared.
17 Exam- MS: (M + H = ple Structure MW + 1) 570 703 291.4 571 704
360.48 572 705 486.64
Example 573
[0549] 706
[0550] Step 1
[0551] To a solution of the product of preparation 16d (3.90 mmol,
1.03 g) in THF (8.0 mL) and TMEDA (1.0 mL) at -78.degree. C. was
added lithium diisopropylamide (4.69 mmol, 2.35 ml of a 2 M
solution in heptane/THF/ethyl benzene) dropwise. After 1 hour the
reaction mixture was saturated with ethylene oxide gas. The
reaction mixture was then warmed to RT over 3 hours, quenched with
1N HCl (30 mL) and extracted with dichloromethane (3.times.30 mL).
The organic phases were concentrated in vacuo and the residue
chromatographed on silica gel (eluted with 10% ethyl acetate in
hexane) to give 220 mg (Y: 22%) of the product of step 1.
[0552] Step 2
[0553] To a solution of the product of step 1 (0.471 mmol, 130 mg)
in dichloromethane (8.0 mL) under nitrogen at 0.degree. C. was
added trimethylaluminum (3.77 mmol, 1.88 ml of a 2 M solution in
toluene). The reaction mixture was allowed to stir at 0.degree. C.
for 20 min and then at RT for 1 h. 2-Aminothiazole (3.77 mmol, 377
mg) in dichloromethane (5.0 mL) was then added. After 16 hours at
reflux the reaction mixture is quenched with 1N HCl (30 mL) and
extracted with dichloromethane (3.times.30 mL). The organic phases
were concentrated in vacuo and the residue chromatographed on
silica gel (eluted with 5% methanol in dichloromethane) to give 91
mg (Y: 51%) of Example 573. (E+) m/z: 376 (MH.sup.+).
Examples 574 to 575
[0554] 707
[0555] Step 1
[0556] To a solution of Example 241 (80 mg, 0.15 mmol) in methanol
(5 mL) was added a sodium hydroxide solution (1.0 mL) (solution is
1:1 of 50% NaOH and water). The reaction solution was heated to
60.degree. C. for 5 hours. The solution was cooled and quenched
with HCl (6N). The product was extracted with ethyl acetate
(3.times.). The combined organic extracts were dried with anhydrous
magnesium sulfate and concentrated in vacuo to give 68 mg (87%
yield) of Example 574. LC/MS (m/z 517, (M+H).sup.+).
[0557] Step 2
[0558] To a solution of the product of step 1 (20 mg, 0.038 mmol,
1.0 equi.) in acetonitrile (2 mL) was added
1-[3-(dimethylamino)propyl]-3-eth- ylcarbodiimide hydrochloride
(DEC) (8.9 mg, 0.046 mmol, 1.2 equi.), 1-hydroxy-7-azabenzotriazole
(HOAt) (6.3 mg. 0.046 mmol, 1.2 equi.), triethylamine (0.013 mL,
0.097 mmol, 2.5 equi.), and ethylamine (2.1 mg, 0.046 mmol, 1.2
equi.). The reaction solution was heated to 80.degree. C. for 18
hours and followed by concentrated in vacuo. The product mixture
was purified by reversed phased PREP HPLC, followed by
neutralization with cation exchange SPE, to yield 3.1 mg (14%) of
Example 575: LC/MS (m/z 544, (M+H).sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 8.22 (m, 1H), 7.89(m, 2H), 7.60 (d, 1H), 7.14-7.53 (m,
11H), 7.03 (s, 1H), 4.46 (s, 1H), 3.69 (q, 2H), 2.85 (d, 1H), 1.83
(d, 1H), 1.36 (t, 3H), 1.12 (s, 3H).
Examples 576 to 578
[0559] In a similar manner the Examples 576 to 578 were
prepared.
18 Exam- MS: (M + H = ple Structure MW + 1) 576 708 581.7 577 709
598.77 578 710 585.73
Example 579
[0560] 711
[0561] To a mixture of Example 240 (28 mg, 0.056 mmol, 1.0 equi.)
and ethylamine (3.0 mg, 0.067 mmol, 1.2 equi.) in methanol (2 mL,
1.0% acetic acid) was added sodium cyanoborohydride (3.5 mg, 0.056
mmol, 1.2 equi.). The solution was stirred at room temperature for
18 hours. The crude product mixture was purified by reversed phase
PREP HPLC, followed by neutralization with cation exchange SPE, to
yield 3.8 mg (13%) of Example 579: LC/MS (m/z 530, (M+H).sup.+);
.sup.1H NMR (CDCl.sub.3) .delta. 8.25 (m, 1H), 7.87 (m, 2H), 7.62
(d, 1H), 7.51 (m, 3H), 7.06-7.52 (m, 7H), 7.06 (s, 1H), 4.40 (s,
1H), 3.7 (s, 2H), 2.99 (q, 2H), 2.60 (d, 1H), 1.58 (d, 1H), 1.28
(t, 3H), 1.19 (s, 3H).
Example 580
[0562] In a similar manner the Example 580 was prepared.
19 Exam- MS: (M + H = ple Structure MW + 1) 580 712 571.75
Example 581
[0563] 713
[0564] Example 252 (25 mg, 0.05 mmol) was dissolved in a solution
of ethanol (5 mL) and hydrochloric acid (concentrated, 0.25 mL) at
room temperature. Zinc dust (20 mg) was added in and the reaction
solution was stirred at room temperature for 24 hours. The reaction
was quenched with sodium bicarbonate solution (10%) and ethyl
acetate. The organic phase was washed with 1N sodium hydroxide
solution, dried and concentrated in vacuo to give the crude product
mixture. The product was purified by PREP HPLC, followed by cation
exchange SPE to give 4.1 mg (16% yield) of Example 581: MS (m/z 502
(M+H).sup.+).
Example 582
[0565] 714
[0566] To a solution of Example 112 (33 mg, 0.070 mmol) in 1.50 mL
anhydrous diethyl ether at room temperature was added 0.18 mL of a
1.0M solution of lithium aluminum hydride in THF (0.180 mmol, 2.6
eq). After stirring at room temperature for 3 h an additional 0.18
mL lithium aluminum hydride solution (0.180 mmol, 2.6 eq) was added
to push the reaction further. The mixture was allowed to stir for
48 h at rt, and quenched by adding 0.15 mL methanol dropwise, then
0.15 mL water, then 20 mL saturated aqueous KOH. Extracted
2.times.30 mL ethyl acetate. Dried over sodium sulfate.
Concentrated under vacuum. Purified the crude material using prep
HPLC. Free-based the product by passing through a basic SCX
cartridge using methanol as the eluent. Removal of the solvent
afforded 2.5 mg of Example 582 as a solid white film (8%) LC/MS
(m/z 459, (M+H).sup.+).
Example 583
[0567] 715
Step 1: 7-methoxy-2-methyl-quinolinyl-4-boronic Acid
[0568] To a solution of 4-bromo-7-methoxy-2-methyl-quinoline (700
mg, 2.8 mmol), prepared according to a known procedure (Reference:
Abe, Y. et. al. J. Med. Chem. 1998, 41, 4062-4097), in THF (15 mL)
at -78.degree. C. were added triisopropyl borate (1.3 mL, 5.6 mmol)
and t-butyllithium (1.7 M, 5.0 mL). The solution was then slowly
warmed to room temperature and kept stirring overnight. Next
morning, the solution was quenched with 1N HCl (1.5 mL) and the
solid was thus obtained after decanting THF. The solid was
dissolved in MeOH and diluted with CH.sub.2Cl.sub.2. The solution
was filtered and the filtrate was concentrated to provide
7-methoxy-2-methyl-quinolinyl-4-boronic acid (560 mg, 90%). MS
(ESI) (M+1)=218.26.
Step 2:
4-(5-bromo-2-nitro-1H-imidazol-4-yl)-7-methoxy-2-methyl-quinoline
[0569] To a solution of the boronic acid from Step 1 (560 mg, 2.6
mmol) and 4,5-dibromo-2-nitro-1H-imidazole (380 mg, 1.4 mmol),
prepared according to a known procedure (Reference: Palmer, B. D.
et. al. J. Chem. Soc. Perkin Trans I, 1989, 95-99), in 50 mL of THF
was added 20 mL of sat. K.sub.2CO.sub.3. To this solution was
bubbled a flow of N.sub.2 for 30 minutes and then 200 mg of
tetrakis(triphenylphosphine)palladium(0) (0.17 mmol) was added. The
solution was heated at 80.degree. C. overnight. After cooling down,
the solution was diluted with EtOAc and the organic layer was
separated and washed with brine. The organic layer was dried over
MgSO.sub.4. After filtration and concentration, the residue was
purified by flash column chromatography to provide the desired
4-(5-bromo-2-nitro-1H-imidazol-4-yl)-7-methoxy-2-methyl-quinoline
(114 mg, 15%). MS (ESI) (M+1)=363.29, 365.29.
Step 3:
4-(7-methoxy-2-methyl-quinolin-4-yl)-1H-imidazole-2-ylamine
[0570] To a solution of the product of Step 2 (114 mg, 0.31 mmol)
in 15 mL of MeOH was added 100 mg of 10% Pd/C and the solution was
purged with H.sub.2. The solution was then stirred under H.sub.2
atmosphere overnight. After filtration and concentration, the
desired 4-(7-methoxy-2-methyl-quinolin-4-yl)-1H-imidazole-2-ylamine
(90 mg, 87%) was obtained as a HBr salt. MS (ESI) (M+1)=255.33.
[0571] Step 4 716
[0572] Following a similar procedure as described in Example 1, the
coupling reaction of the product of Step 3 (32 mg, 0.095 mmol), and
the acid of Preparation 17E (39 mg, 0.12 mmol) provided compound of
Example 583 (26 mg, 50%). MS (ESI) (M+1)=546.33.
Examples 584 to 586
[0573] In a similar manner to the procedure of Example 583,
Examples 584 to 586 were prepared from acid of Preparation 17E and
the appropriate 4-(quinolin-4-yl)-1H-imidazole-2-ylamine or
4-isoquinolin-5-yl-1H-imidazo- l-2-ylamine. The amines were
prepared according to the procedures described in Steps 1 to 3 of
Example 583, i.e. via the Pd-catalyzed coupling reaction of
4,5-dibromo-2-nitro-1H-imidazole and the boronic acid derived from
corresponding bromo-quinoline or bromo-isoquinoline, followed by
the hydrogenation reaction.
20 Example Structure 584 717 585 718 586 719
Example 587
[0574] 720
[0575] A suspension Example 212 (50 mg, 0.091 mmol) and cuprious
cyanide (10 mg, 0.11 mmol) in DMF (2 mL) was introduced into a
dried heavy wall Pyrex tube, flushed with nitrogen and tightly
sealed. The tube was placed in a microwave (Smith Workstation 300W
from Magnetron @ 2.45 GHz) and heated to 200.degree. C. while
stirring for 2.25 h. After the tube had cool down to room
temperature, the reaction mixture was diluted with dichloromethane,
washed with saturated sodium bicarbonate, dried over magnesium
sulfate, filtered and concentrated in vacuo to provide a brown oil.
Flash chromatography (Isco silica gel, 4 g column, 10% ethyl
acetate/hexane) provided Example 587 as an off-white solid (25 mg,
55% yield): .sup.1H NMR (CDCl.sub.3) .delta. 8.67 (bs, NH), 8.36
(d, 1H), 8.32 (d, 1H), 7.95 (d, 1H), 7.73 (t, 1H), 7.62-7.69 (m,
2H), 7.26-7.38 (m, 4H), 7.15-7.20 (m, 3H), 7.14 (s, 1H), 7.09 (t,
1H), 4.37-4.46 (m, 2H), 2.65 (dd, 1H), 1.65 (dd, 1H), 1.18 (s, 3H);
HPLC t.sub.R=4.2 min.; LC/MS m/z 498 (M+H).sup.+.
Examples 588 to 645
[0576] In a similar manner as described in Example 1, Examples 588
to 645 were prepared from the coupling of corresponding acids and
amines. Preparations of amines or acids not commercially available
are described in the preceding preparations section of this
document. All examples in the table are racemic unless specified
otherwise. Examples in the table where one enantiomer predominates
or is the sole component, are designated as either R or S.
Separation of the enantiomers on a chiral column employed
procedures described in the preceding preparations section of this
document.
21 Example Chiral MS: (M + H = No. Structure Compounds MW + 1) 588
721 419.18 589 722 510.34 590 723 448.38 591 724 535.2 592 725
536.21 593 726 460.38 594 727 487.46 595 728 528.32 596 729 501.3
597 730 549.28 598 731 496.16 599 732 467.2 600 733 466.13 601 734
Chiral (R) 532.29 602 735 Chiral (S) 532.26 603 736 Chiral (R)
512.27 604 737 Chiral (S) 512.24 605 738 372.09 606 739 392.04 607
740 498.24 608 741 519.27 609 742 486.07 610 743 486.07 611 744
493.07 612 745 468.13 613 746 496.13 614 747 482.09 615 748 Chiral
(R) 536.25 616 749 Chiral (S) 536.27 617 750 493.01 618 751 565.03
619 752 465.05 620 753 469.05 621 754 424.33 622 755 521.05 623 756
501.09 624 757 504.99 625 758 524.95 626 759 596 627 760 451.15 628
761 508.14 629 762 488.17 630 763 548.03 631 764 551 632 765 515.18
633 766 504.13 634 767 651.11 635 768 484.17 636 769 552 637 770
499.1 638 771 569 639 772 495.05 640 773 506.1 641 774 Chiral (S)
519.05 642 775 Chiral (R) 519.01 643 776 489.07 644 777 519.19 645
778 481.34
Example 646
[0577] 779
[0578] To a solution of Example 178 (100 mg, 0.29 mmol, 1.0 equi.)
in acetonitrile (5 mL) was added N-iodosuccinimide (65 mg, 0.29 mg,
1.0 equi.). The solution was stirred at room temperature for 2
hours. The solution was quenched with saturated sodium bisulfate
solution, and diluted with ethyl acetate. The organic phase was
washed with water, dried with sodium sulfate and concentrated in
vacuo. Purification of the crude product mixture by flash
chromatography (20% ethyl acetate in hexane) yielded 22.7 mg (16%)
of Example 647: LC/MS (m/z 629, (M+H).sup.+).
Examples 647 to 648
[0579] In a manner similar to Example 646, Examples 647 to 649 were
prepared.
22 Chiral MS: (M + H = Example Compounds Structure MW + 1) 647 780
472.35 648 Chiral (S) 781 472.35 649 Chiral (R) 782 472.35
* * * * *