U.S. patent application number 12/369017 was filed with the patent office on 2009-07-09 for thiophene derivative ppar modulators.
Invention is credited to Nathan Bryan Mantlo, Xiaodong Wang, Guoxin Zhu.
Application Number | 20090176863 12/369017 |
Document ID | / |
Family ID | 32713349 |
Filed Date | 2009-07-09 |
United States Patent
Application |
20090176863 |
Kind Code |
A1 |
Mantlo; Nathan Bryan ; et
al. |
July 9, 2009 |
THIOPHENE DERIVATIVE PPAR MODULATORS
Abstract
The present invention is directed to compounds represented by
the following structural formula, Formula I: and stereoisomers,
pharmaceutically acceptable salts, solvates and hydrates thereof,
wherein: (a) X is selected from the group consisting of O, S,
S(O)2, N, and a bond; (b) U is an aliphatic linker wherein one
carbon atom of the aliphatic linker may be replaced with O, NH or
S, and wherein such aliphatic linker is optionally substituted with
R30: (c) Y is selected from the group consisting of C, O, S, NH and
a single bond; and (d) E is C(R3)(R4)A or A.
Inventors: |
Mantlo; Nathan Bryan;
(Brownsburg, IN) ; Wang; Xiaodong; (Carmel,
IN) ; Zhu; Guoxin; (Noblesville, IN) |
Correspondence
Address: |
ELI LILLY & COMPANY
PATENT DIVISION, P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
32713349 |
Appl. No.: |
12/369017 |
Filed: |
February 11, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10540330 |
Jun 21, 2005 |
7504433 |
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PCT/US03/39118 |
Dec 31, 2003 |
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12369017 |
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60438587 |
Jan 6, 2003 |
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Current U.S.
Class: |
514/438 ;
549/79 |
Current CPC
Class: |
A61P 9/00 20180101; C07D
333/16 20130101; C07D 333/18 20130101; A61P 3/10 20180101; A61P
3/00 20180101 |
Class at
Publication: |
514/438 ;
549/79 |
International
Class: |
A61K 31/381 20060101
A61K031/381; C07D 333/22 20060101 C07D333/22; A61P 9/00 20060101
A61P009/00; A61P 3/10 20060101 A61P003/10 |
Claims
1. A compound of the Formula 1': ##STR00082## and stereoisomers,
pharmaceutically acceptable salts, solvates and hydrates thereof,
wherein: (a) R1 is selected from the group consisting of hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, phenyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl, and C3-C6
cycloalkylaryl-C.sub.0-2-alkyl, and wherein C.sub.1-C.sub.8 alkyl
is optionally substituted with from one to three substituents
independently selected from R1'; and further wherein
C.sub.1-C.sub.8 alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl, and C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, are
each optionally substituted with from one to three substituents
independently selected from R2; (b) R1' are each independently
selected from the group consisting of hydroxy, cyano, nitro, halo,
oxo, C.sub.1-C.sub.6 alkyl-COOR12, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkyloxy,
C.sub.3-C.sub.7 cycloalkyl, aryloxy, aryl-C.sub.1-4-alkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; R12, R13, R14, R15, R16, R17, R18, R19,
R20, R21, R22, R23, R24 and R25 are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; (c) R2, R26, R27, R28, and R31 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryloxy,
aryl-C.sub.0-4-alkyl, heteroaryl, heterocycloalkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; (d) X is selected from the group consisting
of O, S, S(O).sub.2, N and a bond; (e) U is an aliphatic linker
wherein one carbon atom of the aliphatic linker is optionally
replaced with O, NH or S, and wherein such aliphatic linker is
optionally substituted with from one to four substituents each
independently selected from R.sup.30; (f) Y is selected from the
group consisting of C, NH, and a single bond; (g) E is
C(R.sup.3)(R.sup.4)A or A and wherein (i) A is selected from the
group consisting of carboxyl, tetrazole, C.sub.1-C.sub.6
alkylnitrile, carboxamide, sulfonamide and acylsulfonamide; wherein
sulfonamide, acylsulfonamide and tetrazole are each optionally
substituted with from one to two groups independently selected from
R.sup.7; (ii) each R.sup.7 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6 haloalkyl, aryl
C.sub.0-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl; (iii) R.sup.3 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.5
alkyl, and C.sub.1-C.sub.5 alkoxy; and (iv) R.sup.4 is selected
from the group consisting of H, C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, aryloxy, C.sub.3-C.sub.6 cycloalkyl, and
aryl C.sub.0-C.sub.4 alkyl, and R3 and R4 are optionally combined
to form a C.sub.3-C.sub.4 cycloalkyl, and wherein alkyl, alkoxy,
cycloalkyl and aryl-alkyl are each optionally substituted with one
to three each independently selected from R26; with the proviso
that when R1 is C.sub.1-C.sub.8 alkyl, Y is in a para substituted
position with relation to X, and X is selected from the group
consisting of a bond and O, then R4 is selected from the group
consisting of C.sub.1-C.sub.5 alkoxy, aryloxy, and
arylC.sub.0-C.sub.4 alkyl; with the additional proviso that when R1
is C.sub.1-C.sub.8 alkyl, Y is in a para substituted position with
relation to X, X is S, and U is optionally substituted methylene,
then R4 is selected from the group consisting of C.sub.1-C.sub.5
alkoxy, aryloxy, and arylC.sub.0-C.sub.4 alkyl; (h) R8 is selected
from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, and halo; (i) R9 is selected from the
group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, halo, aryl-C.sub.0-C.sub.4 alkyl,
heteroaryl, C.sub.1-C.sub.6 allyl, and OR29, and wherein
aryl-C.sub.0-C.sub.4 alkyl, heteroaryl are each optionally
substituted with from one to three independently selected from R27;
R29 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; (j) R10, R11 are each independently selected
from the group consisting of hydrogen, hydroxy, cyano, nitro, halo,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-COOR12'',
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl,
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, aryloxy, C(O)R13',
COOR14', OC(O)R15', OS(O).sub.2R16', N(R17').sub.2, NR18OC(O)R19',
NR20'SO.sub.2R21', SR22', S(O)R23', S(O).sub.2R24', and
S(O).sub.2N(R25').sub.2; and wherein aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three independently selected from R28;
(k) R12', R12'', R13', R14', R15', R16', R17', R18', R19', R20',
R21', R22', R23', R24', and R25' are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; and (l) R30 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and wherein
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three substituents each independently
selected from R31.
2. A compound of the Formula I'': ##STR00083## and stereoisomers,
pharmaceutically acceptable salts, solvates and hydrates thereof,
wherein: (a) R1 is selected from the group consisting of hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, phenyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl, and C3-C6
cycloalkylaryl-C.sub.0-2-alkyl, and wherein C.sub.1-C.sub.8 alkyl
is optionally substituted with from one to three substituents
independently selected from R1'; and further wherein
C.sub.1-C.sub.8 alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl, and C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, are
each optionally substituted with from one to three substituents
independently selected from R2; (b) R1' are each independently
selected from the group consisting of hydroxy, cyano, nitro, halo,
oxo, C.sub.1-C.sub.6 alkyl-COOR12, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6 haloalkyloxy,
C.sub.3-C.sub.7 cycloalkyl, aryloxy, aryl-C.sub.1-4-alkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; R12, R13, R14, R15, R16, R17, R18, R19,
R20, R21, R22, R23, R24 and R25 are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; (c) R2, R26, R27, R28, and R31 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryloxy,
aryl-C.sub.0-4-alkyl, heteroaryl, heterocycloalkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; (d) X is selected from the group consisting
of O, S, S(O).sub.2, N and a bond; (e) U is an aliphatic linker
wherein one carbon atom of the aliphatic linker is optionally
replaced with O, NH or S, and wherein such aliphatic linker is
substituted with from one to four substituents each independently
selected from R.sup.30; (f) Y is selected from the group consisting
of C, O, S, NH and a single bond; (g) E is C(R.sup.3)(R.sup.4)A or
A and wherein (i) A is selected from the group consisting of
carboxyl, tetrazole, C.sub.1-C.sub.6 alkylnitrile, carboxamide,
sulfonamide and acylsulfonamide; wherein sulfonamide,
acylsulfonamide and tetrazole are each optionally substituted with
from one to two groups independently selected from R.sup.7; (ii)
each R.sup.7 is independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6 haloalkyl, aryl C.sub.0-C.sub.4 alkyl and
C.sub.1-C.sub.6 alkyl; (iii) R.sup.3 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.5 alkyl, and C.sub.1-C.sub.5
alkoxy; and (iv) R.sup.4 is selected from the group consisting of
H, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, aryloxy,
C.sub.3-C.sub.6 cycloalkyl, and aryl C.sub.0-C.sub.4 alkyl, and R3
and R4 are optionally combined to form a C.sub.3-C.sub.4
cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and aryl-alkyl
are each optionally substituted with one to three each
independently selected from R26; with the proviso that when R.sup.1
is C.sub.1-C.sub.8 alkyl, Y is in a para substituted position with
relation to X, and X is selected from the group consisting of a
bond and O, then R4 is selected from the group consisting of
C.sub.1-C.sub.5 alkoxy, aryloxy, and arylC.sub.0-C.sub.4 alkyl;
with the additional proviso that when R.sup.1 is C.sub.1-C.sub.8
alkyl, Y is in a para substituted position with relation to X, X is
S, and U is optionally substituted methylene, then R4 is selected
from the group consisting of C.sub.1-C.sub.5 alkoxy, aryloxy, and
arylC.sub.0-C.sub.4 alkyl; (h) R8 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkylenyl, and halo; (i) R9 is selected from the group consisting
of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl,
halo, aryl-C.sub.0-C.sub.4 alkyl, heteroaryl, C.sub.1-C.sub.6
allyl, and OR29, and wherein aryl-C.sub.0-C.sub.4 alkyl, heteroaryl
are each optionally substituted with from one to three
independently selected from R27; R29 is selected from the group
consisting of hydrogen and C.sub.1-C.sub.4 alkyl; (j) R10, R11 are
each independently selected from the group consisting of hydrogen,
hydroxy, cyano, nitro, halo, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkyl-COOR12'', C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkyloxy,
C.sub.3-C.sub.7 cycloalkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl,
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, aryloxy, C(O)R13',
COOR14', OC(O)R15', OS(O).sub.2R16', N(R17').sub.2, NR18OC(O)R19',
NR20'SO.sub.2R21', SR22', S(O)R23', S(O).sub.2R24', and
S(O).sub.2N(R25').sub.2; and wherein aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three independently selected from R28;
(k) R12', R12'', R13', R14', R15', R16', R17', R18', R19', R20',
R21', R22', R23', R24', and R25' are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; and (l) R30 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and wherein
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three substituents each independently
selected from R31.
3. A compound of the Formula I''': ##STR00084## and stereoisomers,
pharmaceutically acceptable salts, solvates and hydrates thereof,
wherein: (a) R1 is selected from the group consisting of hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, phenyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl, and C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, and wherein C.sub.1-C.sub.8 alkyl
is optionally substituted with from one to three substituents
independently selected from R1'; and further wherein
C.sub.1-C.sub.8 alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl, and C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, are
each optionally substituted with from one to three substituents
independently selected from R2; (b) R1' are each independently
selected from the group consisting of hydroxy, cyano, nitro, halo,
oxo, C.sub.1-C.sub.6 alkyl-COOR12, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6 haloalkyloxy,
C.sub.3-C.sub.7 cycloalkyl, aryloxy, aryl-C.sub.1-4-alkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; R12, R13, R14, R15, R16, R17, R18, R19,
R20, R21, R22, R23, R24 and R25 are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; (c) R2, R26, R27, R28, and R31 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryloxy,
aryl-C.sub.0-4-alkyl, heteroaryl, heterocycloalkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; (d) X is selected from the group consisting
of O, S, S(O).sub.2, N and a bond; (e) U is an aliphatic linker
wherein one carbon atom of the aliphatic linker is optionally
replaced with O, NH or S, and wherein such aliphatic linker is
optionally substituted with from one to four substituents each
independently selected from R.sup.30; (f) Y is selected from the
group consisting of C, O, S, NH and a single bond; (g) E is
C(R.sup.3)(R.sup.4)A or A and wherein (i) A is selected from the
group consisting of carboxyl, tetrazole, C.sub.1-C.sub.6
alkylnitrile, carboxamide, sulfonamide and acylsulfonamide; wherein
sulfonamide, acylsulfonamide and tetrazole are each optionally
substituted with from one to two groups independently selected from
R.sup.7; (ii) each R.sup.7 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6 haloalkyl, aryl
C.sub.0-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl; (iii) R.sup.3 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.5
alkyl, and C.sub.1-C.sub.5 alkoxy; and (iv) R.sup.4 is selected
from the group consisting of H, C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, aryloxy, C.sub.3-C.sub.6 cycloalkyl, and
aryl C.sub.0-C.sub.4 alkyl, and R3 and R4 are optionally combined
to form a C.sub.3-C.sub.4 cycloalkyl, and wherein alkyl, alkoxy,
cycloalkyl and aryl-alkyl are each optionally substituted with one
to three each independently selected from R26; with the proviso
that when R1 is C.sub.1-C.sub.8 alkyl, Y is in a para substituted
position with relation to X, and X is selected from the group
consisting of a bond and O, then R4 is selected from the group
consisting of C.sub.1-C.sub.5 alkoxy, aryloxy, and
arylC.sub.0-C.sub.4 alkyl; with the additional proviso that when R1
is C.sub.1-C.sub.8 alkyl, Y is in a para substituted position with
relation to X, X is S, and U is optionally substituted methylene,
then R4 is selected from the group consisting of C.sub.1-C.sub.5
alkoxy, aryloxy, and arylC.sub.0-C.sub.4 alkyl; with the further
proviso that when Y is O then R4 is selected from the group
consisting of C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy,
aryloxy, C.sub.3-C.sub.6 cycloalkyl, and aryl C.sub.0-C.sub.4
alkyl, and R3 and R4 are optionally combined to form a
C.sub.3-C.sub.4 cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl
and aryl-alkyl are each optionally substituted with one to three
each independently selected from R26; (h) R8 is selected from the
group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, and halo; (i) R9 is selected from the
group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, halo, aryl-C.sub.0-C.sub.4alkyl,
heteroaryl, C.sub.1-C.sub.6 allyl, and OR29, and wherein
aryl-C.sub.0-C.sub.4 alkyl, heteroaryl are each optionally
substituted with from one to three independently selected from R27;
R29 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; (j) R10, R11 are each independently selected
from the group consisting of hydrogen, hydroxy, cyano, nitro, halo,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-COOR12'',
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl,
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, aryloxy, C(O)R13',
COOR14', OC(O)R15', OS(O).sub.2R16', N(R17').sub.2, NR18OC(O)R19',
NR20'SO.sub.2R21', SR22', S(O)R23', S(O).sub.2R24', and
S(O).sub.2N(R25').sub.2; and wherein aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three independently selected from R28;
(k) R12', R12'', R13', R14', R15', R16', R17', R18', R19', R20',
R21', R22', R23', R24', and R25' are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; and (l) R30 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and wherein
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three substituents each independently
selected from R31.
4. A compound of the Formula I: ##STR00085## and stereoisomers,
pharmaceutically acceptable salts, solvates and hydrates thereof,
wherein: (a) R1 is selected from the group consisting of hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, phenyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl, and C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, and wherein C.sub.1-C.sub.8 alkyl
is optionally substituted with from one to three substituents
independently selected from R1'; and further wherein
C.sub.1-C.sub.8 alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl, and C3-C6 cycloalkylaryl-C.sub.0-2-alkyl, are each
optionally substituted with from one to three substituents
independently selected from R2; (b) R1' are each independently
selected from the group consisting of hydroxy, cyano, nitro, halo,
oxo, C.sub.1-C.sub.6 alkyl-COOR12, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6 haloalkyloxy,
C.sub.3-C.sub.7 cycloalkyl, aryloxy, aryl-C.sub.1-4-alkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR8C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; R12, R13, R14, R15, R16, R17, R18, R19,
R20, R21, R22, R23, R24 and R25 are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; (c) R2, R26, R27, R28, and R31 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryloxy,
aryl-C.sub.0-4-alkyl, heteroaryl, heterocycloalkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R 17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; (d) X is selected from the group consisting
of O, S, S(O).sub.2, N, and a bond; (e) U is an aliphatic linker
wherein one carbon atom of the aliphatic linker may be replaced
with O, NH or S, and wherein such aliphatic linker is optionally
substituted with R.sup.30; (f) Y is selected from the group
consisting of C, O, S, NH and a single bond; (g) E is
C(R.sup.3)(R.sup.4)A or A and wherein (i) A is selected from the
group consisting of carboxyl, tetrazole, C.sub.1-C.sub.6
alkylnitrile, carboxamide, sulfonamide and acylsulfonamide; wherein
sulfonamide, acylsulfonamide and tetrazole are each optionally
substituted with from one to two groups independently selected from
R.sup.7; (ii) each R.sup.7 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6 haloalkyl, aryl
C.sub.0-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl; (iii) R.sup.3 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.5
alkyl, and C.sub.1-C.sub.5 alkoxy; and (iv) R.sup.4 is selected
from the group consisting of H, C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, aryloxy, C.sub.3-C.sub.6 cycloalkyl, and
aryl C.sub.0-C.sub.4 alkyl, and R3 and R4 are optionally combined
to form a C.sub.3-C.sub.4 cycloalkyl, and wherein alkyl, alkoxy,
cycloalkyl and aryl-alkyl are each optionally substituted with one
to three each independently selected from R26; with the proviso
that when R.sup.1 is C.sub.1-C.sub.8 alkyl, Y is in a para
substituted position with relation to X, and X is selected from the
group consisting of a bond and O, then R4 is selected from the
group consisting of C.sub.1-C.sub.5 alkoxy, aryloxy, and
arylC.sub.0-C.sub.4 alkyl; with the additional proviso that when R1
is C.sub.1-C.sub.8 alkyl, Y is in a para substituted position with
relation to X, X is S, and U is optionally substituted methylene,
then R4 is selected from the group consisting of C.sub.1-C.sub.5
alkoxy, aryloxy, and arylC.sub.0-C.sub.4 alkyl; (h) R8 is selected
from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, and halo; (i) R9 is selected from the
group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, halo, aryl-C.sub.0-C.sub.4 alkyl,
heteroaryl, C.sub.1-C.sub.6 allyl, and OR29, and wherein
aryl-C.sub.0-C.sub.4 alkyl, heteroaryl are each optionally
substituted with from one to three independently selected from R27;
R29 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; (j) R10, R11 are each independently selected
from the group consisting of hydrogen, hydroxy, cyano, nitro, halo,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-COOR12'',
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6
haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl,
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, aryloxy, C(O)R13',
COOR14', OC(O)R15', OS(O).sub.2R16', N(R17').sub.2, NR18OC(O)R19',
NR20'SO.sub.2R21', SR22', S(O)R23', S(O).sub.2R24', and
S(O).sub.2N(R25').sub.2; and wherein aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three independently selected from R28;
(k) R12', R122'', R13', R14', R15', R16', R17', R18', R19', R20',
R21', R22', R23', R24', and R25' are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; and (l) R30 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and wherein
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three substituents each independently
selected from R31.
5. A compound as claimed by any one of claims 1 through 4 wherein X
is --O--.
6. A compound as claimed by any one of claims 1 through 4 wherein X
is --S--.
7. A compound as claimed by claim 1 wherein R4 is selected from the
group consisting of C.sub.1-C.sub.5 alkoxy, aryloxy, and
arylC.sub.0-C.sub.4 alkyl.
8. A compound as claimed by claim 2 wherein Y is O.
9. A compound as claimed by claim 7 wherein Y is C.
10. A compound as claimed by claim 7 wherein Y is S.
11. A compound as claimed by any one of claims 1 through 4 wherein
E is C(R3)(R4)A.
12. A compound as claimed by claim 11 wherein A is carboxyl.
13. A compound as claimed by claim 2 wherein R1 is H.
14. A compound as claimed by claim 13 wherein A is COOH and R1 is
H.
15. A compound as claimed by claim 14 wherein R10 is haloalkyl.
16. A compound as claimed by claim 11 wherein R10 is CF.sub.3.
17. A compound as claimed by claim 14, wherein R10 is
haloalkyloxy.
18. A compound as claimed by claim 5 wherein R10 and R11 are each
independently selected from the group consisting of hydrogen, halo,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-COOR12'',
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, and
C.sub.1-C.sub.6haloalkyloxy.
19. A compound as claimed by claim 5 wherein R10 is selected from
the group consisting of C.sub.3-C.sub.7 cycloalkyl,
aryl-C.sub.0-4-alkyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, and aryloxy.
20. A compound as claimed by claim 5 wherein R8 and R9 are each
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.3 alkyl.
21. A compound as claimed by claim 5 wherein R3, and R4 are each
independently selected from the group consisting of C.sub.1-C.sub.2
alkyl.
22. A compound as claimed by claim 11 wherein R3, and R4 are each
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.2 alkyl.
23. A compound as claimed by claim 6, wherein X--U is optionally
substituted --S(CH.sub.2).sub.2.
24. A compound as claimed by claim 11 wherein U is C.sub.1-C.sub.3
alkyl.
25. A compound as claimed by claim 24 wherein U is saturated.
26. A compound as claimed by claim 24, wherein U is substituted
with C.sub.1-C.sub.3 alkyl.
27. A compound as claimed by claim 24, wherein U is substituted
with arylC.sub.1-C.sub.4alkyl.
28. A compound as claimed by claim 24, wherein one carbon of the U
group is replaced with an --O--.
29. A compound as claimed by claim 11 wherein R1 is selected from
the group consisting of phenyl and pyridyl.
30. A compound as claimed by claim 11 represented by the following
Structural Formula II: ##STR00086## wherein R33 is selected from
the group consisting of hydrogen, C.sub.1-C.sub.3 alkyl, and
arylC.sub.0-C.sub.4 alkyl.
31. A compound as claimed by claim 30 wherein R33 is
arylC.sub.1-C.sub.4 alkyl.
32. A compound as claimed by claim 11 represented by the following
Structural Formula III: ##STR00087## R33 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.3 alkyl, and
arylC.sub.0-C.sub.4 alkyl.
33. A compound as claimed by claim 11 represented by the following
Structural Formula IV: ##STR00088##
34. A compound as claimed by claim 11 wherein the headpiece of
Formula I is: ##STR00089## TABLE-US-00004 Compound Name
##STR00090## 3-{2-Methyl-4-[5-(4- trifluoromethyl-phenyl)-
thiophen-2-ylmethoxy]- phenyl}-propionic acid ##STR00091##
3-{2-Methyl-4-[3-phenyl-5- (4-trifluoromethyl-phenyl)-
thiophen-2-ylmethoxy]- phenyl}-propionic acid ##STR00092##
3-{4-[3,5-Bis-(4- trifluoromethyl-phenyl)- thiophen-2-ylmethoxy]-2-
methyl-phenyl}-propionic acid ##STR00093##
3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-
phenyl)-thiophen-2-yl]- propoxy}-phenyl)-propionic acid
##STR00094## 3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-
phenyl)-thiophen-2-yl]- butoxy}-phenyl)-propionic acid ##STR00095##
3-(2-Methyl-4-{2-methyl-1- [3-methyl-5-(4- trifluoromethyl-phenyl)-
thiophen-2-yl]-propoxy}- phenyl)-propionic acid ##STR00096##
3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-
phenyl)-thiophen-2-yl]-2- phenyl-ethoxy}-phenyl)- propionic acid
##STR00097## 3-(4-{1-[3-(2-Hydroxy- ethyl)-5-(4-trifluoromethyl-
phenyl)-thiophen-2-yl]- ethylsulfanyl}-2-methyl- phenyl)-propionic
acid
35. A compound as claimed by claim 11 wherein R4 is selected from
the group consisting of C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5
alkoxy, aryloxy, C.sub.3-C.sub.6 cycloalkyl, and aryl
C.sub.0-C.sub.4 alkyl, and wherein alkyl, alkoxy, cycloalkyl and
aryl-alkyl are each optionally substituted with one to three each
independently selected from R26.
36. A compound as claimed by claim 5 wherein E is C(R3)(R4)A.
37. A compound as claimed by claim 6 wherein A is COOH.
38. A compound as claimed by claim 1, wherein the compound is
selected from the group consisting of
(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-prop-
ylsulfanyl}-phenoxy)-acetic acid,
(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-prop-
ylsulfanyl}-phenoxy)-acetic acid,
3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-pr-
opylsulfanyl}-phenyl)-propionic acid, and
(3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phen-
yl)-acetic.
39. A compound as claimed by claim 1 that is
(3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phen-
yl)-acetic.
40. A compound as claimed by claim 1 wherein the compound is
selected from the group consisting of
41. A compound as claimed by claim 1 which is selected from the
group consisting of
{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenoxy}--
acetic acid and
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-
-propionic acid.
42. A compound as claimed by claim 11 which is the S
conformation.
43. A compound as claimed by claim 11 which is the R
conformation.
44. A pharmaceutical composition, comprising as an active
ingredient, at least one compound as claimed by claim 11 together
with a pharmaceutically acceptable carrier or diluent.
45. (canceled)
46. A method of treating diabetes mellitus in a mammal, comprising
the step of administering to the mammal in need thereof, a
therapeutically effective amount of at least one compound of claim
11.
47. A method of treating Metabolic syndrome in a mammal, comprising
the step of administering to the mammal in need thereof a
therapeutically effective amount of at least one compound of claim
11.
48. A method of selectively modulating a PPAR delta receptor
comprising administering a compound as claimed by claim 11 to a
mammal in need thereof.
49. (canceled)
50. A method of treating atherosclerosis in a mammal, comprising
the step of administering to the mammal in need thereof a
therapeutically effective amount of at least one compound of claim
11.
51. A method for treating or preventing the progression of
cardiovascular disease in a mammal in need thereof comprising
administering a therapeutically effective amount of a compound as
claimed by claim 11.
52. A method as claimed by claim 51 wherein the mammal is diagnosed
as being in need of such treatment.
53. A method of treating arthritis in a mammal, comprising the step
of administering to the mammal in need thereof, a therapeutically
effective amount of at least one compound as claimed by claim
11.
54. A method of treating demyelating disease in a mammal,
comprising the step of administering to the mammal in need thereof,
a therapeutically effective amount of at least one compound as
claimed by claim 11.
55. A method of treating inflammatory disease in a mammal,
comprising the step of administering to the mammal in need thereof,
a therapeutically effective amount of at least one compound as
claimed by claim 11.
56. A method as claimed by claim 53, wherein such mammal is
diagnosed as being in need of such treatment.
57. A compound as claimed by claim 11 for use as a
pharmaceutical.
58. A compound as claimed by claim 11 wherein the compound is
radiolabeled.
59. (canceled)
60. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] Peroxisome Proliferator Activated Receptors (PPARs) are
members of the nuclear hormone receptor superfamily, a large and
diverse group of proteins that mediate ligand-dependent
transcriptional activation and repression. Three subtypes of PPARs
have been isolated: PPAR.alpha., PPAR.gamma. and PPAR.delta..
[0002] The expression profile of each isoform differs significantly
from the others, whereby PPAR.alpha. is expressed primarily, but
not exclusively in liver; PPAR.gamma. is expressed primarily in
adipose tissue; and PPAR.delta. is expressed ubiquitously. Studies
of the individual PPAR isoforms and ligands have revealed their
regulation of processes involved in insulin resistance and
diabetes, as well as lipid disorders, such as hyperlipidemia and
dyslipidemia. PPAR.gamma. agonists, such as pioglitazone, can be
useful in the treatment of non-insulin dependent diabetes mellitus.
Such PPAR.gamma. agonists are associated with insulin
sensitization.
[0003] PPAR.alpha. agonists, such as fenofibrate, can be useful in
the treatment of hyperlipidemia. Although clinical evidence is not
available to reveal the utility of PPAR.delta. agonists in humans,
several preclinical studies suggest that PPAR.delta. agonists can
be useful in the treatment of diabetes and lipid disorders.
[0004] The prevalence of the conditions that comprise Metabolic
Syndrome (obesity, insulin resistance, hyperlipidemia, hypertension
and atherosclerosis) continues to increase. New pharmaceutical
agents are needed to address the unmet clinical needs of
patients.
[0005] PPAR.delta. agonists have been suggested as a potential
treatment for use in regulating many of the parameters associated
with Metabolic Syndrome and Atherosclerosis. For example, in obese,
non-diabetic rhesus monkeys, a PPAR.delta. agonist reduced
circulating triglycerides and LDL, decreased basal insulin levels
and increased HDL (Oliver, W. R. et al. Proc Natl Acad Sci
98:5306-5311; 2001). The insulin sensitization observed with the
use of a PPAR.delta. agonist is thought to be in part due to
decreased myocellular lipids (Dressel, U. et al. Mol Endocrinol
17:2477-2493; 2003).
[0006] Further, atherosclerosis is considered to be a disease
consequence of dyslipidemia and may be associated with inflammatory
disease. C-reactive protein (CRP) production is part of the
acute-phase response to most forms of inflammation, infection and
tissue damage. It is measured diagnostically as a marker of
low-grade inflammation. Plasma CRP levels of greater than 3 mg/L
have been considered predictive of high risk for coronary artery
disease (J. Clin. Invest 111: 1085-1812, 2003).
[0007] PPAR.delta. agonists are believed to mediate
anti-inflammatory effects. Indeed, treatment of LPS-stimulated
macrophages with a PPAR.delta. agonist has been observed to reduce
the expression of iNOS, IL12, and IL-6 (Welch, J. S. et al. Proc
Natl Acad Sci 100:6712-67172003).
[0008] It may be especially desirable when the active
pharmaceutical agent selectively modulates a PPAR receptor subtype
to provide an especially desirable pharmacological profile. In some
instances, it can be desirable when the active pharmacological
agent selectively modulates more than one PPAR receptor subtype to
provide a desired pharmacological profile.
SUMMARY OF THE INVENTION
[0009] The present invention is directed to compounds represented
by the following structural Formula I':
##STR00001##
and stereoisomers, pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein: [0010] (a) R1 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl, heteroaryl, and C3-C6
cycloalkylaryl-C.sub.0-2-alkyl, and wherein C.sub.1-C.sub.8 alkyl
is optionally substituted with from one to three substituents
independently selected from R1'; and further wherein
C.sub.1-C.sub.8 alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl, and C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, are
each optionally substituted with from one to three substituents
independently selected from R2; [0011] (b) R1' are each
independently selected from the group consisting of hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl-COOR12, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkyloxy,
C.sub.3-C.sub.7 cycloalkyl, aryloxy, aryl-C.sub.1-4-alkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; R12, R13, R14, R15, R16, R17; R18, R19,
R20, R21, R22, R23, R24 and R25 are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; [0012] (c) R2, R26, R27, R28, and R31 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryloxy,
aryl-C.sub.0-4-alkyl, heteroaryl, heterocycloalkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; [0013] (d) X is selected from the group
consisting of O, S, S(O).sub.2, N and a bond; [0014] (e) U is an
aliphatic linker wherein one carbon atom of the aliphatic linker is
optionally replaced with C, NH or S, and wherein such aliphatic
linker is optionally substituted with from one to four substituents
each independently selected from R30; [0015] (f) Y is selected from
the group consisting of C, NH, and a single bond; [0016] (g) E is
C(R3)(R4)A or A and wherein [0017] (i) A is selected from the group
consisting of carboxyl, tetrazole, C.sub.1-C.sub.6 alkylnitrile,
carboxamide, sulfonamide and acylsulfonamide; wherein sulfonamide,
acylsulfonamide and tetrazole are each optionally substituted with
from one to two groups independently selected from R.sup.7; [0018]
(ii) each R.sup.7 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6 haloalkyl, aryl
C.sub.0-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl; [0019] (iii) R3 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.5
alkyl, and C.sub.1-C.sub.5 alkoxy; and [0020] (iv) R.sup.4 is
selected from the group consisting of H, C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, aryloxy, C.sub.3-C.sub.6 cycloalkyl, and
aryl C.sub.0-C.sub.4 alkyl, and R3 and R4 are optionally combined
to form a C.sub.3-C.sub.4 cycloalkyl, and wherein alkyl, alkoxy,
cycloalkyl and aryl-alkyl are each optionally substituted with one
to three each independently selected from R26; [0021] with the
proviso that when R1 is C.sub.1-C.sub.8 alkyl, Y is in a para
substituted position with relation to X, and X is selected from the
group consisting of a bond and O, then R4 is selected from the
group consisting of C.sub.1-C.sub.5 alkoxy, aryloxy, and
arylC.sub.0-C.sub.4 alkyl; with the additional proviso that when R1
is C.sub.1-C.sub.8 alkyl, Y is in a para substituted position with
relation to X, X is S, and U is optionally substituted methylene,
then R4 is selected from the group consisting of C.sub.1-C.sub.5
alkoxy, aryloxy, and arylC.sub.0-C.sub.4 alkyl; [0022] (h) R8 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, and halo; [0023] (i) R9 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, halo, aryl-C.sub.0-C.sub.4 alkyl,
heteroaryl, C.sub.1-C.sub.6 allyl, and OR29, and wherein
aryl-C.sub.0-C.sub.4 alkyl, heteroaryl are each optionally
substituted with from one to three independently selected from R27;
R29 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; [0024] (j) R10, R11 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12'', C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl,
aryl-C.sub.0-4-alkyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, aryloxy, C(O)R13', COOR14',
OC(O)R15', OS(O).sub.2R16', N(R17').sub.2, NR18'C(O)R19',
NR20'SO.sub.2R21', SR22', S(O)R23', S(O).sub.2R24', and
S(O).sub.2N(R25').sub.2; and wherein aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three independently selected from R28;
[0025] (k) R12', R12'', R13', R14', R15', R16', R17', R18', R19',
R20', R21', R22', R23', R24', and R25' are each independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl and aryl; and [0026] (l) R30 is selected from the group
consisting of C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and wherein
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three substituents each independently
selected from R31. A further embodiment of the present invention is
a compound of the Formula I'':
##STR00002##
[0026] and stereoisomers, pharmaceutically acceptable salts,
solvates and hydrates thereof, wherein: [0027] (a) R1 is selected
from the group consisting of hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl, and C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and
wherein C.sub.1-C.sub.8 alkyl is optionally substituted with from
one to three substituents independently selected from R1'; and
further wherein C.sub.1-C.sub.8 alkenyl, phenyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl, and C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, are each optionally substituted
with from one to three substituents independently selected from R2;
[0028] (b) R1' are each independently selected from the group
consisting of hydroxy, cyano, nitro, halo, oxo, C.sub.1-C.sub.6
alkyl-COOR12, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryloxy,
aryl-C.sub.1-4-alkyl, C(O)R13, COOR14, OC(O)R15, OS(O).sub.2R16,
N(R17).sub.2, NR18C(O)R19, NR20SO.sub.2R21, SR22, S(O)R23,
S(O).sub.2R24, and S(O).sub.2N(R25).sub.2; R12, R13, R14, R15, R16,
R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl and aryl; [0029] (c) R2, R26, R27, R28, and
R31 are each independently selected from the group consisting of
hydrogen, hydroxy, cyano, nitro, halo, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkyl-COOR12, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6haloalkyloxy,
C.sub.3-C.sub.7 cycloalkyl, aryloxy, aryl-C.sub.0-4-alkyl,
heteroaryl, heterocycloalkyl, C(O)R13, COOR14, OC(O)R15,
OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19, NR20SO.sub.2R21, SR22,
S(O)R23, S(O).sub.2R24, and S(O).sub.2N(R25).sub.2; [0030] (d) X is
selected from the group consisting of O, S, S(O).sub.2, N and a
bond; [0031] (e) U is an aliphatic linker wherein one carbon atom
of the aliphatic linker is optionally replaced with O, NH or S, and
wherein such aliphatic linker is substituted with from one to four
substituents each independently selected from R.sup.30; [0032] (f)
Y is selected from the group consisting of C, O, S, NH and a single
bond; [0033] (g) E is C(R3)(R4)A or A and wherein [0034] (i) A is
selected from the group consisting of carboxyl, tetrazole,
C.sub.1-C.sub.6 alkylnitrile, carboxamide, sulfonamide and
acylsulfonamide; wherein sulfonamide, acylsulfonamide and tetrazole
are each optionally substituted with from one to two groups
independently selected from R.sup.7; [0035] (ii) each R.sup.7 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 haloalkyl, aryl C.sub.0-C.sub.4 alkyl and
C.sub.1-C.sub.6 alkyl; [0036] (iii) R.sup.3 is selected from the
group consisting of hydrogen, C.sub.1-C.sub.5 alkyl, and
C.sub.1-C.sub.5 alkoxy; and [0037] (iv) R.sup.4 is selected from
the group consisting of H, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5
alkoxy, aryloxy, C.sub.3-C.sub.6 cycloalkyl, and aryl
C.sub.0-C.sub.4 alkyl, and R3 and R4 are optionally combined to
form a C.sub.3-C.sub.4 cycloalkyl, and wherein alkyl, alkoxy,
cycloalkyl and aryl-alkyl are each optionally substituted with one
to three each independently selected from R26; [0038] with the
proviso that when R1 is C.sub.1-C.sub.8 alkyl, Y is in a para
substituted position with relation to X, and X is selected from the
group consisting of a bond and O, then R4 is selected from the
group consisting of C.sub.1-C.sub.8 alkoxy, aryloxy, and
arylC.sub.0-C.sub.4 alkyl; with the additional proviso that when R1
is C.sub.1-C.sub.8 alkyl, Y is in a para substituted position with
relation to X, X is S, and U is optionally substituted methylene,
then R4 is selected from the group consisting of C.sub.1-C.sub.5
alkoxy, aryloxy, and arylC.sub.0-C.sub.4 alkyl; [0039] (h) R8 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, and halo; [0040] (i) R9 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, halo, aryl-C.sub.0-C.sub.4 alkyl,
heteroaryl, C.sub.1-C.sub.6 alkyl, and OR29, and wherein
aryl-C.sub.0-C.sub.4 alkyl, heteroaryl are each optionally
substituted with from one to three independently selected from R27;
R29 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; [0041] (j) R10, R11 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12'', C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl,
aryl-C.sub.0-4-alkyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, aryloxy, C(O)R13', COOR14',
OC(O)R15', OS(O).sub.2R16', N(R17').sub.2, NR18'C(O)R19',
NR20'SO.sub.2R21', SR22', S(c)R23', S(O).sub.2R24', and
S(Q).sub.2N(R25').sub.2; and wherein aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three independently selected from R28;
[0042] (k) R12', R12'', R13', R14', R15', R16', R17', R18', R19',
R20', R21', R22', R23', R24', and R25' are each independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl and aryl; and [0043] (l) R30 is selected from the group
consisting of C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and wherein
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three substituents each independently
selected from R31.
[0044] Yet another embodiment of the present invention is a
compound of the Formula I''':
##STR00003##
and stereoisomers, pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein: [0045] (a) R1 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl, heteroaryl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and wherein
C.sub.1-C.sub.8 alkyl is optionally substituted with from one to
three substituents independently selected from R1'; and further
wherein C.sub.1-C.sub.8 alkenyl, phenyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl, and C3-C6
cycloalkylaryl-C.sub.0-2-alkyl, are each optionally substituted
with from one to three substituents independently selected from R2;
[0046] (b) R1' are each independently selected from the group
consisting of hydroxy, cyano, nitro, halo, oxo, C.sub.1-C.sub.6
alkyl-COOR12, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryloxy,
aryl-C.sub.1-4-alkyl, C(O)R13, COOR14, OC(O)R15, OS(O).sub.2R16,
N(R17).sub.2, NR18C(O)R19, NR20SO.sub.2R21, SR22, S(O)R23,
S(O).sub.2R24, and S(O).sub.2N(R25).sub.2; R12, R13, R14, R15, R16,
R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl and aryl; [0047] (c) R2, R26, R27, R28, and
R31 are each independently selected from the group consisting of
hydrogen, hydroxy, cyano, nitro, halo, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkyl-COOR12, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkyloxy,
C.sub.3-C.sub.7 cycloalkyl, aryloxy, aryl-C.sub.0-4-alkyl,
heteroaryl, heterocycloalkyl, C(O)R13, COOR14, OC(O)R15,
OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19, NR20SO.sub.2R21, SR22,
S(O)R23, S(O).sub.2R24, and S(O).sub.2N(R25).sub.2; [0048] (d) X is
selected from the group consisting of O, S, S(O).sub.2, N and a
bond; [0049] (e) U is an aliphatic linker wherein one carbon atom
of the aliphatic linker is optionally replaced with O, NH or S, and
wherein such aliphatic linker is optionally substituted with from
one to four substituents each independently selected from R.sup.30;
[0050] (f) Y is selected from the group consisting of C, O, S, NH
and a single bond; [0051] (g) E is C(R.sup.3)(R.sup.4)A or A and
wherein [0052] (i) A is selected from the group consisting of
carboxyl, tetrazole, C.sub.1-C.sub.6 alkylnitrile, carboxamide,
sulfonamide and acylsulfonamide; wherein sulfonamide,
acylsulfonamide and tetrazole are each optionally substituted with
from one to two groups independently selected from R.sup.7; [0053]
(ii) each R.sup.7 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6 haloalkyl, aryl
C.sub.0-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl; [0054] (iii) R3 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.5
alkyl, and C.sub.1-C.sub.5 alkoxy; and [0055] (iv) R4 is selected
from the group consisting of H, C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.8 alkoxy, aryloxy, C.sub.3-C.sub.6 cycloalkyl, and
aryl C.sub.0-C.sub.4 alkyl, and R3 and R4 are optionally combined
to form a C.sub.3-C.sub.4 cycloalkyl, and wherein alkyl, alkoxy,
cycloalkyl and aryl-alkyl are each optionally substituted with one
to three each independently selected from R26; [0056] with the
proviso that when R1 is C.sub.1-C.sub.8 alkyl, Y is in a para
substituted position with relation to X, and X is selected from the
group consisting of a bond and O, then R4 is selected from the
group consisting of C.sub.1-C.sub.5 alkoxy, aryloxy, and
arylC.sub.0-C.sub.4 alkyl; with the additional proviso that when R1
is C.sub.1-C.sub.10 alkyl, Y is in a para substituted position with
relation to X, X is S, and U is optionally substituted methylene,
then R4 is selected from the group consisting of C.sub.1-C.sub.5
alkoxy, aryloxy, and arylC.sub.0-C.sub.4 alkyl; [0057] with the
further proviso that when Y is O then R4 is selected from the group
consisting of C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy,
aryloxy, C.sub.3-C.sub.6 cycloalkyl, and aryl C.sub.0-C.sub.4
alkyl, and R3 and R4 are optionally combined to form a
C.sub.3-C.sub.4 cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl
and aryl-alkyl are each optionally substituted with one to three
each independently selected from R26; [0058] (h) R8 is selected
from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, and halo; [0059] (i) R9 is selected from
the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, halo, aryl-C.sub.0-C.sub.4 alkyl,
heteroaryl, C.sub.1-C.sub.6 allyl, and OR29, and wherein
aryl-C.sub.0-C.sub.4 alkyl, heteroaryl are each optionally
substituted with from one to three independently selected from R27;
R29 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; [0060] (j) R10, R11 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12'', C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl,
aryl-C.sub.0-4-alkyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, aryloxy, C(O)R13', COOR14',
OC(O)R15', OS(O).sub.2R16', N(R17').sub.2, NR18OC(O)R19',
NR20'SO.sub.2R21', SR22', S(O)R23', S(O).sub.2R24', and
S(O).sub.2N(R25').sub.2; and wherein aryl-CO.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three independently selected from R28;
[0061] (k) R12', R12'', R13', R14', R15', R16', R17', R18', R19',
R20', R21', R22', R23', R24', and R25' are each independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl and aryl; and [0062] (l) R30 is selected from the group
consisting of C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and wherein
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three substituents each independently
selected from R31.
[0063] An embodiment of the present invention is a compound of the
structural Formula I:
##STR00004##
and stereoisomers, pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein: [0064] (a) R1 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl, heteroaryl, and C3-C6
cycloalkylaryl-C.sub.0-2-alkyl, and wherein C.sub.1-C.sub.8 alkyl
is optionally substituted with from one to three substituents
independently selected from R1'; and further wherein
C.sub.1-C.sub.8 alkenyl, phenyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl, and C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, are
each optionally substituted with from one to three substituents
independently selected from R2; [0065] (b) R1' are each
independently selected from the group consisting of hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl-COOR12, C.sub.3-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkyloxy,
C.sub.3-C.sub.7 cycloalkyl, aryloxy, aryl-C.sub.1-4-alkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; R12, R13, R14, R15, R16, R17, R18, R19,
R20, R21, R22, R23, R24 and R25 are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl and
aryl; [0066] (c) R2, R26, R27, R28, and R31 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl, aryloxy,
aryl-C.sub.0-4-alkyl, heteroaryl, heterocycloalkyl, C(O)R13,
COOR14, OC(O)R15, OS(O).sub.2R16, N(R17).sub.2, NR18C(O)R19,
NR20SO.sub.2R21, SR22, S(O)R23, S(O).sub.2R24, and
S(O).sub.2N(R25).sub.2; [0067] (d) X is selected from the group
consisting of O, S, S(O).sub.2, N and a bond; [0068] (e) U is an
aliphatic linker wherein one carbon atom of the aliphatic linker
may be replaced with O, NH or S, and wherein such aliphatic linker
is optionally substituted with R.sup.30; [0069] (f) Y is selected
from the group consisting of C, O, S, NH and a single bond; [0070]
(g) E is C(R.sup.3)(R.sup.4)A or A and wherein [0071] (i) A is
selected from the group consisting of carboxyl, tetrazole,
C.sub.1-C.sub.6 alkylnitrile, carboxamide, sulfonamide and
acylsulfonamide; wherein sulfonamide, acylsulfonamide and tetrazole
are each optionally substituted with from one to two groups
independently selected from R.sup.7; [0072] (ii) each R.sup.7 is
independently selected from the group consisting of hydrogen,
C.sub.2-C.sub.6 haloalkyl, aryl C.sub.0-C.sub.4 alkyl and
C.sub.0-C.sub.6 alkyl; [0073] (iii) R.sup.3 is selected from the
group consisting of hydrogen, C.sub.1-C.sub.5 alkyl, and
C.sub.1-C.sub.5 alkoxy; and [0074] (iv) R.sup.4 is selected from
the group consisting of H, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5
alkoxy, aryloxy, C.sub.3-C.sub.6 cycloalkyl, and aryl
C.sub.0-C.sub.4 alkyl, and R.sup.3 and R4 are optionally combined
to form a C.sub.3-C.sub.4 cycloalkyl, and wherein alkyl, alkoxy,
cycloalkyl and aryl-alkyl are each optionally substituted with one
to three each independently selected from R26; [0075] with the
proviso that when R1 is C.sub.1-C.sub.8 alkyl, Y is in a para
substituted position with relation to X, and X is selected from the
group consisting of a bond and O, then R4 is selected from the
group consisting of C.sub.1-C.sub.5 alkoxy, aryloxy, and
arylC.sub.0-C.sub.4 alkyl; with the additional proviso that when R1
is C.sub.1-C.sub.8 alkyl, Y is in a para substituted position with
relation to X, X is S, and U is optionally substituted methylene,
then R4 is selected from the group consisting of C.sub.1-C.sub.5
alkoxy, aryloxy, and arylCO.sub.0--C.sub.4 alkyl; [0076] (h) R8 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, and halo; [0077] (i) R9 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, halo, aryl-C.sub.0-C.sub.4 alkyl,
heteroaryl, C.sub.1-C.sub.6 allyl, and OR29, and wherein
aryl-C.sub.0-C.sub.4 alkyl, heteroaryl are each optionally
substituted with from one to three independently selected from R27;
R29 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; [0078] (j) R10, R11 are each independently
selected from the group consisting of hydrogen, hydroxy, cyano,
nitro, halo, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkyl-COOR12'', C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyloxy, C.sub.3-C.sub.7 cycloalkyl,
aryl-C.sub.0-4-alkyl, aryl-C.sub.1-4-heteroalkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, aryloxy, C(O)R13', COOR14',
OC(O)R15', OS(O).sub.2R16', N(R17').sub.2, NR18'C(O)R19',
NR20'SO.sub.2R21', SR22', S(O)R23', S(O).sub.2R24', and
S(O).sub.2N(R25').sub.2; and wherein aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three independently selected from R28;
[0079] (k) R12', R12'', R13', R14', R15', R16', R17', R18', R19',
R20', R21', R22', R23', R24', and R25' are each independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl and aryl; and [0080] (l) R30 is selected from the group
consisting of C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl, and wherein
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
aryl-C.sub.1-4-heteroalkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl are each optionally
substituted with from one to three substituents each independently
selected from R31.
[0081] In one embodiment, the present invention also relates to
pharmaceutical compositions comprising at least one compound of the
present invention, or a pharmaceutically acceptable salt, solvate,
hydrate, or stereioisomer thereof, and a pharmaceutically
acceptable carrier.
[0082] In another embodiment, the present invention relates to a
method of selectively modulating a PPAR delta receptor by
contacting the receptor with at least one compound represented by
Structural Formula I, or a pharmaceutically acceptable salt,
solvate, hydrate, or stereioisomer thereof.
[0083] In another embodiment, the present invention relates to a
method of modulating one or more of the PPAR alpha, beta, gamma,
and/or delta receptors.
[0084] In a further embodiment, the present invention relates to a
method of making a compound represented by Structural Formula
I.
[0085] The compounds of the present invention are believed to be
effective in treating and preventing Metabolic syndrome, Type II
diabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy,
hypertension, atherosclerosis, and other disorders related to
Metabolic syndrome and cardiovascular diseases. Further, compounds
of this invention can be useful for lowering fibrinogen, increasing
HDL levels, treating renal disease, controlling desirable weight,
treating demyelinating diseases, treating certain viral infections,
and treating liver disease. In addition, the compounds can be
associated with fewer clinical side effects than compounds
currently used to treat such conditions.
DETAILED DESCRIPTION OF THE INVENTION
[0086] The terms used to describe the instant invention have the
following meanings.
[0087] As used herein, the term "aliphatic linker" or "aliphatic
group" is a non-aromatic, consisting solely of carbon and hydrogen
and may optionally contain one or more units of unsaturation, e.g.,
double and/or triple bonds (also refer herein as "alkenyl" and
"alkynyl"). An aliphatic or aliphatic group may be straight
chained, branched (also refer herein as "alkyl") or cyclic (also
refer herein as "cycloalkyl). When straight chained or branched, an
aliphatic group typically contains between about 1 and about 10
carbon atoms, more typically between about 1 and about 6 carbon
atoms. When cyclic, an aliphatic typically contains between about 3
and about 10 carbon atoms, more typically between about 3 and about
7 carbon atoms. Aliphatics are preferably C.sub.1-C.sub.10 straight
chained or branched alkyl groups (i.e. completely saturated
aliphatic groups), more preferably C.sub.1-C.sub.6 straight chained
or branched alkyl groups. Examples include, but are not limited to
methyl, ethyl, propyl, n-propyl, iso-propyl, n-butyl, sec-butyl,
and tert-butyl. Additional examples include, but are not limited
to, cyclopropyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexylyl
and the like. It can be a preferred embodiment of the present
invention that one carbon atom of the aliphatic linker is replaced
with an O, NH, or S. It may further be preferred that the aliphatic
linker is substituted with from one to four substituents each
independently selected from R30. It may be preferred that the
aliphatic linker is substituted with two substituents each
independently selected from R30.
[0088] The term "alkyl," unless otherwise indicated, refers to
those alkyl groups of a designated number of carbon atoms of either
a straight or branched saturated configuration. As used herein,
"C.sub.0 alkyl" means that there is no carbon and therefore
represents a bond. Examples of "alkyl" include, but are not limited
to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl and tert-butyl, pentyl, hexyl, isopentyl and the like.
Alkyl as defined above may be optionally substituted with a
designated number of substituents as set forth in the embodiment
recited above. As used herein, the term "alkyloxo" means an alkyl
group of the designated number of carbon atoms with a ".dbd.O"
substituent.
[0089] The term "alkenyl" means hydrocarbon chain of a specified
number of carbon atoms of either a straight or branched
configuration and having at least one carbon-carbon double bond,
which may occur at any point along the chain, such as ethenyl,
propenyl, butenyl, pentenyl, vinyl, alkyl, 2-butenyl and the like.
Alkenyl as defined above may be optionally substituted with
designated number of substituents as set forth in the embodiment
recited above.
[0090] The term "alkynyl" means hydrocarbon chain of a specified
number of carbon atoms of either a straight or branched
configuration and having at least one carbon-carbon triple bond,
which may occur at any point along the chain. Example of alkynyl is
acetylene. Alkynyl as defined above may be optionally substituted
with designated number of substituents as set forth in the
embodiment recited above.
[0091] The term "heteroalkyl" refers to a means hydrocarbon chain
of a specified number of carbon atoms wherein at least one carbon
is replaced by a heteroatom selected from the group consisting of
O, N and S.
[0092] The term "cycloalkyl" refers to a saturated or partially
saturated carbocycle containing one or more rings of from 3 to 12
carbon atoms, typically 3 to 7 carbon atoms. Examples of cycloalkyl
includes, but are not limited to cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl, and the like.
"Cycloalkyaryl" means that an aryl is fused with a cycloalkyl, and
"Cycloalkylaryl-alkyl" means that the cycloalkylaryl is linked to
the parent molecule through the alkyl. Cycloalkyl as defined above
may be optionally substituted with a designated number of
substituents as set forth in the embodiment recited above.
[0093] The term "halo" refers to fluoro, chloro, bromo and
iodo.
[0094] The term "haloalkyl" is a C.sub.1-C.sub.6 alkyl group, which
is substituted with one or more halo atoms selected from F, Br, Cl
and I. An example of a haloalkyl group is trifluoromethyl
(CF.sub.3); however, the term is in no way limited to
trifluoromethyl. Trihalomethyl can be a preferred haloalkyl
group.
[0095] The term "alkoxy" represents an alkyl group of indicated
number of carbon atoms attached through an oxygen bridge, such as
methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy,
and the like. Alkoxy as defined above may be optionally substituted
with a designated number of substituents as set forth in the
embodiment recited above.
[0096] The term "haloalkyloxy" represents a C.sub.1-C.sub.6
haloalkyl group attached through an oxygen bridge, such as
OCF.sub.3. The "haloalkyloxyl" as defined above may be optionally
substituted with a designated number of substituents as set forth
in the embodiment recited above.
[0097] The term "aryl" includes carbocyclic aromatic ring systems
(e.g. phenyl), fused polycyclic aromatic ring systems (e.g.
naphthyl and anthracenyl) and aromatic ring systems fused to
carbocyclic non-aromatic ring systems (e.g.,
1,2,3,4-tetrahydronaphthyl). "Aryl" as defined above may be
optionally substituted with a designated number of substituents as
set forth in the embodiment recited above. A preferred aryloxy
group can be phenoxy, wherein the 0 is linked to the parent
molecule.
[0098] The term "arylalkyl" refers to an aryl alkyl group which is
linked to the parent molecule through the alkyl group, which may be
further optionally substituted with a designated number of
substituents as set forth in the embodiment recited above. One
preferred arylalkyl group can be benzyl or phenyl. When arylalkyl
is arylcoalkyl, then the aryl group is bonded directly to the
parent molecule. Likewise, arylheteroalkyl means an aryl group
linked to the parent molecule through the heteroalkyl group.
[0099] The term "acyl" refers to alkylcarbonyl species.
[0100] The term "heteroaryl" group, as used herein, is an aromatic
ring system having at least one heteroatom such as nitrogen, sulfur
or oxygen and includes monocyclic, bicyclic or tricyclic aromatic
ring of 5- to 14-carbon atoms containing one or more heteroatoms
selected from the group consisting of O, N, and S. The "heteroaryl"
as defined above may be optionally substituted with a designated
number of substituents as set forth in the embodiment recited
above. Examples of heteroaryl are, but are not limited to, furanyl,
indolyl, thienyl (also referred to herein as "thiophenyl")
thiazolyl, imidazolyl, isoxazoyl, oxazoyl, pyrazoyl, pyrrolyl,
pyrazinyl, pyridyl, pyrimidyl, pyrimidinyl and purinyl, cinnolinyl,
benzofuranyl, benzothienyl, benzotriazolyl, benzoxazolyl,
quinoline, isoxazolyl, isoquinoline and the like. The term
"heteroarylalkyl" means that the heteroaryl group is linked to the
parent molecule through the alkyl portion of the
heteroarylalkyl.
[0101] The term "heterocycloalkyl" refers to a non-aromatic ring
which contains one or more oxygen, nitrogen or sulfur and includes
a monocyclic, bicyclic or tricyclic non-aromatic ring of 5 to 14
carbon atoms containing one or more heteroatoms selected from O, N
or S. The "heterocycloalkyl" as defined above may be optionally
substituted with a designated number of substituents as set forth
in the embodiment recited above. Examples of heterocycloalkyl
include, but are not limited to, morpholine, piperidine,
piperazine, pyrrolidine, and thiomorpholine. As used herein, alkyl
groups include straight chained and branched hydrocarbons, which
are completely saturated.
[0102] As used herein, the phrase "selectively modulate" means a
compound whose EC50 for the stated PPAR receptor is at least ten
fold lower than its EC50 for the other PPAR receptor subtypes.
[0103] When a compound represented by Structural Formula I has more
than one chiral substituent it may exist in diastereoisomeric
forms. The diastereoisomeric pairs may be separated by methods
known to those skilled in the art, for example chromatography or
crystallization and the individual enantiomers within each pair may
be separated using methods familiar to the skilled artisan. The
present invention includes each diastereoisomer of compounds of
Structural Formula I and mixtures thereof.
[0104] Certain compounds of Structural Formula I may exist in
different stable conformational forms which may be separable.
Torsional asymmetry due to restricted rotation about an asymmetric
single bond, for example because of steric hindrance or ring
strain, may permit separation of different conformers. The present
invention includes each conformational isomer of compounds of
Structural Formula I and mixtures thereof.
[0105] Certain compounds of Structural Formula I may exist in
zwitterionic form and the present invention includes each
zwitterionic form of compounds of Structural Formula I and mixtures
thereof.
[0106] "Pharmaceutically-acceptable salt" refers to salts of the
compounds of the Structural Formula I which are considered to be
acceptable for clinical and/or veterinary use. Typical
pharmaceutically-acceptable salts include those salts prepared by
reaction of the compounds of the present invention with a mineral
or organic acid or an organic or inorganic base. Such salts are
known as acid additional salts and base addition salts,
respectively. It will be recognized that the particular counterion
forming a part of any salt of this invention is not of a critical
nature, so long as the salt as a whole is
pharmaceutically-acceptable and as long as the counterion does not
contribute undesired qualities to the salt as a whole. These salts
may be prepared by methods known to the skilled artisan.
[0107] The compounds of Structural Formula I may contain one or
more chiral centers, and exist in different optically active forms.
When compounds of Structural Formula I contain one chiral center,
the compounds exist in two enantiomeric forms and the present
invention includes both enantiomers and mixtures of enantiomers,
such as racemic mixtures. The enantiomers may be resolved by
methods known to those skilled in the art, for example by formation
of diastereoisomeric salts which may be separated, for example, by
crystallization; formation of diastereoisomeric derivatives or
complexes which may be separated, for example, by crystallization,
gas-liquid or liquid chromatography; selective reaction of one
enantiomer with an enantiomer-specific reagent, for example
enzymatic esterification; or gas-liquid or liquid chromatography in
a chiral environment, for example on a chiral support for example
silica with a bound chiral ligand or in the presence of a chiral
solvent. It will be appreciated that where the desired enantiomer
is converted into another chemical entity by one of the separation
procedures described above, a further step is required to liberate
the desired enantiomeric form. Alternatively, specific enantiomers
may be synthesized by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer into the other by asymmetric transformation.
[0108] Certain compounds of Structural Formula I may exist in
different stable conformational forms that may be separable.
Torsional asymmetry due to restricted rotation about an asymmetric
single bond, for example because of steric hindrance or ring
strain, may permit separation of different conformers. The present
invention includes each conformational isomer of compounds of
Structural Formula I and mixtures thereof.
[0109] Certain compounds of Structural Formula I may exist in
zwitterionic form and the present invention includes each
zwitterionic form of compounds of Structural Formula I and mixtures
thereof.
[0110] Certain compounds of Structural Formula I and their salts
may also exist in the form of solvates, for example hydrates, and
the present invention includes each solvate and mixtures
thereof.
[0111] The term, "active ingredient" means the compounds
generically described by Structural Formula I as well as the
sterioisomers, salts, solvates, and hydrates,
[0112] The term "pharmaceutically acceptable" means that the
carrier, diluent, excipients and salt are pharmaceutically
compatible with the other ingredients of the composition.
Pharmaceutical compositions of the present invention are prepared
by procedures known in the art using well known and readily
available ingredients.
[0113] "Preventing" refers to reducing the likelihood that the
recipient will incur or develop any of the pathological conditions
described herein. The term "preventing" is particularly applicable
to a patient that is susceptible to the particular patholical
condition.
[0114] "Treating" refers to mediating a disease or condition and
preventing, or mitigating, its further progression or ameliorate
the symptoms associated with the disease or condition.
[0115] "Pharmaceutically-effective amount" means that amount of
active ingredient, that will elicit the biological or medical
response of a tissue, system, or mammal. Such an amount can be
administered prophylactically to a patient thought to be
susceptible to development of a disease or condition. Such amount
when administered prophylactically to a patient can also be
effective to prevent or lessen the severity of the mediated
condition. Such an amount is intended to include an amount which is
sufficient to modulate a selected PPAR receptor or to prevent or
mediate a disease or condition. Generally, the effective amount of
a Compound of Formula I will be between 0.02 through 5000 mg per
day. Preferably the effective amount is between 1 through 1,500 mg
per day. Preferably the dosage is from 1 through 1,000 mg per
day.
[0116] The desired dose may be presented in a single dose or as
divided doses administered at appropriate intervals.
[0117] A "mammal" is an individual animal that is a member of the
taxonomic class Mammalia. The class Mammalia includes humans,
monkeys, chimpanzees, gorillas, cattle, swine, horses, sheep, dogs,
cats, mice, and rats.
[0118] Administration to a human is most preferred. The compounds
and compositions of the present invention are useful for the
treatment and/or prophylaxis of cardiovascular disease, for raising
serum HDL cholesterol levels, for lowering serum triglyceride
levels and for lower serum LDL cholesterol levels. Elevated
triglyceride and LDL levels, and low HDL levels, are risk factors
for the development of heart disease, stroke, and circulatory
system disorders and diseases.
[0119] The compounds and compositions of the present invention are
also useful for treating and/or preventing obesity.
[0120] Further, these compounds and compositions are useful for the
treatment and/or prophylaxis of non-insulin dependent diabetes
mellitus (NIDDM) with reduced or no body weight gains by the
patients. Furthermore, the compounds and compositions of the
present invention are useful to treat or prevent acute or transient
disorders in insulin sensitivity, such as sometimes occur following
surgery, trauma, myocardial infarction, and the like. The physician
of ordinary skill will know how to identify humans who will benefit
from administration of the compounds and compositions of the
present invention.
[0121] The present invention further provides a method for the
treatment and/or prophylaxis of hyperglycemia in a human or
non-human mammal which comprises administering an effective amount
of active ingredient, as defined herein, to a hyperglycemic human
or non-human mammal in need thereof.
[0122] The invention also relates to the use of a compound of
Formula I as described above, for the manufacture of a medicament
for treating a PPAR receptor mediated condition.
[0123] A therapeutically effective amount of a compound of
Structural Formula I can be used for the preparation of a
medicament useful for treating Metabolic syndrome, diabetes,
treating obesity, lowering tryglyceride levels, lowering serum LDL
levels, raising the plasma level of high density lipoprotein, and
for treating, preventing or reducing the risk of developing
atherosclerosis, and for preventing or reducing the risk of having
a first or subsequent atherosclerotic disease event in mammals,
particularly in humans. In general, a therapeutically effective
amount of a compound of the present invention typically reduces
serum triglyceride levels of a patient by about 20% or more, and
increases serum HDL levels in a patient. Preferably, HDL levels
will be increased by about 30% or more. In addition, a
therapeutically effective amount of a compound, used to prevent or
treat NIDDM, typically reduces serum glucose levels, or more
specifically HbAlc, of a patient by about 0.7% or more.
[0124] When used herein Metabolic syndrome includes pre-diabetic
insulin resistance syndrome and the resulting complications
thereof, insulin resistance, non-insulin dependent diabetes,
dyslipidemia, hyperglycemia obesity, coagulopathy, hypertension and
other complications associated with diabetes. The methods and
treatments mentioned herein include the above and encompass the
treatment and/or prophylaxis of any one of or any combination of
the following: pre-diabetic insulin resistance syndrome, the
resulting complications thereof, insulin resistance, Type II or
non-insulin dependent diabetes, dyslipidemia, hyperglycemia,
obesity and the complications associated with diabetes including
cardiovascular disease, especially atherosclerosis.
[0125] The compositions are formulated and administered in the same
general manner as detailed herein. The compounds of the instant
invention may be used effectively alone or in combination with one
or more additional active agents depending on the desired target
therapy. Combination therapy includes administration of a single
pharmaceutical dosage composition which contains a compound of
Structural Formula I, a stereoisomer, salt, solvate and/or hydrate
thereof ("Active Igredient") and one or more additional active
agents, as well as administration of a compound of Active
Ingredient and each active agent in its own separate pharmaceutical
dosage formulation. For example, an Active Ingredient and an
insulin secretogogue such as biguanides, thiazolidinediones,
sulfonylureas, insulin, or .alpha.-glucosidose inhibitors can be
administered to the patient together in a single oral dosage
composition such as a tablet or capsule, or each agent administered
in separate oral dosage formulations. Where separate dosage
formulations are used, an Active Ingredient and one or more
additional active agents can be administered at essentially the
same time, i.e., concurrently, or at separately staggered times,
i.e., sequentially; combination therapy is understood to include
all these regimens.
[0126] An example of combination treatment or prevention of
atherosclerosis may be wherein an Active Ingredient is administered
in combination with one or more of the following active agents:
antihyperlipidemic agents; plasma HDL-raising agents;
antihypercholesterolemic agents, fibrates, vitamins, aspirin, and
the like. As noted above, the Active Ingredient can be administered
in combination with more than one additional active agent.
[0127] Another example of combination therapy can be seen in
treating diabetes and related disorders wherein the Active
Ingredient can be effectively used in combination with, for
example, sulfonylureas, biguanides, thiazolidinediones,
.alpha.-glucosidase inhibitors, other insulin secretogogues,
insulin as well as the active agents discussed above for treating
atherosclerosis.
[0128] The Active Ingredients of the present invention, have
valuable pharmacological properties and can be used in
pharmaceutical compositions containing a therapeutically effective
amount of Active Ingredient of the present invention, in
combination with one or more pharmaceutically acceptable
excipients. Excipients are inert substances such as, without
limitation carriers, diluents, fillers, flavoring agents,
sweeteners, lubricants, solubilizers, suspending agents, wetting
agents, binders, disintegrating agents, encapsulating material and
other conventional adjuvants. Proper formulation is dependent upon
the route of administration chosen. Pharmaceutical compositions
typically contain from about 1 to about 99 weight percent of the
Active Ingredient of the present invention.
[0129] Preferably, the pharmaceutical formulation is in unit dosage
form. A "unit dosage form" is a physically discrete unit containing
a unit dose, suitable for administration in human subjects or other
mammals. For example, a unit dosage form can be a capsule or
tablet, or a number of capsules or tablets. A "unit dose" is a
predetermined quantity of the Active Ingredient of the present
invention, calculated to produce the desired therapeutic effect, in
association with one or more pharmaceutically-acceptable
excipients. The quantity of active ingredient in a unit dose may be
varied or adjusted from about 0.1 to about 1500 milligrams or more
according to the particular treatment involved. It may be preferred
that the unit dosage is from about 1 mg to about 1000 mg.
[0130] The dosage regimen utilizing the compounds of the present
invention is selected by one of ordinary skill in the medical or
veterinary arts, in view of a variety of factors, including,
without limitation, the species, age, weight, sex, and medical
condition of the recipient, the severity of the condition to be
treated, the route of administration, the level of metabolic and
excretory function of the recipient, the dosage form employed, the
particular compound and salt thereof employed, and the like.
[0131] Advantageously, compositions containing the compound of
Structural Formula I or the salts thereof may be provided in dosage
unit form, preferably each dosage unit containing from about 1 to
about 500 mg be administered although it will, of course, readily
be understood that the amount of the compound or compounds of
Structural Formula I actually to be administered will be determined
by a physician, in the light of all the relevant circumstances.
[0132] Preferably, the compounds of the present invention are
administered in a single daily dose, or the total daily dose may be
administered in divided doses, two, three, or more times per day.
Where delivery is via transdermal forms, of course, administration
is continuous.
[0133] Suitable routes of administration of pharmaceutical
compositions of the present invention include, for example, oral,
eyedrop, rectal, transmucosal, topical, or intestinal
administration; parenteral delivery (bolus or infusion), including
intramuscular, subcutaneous, intramedullary injections, as well as
intrathecal, direct intraventricular, intravenous, intraperitoneal,
intranasal, or intraocular injections. The compounds of the
invention can also be administered in a targeted drug delivery
system, such as, for example, in a liposome coated with endothelial
cell-specific antibody.
[0134] Solid form formulations include powders, tablets and
capsules.
[0135] Sterile liquid formulations include suspensions, emulsions,
syrups, and elixirs.
[0136] Pharmaceutical compositions of the present invention can be
manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or lyophilizing
processes.
[0137] The following pharmaceutical formulations 1 and 2 are
illustrative only and are not intended to limit the scope of the
invention in any way.
Formulation 1
[0138] Hard gelatin capsules are prepared using the following
ingredients:
TABLE-US-00001 Quantity (mg/capsule) Active Ingredient 250 Starch,
dried 200 Magnesium stearate 10 Total 460 mg
Formulation 2
[0139] A tablet is prepared using the ingredients below:
TABLE-US-00002 Quantity (mg/tablet) Active Ingredient 250
Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic
acid 5 Total 665 mg
The components are blended and compressed to form tablets each
weighing 665 mg.
[0140] In yet another embodiment of the compounds of the present
invention, the compound is radiolabelled, such as with carbon-14,
or tritiated. Said radiolabelled or tritiated compounds are useful
as reference standards for in vitro assays to identify new
selective PPAR receptor agonists.
[0141] The compounds of the present invention can be useful for
modulating insulin secretion and as research tools. Certain
compounds and conditions within the scope of this invention are
preferred. The following conditions, invention embodiments, and
compound characteristics listed in tabular form are preferred
features and may be independently combined to produce a variety of
preferred compounds and process conditions. The following list of
embodiments of this invention is not intended to limit the scope of
this invention in any way.
[0142] Some preferred characteristics of compounds of formula I
are: [0143] (a) R3 is methyl; [0144] (b) R4 is hydrogen; [0145] (c)
R3 and R4 are each hydrogen; [0146] (d) R3 and R4 are each methyl;
[0147] (e) A is carboxyl; [0148] (f) X is --O--; [0149] (g) X is
--S--; [0150] (h) X is a bond; [0151] (i) U is CH; [0152] (j) U is
CH.sub.2CH; [0153] (k) U is substituted with
arylC.sub.1-C.sub.4alkyl; [0154] (l) R9 is methyl; [0155] (m) R9 is
hydrogen; [0156] (n) R9 is C.sub.1-C.sub.3 alkyl; [0157] (o) R8 is
methyl; [0158] (p) R8 and R9 are each hydrogen; [0159] (g) R10 is
CF.sub.3; [0160] (r) R10 is haloalkyl; [0161] (s) R10 is
haloalkyloxy; [0162] (t) R11 is hydrogen [0163] (u) R10 and R11 are
each hydrogen; [0164] (v) R11 is haloalkyl; [0165] (w) R1 is
substituted C.sub.1-C.sub.4 alkyl; [0166] (x) R1 is hydrogen;
[0167] (y) Y is O; [0168] (z) Y is S; [0169] (aa) Y is C; [0170]
(bb) E is C(R3)(R4)A; [0171] (cc) R3 is hydrogen; [0172] (dd) R3 is
C.sub.1-22 alkyl; [0173] (ee) R.sup.4 is C.sub.1-C.sub.2 alkyl;
[0174] (ff) R4 is selected from the group consisting of alkoxy and
aryloxy; [0175] (gg) A is COOH; [0176] (hh) Aliphatic linker is
saturated; [0177] (ii) Aliphatic linker is substituted with
C.sub.1-C.sub.3 alkyl; [0178] (jj) Aliphatic linker is substituted
with arylC.sub.1-C.sub.4alkyl; [0179] (kk) Aliphatic linker is
C.sub.1-C.sub.3 alkyl; [0180] (ll) Aliphatic linker is
C.sub.1-C.sub.2 alkyl; [0181] (mm) Aliphatic linker is
C.sub.2-C.sub.3 alkyl and one carbon is replaced with an --O--;
[0182] (nn) Aliphatic linker is C.sub.1-C.sub.3 alkyl and one
carbon is replaced with an --S--; [0183] (oo) Aryl is a phenyl
group; [0184] (pp) A compound of Formula I that selectively
modulates a delta receptor; [0185] (qq) An Active Ingredient, as
described herein, that is a PPAR coagaonist that modulates a gamma
receptor and a delta receptor; [0186] (rr) An Active Ingredient, as
described herein, for use in the treatment of cardiovascular
disease; [0187] (ss) An Active Ingredient, as described herein, for
use in the treatment of Metabolic syndrome; [0188] (tt) An Active
Ingredient for use in the control of obesity; [0189] (uu) An Active
Ingredient for use in treating diabetes; [0190] (vv) An Active
Ingredient that is a PPAR receptor agonist; [0191] (ww) A compound
of Formula I wherein the headpiece of Formula I is:
[0191] ##STR00005## [0192] (xx) A compound of Formula I selected
from the group consisting of
(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-prop-
ylsulfanyl}-phenoxy)-acetic acid,
(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-prop-
ylsulfanyl}-phenoxy)-acetic acid,
3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-pr-
opylsulfanyl}-phenyl)-propionic acid, and
(3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phen-
yl)-acetic; [0193] (yy) A compound of Formula I that is
(3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phen-
yl)-acetic; [0194] (zz) A compound of Formula I selected from the
group consisting of:
TABLE-US-00003 [0194] Compound Name ##STR00006##
3-{2-Methyl-4-[5-(4- trifluoromethyl-phenyl)-
thiophen-2-ylmethoxy]- phenyl}-propionic acid ##STR00007##
{2-Methyl-4-[5-(4- trifluoromethyl-phenyl)- thiophen-2-ylmethoxy]-
phenoxy}-acetic acid ##STR00008## 3-{2-Methyl-4-[3-phenyl-5-
(4-trifluoromethyl-phenyl)- thiophen-2-ylmethoxy]-
phenyl}-propionic acid ##STR00009## 3-{4-[3,5-Bis-(4-
trifluoromethyl-phenyl)- thiophen-2-ylmethoxy]-2-
methyl-phenyl}-propionic acid ##STR00010##
3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-
phenyl)-thiophen-2-yl]- propoxy}-phenyl)-propionic acid
##STR00011## 3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-
phenyl)-thiophen-2-yl]- butoxy}-phenyl)-propionic acid ##STR00012##
3-(2-Methyl-4-{2-methyl-1- [3-methyl-5-(4- trifluoromethyl-phenyl)-
thiophen-2-yl]-propoxy}- phenyl)-propionic acid ##STR00013##
3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-
phenyl)-thiophen-2-yl]-2- phenyl-ethoxy}-phenyl)- propionic acid
##STR00014## 3-(4-{1-[3-(2-Hydroxy- ethyl)-5-(4-trifluoromethyl-
phenyl)-thiophen-2-yl]- ethylsulfanyl}-2-methyl- phenyl)-propionic
acid
Synthesis
[0195] Compounds of the present invention have been formed as
specifically described in the examples. Further, many compounds are
prepared as more generally using a) alkylation of phenol/thiophenol
with a halide, b) a Mitsunobu protocol (O. Mitsunobu, 1981
Synthesis, p1); c) and other methods known to the skilled artisan.
Alternative synthesis methods may also be effective and known to
the skilled artisan.
[0196] For example, an intermediate like A is alkylated with an
alkylating agent B in the presence of a base (e.g. K2CO3, Cs2CO3
etc.). Hydrolysis in the presence of aqueous NaOH or LiOH gave the
acid product.
##STR00015##
[0197] Alternatively, an intermediate like A is coupled with an
alcohol C under Mitsunobu reaction condition (DEAD/PPh3, ADDP/Pbu3
etc.). Hydrolysis in the presence of aqueous NaOH or LiOH gave the
acid product:
##STR00016##
[0198] Thioether analogs could also be prepared by a ZnI2 mediated
thioether formation reaction as shown below:
##STR00017##
[0199] 3-Substituted thiophene analogs can be made by the following
schemes:
##STR00018##
##STR00019##
[0200] Thiophene intermediates B and C can be made in one of the
following methods:
##STR00020##
##STR00021##
##STR00022##
EXEMPLIFICATION
[0201] The Examples provided herein are illustrative of the
invention claimed herein and are not intended to limit the scope of
the claimed invention in any way.
Instrumental Analysis
[0202] Infrared spectra are recorded on a Perkin Elmer 781
spectrometer. .sup.1H NMR spectra are recorded on a Varian 400 MHz
spectrometer at ambient temperature. Data are reported as follows:
chemical shift in ppm from internal standard tetramethylsilane on
the .delta. scale, multiplicity (b=broad, s=singlet, d=doublet,
t=triplet, q=quartet, qn=quintet and m=multiplet), integration,
coupling constant (Hz) and assignment. .sup.13C NMR are recorded on
a Varian 400 MHz spectrometer at ambient temperature. Chemical
shifts are reported in ppm from tetramethylsilane on the .delta.
scale, with the solvent resonance employed as the internal standard
(CDCl.sub.3 at 77.0 ppm and DMSO-D.sub.6 at 39.5 ppm). Combustion
analyses are performed by Eli Lilly & Company Microanalytical
Laboratory. High resolution mass spectra are obtained on VG ZAB 3F
or VG 70 SE spectrometers. Analytical thin layer chromatography is
performed on EM Reagent 0.25 mm silica gel 60-F plates.
Visualization is accomplished with UV light.
Preparation 1
2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic Acid
##STR00023##
[0203] Step A
2-(4-Benzyloxy-2-formylphenoxy)-2-methyl Propionic Acid Ethyl
Ester
[0204] 5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj,
T. Arch. Pharm., 1975, 308 (5), 339-346) (2.28 g, 10.0 mmol), ethyl
bromoisobutyrate (2.2 mL, 15 mmol), and cesium carbonate (3.26 g,
10.0 mmol) in dry DMF (25 mL) are heated at 80.degree. C. for 18 h.
The reaction mixture is cooled and partitioned between water (30
mL) and ether (75 mL). The organic layer is washed with brine (15
mL). The aqueous layers are back-extracted with ethyl acetate (30
mL), and the organic layer is washed with brine (20 mL). The
combined organic layers are dried (Na.sub.2SO.sub.4) and
concentrated to a brown oil. The crude product is purified by flash
chromatography using hexanes:ethyl acetate (2.5:1) to give a pale
yellow solid (3.04 g, 89%): mp 65.degree. C.; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q,
2H, J=7.1 Hz), 6.81 (d, 1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0
Hz), 7.30-7.43 (m, 6H); MS (ES) m/e 343.1 [M+1].
Step B
2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic Acid Ethyl
Ester
[0205] 2-(4-Benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid
ethyl ester (9.00 g, 26.3 mmol) in ethanol (250 mL) is treated with
5% Pd/C (1.25 g) and hydrogen (60 psi, rt, overnight). Additional
5% Pd/C (1.25 g) is added, and the reaction is continued for 6 h at
40.degree. C. The mixture is filtered and concentrated to a tan oil
(6.25 g). This oil contained 9 mol % of
2-(4-Hydroxy-2-hydroxymethyl-phenoxy)-2-methyl-propionic acid ethyl
ester. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.26 (t, 3H, J=7.3
Hz), 1.51 (s, 6H), 2.14 (s, 3H), 4.24 (q, 2H, J=7.3 Hz), 5.68 (brs,
1H), 6.47 (dd, 1H, J=3.4, 8.8 Hz), 6.59 (d, 1H, J=8.3 Hz), 6.60
(brs, 1H).
[0206] The following compound is prepared in a similar manner:
Preparation 2
2-(4-Hydroxy-2-methyl-phenoxy)-acetic Acid
##STR00024##
[0208] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.28 (t, 3H, J=7.1
Hz), 2.24 (s, 3H), 4.25 (q, 2H, J=7.1 Hz), 4.55 (s, 2H), 6.56 (dd,
1H, J=2.7, 8.5 Hz), 6.61 (d, 1H, J=8.3 Hz), 6.65 (d, 2H, J=2.9
Hz).
Preparation 3
(4-Hydroxy-2-propyl-phenoxy)-acetic Acid Ethyl Ester
##STR00025##
[0209] Step A
4-Benzyloxy-2-propylphenol
[0210] 2-Allyl-4-benzyloxyphenol (WO 9728137 A1 19970807, Adams, A.
D. et al.) (5.00 g, 20.8 mmol) in ethyl acetate (40 mL) is treated
with 5% Pd/C (0.25 g) and hydrogen (1 atm) at ambient temperature
for 18 h. The mixture is filtered and concentrated. The crude
product is purified on a Biotage medium pressure chromatography
system using a 40 L normal phase cartridge and eluted with 10%
ethyl acetate in hexanes to give a tan solid (2.8 g, 56%). Rf=0.33
(25% EtOAc/Hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.44-7.31 (m, 5H) 6.78 (s, 1H), 6.69 (d, J=1.5 Hz, 2H), 5.00 (s,
2H), 4.31 (s, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H),
0.97 (t, J=7.3 Hz, 3H).
Step B
(4-Benzyloxy-2-propylphenoxy)acetic Acid Ethyl Ester
[0211] A solution of 4-benzyloxy-2-propylphenol (0.50 g, 1.94 mmol)
in dry DMF (7 mL) is cooled in an ice bath and treated with NaH
(0.15 g, 3.8 mmol, 60% oil dispersion). The ice bath is removed,
ethyl bromoacetate (0.43 mL, 3.9 mmol) is added, and the mixture is
placed in an oil bath (T=85.degree. C.). After 18 h, the reaction
mixture is cooled and concentrated in vacuo. The residue is diluted
with EtOAc, washed with brine (2.times.), dried (Na.sub.2SO.sub.4),
and concentrated. The crude product is purified by radial
chromatography using 10% ethyl acetate in hexanes to give a tan
solid (0.62 g, 97%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.44-7.31 (m, 5H), 6.82 (d, J=2.9 Hz, 1H), 6.72 (dd, J=8.8, 2.9 Hz,
1H), 6.66 (d, J=8.8 Hz, 1H), 5.00 (s, 2H), 4.57 (s, 2H), 4.25 (q,
J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2-H),
1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 329
(M+1).
Step C
(4-Hydroxy-2-propylphenoxy)acetic Acid Ethyl Ester
[0212] A solution of (4-benzyloxy-2-propylphenoxy)acetic acid ethyl
ester (0.60 g, 1.83 mmol) in THF (15 mL) is treated with 5% Pd/C
(75 mg) and hydrogen (60 psi) at ambient temperature for 24 h. The
mixture is filtered and concentrated. The crude product is purified
by radial chromatography using 15% ethyl acetate in hexanes to give
a tan solid (0.25 g, 57%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.66 (d, J=2.9 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.57 (dd,
J=8.8, 2.9 Hz, 1H), 4.56 (s, 1H), 4.40 (s, 1H), 4.25 (q, J=7.2 Hz,
2H), 2.61 (t, J=7.6 Hz, 2H), 1.63 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1
Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 239 (M+1).
Preparation 4
(3-Bromo-4-hydroxy-phenoxy)-acetic Acid Ethyl Ester
##STR00026##
[0214] To a solution of (4-hydroxy-phenoxy)-acetic acid ethyl ester
(0.59 g, 3 mmol) in acetic acid (1.5 mL) is added bromine (0.48 g,
9 mmol) in acetic acid (0.5 mL) at room temperature. After 5 min,
solvent is evaporated and purified by column chromatography on
silica gel giving the title compound (0.6 g).
Preparation 5
(4-Mercapto-Phenoxy)-acetic Acid Ethyl Ester
##STR00027##
[0215] Step A
(4-Chlorosulfonyl-phenoxy)-acetic Acid Ethyl Ester
[0216] Phenoxy-acetic acid ethyl ester (9.1 mL) is added to
chlorosulfonic acid (15 mL) at 0.degree. C. dropwise. The reaction
is stirred at 0.degree. C. for 30 min, it is allowed to warm to
room temperature. After 2 hrs, the reaction mixture is poured into
ice, solid product is collected by filtration and dried under
vacuum.
Step B
(4-Mercapto-phenoxy)-acetic Acid Ethyl Ester
[0217] To a mixture of (4-chlorosulfonyl-phenoxy)-acetic acid ethyl
ester (0.98 g, 3.5 mmol) and tin powder (2.1 g) in ethanol (4.4 mL)
is added HCl in dioxane (1.0 M, 4.4 mL) under nitrogen. The mixture
is heated to reflux for 2 hrs, it is poured into ice and methylene
chloride and filtered. The layers are separated and extracted with
methylene chloride, dried and concentrated. The crude product is
used for next step without purification.
[0218] The following compounds are made in a similar manner:
Preparation 6
(4-Mercapto-2-methyl-phenoxy)-acetic Acid Ethyl Ester
##STR00028##
[0220] This compound can also be made by the following procedure:
To a stirred suspension of Zn powder (10 .mu.m, 78.16 g, 1.2 mol)
and dichlorodimethyl silane (154.30 g, 145.02 mL, 1.2 mol) in 500
mL of dichloroethane is added a solution of
(4-chlorosulfonyl-2-methyl-phenoxy)-acetic acid ethyl ester (100 g,
0.34 mol) and 1,3-dimethylimidazolidin-2-one (116.98 g, 112.05 mL,
1.02 mol) in 1 L of DCE. Addition is at a rate so as to maintain
the internal temperature at .about.52.degree. C., cooling with
chilled water as necessary. After addition is complete, the mixture
is heated at 75.degree. C. for 1 hour. It is then cooled to room
temperature, filtered and concentrated iv. Add MTBE, washed twice
with saturated LiCl solution concentrate iv again. Take up the
residue in CH.sub.3CN, wash with hexane (4.times.) and concentrate
iv to yield a biphasic mixture. Let stand in a separatory funnel
and separate layers, keeping the bottom layer for product.
Filtration through a plug of silica gel (1 Kg, 25% EtOAc/hexane)
and subsequent concentration yields 61 g (79%) of a clear,
colorless oil.
[0221] NMR (DMSO-d.sub.6) .delta. 7.1 (s, 1H), 7.05 (dd, 1H), 6.75
(d, 1H), 5.03 (s, 1H), 4.75 (s, 2H), 4.15 (q, 2H), 2.15 (s, 3H),
1.2 (t, 3H).
Preparation 7
(4-Mercapto-2-propyl-phenoxy)-acetic Acid Ethyl Ester
##STR00029##
[0222] Preparation 8
3-(4-Hydroxy-2-methyl-phenyl)-propionic Acid Methyl Ester
##STR00030##
[0223] Step A
4-Bromo-3-methyl-phenyl Benzyl Ester
[0224] To a solution of 4-Bromo-3-methyl-phenol (20.6 g, 0.0.11
mol) in DMF (100 mL) is added Cs2CO3 (54 g, 0.165 mol), followed by
benzyl bromide (14.4 mL). After stirred at 60.degree. C. for 40 h,
the reaction mixture is diluted with ethyl acetate, filtered
through celite. The filtrate is washed with water and brine, dried
over sodium sulfate, concentration yields the title product (27
g).
Step B
3-(4-Benzyloxy-2-methyl-phenyl)-propionic Acid Methyl Ester
[0225] To a solution of 4-bromo-3-methyl-phenyl benzyl ester (7.6
g, 27.4 mmol) in propronitrile (200) mL) is added methyl acrylate
(10 mL) and diisopropylethyl amine (9.75 mL), the solution is
degassed and filled with nitrogen for three times. To this mixture
are added tri-o-tolyl-phosphane (3.36 g) and palladium acetate
(1.25 g) under nitrogen, then heated at 110.degree. C. overnight,
cooled to room temperature, filtered through celite. The solvent is
evaporated, the residue is taken into ethyl acetate and washed with
water and brine, dried over sodium sulfate. Concentration and
column chromatography on silica gel eluted with hexanes and ethyl
acetate yields the title compound (6.33 g).
Step C
3-(4-Hydroxy-2-methyl-phenyl)-propionic Acid Methyl Ester
[0226] A mixture of 3-(4-Benzyloxy-2-methyl-phenyl)-propionic acid
methyl ester (13.7 g, 48.5 mmol) and Pd/C (5%, 13.7 g) in MeOH (423
mL) is stirred under 60 psi of hydrogen for 24 hrs. Catalyst is
filtered off, filtrate is concentrated giving the title compound
(8.8 g, 93.5%).
Preparation 9
3-(4-Mercapto-2-methyl-phenyl)-propionic Acid Methyl Ester
##STR00031##
[0227] Step A
3-(4-Dimethylthiocarbamoyloxy-2-methyl-phenyl)-propionic Acid
Methyl Ester
[0228] 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester
(5.0 g, 25.75 mmol) is dissolved into dry dioxane (100 mL) and
combined with 4-dimethylamino pyridine (0.500 g, 2.6 mmol),
triethylamine (7.0 mL, 51.5 mmol), and dimethylaminothiocarbomoyl
chloride (4.5 g, 32.17 mmol). The reaction is heated to reflux
under nitrogen. The reaction is monitored by TLC until all of the
phenol is consumed, 20 h. After cooling to room temperature, the
reaction is diluted with ethyl acetate (200 mL). Water (75 mL) is
added and the two layers are separated. The organic layer is washed
with brine (75 mL) then dried over anhydrous sodium sulfate. The
solvent is removed and the residue is dried under vacuum.
Step B
3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic Acid
Methyl Ester
[0229] 3-(4-Dimethylthiocarbamoyloxy-2-methyl-phenyl)-propionic
acid methyl ester, taken crude from the previous step, is diluted
with 75 mL of tetradecane and heated to reflux under nitrogen. The
reaction is monitored by TLC until all the conversion is complete,
20 h. The reaction is allowed to cool to room temperature, then the
tetradecane is decanted away from the resulting oil. The residue is
rinsed several times with hexanes. This oil is then purified using
flash column chromatography, yielding 5.01 g, or 69% (2 steps) of
the product.
Step C
3-(4-Mercapto-2-methyl-phenyl)-propionic Acid Methyl Ester
[0230] 3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic
acid methyl ester (5.01 g, 17.8 mmol) is diluted with methanol (30
mL) and to this is added sodium methoxide (1.7 mL of 4M in
methanol, 7.23 mmol). The reaction is heated to reflux under
nitrogen and monitored by TLC. After complete conversion, 20 h.,
the reaction is allowed to cool to room temperature. The reaction
is neutralized with 1N HCl (7.23 mL) and diluted with ethyl acetate
(150 mL). The two phases are separated and the organic layer is
washed with water (75 mL), then brine (75 mL). The organic layer is
then dried over anhydrous sodium sulfate, then concentrated to
yield 4.43 g crude product that is used without further
purification.
Preparation 10
4-(2-Methoxycarbonyl-ethyl)-3-methyl-benzoic acid
##STR00032##
[0231] Step A
4-Bromo-3-methyl-benzoic Acid Benzyl Ester
[0232] To a solution of 4-Bromo-3-methyl-benzoic acid benzyl (25.3
g, 0.118 mol) in DMF (200 mL) is added Cs2CO3 (76.6 g, 0.235 mol),
followed by benzyl bromide (15.4 mL). After stirred at room
temperature for 2 h, the reaction mixture is diluted with ethyl
acetate, filtered through celite. The filtrate is washed with water
and brine, dried over sodium sulfate, concentration yields the
title product.
Step B
4-(2-Methoxycarbonyl-vinyl)-3-methyl-benzoic Acid Benzyl Ester
[0233] To a solution of 4-bromo-3-methyl-benzoic acid benzyl ester
(36 g, 118 mmol) in propronitrile (1000 mL) is added methyl
acrylate (43.3 mL) and diisopropylethyl amine (42 mL), the solution
is degassed and filled with nitrogen for three times. To this
mixture are added tri-o-tolyl-phosphane (14.5 g) and palladium
acetate (5.34 g) under nitrogen, then heated at 110.degree. C.
overnight, cooled to room temperature, filtered through celite. The
solvent is evaporated, the residue is taken into ethyl acetate and
washed with water and brine, dried over sodium sulfate.
Concentration and column chromatography on silica gel eluted with
hexanes and ethyl acetate yields the title compound (31 g,
84.7%).
Step C
4-(2-Methoxycarbonyl-ethyl)-3-methyl-benzoic Acid
[0234] A mixture of 4-(2-methoxycarbonyl-vinyl)-3-methyl-benzoic
acid benzyl ester (11.6 g, 37.4 mmol) and Pd/C (5%, 1.5 g) in THF
(300 mL) and methanol (100 mL) is stirred under 60 psi of hydrogen
overnight. Catalyst is filtered off, filtrate is concentrated
giving the title compound (8.3 g, 100%).
Preparation 11
(4-Hydroxy-2-methyl-phenyl)-acetic Acid Methyl Ester
##STR00033##
[0235] Step A
[0236] 4-Methoxy-2-methylbenzoic acid (2.5 g, 15.04 mmol) is
stirred in thionyl chloride (50 mL) at reflux 2 hr. The mixture is
concentrated and diluted with toluene (10 mL) and concentrated. The
resulting solid is dried under vacuum 18 hr. The resulting acid
chloride is stirred in 20 mL ether at 0 deg C. A solution of
diazomethane (39.6 mmol) in ether (150 mL) is added to the acid
chloride solution and stirred 18 hr. The resulting diazoketone
solution is concentrated. The residue is stirred in methanol (100
mL) and a solution of silver benzoate in triethylamine (1.0 g in 10
mL) is added and the reaction is heated to 60 deg C. and stirred 1
hr. The mixture is concentrated, diluted with 1.0 N aqueous
hydrochloric acid (20 mL), extracted to three portions of ethyl
acetate (50 mL each). The extracts are combined, washed with
aqueous saturated sodium hydrogen carbonate, water, and brine (50
mL each), dried over anhydrous magnesium sulfate, filtered and
concentrated. The residue is purified via silica gel chromatography
eluting with 9:1 hexanes:ethyl acetate to afford 1.5 g (51%) of the
homologated ester as a white solid.
Step B
[0237] (4-Methoxy-2-methyl-phenyl)-acetic acid methyl ester (1.5 g,
7.72 mmol) is stirred in dichloromethane (50 mL) at 0 deg. C.
Aluminum chloride (4.13 g, 31 mmol) is added followed by ethane
thiol (2.9 mL, 38.6 mmol). The resulting mixture is stirred at room
temperature for 2 hr. Water (50 mL) is added and the product is
extracted into ethyl acetate (3.times.50 ml), the extracts are
combined, dried over anhydrous magnesium sulfate, filtered, and
concentrated to afford the title compound as a colorless oil, 1.4
g, 100%. MS M.sup.++1 181. The structure is confirmed by .sup.1H
NMR spectroscopy.
Preparation 12
(3-Hydroxy-phenyl)-acetic Acid Methyl Ester
##STR00034##
[0238] Step A
(3-Hydroxy-phenyl)-acetic Acid Methyl Ester
[0239] (3-Hydroxy-phenyl)-acetic acid (5.0 g, 32.86 mmol) is
stirred in methanol (100 mL) and concentrated (98%) sulfuric acid
(3.0 mL) is added. The mixture is heated to reflux 18 hr. The
reaction is cooled and concentrated. The residue is diluted with
water (100 mL) and extracted with ethyl acetate (3.times.50 mL).
The combined extracts are dried over anhydrous magnesium sulfate,
filtered, and concentrated to yield the title compound as an orange
oil, 5.46 g, 100%. MS M.sup.++1 167. The structure is confirmed by
.sup.1H NMR spectroscopy.
[0240] The following compounds are made in a similar manner:
Preparation 13
(3-Hydroxy-4-methoxy-phenyl)-acetic Acid Methyl Ester
##STR00035##
[0242] An orange oil. MS M.sup.++1 197. The structure is confirmed
by .sup.1H NMR spectroscopy.
Preparation 14
3-(3-Hydroxy-phenyl)-propionic Acid Methyl Ester
##STR00036##
[0243] Step A
3-(3-Hydroxy-phenyl)-propionic Acid Methyl Ester
[0244] An orange oil. MS M.sup.++1 181. The structure is confirmed
by .sup.1H NMR spectroscopy.
Preparation 15
(3-Mercapto-phenyl)-acetic Acid Methyl Ester
##STR00037##
[0245] Step A
(3-Dimethylthiocarbamoyloxy-phenyl)-acetic Acid Methyl Ester
[0246] A mixture of (3-Hydroxy-phenyl)-acetic acid methyl ester
(5.5 g, 33.1 mmol), N,N-dimethyl thiocarbamoyl chloride (5.11 g,
41.38 mmol), triethylamine (9.2 mL, 66.2 mmol), N,N-dimethylamino
pyridine (0.4 g, 3.31 mmol) and dioxane (50 mL) is stirred at
reflux 18 hr. The mixture is concentrated, partioned between 1M
aqueous hydrochloric acid (200 mL) and ethyl acetate (3.times.75
mL). The combined organic extracts are dried over anhydrous
magnesium sulfate, filtered, concentrated, and purified via silica
chromatography eluting the product with dichloromethane to afford
the title compound as a brown oil, 6.8 g, 81%. MS M.sup.++1 254.
The structure is confirmed by .sup.1H NMR spectroscopy.
Step B
(3-Dimethylcarbamoylsulfanyl-phenyl)-acetic Acid Methyl Ester
[0247] (3-Dimethylthiocarbamoyloxy-phenyl)-acetic acid methyl ester
(6.8 g, 26.84 mmol) is stirred in tetradecane (30 mL) at 255 deg C.
for 8 hr. The mixture is cooled, the residue is purified by silica
chromatography eluting the product with hexanes to 1:1
hexanes:ethyl acetate to afford the title compound as an orange
oil, 4.9 g, 58 W. MS M.sup.++1 254. The structure is confirmed by
.sup.1H NMR spectroscopy.
Step C
(3-Mercapto-phenyl)-acetic Acid Methyl Ester
[0248] A mixture of (3-dimethylcarbamoylsulfanyl-phenyl)-acetic
acid methyl ester (2.0 g, 7.9 mmol), potassium hydroxide (1.4 g, 24
mmol) methanol (50 mL), and water (5 mL) is stirred at reflux 3 hr.
The mixture is concentrated, and product partitioned between 1M
aqueous hydrochloric acid (50 mL) and ethyl acetate (3.times.75
mL). The combined extracts are dried over anhydrous magnesium
sulfate, filtered and concentrated. The residue is taken up in
methanol (50 mL), 2 mL concentrated sulfuric acid is added, and the
mixture refluxed 3 hr. The mixture is concentrated, and the residue
purified by silica chromatography eluting with 7:3 hexanes:ethyl
acetate to afford the title compound as a pale yellow oil, 1.0 g,
69%. MS M.sup.++1 183. The structure is confirmed by .sup.1H NMR
spectroscopy.
Preparation 16
3-(4-Iodomethyl-2-methyl-phenyl)-propionic Acid Methyl Ester
##STR00038##
[0249] Step A
3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic Acid Methyl Ester
[0250] A mixture of methyl-4-bromo-3-methylbenzoate (5.7 g, 24.88
mmol), lithium aluminum hydride (29 mL, 29 mmol, 1 M solution in
tetrahydrofuran) and tetrahydrofuran (100 mL) is stirred in
ice/water for 1 hr. The reaction is quenched with aqueous
hydrochloric acid (50 mL, 1 M). The product is extracted into ethyl
acetate (3.times.100 mL). The combined extracts are dried over
anhydrous magnesium sulfate, filtered and concentrated. The crude
product is taken up in propionitrile (100 mL). Methylacrylate (10
mL, 121.5 mmol), palladium acetate (1.12 g, 5 mmol),
tri-o-tolylphosphine (3.0 g, 10 mmol), and N,N-diisopropyl
ethylamine (8.7 mL, 50 mmol) are sequentially added and the
resulting reaction mixture is heated to 110 deg C. 3 hr. The
mixture is concentrated, and the residue diluted with aqueous
hydrochloric acid (100 mL, 1M). The product is extracted with
dichloromethane (2.times.100 mL) and ethyl acetate (100 mL). The
combined extracts are dried over anhydrous magnesium sulfate,
filtered, concentrated, and purified via silica chromatography
eluting with 7:3 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate
to afford the pure product as a yellow oil, 4.7 g, 91%. MS
M.sup.++1 207. The structure is confirmed by .sup.1H NMR
spectroscopy.
Step B
3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic Acid Methyl Ester
[0251] A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic
acid methyl ester (4.7 g, 22.8 mmol), Raney nickel (0.668 g) and
tetrahydrofuran (618 mL) is shaken under 60 psig. Hydrogen 24 hr.
The catalyst is filtered off, and the mixture is concentrated to
afford the product as a pale yellow oil, 4.3 g, 91%. The structure
is confirmed by .sup.1H NMR spectroscopy.
Step C
3-(4-Iodomethyl-2-methyl-phenyl)-propionic Acid Methyl Ester
[0252] A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic
acid methyl ester (0.62 g, 2.98 mmol), triphenyl phosphine (0.86 g,
3.27 mmol) and dichloromethane (10 mL) is stirred at room
temperature. A solution of iodine (0.83 g, 3.27 mmol) in benzene (5
mL) is added and the black mixture is stirred at room temperature 2
hr. The brown mixture is diluted with 10% aqueous sodium hydrogen
sulfite (5 mL) and the resulting clear mixture is washed with ethyl
acetate (3.times.50 mL). The combined extracts are dried over
anhydrous magnesium sulfate, filtered and concentrated. The residue
is purified via silica chromatography eluting with 9:1
hexanes:ethyl acetate to afford the title compound as a crystalline
ivory solid, 0.68 g, 72%. MS M.sup.++1 319. The structure is
confirmed by .sup.1H NMR spectroscopy.
Preparation 17
(4-Bromo-2-methyl-phenoxy)-acetic Acid Methyl Ester
##STR00039##
[0253] Step A
(4-Bromo-2-methyl-phenoxy)-acetic Acid Methyl Ester
[0254] A mixture of 4-bromo-2-methylphenol (1.0 g, 5.35 mmol),
sodium hydride (0.26 g, 6.42 mmol, 60% mineral oil),
N,N-dimethylformamide (10 mL), and methyl-2-bromoacetate (0.56 mL,
5.88 mmol) is stirred at room temperature 18 hr. The mixture is
diluted with water (50 mL) and the product extracted to ethyl
acetate (3.times.50 mL). The combined extracts are dried over
anhydrous magnesium sulfate, filtered, concentrated and purified
via silica chromatography eluting with 8:2 hexanes:ethyl acetate to
afford title compound as a colorless oil, 1.03 g, 74%. MS M.sup.+
259. The structure is confirmed by .sup.1H NMR spectroscopy.
Preparation 18
3-(4-Amino-2-methyl-phenyl)-propionic Acid Methyl Ester
##STR00040##
[0255] Step A
3-(2-Methyl-4-nitro-phenyl)-acrylic Acid Methyl Ester
[0256] To a solution of 2-bromo-5-nitrotoluene (3.11 g, 14.39 mmol)
in propionitrile (105 mL) is added DIPEA (5.1 mL, 29.28 mmol). The
mixture is degassed three times. Methyl acrylate (5.2 mL, 57.74
mmol) is added and the mixture is degassed. Tri-o-tolylphosphine
(1.77 g, 5.82 mmol) and Pd(OAc).sub.2 (0.64 g, 2.85 mmol) are added
and the mixture is degassed a final two times followed by heating
at 110.degree. C. for 4 h. Upon cooling, the mixture is passed
through Celite and the filtrate is concentrated. The residue is
partitioned between Et.sub.2O and 1N HCl. The organics are washed
with saturated NaHCO.sub.3 and brine, and dried with
Na.sub.2SO.sub.4. The crude material is purified by flash
chromatography to yield the title compound (2.90 g, 91%).
Step B
3-(4-Amino-2-methyl-phenyl)-propionic Acid Methyl Ester
[0257] A mixture of 3-(2-Methyl-4-nitro-phenyl)-acrylic acid methyl
ester (1.47 g, 6.64 mmol) and 5% Pd/C (0.29 g) in MeOH (100 mL) is
exposed to a hydrogen atmosphere (60 psi) for 12 h. The mixture is
filtered through Celite and purified by flash chromatography to
yield the title compound (0.99 g, 77%).
Preparation 19
3-(2-Methyl-4-methylaminomethyl-phenyl)-propionic Acid Methyl Ester
TFA Salt
##STR00041##
[0258] Step A
3-(4-Formyl-2-methyl-phenyl)-propionic Acid Methyl Ester
[0259] A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic
acid methyl ester (0.49 g, 2.35 mmol) and MnO.sub.2 (0.80 g, 9.20
mmol) in chloroform (5 mL) is stirred at RT for 4 days. The mixture
is filtered through Celite; the Celite is washed with copious
amounts of EtOAc. The filtrate is concentrated and purified by
flash chromatography to yield the title compound (0.29 g, 60%).
Step B
3-(2-Methyl-4-methylaminomethyl-phenyl)-propionic Acid Methyl Ester
Trifluoroacetic Acid
[0260] To a mixture of 3-(4-Formyl-2-methyl-phenyl)-propionic acid
methyl ester (0.27 g, 1.31 mmol) and methylamine (2M in THF, 0.60
mL, 1.20 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) is added 4
.ANG. molecular sieves followed by acetic acid (0.090 mL, 1.57
mmol). The mixture is stirred at RT for 1.5 h. Sodium
triacetoxyborohydride (0.39 g, 1.85 mmol) is added, and the mixture
is stirred overnight. The reaction is quenched with saturated
NaHCO.sub.3. The organics are washed with saturated NaHCO.sub.3 and
brine, and dried with MgSO.sub.4. Upon concentration, the mixture
is purified by reverse phase chromatography to yield the title
compound (0.12 g, 45%).
Preparation 20
3-(4-Aminomethyl-2-methyl-phenyl)-propionic Acid Methyl Ester
##STR00042##
[0261] Step A
3-(4-Chloromethyl-2-methyl-phenyl)-propionic Acid Methyl Ester
[0262] To a 0.degree. C. solution of
3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester
(1.02 g, 4.90 mmol) in anhydrous CH.sub.2Cl.sub.2 (15 mL) is added
triethylamine (0.75 mL, 5.38 mmol) followed by thionyl chloride
(0.40 mL, 5.48 mmol). The mixture is allowed to warm to RT
overnight. Water is added, and the mixture is extracted with
CH.sub.2Cl.sub.2. The organics are dried with MgSO.sub.4 and
concentrated. The crude material is purified by flash
chromatography to yield the title compound (1.01 g, 91%).
Step B
3-(4-Azidomethyl-2-methyl-phenyl)-propionic Acid Methyl Ester
[0263] To a solution of
3-(4-Chloromethyl-2-methyl-phenyl)-propionic acid methyl ester
(0.52 g, 2.31 mmol) in DMF (7 mL) is added sodium azide (0.25 g,
3.84 mmol). The mixture is stirred overnight. Water is added, and
the mixture is extracted with EtOAc. The organics are dried with
Na.sub.2SO.sub.4 and concentrated to yield the title compound (0.49
g, 91%). The material is used without further purification.
Step C
3-(4-Aminomethyl-2-methyl-phenyl)-propionic Acid Methyl Ester
[0264] A mixture of 3-(4-Azidomethyl-2-methyl-phenyl)-propionic
acid methyl ester (0.20 g, 0.86 mmol) and 5% Pd/C (32 mg) in EtOH
(50 mL) is exposed to a hydrogen atmosphere (60 psi) at RT
overnight. Upon filtering the mixture through Celite, the filtrate
is concentrated to yield the title compound (0.14 g, 78%). The
material is used without further purification.
Preparation 21
2-Chloromethyl-5-(4-trifluoromethyl-phenyl)-thiophene
##STR00043##
[0265] Step A
5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
[0266] To a mixture of 4-(trifluoromethyl)phenyl-boronic acid (5.18
g, 27.3 mmole), 5-bromo-2-thiophenecarboxyaldehyde (5.39 g, 27.3
mmole) and cesium fluoride (14.5 g, 95.5 mmole) in dioxane (100
mL), is bubbled with nitrogen gas for 15 minutes. The catalyst
PdCl.sub.2(dppf) (0.52 g) is then added to the mixture. The
reaction is heated under reflux for 16 hours. The solvent is
removed on rota vapor, and the resulting residue is partitioned
between ethyl acetate (500 ml) and water (500 mL). The aqueous
layer is extracted with more ethyl acetate (100 mL). The combined
organic solution is washed with brine (3.times.500 mL), dried over
Na.sub.2SO.sub.4 and concentrated. The crude product is purified on
a silica gel column, eluting with 0-15% ethyl acetate in hexane and
concentrated to provide the titled compound as yellow solid.
Step B
[5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
[0267] To a solution of
5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (3.02 g, 11.8
mmole) in THF (100 mL), is added to LiBH.sub.4 (1.75 g, 80.24
mmole) in one portion at 0.degree. C. The reaction is kept at
0.degree. C. for 15 minutes and warmed up to room temperature for 1
hour. The reaction is quenched using 5N HCl (100 mL) at 0.degree.
C. The THF is removed on rota vapor, the aqueous solution is then
extracted with ethyl acetate (2.times.100 mL). The combined organic
solution is washed with brine (3.times.200 mL), dried over
Na.sub.2SO.sub.4 and concentrated. The crude product is purified on
a silica gel column, eluting with 20% ethyl acetate in hexane and
concentrated to provide the titled compound as off-white solid.
Step C
2-Chloromethyl-5-(4-trifluoromethyl-phenyl)-thiophene
[0268] To a mixture of
[5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol (1.52 g, 5.89
mmole) and triethyl amine (1.64 mL, 11.78 mmole) in DCM (100 mL) at
0.degree. C., is injected methanesulfonyl chloride (0.91 mL, 11.78
mmole) dropwise. The reaction is kept at 0.degree. C. for an hour
and warmed up to room temperature for an hour. The reaction mixture
is concentrated on rota vapor, and the resulting residue is
purified on a silica gel column, eluting with 0-15% ethyl acetate
in hexane and concentrated to provide the titled compound as
off-white solid.
Preparation 22
[5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
##STR00044##
[0269] Step A
3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
[0270] To a solution of trimethylethylenediamine (0.296 mL, 2.28
mmole) in THF at -78.degree. C., is injected 2.0M n-butyllithium in
cyclohexane (1.14 mL, 2.28 mmole) dropwise. The mixture is stirred
for 15 minutes, then added a solution of
5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.530 g,
2.07 mmole) in THF (5 mL) and stirred for another 15 minutes. To
the resulting mixture is injected 2.0M n-butyllithium in
cyclohexane (1.55 ml, 3.10 mmole) at -78.degree. C. and warmed up
to -18.degree. C. for an hour. The reaction is cooled down to
-78.degree. C. again, quenched with excess amount of iodomethane
(0.644 mL, 10.35 mmole) and allowed to warm up to room temperature,
then poured into well stirred ice-water (30 mL). The aqueous
solution is then extracted with ethyl acetate (2.times.30 mL). The
combined organic solution is washed with brine (3.times.30 mL),
dried over Na.sub.2SO.sub.4 and concentrated. The crude product is
purified on a silica gel-column, gradient eluting with 0-20% ethyl
acetate in hexane and concentrated to provide the titled compound
as yellow crystalline.
Step B
[0271] To a solution of
3-methyl-5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
(0.140 g, 0.518 mmole) in THF (5 mL), is added to LiBH.sub.4 (0.056
g, 2.57 mmole) in one portion at 0.degree. C. The reaction is kept
at 0.degree. C. for 15 minutes and warmed up to room temperature
for 1 hour. The reaction is quenched using 1N HCl (10 mL) at
0.degree. C. The THF is removed on rota vapor, the aqueous solution
is then extracted with ethyl acetate (2.times.10 mL). The combined
organic solution is washed with brine (3.times.20 mL), dried over
Na.sub.2SO.sub.4 and concentrated. The crude product is purified on
a silica gel column, eluting with 20% ethyl acetate in hexane and
concentrated to provide the titled compound as white solid.
Preparation 23
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol
##STR00045##
[0273] To a solution of
3-methyl-5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
(0.130 g, 0.481 mmole) in THF (5 mL), is injected 3.0 M MeMgBr in
ethyl ether (0.27 mL, 0.810 mmole) dropwise. The reaction is
stirred for 2 hours. The reaction is quenched with saturated
NH.sub.4Cl.sub.(aq) (10 mL), then the aqueous solution is extracted
with ethyl acetate (3.times.15 mL). The combined organic solution
is washed with brine (3.times.50 mL), dried over Na.sub.2SO.sub.4
and concentrated. The crude product is purified on a silica gel
column, eluting with 0-20% ethyl acetate in hexane and concentrated
to provide the titled compound as yellow solid.
[0274] The following compounds are made in a similar manner:
Preparation 24
[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
##STR00046##
[0275] Preparation 25
1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol
##STR00047##
[0276] Preparation 26
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol
##STR00048##
[0277] Preparation 27
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-butan-1-ol
##STR00049##
[0278] Preparation 28
2-Methyl-1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1--
ol
##STR00050##
[0279] Preparation 29
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-phenyl-ethanol
##STR00051##
[0280] Preparation 30
[3-Isopropyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
##STR00052##
[0281] Step A
2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid
[0282] The titled compound is prepared from
5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (2.70 g, 10
mmole) and trimethyl borate (5.68 g, 50.0 mmole) in a similar
manner to
3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde.
Step B
3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
[0283] To a mixture of
2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid
(0.330 g, 1.10 mmole), 2-Bromo-propene (0.399 g, 3.30 mmole) and
cesium fluoride (0.585 g, 3.85 mmole) in dioxane (5 mL), is bubbled
with nitrogen gas for 15 minutes. The catalyst PdCl.sub.2(dppf)
(0.033 g) is then added to the mixture. The reaction is heated
under reflux for 16 hours. The solvent is removed on rota vapor,
and the resulting residue is partitioned between ethyl acetate (20
ml) and water (20 mL). The aqueous layer is extracted with more
ethyl acetate (20 mL). The combined organic solution is washed with
brine (3.times.50 mL), dried over Na.sub.2SO.sub.4 and
concentrated. The crude product is purified on a silica gel column,
eluting with 0-15% ethyl acetate in hexane and concentrated to
provide the titled compound as pale yellow crystalline.
Step C
[3-Isopropenyl-S-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
[0284] To a solution of
3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
(0.084 g, 0.283 mmole) in THF (3 mL), is added to NaBH.sub.4 (0.023
g, 0.622 mmole) in one portion at 0.degree. C. The reaction is kept
at 0.degree. C. for 15 minutes and warmed up to room temperature
for 2 hours. The reaction is quenched using saturated
NH.sub.4Cl.sub.(aq) (20 mL) at 0.degree. C. The THF is removed on
rota vapor, the aqueous solution is then extracted with ethyl
acetate (2.times.10 mL). The combined organic solution is washed
with brine (3.times.20 mL), dried over Na.sub.2SO.sub.4 and
concentrated to provide the titled compound as yellow solid, which
is used for the next step without further purification.
Step D
[3-Isopropyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
[0285] The solution of
[3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
(0.084 g, 0.282 mmole) is stirred under nitrogen gas in presence of
10% palladium on carbon (0.085 g) for 16 hours. The catalyst is
removed by filtration, and the filtrate is concentrated to provide
the titled compound as white solid, which is used for the next step
without further purification.
Preparation 31
2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol
##STR00053##
[0286] Step A
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone
[0287] To a solution of
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol
(see Preparation 8) (4.40 g, 15.4 mmole), is added MnO.sub.2 (7.88
g, 77.0 mmole) in one portion.
[0288] The mixture is heated under reflux for 16 hours, more
MnO.sub.2 (7.88 g, 77.0 mmole) is added to the reaction and
continued to reflux for 4 hours. The mixture is filtered through a
celite pad, and the mother liquid is concentrated. The crude
product is purified on a silica gel column, gradient eluting with
0-20% ethyl acetate in hexane and concentrated to provide the
titled compound as yellow solid.
Step B
2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionaldehyde
[0289] To a solution of (methoxymethyl)triphenyl phosphonium
chloride (3.96 g, 10.76 mmole) in toluene/THF (2:1, 60 mL), is
added potassium t-butoxide (1.21 g, 10.76 mmole) in one portion and
stirred for 30 minutes. To the resulting ylide, is injected into a
solution of
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone
(1.53 g, 5.38 mmole). The reaction is stirred for 2 hours, and then
concentrated on rota vapor. The residue is purified on a silica gel
column, eluting with 0-10% ethyl acetate in hexane and concentrated
to provide
2-(2-Methoxy-1-methyl-vinyl)-3-methyl-5-(4-trifluoromethyl-phenyl)-thioph-
ene as brown oil. The generated vinyl ether is treated with
concentrated HCl.sub.(aq) (2 mL) in THF (60 mL) at 60.degree. C.
for 2 hours. The solvents are removed on rota vapor, and the
residue is purified on a silica gel column, eluting with 0-20%
ethyl acetate in hexane and concentrated to provide the titled
compound as colorless oil.
Step C
2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol
[0290] To a solution of
2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionaldehyde
(1.40 g, 4.69 mmole) in THF (20 mL), is added to NaBH.sub.4 (0.266
g, 7.04 mmole) in one portion at 0.degree. C. The reaction is kept
at 0.degree. C. for 15 minutes and warmed up to room temperature
for 2 hours. The reaction is quenched using NH.sub.4Cl.sub.(aq) (50
mL) at 0.degree. C. The THF is removed on rota vapor, the aqueous
solution is then extracted with ethyl acetate (2.times.50 mL). The
combined organic solution is washed with brine (3.times.100 mL),
dried over Na.sub.2SO.sub.4 and concentrated. The crude product is
purified on a silica gel column, gradient eluting with 0-20% ethyl
acetate in hexane and concentrated to provide the titled compound
as white solid.
[0291] The racemic material is resolved on a Chiralpak AD column
(4.6.times.250 mm). Eluted with 200' methanol and concentrated the
fractions of the faster component to provide pure enantiomer
(isomer 1, 100% ee) and slower component to provide another
enantiomer (isomer II, >99.5% ee).
Preparation 32
1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanol
##STR00054##
[0293] To a solution of
1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanone (1.08 g, 5.00 mmole)
in THF (20 mL), is added to LiBH.sub.4 (0.327 g, 15.0 mmole) in one
portion at 0.degree. C. The reaction is kept at 0.degree. C. for 30
minutes and warmed up to room temperature for 2 hours. The reaction
is quenched using NH.sub.4Cl.sub.(aq) (50 mL) at 0.degree. C. The
THF is removed on rota vapor, the aqueous solution is then
extracted with ethyl acetate (3.times.50 mL). The combined organic
solution is dried over Na.sub.2SO.sub.4 and concentrated to provide
the titled compound as white solid, which is used for the next step
without further purification.
Preparation 33
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol
##STR00055##
[0295] To a solution of
3-methyl-5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
(0.130 g, 0.481 mmole) in THF (5 mL), is injected 3.0 M MeMgBr in
ethyl ether (0.27 mL, 0.810 mmole) dropwise. The reaction is
stirred for 2 hours. The reaction is quenched with saturated
NH.sub.4Cl.sub.(aq) (10 mL), then the aqueous solution is extracted
with ethyl acetate (3.times.15 mL). The combined organic solution
is washed with brine (3.times.50 mL), dried over Na.sub.2SO.sub.4
and concentrated. The crude product is purified on a silica gel
column, eluting with 0-20% ethyl acetate in hexane and concentrated
to provide the titled compound as yellow solid.
[0296] The following compounds (Preparation 34 to 39) are made in a
similar manner:
Preparation 34
[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
##STR00056##
[0297] Preparation 35
1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol
##STR00057##
[0298] Preparation 36
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol
##STR00058##
[0299] Preparation 37
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-butan-1-ol
##STR00059##
[0300] Preparation 38
2-Methyl-1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1--
ol
##STR00060##
[0301] Preparation 39
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-phenyl-ethanol
##STR00061##
[0302] Preparation 40
[3-Isopropyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
##STR00062##
[0303] Step A
2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid
[0304] The titled compound is prepared from
5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (2.70 g, 10
mmole) and trimethyl borate (5.68 g, 50.0 mmole) in a similar
manner to
3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
(Preparation 2, Step A).
Step B
3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
[0305] To a mixture of
2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid
(0.330 g, 1.10 mmole), 2-Bromo-propene (0.399 g, 3.30 mmole) and
cesium fluoride (0.585 g, 3.85 mmole) in dioxane (5 mL), is bubbled
with nitrogen gas for 15 minutes. The catalyst PdCl.sub.2(dppf)
(0.033 g) is then added to the mixture. The reaction is heated
under reflux for 16 hours. The solvent is removed on rota vapor,
and the resulting residue is partitioned between ethyl acetate (20
ml) and water (20 mL). The aqueous layer is extracted with more
ethyl acetate (20 mL). The combined organic solution is washed with
brine (3.times.50 mL), dried over Na.sub.2SO.sub.4 and
concentrated. The crude product is purified on a silica gel column,
eluting with 0-15% ethyl acetate in hexane and concentrated to
provide the titled compound as pale yellow crystalline.
Step C
[3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
[0306] To a solution of
3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde
(0.084 g, 0.283 mmole) in THF (3 mL), is added to NaBH.sub.4 (0.023
g, 0.622 mmole) in one portion at 0.degree. C. The reaction is kept
at 0.degree. C. for 15 minutes and warmed up to room temperature
for 2 hours. The reaction is quenched using saturated
NH.sub.4Cl.sub.(aq) (20 mL) at 0.degree. C. The THF is removed on
rota vapor, the aqueous solution is then extracted with ethyl
acetate (2.times.10 mL). The combined organic solution is washed
with brine (3.times.20 mL), dried over Na.sub.2SO.sub.4 and
concentrated to provide the titled compound as yellow solid, which
is used for the next step without further purification.
Step D
[3-Isopropyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
[0307] The solution of
[3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol
(0.084 g, 0.282 mmole) is stirred under nitrogen gas in presence of
10% palladium on carbon (0.085 g) for 16 hours. The catalyst is
removed by filtration, and the filtrate is concentrated to provide
the titled compound as white solid, which is used for the next step
without further purification.
Preparation 41
2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol
##STR00063##
[0308] Step A
[0309]
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone
[0310] To a solution of
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol
(see Preparation 2) (4.40 g, 15.4 mmole), is added MnO.sub.2 (7.88
g, 77.0 mmole) in one portion. The mixture is heated under reflux
for 16 hours, more MnO.sub.2 (7.88 g, 77.0 mmole) is added to the
reaction and continued to reflux for 4 hours. The mixture is
filtered through a celite pad, and the mother liquid is
concentrated. The crude product is purified on a silica gel column,
gradient eluting with 0-20% ethyl acetate in hexane and
concentrated to provide the titled compound as yellow solid.
Step B
[0311]
2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionalde-
hyde
[0312] To a solution of (methoxymethyl)triphenyl phosphonium
chloride (3.96 g, 10.76 mmole) in toluene/THF (2:1, 60 mL), is
added potassium t-butoxide (1.21 g, 10.76 mmole) in one portion and
stirred for 30 minutes. To the resulting ylide, is injected into a
solution of
1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone
(1.53 g, 5.38 mmole). The reaction is stirred for 2 hours, and then
concentrated on rota vapor. The residue is purified on a silica gel
column, eluting with 0-10% ethyl acetate in hexane and concentrated
to provide
2-(2-Methoxy-1-methyl-vinyl)-3-methyl-5-(4-trifluoromethyl-phenyl)-thioph-
ene as brown oil. The generated vinyl ether is treated with
concentrated HCl.sub.(aq) (2 mL) in THF (60 mL) at 60.degree. C.
for 2 hours. The solvents are removed on rota vapor, and the
residue is purified on a silica gel column, eluting with 0-20%
ethyl acetate in hexane and concentrated to provide the titled
compound as colorless oil.
Step C
2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol
[0313] To a solution of
2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionaldehyde
(1.40 g, 4.69 mmole) in THF (20 mL), is added to NaBH.sub.4 (0.266
g, 7.04 mmole) in one portion at 0.degree. C. The reaction is kept
at 0.degree. C. for 15 minutes and warmed up to room temperature
for 2 hours. The reaction is quenched using NH.sub.4Cl.sub.(aq) (50
mL) at 0.degree. C. The THF is removed on rota vapor, the aqueous
solution is then extracted with ethyl acetate (2.times.50 mL). The
combined organic solution is washed with brine (3.times.100 mL),
dried over Na.sub.2SO.sub.4 and concentrated. The crude product is
purified on a silica gel column, gradient eluting with 0-20% ethyl
acetate in hexane and concentrated to provide the titled compound
as white solid.
[0314] The racemic material is resolved on a Chiralpak AD column
(4.6.times.250 mm). Eluted with 100% methanol and concentrated the
fractions of the faster component to provide pure enantiomer
(isomer 1, 100% ee) and slower component to provide another
enantiomer (isomer II, >99.5% ee).
Preparation 42
1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanol
##STR00064##
[0316] To a solution of
1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanone (1.08 g, 5.00 mmole)
in THF (20 mL), is added to LiBH.sub.4 (0.327 g, 15.0 mmole) in one
portion at 0.degree. C. The reaction is kept at 0.degree. C. for 30
minutes and warmed up to room temperature for 2 hours. The reaction
is quenched using NH.sub.4Cl.sub.(aq) (50 mL) at 0.degree. C. The
THF is removed on rota vapor, the aqueous solution is then
extracted with ethyl acetate (3.times.50 mL). The combined organic
solution is dried over Na.sub.2SO.sub.4 and concentrated to provide
the titled compound as white solid, which is used for the next step
without further purification.
Example 1
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}--
propionic Acid
##STR00065##
[0317] Step A
[0318]
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-p-
henyl}-propionic Acid Methyl Ester
[0319] To a solution of
2-Chloromethyl-5-(4-trifluoromethyl-phenyl)-thiophene (0.210 g,
0.760 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid
methyl ester (0.147 g, 0.760 mmole) in acetonitrile (5 mL), is
added cesium carbonate (0.248 mL, 0.760 mmole) in one portion. The
reaction is heated at 50.degree. C. overnight, then concentrated.
The residue is loaded to a silica gel column, eluted with ethyl
acetate in hexane (0-15%) and concentrated to provide the titled
compound as a white solid.
Step B
[0320]
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-p-
henyl}-propionic Acid
[0321]
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-p-
henyl}-propionic acid methyl ester (0.170 g, 0.390 mmole) is
treated with a mixture of NaOH.sub.(aq) (1 mL)/THF (3 mL)/MeOH (3
mL) at room temperature overnight. The organic solvents are removed
on rota-vapor. The residue is diluted with water (10 mL), acidified
to pH=2 with 6N HCl.sub.(aq). The precipitate is collected through
filtration, washed with cold water (30 mL) and dried to provide the
titled compound as white solid. MS (ES): 419 (M+H).sup.-, the
structure is also confirmed by proton NMR.
[0322] The following compound (Example 2) is made in a similar
manner:
Example 2
{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenoxy}-a-
cetic acid
##STR00066##
[0324] MS (ES): 421 (M+H).sup.-, the structure is also confirmed by
proton NMR.
Synthesis Method for Examples 3-8
[0325] Examples 3 through 8 are made substantially as
described:
Step A
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}--
propionic Acid Methyl Ester
[0326] To a solution of
[5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol (0.063 g,
0.232 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid
methyl ester (0.045 g, 0.232 mmole) in toluene (2 mL) at room
temperature, is added tributylphosphine (0.087 mL, 0.348 mmole)
followed by a solution of 1,1'-(azodicarbonyl)-dipiperidine (0.088
g, 0.348 mmole) in toluene (2 mL). The reaction is stirred
overnight, and then diluted with hexane (10 mL). The precipitate is
removed through filtration and the filtrate is concentrated, loaded
to a silica gel column, eluted with ethyl acetate in hexane (0-15%)
and concentrated to provide the titled compound as white solid.
Step B
3-{2-Methyl-4-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-
-phenyl}-propionic Acid
[0327]
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-p-
henyl}-propionic acid methyl ester (0.043 g, 0.0959 mmole) is
treated with a mixture of NaOH.sub.(aq) (1 mL)/THF (3 mL)/MeOH (3
mL) at room temperature overnight. The organic solvents are removed
on rota-vapor. The residue is diluted with water (10 mL), acidified
to pH=2 with 6N HCl.sub.(aq). The precipitate is collected through
filtration, washed with cold water (30 mL) and dried to provide the
titled compound as a white solid. MS (ES): 433 (M+H).sup.-, the
structure is also confirmed by proton NMR.
Example 3
3-{2-Methyl-4-[3-phenyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-
-phenyl}-propionic Acid
##STR00067##
[0329] MS (ES): 495 (M+H).sup.-, the structure is also confirmed by
proton NMR.
Example 4
3-{4-[3,5-Bis-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-2-methyl-ph-
enyl}-propionic Acid
##STR00068##
[0331] MS (ES): 563 (M+H), the structure is also confirmed by
proton NMR.
Example 5
3-(2-Methyl-4-{1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-pro-
poxy}-phenyl)-propionic Acid
##STR00069##
[0333] MS (ES): 447 (M+H).sup.-, the structure is also confirmed by
proton NMR.
Example 6
3-(2-Methyl-4-{1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-but-
oxy}-phenyl)-propionic Acid
##STR00070##
[0335] MS (ES): 461 (M+H).sup.-, the structure is also confirmed by
proton NMR.
Example 7
3-(2-Methyl-4-{2-methyl-1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen--
2-yl]-propoxy}-phenyl)-propionic Acid
##STR00071##
[0337] MS (ES): 461 (M+H).sup.-, the structure is also confirmed by
proton NMR.
Example 8
3-(2-Methyl-4-{1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-p-
henyl-ethoxy}-phenyl)-propionic Acid
##STR00072##
[0339] MS (ES): 509 (M+H).sup.-, the structure is also confirmed by
proton NMR.
Synthesis Method for Example 9
Step A
3-(4-{1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethylsulfanyl}-
-2-methyl-phenyl)-propionic Acid Methyl Ester
[0340] To a solution of
1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol (1.52
g, 3.96 mmole) and 3-(4-Mercapto-2-methyl-phenyl)-propionic acid
methyl ester (0.769 g, 3.96 mmole) in toluene (20 mL) at room
temperature, is added tributylphosphine (1.98 mL, 7.92 mmole)
followed by a solution of 1,1'-(azodicarbonyl)-dipiperidine (1.99
g, 7.92 mmole) in toluene (20 mL). The reaction is stirred
overnight, and then diluted with hexane (100 mL). The precipitate
is removed through filtration and the filtrate is concentrated,
loaded to a silica gel column, eluted with ethyl acetate in hexane
(0-15%) and concentrated to provide the titled compound as yellow
solid.
Step B
3-(2-Methyl-4-{1-[5-(4-trifluoromethyl-phenyl)-3-vinyl-thiophen-2-yl]-ethy-
lsulfanyl}-phenyl)-propionic Acid Methyl Ester
[0341] The solution of
3-(4-{1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethylsulfanyl-
}-2-methyl-phenyl)-propionic acid methyl ester (0.195 g, 0.348
mmole) and tributyl(vinyl)tin (0.331 g, 1.04 mmole) in toluene (3
mL) is bubbled with nitrogen gas for 10 minutes. To it is added
tetrakis(triphenylphosphine)palladium(0) (0.020 g). The reaction is
heated under 80.degree. C. overnight. The mixture is concentrated,
loaded to a silica gel column, eluted with ethyl acetate in hexane
(0-15%) and concentrated to provide the titled compound as
colorless oil.
Step C
3-(4-{1-[3-(2-Hydroxy-ethyl)-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-e-
thylsulfanyl}-2-methyl-phenyl)-propionic Acid
[0342] To a solution of
3-(2-Methyl-4-{1-[5-(4-trifluoromethyl-phenyl)-3-vinyl-thiophen-2-yl]-eth-
ylsulfanyl}-phenyl)-propionic acid methyl ester (0.365 g, 0.744
mmole) in THF (5 mL) at 0.degree. C., is added dropwise 1.0N
BH.sub.3/THF complex (3.0 mL, 3.0 mmole). The mixture is warmed up
to room temperature and stirred for an hour. To it is added 30%
H.sub.2O.sub.2 (10 mL) and 1.0N NaOH.sub.(aq) (10 mL), and the
reaction is heated under reflux for 2 hours. It is then acidified
by adding concentrated HCl carefully to pH=2. The aqueous solution
is extracted with ethyl acetate (3.times.20 mL), and the combine
organic solution is dried and concentrated. The crude product is
purified by reverse phase preparative HPLC, eluting with 5.0 nM
NH.sub.4HCO.sub.3(aq)/CH.sub.3CN and concentration of fractions to
provide the titled compound as a white solid.
Example 9
3-(4-{1-[3-(2-Hydroxy-ethyl)-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-e-
thylsulfanyl}-2-methyl-phenyl)-propionic Acid
##STR00073##
[0344] MS (ES): 493 (M+H).sup.-, the structure is also confirmed by
proton NMR.
Example 10
Isomer II
2-Methoxy-3-(4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-pr-
opoxy}-phenyl)-propionic Acid
##STR00074##
[0346] MS (ES): 479 (M+H).sup.+, 477 (M+H).sup.-, the structure is
also confirmed by proton NMR.
Example 11
Isomer II
2-Methyl-3-(4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-pro-
poxy}-phenyl)-2-phenoxy-propionic Acid
##STR00075##
[0348] MS (ES): 572 (M+NH.sub.4).sup.+, 553 (M+H), the structure is
also confirmed by proton NMR.
Example 12
Isomer I
(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propy-
lsulfanyl}-phenoxy)-acetic Acid
##STR00076##
[0350] MS (ES): 481 (M+H).sup.+, 479 (M-H).sup.-, the structure is
also confirmed by proton NMR.
Example 13
Isomer II
(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propy-
lsulfanyl}-phenoxy)-acetic Acid
##STR00077##
[0352] MS (ES): 481 (M+H).sup.+, 479 (M-H), the structure is also
confirmed by proton NMR.
Example 14
Isomer II
3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-pro-
pylsulfanyl}-phenyl)-propionic Acid
##STR00078##
[0354] MS (ES): 479 (M+H).sup.+, 477 (M-H).sup.-, the structure is
also confirmed by proton NMR.
Example 15
Isomer II
(3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-pheny-
l)-acetic Acid
##STR00079##
[0356] MS (ES): 435 (M+H).sup.+, 433 (M-H) the structure is also
confirmed by proton NMR.
Example 16
##STR00080##
[0358] The newly developed three-step sequence from 2 to 5, affords
in an overall 78% yield (avg. 92% per step).
[0359] The final saponification and crystallization proceed without
incident.
[0360] Compound 1 is obtained in an overall yield of 17%.
##STR00081##
[0361]
3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethylphenyl)thiophen-2-yl-
]propoxy}phenyl)propionic acid (isomer 2) (1).sup.1
3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethylphenyl)thiophen-2-yl]propo-
xy}phenyl)propionic acid methyl ester (isomer 2, 398 g, 0.84 mol)
is dissolved in THF and MeOH (3800 mL). To the resulting clear
yellow solution is added aq. NaOH (335 mL, 1.68 mol) over 15
minutes. The solution is stirred at rt for 2 h, then transferred to
rotary evaporator and concentrated in vacuo at 40.degree. C. to a
pale yellow paste. This paste is partitioned between 1N aq. HCl
(1700 mL, 1.7 mol) and EtOAc (2000 mL). The aq. layer is
back-extracted with EtOAc (2000 mL) and the combined organic layers
are washed with sat'd aq. NaCl (2000 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated to a pale yellow solid. This solid is
recrystallized from a mixture of EtOAc (1000 mL) and n-heptane
(3000 mL), cooled to 0.degree. C. and filtered. The solids are
rinsed with cold hexanes (1000 mL). The product is dried in vacuo
at 45.degree. C. to afford the title compound as a white
crystalline solid (338 g, 88%). mp: 126.2-132.6.degree. C. .sup.1H
NMR (CDCl.sub.3) .delta. (dd, 4H, J=25, 8 Hz), 7.14 (s, 1H), 7.07
(d, 1H, J=8 Hz), 6.76 (s, 1H), 6.72 (d, 1H, J=8 Hz), 4.08 (t, 1H,
J=6 Hz), 3.69 (t, 1H, J=7 Hz), 3.61 (m, 1H), 2.91 (t, 2H, J=8 Hz),
2.64 (t, 2H, J=8 Hz), 2.31 (s, 3H), 2.27 (s, 3H), 1.49 (d, 3H, J=8
Hz); .sup.13C NMR (CDCl.sub.3) .delta. 179.7, 157.5, 142.5, 138.6,
138.2, 137.6, 134.9, 130.9, 129.7, 128.9 (q, J=33 Hz), 127.6,
126.0, 125.6, 123.4, 116.9, 112.1, 73.2, 34.9, 34.0, 27.5, 19.7,
19.5, 14.2; IR (CHCl.sub.3) 2963, 2923, 1713, 1614, 1502, 1329,
1194, 1120, 1070, 823 cm.sup.-1; Anal. Calcd. for
C.sub.25H.sub.25F.sub.3O.sub.3S: C, 64.92; H, 5.45; F, 12.32; S,
6.93. Found: C, 64.95; H, 5.49; F, 12.05; S, 6.95.
Biological Assays
Binding and Cotransfection Studies
[0362] The in vitro potency of compounds in modulating PPAR.alpha.
receptors are determined by the procedures detailed below.
DNA-dependent binding (ABCD binding) is carried out using SPA
technology with PPAR receptors. Tritium-labeled PPAR.alpha.
agonists are used as radioligands for generating displacement
curves and IC.sub.50 values with compounds of the invention.
Cotransfection assays are carried out in CV-1 cells. The reporter
plasmid contained an acylCoA oxidase (AOX) PPRE and TK promoter
upstream of the luciferase reporter cDNA. Appropriate PPARs are
constitutively expressed using plasmids containing the CMV
promoter. For PPAR.alpha., interference by endogenous PPAR.gamma.
in CV-1 cells is an issue. In order to eliminate such interference,
a GAL4 chimeric system is used in which the DNA binding domain of
the transfected PPAR is replaced by that of GAL4, and the GAL4
response element is utilized in place of the AOX PPRE.
Cotransfection efficacy is determined relative to PPAR.alpha.
agonist reference molecules. Efficacies are determined by computer
fit to a concentration-response curve, or in some cases at a single
high concentration of agonist (10 .mu.M).
[0363] These studies are carried out to evaluate the ability of
compounds of the invention to bind to and/or activate various
nuclear transcription factors, particularly huPPAR.alpha. ("hu"
indicates "human"). These studies provide in vitro data concerning
efficacy and selectivity of compounds of the invention.
Furthermore, binding and cotransfection data for compounds of the
invention are compared with corresponding data for marketed
compounds that act on huPPAR.alpha..
[0364] The binding and cotransfection efficacy values for compounds
of the invention which are especially useful for modulating a PPAR
receptor, are .ltoreq.100 nM and .gtoreq.50%, respectively.
Evaluation of Triglyceride Reduction and HDL Cholesterol Elevation
in HuapoAI Transgenic Mice
[0365] Compounds of the present invention are studied for effects
upon HDL and triglyceride levels in human apoAI mice. For each
compound tested, seven to eight week old male mice, transgenic for
human apoAI (C57BL/6-tgn(apoa1)1rub, Jackson Laboratory, Bar
Harbor, Me.) are acclimated in individual cages for two weeks with
standard chow diet (Purina 5001) and water provided ad libitum.
After the acclimation, mice and chow are weighed and assigned to
test groups (n=5) with randomization by body weight. Mice are dosed
daily by oral gavage for 8 days using a 29 gauge, 11/2 inch curved
feeding needle (Popper & Sons). The vehicle for the controls,
test compounds and the positive control (fenofibrate 100 mg/kg) is
1% carboxymethylcellulose (w/v) with 0.25% tween 80 (w/v). All mice
are dosed daily between 6 and 8 a.m. with a dosing volume of 0.2
ml. Prior to termination, animals and diets are weighed and body
weight change and food consumption are calculated. Three hours
after last dose, mice are euthanized with CO2 and blood is removed
(0.5-1.0 ml) by cardiac puncture. After sacrifice, the liver,
heart, and epididymal fat pad are excised and weighed. Blood is
permitted to clot and serum is separated from the blood by
centrifugation.
[0366] Cholesterol and triglycerides are measured calorimetrically
using commercially prepared reagents (for example, as available
from Sigma #339-1000 and Roche #450061 for triglycerides and
cholesterol, respectively). The procedures are modified from
published work (McGowan M. W. et al., Clin Chem 29:538-542, 1983;
Allain C. C. et al., Clin Chem 20:470-475, 1974. Commercially
available standards for triglycerides and total cholesterol,
respectively, commercial quality control plasma, and samples are
measured in duplicate using 200 .mu.l of reagent. An additional
aliquot of sample, added to a well containing 200 .mu.l water,
provided a blank for each specimen. Plates are incubated at room
temperature on a plate shaker and absorbance is read at 500 nm and
540 nm for total cholesterol and triglycerides, respectively.
Values for the positive control are always within the expected
range and the coefficient of variation for samples is below 10%.
All samples from an experiment are assayed at the same time to
minimize inter-assay variability.
[0367] Serum lipoproteins are separated and cholesterol quantitated
by fast protein liquid chromatography (FPLC) coupled to an in line
detection system. Samples are applied to a Superose 6 HR size
exclusion column (Amersham Pharmacia Biotech) and eluted with
phosphate buffered saline-EDTA at 0.5 ml/min. Cholesterol reagent
(Roche Diagnostics Chol/HP 704036) at 0.16 ml/min mixed with the
column effluent through a T-connection and the mixture passed
through a 15 m.times.0.5 mm id knitted tubing reactor immersed in a
37 C water bath. The colored product produced in the presence of
cholesterol is monitored in the flow stream at 505 nm and the
analog voltage from the monitor is converted to a digital signal
for collection and analysis. The change in voltage corresponding to
change in cholesterol concentration is plotted vs time and the area
under the curve corresponding to the elution of very low density
lipoprotein (VLDL), low density lipoprotein (LDL) and high density
lipoprotein (HDL) is calculated using Perkin Elmer Turbochrome
software.
[0368] Triglyceride Serum Levels in Mice Dosed with a Compound of
the Invention is Compared to Mice Receiving the Vehicle to identify
compounds which could be particularly useful for lowering
triglycerides. Generally, triglyceride decreases of greater than or
equal to 30% (thirty percent) compared to control following a 30
mg/kg dose suggests a compound that can be especially useful for
lowering triglyceride levels.
[0369] The percent increase of HDLc serum levels in mice receiving
a compound of the invention is compared to mice receiving vehicle
to identify compounds of the invention that could be particularly
useful for elevating HDL levels. Generally, and increase of greater
than or equal to 25% (twenty five percent) increase in HDLc level
following a 30 mg/kg dose suggests a compound that can be
especially useful for elevating HDLc levels.
[0370] It may be particularly desirable to select compounds of this
invention that both lower triglyceride levels and increase HDLc
levels. However, compounds that either lower triglyceride levels or
increase HDLc levels may be desirable as well.
Evaluation of Glucose Levels in db/db Mice
[0371] The effects upon plasma glucose associated with
administering various dose levels of different compounds of the
present invention and the PPAR gamma agonist rosiglitazone
(BRL49653) or the PPAR alpha agonist fenofibrate, and the control,
to male db/db mice, are studied.
[0372] Five week old male diabetic (db/db) mice [for example,
C57BlKs/j-m+/+Lepr(db), Jackson Laboratory, Bar Harbor, Me.] or
lean littermates are housed 6 per cage with food and water
available at all times. After an acclimation period of 2 weeks,
animals are individually identified by ear notches, weighed, and
bled via the tail vein for determination of initial glucose levels.
Blood is collected (100 .mu.l) from unfasted animals by wrapping
each mouse in a towel, cutting the tip of the tail with a scalpel,
and milking blood from the tail into a heparinized capillary tube.
Sample is discharged into a heparinized microtainer with gel
separator and retained on ice. Plasma is obtained after
centrifugation at 4.degree. C. and glucose measured immediately.
Remaining plasma is frozen until the completion of the experiment,
when glucose and triglycerides are assayed in all samples. Animals
are grouped based on initial glucose levels and body weights.
Beginning the following morning, mice are dosed daily by oral
gavage for 7 days. Treatments are test compounds (30 mg/kg), a
positive control agent (30 mg/kg) or vehicle [1%
carboxymethylcellulose (w/v)/0.25% Tween80 (w/v); 0.3 ml/mouse]. On
day 7, mice are weighed and bled (tail vein) 3 hours after dosing.
Twenty-four hours after the 7.sup.th dose (i.e., day 8), animals
are bled again (tail vein). Samples obtained from conscious animals
on days 0, 7 and 8 are assayed for glucose. After the 24-hour
bleed, animals are weighed and dosed for the final time. Three
hours after dosing on day 8, animals are anesthetized by inhalation
of isoflurane and blood obtained via cardiac puncture (0.5-0.7 ml).
Whole blood is transferred to serum separator tubes, chilled on ice
and permitted to clot. Serum is obtained after centrifugation at
4.degree. C. and frozen until analysis for compound levels. After
sacrifice by cervical dislocation, the liver, heart and epididymal
fat pads are excised and weighed.
[0373] Glucose is measured calorimetrically using commercially
purchased reagents. According to the manufacturers, the procedures
are modified from published work (McGowan, M. W., Artiss, J. D.,
Strandbergh, D. R. & Zak, B. Clin Chem, 20:470-5 (1974) and
Keston, A. Specific calorimetric enzymatic analytical reagents for
glucose. Abstract of papers 129th Meeting ACS, 31C (1956)); and
depend on the release of a mole of hydrogen peroxide for each mole
of analyte, coupled with a color reaction first described by
Trinder (Trinder, P. Determination of glucose in blood using
glucose oxidase with an alternative oxygen acceptor. Ann Clin
Biochem, 6:24 (1969)). The absorbance of the dye produced is
linearly related to the analyte in the sample. The assays are
further modified in our laboratory for use in a 96 well format. The
commercially available standard for glucose, commercially available
quality control plasma, and samples (2 or 5 .mu.l/well) are
measured in duplicate using 200 .mu.l of reagent. An additional
aliquot of sample, pipetted to a third well and diluted in 200
.mu.l water, provided a blank for each specimen. Plates are
incubated at room temperature for 18 minutes for glucose on a plate
shaker (DPC Micormix 5) and absorbance read at 500 nm on a plate
reader. Sample absorbances are compared to a standard curve
(100-800 for glucose). Values for the quality control sample are
always within the expected range and the coefficient of variation
for samples is below 10%. All samples from an experiment are
assayed at the same time to minimize inter-assay variability.
Evaluation of the Effects of compounds of the Present Invention
upon A.sup.y Mice Body Weight, Fat Mass, Glucose and Insulin
Levels
Female A.sup.y Mice
[0374] Female A.sup.y mice are singly housed, maintained under
standardized conditions (22.degree. C., 12 h light:dark cycle), and
provided free access to food and water throughout the duration of
the study. At twenty weeks of age the mice are randomly assigned to
vehicle control and treated groups based on body weight and body
fat content as assessed by DEXA scanning (N=6). Mice are then dosed
via oral gavage with either vehicle or a Compound of this invention
(50 mg/kg) one hour after the initiation of the light cycle (for
example, about 7 A.M.) for 18 days. Body weights are measured daily
throughout the study. On day 14 mice are maintained in individual
metabolic chambers for indirect calorimetry assessment of energy
expenditure and fuel utilization. On day 18 mice are again
subjected to DEXA scanning for post treatment measurement of body
composition.
[0375] The results of p.o. dosing of compound for 18 days on body
weight, fat mass, and lean mass are evaluated and suggest which
compounds of this invention can be especially useful for
maintaining desirable weight and/or promoting desired lean to fat
mass.
[0376] Indirect calorimetry measurements revealing a significant
reduction in respiratory quotient (RQ) in treated animals during
the dark cycle [0.864.+-.0.013 (Control) vs. 0.803.+-.0.007
(Treated); p<0.001] is indicative of an increased utilization of
fat during the animals' active (dark) cycle and can be used to
selected especially desired compounds of this invention.
Additionally, treated animals displaying Significantly higher rates
of energy expenditure than control animals suggest such compounds
of this invention can be especially desired.
Male KK/A.sup.y Mice
[0377] Male KK/A.sup.y mice are singly housed, maintained under
standardized conditions (22.degree. C., 12 h light:dark cycle), and
provided free access to food and water throughout the duration of
the study. At twenty-two weeks of age the mice are randomly
assigned to vehicle control and treated groups based on plasma
glucose levels. Mice are then dosed via oral gavage with either
vehicle or a Compound of this invention (30 mg/kg) one hour after
the initiation of the light cycle (7 A.M.) for 14 days. Plasma
glucose, triglyceride, and insulin levels are assessed on day
14.
[0378] The results of p.o. dosing of compound for 14 days on plasma
glucose, triglycerides, and insulin are evaluated to identify
compounds of this invention which may be especially desired.
Method to Elucidate the LDL-Cholesterol Total-Cholesterol and
Triglyceride Lowering Effect
[0379] Male Syrian hamsters (Harlan Sprague Dawley) weighing 80-120
g are placed on a high-fat cholesterol-rich diet for two to three
weeks prior to use. Feed and water are provided ad libitum
throughout the course of the experiment. Under these conditions,
hamsters become hypercholesterolemic showing plasma cholesterol
levels between 180-280 mg/dl. (Hamsters fed with normal chow have a
total plasma cholesterol level between 100-150 mg/dl.) Hamsters
with high plasma cholesterol (180 mg/dl and above) are randomized
into treatment groups based on their total cholesterol level using
the GroupOptimizeV211.xls program.
[0380] A Compound of this invention is dissolved in an aqueous
vehicle (containing CMC with Tween 80) such that each hamster
received once a day approx. 1 ml of the solution by garvage at
doses 3 and 30 mg/kg body weight. Fenofibrate (Sigma Chemical,
prepared as a suspension in the same vehicle) is given as a known
alpha-agonist control at a dose of 200 mg/kg, and the blank control
is vehicle alone. Dosing is performed daily in the early morning
for 14 days.
[0381] Quantification of Plasma Lipids:
[0382] On the last day of the test, hamsters are bled (400 ul) from
the suborbital sinus while under isoflurane anesthesia 2 h after
dosing. Blood samples are collected into heparinized microfuge
tubes chilled in ice bath. Plasma samples are separated from the
blood cells by brief centrifugation. Total cholesterol and
triglycerides are determined by means of enzymatic assays carried
out automatically in the Monarch equipment (Instrumentation
Laboratory) following the manufacturer's precedure. Plasma
lipoproteins (VLDL, LDL and HDL) are resolved by injecting 25 ul of
the pooled plasma samples into an FPLC system eluted with phosphate
buffered saline at 0.5 ml/min through a Superose 6 HR 10/30 column
(Pharmacia) maintained room temp. Detection and characterization of
the isolated plasma lipids are accomplished by postcolumn
incubation of the effluent with a Cholesterol/HP reagent (for
example, Roche Lab System; infused at 0.12 ml/min) in a knitted
reaction coil maintained at 37.degree. C. The intensity of the
color formed is proportional to the cholesterol concentration and
is measured photometrically at 505 nm.
[0383] The effect of administration of a Compound of this invention
for 14 days is studied for the percent reduction in LDL level with
reference to the vehicle group. Especially desired compounds are
markedly more potent than fenofibrate in LDL-lowering efficacy.
Compounds of this invention that decrease LDL greater than or equal
to 30% (thirty percent) compared to vehicle can be especially
desired.
[0384] The total-cholesterol and triglyceride lowering effects of a
Compound of this invention is also studied. The data for reduction
in total cholesterol and triglyceride levels after treatment with a
compound of this invention for 14 days is compared to the vehicle
to suggest compounds that can be particularly desired. The known
control fenofibrate did not show significant efficacy under the
same experimental conditions.
Method to Elucidate the Fibrinogen-Lowering Effect of PPAR
Modulators
Zucker Fatty Rat Model:
[0385] The life phase of the study on fibrinogen-lowering effect of
compounds of this invention is part of the life phase procedures
for the antidiabetic studies of the same compounds. On the last
(14.sup.th) day of the treatment period, with the animals placed
under surgical anesthesia, .about.3 ml of blood is collected, by
cardiac puncture, into a syringe containing citrate buffer. The
blood sample is chilled and centrifuged at 4.degree. C. to isolate
the plasma that is stored at -70.degree. C. prior to fibrinogen
assay.
Quantification of Rat Plasma Fibrinogen:
[0386] Rat plasma fibrinogen levels are quantified by using a
commercial assay system consists of a coagulation instrument
following the manufacturer's protocol. In essence, 100 ul of plasma
is sampled from each specimen and a 1/20 dilution is prepared with
buffer. The diluted plasma is incubated at 37.degree. C. for 240
seconds. Fifty microliters of clotting reagent thrombin solution
(provided by the instrument's manufacturer in a standard
concentration) is then added. The instrument monitors the clotting
time, a function of fibrinogen concentration quantified with
reference to standard samples. Compounds that lower fibrinogen
level greater than vehicle can be especially desired.
[0387] Cholesterol and triglyceride lowering effects of compounds
of this invention are also studied in Zucker rats.
Method to Elucidate the Anti-Body Weight Gain and Anti-Appetite
Effects of Compounds of this Invention
Fourteen-Day Study in Zucker Fatty Rat.sup.1 or ZDF Rat.sup.2
Models
[0388] Male Zucker Fatty rats, non-diabetic (Charles River
Laboratories, Wilmington, Mass.) or male ZDF rats (Genetic Models,
Inc, Indianapolis, Ind.) of comparable age and weight are
acclimated for 1 week prior to treatment. Rats are on normal chow
and water is provided ad libitum throughout the course of the
experiment.
[0389] Compounds of this invention are dissolved in an aqueous
vehicle such that each rat received once a day approximately 1 ml
of the solution by garvage at doses 0.1, 0.3, 1 and 3 mg/kg body
weight. Fenofibrate (Sigma Chemical, prepared as a suspension in
the same vehicle) a known alpha-agonist given at doses of 300
mg/kg, as well as the vehicle are controls. Dosing is performed
daily in the early morning for 14 days. Over the course of the
experiment, body weight and food consumption are monitored.
[0390] Using this assay, compounds of this invention are identified
to determine which can be associated with significant weight
reduction.
Method to Elucidate the Activation of the PPAR Delta Receptor In
Vivo
[0391] This method is particularly useful for measuring the in vivo
PPARdelta receptor activation of compounds of this invention that
are determined to possess significant in vitro activity for that
receptor isoform over the PPAR gamma isoform.
[0392] Male PPARa null mice (129s4 SvJae-PPARa<tm1Gonz> mice;
Jackson Laboratories) of 8-9 weeks of age are maintained on Purina
5001 chow with water ad libitum for at least one week prior to use.
Feed and water are provided ad libitum throughout the course of the
experiment. Using the GroupOptimizeV211.xls program, mice are
randomized into treatment groups of five animals each based on
their body weight.
[0393] Compounds of this invention are suspended in an aqueous
vehicle of 1% (w/v) carboxymethylcellulose and 0.25% Tween 80 such
that each mouse receives once a day approx. 0.2 ml of the solution
by gavage at doses ranging from 0.2 to 20 mg/kg body weight. A
control group of mice is included in each experiment whereby they
are dosed in parallel with vehicle alone. Dosing is performed daily
in the early morning for 7 days.
[0394] On the last day of dosing, mice are euthanized by CO2
asphyxiation 3 hours after the final dose. Blood samples are
collected by heart draw into EDTA-containing microfuge tubes and
chilled on ice. Liver samples are collected by necropsy and are
flash-frozen in liquid nitrogen and stored at -80 degrees Celsius.
For RNA isolation from liver, five to ten mg of frozen liver is
placed in 700 .mu.l of 1.times. Nucleic Acid Lysis Solution
(Applied Biosystems Inc., Foster City, Calif.) and homogenized
using a hand-held tissue macerator (Biospec Products Inc.,
Bartlesville, Okla.). The homogenate is filtered through an ABI
Tissue pre-filter (Applied Biosystems Inc., Foster City, Calif.)
and collected in a deep well plate on an ABI 6100 Nucleic Acid prep
station (Applied Biosystems Inc., Foster City, Calif.). The
filtered homogenate is then loaded onto an RNA isolation plate and
the RNA Tissue-Filter-DNA method is run on the ABI 6100. The
isolated RNA is eluted in 150 .mu.l of RNase free water. For
quality assessment, 9 .mu.l of the isolated RNA solution is loaded
onto a 1% TBE agarose gel, and the RNA is visualized by ethidium
bromide fluorescence.
[0395] Complementary DNA (cDNA) is synthesized using the ABI High
Capacity Archive Kit (Applied Biosystems Inc., Foster City,
Calif.). Briefly, a 2.times. reverse transcriptase Master Mix is
prepared according to the manufacturer's protocol for the
appropriate number of samples (RT Buffer, dNTP, Random Primers,
MultiScribe RT (50 U/.mu.l), RNase free water). For each reaction,
50 .mu.l of 2.times.RT Master Mix is added to 50 .mu.l of isolated
RNA in a PCR tube that is incubated in a thermocycler (25.degree.
C. for 10 minutes followed by 37.degree. C. for 2 hours). The
resultant cDNA preparation is diluted 1:100 in dH2O for analysis by
real-time PCR. Also, a standard curve of cDNA is diluted 1:20,
1:100, 1:400, 1:2000, 1:10,000 for use in final quantitation.
[0396] A real-time PCR Master Mix for mouse Cyp4A1 gene expression
is mixed to contain: [0397] 1.times. Taqman Universal PCR Master
Mix (Applied Biosystems Inc., Foster City, Calif.) [0398] 6
micromolar final concentration Forward primer; Qiagen/Operon
Technologies, Alameda, Calif.) [0399] 6 micromolar final
concentration Reverse primer (Qiagen/Operon Technologies, Alameda,
Calif.) [0400] 0.15 micromolar final concentration Probe (5' 6-FAM
and 3' Tamra-Q; Qiagen/Operon Technologies, Alameda, Calif.) [0401]
RNase free water to 10 microliters
[0402] A real-time PCR Master Mix for the 18S ribosomal RNA control
gene expression is mixed to contain [0403] 1.times. Taqman
Universal PCR Master Mix (Applied Biosystems Inc., Foster City,
Calif.) [0404] 0.34 micromolar Probe/Primer TaqMan.RTM. Ribosomal
RNA Control Reagents #4308329 Applied Biosystems Inc., Foster City,
Calif.) [0405] RNase free water to 10 microliters
[0406] For the real-time PCR analysis, 6 ul of the respective
Master Mix solution (either Cyp4A1 or 18S) and 4 ul either of
diluted cDNA or of Standard Curve samples is added to individual
wells of a 384-well plate (n=2 for Standards; n=4 for unknowns).
Reactions are performed using the ABI 7900 HT standard universal
RT-PCR cycling protocol. Data are analyzed using SDS 2.1 (Applied
Biosystems Inc., Foster City, Calif.). Average quantity and
standard deviation are calculated automatically for each individual
sample, according to the standard curve values. Using Microsoft
Excel 2000, mean values for each group of five individual mice is
calculated. The mean value of each compound-treated group is
divided by the mean value of the vehicle-treated group. The fold
induction over the vehicle group is determined by assigning the
vehicle group to the value of 1.0, and the fold change of the mean
value for each group is expressed as fold-induction versus vehicle
(1.0). Data are plotted using Jandel SigmaPlot 8.0.
Monkey Studies
Efficacy Studies
[0407] Compounds of the invention may be examined in a dyslipidemic
rhesus monkey model. After an oral dose-escalation study for 28
days in obese, non-diabetic rhesus monkeys a determination of HDL-c
elevation is made with each dose and compared with pretreatment
levels. LDL cholesterol is also determined with each dose.
C-reactive protein levels are measured and compared to pretreatment
levels.
[0408] Compound of Formula 1 may be shown to elevate plasma
HDL-cholesterol levels in an African Green Monkey model in a manner
similar to that described above in rhesus monkeys.
[0409] Two groups of monkeys are placed in a dose-escalating study
that consists of one week of baseline measurements, 9 weeks of
treatments (vehicle, Compound of Formula I), and four weeks of
washout. During baseline, monkeys in all three groups are
administered vehicle once daily for seven days. Test compound of
Formula I, is administered in vehicle once daily for three weeks,
then at a greater concentration (double the dose may be desired)
once daily for three weeks, and then a still greater concentration
(double the most recent dose may be desired) once daily for three
weeks. At the completion of treatment, monkeys in both groups are
administered vehicle once daily and monitored for an additional six
weeks.
[0410] Animals are fasted overnight and then sedated for body
weight measurements and blood collection at weeks 1 (vehicle), 2,
3, 4, 6, 7, 9, 10, 12, and 14 of the study.
[0411] Parameters to measured, for example:
Body weight Total plasma cholesterol
HDL
LDL
Triglycerides
Insulin
Glucose
[0412] PK parameters at week 4, 7, and 10 (plasma drug
concentration at last week of each dose)
ApoAI
ApoAII
ApoB
ApoCIII
[0413] Liver enzymes (SGPT, SGOT, .quadrature.GT) Complete blood
count
[0414] Additionally, other measures may be made, as appropriate,
and consistent with the stated study design.
EQUIVALENTS
[0415] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *