U.S. patent application number 10/176825 was filed with the patent office on 2003-02-27 for tetrazole compounds as thyroid receptor ligands.
Invention is credited to Aspnes, Gary E., Chiang, Yuan-Ching P..
Application Number | 20030040535 10/176825 |
Document ID | / |
Family ID | 22650723 |
Filed Date | 2003-02-27 |
United States Patent
Application |
20030040535 |
Kind Code |
A1 |
Aspnes, Gary E. ; et
al. |
February 27, 2003 |
Tetrazole compounds as thyroid receptor ligands
Abstract
The present invention relates to tetrazole compounds of Formula
1, stereoisomers, pharmaceutically acceptable salts and prodrugs
thereof, and pharmaceutically acceptable salts of the prodrugs. 1
The invention also relates to compositions comprising the tetrazole
compounds and to methods of treating obesity, diabetes,
atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias,
congestive heart failure, and osteoporosis using the tetrazole
compounds.
Inventors: |
Aspnes, Gary E.; (Rockville,
RI) ; Chiang, Yuan-Ching P.; (East Lyme, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Family ID: |
22650723 |
Appl. No.: |
10/176825 |
Filed: |
June 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10176825 |
Jun 21, 2002 |
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09767771 |
Jan 23, 2001 |
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6441015 |
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60177987 |
Jan 25, 2000 |
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Current U.S.
Class: |
514/381 ;
514/382; 548/252; 548/253 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
25/24 20180101; A61P 9/04 20180101; A61P 27/06 20180101; A61P 9/06
20180101; A61P 43/00 20180101; A61P 35/00 20180101; A61P 9/10
20180101; C07D 257/04 20130101; A61P 9/12 20180101; A61P 19/10
20180101; A61P 3/06 20180101; A61P 3/10 20180101; A61P 5/14
20180101; A61P 3/04 20180101 |
Class at
Publication: |
514/381 ;
514/382; 548/252; 548/253 |
International
Class: |
A61K 031/41; C07D 43/02;
C07D 257/04 |
Claims
What is claimed is:
1. A compound of Formula I 24or a stereoisomer, pharmaceutically
acceptable salt or prodrugs thereof, or a pharmaceutically
acceptable salt of the prodrug, wherein: W is O, S, SO, SO.sub.2,
CH.sub.2, CF.sub.2, CHF, C(.dbd.O), CH(OH), NR.sup.a, or 25X is O,
CH.sub.2, CH.sub.2CH.sub.2, S, SO, SO.sub.2, CH.sub.2NR.sup.a,
NR.sup.a, or a bond; each R.sup.a is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkyl substituted with one
substituent selected from C.sub.3-C.sub.6cycloalkyl or methoxy;
R.sup.1, R.sup.2, R.sup.3 and R.sup.6 are independently hydrogen,
halogen, C.sub.1-C.sub.8alkyl, --CF.sub.3, --OCF.sub.3,
--OC.sub.1-C.sub.8alkyl, or --CN; R.sup.4 is hydrogen,
C.sub.1-C.sub.12alkyl, [C.sub.1-C.sub.12alkyl that is substituted
with from one to three substituents independently selected from
Group V], C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl,
halogen, --CN, --OR.sup.b, --SR.sup.c, --S(.dbd.O)R.sup.c,
--S(.dbd.O).sub.2R.sup.c, aryl, heteroaryl,
C.sub.3-C.sub.10cycloalkyl, heterocycloalkyl,
--S(.dbd.O).sub.2NR.sup.cR.sup.d, --C(.dbd.O)NR.sup.cR.sup.d,
C(.dbd.O)OR.sup.c, --NR.sup.aC(.dbd.O)R.sup.d- ,
--NR.sup.aC(.dbd.O)NR.sup.cR.sup.d,
--NR.sup.aS(.dbd.O).sub.2R.sup.d, --NR.sup.aR.sup.d,
--C(.dbd.O)R.sup.c, or R.sup.3 and R.sup.4 may be taken together
with the carbon atoms to which they are attached to form an
unsubstituted or substituted carbocyclic ring of formula
--(CH.sub.2).sub.i-- or an unsubstituted or substituted
heterocyclic ring selected from the group consisting of
--Q--(CH.sub.2).sub.j-- and
--(CH.sub.2).sub.k--Q--(CH.sub.2).sub.i-- wherein Q is O, S or
NR.sup.a; i is 3, 4, 5, 6 or 7; j is 2, 3, 4, 5, or 6; k and I are
each independently 1, 2, 3, 4, or 5, and any substituents up to
four are selected from C.sub.1-C.sub.4alkyl, --OR.sup.b, oxo, --CN,
phenyl, or R.sup.b is hydrogen, C.sub.1-C.sub.12alkyl,
[C.sub.1-C.sub.12alkyl substituted with one to three substituents
independently selected from Group V], aryl, heteroaryl,
C.sub.3-C.sub.10 cycloalkyl, heterocycloalkyl,
--C(.dbd.O)NR.sup.cR.sup.d, or R.sup.c and R.sup.d are each
independently selected from hydrogen, C.sub.1-C.sub.12alkyl,
[C.sub.1-C.sub.12alkyl substituted with one to three substituents
independently selected from Group VI], C.sub.2-C.sub.12alkenyl,
C.sub.2-C.sub.12alkynyl, aryl, heteroaryl, C.sub.3-C.sub.10
cycloalkyl, heterocycloalkyl, or R.sup.c and R.sup.d may together
along with the atom(s) to which they are attached form a 3-10
membered unsubstituted or substituted heterocyclic ring, which may
contain a second heterogroup selected from O, NR.sup.e, or S,
wherein any substitutents up to four are selected from
C.sub.1-C.sub.4alkyl, --OR.sup.b, oxo, --CN, phenyl, or
--NR.sup.aR.sup.g; R.sup.5 is --OH, --OC.sub.1-C.sub.6alkyl,
--OC(.dbd.O)R.sup.f, --F, --C(.dbd.O)OR.sup.c, or R.sup.4 and
R.sup.5 may together with the atom(s) to which they are attached
form a heterocyclic ring selected from the group consisting of
--CR.sup.c.dbd.CR.sup.a--NH--, --N.dbd.CR.sup.a--NH--,
--CR.sup.c.dbd.CR.sup.a--O--, --CR.sup.c.dbd.CR.sup.a--S--,
--CR.sup.c.dbd.N--NH--, or
--CR.sup.a.dbd.CR.sup.a--CR.sup.a.dbd.N--; Group V is halogen,
--CF.sub.3, --OCF.sub.3, hydroxy, oxo, C.sub.1-C.sub.6alkoxy, --CN,
aryl, heteroaryl, C.sub.3-C.sub.10 cycloalkyl, heterocycloalkyl,
--SR.sup.f, --S(.dbd.O)R.sup.f, --S(.dbd.O).sub.2R.sup.f,
[--S(.dbd.O).sub.2NR.sup.aR- .sup.f, wherein R.sup.a and R.sup.f
may together along with the atom(s) to which they are attached form
a 3-8 membered heterocyclic ring, which may contain a second
heterogroup selected from O, NR.sup.e or S], --NR.sup.aR.sup.g, or
[--C(.dbd.O)NR.sup.aR.sup.f, wherein R.sup.a and R.sup.f may
together along with the atom(s) to which they are attached form a
3-8 membered heterocyclic ring, which may contain a second
heterogroup selected from O, NR.sup.e or S]; Group VI is halogen,
hydroxy, oxo, C.sub.1-C.sub.6alkoxy, aryl, heteroaryl,
C.sub.3-C.sub.8cycloalkyl, heterocycloalkyl, --CN, or --OCF.sub.3;
R.sup.e is hydrogen, --CN, C.sub.1-C.sub.10 alkyl,
[C.sub.1-C.sub.10 alkyl substituted with one to three substitutents
independently selected from Group V], C.sub.2-C.sub.10alkenyl,
C.sub.2-C.sub.10alkoxy, C.sub.3-C.sub.10cycloalkyl, aryl,
heteroaryl, --C(.dbd.O)R.sup.f, --C(.dbd.O)OR.sup.f,
--C(.dbd.O)NR.sup.aR.sup.f--S(.dbd.O).sub.2NR.sup.aR- .sup.f, or
--S(.dbd.O).sub.2R.sup.f; R.sup.f is hydrogen,
C.sub.1-C.sub.10alkyl, [C.sub.1-C.sub.10alkyl substituted with from
one to three substituents selected from Group VI],
C.sub.2-C.sub.10alkenyl, C.sub.2-C.sub.10alkoxy,
C.sub.3-C.sub.10cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
and R.sup.g is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.6 alkenyl, aryl,
--C(.dbd.O)R.sup.f, --C(.dbd.O)OR.sup.f,
--C(.dbd.O)NR.sup.aR.sup.f, or --S(.dbd.O).sub.2R.sup.f, provided
that R.sup.1 and R.sup.2are not both hydrogen, further provided
that when X is CH.sub.2, W is NR.sup.a, R.sup.3 is hydrogen and
R.sup.5 is --OH, then R.sup.6 and R.sup.4 are not both
--C(CH.sub.3).sub.3, further provided that when X is CH.sub.2 or
CH.sub.2CH.sub.2, W is O, and R.sup.3 and R.sup.6 are hydrogen,
then R.sup.4is not halogen, --CF.sub.3, C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.7cycloalkyl, and further provided that when R.sup.3
and R.sup.4 are hydrogen and W is O then R.sup.6 is not halogen,
--CF.sub.3, C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.7cycloalkyl.
2. A compound of claim 1 wherein W is O.
3. A compound of claim 1 wherein X is a bond, NH, or CH.sub.2.
4. A compound of claim 1 wherein R.sup.1and R.sup.2 are
independently C.sub.1-C.sub.8alkyl, halogen, or --CN.
5. A compound of claim 4 wherein the C.sub.1-C.sub.8alkyl groups
are --CH.sub.3 and the halogens are chlorine, bromine, or
iodine.
6. A compound of claim 1 wherein R.sup.6 is hydrogen.
7. A compound of claim 1 wherein R.sup.5 is --OH,
--OC(.dbd.O)R.sup.f, or --F.
8. A compound of claim 1 wherein W is O; X is a bond, NH, or
CH.sub.2; R.sup.1and R.sup.2 are independently --CH.sub.3, Cl, Br,
or I; R.sup.6 is hydrogen; R.sup.5 is --OH; R.sup.3 is hydrogen,
halogen, C.sub.1-C.sub.6alkyl, --CF.sub.3, --OCF.sub.3,
--OC.sub.1-C.sub.6alkyl, or --CN; and R.sup.4 is hydrogen,
C.sub.1-C.sub.12alkyl, [C.sub.1-C.sub.12alkyl that is substituted
with from one to three substituents independently selected from
Group V], C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl,
halogen, --CN, --OR.sup.b, --SR.sup.c, --S(.dbd.O)R.sup.c,
--S(.dbd.O).sub.2R.sup.c, aryl, heteroaryl, C.sub.3-C.sub.10
cycloalkyl, heterocycloalkyl, --S(.dbd.O).sub.2NR.sup.cR- .sup.d,
--C(.dbd.O)NR.sup.cR.sup.d, --C(.dbd.O)OR.sup.c,
--NR.sup.aC(.dbd.O)R.sup.d, --NR.sup.aC(.dbd.O)NR.sup.cR.sup.d,
--NR.sup.aS(.dbd.O).sub.2R.sup.d, --NR.sup.aR.sup.d, wherein aryl
is phenyl or naphthyl either unsubstituted or substituted with from
one to four substituents selected from halogen,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, --OCF.sub.3, --CN,
--SR.sup.f, --S(.dbd.O)R.sup.f, --S(.dbd.O).sub.2R.sup.f,
C.sub.3-C.sub.6cycloalkyl, --S(.dbd.O).sub.2NR.sup.aR.sup.f,
--NR.sup.aR.sup.g, --C(.dbd.O)NR.sup.aR.sup.f, --OH, or
C.sub.1-C.sub.4perfluoroalkyl; wherein heteroaryl is an
unsubstituted, monosubstituted or disubstituted five or six
membered aromatic ring having from 1 to 3 heteroatoms independently
selected from O, N, or S, and wherein any substituents are selected
from halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
--CF.sub.3, --OH, --NR.sup.aR.sup.g, --CO.sub.2R.sup.f, or form a
fused benzo group; and heterocycloalkyl is either unsubstituted or
substituted with from one to four substituents selected from
C.sub.1-C.sub.4 alkyl, --OH, oxo, C.sub.1-C.sub.4alkoxy, --CN,
phenyl, or --NR.sup.aR.sup.e. or R.sup.3 and R.sup.4 may be taken
together with the carbon atoms to which they are attached to form a
carbocyclic ring of formula --(CH.sub.2).sub.i-- or a heterocyclic
ring selected from the group consisting of --Q--(CH.sub.2).sub.j--
and --(CH.sub.2).sub.k--Q--(CH.sub.- 2).sub.l-- wherein Q is O, S
or NR.sup.a; i is 3, 4, 5, 6 or 7; j is 2, 3, 4, 5, or 6; and k and
I are each independently 2, 3, 4, 5, or 6.
10. A compound of Formula I 26or a stereoisomer, pharmaceutically
acceptable salt or prodrug thereof, or a pharmaceutically
acceptable salt of the prodrug, wherein: W is O; X is a bond or NH;
R.sup.1and R.sup.2 are independently halogen or
C.sub.1-C.sub.8alkyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.5is
--OH; R.sup.4 is C.sub.1-C.sub.8 alkyl,
--S(.dbd.O).sub.2NR.sup.cR.sup.d, --C(.dbd.O)NR.sup.cR.sup.d, or
--S(.dbd.O).sub.2R.sup.c, and R.sup.c and R.sup.d are independently
hydrogen, C.sub.1-C.sub.1-2alkyl, C.sub.3-C.sub.10cycloalkyl, aryl,
heteroaryl, substituted cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, or R.sup.c and R.sup.d taken together with the nitrogen
atom to which they are attached form a heterocycloalkyl ring or a
substituted heterocycloalkyl ring.
11. The compound:
4-[2,6-dimethyl-4-(2H-tetrazol-5-yl)-phenoxy]-2-isopropy- l-phenol;
4-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-isopropyl-phenol- ;
4-[2,6-dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(pyrrolidine-1-sulfonyl)-
-phenol;
4-[2,6-dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(piperidine-1-sul-
fonyl)-phenol;
4-[2,6-dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(3,3-dimeth-
yl-piperidine-1-sulfonyl)-phenol;
N-cyclopropyl-5-[2,6-dichloro-4-(2H-tetr-
azol-5-yl)-phenoxy]-2-hydroxy-benzenesulfonamide;
5-[2,6-dichloro-4-(2H-te-
trazol-5-yl)-phenoxy]-2-hydroxy-N,N-dimethyl-benzenesulfonamide;
{5-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydroxy-phenyl}-piperidi-
n-1-yl-methanone;
N-cyclobutyl-5-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phenox-
y]-2-hydroxy-benzamide;
N-cyclohexyl-5-[2,6-dichloro-4-(1H-tetrazol-5-yl)--
phenoxy]-2-hydroxy-benzamide; or a stereoisomer, pharmaceutically
acceptable salt or prodrug thereof, or a pharmaceutically
acceptable salt of the prodrug.
12. The compound:
{5-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydroxy-
-phenyl}-pyrrolidin-1-yl-methanone;
N-bicyclo[2.2.1]hept-2-yl-5-[2,6-dichl-
oro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydroxy-benzamide;
4-[2,6-dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-isopropyl-phenol;
5-[2-chloro-6-methyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-N-cyclopropyl-2-h-
ydroxy-benzenesulfonamide;
N-cyclopropyl-5-[2,6-dichloro-4-(1H-tetrazol-5--
ylamino)-phenoxy]-2-hydroxy-benzenesulfonamide;
N-cyclobutyl-5-[2,6-dimeth-
yl-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide;
2-cyclopropylmethanesulfonyl-4-[2,6-dimethyl-4-(1H-tetrazol-5-ylamino)-ph-
enoxy]-phenol; or a stereoisomer, pharmaceutically acceptable salt
or prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug.
13. The compound:
2-cyclobutylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetraz-
ol-5-ylamino)-phenoxy]-phenol;
2-cyclobutylmethanesulfonyl-4-[2,6-dichloro-
l-4-(2H-tetrazol-5-ylamino)-phenoxy]-phenol;
4-[2-chloro-6-methyl-4-(2H-te-
trazol-5-ylamino)-phenoxy]-2-cyclobutylmethanesulfonyl-phenol;
2-cyclopentylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamino)-ph-
enoxy]-phenol;
2-cyclopentylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazo-
l-5-ylamino)-phenoxy]-phenol;
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamin-
o)-phenoxy]-2-cyclopentylmethanesulfonyl-phenol;
2-cyclohexylmethanesulfon-
yl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-phenol;
2-cyclohexylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazol-5-ylamino)-ph-
enoxy]-phenol;
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-c-
yclohexylmethanesulfonyl-phenol;
4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamino)-
-phenoxy]-2-(4-fluoro-benzenesulfonyl)-phenol;
4-[2,6-dichloro-4-(2H-tetra-
zol-5-ylamino)-phenoxy]-2-(4-fluoro-benzenesulfonyl)-phenol;
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-benze-
nesulfonyl)-phenol,
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-h-
ydroxy-N-methyl-benzamide;
N-butyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamin-
o)-phenoxy]-2-hydroxy-benzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-
-phenoxy]-2-hydroxy-N-isopropyl-benzamide;
5-[2,6-dichloro-4-(2H-tetrazol--
5-ylamino)-phenoxy]-N-heptyl-2-hydroxy-benzamide;
5-[2,6-dichloro-4-(2H-te-
trazol-5-ylamino)-phenoxy]-2-hydroxy-N-nonylbenzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-N-(4-fluoro-phenyl)-2--
hydroxy-benzamide;
N-cyclopentyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-
-phenoxy]-2-hydroxy-benzamide;
N-cyclohexyl-5-[2,6-dichloro-4-(2H-tetraol--
5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N-cycloheptyl-5-[2,6-dichloro-4-(-
2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N-cyclooctyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-
-benzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-
-(11-isopropyl-2-methyl-propyl)-benzamide;
N-cyclohexylmethyl-5-[2,6-dichl-
oro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N--(R-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-pheno-
xy]-2-hydroxy-benzamide;
N--(S-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(1H-t-
etrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N-cyclopentyl-5-[2,6-dich-
loro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide;
N-cyclohexyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-
-N-methyl-benzamide;
N-cycloheptyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamin-
o)-phenoxy]-2-hydroxy-N-methyl-benzamide;
N-cyclooctyl-5-[2,6-dichloro-4-(-
2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-(1-isoprop-
yl-2-methyl-propyl)-N-methyl-benzamide;
N-cyclohexylmethyl-5-[2,6-dichloro-
-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide;
N--(R-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-pheno-
xy]-2-hydroxy-N-methyl-benzamide;
N--(S-1-cyclohexyl-ethyl)-5-[2,6-dichlor-
o-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide,
or a stereoisomer, pharmaceutically acceptable salt or prodrug
thereof, or a pharmaceutically acceptable salt of the prodrug.
14. A method of treating diabetes, the method comprising the step
of administering to a patient having or at risk of having diabetes,
a therapeutically effective amount of a compound of claim 1, or a
stereoisomer, pharmaceutically acceptable salt or prodrug thereof,
or a pharmaceutically acceptable salt of the prodrug.
15. The method of claim 14 wherein the diabetes is Type I
diabetes.
16. The method of claim 14 wherein the diabetes is Type II
diabetes.
17. A method of treating atherosclerosis, the method comprising the
step of administering to a patient having or at risk of having
atherosclerosis, a therapeutically effective amount of a compound
of claim 1, or a stereoisomer, pharmaceutically acceptable salt or
prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug.
18. A method of treating hypertension, the method comprising the
step of administering to a patient having or at risk of having
hypertension, a therapeutically effective amount of a compound of
claim 1, or a stereoisomer, pharmaceutically acceptable salt or
prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug.
19. A method of treating coronary heart disease, the method
comprising the step of administering to a patient having or at risk
of having coronary heart disease, a therapeutically effective
amount of a compound of claim 1, or a stereoisomer,
pharmaceutically acceptable salt or prodrug thereof, or a
pharmaceutically acceptable salt of the prodrug.
20. A method of treating hypercholesterolemia, the method
comprising the step of administering to a patient having or at risk
of having hypercholesterolemia, a therapeutically effective amount
of a compound of claim 1, or a stereoisomer, pharmaceutically
acceptable salt or prodrug thereof, or a pharmaceutically
acceptable salt of the prodrug.
21. A method of treating hyperlipidemia, the method comprising the
step of administering to a patient having or at risk of having
hyperlipidemia, a therapeutically effective amount of a compound of
claim 1, or a stereoisomer, pharmaceutically acceptable salt or
prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug.
22. A method of treating thyroid disease, the method comprising the
step of administering to a patient having or at risk of having
thyroid disease, a therapeutically effective amount of a compound
of claim 1, or a stereoisomer, pharmaceutically acceptable salt or
prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug.
23. A method of treating hypothyroidism, the method comprising the
step of administering to a patient having or at risk of having
hypothyroidism, a therapeutically effective amount of a compound of
claim 1, or a stereoisomer, pharmaceutically acceptable salt or
prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug.
24. A method of treating depression, the method comprising the step
of administering to a patient having or at risk of having
depression, a therapeutically effective amount of a compound of
claim 1, or a stereoisomer, pharmaceutically acceptable salt or
prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug.
25. A method of treating obesity, the method comprising the step of
administering to an obese patient or a patient at risk of becoming
obese, a therapeutically effective amount of a compound of claim 1,
or a stereoisomer, pharmaceutically acceptable salt or prodrug
thereof, or a pharmaceutically acceptable salt of the prodrug.
26. A method of treating osteoporosis, the method comprising the
step of administering to a patient having or at risk of having
osteoporosis, a therapeutically effective amount of a compound of
claim 1, or a stereoisomer, pharmaceutically acceptable salt or
prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug.
27. A method of treating thyroid cancer, the method comprising the
step of administering to a patient having or at risk of having
thyroid cancer, a therapeutically effective amount of a compound of
claim 1, or a stereoisomer, pharmaceutically acceptable salt or
prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug.
28. A method of treating glaucoma, the method comprising the step
of administering to a patient having or at risk of having glaucoma,
a therapeutically effective amount of a compound of claim 1, or a
stereoisomer, pharmaceutically acceptable salt or prodrug thereof,
or a pharmaceutically acceptable salt of the prodrug.
29. A method of treating cardiac arrhythmias, the method comprising
the step of administering to a patient having or at risk of having
cardiac arrhythmias, a therapeutically effective amount of a
compound of claim 1, or a stereoisomer, pharmaceutically acceptable
salt or prodrug thereof, or a pharmaceutically acceptable salt of
the prodrug.
30. A method of treating congestive heart failure, the method
comprising the step of administering to a patient having or at risk
of having congestive heart failure, a therapeutically effective
amount of a compound of claim 1, or a stereoisomer,
pharmaceutically acceptable salt or prodrug thereof, or a
pharmaceutically acceptable salt of the prodrug.
31. A method of increasing energy expenditure, the method
comprising the step of administering to a patient who needs an
energy expenditure increase a therapeutically effective amount of a
compound of claim 1, or a stereoisomer, pharmaceutically acceptable
salt or prodrug thereof, or a pharmaceutically acceptable salt of
the prodrug.
32. A pharmaceutical composition comprising a compound of claim 1,
or a stereoisomer, pharmaceutically acceptable salt or prodrug
thereof, or a pharmaceutically acceptable salt of the prodrug.
33. A kit for the treatment of obesity, diabetes, atherosclerosis,
hypertension, coronary heart disease, hypercholesterolemia,
hyperlipidemia, thyroid disease, thyroid cancer, hypothyroidism,
depression, glaucoma, cardiac arrhythmias, congestive heart
failure, or osteoporosis, the kit comprising: a) a first
pharmaceutical composition comprising a compound of claim 1, or a
stereoisomer, pharmaceutically acceptable salt or prodrug thereof,
or a pharmaceutically acceptable salt of the prodrug; b) a second
pharmaceutical composition comprising an additional compound useful
for the treatment of obesity, diabetes, atherosclerosis,
hypertension, coronary heart disease, hypercholesterolemia,
hyperlipidemia, thyroid disease, thyroid cancer, hypothyroidism,
depression, glaucoma, cardiac arrhythmias, congestive heart
failure, or osteoporosis; and c) a container for containing the
first and second compositions.
34. A method of treating obesity, diabetes, atherosclerosis,
hypertension, coronary heart disease, hypercholesterolemia,
hyperlipidemia, thyroid disease, thyroid cancer, hypothyroidism,
depression, glaucoma, cardiac arrhythmias, congestive heart
failure, or osteoporosis, the method comprising the step of
administering to an obese patient, a patient at risk of becoming
obese, or a patient having or at risk of having diabetes,
atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias,
congestive heart failure, or osteoporosis a therapeutically
effective amount of 1) a compound of claim 1, or a stereoisomer,
pharmaceutically acceptable salt or prodrug thereof, or a
pharmaceutically acceptable salt of the prodrug and 2) an
additional compound useful for treating obesity, diabetes,
atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias,
congestive heart failure, or osteoporosis.
35. A pharmaceutical composition comprising a compound of claim 1,
or a stereoisomer, pharmaceutically acceptable salt or prodrug
thereof, or a pharmaceutically acceptable salt of the prodrug, and
an additional compound useful to treat obesity, diabetes,
atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias,
congestive heart failure, or osteoporosis.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority of U.S. Non-Provisional
application Ser. No. 09/767,771, filed Jan. 23, 2001, now allowed,
which claims priority of Provisional application No. 60/177,987,
filed Jan. 25, 2000.
FIELD OF THE INVENTION
[0002] The present invention relates to tetrazole compounds that
are thyroid receptor ligands. The invention also relates to
compositions and kits comprising the tetrazole compounds and to
methods of treatment of obesity, diabetes, atherosclerosis,
hypertension, coronary heart disease, hypercholesterolemia,
hyperlipidemia, thyroid disease, thyroid cancer, hypothyroidism,
depression, glaucoma, cardiac arrhythmias, congestive heart
failure, and osteoporosis using the tetrazole compounds.
BACKGROUND OF THE INVENTION
[0003] Thyroid hormones are important in normal development and in
maintaining metabolic homeostasis. For example, thyroid hormones
stimulate the metabolism of cholesterol to bile acids and enhance
the lipolytic responses of fat cells to other hormones.
[0004] Thyroid hormones also affect cardiac function both directly
and indirectly, e.g., by increasing the metabolic rate. For
example, tachycardia, increased stroke volume, increased cardiac
index, cardiac hypertrophy, decreased peripheral vascular
resistance and increased pulse pressure are observed in patients
with hyperthyroidism.
[0005] Disorders of the thyroid gland are generally treated by
administering either naturally occurring thyroid hormones or
analogues that mimic the effects of thyroid hormones. Such
analogues are called thyromimetics or thyroid receptor ligands.
[0006] Two naturally occurring thyroid hormones,
3,5,3',5'-tetraiodo-L-thy- ronine (also referred to as "T.sub.4" or
thyroxine) and 3,5,3'-triiodo-L-thyronine (also referred to as
"T.sub.3"), are shown below: 2
[0007] T.sub.3 is more biologically active than T.sub.4, and
differs from T.sub.4 by the absence of the 5' iodine. T.sub.3 may
be produced directly in the thyroid gland, or in peripheral
tissues, by the removal of the 5' iodine of T.sub.4 by deiodinase
enzymes. Thyroid receptor ligands can be designed to be
structurally similar to T.sub.3. In addition, naturally occurring
metabolites of T.sub.3 are known.
[0008] As discussed above, thyroid hormones affect cardiac
functioning, for example, by causing an increase in heart rate, and
accordingly, an increase in oxygen consumption. While the increase
in oxygen consumption can result in certain desired metabolic
effects, nonetheless, it does place an extra burden on the heart,
which in some situations, may give rise to damaging side effects.
Consequently, efforts have been made to synthesize thyroid hormone
analogs that function to lower lipids and serum cholesterol, but
which have reduced adverse cardiac effects.
[0009] U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; and
5,061,798 disclose thyroid hormone mimetics, namely,
3,5-dibromo-3'-[6-oxo-3 (1H)-pyridazinylmethyl]-thyronines.
[0010] U.S. Pat. No. 5,284,971 discloses thyromimetic cholesterol
lowering agents, namely, 4-(3-cyclohexyl-4-hydroxy or -methoxy
phenylsulfonyl)-3,5 dibromo-phenylacetic compounds.
[0011] U.S. Pat. Nos. 5,654,468 and 5,569,674 disclose certain
lipid lowering agents, namely, heteroacetic acid derivatives, which
compete with radiolabeled T.sub.3 in binding assays using rat liver
nuclei and plasma membrane preparations.
[0012] Certain oxamic acids and derivatives thereof are known in
the art, e.g., U.S. Pat. No. 4,069,343 describes the use of certain
oxamic acids to prevent immediate type hypersensitivity reactions;
U.S. Pat. No. 4,554,290 describes the use of certain oxamic acids
to control pests on animals and plants; U.S. Pat. No. 5,232,947
describes the use of certain oxamic acids to improve damaged
cerebral functions of the brain; and European Patent Specification
published as EP 580,550 (also U.S. Pat. No. 5,401,772) discloses
certain oxamic acid derivatives as hypocholesterolemic agents.
[0013] In addition, certain oxamic acid derivatives of thyroid
hormones are known in the art. For example, N. Yokoyama et al. in
an article published in the Journal of Medicinal Chemistry, 38 (4):
695-707 (1995) describe replacing a --CH.sub.2 group in a naturally
occurring metabolite of T.sub.3 with an --NH group resulting in
--HNCOCO.sub.2H. Likewise, R. E. Steele et al. in an article
published in International Congressional Service (Atherosclerosis
X) 106: 321-324 (1995) and Z. F. Stephan et al. in an article
published in Atherosclerosis, 126: 53-63 (1996), describe certain
oxamic acid derivatives useful as lipid-lowering thyromimetic
agents that have reduced adverse cardiac activities.
[0014] European Patent Application EP 276,064 discloses some
tetrazole compounds that are leukotriene antagonists as
anti-inflammatory agents. Similarly, U.S. Pat. No. 5,347,036
discloses some tetrazole compounds that are leukotriene inhibitors.
The tetrazole compounds disclosed in EP 276,064 and U.S. Pat. No.
5,347,036 are structurally different from the compounds of the
present invention.
[0015] Obesity is a devastating disease. In addition to harming
physical health, obesity can wreak havoc on mental health because
obesity affects self-esteem, which ultimately can affect a person's
ability to interact socially with others. Unfortunately, obesity is
not well understood, and societal stereotypes and presumptions
regarding obesity only tend to exacerbate the psychological effects
of the disease. Because of the impact of obesity on individuals and
society, much effort has been expended to find ways to treat
obesity, but little success has been achieved in the long-term
treatment and/or prevention of obesity. The present invention
provides methods of treating obesity by administering to an obese
patient or a patient at risk of becoming obese a therapeutically
effective amount of a thyromimetic of the present invention. It is
believed that the thyromimetics of the present invention act to
treat obesity by increasing energy expenditure, and thus promoting
weight loss.
[0016] The thyromimetics of the present invention can also be used
to treat diabetes, atherosclerosis, hypertension, coronary heart
disease, hypercholesterolemia, hyperlipidemia, thyroid disease,
thyroid cancer, hypothyroidism, depression, glaucoma, cardiac
arrhythmias, congestive heart failure, and osteoporosis.
[0017] In spite of the early discovery of insulin and its
subsequent widespread use in the treatment of diabetes, and the
later discovery of and use of sulfonylureas, biguamides and
thiazolidenediones, such as troglitazone, rosiglitazone or
pioglitazone, as oral hypoglycemic agents, the treatment of
diabetes remains less than satisfactory.
[0018] The use of insulin currently requires multiple daily doses,
usually by self-injection. Determination of the proper dosage of
insulin requires frequent estimations of the sugar in urine or
blood. The administration of an excess dose of insulin causes
hypoglycemia, with effects ranging from mild abnormalities in blood
glucose to coma, or even death. Treatment of non-insulin dependent
diabetes mellitus (Type II diabetes, NIDDM) usually consists of a
combination of diet, exercise, oral hypoglycemic agents, e.g.,
thiazolidenediones, and, in more severe cases, insulin. However,
the clinically available hypoglycemic agents can have side effects
that limit their use, or an agent may not be effective with a
particular patient. In the case of insulin dependent diabetes
mellitus (Type I), insulin is usually the primary course of
therapy. Hypoglycemic agents that have fewer side effects or
succeed where others fail are needed.
[0019] Atherosclerosis, a disease of the arteries, is recognized to
be a leading cause of death in the United States and Western
Europe. The pathological sequence leading to atherosclerosis and
occlusive heart disease is well known. The earliest stage in this
sequence is the formation of "fatty streaks" in the carotid,
coronary and cerebral arteries and in the aorta. These lesions are
yellow in color due to the presence of lipid deposits found
principally within smooth-muscle cells and in macrophages of the
intima layer of the arteries and aorta. Further, it is postulated
that most of the cholesterol found within the fatty streaks, in
turn, give rise to development of "fibrous plaques," which consist
of accumulated intimal smooth muscle cells laden with lipid and are
surrounded by extra-cellular lipid, collagen, elastin and
proteoglycans. The cells plus matrix form a fibrous cap that covers
a deeper deposit of cell debris and more extra-cellular lipid. The
lipid is primarily free and esterified cholesterol. A fibrous
plaque forms slowly, and is likely in time to become calcified and
necrotic, advancing to a "complicated lesion," which accounts for
arterial occlusion and tendency toward mural thrombosis and
arterial muscle spasm that characterize advanced
atherosclerosis.
[0020] Epidemiological evidence has firmly established
hyperlipidemia as a primary risk factor in causing cardiovascular
disease (CVD) due to atherosclerosis. In recent years, leaders of
the medical profession have placed renewed emphasis on lowering
plasma cholesterol levels, and low density lipoprotein cholesterol
in particular, as an essential step in prevention of CVD. The upper
limits of "normal" are now known to be significantly lower than
heretofore appreciated. As a result, large segments of Western
populations are now realized to be at particularly high risk. Such
independent risk factors include glucose intolerance, left
ventricular hypertrophy, hypertension, and being of the male sex.
Cardiovascular disease is especially prevalent among diabetic
subjects, at least in part because of the existence of multiple
independent risk factors in this population. Successful treatment
of hyperlipidemia in the general population, and in diabetic
subjects in particular, is therefore of exceptional medical
importance.
[0021] Hypertension (or high blood pressure) is a condition that
occurs in the human population as a secondary symptom to various
other disorders such as renal artery stenosis, pheochromocytoma or
endocrine disorders. However, hypertension is also evidenced in
many patients in whom the causative agent or disorder is unknown.
While such "essential" hypertension is often associated with
disorders such as obesity, diabetes and hypertriglyceridemia, the
relationship between these disorders has not been elucidated.
Additionally, many patients display the symptoms of high blood
pressure in the complete absence of any other signs of disease or
disorder.
[0022] It is known that hypertension can directly lead to heart
failure, renal failure and stroke (brain hemorrhaging). These
conditions are capable of causing death in a patient. Hypertension
can also contribute to the development of atherosclerosis and
coronary disease. These conditions gradually weaken a patient and
can lead to death.
[0023] The exact cause of essential hypertension is unknown, though
a number of factors are believed to contribute to the onset of the
disease. Among such factors are stress, uncontrolled emotions,
unregulated hormone release (the renin, angiotensin, aldosterone
system), excessive salt and water due to kidney malfunction, wall
thickening and hypertrophy of the vasculature resulting in
constricted blood vessels and genetic factors.
[0024] The treatment of essential hypertension has been undertaken
bearing the foregoing factors in mind. Thus, a broad range of
beta-blockers, vasoconstrictors, angiotensin converting enzyme
inhibitors and the like have been developed and marketed as
antihypertensives. The treatment of hypertension utilizing these
compounds has proven beneficial in the prevention of short-interval
deaths such as heart failure, renal failure and brain
hemorrhaging.
[0025] Hypertension has been associated with elevated blood insulin
levels, a condition known as hyperinsulinemia. Insulin, a peptide
hormone whose primary actions are to promote glucose utilization,
protein synthesis and the formation and storage of neutral lipids,
also acts to promote vascular cell growth and increase renal sodium
retention, among other things. These latter functions can be
accomplished without affecting glucose levels and are known causes
of hypertension. Peripheral vasculature growth, for example, can
cause constriction of peripheral capillaries while sodium retention
increases blood volume. Thus, the lowering of insulin levels in
hyperinsulinemics can prevent abnormal vascular growth and renal
sodium retention caused by high insulin levels and thereby
alleviate hypertension.
SUMMARY OF THE INVENTION
[0026] The present invention provides compounds of Formula I 3
[0027] stereoisomers, pharmaceutically acceptable salts and
prodrugs thereof, and pharmaceutically acceptable salts of the
prodrugs, wherein:
[0028] W is O, S, SO, SO.sub.2, CH.sub.2, CF.sub.2, CHF, C(.dbd.O),
CH(OH),NR.sup.a, or 4
[0029] X is O, CH.sub.2, CH.sub.2CH.sub.2, S, SO, SO.sub.2,
CH.sub.2NR.sup.a, NR.sup.a, or a bond;
[0030] each R.sup.a is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkyl substituted with one
substituent selected from C.sub.3-C.sub.6cycloalkyl or methoxy;
[0031] R.sup.1, R.sup.2, R.sup.3 and R.sup.6 are independently
hydrogen, halogen, C.sub.1-C.sub.8alkyl, --CF.sub.3, --OCF .sub.3,
--OC.sub.1-C.sub.8alkyl, or --CN;
[0032] R.sup.4is hydrogen, C.sub.1-C.sub.12alkyl,
[C.sub.1-C.sub.12alkyl that is substituted with from one to three
substituents independently selected from Group V], C.sub.2-C.sub.12
alkenyl, C.sub.2-C.sub.12 alkynyl, halogen, --CN, --OR.sup.b,
--SR.sup.c, --S(.dbd.O)R.sup.c, --S(.dbd.O).sub.2R.sup.c, aryl,
heteroaryl, C.sub.3-C.sub.10 cycloalkyl, heterocycloalkyl,
--S(.dbd.O).sub.2NR.sup.cR.sup.d, --C(.dbd.O)NR.sup.cR.sup.d,
--C(.dbd.O)OR.sup.c, --NR.sup.aC(.dbd.O)R.sup- .d,
--NR.sup.aC(.dbd.O)NR.sup.cR.sup.d,
--NR.sup.aS(.dbd.O).sub.2R.sup.d, --NR.sup.aR.sup.d,
--C(.dbd.O)R.sup.c,
[0033] or R.sup.3 and R.sup.4 may be taken together with the carbon
atoms to which they are attached to form an unsubstituted or
substituted carbocyclic ring of formula --(CH.sub.2).sub.i-- or an
unsubstituted or substituted heterocyclic ring selected from the
group consisting of --Q--(CH.sub.2).sub.j-- and
--(CH.sub.2).sub.k--Q--(CH.sub.2)1- wherein Q is O, S or NR.sup.a;
i is 3, 4, 5, 6 or 7; j is 2, 3, 4, 5, or 6; k and I are each
independently 1, 2, 3, 4, or 5, and any substituents up to four are
selected from C.sub.1-C.sub.4alkyl, --OR.sup.b, oxo, --CN, phenyl,
or --NR.sup.aR.sup.g.;
[0034] R.sup.b is hydrogen, C.sub.1-C.sub.12alkyl,
[C.sub.1-C.sub.12alkyl substituted with one to three substituents
independently selected from Group V], aryl, heteroaryl,
C.sub.3-C.sub.10 cycloalkyl, heterocycloalkyl,
--C(.dbd.O)NR.sup.cR.sup.d, or --C(.dbd.O)R.sup.f.,
[0035] R.sup.c and R.sup.d are each independently selected from
hydrogen, C.sub.1-C.sub.12alkyl, [C.sub.1-C.sub.12alkyl substituted
with one to three substituents independently selected from Group
VI], C.sub.2-C.sub.12alkenyl, C.sub.2-C.sub.12alkynyl, aryl,
heteroaryl, C.sub.3-C.sub.10 cycloalkyl, heterocycloalkyl,
[0036] or R.sup.c and R.sup.d may together along with the atom(s)
to which they are attached form a 3-10 membered unsubstituted or
substituted heterocyclic ring, which may contain a second
heterogroup selected from O, NR.sup.e, or S, wherein any
substitutents up to four are selected from C.sub.1-C.sub.4alkyl,
--OR.sup.b, oxo, --CN, phenyl, or --NR.sup.aR.sup.g;
[0037] R.sup.5 is --OH, --OC.sub.1--C.sub.6alkyl,
--OC(.dbd.O)R.sup.f, --F, --C(.dbd.O)OR.sup.c,
[0038] or R.sup.4 and R.sup.5 may together with the atom(s) to
which they are attached form a heterocyclic ring selected from the
group consisting of --CR.sup.c.dbd.CR.sup.a--NH--,
--N.dbd.CR.sup.a--NH--, --CR.sup.c.dbd.CR.sup.a--O--,
--CR.sup.c.dbd.CR.sup.a--S, --CR.sup.c.dbd.N--NH--, or
--CR.sup.a.dbd.CRa--CRa.dbd.N--;
[0039] Group V is halogen, --CF.sub.3, --OCF.sub.3, hydroxy, oxo,
C.sub.1-C.sub.6alkoxy, --CN, aryl, heteroaryl,
C.sub.3-C.sub.10cycloalkyl- , heterocycloalkyl, --SR.sup.f,
--S(.dbd.O)R.sup.f, --S(.dbd.O).sub.2R.sup.f,
[--S(.dbd.O).sub.2NR.sup.aR.sup.f, wherein R.sup.a and R.sup.f may
together along with the atom(s) to which they are attached form a
3-8 membered heterocyclic ring, which may contain a second
heterogroup selected from O, NR.sup.e or S], --NR.sup.aR.sup.g, or
[--C(.dbd.O)NR.sup.aR.sup.f, wherein R.sup.a and R.sup.f may
together along with the atom(s) to which they are attached form a
3-8 membered heterocyclic ring, which may contain a second
heterogroup selected from O, NR.sup.e or S];
[0040] Group VI is halogen, hydroxy, oxo, C.sub.1-C.sub.6alkoxy,
aryl, heteroaryl, C.sub.3-C.sub.8cycloalkyl, heterocycloalkyl,
--CN, or --OCF.sub.3;
[0041] R.sup.e is hydrogen, --CN, C.sub.1-C.sub.10 alkyl,
[C.sub.1-C.sub.10alkyl substituted with one to three substitutents
independently selected from Group V], C.sub.2-C.sub.10alkenyl,
C.sub.2-C.sub.10alkoxy, C.sub.3-C.sub.10 cycloalkyl, aryl,
heteroaryl, --C(.dbd.O)R.sup.f, --C(.dbd.O)OR.sup.f,
--C(.dbd.O)NR.sup.aR.sup.f --S(.dbd.O).sub.2NR.sup.aR.sup.f, or
--S(.dbd.O).sub.2R.sup.f;
[0042] R.sup.f is hydrogen, C.sub.1-C.sub.10alkyl,
[C.sub.1-C.sub.10 alkyl substituted with from one to three
substituents selected from Group VI], C.sub.2-C.sub.10alkenyl,
C.sub.2-C.sub.10alkoxy, C.sub.3-C.sub.10cycloalk- yl,
heterocycloalkyl, aryl, or heteroaryl; and
[0043] R.sup.9 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalky- l, C.sub.2-C.sub.6 alkenyl, aryl,
--C(.dbd.O)R.sup.f, --C(.dbd.O)OR.sup.f, C(.dbd.O)NR.sup.aR.sup.f,
or --S(.dbd.O).sub.2R.sup.f, provided that R.sup.1and R.sup.2 are
not both hydrogen, further provided that when X is CH.sub.2, W is
NR.sup.a, R.sup.3is hydrogen and R.sup.5 is --OH, then R.sup.6 and
R.sup.4are not both --C(CH.sub.3).sub.3, further provided that when
X is CH.sub.2 or CH.sub.2CH.sub.2, W is O, and R.sup.3 and R.sup.6
are hydrogen, then R.sup.4 is not halogen, --CF.sub.3,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.7cycloalkyl, and further
provided that when R.sup.3 and R.sup.4 are hydrogen and W is O then
R.sup.6 is not halogen, --CF.sub.3, C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.7cycloalkyl.
[0044] In a preferred embodiment of the compounds of Formula I, W
is O.
[0045] In another preferred embodiment of the compounds of Formula
I, X is a bond, NH, or CH.sub.2.
[0046] In another preferred embodiment of the compounds of Formula
I, R.sup.1and R.sup.2 are independently C.sub.1-C.sub.8alkyl,
halogen, or --CN.
[0047] In a more preferred embodiment of the compounds of Formula
I, when R.sup.1 and R.sup.2 are independently C.sub.1-C.sub.8alkyl
or halogen, the C.sub.1-C.sub.8alkyl group is --CH.sub.3 and
halogen group is chlorine, bromine, or iodine.
[0048] In another preferred embodiment of the compounds of Formula
I, R.sup.6 is hydrogen.
[0049] In another preferred embodiment of the compounds of Formula
I, R.sup.5 is --OH, --OC(.dbd.O)R.sup.f, or --F.
[0050] In another preferred embodiment of the compounds of Formula
I
[0051] W is O;
[0052] X is a bond, NH or CH.sub.2;
[0053] R.sup.1 and R.sup.2 are independently --CH.sub.3, Cl, Br, or
I;
[0054] R.sup.6 is hydrogen;
[0055] R.sup.5 is --OH;
[0056] R.sup.3 is hydrogen, halogen, C.sub.1-C.sub.6alkyl,
--CF.sub.3, --OCF.sub.3, --OC.sub.1-C.sub.6alkyl, or --CN; and
[0057] R.sup.4 is hydrogen, C.sub.1-C.sub.12alkyl,
[C.sub.1-C.sub.12alkyl that is substituted with from one to three
substituents independently selected from Group V], C.sub.2-C.sub.12
alkenyl,
[0058] C.sub.2-C.sub.12alkynyl, halogen, --CN, --OR.sup.b,
--SR.sup.c, --S(.dbd.O)R.sup.c, --S(.dbd.O).sub.2R.sup.c, aryl,
heteroaryl, C.sub.3-C.sub.10 cycloalkyl, heterocycloalkyl,
--S(.dbd.O).sub.2NR.sup.cR- .sup.d, --C(.dbd.O)NR.sup.cR.sup.d,
--C(.dbd.O)OR.sup.c, --NR.sup.aC(.dbd.O)R.sup.d,
--NR.sup.aC(.dbd.O)NR.sup.cR.sup.d,
--NR.sup.aS(.dbd.O).sub.2R.sup.d, --NR.sup.cR.sup.d, wherein aryl
is phenyl or naphthyl either unsubstituted or substituted with from
one to four substituents selected from halogen,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, --OCF.sub.3, --CN,
--SR.sup.f, --S(.dbd.O)R.sup.d, --S(.dbd.O).sub.2R.sup.f,
[0059] C.sub.3-C.sub.6cycloalkyl,
--S(.dbd.O).sub.2NR.sup.aR.sup.f--NR.sup- .aR,
--C(.dbd.O)NR.sup.aR.sup.f, --OH, or C.sub.1-C.sub.4perfluoroalkyl;
wherein heteroaryl is an unsubstituted, monosubstituted or
disubstituted five or six membered aromatic ring having from 1 to 3
heteroatoms independently selected from O, N, or S, and wherein any
substituents are selected from halogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, --CF.sub.3, --OH, --NR.sup.aR.sup.g,
--CO.sub.2R.sup.f, or form a fused benzo group; and
heterocycloalkyl is either unsubstituted or substituted with from
one to four substituents selected from C.sub.1-C.sub.4 alkyl, --OH,
oxo, C.sub.1-C.sub.4alkoxy, --CN, phenyl, or --NR.sup.aR.sup.e,
[0060] or R.sup.3 and R.sup.4 may be taken together with the carbon
atoms to which they are attached to form a carbocyclic ring of
formula --(CH.sub.2).sub.j-- or a heterocyclic ring selected from
the group consisting of --Q--(CH.sub.2).sub.j-- and
--(CH.sub.2).sub.k--Q--(CH.sub.- 2).sub.j-- wherein Q is O, S or
NR.sup.a; i is 3, 4, 5, 6 or 7; j is 2, 3, 4, 5, or 6; k, and I are
each independently 1, 2, 3, 4, or 5.
[0061] The present invention provides compounds of Formula I 5
[0062] stereoisomers, pharmaceutically acceptable salts and
prodrugs thereof, and pharmaceutically acceptable salts of the
prodrugs, wherein:
[0063] W is O;
[0064] X is a bond or NH;
[0065] R.sup.1and R.sup.2 are independently halogen or
C.sub.1-C.sub.8alkyl;
[0066] R.sup.3 and R.sup.6 are hydrogen;
[0067] R.sup.5is --OH;
[0068] R.sup.4 is C.sub.1-C.sub.8 alkyl,
--S(.dbd.O).sub.2NR.sup.cR.sup.d, --C(.dbd.O)NR.sup.cR.sup.d or
--S(.dbd.O).sub.2R.sup.c; and
[0069] R.sup.c and R.sup.d are independently hydrogen,
C.sub.1-C.sub.12alkyl, C.sub.3-C.sub.10cycloalkyl,
--S(.dbd.O).sub.2R.sup.c, or substituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl, or R.sup.c and R.sup.d taken
together with the nitrogen atom to which they are attached form a
heterocycloalkyl ring or a substituted heterocycloalkyl ring.
[0070] The present invention provides the compounds:
[0071]
4-[2,6-dimethyl-4-(2H-tetrazol-5-yl)-phenoxy]-2-isopropyl-phenol;
[0072]
4-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-isopropyl-phenol;
[0073]
4-[2,6-dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(pyrrolidine-1-sulf-
onyl)-phenol;
[0074]
4-[2,6-dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(piperidine-1-sulfo-
nyl)-phenol;
[0075]
4-[2,6-dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(3,3-dimethyl-piper-
idine-1-sulfonyl)-phenol;
[0076]
N-cyclopropyl-5-[2,6-dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-hydro-
xy-benzenesulfonamide;
[0077]
5-[2,6-dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-hydroxy-N,N-dimethy-
l-benzenesulfonamide;
[0078]
{5-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydroxy-phenyl}-pi-
peridin-1-yl-methanone;
[0079]
N-cyclobutyl-5-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydrox-
y-benzamide;
[0080]
N-cyclohexyl-5-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydrox-
y-benzamide;
[0081]
{5-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydroxy-phenyl}-py-
rrolidin-1-yl-methanone;
[0082]
N-bicyclo[2.2.1]hept-2-yl-5-[2,6-dichloro-4-(1H-tetrazol-5-yl)-phen-
oxy]-2-hydroxy-benzamide;
[0083]
4-[2,6-dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-isopropyl-phen-
ol;
[0084]
5-[2-chloro-6-methyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-N-cycloprop-
yl-2-hydroxy-benzenesulfonamide;
[0085]
N-cyclopropyl-5-[2,6-dichloro-4-(1H-tetrazol-5-ylamino)-phenoxy]-2--
hydroxy-benzenesulfonamide;
[0086]
N-cyclobutyl-5-[2,6-dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-h-
ydroxy-N-methyl-benzamide;
[0087]
2-cyclopropylmethanesulfonyl-4-[2,6-dimethyl-4-(1H-tetrazol-5-ylami-
no)-phenoxy]-phenol; and stereoisomers, pharmaceutically acceptable
salts and prodrugs thereof, and pharmaceutically acceptable salts
of the prodrugs.
[0088] The present invention also provides the compounds:
[0089]
2-cyclobutylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamin-
o)-phenoxy]-phenol;
[0090]
2-cyclobutylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazol-5-ylami-
no)-phenoxy]-phenol;
[0091]
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-cyclobuty-
lmethanesulfonyl-phenol;
[0092]
2-cyclopentylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylami-
no)-phenoxy]-phenol;
[0093]
2-cyclopentylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazo1-5-ylam-
ino)-phenoxy]-phenol;
[0094]
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-cyclopent-
ylmethanesulfonyi-phenol;
[0095]
2-cyclohexylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamin-
o)-phenoxy]-phenol;
[0096]
2-cyclohexylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazol-5-ylami-
no)-phenoxy]-phenol;
[0097]
4-[2-chloro-6-methyl-4-(2H-tetrazol-5ylamino)-phenoxy]-2-cyclohexyl-
methanesulfonyl-phenol;
[0098]
4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-benz-
enesulfonyl)-phenol;
[0099]
4-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-benz-
enesulfonyl)-phenol;
[0100]
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-
-benzenesulfonyl)-phenol;
[0101]
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-meth-
yl-benzamide;
[0102]
N-butyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydrox-
y-benzamide;
[0103]
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-isop-
ropyl-benzamide;
[0104]
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-N-heptyl-2-hydro-
xy-benzamide;
[0105]
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-nony-
lbenzamide;
[0106]
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-N-(4-fluoro-phen-
yl)-2-hydroxy-benzamide;
[0107]
N-cyclopentyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2--
hydroxy-benzamide;
[0108]
N-cyclohexyl-5-[2,6-dichloro-4-(2H-tetraol-5-ylamino)-phenoxy]-2-hy-
droxy-benzamide;
[0109]
N-cycloheptyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2--
hydroxy-benzamide;
[0110]
N-cyclooctyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-h-
ydroxy-benzamide;
[0111]
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-(1-i-
sopropyl-2-methyl-propyl)-benzamide;
[0112]
N-cyclohexylmethyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenox-
y]-2-hydroxy-benzamide;
[0113]
N--(R-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-
-phenoxy]-2-hydroxy-benzamide;
[0114]
N--(S-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(1H-tetrazol-5-ylamino)-
-phenoxy]-2-hydroxy-benzamide;
[0115]
N-cyclopentyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2--
hydroxy-N-methyl-benzamide;
[0116]
N-cyclohexyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-h-
ydroxy-N-methyl-benzamide;
[0117]
N-cycloheptyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2--
hydroxy-N-methyl-benzamide;
[0118]
N-cyclooctyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-h-
ydroxy-N-methyl-benzamide;
[0119]
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-(1-i-
sopropyl-2methyl-propyl)-N-methyl-benzamide;
[0120]
N-cyclohexylmethyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenox-
y]-2-hydroxy-N-methyl-benzamide;
[0121]
N--(R-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-
-phenoxy]-2-hydroxy-N-methyl-benzamide;
[0122]
N--(S-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(1H-tetrazol-5-ylamino)-
-phenoxy]-2-hydroxy-N-methyl-benzamide;and stereoisomers,
pharmaceutically acceptable salts and prodrugs thereof, and
pharmaceutically acceptable salts of the prodrugs.
[0123] Also provided are methods of treating diabetes, the methods
comprising the step of administering to a patient having or at risk
of having diabetes, a therapeutically effective amount of a
compound of Formula I, stereoisomers, pharmaceutically acceptable
salts and prodrug thereof, and pharmaceutically acceptable salts of
the prodrugs.
[0124] In a preferred embodiment of the method of treating
diabetes, the diabetes is Type I diabetes.
[0125] In a preferred embodiment of the method of treating
diabetes, the diabetes is Type II diabetes.
[0126] Also provided are methods of treating atherosclerosis, the
methods comprising the step of administering to a patient having or
at risk of having atherosclerosis, a therapeutically effective
amount of a compound of Formula I, stereoisomers, pharmaceutically
acceptable salts and prodrugs thereof, and pharmaceutically
acceptable salts of the prodrugs.
[0127] Also provided are methods of treating hypertension, the
methods comprising the step of administering to a patient having or
at risk of having hypertension, a therapeutically effective amount
of a compound of Formula I, stereoisomers, pharmaceutically
acceptable salts and prodrugs thereof, and pharmaceutically
acceptable salts of the prodrugs.
[0128] Also provided are methods of treating coronary heart
disease, the methods comprising the step of administering to a
patient having or at risk of having coronary heart disease, a
therapeutically effective amount of a compound of Formula I,
stereoisomers, pharmaceutically acceptable salts and prodrugs
thereof, and pharmaceutically acceptable salts of the prodrugs.
[0129] Also provided are methods of treating hypercholesterolemia,
the method comprising the step of administering to a patient having
or at risk of having hypercholesterolemia, a therapeutically
effective amount of a compound of Formula I, stereoisomers,
pharmaceutically acceptable salts or prodrugs thereof, and
pharmaceutically acceptable salts of the prodrugs.
[0130] Also provided are methods of treating hyperlipidemia, the
methods comprising the step of administering to a patient having or
at risk of having hyperlipidemia, a therapeutically effective
amount of a compound of Formula I, stereoisomers, pharmaceutically
acceptable salts and prodrugs thereof, and pharmaceutically
acceptable salts of the prodrugs.
[0131] Also provided are methods of treating thyroid disease, the
methods comprising the step of administering to a patient having or
at risk of having thyroid disease, a therapeutically effective
amount of a compound of Formula I, stereoisomers, pharmaceutically
acceptable salts and prodrugs thereof, and pharmaceutically
acceptable salts of the prodrugs.
[0132] Also provided are methods of treating hypothyroidism, the
methods comprising the step of administering to a patient having or
at risk of having hypothyroidism, a therapeutically effective
amount of a compound of Formula I, stereoisomers, pharmaceutically
acceptable salts and prodrugs thereof, and pharmaceutically
acceptable salts of the prodrugs.
[0133] Also provided are methods of treating depression, the
methods comprising the step of administering to a patient having or
at risk of having depression, a therapeutically effective amount of
a compound of Formula I, stereoisomers, pharmaceutically acceptable
salts and prodrugs thereof, and pharmaceutically acceptable salts
of the prodrugs.
[0134] Also provided are methods of treating obesity, the methods
comprising the step of administering to an obese patient or a
patient at risk of becoming obese, a therapeutically effective
amount of a compound of Formula I, stereoisomers, pharmaceutically
acceptable salts and prodrugs thereof, and pharmaceutically
acceptable salts of the prodrugs.
[0135] Also provided are methods of treating osteoporosis, the
methods comprising the step of administering to a patient having or
at risk of having osteoporosis, a therapeutically effective amount
of a compound of Formula I, stereoisomers, pharmaceutically
acceptable salts and prodrugs thereof, and pharmaceutically
acceptable salts of the prodrugs.
[0136] Also provided are methods of treating thyroid cancer, the
method comprising the step of administering to a patient having or
at risk of having thyroid cancer, a therapeutically effective
amount of a compound of Formula I, stereoisomers, pharmaceutically
acceptable salts and prodrugs thereof, and pharmaceutically
acceptable salts of the prodrugs.
[0137] Also provided are methods of treating glaucoma, the methods
comprising the step of administering to a patient having or at risk
of having glaucoma, a therapeutically effective amount of a
compound of Formula I, stereoisomers, pharmaceutically acceptable
salts and prodrugs thereof, and pharmaceutically acceptable salts
of the prodrugs.
[0138] Also provided are methods of treating cardiac arrhythmias,
the methods comprising the step of administering to a patient
having or at risk of having cardiac arrhythmias, a therapeutically
effective amount of a compound of Formula I, stereoisomers,
pharmaceutically acceptable salts and prodrugs thereof, and
pharmaceutically acceptable salts of the prodrugs.
[0139] Also provided are methods of treating congestive heart
failure, the methods comprising the step of administering to a
patient having or at risk of having congestive heart failure, a
therapeutically effective amount of a compound of Formula I,
stereoisomers, pharmaceutically acceptable salts and prodrugs
thereof, and pharmaceutically acceptable salts of the prodrugs.
[0140] Also provided are methods of increasing energy expenditure,
the methods comprising the step of administering to a patient who
needs an energy expenditure increase a therapeutically effective
amount of a compound of Formula I, or a stereoisomer,
pharmaceutically acceptable salt or prodrug thereof, or a
pharmaceutically acceptable salt of the prodrug.
[0141] Also provided are pharmaceutical compositions comprising a
compound of Formula I, stereoisomers, pharmaceutically acceptable
salts and prodrugs thereof, and pharmaceutically acceptable salts
of the prodrugs.
[0142] Also provided are kits for the treatment of obesity,
diabetes, atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias,
congestive heart failure, or osteoporosis, the kits comprising:
[0143] a) a first pharmaceutical composition comprising a compound
of Formula I, stereoisomers, pharmaceutically acceptable salts and
prodrugs thereof, and pharmaceutically acceptable salts of the
prodrugs;
[0144] b) a second pharmaceutical composition comprising an
additional compound useful for the treatment of obesity, diabetes,
atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias,
congestive heart failure, or osteoporosis; and
[0145] c) a container for containing the first and second
compositions.
[0146] Also provided are methods of treating obesity, diabetes,
atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias,
congestive heart failure, or osteoporosis, the methods comprising
the step of administering to an obese patient, a patient at risk of
becoming obese, or a patient having or at risk of having diabetes,
atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias,
congestive heart failure, or osteoporosis a therapeutically
effective amount of 1) a compound of Formula I, stereoisomers,
pharmaceutically acceptable salts or prodrugs thereof, and
pharmaceutically acceptable salts of the prodrugs and 2) an
additional compound useful for treating obesity, diabetes,
atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias,
congestive heart failure, or osteoporosis.
[0147] Also provided are pharmaceutical compositions comprising a
compound of Formula I, stereoisomers, pharmaceutically acceptable
salts and prodrugs thereof, and pharmaceutically acceptable salts
of the prodrugs, and an additional compound useful to treat
obesity, diabetes, atherosclerosis, hypertension, coronary heart
disease, hypercholesterolemia, hyperlipidemia, thyroid disease,
thyroid cancer, hypothyroidism, depression, glaucoma, cardiac
arrhythmias, congestive heart failure, or osteoporosis.
DETAILED DESCRIPTION OF THE INVENTION
[0148] The present invention relates to compounds of Formula I,
pharmaceutically acceptable salts of the compounds of Formula I,
prodrugs of the compounds of Formula I, and pharmaceutically
acceptable salts of the prodrugs of compounds of Formula I. This
invention also relates to methods of treating of obesity, diabetes,
atherosclerosis, hypertension, coronary heart disease,
hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid
cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias
(including atrial and ventricular arrhythmias), congestive heart
failure, and osteoporosis. This invention also relates to
pharmaceutical compositions and kits.
[0149] The term "alkyl" means a straight or branched chain
hydrocarbon. Representative examples of alkyl groups include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
sec-butyl, pentyl, and hexyl. Preferred alkyl groups are
C.sub.1-C.sub.12alkyl.
[0150] The term "alkoxy" means an alkyl group bonded to an oxygen
atom. Representative examples of alkoxy groups include methoxy,
ethoxy, tert-butoxy, propoxy, and isobutoxy. Preferred alkoxy
groups are C.sub.1-C.sub.12alkoxy.
[0151] The term "halogen" means chlorine, fluorine, bromine, or
iodine.
[0152] The term "alkenyl" means a branched or straight chain
hydrocarbon having one or more carbon-carbon double bonds.
[0153] The term "alkynyl" means a branched or straight chain
hydrocarbon having one or more carbon-carbon triple bonds.
[0154] The term "cycloalkyl" means a cyclic hydrocarbon. Examples
of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and cycloheptyl. Preferred cycloalkyl groups are
C.sub.3-C.sub.10cyloalkyl. It is also possible for the cycloalkyl
group to have one or more double bonds or triple bonds, or a
combination of double bonds and triple bonds, but is not aromatic.
Examples of cycloalkyl groups having a double or triple bond
include cyclopentenyl, cyclohexenyl, cyclohexadienyl,
cyclobutadienyl, and the like. It is also noted that the term
cycloalkyl includes polycylic compounds such as bicyclic or
tricyclic compounds. The cycloalkyl groups may be substituted or
unsubsituted with from one to four substitutents. Examples of
substitutents that are suitable are recited below under the
definitions of aryl, heteroaryl and substituents.
[0155] The term "perfluoroalkyl" means an alkyl group in which all
of the hydrogen atoms have been replaced with fluorine atoms.
[0156] The term "acyl" means a group derived from an organic acid
(--COOH) by removal of the hydroxy group (--OH).
[0157] The term "aryl" means a cyclic, aromatic hydrocarbon.
Examples of aryl groups include phenyl and naphthyl. The aryl group
can be unsubstituted or substituted. Examples of preferred
substituents include halogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, --OCF.sub.3, --CN, --SR.sup.f,
--S(.dbd.O)R.sup.f, --S(.dbd.O).sub.2R.sub.f,
C.sub.3-C.sub.6cycloalkyl, --S(.dbd.O.sub.2)NR.sup.aR.sup.f,
--NR.sup.aR.sup.g, --C(.dbd.O)NR.sup.aR.sup.f, --OH, or
C.sub.1-C.sub.4perfluoroalkyl, where R.sup.a, R.sup.f, and R.sup.g
are as defined herein.
[0158] The term "heteroatom" includes oxygen, nitrogen, sulfur, and
phosphorous.
[0159] The term "heteroaryl" means a cyclic, aromatic hydrocarbon
in which one or more carbon atoms have been replaced with
heteroatoms. If the heteroaryl group contains more than one
heteroatom, the heteroatoms may be the same or different. Examples
of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl,
thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl, isobenzofuranyl,
chromenyl, xanthenyl, indolyl, isoindolyl, indolizinyl, triazolyl,
pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl,
quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl,
and benzo[b]thienyl. Preferred heteroaryl groups are five and six
membered rings and contain from one to three heteroatoms selected
from O, N, and S. The heteroaryl group can be unsubstituted or
substituted with from 1 to 4 substituents. Examples of preferred
substituents include halogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, --CF.sub.3, --OH, --NR.sup.aR.sup.e,
--CO.sub.2R.sup.f or a fused benzo group, where R.sup.a, R.sup.c,
and R.sup.f are as defined herein.
[0160] The term "heterocycloalkyl" mean a cycloalkyl group in which
one or more of the carbon atoms has been replaced with heteroatoms.
If the heterocycloalkyl group contains more than one heteroatom,
the heteroatoms may be the same or different. Examples of
heterocycloalkyl groups include tetrahydrofuryl, morpholinyl,
piperazinyl, piperidyl, and pyrrolidinyl. Preferred
heterocycloalkyl groups are five and six membered rings and contain
from one to three heteroatoms. It is also possible for the
heterocycloalkyl group to have one or more double bonds or triple
bonds or a combination of double bonds and triple bonds, but is not
aromatic. Examples of heterocycloalkyl groups containing double or
triple bonds include dihydrofuran, and the like. A heterocycloalkyl
group can be unsubstituted or substituted with from 1 to 4
substituents. Examples of preferred substituents include
C.sub.1-C.sub.4alkyl, --OH, oxo, C.sub.1-C.sub.4alkoxy, --CN,
phenyl, or --NR.sup.aR.sup.e, where R.sup.a and R.sup.e are as
defined herein.
[0161] It is also noted that the cyclic ring groups, i.e., aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, can comprise more than
one ring. For example, the naphthyl group is a fused bicyclic ring
system. It is also intended that the present invention include ring
groups that have bridging atoms, or ring groups that have a spiro
orientation.
[0162] Representative examples of five to six membered aromatic
rings, optionally having one or two heteroatoms, are phenyl, furyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, and
pyrazinyl.
[0163] Representative examples of partially saturated, fully
saturated or fully unsaturated five to eight membered rings,
optionally having one to three heteroatoms, are cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary
five membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl,
3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl,
imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl,
pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,
1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,3-triazolyl, 1,2,4-trizaolyl, 1,3,4-thiadiazolyl,
3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl,
1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl, and 1,3-oxathiolyl.
[0164] Further exemplary six membered rings are 2H-pyranyl,
4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl,
1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl,
1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl,
4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl,
1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl,
1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl,
1,2,6-oxathiazinyl, and 1,4,2-oxadiazinyl.
[0165] Further exemplary seven membered rings are azepinyl,
oxepinyl, thiepinyl and 1 ,2,4-triazepinyl.
[0166] Further exemplary eight membered rings are cyclooctyl,
cyclooctenyl and cyclooctadienyl.
[0167] Exemplary bicyclic rings consisting of two fused partially
saturated, fully saturated or fully unsaturated five and/or six
membered rings, taken independently, optionally having one to four
heteroatoms are indolizinyl, indolyl, isoindolyl, indolinyl,
cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl,
isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl,
indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl,
benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl,
2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl,
pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl,
2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl,
4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and
4H-1,4-benzoxazinyl.
[0168] A cyclic ring group may be bonded to another group in more
than one way. If no particular bonding arrangement is specified,
then all possible arrangements are intended. For example, the term
"pyridyl" includes 2-, 3-, or 4-pyridyl, and the term "thienyl"
includes 2-, or 3-thienyl.
[0169] The term "substituted" means that a hydrogen atom on a
molecule has been replaced with a different atom or molecule. The
atom or molecule replacing the hydrogen atom is called a
substituent. Examples of suitable substituents include, halogens,
--OC.sub.1--C.sub.8alkyl, --C.sub.1-C.sub.8alkyl,
--C.sub.2-C.sub.6alkenyl, --C.sub.3-C.sub.8cycloa- lkyl,
heterocycloalkyl, --CF.sub.3, --OCF.sub.3, --NH.sub.2, --NHC,
--C.sub.alkyl, --N(C.sub.1-C.sub.8alkyl).sub.2, --NO.sub.2, --CN,
--CO.sub.2H, --CO.sub.2C.sub.1-C.sub.8alkyl, and the like.
[0170] The symbol "--" represents a covalent bond.
[0171] The phrase "therapeutically effective amount" means an
amount of a compound or combination of compounds that ameliorates,
attenuates, or eliminates one or more symptoms of a particular
disease or condition or prevents or delays the onset of one of more
symptoms of a particular disease or condition.
[0172] The term "patient" means animals, such as dogs, cats, cows,
horses, sheep, and humans. Particularly preferred patients are
mammals, including both males and females.
[0173] The phrase "pharmaceutically acceptable" means that the
substance or composition must be compatible with the other
ingredients of a formulation, and not deleterious to the
patient.
[0174] The phrases "a compound of the present invention, a compound
of Formula I, or a compound in accordance with Formula I" and the
like, include the pharmaceutically acceptable salts of the
compounds, prodrugs of the compounds, and pharmaceutically
acceptable salts of the prodrugs.
[0175] The phrase "reaction-inert solvent" or "inert solvent" refer
to a solvent or mixture of solvents that does not interact with
starting materials, reagents, intermediates or products in a manner
that adversely affects the desired product.
[0176] The terms "treating", "treat" or "treatment" include
preventative (e.g., prophylactic) and palliative treatment.
[0177] The characteristics of patients at risk of having
atherosclerosis are well known to those in the art and include
patients who have a family history of cardiovascular disease,
including hypertension and atherosclerosis, obese patients,
patients who exercise infrequently, patients with
hypercholesterolemia, hyperlipidemia and/or hypertriglyceridemia,
patients having high levels of LDL or Lp(a), patients having low
levels of HDL, and the like.
[0178] In one aspect, the present invention concerns the treatment
of diabetes, including impaired glucose tolerance, insulin
resistance, insulin dependent diabetes mellitus (Type I) and
non-insulin dependent diabetes mellitus (NIDDM or Type II). Also
included in the treatment of diabetes are the diabetic
complications, such as neuropathy, nephropathy, retinopathy or
cataracts.
[0179] The preferred type of diabetes to be treated by the
compounds of the present invention is non-insulin dependent
diabetes mellitus, also known as Type II diabetes or NIDDM.
[0180] Diabetes can be treated by administering to a patient having
diabetes (Type I or Type II), insulin resistance, impaired glucose
tolerance, or any of the diabetic complications such as neuropathy,
nephropathy, retinopathy or cataracts, a therapeutically effective
amount of a compound of the present invention. It is also
contemplated that diabetes be treated by administering a compound
of the present invention along with other agents that can be used
to treat diabetes.
[0181] Representative agents that can be used to treat diabetes in
combination with a compound of the present invention include
insulin and insulin analogs (e.g. LysPro insulin); GLP-1 (7-37)
(insulinotropin) and GLP-1 (7-36)--NH.sub.2; sulfonylureas and
analogs: chlorpropamide, glibenclamide, tolbutamide, tolazamide,
acetohexamide, glypizide, glimepiride, repaglinide, meglitinide;
biguamides: metformin, phenformin, buformin; .alpha.2-antagonists
and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan,
efaroxan, fluparoxan; other insulin secretagogues: linogliride,
A-4166; glitazones: ciglitazone, pioglitazone, englitazone,
troglitazone, darglitazone, BRL49653; fatty acid oxidation
inhibitors: clomoxir, etomoxir; .alpha.-glucosidase inhibitors:
acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose,
MDL-73,945;.beta.-agonist- s: BRL 35135, BRL 37344, RO 16-8714, ICI
D7114, CL 316,243; phosphodiesterase inhibitors: L-386,398;
lipid-lowering agents: benfluorex; antiobesity agents:
fenfluramine; vanadate and vanadium complexes (e.g. Naglivan.RTM.)
and peroxovanadium complexes; amylin antagonists; glucagon
antagonists; gluconeogenesis inhibitors; somatostatin analogs;
antilipolytic agents: nicotinic acid, acipimox, WAG 994. Also
contemplated to be used in combination with a compound of the
present invention are pramlintide (symlin.TM.), AC 2993 and
nateglinide. Any agent or combination of agents can be administered
as described above.
[0182] In addition, the compounds of the present invention can be
used in combination with one or more aldose reductase inhibitors,
glycogen phosphorylase inhibitors, sorbitol dehydrogenase
inhibitors, NHE-1 inhibitors and/or glucocorticoid receptor
antagonists.
[0183] The compounds of the present invention can be used in
combination with an aldose reductase inhibitor. Aldose reductase
inhibitors constitute a class of compounds that have become widely
known for their utility in preventing and treating conditions
arising from complications of diabetes, such as diabetic neuropathy
and nephropathy. Such compounds are well known to those skilled in
the art and are readily identified by standard biological tests.
For example, the aldose reductase inhibitor zopolrestat,
1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-(trifluoro-
methyl)-2-benzothiazolyl]methyl]-, and related compounds are
described in U.S. Pat. No. 4,939,140 to Larson et al.
[0184] Aldose reductase inhibitors have been taught for use in
lowering lipid levels in mammals. See, for example, U.S. Pat. No.
4,492,706 to Kallai-sanfacon and EP 0 310 931 A2 (Ethyl
Corporation).
[0185] U.S. Pat. No. 5,064,830 to Going discloses the use of
certain oxophthalazinyl acetic acid aldose reductase inhibitors,
including zopolrestat, for lowering of blood uric acid levels.
[0186] Commonly assigned U.S. Pat. No. 5,391,551 discloses the use
of certain aldose reductase inhibitors, including zopolrestat, for
lowering blood lipid levels in humans. The disclosure teaches that
therapeutic utilities derive from the treatment of diseases caused
by an increased level of triglycerides in the blood, such diseases
include cardiovascular disorders such as thrombosis,
arteriosclerosis, myocardial infarction, and angina pectoris. A
preferred aldose reductase inhibitor is zopolrestat.
[0187] The term aldose reductase inhibitor refers to compounds that
inhibit the bioconversion of glucose to sorbitol, which is
catalyzed by the enzyme aldose reductase.
[0188] Any aldose reductase inhibitor may be used in a combination
with a compound of the present invention. Aldose reductase
inhibition is readily determined by those skilled in the art
according to standard assays (J. Malone, Diabetes, 29:861-864
(1980) "Red Cell Sorbitol, an Indicator of Diabetic Control"). A
variety of aldose reductase inhibitors are described herein;
however, other aldose reductase inhibitors useful in the
compositions and methods of this invention will be known to those
skilled in the art.
[0189] The activity of an aldose reductase inhibitor in a tissue
can be determined by testing the amount of aldose reductase
inhibitor that is required to lower tissue sorbitol (i.e., by
inhibiting the further production of sorbitol consequent to
blocking aldose reductase) or lower tissue fructose (by inhibiting
the production of sorbitol consequent to blocking aldose reductase
and consequently the production of fructose).
[0190] Accordingly, additional examples of aldose reductase
inhibitors useful in the compositions, combinations and methods of
the present invention include:
[0191] 1.
3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4-oxo-1-phthalazineacetic
acid (ponalrestat, U.S. Pat. No. 4,251,528);
[0192] 2.
N-[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-
-methylglycine (tolrestat, U.S. Pat. No. 4,600,724);
[0193] 3.
5-[(Z,E)-.beta.-methylcinnamylidene]-4-oxo-2-thioxo-3-thiazolide-
neacetic acid (epalrestat, U.S. Pat. No. 4,464,382, U.S. Pat. No.
4,791,126, U.S. Pat. No. 4,831,045);
[0194] 4.
3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1
(2H)-quinazolineacetic acid (zenarestat, U.S. Pat. No. 4,734,419,
and 4,883,800);
[0195] 5. 2R,4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic
acid (U.S. Pat. No. 4,883,410);
[0196] 6.
2R,4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid
(U.S. Pat. No. 4,883,410);
[0197] 7.
3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid
(U.S. Pat. No. 4,771,050);
[0198] 8.
3,4-dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl)methyl]-2-
H-1,4-benzothiazine-2-acetic acid (SPR-210, U.S. Pat. No.
5,252,572);
[0199] 9.
N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-methyl-benzen-
eacetamide (ZD5522, U.S. Pat. No. 5,270,342 and U.S. Pat. No.
5,430,060);
[0200] 10. (S)-6-fluorospiro[chroman-4,4'-imidazolidine]-2,5'-dione
(sorbinil, U.S. Pat. No. 4,130,714);
[0201] 11.
d-2-methyl-6-fluoro-spiro(chroman-4',4'-imidazolidine)-2',5'-di-
one (U.S. Pat. No. 4,540,704);
[0202] 12.
2-fluoro-spiro(9H-fluorene-9,4'-imidazolidine)2',5'-dione (U.S.
Pat. No. 4,438,272);
[0203] 13.
2,7-di-fluoro-spiro(9H-fluorene-9,4'-imidazolidine)2',5'-dione
(U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);
[0204] 14.
2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4'-imidazolidine)2'-
,5'-dione (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);
[0205] 15.
7-fluoro-spiro(5H-indenol[1,2-b]pyridine-5,3'-pyrrolidine)2,5'--
dione (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);
[0206] 16.
d-cis-6'-chloro-2',3'-dihydro-2'-methyl-spiro-(imidazolidine-4,-
4'-4'-H-pyrano(2,3-b)pyridine)-2,5-dione (U.S. Pat. No.
4,980,357);
[0207] 17.
spiro[imidazolidine-4,5'(6H)-quinoline]2,5-dione-3'-chloro-7,8'-
-dihydro-7'-methyl-(5'-cis)(U.S. Pat. No. 5,066,659);
[0208] 18.
(2S,4S)-6-fluoro-2',5'-dioxospiro(chroman-4,4'-imidazolidine)-2-
-carboxamide (U.S. Pat. No. 5,447,946); and
[0209] 19.
2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4
(1H), 3'-pyrrolidine]-1,2',3,5'(2H)-tetrone (AR1-509, U.S. Pat. No.
5,037,831).
[0210] Other aldose reductase inhibitors include compounds having
formula la below 6
[0211] and pharmaceutically acceptable salts and prodrugs thereof,
wherein
[0212] Z is O or S;
[0213] R.sup.1 is hydroxy or a group capable of being removed in
vivo to produce a compound of formula I wherein R.sup.1 is OH;
and
[0214] X and Y are the same or different and are selected from
hydrogen, trifluoromethyl, fluoro, and chloro.
[0215] A preferred subgroup within the above group of aldose
reductase inhibitors includes numbered compounds 1, 2, 3, 4, 5, 6,
9, 10, and 17, and the following compounds of Formula Ia:
[0216] 20.
3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl)-4-oxophthalazin-
-1-yl-acetic acid [R.sup.1 =hydroxy; X.dbd.F; Y.dbd.H];
[0217] 21.
3-(5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthal-
azin-1-ylacetic acid [R.sup.1 =hydroxy; X.dbd.Y=F];
[0218] 22.
3-(5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-
-1-ylacetic acid [R.sup.1 =hydroxy; X.dbd.CI; Y.dbd.H];
[0219] 23.
3-(5,7-dichlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthal-
azin-1-ylacetic acid [R1 =hydroxy; X.dbd.Y.dbd.Cl];
[0220] 24.
3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-ylmethyl)pht-
halazin-1-ylacetic acid [R.sup.1=hydroxy; X.dbd.CF.sub.3;
Y.dbd.H];
[0221] 25.
3,4-dihydro-3-(5-fluorobenzoxazol-2-ylmethyl)-4-oxophthalazin-1-
-yl-acetic acid [R.sup.1=hydroxy; X.dbd.F; Y.dbd.H];
[0222] 26.
3-(5,7-difluorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalaz-
in-1-ylacetic acid [R.sup.1=hydroxy; X.dbd.Y.dbd.F];
[0223] 27.
3-(5-chlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-
-ylacetic acid [R.sup.1=hydroxy; X.dbd.Cl; Y.dbd.H];
[0224] 28.
3-(5,7-dichlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalaz-
in-1-ylacetic acid [R.sup.1=hydroxy; X.dbd.Y.dbd.Cl]; and
[0225] 29. zopolrestat; 1-phthalazineacetic acid,
3,4-dihydro-4-oxo-3-[[5--
(trifluoromethyl)-2-benzothiazolyl]methyl]-[R.sup.1=hydroxy;
X=trifluoromethyl; Y.dbd.H].
[0226] In compounds 20-23, and 29 Z is S. In compounds 24-28, Z is
O.
[0227] Of the above subgroup, compounds 20-29 are more preferred
with 29 especially preferred. Procedures for making the aldose
reducatase inhibitors of formula Ia can be found in PCT publication
number WO 99/26659.
[0228] The compounds of the present invention can also be used in
combination with a glucocorticoid receptor antagonist. The
glucocorticoid receptor (GR) is present in glucocorticoid
responsive cells where it resides in the cytosol in an inactive
state until it is stimulated by an agonist. Upon stimulation the
glucocorticoid receptor translocates to the cell nucleus where it
specifically interacts with DNA and/or protein(s) and regulates
transcription in a glucocorticoid responsive manner. Two examples
of proteins that interact with the glucocorticoid receptor are the
transcription factors, API and NF.kappa.-.beta.. Such interactions
result in inhibition of API-- and NF.kappa.-.beta.-mediated
transcription and are believed to be responsible for the
anti-inflammatory activity of endogenously administered
glucocorticoids. In addition, glucocorticoids may also exert
physiologic effects independent of nuclear transcription.
Biologically relevant glucocorticoid receptor agonists include
cortisol and corticosterone. Many synthetic glucocorticoid receptor
agonists exist including dexamethasone, prednisone and
prednisilone. By definition, glucocorticoid receptor antagonists
bind to the receptor and prevent glucocorticoid receptor agonists
from binding and eliciting GR mediated events, including
transcription. RU486 is an example of a non-selective
glucocorticoid receptor antagonist. GR antagonists can be used in
the treatment of diseases associated with an excess or a deficiency
of glucocorticoids in the body. As such, they may be used to treat
the following: obesity, diabetes, cardiovascular disease,
hypertension, Syndrome X, depression, anxiety, glaucoma, human
immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS), neurodegeneration (for example, Alzheimer's and
Parkinson's), cognition enhancement, Cushing's Syndrome, Addison's
Disease, osteoporosis, frailty, inflammatory diseases (such as
osteoarthritis, rheumatoid arthritis, asthma and rhinitis), tests
of adrenal function, viral infection, immunodeficiency,
immunomodulation, autoimmune diseases, allergies, wound healing,
compulsive behavior, multi-drug resistance, addiction, psychosis,
anorexia, cachexia, post-traumatic stress syndrome, post-surgical
bone fracture, medical catabolism and prevention of muscle frailty.
Examples or GR antagonists that can be used in combination with a
compound of the present invention include compounds of formula Ib
below: 7
[0229] isomers thereof, prodrugs of said compounds and isomers, and
pharmaceutically acceptable salts of said compounds, isomers and
prodrugs;
[0230] wherein m is 1 or 2;
[0231] represents an optional bond;
[0232] A is selected from the group consisting of 8 9
[0233] D is CR.sub.7, CR.sub.7R.sub.16, N, NR.sub.7 or O;
[0234] E is C, CR.sub.6 or N;
[0235] F is CR,CR.sub.4R.sub.5 or O;
[0236] G, H and I together with 2 carbon atoms from the A-ring or 2
carbon atoms from the B-ring form a 5-membered heterocyclic ring
comprising one or more N, O or S atoms; provided that there is at
most one of O and S per ring;
[0237] J, K, L and M together with 2 carbon atoms from the B-ring
forms a 6-membered heterocyclic ring comprising 1 or more N
atoms;
[0238] X is a) absent, b) --CH.sub.2--, c) --CH(OH)-- or d)
--C(O)--;
[0239] R.sub.1 is a) --H, b) --Z--CF.sub.3, c)
--(C.sub.1-C.sub.6)alkyl, d) --(C.sub.2-C.sub.6)alkenyl, e)
--(C.sub.2-C.sub.6)alkynyl, f) --CHO, g) --CH.dbd.N--OR.sub.12, h)
--Z--C(O)OR.sub.12, i) --Z--C(O)--NR.sub.12R.sub.13, j)
--Z--C(O)--NR.sub.12--Z-het, k) --Z--NR.sub.12R.sub.13, I)
--Z--NR.sub.12het, m) --Z-het, n) --Z--O-het, o) --Z-aryl', p)
--Z--O-aryl', q) --CHOH-aryl' or r) --C(O)-aryl' wherein aryl' in
substituents o) to r) is substituted independently with 0, 1 or 2
of the following: --Z--OH, --Z--NR.sub.12R.sub.13,
--Z--NR.sub.12-het, --C(O)NR.sub.12R.sub.13,
--C(O)O(C.sub.1-C.sub.6)alkyl, --C(O)OH, --C(O)-het,
--NR.sub.12--C(O)--(C.sub.1-C.sub.6)alkyl,
--NR.sub.12--C(O)--(C.sub.2-C.sub.6)alkenyl,
--NR.sub.12--C(O)--(C.sub.2-- C.sub.6)alkynyl,
--NR.sub.12--C(O)--Z-het, --CN, --Z-het,
--O--(C.sub.1-C.sub.3)alkyl-C(O)--NR.sub.12 .mu.l.sub.3,
--O--(C.sub.1-C.sub.3)alkyl-C(O)O(C.sub.1-C.sub.6)alkyl,
--NR.sub.12--Z--C(O)O(C.sub.1-C.sub.6)alkyl,
--N(Z--C(O)O(C.sub.1-C.sub.6- )alkyl).sub.2,
--NR.sub.12--Z--C(O)--NR.sub.12 .mu.l.sub.3,
--Z--NR.sub.12--SO.sub.2--R.sub.13, --NR.sub.12--SO.sub.2-het,
--C(O)H, --Z--NR.sub.12--Z--O(C.sub.1-C.sub.6)alkyl,
--Z--NR.sub.12--Z--NR.sub.12R- .sub.13,
--Z--NR.sub.12--(C.sub.3-C.sub.6)cycloalkyl,
--Z--N(Z--O(C.sub.1-C.sub.6)alkyl).sub.2, --SO.sub.2R.sub.12,
--SOR.sub.12, --SR.sub.12, --SO.sub.2NR.sub.12R.sub.13,
--O--C(O)--(C.sub.1-C.sub.4)alkyl,
--O--SO.sub.2--(C.sub.1-C.sub.4)alkyl, -halo or --CF.sub.3;
[0240] Z for each occurrence is independently a)
--(C.sub.0-C.sub.6)alkyl, b) --(C.sub.2-C.sub.6)alkenyl or c)
--(C.sub.2-C.sub.6)alkynyl;
[0241] R.sub.2 is a) --H, b) -halo, c) --OH, d)
--(C.sub.1-C.sub.6)alkyl substituted with 0 or 1 --OH, e)
--NR.sub.12 .mu.l.sub.3, f) --Z--C(O)O(C.sub.1-C.sub.6)alkyl, g)
--Z--C(O)NR.sub.12R.sub.13, h) --O--(C.sub.1-C.sub.6)alkyl, i)
--Z--O--C(O)--(C.sub.1-C.sub.6)alkyl, j)
--Z--O--(C.sub.1-C.sub.3)alkyl--C(O)--NR.sub.12R.sub.13, k)
--Z--O--(C.sub.1-C.sub.3)alkyl--C(O)--O(C.sub.1-C.sub.6)alkyl, I)
--O--(C.sub.2-C.sub.6)alkenyl, m) --O--(C.sub.2-C.sub.6)alkynyl, n)
--O--Z-het, o) --COOH, p) --C(OH)R.sub.12R.sub.13 or q)
--Z--CN;
[0242] R.sub.3 is a) --H, b) --(C.sub.1-C.sub.10)alkyl wherein 1 or
2 carbon atoms, other than the connecting carbon atom, may
optionally be replaced with 1 or 2 heteroatoms independently
selected from S, O and N and wherein each carbon atom is
substituted with 0, 1 or 2 R.sub.y, c) --(C.sub.2-C.sub.10)alkenyl
substituted with 0, 1 or 2 R.sub.y, d) --(C.sub.2-C.sub.10)alkynyl
wherein 1 carbon atom, other than the connecting carbon atom, may
optionally be replaced with 1 oxygen atom and wherein each carbon
atom is substituted with 0, 1 or 2 R.sub.y, e)
--CH.dbd.C.dbd.CH.sub.2, f)--CN, g) --(C.sub.3-C.sub.6)cycloalkyl,
h) --Z-aryl, i) --Z-het, j) --C(O)O(C.sub.1-C.sub.6)alkyl, k)
--O(C.sub.1-C.sub.6)alkyl, 1) --Z--S--R.sub.12, m)
--Z--S(O)--R.sub.12, n) --Z--S(O).sub.2--R.sub.12, o) --CF.sub.3 p)
--NR.sub.120-(C.sub.1-C.su- b.6)alkyl or q) --CH.sub.2OR.sub.y;
[0243] provided that one of R.sub.2 and R.sub.3 is absent when
there is a double bond between CR.sub.2R.sub.3 (the 7 position) and
the F moiety (the 8 position) of the C-ring;
[0244] R.sub.y for each occurrence is independently a) --OH, b)
-halo, c)--Z--CF.sub.3 d) --Z--CF(C.sub.1-C.sub.3 alkyl).sub.2, e)
--CN, f) --NR.sub.12R.sub.13, g) --(C.sub.3-C.sub.6)cycloalkyl, h)
--(C.sub.3-C.sub.6)cycloalkenyl, i) --(C.sub.0-C.sub.3)alkyl-aryl,
j) -het or k) --N.sub.3;
[0245] or R.sub.2 and R.sub.3 are taken together to form
a)=CHR.sub.11, b)=NOR.sub.11, c)=0, d).dbd.N--NR.sub.12,
e).dbd.N--NR.sub.12--C(O)--R.su- b.12, f) oxiranyl or g) 1
,3-dioxolan-4-yl;
[0246] R.sub.4 and R.sub.5 for each occurrence are independently a)
--H, b) --CN, c) --(C.sub.1-C.sub.6)alkyl substituted with 0 to 3
halo, d) --(C.sub.2-C.sub.6)alkenyl substituted with 0 to 3 halo,
e) --(C.sub.2-C.sub.6)alkynyl substituted with 0 to 3 halo, f)
--O--(C.sub.1-C.sub.6)alkyl substituted with 0 to 3 halo, g)
--O--(C.sub.2-C.sub.6)alkenyl substituted with 0 to 3 halo, h)
--O--(C.sub.2-C.sub.6)alkynyl substituted with 0 to 3 halo, i)
halo, j) --OH, k) (C.sub.3-C.sub.6)cycloalkyl or 1) (C.sub.3
-C.sub.6)cycloalkenyl;
[0247] or R.sub.4 and R.sub.5 are taken together to form
.dbd.O;
[0248] R.sub.6 is a) --H, b) --CN, c) --(C.sub.1-C.sub.6)alkyl
substituted with 0 to 3 halo, d) --(C.sub.2-C.sub.6)alkenyl
substituted with 0 to 3 halo, e) --(C.sub.2-C.sub.6)alkynyl
substituted with 0 to 3 halo or f) --OH;
[0249] R.sub.7 and R.sub.16 for each occurrence are independently
a) --H, b) -halo, c) --CN, d) --(C.sub.1-C.sub.6)alkyl substituted
with 0 to 3 halo, e) --(C.sub.2-C.sub.6)alkenyl substituted with 0
to 3 halo or f) --(C.sub.2-C.sub.6)alkynyl substituted with 0 to 3
halo; provided that R.sub.7 is other than --CN or -halo when D is
NR.sub.7;
[0250] or R.sub.7 and R.sub.16 are taken together to form
.dbd.O;
[0251] R.sub.8, R.sub.9, R.sub.14 and R.sub.15 for each occurrence
are independently a) --H, b) -halo, c) (C.sub.1-C.sub.6)alkyl
substituted with 0 to 3 halo, d) --(C.sub.2-C.sub.6)alkenyl
substituted with 0 to 3 halo, e) --(C.sub.2-C.sub.6)alkynyl
substituted with 0 to 3 halo, f) --CN, g)
--(C.sub.3-C.sub.6)cycloalkyl, h) --(C.sub.3-C.sub.6)cycloalkeny-
l, i) --OH, j) --O--(C.sub.1-C.sub.6)alkyl, k)
--O--(C.sub.1-C.sub.6)alken- yl, I) --O--(C.sub.1-C.sub.6)alkynyl,
m) --NR.sub.12R.sub.13, n) --C(O)OR.sub.12 or o)
--C(O)NR.sub.12R.sub.13;
[0252] or R.sub.8 and R.sub.9 are taken together on the C-ring to
form .dbd.O; provided that when m is 2, only one set of R.sub.8 and
R.sub.9 are taken together to form .dbd.O;
[0253] or R.sub.14 and R.sub.15 are taken together to form .dbd.O;
provided that when R.sub.14 and R.sub.15 are taken together to form
.dbd.O, D is other than CR.sub.7 and E is other than C;
[0254] R.sub.10 is a) --(C.sub.1-C.sub.10)alkyl substituted with 0
to 3 substituents independently selected from -halo, --OH and
--N.sub.3, b) --(C.sub.2-C.sub.10)alkenyl substituted with 0 to 3
substituents independently selected from -halo, --OH and --N.sub.3,
c) --(C.sub.2-C.sub.1-0)alkynyl substituted with 0 to 3
substituents independently selected from -halo, --OH and --N.sub.3,
d) -halo, e) --Z--CN, f) --OH, g) --Z-het, h)
--Z--NR.sub.12R.sub.13, i) --Z--C(O)-het, j)
[0255] --Z--C(O)--(C.sub.1-C.sub.6)alkyl, k)
--Z--C(O)--NR.sub.12R.sub.13, I) --Z--C(O)--NR.sub.12--Z--CN,
m)
[0256] --Z--C(O)--NR.sub.12--Z-het, n)
--Z--C(O)--NR.sub.12--Z-aryl, o)
--Z--C(O)--NR.sub.12--Z--NR.sub.12R.sub.13, p)
[0257] --Z--C(O)--NR.sub.12--Z--O(C.sub.1-C.sub.6)alkyl, q)
--(C.sub.1-C.sub.6)alkyl-C(O)OH, r)
--Z--C(O)O(C.sub.1-C.sub.6)alkyl, s)
[0258] --Z--O--(C.sub.0-C.sub.6)alkyl-het, t)
--Z--O--(C.sub.0-C.sub.6)alk- yl-aryl, u)
--Z--O--(C.sub.1-C.sub.6)alkyl substituted with 0 to 2 R.sub.x, v)
--Z--O--(C.sub.1-C.sub.6)alkyl-CH(O), w)
--Z--O--(C.sub.1-C.sub.6)alkyl-NR.sub.12-het, x)
[0259] --Z--O--Z-het-Z-het, y) --Z--O--Z-het-Z--NR.sub.12R.sub.13,
z) --Z--O--Z-het-C(O)-het, a11)
[0260] --Z--O--Z--C(O)-het, b1) --Z--O--Z--C(O)-het-het, c.sub.1)
--Z--O--Z--C(O)--(C.sub.1-C.sub.6)alkyl, d1)
[0261] --Z--O--Z--C(S)--NR.sub.12 .mu.l.sub.3, el)
--Z--O--Z--C(O)--NR.sub- .12R.sub.13, f1)
[0262] --Z--O--Z--(C.sub.1-C.sub.3)alkyl-C(O)--NR.sub.12R.sub.13,
g1) --Z--O--Z--C(O)--O(C.sub.1-C.sub.6)alkyl, h1)
[0263] --Z--O--Z--C(O)--OH, i1)
--Z--O--Z--C(O)--NR.sub.12--O(C.sub.1-C.su- b.6)alkyl, j1)
--Z--O--Z--C(O)--NR.sub.12--OH, k1)
[0264] --Z--O--Z--C(O)--NR.sub.12--Z--NR.sub.12R.sub.13, 11)
--Z--O--Z--C(O)--NR.sub.12--Z-het, ml)
[0265]
--Z--O--Z--C(O)--NR.sub.12--SO.sub.2--(C.sub.1-C.sub.6)alkyl, n11)
--Z--O--Z--C(.dbd.NR.sub.12)(NR.sub.12R.sub.13), 01)
[0266] --Z--O--Z--C(.dbd.NOR.sub.12)(NR.sub.12 .mu.l.sub.3), p1)
--Z--NR.sub.12--C(O)--O--Z--NR.sub.12 .mu.l.sub.3, q1)
--Z--S--C(O)--NR.sub.12 .mu.l.sub.3,
[0267] --Z--O--SO.sub.2--(C.sub.1-C.sub.6)alkyl, s1)
--Z--O--SO.sub.2-aryl, t1) --Z--O--SO.sub.2--NR.sub.12R.sub.13,
u1)
[0268] --Z--O--SO.sub.2--CF.sub.3, v1) --Z--NR.sub.12C(O)OR.sub.13
or w1) --Z--NR.sub.12C(O)R.sub.13;
[0269] or R.sub.9 and R.sub.10 are taken together on the moiety of
formula A-5 to form a)=O or b)=NOR.sub.12;
[0270] R.sub.11 is a) --H, b) --(C.sub.1-C.sub.5)alkyl, c)
--(C.sub.3-C.sub.6)cycloalkyl or d)
--(C.sub.0-C.sub.3)alkyl-aryl;
[0271] R.sub.12 and R.sub.13 for each occurrence are each
independently a) --H, b) --(C.sub.1-C.sub.6)alkyl wherein 1 or 2
carbon atoms, other than the connecting carbon atom, may optionally
be replaced with 1 or 2 heteroatoms independently selected from S,
O and N and wherein each carbon atom is substituted with 0 to 6
halo, c) --(C.sub.2-C.sub.6)alkeny- l substituted with 0 to 6 halo
or d) --(C.sub.1-C.sub.6)alkynyl wherein 1 carbon atom, other than
the connecting carbon atom, may optionally be replaced with 1
oxygen atom and wherein each carbon atom is substituted with 0 to 6
halo;
[0272] or R.sub.12 and R.sub.13 are taken together with N to form
het;
[0273] or R.sub.6 and R.sub.14 or R.sub.15 are taken together to
form 1 ,3-dioxolanyl;
[0274] aryl is a) phenyl substituted with 0 to 3 R.sub.x, b)
naphthyl substituted with 0 to 3 R.sub.x or c) biphenyl substituted
with 0 to 3 R.sub.x;
[0275] het is a 5-,6- or 7-membered saturated, partially saturated
or unsaturated ring containing from one (1) to three (3)
heteroatoms independently selected from the group consisting of
nitrogen, oxygen and sulfur; and including any bicyclic group in
which any of the above heterocyclic rings is fused to a benzene
ring or another heterocycle; and the nitrogen may be in the
oxidized state giving the N-oxide form; and substituted with 0 to 3
R.sub.x;
[0276] R.sub.x for each occurrence is independently a) -halo, b)
--OH, c) --(C.sub.1-C.sub.6)alkyl, d) --(C.sub.2-C.sub.6)alkenyl,
e) --(C.sub.2-C.sub.6)alkynyl, f) --O(C.sub.1-C.sub.6)alkyl, g)
--O(C.sub.2-C.sub.6)alkenyl, h) --O(C.sub.2-C.sub.6)alkynyl, i)
--(C.sub.0-C.sub.6)alkyl-NR.sub.12R.sub.13, j)
--C(O)--NR.sub.12R.sub.13, k) --Z--SO.sub.2R.sub.12,
I)--Z--SOR.sub.12, m) --Z--SR.sub.12, n) --NR.sub.12--SO.sub.2
.mu.l.sub.3, o) --NR.sub.12--C(O)--R.sub.13, p)
--NR.sub.12--OR.sub.13, q) --SO.sub.2--NR.sub.12R.sub.13, r) --CN,
s) --CF.sub.3, t) --C(O)(C.sub.1-C.sub.6)alkyl, u).dbd.O, v)
--Z--SO.sub.2-phenyl or w) --Z--SO.sub.2-het';
[0277] aryl' is phenyl, naphthyl or biphenyl;
[0278] het' is a 5-,6- or 7-membered saturated, partially saturated
or unsaturated ring containing from one (1) to three (3)
heteroatoms independently selected from the group consisting of
nitrogen, oxygen and sulfur; and including any bicyclic group in
which any of the above heterocyclic rings is fused to a benzene
ring or another heterocycle;
[0279] provided that:
[0280] 1) X--R.sub.1 is other than hydrogen or methyl;
[0281] 2) when R.sub.9 and R.sub.10 are substituents on the A-ring,
they are other than mono- or di-methoxy;
[0282] 3) when R.sub.2 and R.sub.3 are taken together to form
.dbd.CHR.sub.11 or .dbd.O wherein R.sub.11 is
--O(C.sub.1-C.sub.6)alkyl, then --X--R.sub.1 is other than
(C.sub.1-C.sub.4)alkyl;
[0283] 4) when R.sub.2 and R.sub.3 taken together are C.dbd.O and
R.sub.9 is hydrogen on the A-ring; or when R.sub.2 is hydroxy,
R.sub.3 is hydrogen and R.sub.9 is hydrogen on the A-ring, then
R.sub.10 is other than --O--(C.sub.1-C.sub.6)alkyl or
--O--CH.sub.2-phenyl at the 2-position of the A-ring;
[0284] 5) when X--R.sub.1 is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl or (C.sub.2-C.sub.4)alkynyl, R.sub.9 and
R.sub.10 are other than mono-hydroxy or .dbd.O, including the diol
form thereof, when taken together; and
[0285] 6) when X is absent, R.sub.1 is other than a moiety
containing a heteroatom independently selected from N, O or S
directly attached to the juncture of the B-ring and the C-ring.
(See U.S. Provisional Patent Application No. 60/132,130.)
[0286] The compounds of the present invention can also be used in
combination with a sorbitol dehydrogenase inhibitor. Sorbitol
dehydrogenase inhibitors lower fructose levels and have been used
to treat or prevent diabetic complications such as neuropathy,
retinopathy, nephropathy, cardiomyopathy, microangiopathy, and
macroangiopathy. U.S. Pat. Nos. 5,728,704 and 5,866,578 disclose
compounds and a method for treating or preventing diabetic
complications by inhibiting the enzyme sorbitol dehydrogenase.
[0287] A compound of the present invention can also be used in
combination with a sodium-hydrogen exchanger type 1 (NHE-1)
inhibitor. Examples of NHE-1 inhibitors include a compound having
the Formula Ic 10
[0288] Formula Ic
[0289] a prodrug thereof or a pharmaceutically acceptable salt of
said compound or of said prodrug, wherein
[0290] Z is carbon connected and is a five-membered, diaza,
diunsaturated ring having two contiguous nitrogens, said ring
optionally mono-, di-, or tri-substituted with up to three
substituents independently selected from R.sup.1, R.sup.2 and
R.sup.3; or
[0291] Z is carbon connected and is a five-membered, triaza,
diunsaturated ring, said ring optionally mono- or di-substituted
with up to two substituents independently selected from R.sup.4 and
R.sup.5;
[0292] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
each independently hydrogen, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylthio,
(C.sub.3-C.sub.4)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)al- kyl, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylcarbamoyl, M or
M(C.sub.1-C.sub.4)alkyl, any of said previous
(C.sub.1-C.sub.4)alkyl moieties optionally having from one to nine
fluorines; said (C.sub.1-C.sub.4)alkyl or
(C.sub.3-C.sub.4)cycloalkyl optionally mono-or di-substituted
independently with hydroxy, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, (C.sub.1-C.sub.4)alkyl, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylcarbamoyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylaminosulfonyl; and said
(C.sub.3-C.sub.4)cycloalkyl optionally having from one to seven
fluorines;
[0293] wherein M is a partially saturated, fully saturated or fully
unsaturated five to eight membered ring optionally having one to
three heteroatoms selected independently from oxygen, sulfur and
nitrogen, or, a bicyclic ring consisting of two fused partially
saturated, fully saturated or fully unsaturated three to six
membered rings, taken independently, optionally having one to four
heteroatoms selected independently from nitrogen, sulfur and
oxygen;
[0294] said M is optionally substituted, on one ring if the moiety
is monocyclic, or one or both rings if the moiety is bicyclic, on
carbon or nitrogen with up to three substituents independently
selected from R.sup.6, R.sup.7 and R.sup.8, wherein one of R.sup.6,
R.sup.7 and R.sup.8 is optionally a partially saturated, fully
saturated, or fully unsaturated three to seven membered ring
optionally having one to three heteroatoms selected independently
from oxygen, sulfur and nitrogen optionally substituted with
(C.sub.1-C.sub.4)alkyl and additionally R.sup.6, R.sup.7 and
R.sup.8 are optionally hydroxy, nitro, halo,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkoxycarbonyl,
(C.sub.1-C.sub.4)alkyl, formyl, (C.sub.1-C.sub.4)alkanoyl,
(C.sub.1-C.sub.4)alkanoyloxy, (C.sub.1-C.sub.4)alkanoylamino,
(C.sub.1-C.sub.4)alkoxycarbonylamino, sulfonamido,
(C.sub.1-C.sub.4)alkylsulfonamido, amino, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylamino, carbamoyl, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylcarbamoyl, cyano, thiol,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alky- laminosulfonyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl or
(C.sub.5-C.sub.7)cycloalkenyl, wherein said
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.7)alkanoyl, (C.sub.1-C.sub.4)alkylthio, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylami- no or
(C.sub.3-C.sub.7)cycloalkyl R.sup.6, R.sup.7 and R.sup.8
substituents are optionally mono- substituted independently with
hydroxy, (C.sub.1-C.sub.4)alkoxycarbonyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.4)alkanoyl,
(C.sub.1-C.sub.4)alkanoylamino, (C.sub.1-C.sub.4)alkanoyloxy,
(C.sub.1-C.sub.4)alkoxycarbonylamino, sulfonamido,
(C.sub.1-C.sub.4)alkylsulfonamido, amino, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylamino, carbamoyl, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylcarbamoyl, cyano, thiol, nitro,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.4)al- kylaminosulfonyl or optionally
substituted with one to nine fluorines. (See PCT publication number
WO 99/43663) A compound of the present invention can also be used
in combination with a glycogen phosphorylase inhibitor. Examples of
glycogen phosphorylase inhibitors are set forth below.
[0295] One group of glycogen phosphorylase inhibitors that can be
used includes compounds of Formula AA: 11
[0296] a stereoisomer, pharmaceutically acceptable salt or prodrug
thereof, or a pharmaceutically acceptable salt of the prodrug,
[0297] wherein
[0298] Q is aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0299] each Z and X are independently (C, CH or CH.sub.2), N, O or
S;
[0300] X.sup.1 is NR.sup.a, --CH.sub.2--, O or S;
[0301] each --is independently a bond or is absent, provided that
both--are not simultaneously bonds;
[0302] R.sup.1 is hydrogen, halogen, --OC.sub.1-C.sub.8alkyl,
--SC.sub.1, --C.sub.8alkyl,
[0303] --C.sub.1-C.sub.8alkyl, --CF.sub.3, --NH.sub.2, --NHC,
--C.sub.8alkyl, --N(C.sub.1-C.sub.8alkyl).sub.2, --NO.sub.2,
--CN,
[0304] --CO.sub.2H, --CO.sub.2C.sub.1-C.sub.alkyl,
--C.sub.2-C.sub.8alkeny- l, or --C.sub.2-C.sub.8alkynyl;
[0305] each R.sup.a and R.sup.b is independently hydrogen or
--C.sub.1-C.sub.8alkyl;
[0306] Y is 12
[0307] or absent;
[0308] R.sup.2 and R.sup.3 are independently hydrogen, halogen,
--C.sub.1-C.sub.8alkyl, --CN, --C.ident.C-Si(CH.sub.3).sub.3,
--OC.sub.1-C.sub.8alkyl, --SC.sub.1-C.sub.8alkyl, --CF.sub.3,
--NH.sub.2, --NHC, --C.sub.8alkyl, --N(C.sub.1-C.sub.8alkyl).sub.2,
--NO.sub.2, --CO.sub.2H, --CO.sub.2C.sub.1-C.sub.8alkyl,
--C.sub.2-C.sub.8alkenyl, or --C.sub.2-C.sub.8alkynyl, or R.sup.2
and R.sup.3 together with the atoms on the ring to which they are
attached form a five or six membered ring containing from 0 to 3
heteroatoms and from 0 to 2 double bonds;
[0309] R.sup.4 is --C(.dbd.O)--A;
[0310] A is --NR.sup.dR.sup.d, --NR.sup.aCH.sub.2CH.sub.2OR.sup.a,
13
[0311] each R.sup.d is independently hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, aryl, substituted
aryl, heteroaryl, or substituted heteroaryl;
[0312] each R.sup.c is independently hydrogen, --C(.dbd.O)OR.sup.a,
--OR.sup.a, --SR.sup.a, or --NR.sup.aR.sup.a and each n is
independently 1-3.
[0313] Preferred examples of glycogen phosphorylase inhibitors of
Formula AA include 6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0314] 2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0315] 2-methyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0316] (.+-.)-2-methyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[1-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0317] 2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0318] 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0319] 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0320] 2,4-dichloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0321] (.+-.)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[1-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0322] 2-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0323] 4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-d-
ihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
[0324] 2-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid
[1-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0325] 2-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0326] 6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-d-
ihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0327] 2-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0328] 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0329] 2,4-dichloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0330] 2-cyano-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
[0331] 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-morpholin-4-yl-2-oxo-ethyl]-amide;
[0332] 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-dimethylcarbamoyl-2-phenyl-ethyl]-amide;
[0333] 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-(1,1-dioxo-1-thiazolidin-3-yl)-2-oxo-ethyl]-amide;
[0334]
1-{(2S)-[(2-chloro-6H-thieno[2,3-b]pyrrole-5-carbonyl)-amino]-3-phe-
nyl-propionyl}-piperidine-4-carboxylic acid ethyl ester;
[0335] 2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
[0336] 2-methyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0337]
2-trimethylsilanylethynyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
[0338] 2-ethynyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
[0339] 2-fluoro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0340] 2-cyano-4H-furo[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
[0341] 2-chloro-4H-furo[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0342] 2-chloro-4H-furo[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0343]
1-{(2S)-[(2-chloro-6H-thieno[2,3-b]pyrrole-5-carbonyl)-amino]-3-phe-
ny-propionyl}-piperidine-4-carboxylic acid;
[0344] 3-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0345] 3-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0346] 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0347] 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0348] 2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0349] 2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0350] 3-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0351] 3-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0352] 2-cyano-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0353] 2-cyano-4H-furo[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0354] 3-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0355] 3-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0356] 4H-1,7-dithia-4-aza-cyclopenta[a]pentalene-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0357] 4H-1,7-dithia-4-aza-cyclopenta[a]pentalene-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0358] 2-chloro-3-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0359] 2-chloro-3-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-pro-
pyl]-amide;
[0360] 2-methylsulfanyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0361] 2-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
[0362] 2-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-(1,1-dioxo-1-thiazolidin-3-yl)-2-oxo-ethyl]-amide;
[0363] 2-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-morpholin-4-yl-2-oxo-ethyl]-amide;
[0364] 2-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0365] 2-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-((3R,4R)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
and
[0366] 2-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
[(1S)-benzyl-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide, and
the stereoisomers, pharmaceutically acceptable salts and prodrugs
of the compounds, and the pharmaceutically acceptable salts of the
prodrugs.
[0367] Methods for making the above recited glycogen phosphorylase
inhibitors of Formula AA can be found in U.S. provisional patent
application No. 60/157,148, filed Sep. 30, 1999.
[0368] Commonly assigned PCT published applications WO 96/39384 and
WO 96/39385 disclose glycogen phosphorylase inhibitors of Formulas
IQ and IAQ.
[0369] One group of glycogen phosphorylase inhibitors that can be
used in the present invention includes compounds of Formula IQ
14
Formula IQ
[0370] and the pharmaceutically acceptable salts and prodrugs
thereof wherein
[0371] the dotted line (--) is an optional bond;
[0372] A is --C(H).dbd., --C((C.sub.1-C.sub.4)alkyl).dbd. or
--C(halo).dbd. when the dotted line (--) is a bond, or A is
methylene or --CH((C.sub.1-C.sub.4)alkyl)- when the dotted line
(--) is not a bond;
[0373] R.sub.1, R.sub.10 or R.sub.11 are each independently H,
halo, 4-, 6- or 7-nitro, cyano, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, fluoromethyl, difluoromethyl or
trifluoromethyl;
[0374] R.sub.2is H;
[0375] R.sub.3 is H or (C.sub.1-C.sub.5)alkyl;
[0376] R.sub.4 is H, methyl, ethyl, n-propyl,
hydroxy(C.sub.1-C.sub.3)alky- l,
(C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl,
phenyl(C.sub.1-C.sub.4)a- lkyl,
phenylhydroxy(C.sub.1-C.sub.4)alkyl,
phenyl(C.sub.1-C.sub.4)alkoxy(C- .sub.1-C.sub.4)alkyl, thien-2- or
-3-yl(C.sub.1-C.sub.4)alkyl or fur-2- or
-3-yl(C.sub.1-C.sub.4)alkyl wherein said R4 rings are mono-, di- or
tri-substituted independently on carbon with H, halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, trifluoromethyl,
hydroxy, amino or cyano; or
[0377] R.sub.4 is pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.4)alkyl,
thiazol-2-, -4- or -5-yl(C.sub.1-C.sub.4)alkyl, imidazol -1-, -2-,
-4- or -5-yl(C.sub.1-C.sub.4)alkyl, pyrrol-2- or
-3-yl(C.sub.1-C.sub.4)alkyl, oxazol-2-, -4- or
-5-yl-(C.sub.1-C.sub.4)alkyl, pyrazol-3-, -4- or
-5-yl(C.sub.1-C.sub.4)alkyl, isoxazol-3-, -4- or
-5-yl(C.sub.1-C.sub.4)al- kyl, isothiazol-3-, -4- or
-5-yl(C.sub.1-C.sub.4)alkyl, pyridazin-3- or
-4-yl-(C.sub.1-C.sub.4)alkyl, pyrimidin-2-, -4-, -5- or
-6-yl(C.sub.1-C.sub.4)alkyl, pyrazin-2- or
-3-yl(C.sub.1-C.sub.4)alkyl or
1,3,5-triazin-2-yl(C.sub.1-C.sub.4)alkyl, wherein said preceding R4
heterocycles are optionally mono- or di-substituted independently
with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, amino or hydroxy and said mono-or
di-substituents are bonded to carbon;
[0378] R.sub.5 is H, hydroxy, fluoro, (C.sub.1-C.sub.5)alkyl,
(C.sub.1-C.sub.5)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
amino(C.sub.1-C.sub.4)alkoxy, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkyla- mino(C.sub.1-C.sub.4)alkoxy,
carboxy(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.5)alkoxy-carbonyl(C.sub.1-C.sub.4)alkoxy,
benzyloxycarbonyl(C.sub.1-C.sub.4)alkoxy, or carbonyloxy wherein
said carbonyloxy is carbon-carbon linked with phenyl, thiazolyl,
imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl or
1,3,5-triazinyl and wherein said preceding R.sub.5 rings are
optionally mono-substituted with halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, hydroxy, amino or trifluoromethyl and said
mono-substituents are bonded to carbon;
[0379] R.sub.7 is H, fluoro or (C.sub.1-C.sub.5)alkyl; or
[0380] R.sub.5 and R.sub.7 can be taken together to be oxo;
[0381] R.sub.6 is carboxy, (C.sub.1-C.sub.8)alkoxycarbonyl,
C(O)NR.sub.8R.sub.9 or C(O)R.sub.12, wherein
[0382] R.sub.8 is H, (C.sub.1-C.sub.3)alkyl, hydroxy or
(C.sub.1-C.sub.3)alkoxy; and
[0383] R.sub.9 is H, (C.sub.1-C.sub.8)alkyl, hydroxy,
(C.sub.1-C.sub.8)alkoxy,
methylene-perfluorinated(C.sub.1-C.sub.8)alkyl, phenyl, pyridyl,
thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl,
imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl,
isothiazolyl, pyranyl, piperidinyl, morpholinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, piperazinyl or 1,3,5-triazinyl wherein said
preceding R.sub.9 rings are carbon-nitrogen linked; or
[0384] R.sub.9 is mono-, di- or tri-substituted
(C.sub.1-C.sub.5)alkyl, wherein said substituents are independently
H, hydroxy, amino, mono-N-- or di-N,N--(C.sub.1-C.sub.5)alkylamino;
or
[0385] R.sub.9 is mono- or di-substituted (C.sub.1-C.sub.5)alkyl,
wherein said substituents are independently phenyl, pyridyl, furyl,
pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl,
pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, piperazinyl or 1,3,5-triazinyl
[0386] wherein the nonaromatic nitrogen-containing R.sub.9 rings
are optionally mono-substituted on nitrogen with
(C.sub.1-C.sub.6)alkyl, benzyl, benzoyl or
(C.sub.1-C.sub.6)alkoxycarbonyl and wherein the R.sub.9 rings are
optionally mono-substituted on carbon with halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, hydroxy, amino, or
mono-N-- and di-N,N(C.sub.1-C.sub.5)alkylamino provided that no
quaternized nitrogen is included and there are no nitrogen-oxygen,
nitrogen-nitrogen or nitrogen-halo bonds;
[0387] R.sub.12 is piperazin-1-yl,
4-(C.sub.1-C.sub.4)alkylpiperazin-1-yl, 4-formylpiperazin-1-yl,
morpholino, thiomorpholino, 1-oxothiomorpholino,
1,1-dioxo-thiomorpholino, thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl,
1,1-dioxo-thiazolidin-3-yl,
2-(C.sub.1-C.sub.6)alkoxycarbonylpyrrolidin-1- -yl, oxazolidin-3-yl
or 2(R)-hydroxymethylpyrrolidin-1-yl; or
[0388] R.sub.12 is 3- and/or 4-mono-or di-substituted
oxazetidin-2-yl, 2-, 4-, and/or 5-mono- or di-substituted
oxazolidin-3-yl, 2-, 4-, and/or 5- mono- or di- substituted
thiazolidin-3-yl, 2-, 4-, and/or 5- mono- or di- substituted
1-oxothiazolidin-3-yl, 2-, 4-, and/or 5- mono- or di- substituted 1
,1-dioxothiazolidin-3-yl, 3- and/or 4-, mono- or di-substituted
pyrrolidin-1-yl, 3-, 4- and/or 5-, mono-, di- or tri-substituted
piperidin-1-yl, 3-, 4-, and/or 5- mono-, di-, or trj-substituted
piperazin-1-yl, 3-substituted azetidin-1-yl, 4- and/or 5-, mono- or
di-substituted 1 ,2-oxazinan-2-yl, 3-and/or 4-mono- or
di-substituted pyrazolidin-1-yl, 4- and/or 5-, mono- or
di-substituted isoxazolidin-2-yl, 4-and/or 5-, mono- and/or
di-substituted isothiazolidin-2-yl wherein said R.sub.12
substituents are independently H, halo, (C.sub.1-C.sub.5)-alkyl,
hydroxy, amino, mono-N-- or di-N,N--(C.sub.1-C.sub.5)alkylamino,
formyl, oxo, hydroxyimino, (C.sub.1-C.sub.5)alkoxy, carboxy,
carbamoyl, mono-N- or di-N,N--(C.sub.1-C.sub.4)alkylcarbamoyl,
(C.sub.1-C.sub.4)alkoxyimino, (C.sub.1-C.sub.4)alkoxymethoxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, carboxy(C.sub.1-C.sub.5)alkyl or
hydroxy(C.sub.1-C.sub.5)alkyl;
[0389] with the proviso that if R.sub.4 is H, methyl, ethyl or
n-propyl R.sub.5 is OH;
[0390] with the proviso that if R.sub.5 and R.sub.7 are H, then
R.sub.4 is not H, methyl, ethyl, n-propyl,
hydroxy(C.sub.1-C.sub.3)alkyl or
(C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl and R.sub.6 is
C(O)NR.sub.8R.sub.9, C(O)R.sub.12 or
(C.sub.1-C.sub.4)alkoxycarbonyl.
[0391] A first group of preferred compounds of Formula IQ consists
of those compounds wherein
[0392] R.sub.1 is 5-H, 5-halo, 5-methyl or 5-cyano;
[0393] R.sub.10 and R.sub.11 are each independently H or halo;
[0394] A is --C(H).dbd.;
[0395] R.sub.2 and R.sub.3 are H;
[0396] R.sub.4 is phenyl(C.sub.1-C.sub.2)alkyl wherein said phenyl
groups are mono-, di- or tri-substituted independently with H or
halo or mono- or di- substituted independently with H, halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, trifluoromethyl,
hydroxy, amino or cyano; or
[0397] R.sub.4 is thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.2)alkyl, thiazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, imidazol -1-, -2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrrol-2- or -3-yl(C.sub.1-C.sub.2)alkyl, oxazol-2-, -4- or
-5-yl-(C.sub.1-C.sub.2)alkyl, pyrazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)al- kyl, isoxazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl wherein said preceding R.sub.4
heterocycles are optionally mono- or di-substituted independently
with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, amino or hydroxy and said mono- or
di-substituents are bonded to carbon;
[0398] R.sub.5 is hydroxy;
[0399] R.sub.6 is C(O)NR.sub.8R.sub.9 or C(O)R.sub.12; and
[0400] R.sub.7 is H.
[0401] Within the above first group of preferred compounds of
Formula IQ is a first group of especially preferred compounds
wherein
[0402] the carbon atom a has (S) stereochemistry;
[0403] the carbon atom b has (R) stereochemistry;
[0404] R.sub.4 is phenyl(C.sub.1-C.sub.2)alkyl,
thien-2-yl-(C.sub.1-C.sub.- 2)alkyl,
thien-3-yl-(C.sub.1-C.sub.2)alkyl, fur-2-yl-(C.sub.1-C.sub.2)alky-
l or fur-3-yl-(C.sub.1-C.sub.2)alkyl wherein said rings are mono-
or di- substituted independently with H or fluoro;
[0405] R.sub.6 is C(O)NR.sub.8R.sub.9;
[0406] R.sub.8 is (C.sub.1-C.sub.3)alkyl, hydroxy or
(C.sub.1-C.sub.3)alkoxy; and
[0407] R.sub.9 is H, (C.sub.1-C.sub.8)alkyl, hydroxy,
hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.8)alkoxy, pyridyl,
morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, imidazolyl or
thiazolyl or (C.sub.1-C.sub.4)alkyl mono-substituted with pyridyl,
morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, imidazolyl or
thiazolyl.
[0408] Within the above first group of especially preferred
compounds are the particularly preferred compounds
[0409] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-((R)-hydroxy-dimethylcar-
bamoyl-methyl)-2-phenyl-ethyl]-amide,
[0410] 5,6-dichloro-1H-indole-2-carboxylic acid
{(1S)-[(R)-hydroxy-(methox-
y-methyl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide,
[0411] 5-chloro-1H-indole-2-carboxylic acid
{(1S)-[(R)-hydroxy-(methoxy-me-
thyl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide,
[0412] 5-chloro-1H-indole-2-carboxylic acid
((1S)-{(R)-hydroxy-[(2-hydroxy-
-ethyl)-methyl-carbamoyl]-methyl}-2-phenyl-ethyl)-amide,
[0413] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-3-((3R,4S)-dihydr-
oxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide,
[0414] 5-chloro-1H-indole-2-carboxylic acid
{(1S)-[(R)-hydroxy-(methyl-pyr-
idin-2-yl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide, and
[0415] 5-chloro-1H-indole-2-carboxylic acid
((1S)-{(R)-hydroxy-[methyl-(2--
pyridin-2-yl-ethyl)-carbamoyl]-methyl}-2-phenyl-ethyl)-amide.
[0416] Within the above first group of especially preferred
compounds are the compounds wherein
[0417] a. R.sub.1 is 5-chloro;
[0418] R.sub.10 and R.sub.11 are H;
[0419] R.sub.4 is benzyl;
[0420] R.sub.8 is methyl; and
[0421] R.sub.9 is methyl;
[0422] b. R.sub.1 is 5-chloro;
[0423] R.sub.1, is H;
[0424] R.sub.10 is 6-chloro;
[0425] R.sub.4 is benzyl;
[0426] R.sub.8 is methyl; and
[0427] R.sub.9 is methoxy;
[0428] c. R.sub.1 is 5-chloro;
[0429] R.sub.10 and R.sub.1, are H;
[0430] R.sub.4 is benzyl;
[0431] R.sub.8 is methyl; and
[0432] R.sub.9 is methoxy;
[0433] d. R.sub.1 is 5-chloro;
[0434] R.sub.10 and R.sub.11, are H;
[0435] R.sub.4 is benzyl;
[0436] R.sub.8 is methyl; and
[0437] R.sub.9 is 2-(hydroxy)ethyl;
[0438] e. R.sub.1 is 5-chloro;
[0439] R.sub.10 and R.sub.11 are H;
[0440] R.sub.4 is benzyl;
[0441] R.sub.8 is methyl; and
[0442] R.sub.9 is pyridin-2-yl; and
[0443] f. R.sub.1 is 5-chloro;
[0444] R.sub.10 and R.sub.11 are H;
[0445] R.sub.4 is benzyl;
[0446] R.sub.8 is methyl; and
[0447] R.sub.9 is 2-(pyridin-2-yl)ethyl.
[0448] Within the above first group of preferred compounds of
Formula IQ is a second group of especially preferred compounds
wherein
[0449] the carbon atom a is (S) stereochemistry;
[0450] the carbon atom b is (R) stereochemistry;
[0451] R.sub.4 is phenyl(C.sub.1-C.sub.2)alkyl,
thien-2-yl-(C.sub.1-C.sub.- 2)alkyl,
thien-3-yl-(C.sub.1-C.sub.2)alkyl, fur-2-yl-(C.sub.1-C.sub.2)alky-
l or fur-3-yl-(C.sub.1-C.sub.2)alkyl wherein said rings are mono-
or di- substituted independently with H or fluoro;
[0452] R.sub.6 is C(O)R.sub.12; and
[0453] R.sub.12 is morpholino,
4-(C.sub.1-C.sub.4)alkylpiperazin-1-yl, 3-substituted
azetidin-1-yl, 3-and/or 4-, mono- or di-substituted
pyrrolidin-1-yl, 4- and/or 5- mono- or di-substituted
isoxazolidin-2-yl, 4- and/or 5-, mono- or di-substituted
1,2-oxazinan-2-yl wherein said substituents are each independently
H, halo, hydroxy, amino, mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylamino, oxo, hydroxyimino or
alkoxy.
[0454] Within the above second group of especially preferred
compounds are the particularly preferred compounds
[0455] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-(2R)-hydroxy-3-(4-
-methyl-piperazin-1-yl)-3-oxo-propyl]-amide hydrochloride,
[0456] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-(2R)-hydroxy-3-(3-
-hydroxy-azetidin-1-yl)-3-oxo-propyl]-amide,
[0457] 5-chloro-1H-indole-2-carboxylic acid
((1S)-benzyl-(2R)-hydroxy-3-is-
oxazolidin-2-yl-3-oxo-propyl)-amide,
[0458] 5-chloro-1H-indole-2-carboxylic acid
((1S)-benzyl-(2R)-hydroxy-3-[1-
,2]oxazinan-2-yl-3-oxo-propyl)-amide,
[0459] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-(2R)-hydroxy-3-((-
3S)-hydroxy-pyrrolidin-1-yl)-3-oxo-propyl]-amide,
[0460] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-3-((3S,4S)-dihydr-
oxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide,
[0461] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-3-(cis-3,4-dihydr-
oxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide, and
[0462] 5-chloro-1H-indole-2-carboxylic acid
((1S)-benzyl-(2R)-hydroxy-3-mo-
rpholin-4-yl-3-oxo-propyl)-amide.
[0463] Within the above second group of especially preferred
compounds are the compounds wherein
[0464] a. R.sub.1 is 5-chloro;
[0465] R.sub.10 and R.sub.11 are H;
[0466] R.sub.4 is benzyl; and
[0467] R.sub.12 is 4-methylpiperazin-1-yl;
[0468] b. R.sub.1 is 5-chloro;
[0469] R.sub.10 and R.sub.11, are H;
[0470] R.sub.4 is benzyl; and
[0471] R.sub.12 is 3-hydroxyazetidin-1-yl;
[0472] c. R.sub.1 is 5-chloro;
[0473] R.sub.10 and R.sub.11 are H;
[0474] R.sub.4is benzyl; and
[0475] R.sub.12 is isoxazolidin-2-yl;
[0476] d. R.sub.1 is 5-chloro;
[0477] R.sub.10 and R.sub.11 are H;
[0478] R.sub.4 is benzyl; and
[0479] R.sub.12 is (1,2)-oxazinan-2-yl;
[0480] e. R.sub.1 is 5-chloro;
[0481] R.sub.10 and R.sub.11 are H;
[0482] R.sub.4 is benzyl; and
[0483] R.sub.12 is 3(S)-hydroxypyrrolidin-1-yl;
[0484] f. R.sub.1 is 5-chloro;
[0485] R.sub.10 and R.sub.11, are H;
[0486] R.sub.4 is benzyl; and
[0487] R.sub.12 is (3S,4S)-dihydroxypyrrolidin-1-yl;
[0488] g. R.sub.11 is 5-chloro;
[0489] R.sub.10 and R.sub.11, are H;
[0490] R.sub.4 is benzyl; and
[0491] R.sub.12 is cis-3,4-dihydroxypyrrolidin-1-yl; and
[0492] h. R.sub.1 is 5-chloro;
[0493] R.sub.10 and R.sub.11 are H;
[0494] R.sub.4 is benzyl; and
[0495] R.sub.12 is morpholino.
[0496] A second group of preferred compounds of Formula IQ consists
of those compounds wherein
[0497] R.sub.1 is H, halo, methyl or cyano;
[0498] R.sub.10 and R.sub.11, are each independently H or halo;
[0499] A is --C(H).dbd.;
[0500] R.sub.2 and R.sub.3 are H;
[0501] R.sub.4 is phenyl(C.sub.1-C.sub.2)alkyl wherein said phenyl
groups are mono-, di- or tri-substituted independently with H or
halo or mono- or di- substituted independently with H, halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, trifluoromethyl,
hydroxy, amino or cyano; or
[0502] R.sub.4 is thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.2)alkyl, thiazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, imidazol -1-, -2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrrol-2- or -3-yl(C.sub.1-C.sub.2)alkyl, oxazol-2-, -4- or
-5-yl-(C.sub.1-C.sub.2)alkyl, pyrazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)al- kyl, isoxazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl wherein said preceding R4 heterocycles
are optionally mono- or di-substituted independently with halo,
trifluoromethyl, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
amino or hydroxy and said mono- or di-substituents are bonded to
carbon;
[0503] R.sub.5 is hydroxy;
[0504] R.sub.6 is carboxy or (C.sub.1-C.sub.8)alkoxycarbonyl;
and
[0505] R.sub.7 is H, fluoro or (C.sub.1-C.sub.6)alkyl.
[0506] Within the second group of preferred compounds of Formula IQ
is a group of especially preferred compounds wherein
[0507] the carbon atom a is (S) stereochemistry;
[0508] the carbon atom b is (R) stereochemistry;
[0509] R.sub.4 is phenyl(C.sub.1-C.sub.2)alkyl,
thien-2-yl-(C.sub.1-C.sub.- 2)alkyl,
thien-3-yl-(C.sub.1-C.sub.2)alkyl, fur-2-yl-(C.sub.1-C.sub.2)alky-
l or fur-3-yl-(C.sub.1-C.sub.2)alkyl wherein said rings are mono-
or di- substituted independently with H or fluoro;
[0510] R.sub.10 and R.sub.11, are H;
[0511] R.sub.6 is carboxy; and
[0512] R.sub.7 is H.
[0513] Preferred within the immediately preceding group is a
compound wherein
[0514] R.sub.1 is 5-chloro;
[0515] R.sub.10 and R.sub.11 are H; and
[0516] R.sub.4 is benzyl.
[0517] A third group of preferred compounds of Formula IQ consists
of those compounds wherein
[0518] R.sub.1 is H, halo, methyl or cyano;
[0519] R.sub.10 and R.sub.11 are each independently H or halo;
[0520] A is --C(H).dbd.;
[0521] R.sub.2 and R.sub.3 are H;
[0522] R.sub.4 is phenyl(C.sub.1-C.sub.2)alkyl wherein said phenyl
groups are mono-, di- or tri-substituted independently with H or
halo or mono- or di- substituted independently with H, halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, trifluoromethyl,
hydroxy, amino or cyano; or
[0523] R.sub.4 is thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.2)alkyl, thiazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, imidazol -1-, -2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrrol-2- or -3-yl(C.sub.1-C.sub.2)alkyl, oxazol-2-, -4- or
-5-yl-(C.sub.1-C.sub.2)alkyl, pyrazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)al- kyl, isoxazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl wherein said preceding R.sub.4
heterocycles are optionally mono- or di-substituted independently
with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, amino or hydroxy and said mono- or
di-substituents are bonded to carbon;
[0524] R.sub.5 is fluoro, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.5)alkoxy, amino(C.sub.1-C.sub.4)alkoxy, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkyla- mino(C.sub.1-C.sub.4)alkoxy,
carboxy(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.5)alkoxy-carbonyl(C.sub.1-C.sub.4)alkoxy,
benzyloxycarbonyl(C.sub.1-C.sub.4)alkoxy;
[0525] R.sub.6 is carboxy or (C.sub.1-C.sub.8)alkoxycarbonyl;
and
[0526] R.sub.7 is H, fluoro or (C.sub.1-C.sub.6)alkyl.
[0527] A fourth group of preferred compounds of Formula IQ consists
of those compounds wherein
[0528] R.sub.1 is H, halo, methyl or cyano;
[0529] R.sub.10 and R.sub.11 are each independently H or halo;
[0530] A is --C(H).dbd.;
[0531] R.sub.2 and R.sub.3 are H;
[0532] R.sub.4 is phenyl(C.sub.1-C.sub.2)alkyl wherein said phenyl
groups are mono-, di- or tri-substituted independently with H or
halo or mono- or di- substituted independently with H, halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, trifluoromethyl,
hydroxy, amino or cyano; or
[0533] R.sub.4 is thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.2)alkyl, thiazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, imidazol -1-, -2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrrol-2- or -3-yl(C.sub.1-C.sub.2)alkyl, oxazol-2-, -4- or
-5-yl-(C.sub.1-C.sub.2)alkyl, pyrazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)al- kyl, isoxazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl wherein said preceding R.sub.4
heterocycles are optionally mono- or di-substituted independently
with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, amino or hydroxy and said mono- or
di-substituents are bonded to carbon;
[0534] R.sub.5 is fluoro, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.5)alkoxy, amino(C.sub.1-C.sub.4)alkoxy, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkyla- mino(C.sub.1-C.sub.4)alkoxy,
carboxy(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.5)alkoxy-carbonyl(C.sub.1-C.sub.4)alkoxy,
benzyloxycarbonyl(C.sub.1-C.sub.4)alkoxy;
[0535] R.sub.6 is C(O)NR.sub.8R.sub.9 or C(O)R.sub.12; and
[0536] R.sub.7 is H, fluoro or (C.sub.1-C.sub.6)alkyl.
[0537] Another group of glycogen phosphorylase inhibitors includes
compounds of the Formula IAQ 15
Formula IAQ
[0538] and the pharmaceutically acceptable salts and prodrugs
thereof wherein
[0539] the dotted line (--) is an optional bond;
[0540] A is --C(H).dbd., --C((C.sub.1-C.sub.4)alkyl).dbd.,
--C(halo).dbd. or --N.dbd., when the dotted line (--) is a bond, or
A is methylene or --CH((C.sub.1-C.sub.4)alkyl)--, when the dotted
line (--) is not a bond;
[0541] R.sub.1, R.sub.10 or R.sub.11 are each independently H,
halo, cyano, 4-, 6-, or 7-nitro, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, fluoromethyl, difluoromethyl or
trifluoromethyl;
[0542] R.sub.2 is H;
[0543] R.sub.3 is H or (C.sub.1-C.sub.5)alkyl;
[0544] R.sub.4 is H, methyl, ethyl, n-propyl,
hydroxy(C.sub.1-C.sub.3)alky- l,
(C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl,
phenyl(C.sub.1-C.sub.4)a- lkyl,
phenylhydroxy(C.sub.1-C.sub.4)alkyl,
(phenyl)((C.sub.1-C.sub.4)-alky- l)(C.sub.1-C.sub.4)alkyl, thien-2-
or -3-yl(C.sub.1-C.sub.4)alkyl or fur-2- or
-3-yl(C.sub.1-C.sub.4)alkyl wherein said R.sub.4 rings are mono-,
di- or tri-substituted independently on carbon with H, halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, trifluoromethyl,
hydroxy, amino, cyano or 4,5-dihydro-1H-imidazol-2-yl; or
[0545] R.sub.4 is pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.4)alkyl,
thiazol-2-, -4- or -5-yl(C.sub.1-C.sub.4)alkyl, imidazol-2-, -4- or
-5-yl(C.sub.1-C.sub.4)alkyl, pyrrol-2- or
-3-yl(C.sub.1-C.sub.4)alkyl, oxazol-2-, -4- or
-5-yl(C.sub.1-C.sub.4)alkyl, pyrazol-3-, -4- or
-5-yl(C.sub.1-C.sub.4)alkyl, isoxazol-3-, -4- or
-5-yl(C.sub.1-C.sub.4)al- kyl, isothiazol-3-, -4- or
-5-yl(C.sub.1-C.sub.4)alkyl, pyridazin-3- or
-4-yl(C.sub.1-C.sub.4)alkyl, pyrimidin-2-, -4-, -5- or
-6-yl(C.sub.1-C.sub.4)alkyl, pyrazin-2- or
-3-yl(C.sub.1-C.sub.4)alkyl,
1,3,5-triazin-2-yl(C.sub.1-C.sub.4)alkyl or
indol-2-(C.sub.1-C.sub.4)alky- l, wherein said preceding R.sub.4
heterocycles are optionally mono- or di-substituted independently
with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, amino, hydroxy or cyano and said
substituents are bonded to carbon; or
[0546] R.sub.4 is R.sub.15-carbonyloxymethyl, wherein said R.sub.15
is phenyl, thiazolyl, imidazolyl, 1H-indolyl, furyl, pyrrolyl,
oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and wherein
said preceding R.sub.15 rings are optionally mono- or
di-substituted independently with halo, amino, hydroxy,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy or trifluoromethyl
and said mono- or di-substituents are bonded to carbon;
[0547] R.sub.5 is H;
[0548] R.sub.6 is carboxy, (C.sub.1-C.sub.8)alkoxycarbonyl,
benzyloxycarbonyl, C(O)NR.sub.8R.sub.9 or C(O)R.sub.12
[0549] wherein
[0550] R.sub.8 is H, (C.sub.1-C.sub.6)alkyl,
cyclo(C.sub.3-C.sub.6)alkyl,
cyclo(C.sub.3-C.sub.6)alkyl(C.sub.1-C.sub.5)alkyl, hydroxy or
(C.sub.1-C.sub.8)alkoxy; and
[0551] R.sub.9 is H, cyclo(C.sub.3-C.sub.8)alkyl,
cyclo(C.sub.3-C.sub.8)al- kyl(C.sub.1-C.sub.5)alkyl,
cyclo(C.sub.4-C.sub.7)alkenyl,
cyclo(C.sub.3-C.sub.7)alkyl(C.sub.1-C.sub.5)alkoxy,
cyclo(C.sub.3-C.sub.7)alkyloxy, hydroxy,
methylene-perfluorinated(C.sub.1- -C.sub.8)alkyl, phenyl, or a
heterocycle wherein said heterocycle is pyridyl, furyl, pyrrolyl,
pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl,
pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, piperazinyl, 1,3,5-triazinyl, benzothiazolyl,
benzoxazolyl, benzimidazolyl, thiochromanyl or
tetrahydrobenzothiazolyl wherein said heterocycle rings are
carbon-nitrogen linked; or
[0552] R.sub.9 is (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.8)alkoxy
wherein said (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.8)alkoxy is
optionally monosubstituted with cyclo(C.sub.4-C.sub.7)alken-1-yl,
phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,
isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl
or indolyl and wherein said (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.8)alkoxy are optionally additionally independently
mono- or di-substituted with halo, hydroxy,
(C.sub.1-C.sub.5)alkoxy, amino, mono-N-- or
di-N,N--(C.sub.1-C.sub.5)alky- lamino, cyano, carboxy, or
(C.sub.1-C.sub.4)alkoxycarbonyl; and
[0553] wherein the R.sub.9 rings are optionally mono- or
di-substituted independently on carbon with halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, hydroxy,
hydroxy(C.sub.1-C.sub.4)alkyl, amino(C.sub.1-C.sub.4)alkyl,
mono-N-- or di-N,N--(C.sub.1-C.sub.4)alkylam-
ino(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl, amino, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylamino, cyano, carboxy,
(C.sub.1-C.sub.5)alkoxycarbonyl, carbamoyl, formyl or
trifluoromethyl and said R.sub.9 rings may optionally be
additionally mono- or di-substituted independently with
(C.sub.1-C.sub.5)alkyl or halo;
[0554] with the proviso that no quaternized nitrogen on any R.sub.9
heterocycle is included;
[0555] R.sub.12 is morpholino, thiomorpholino, 1-oxothiomorpholino,
1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl,
1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl,
piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl,
pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl,
1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4-dihydroisoquinolin-2-yl,
1,3-dihydroisoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl,
2,3-dihydro-benzo[1,4]oxazin-4-yl,
2,3-dihydro-benzo[1,4]-thiazine-4-yl,
3,4-dihydro-2H-quinoxalin-1-yl,
3,4-dihydro-benzo[c][1,2]oxazin-1-yl,
1,4-dihydro-benzo[d][1,2]oxazin-3-yl,
3,4-dihydro-benzo[e][1,2]-oxazin-2-- yl, 3H-benzo[d]isoxazol-2-yl,
3H-benzo[c]isoxazol-1-yl or azepan-1-yl,
[0556] wherein said R.sub.12 rings are optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.5)alkyl,
(C.sub.1-C.sub.5)alkoxy, hydroxy, amino, mono-N-- or
di-N,N--(C.sub.1-C.sub.5)alkylamino, formyl, carboxy, carbamoyl,
mono-N-- or di-N,N--(C.sub.1-C.sub.5)alkylcarbamoyl,
(C.sub.1-C.sub.6)alkoxy(C.sub- .1-C.sub.3)alkoxy,
(C.sub.1-C.sub.5)alkoxycarbonyl, benzyloxycarbonyl,
(C.sub.1-C.sub.5)alkoxycarbonyl(C.sub.1-C.sub.5)alkyl,
(C.sub.1-C.sub.4)alkoxycarbonylamino,
carboxy(C.sub.1-C.sub.5)alkyl, carbamoyl(C.sub.1-C.sub.5)alkyl,
mono-N-- or di-N,N--(C.sub.1-C.sub.5)alk-
ylcarbamoyl(C.sub.1-C.sub.5)alkyl, hydroxy(C.sub.1-C.sub.5)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
amino(C.sub.1-C.sub.4)alky- l, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylamino(C.sub.1-C.sub.4)alkyl, oxo,
hydroxyimino or (C.sub.1-C.sub.6)alkoxyimino and wherein no more
than two substituents are selected from oxo, hydroxyimino or
(C.sub.1-C.sub.6)alkoxyimino and oxo, hydroxyimino or
(C.sub.1-C.sub.6)alkoxyimino are on nonaromatic carbon; and
[0557] wherein said R.sub.12 rings are optionally additionally
mono- or di-substituted independently with (C.sub.1-C.sub.5)alkyl
or halo;
[0558] with the proviso that when R.sub.6 is
(C.sub.1-C.sub.5)alkoxycarbon- yl or benzyloxycarbonyl then R.sub.1
is 5-halo, 5-(C.sub.1-C.sub.4)alkyl or 5-cyano and R.sub.4 is
(phenyl)(hydroxy)(C.sub.1-C.sub.4)alkyl,
(phenyl)((C.sub.1-C.sub.4)alkoxy)(C.sub.1-C.sub.4)alkyl,
hydroxymethyl or Ar(C.sub.1-C.sub.2)alkyl, wherein Ar is thien-2-
or -3-yl, fur-2- or -3-yl or phenyl wherein said Ar is optionally
mono- or di-substituted independently with halo; with the proviso
that when R.sub.1 and R.sub.10 and R.sub.11 are H, R.sub.4 is not
imidazol-4-ylmethyl, 2-phenylethyl or 2-hydroxy-2-phenylethyl;
[0559] with the proviso that when R.sub.8 is H and R.sub.9 is
(C.sub.1-C.sub.6)alkyl, R.sub.9 is not substituted with carboxy or
(C.sub.1-C.sub.4)alkoxycarbonyl on the carbon which is attached to
the nitrogen atom N of NHR.sub.9;
[0560] with the proviso that when R.sub.6 is carboxy and R.sub.1,
R.sub.10, R.sub.11 and R.sub.5 are all H, then R.sub.4 is not
benzyl, H, (phenyl)(hydroxy)methyl, methyl, ethyl or n-propyl;
and
[0561] with the proviso that when R.sub.8 and R.sub.9 are both
n-pentyl, R.sup.1 is 5-chloro, 5-bromo, 5-cyano, 5-(C.sub.1-C.sub.5
alkyl), 5-(C.sub.1-C.sub.5alkoxy), or 5-trifluoromethyl.
[0562] A first group of preferred compounds of Formula IAQ consists
of those compounds wherein
[0563] R.sub.1 is 5-H, 5-halo, 5-methyl, 5-cyano or
5-trifluoromethyl;
[0564] R.sub.10 and R.sub.11 are each independently H or halo;
[0565] A is --C(H).dbd.;
[0566] R.sub.2 and R.sub.3 are H;
[0567] R.sub.4 is H, methyl, phenyl(C.sub.1-C.sub.2)alkyl, wherein
said phenyl groups are mono- or di-substituted independently with
H, halo, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
trifluoromethyl, hydroxy, amino or cyano and wherein said R.sub.4
groups are optionally additionally mono-substituted with halo;
or
[0568] R.sub.4 is thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.2)alkyl, thiazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, imidazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)al- kyl, fur-2- or
-3-yl(C.sub.1-C.sub.2)alkyl, pyrrol-2- or
-3-yl(C.sub.1-C.sub.2)alkyl, oxazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)alky- l, pyrazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, isoxazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, isothiazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, pyridazin-3- or
-4-yl(C.sub.1-C.sub.2)alkyl, pyrimidin-2-, -4-, -5- or
-6-yl(C.sub.1-C.sub.2)alkyl, pyrazin-2- or
-3-yl(C.sub.1-C.sub.2)alkyl or
1,3,5-triazin-2-yl(C.sub.1-C.sub.2)alkyl wherein said preceding
R.sub.4 heterocycles are optionally mono- or di-substituted
independently with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, amino or hydroxy and said mono- or
di-substituents are bonded to carbon;
[0569] R.sub.5 is H; and
[0570] R.sub.6 is C(O)NR.sub.8R.sub.9 or C(O)R.sub.12.
[0571] Within the above first group of preferred compounds of
Formula IAQ is a first group of especially preferred compounds
wherein
[0572] R.sub.4 is H, phenyl(C.sub.1-C.sub.2)alkyl, thien-2- or
-3-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl
wherein said R.sub.4 rings are mono- or di-substituted
independently with H or fluoro;
[0573] R.sub.6 is C(O)R.sub.12; and
[0574] R.sub.12 is morpholino, thiomorpholino, 1-oxothiomorpholino,
1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl,
1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl,
piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl,
isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl,
oxazolidin-3-yl, 1,3-dihydroisoindol-2-yl, or azepan-1-yl,
[0575] wherein said R.sub.12 rings are optionally mono- or
di-substituted independently with halo, (C.sub.1-C.sub.5)alkyl,
(C.sub.1-C.sub.5)alkoxy, hydroxy, amino, mono-N-or
di-N,N--(C.sub.1-C.sub.5)alkylamino, formyl, carboxy, carbamoyl,
mono-N-- or di-N,N--(C.sub.1-C.sub.5)alkylcarbamoyl,
(C.sub.1-C.sub.5)alkoxycarbonyl, hydroxy(C.sub.1-C.sub.5)alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or
di-N,N--(C.sub.1-C.sub.4)alkylam- ino(C.sub.1-C.sub.4)alkyl, oxo,
hydroxyimino or (C.sub.1-C.sub.6)alkoxyimi- no with the proviso
that only the R.sub.12 heterocycles thiazolidin-3-yl,
pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl,
azetidin-1-yl, 1,2-oxazinan-2-yl, isoxazolidin-2-yl, or
oxazolidin-3-yl are optionally mono- or di-substituted with oxo,
hydroxyimino, or (C.sub.1-C.sub.6)alkoxyimino; and
[0576] wherein said R.sub.12 rings are optionally additionally
mono- or di-substituted independently with
(C.sub.1-C.sub.5)alkyl.
[0577] Within the above group of especially preferred compounds are
the compounds
[0578] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-(3-hydroxyimino-
-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,
[0579] 5-chloro-1H-indole-2-carboxylic acid
[2-(cis-3,4-dihydroxy-pyrrolid- in-1-yl)-2-oxo-ethyl]-amide,
[0580] 5-chloro-1H-indole-2-carboxylic acid
[2-((3S,4S)-dihydroxy-pyrrolid- in-1-yl)-2-oxo-ethyl]-amide,
[0581] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-(cis-3,4-dihydr-
oxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,
[0582] 5-chloro-1H-indole-2-carboxylic acid
[2-(1,1-dioxo-thiazolidin-3-yl- )-2-oxo-ethyl]-amide,
[0583] 5-chloro-1H-indole-2-carboxylic acid
(2-oxo-2-thiazolidin-3-yl-ethy- l)-amide,
[0584] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-(4-fluoro-benzyl)-2-(4-h-
ydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,
[0585] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-((3RS)-hydroxy--
piperidin-1-yl)-2-oxo-ethyl]-amide,
[0586] 5-chloro-1H-indole-2-carboxylic acid
[2-oxo-2-((1RS)-oxo-1-thiazoli- din-3-yl)-ethyl]-amide,
[0587] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-(2-fluoro-benzyl)-2-(4-h-
ydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,
[0588] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-((3S,4S)-dihydr-
oxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,
[0589] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-(3-hydroxy-azet- idin-1-yl)-2-oxo-ethyl]-amide,
[0590] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-(3-hydroxyimino-
-azetidin-1-yl)-2-oxo-ethyl]-amide,
[0591] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-(4-hydroxyimino-
-piperidin-1-yl)-2-oxo-ethyl]-amide, and
[0592] 5-chloro-1H-indole-2-carboxylic acid
[1-benzyl-2-(3-hydroxypyrrolid- in-1-yl)-2-oxo-ethyl]amide.
[0593] Within the above group of especially preferred compounds is
a first group of particularly preferred compounds wherein
[0594] R.sub.4 is H; and
[0595] R.sub.12 is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl,
1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or said R.sub.12
substituents optionally mono- or di-substituted independently with
carboxy, (C.sub.1-C.sub.5)alkoxycarbonyl,
hydroxy(C.sub.1-C.sub.3)alkyl, amino(C.sub.1-C.sub.3)alkyl,
mono-N-- or di-N,N--(C.sub.1-C.sub.3)alkylam-
ino(C.sub.1-C.sub.3)alkyl or R.sub.12 is mono- or di-substituted
pyrrolidin-1-yl wherein said substituents are independently
carboxy, (C.sub.1-C.sub.5)alkoxycarbonyl, (C.sub.1-C.sub.5)alkoxy,
hydroxy, hydroxy(C.sub.1-C.sub.3)alkyl, amino,
amino(C.sub.1-C.sub.3)alkyl, mono-N-- or
di-N,N--(C.sub.1-C.sub.3)alkylamino(C.sub.1-C.sub.3)alkyl or
mono-N-- or di-N,N--(C.sub.1-C.sub.4)alkylamino; and
[0596] the R.sub.12 rings are optionally additionally independently
disubstituted with (C.sub.1-C.sub.5)alkyl.
[0597] Preferred compounds within the immediately preceding group
of particularly preferred compounds are compounds wherein
[0598] a. R.sub.1 is 5-chloro;
[0599] R.sub.10 and R.sub.11, are H; and
[0600] R.sub.12 is cis-3,4-dihydroxy-pyrrolidin-1-yl;
[0601] b. R.sub.1 is 5-chloro;
[0602] R.sub.10 and R.sub.11, are H; and
[0603] R.sub.12 is (3S,4S)-dihydroxy-pyrrolidin-1-yl;
[0604] c. R.sub.1 is 5-chloro;
[0605] R.sub.10 and R.sub.11, are H; and
[0606] R.sub.12 is 1,1-dioxo-thiazolidin-3-yl;
[0607] d. R.sub.1 is 5-chloro;
[0608] R.sub.10 and R.sub.11 are H; and
[0609] R.sub.12 is thiazolidin-3-yl; and
[0610] e. R.sub.1 is 5-chloro;
[0611] R.sub.10 and R.sub.11 are H; and
[0612] R.sub.12 is 1-oxo-thiazolidin-3-yl.
[0613] Within the above group of especially preferred compounds is
a second group of particularly preferred compounds wherein
[0614] R.sub.4 is phenylmethyl, thien-2- or -3-ylmethyl wherein
said R.sub.4 rings are optionally mono- or di-substituted with
fluoro; and
[0615] R.sub.12 is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl,
1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or said R.sub.12
substituents optionally mono- or di-substituted independently with
carboxy or (C.sub.1-C.sub.5)alkoxycarbonyl,
hydroxy(C.sub.1-C.sub.3)alkyl- , amino(C.sub.1-C.sub.3)alkyl or
mono-N-- or di-N,N--(C.sub.1-C.sub.3)alky-
lamino(C.sub.1-C.sub.3)alkyl or R.sub.12 is mono- or di-substituted
azetidin-1-yl or mono- or di-substituted pyrrolidin-1-yl or mono-
or di-substituted piperidin-1-yl wherein said substituents are
independently carboxy, (C.sub.1-C.sub.5)alkoxycarbonyl,
hydroxy(C.sub.1-C.sub.3)alkyl, amino(C.sub.1-C.sub.3)alkyl,,
mono-N-- or di-N,N--(C.sub.1-C.sub.3)alkyla-
mino(C.sub.1-C.sub.3)alkyl, hydroxy, (C.sub.1-C.sub.5)alkoxy,
amino, mono-N-- or di-N,N--(C.sub.1-C.sub.5)alkylamino, oxo,
hydroxyimino or (C.sub.1-C.sub.5)alkoxyimino; and
[0616] the R.sub.12 rings are optionally additionally mono- or
di-substituted independently with (C.sub.1-C.sub.5)alkyl.
[0617] Preferred compounds within the immediately preceding group
of particularly preferred compounds are compounds wherein
[0618] a. R.sub.1 is 5-chloro;
[0619] R.sub.10 and R.sub.11 are H;
[0620] R.sub.4 is 4-fluorobenzyl;
[0621] R.sub.12 is 4-hydroxypiperidin-1-yl; and
[0622] the stereochemistry of carbon (a) is (S);
[0623] b. R.sub.1 is 5-chloro;
[0624] R.sub.10 and R.sub.11 are H;
[0625] R.sub.4 is benzyl;
[0626] R.sub.12 is 3-hydroxypiperidin-1-yl; and
[0627] the stereochemistry of carbon (a) is (S);
[0628] c. R.sub.1 is 5-chloro;
[0629] R.sub.10 and R.sub.11 are H;
[0630] R.sub.4 is benzyl;
[0631] R.sub.12 is cis-3,4-dihydroxy-pyrrolidin-1-yl; and
[0632] the stereochemistry of carbon (a) is S;
[0633] d. R.sub.1 is 5-chloro;
[0634] R.sub.10 and R.sub.11 are H; R4 is benzyl;
[0635] R.sub.12 is 3-hydroxyimino-pyrrolidin-1-yl; and
[0636] the stereochemistry of carbon (a) is (S);
[0637] e. R.sub.1 is 5-chloro;
[0638] R.sub.10 and R.sub.11 are H;
[0639] R.sub.4 is 2-fluorobenzyl;
[0640] R.sub.12 is 4-hydroxypiperidin-1-yl; and
[0641] the stereochemistry of carbon (a) is (S);
[0642] f. R.sub.1 is 5-chloro;
[0643] R.sub.10 and R.sub.11 are H;
[0644] R.sub.4 is benzyl;
[0645] R.sub.12 is (3S,4S)-dihydroxy-pyrrolidin-1-yl; and
[0646] the stereochemistry of carbon (a) is (S);
[0647] g. R.sub.1 is 5-chloro;
[0648] R.sub.10 and R.sub.1 are H;
[0649] R.sub.4 is benzyl;
[0650] R.sub.12 is 3-hydroxy-azetidin-1-yl; and
[0651] the stereochemistry of carbon (a) is (S);
[0652] h. R.sub.1 is 5-chloro;
[0653] R.sub.10 and R.sub.11 are H;
[0654] R.sub.4 is benzyl;
[0655] R.sub.12 is 3-hydroxyimino-azetidin-1-yl; and
[0656] the stereochemistry of carbon (a) is (S); and
[0657] i. R.sub.1 is 5-chloro;
[0658] R.sub.10 and R.sub.11 are H;
[0659] R.sub.4 is benzyl;
[0660] R.sub.12 is 4-hydroxyimino-piperidin-1-yl; and
[0661] the stereochemistry of carbon (a) is (S).
[0662] A second group of especially preferred compounds within the
first group of preferred compounds are the compounds wherein
[0663] R.sub.4 is H, phenyl(C.sub.1-C.sub.2)alkyl, thien-2- or
-3-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl
wherein said R.sub.4 rings are mono- or di-substituted
independently with H or fluoro;
[0664] R.sub.6 is C(O)NR.sub.8R.sub.9;and
[0665] R.sub.8 is H, (C.sub.1-C.sub.5)alkyl, hydroxy or
(C.sub.1-C.sub.4)alkoxy; and
[0666] R.sub.9 is H, cyclo(C.sub.4-C.sub.6)alkyl,
cyclo(C.sub.3-C.sub.6)al- kyl(C.sub.1-C.sub.5)alkyl,
methylene-perfluorinated(C.sub.1-C.sub.3)alkyl, pyridyl,
pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, piperidinyl,
benzothiazolyl or thiochromanyl; or
[0667] R.sub.9 is (C.sub.1-C.sub.5)alkyl wherein said
(C.sub.1-C.sub.5)alkyl is optionally substituted with
cyclo(C.sub.4-C.sub.6)alkenyl, phenyl, thienyl, pyridyl,
pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, or
1,1-dioxothiomorpholinyl and wherein said (C.sub.1-C.sub.5)alkyl or
(C.sub.1-C.sub.4)alkoxy is optionally additionally independently
mono- or di-substituted with halo, hydroxy,
(C.sub.1-C.sub.5)alkoxy, amino, mono-N-- or
di-N,N--(C.sub.1-C.sub.5)alkylamino, cyano, carboxy, or
(C.sub.1-C.sub.4)alkoxycarbonyl; and
[0668] wherein the R.sub.9 rings are optionally mono- or
di-substituted independently on carbon with halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, hydroxy, amino,
mono-N-- or di-N,N--(C.sub.1-C.sub.4)alkylamino, carbamoyl,
(C.sub.1-C.sub.5)alkoxyca- rbonyl or carbamoyl.
[0669] Within the immediately preceding second group of especially
preferred compounds are the compounds wherein
[0670] a. R.sub.1 is 5-chloro;
[0671] R.sub.10 and R.sub.11 are H;
[0672] R.sub.4 is benzyl;
[0673] R.sub.8 is methyl; and
[0674] R.sub.9 is 3-(dimethylamino)propyl;
[0675] b. the stereochemistry of carbon (a) is (S);
[0676] R.sub.1 is 5-chloro;
[0677] R.sub.10 and R.sub.11 are H;
[0678] R.sub.4 is benzyl;
[0679] R.sub.8 is methyl; and
[0680] R.sub.9 is 3-pyridyl;
[0681] c the stereochemistry of carbon (a) is (S);
[0682] R.sub.1 is 5-chloro;
[0683] R.sub.10 and R.sub.11 are H;
[0684] R.sub.4 is benzyl;
[0685] R.sub.8 is methyl; and
[0686] R.sub.9 is 2-hydroxyethyl; and
[0687] d. the stereochemistry of carbon (a) is (S);
[0688] R.sub.1 is 5-fluoro;
[0689] R.sub.10 and R.sub.11 are H;
[0690] R.sub.4 is 4-fluorophenylmethyl;
[0691] R.sub.8 is methyl; and
[0692] R.sub.9 is 2-morpholinoethyl.
[0693] A third group of especially preferred compounds within the
first group of preferred compounds are the compounds wherein
[0694] R.sub.4 is H, phenyl(C.sub.1-C.sub.2)alkyl, thien-2- or
-3-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl
wherein said R4 rings are mono- or di-substituted independently
with H or fluoro;
[0695] R.sub.6 is C(O)NR.sub.8R.sub.9;and
[0696] R.sub.8 is H, (C.sub.1-C.sub.5)alkyl, hydroxy or
(C.sub.1-C.sub.4)alkoxy; and
[0697] R.sub.9 is (C.sub.1-C.sub.4)alkoxy wherein said
(C.sub.1-C.sub.4)alkoxy is optionally substituted with
cyclo(C.sub.4-C.sub.6)alkenyl, phenyl, thienyl, pyridyl,
pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, or
1,1-dioxothiomorpholinyl and wherein said (C.sub.1-C.sub.5)alkyl or
(C.sub.1-C.sub.4)alkoxy is optionally additionally independently
mono- or di-substituted with halo, hydroxy,
(C.sub.1-C.sub.5)alkoxy, amino, mono-N-- or
di-N,N--(C.sub.1-C.sub.5)alkylamino, cyano, carboxy, or
(C.sub.1-C.sub.4)alkoxycarbonyl; and
[0698] wherein the R.sub.9 rings are optionally mono- or
di-substituted independently on carbon with halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, hydroxy, amino,
mono-N-- or di-N,N--(C.sub.1-C.sub.4)alkylamino, carbamoyl,
(C.sub.1-C.sub.5)alkoxyca- rbonyl or carbamoyl.
[0699] Within the immediately preceding third group of especially
preferred compounds are the compounds wherein
[0700] a. R.sub.1 is 5-chloro;
[0701] R.sub.10 and R.sub.11 are H;
[0702] R.sub.4 is benzyl;
[0703] R.sub.8 is methyl; and
[0704] R.sub.9 is 2-hydroxyethoxy;
[0705] b. the stereochemistry of carbon (a) is (S);
[0706] R.sub.1 is 5-chloro;
[0707] R.sub.10 and R.sub.11, are H;
[0708] R.sub.4 is 4-fluorophenylmethyl;
[0709] R.sub.8 is methyl; and
[0710] R.sub.9 is methoxy;
[0711] c. the stereochemistry of carbon (a) is (S);
[0712] R.sub.1 is 5-chloro;
[0713] R.sub.10 and R.sub.11 are H;
[0714] R.sub.4 is benzyl;
[0715] R.sub.8 is methyl; and
[0716] R.sub.9 is methoxy;
[0717] A second group of preferred compounds of Formula IAQ are
those compounds wherein
[0718] R.sub.1 is 5-halo, 5-methyl, 5-cyano or trifluoromethyl;
[0719] R.sub.10 and R.sub.11 are each independently H or halo;
[0720] A is --C(H).dbd.;
[0721] R.sub.2 and R.sub.3 are H;
[0722] R.sub.4 is H, phenyl(C.sub.1-C.sub.2)alkyl, thien-2- or
-3-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl
wherein said rings are mono- or di-substituted independently with H
or fluoro;
[0723] R.sub.5 is H; and
[0724] R.sub.6 is (C.sub.1-C.sub.5)alkoxycarbonyl.
[0725] A third group of preferred compounds of Formula IAQ are
those compounds wherein
[0726] R.sub.1 is 5-halo, 5-methyl, 5-cyano or trifluoromethyl;
[0727] R.sub.10 and R.sub.11 are each independently H or halo;
[0728] A is --C(H).dbd.;
[0729] R.sub.2 and R.sub.3 are H;
[0730] R.sub.4 is H, methyl or phenyl(C.sub.1-C.sub.2)alkyl,
wherein said phenyl groups are mono- or di-substituted
independently with H, halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano
and wherein said phenyl groups are additionally mono- or
di-substituted independently H or halo; or R.sub.4 is thien-2- or
-3-yl(C.sub.1-C.sub.2)alkyl, pyrid-2-, -3- or
-4-yl(C.sub.1-C.sub.2)al- kyl, thiazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, imidazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl,
pyrrol-2- or -3-yl(C.sub.1-C.sub.2)alkyl, oxazol-2-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, pyrazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alk- yl, isoxazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, isothiazol-3-, -4- or
-5-yl(C.sub.1-C.sub.2)alkyl, pyridazin-3- or
-4-yl(C.sub.1-C.sub.2)alkyl, pyrimidin-2-, -4-, -5- or
-6-yl(C.sub.1-C.sub.2)alkyl, pyrazin-2- or
-3-yl(C.sub.1-C.sub.2)alkyl or
1,3,5-triazin-2-yl(C.sub.1-C.sub.2)alkyl wherein said preceding
R.sub.4 heterocycles are optionally mono- or di-substituted
independently with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, amino or hydroxy and said mono- or
di-substituents are bonded to carbon;
[0731] R.sub.5 is H; and
[0732] R.sub.6 is carboxy.
[0733] Within the third group of preferred compounds is a first
group of especially preferred compounds wherein
[0734] R.sub.10 and R.sub.11 are H; and
[0735] R.sub.4 is H.
[0736] Particularly preferred within the immediately preceding
especially preferred group is a compound wherein
[0737] R.sub.1 is 5-chloro.
[0738] Another group of preferred glycogen phosphorylase inhibitors
includes:
[0739] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-((R)-hydroxy-dimethylcar-
bamoyl-methyl)-2-phenyl-ethyl]-amide;
[0740] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-((R)-hydroxy-(methoxy-me-
thyl-carbamoyl)-methyl)-2-phenyl-ethyl]-amide;
[0741] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-3-((3-hydroxy
azetidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide;
[0742] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-((R)-hydroxy-[methyl-(2--
hydroxyethyl)-carbamoyl]-methyl)-2-phenyl-ethyl]-amide;
[0743] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-(2R)-hydroxy-3-((-
3S)-hydroxy-pyrrolidin-1-yl)-3-oxopropyl]-amide;
[0744] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-(2R)-hydroxy
-3-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-3-oxopropyl]-amide;
[0745] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-3-(cis-3,4-dihydr-
oxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide;
[0746] 5-chloro-1H-indole-2-carboxylic acid
[1-benzyl-2-(3-hydroxypyrrolid- in-1-yl)-2-oxo-ethyl]-amide;
[0747] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-(cis-3,4-dihydr-
oxypyrrolidin-1-yl)-2-oxo-ethyl]-amide;
[0748] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-(4-fluorobenzyl-2-(4-hyd-
roxy-piperidin-1-yl)-2-oxo-ethyl]-amide;
[0749] 5-chloro-1H-indole-2-carboxylic acid
(2-oxo-2-thiazolidin-3-yl-ethy- l)-amide;
[0750] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-(3-hydroxy-azet- idin-1-yl)-2-oxo-ethyl]-amide;
[0751] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-(3-hydroxyimino- -azetidin-1-yl)-2-oxo-ethyl]-amide;
and
[0752] 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-2-((3S,4S)-dihydr-
oxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, and the pharmaceutically
acceptable salts, and prodrugs and salts of the prodrugs.
[0753] Any glycogen phosphorylase inhibitor may be used in
combination with a compound of the present invention. Glycogen
phosphorylase inhibition is readily determined by those skilled in
the art according to standard assays (for example, Pesce, et al.
(1977) Clinical Chemistry 23:1711-1717). A variety of glycogen
phosphorylase inhibitors are described above, however, other
glycogen phosphorylase inhibitors will be known to those skilled in
the art (e.g., WO 95/24391-A and those disclosed in U.S. Pat. No.
5,952,363). The following documents also disclose glycogen
phosphorylase inhibitors that can be used in the present invention:
U.S. Pat. No. 5,998,463; Oikanomakos et al., Protein Science, 1999
8(10) 1930-1945, which in particular discloses the compound
3-isopropyl-4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methylpyridine;
WO 9524391; WO 9709040; WO 9840353; WO 9850359; WO 9731901; EP
884050; and Hoover et al., J. Med. Chem., 1998, 41, 2934-2938.
[0754] Moreover, the compounds of the present invention can be
administered in combination with other pharmaceutical agents such
as a cholesterol biosynthesis inhibitor or a cholesterol absorption
inhibitor, especially a HMG-CoA reductase inhibitor, or a HMG-CoA
synthase inhibitor, or a HMG-CoA reductase or synthase gene
expression inhibitor, a CETP inhibitor, a bile acid sequesterant, a
fibrate, an ACAT inhibitors, a squalene synthetase inhibitor, an
anti-oxidant or niacin. The compounds of the present invention may
also be administered in combination with a naturally occurring
compound that act to lower plasma cholesterol levels. Such
naturally occurring compounds are commonly called nutraceuticals
and include, for example, garlic extract and niacin.
[0755] In addition, the compounds of the present invention can be
used in combination with an apolipoprotein B secretion inhibitor
and/or microsomal triglyceride transfer protein (MTP) inhibitor.
Some preferred apolipoprotein B secretion inhibitors and/or MTP
inhibitors are disclosed in commonly assigned U.S. Pat. No.
5,919,795.
[0756] A variety of apo B secretion/MTP inhibitors are known to one
of ordinary skill in the art. Although any apo B secretion/MTP
inhibitor may be used in the practice of the methods and
pharmaceutical compositions of the instant invention, generally
preferred apo B secretion/MTP inhibitors include those compounds
that are disclosed in, for example, European Patent Application
Publication Numbers EP 643057, EP 719763, EP 753517, EP 764647, EP
765878, EP 779276, EP 779279, EP 799828, EP 799829, EP 802186, EP
802188, EP 802192, and EP 802197; PCT Application Publication
Numbers WO 96/13499, WO 96/33193, WO 96/40640, WO 97/26240, WO
97/43255, WO 97/43257, WO 98/16526 and WO 98/23593; and U.S. Pat.
Nos. 5,595,872; 5,646,162; 5,684,014; 5,712,279; 5,739,135 and
5,789,197.
[0757] Especially preferred apo-B secretion/MTP inhibitors are
those biphenyl-2-carboxylic acid-tetrahydroisoquinolin-6-yl amide
derivatives disclosed in PCT Application Publication Numbers WO
96/40640 and WO 98/23593. Especially preferred apo B secretion/MTP
inhibitors disclosed in PCT Application Publication Numbers WO
96/40640 and WO 98/23593, and useful in the methods and
pharmaceutical compositions of the present invention, are
4'-trifluoromethyl-biphenyl-2-carboxylic
acid-[2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquin-6-yl]-am-
ide and 4'-trifluoromethyl-biphenyl-2-carboxyiic
acid-[2-(acetylaminoethyl-
)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.
[0758] Another especially preferred class of apo B secretion/MTP
inhibitors is disclosed in U.S. Pat. Nos. 5,595,872; 5,721,279;
5,739,135 and 5,789,197.
[0759] Especially preferred apo B secretion/MTP inhibitors
disclosed in U.S. Pat. Nos. 5,595,872; 5,721,279; 5,739,135 and
5,789,197 and useful in the methods and pharmaceutical compositions
of the present invention, are
9-(4-{4-[4'trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl-
}-butyl-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide
and
9-{4-[4-(2-benzothiazol-2-yl-benzoylamino)-piperidin-1-yl]-butyl}-9H-fluo-
rene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
[0760] Another class of especially preferred apo B secretion/MTP
inhibitors is disclosed in PCT Application PublicatiQn Number WO
98/16526.
[0761] Especially preferred apo B secretion/MTP inhibitors
disclosed in PCT Application Publication Number WO 98/16526, and
useful in the methods and pharmaceutical compositions of the
present invention, are [11
a-R]-8-[(4-cyanophenyl)methoxy]-2-cyclopentyl-7-(prop-2-enyl)-2,3,11,11
a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione and [11
a-R]-cyclopentoyl-7-(prop-2-enyl)-8-[(pyridin-2-yl)methoxy]-2,3,
11,11 a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione.
[0762] Another especially preferred class of apo B secretion/MTP
inhibitors is disclosed in U.S. Pat. No. 5,684,014.
[0763] An especially preferred apo B secretion/MTP inhibitor
disclosed in U.S. Pat. No. 5,684,014, and useful in the methods and
pharmaceutical compositions of the present invention, is
2-cyclopentyl-2-[4-(2,4-dimethy-
l-pyrido[2,3-b]indol-9-ylmethyl)-phenyl]-N-(2-hydroxy-1-phenyl-ethyl)-acet-
amide.
[0764] Yet another class of especially preferred apo B
secretion/MTP inhibitors is disclosed in U.S. Pat. No.
5,646,162.
[0765] An especially preferred apo B secretion/MTP inhibitor
disclosed in U.S. Pat. No. 5,646,162 and useful in the methods and
pharmaceutical compositions of the present invention, is
2-cyclopentyl-N-(2-hydroxy-1-ph-
enylethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl]-acetamide.
[0766] Additional apo B secretion/MTP inhibitors that can be used
in combination with compounds identified by the present invention
are disclosed in U.S. provisional patent application No.
60/164,803, filed Nov. 11, 1999. Examples of specific preferred apo
B secretion/MTP inhibitors disclosed in this application
include:
[0767] 7-amino-quinoline-3-carboxylic acid ethyl ester;
[0768]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid ethyl ester;
[0769]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid;
[0770]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (dipyridin-2-yl-methyl)-amide;
[0771]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (dipyridin-2-yl-methyl)-amide, ethanesulfonate;
[0772]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (dipyridin-2-yl-methyl)-amide, bis-ethanesulfonate;
[0773]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
[0774]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (phenyl-pyridin-2-yl-methyl)-amide,
ethanesulfonate;
[0775]
(S)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
[0776]
(S)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide,
ethanesulfonate;
[0777]
(S)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide,
bis-ethanesulfonate;
[0778]
(R)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
[0779]
(R)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide,
ethanesulfonate;
[0780]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (phenyl-pyridin-2-yl-methyl)-amide,
bis-ethanesulfonate;
[0781]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (1-carbamoyl-2-phenyl-ethyl)-amide;
[0782]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (carbamoyl-phenyl-methyl)-amide;
[0783]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid propylamide;
[0784]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (2,2,2-trifluoro-ethyl)-amide;
[0785]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (1-methyl-1-phenyl-ethyl)-amide;
[0786]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid cyclopentylamide;
[0787]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (1-phenyl-propyl)-amide;
[0788]
(R)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (1-phenyl-ethyl)-amide, ethanesulfonate;
[0789]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (1-phenyl-ethyl)-amide;
[0790]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (1-pyridin-2-yl-propyl)-amide;
[0791]
(R)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (1-pyridin-2-yl-propyl)-amide;
[0792]
(R)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (1-pyridin-2-yl-propyl)-amide, ethanesulfonate;
[0793]
(S)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (1-pyridin-2-yl-propyl)-amide;
[0794]
(S)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (1-pyridin-2-yl-propyl)-amide ethanesulfonate;
[0795]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (1-pyridin-2-yl-propyl)-amide, ethanesulfonate;
[0796]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (pyridin-2-ylmethyl)-amide, ethanesulfonate;
[0797]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (2-pyridin-2-yl-ethyl)-amide, ethanesulfonate;
[0798]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid ethylamide, ethanesulfonate;
[0799]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid butylamide, ethanesulfonate;
[0800]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (thiophen-2-ylmethyl)-amide, ethanesulfonate;
[0801]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;
[0802]
(S)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
[0803]
(R)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3--
carboxylic acid (1-pyridin-2-yl-ethyl)-amide ethanesulfonate;
[0804]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (1-pyridin-2-yl-ethyl)-amide;
[0805]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid (1-pyridin-2-yl-ethyl)-amide ethanesulfonate;
[0806]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid amide;
[0807]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid benzylamide;
[0808]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 4-methoxy-benzylamide;
[0809]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 4-chloro-benzylamide;
[0810]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 4-methyl-benzylamide;
[0811]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid cyclopropylmethyl-amide;
[0812]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 4-fluoro-benzylamide;
[0813]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid isopropyl-amide;
[0814]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid benzhydryl-amide;
[0815]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid cyclopropylamide;
[0816]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid [1-(4-fluoro-phenyl)-ethyl]-amide;
[0817]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 3-methyl-benzylamide;
[0818]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 3-methoxy-benzylamide;
[0819]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 3-chloro-benzylamide;
[0820]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 2-fluoro-benzylamide;
[0821]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 3-fluoro-benzylamide;
[0822]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 2-methyl-benzylamide;
[0823]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 2-methoxy-benzylamide;
[0824]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid 2-chloro-benzylamide;
[0825] 4'-trifluoromethyl-biphenyl-2-carboxylic acid
[3-(pyrrolidine-1-carbonyl)-quinolin-7-yl]-amide;
[0826] 4'-trifluoromethyl-biphenyl-2-carboxylic acid
[3-(morpholine-4-carbonyl)-quinolin-7-yl]-amide;
[0827]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid diethylamide;
[0828] 4'-trifluoromethyl-biphenyl-2-carboxylic acid
[3-(piperidine-1-carbonyl)-quinolin-7-yl]-amide; and
pharmaceutically acceptable salts and prodrugs thereof, and salts
of the prodrugs.
[0829] Specific cholesterol absorption inhibitors and cholesterol
biosynthesis inhibitors are described in detail below. Additional
cholesterol absorption inhibitors are known to those skilled in the
art and are described, for example, in WO 94/00480.
[0830] Any HMG-CoA reductase inhibitor may be employed as an
additional compound in the combination therapy aspect of the
present invention. The term HMG-CoA reductase inhibitor refers to a
compound that inhibits the biotransformation of
hydroxymethylglutaryl-coenzyme A to mevalonic acid as catalyzed by
the enzyme HMG-CoA reductase. Such inhibition may be determined
readily by one of skill in the art according to standard assays
(e.g., Methods of Enzymology, 71: 455-509 (1981); and the
references cited therein). A variety of these compounds are
described and referenced below. U.S. Pat. No. 4,231,938 discloses
certain compounds isolated after cultivation of a microorganism
belonging to the genus Aspergillus, such as lovastatin. Also, U.S.
Pat. No. 4,444,784 discloses synthetic derivatives of the
aforementioned compounds, such as simvastatin. Additionally, U.S.
Pat. No. 4,739,073 discloses certain substituted indoles, such as
fluvastatin. Further, U.S. Pat. No. 4,346,227 discloses ML-236B
derivatives, such as pravastatin. In addition, EP 491,226 teaches
certain pyridyldihydroxyheptenoic acids, such as rivastatin. Also,
U.S. Pat. No. 4,647,576 discloses certain
6-[2-(substituted-pyrrol-1-yl)-alkyl]-pyran-2-ones such as
atorvastatin. Other HMG-CoA reductase inhibitors will be known to
those skilled in the art. Examples of marketed products containing
HMG-CoA reductase inhibitors include Baycol.RTM., Lescol.RTM.,
Lipitor.RTM., Mevacor.RTM., Pravachol.RTM. and Zocor.RTM..
[0831] Any HMG-CoA synthase inhibitor may be used as an additional
compound in the combination therapy aspect of this invention. The
term HMG-CoA synthase inhibitor refers to a compound that inhibits
the biosynthesis of hydroxymethylglutaryl-coenzyme A from
acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the
enzyme HMG-CoA synthase. Such inhibition may be determined readily
by one of skill in the art according to standard assays (e.g.,
Methods of Enzymology, 35: 155-160 (1975); and Methods of
Enzymology, 110: 19-26 (1985); and the references cited therein). A
variety of these compounds are described and referenced below. U.S.
Pat. No. 5,120,729 discloses certain beta-lactam derivatives. U.S.
Pat. No. 5,064,856 discloses certain spiro-lactone derivatives
prepared by culturing the microorganism MF5253. U.S. Pat. No.
4,847,271 discloses certain oxetane compounds such as
11-(3-hydroxymethyl-4-oxo-2-o-
xetayl)-3,5,7-trimethyl-2,4-undecadienoic acid derivatives. Other
HMG-CoA synthase inhibitors useful in the methods, compositions and
kits of the present invention will be known to those skilled in the
art.
[0832] Any compound that decreases HMG-CoA reductase gene
expression may be used as an additional compound in the combination
therapy aspect of this invention. These agents may be HMG-CoA
reductase transcription inhibitors that block the transcription of
DNA or translation inhibitors that prevent translation of mRNA
coding for HMG-CoA reductase into protein. Such inhibitors may
either affect transcription or translation directly, or may be
biotransformed into compounds that have the aforementioned
attributes by one or more enzymes in the cholesterol biosynthetic
cascade or may lead to the accumulation of an isoprene metabolite
that has the aforementioned activities. Such regulation is readily
determined by those skilled in the art according to standard assays
(Methods of Enzymology, 110: 9-19 1985). Several such compounds are
described and referenced below; however, other inhibitors of
HMG-CoA reductase gene expression will be known to those skilled in
the art, for example, U.S. Pat. No. 5,041,432 discloses certain
15-substituted lanosterol derivatives that are inhibitors of
HMG-CoA reductase gene expression. Other oxygenated sterols that
suppress the biosynthesis of HMG-CoA reductase are discussed by
E.I. Mercer (Prog. Lip. Res., 32:357-416 1993).
[0833] Any compound having activity as a CETP inhibitor can serve
as the second compound in the combination therapy aspect of the
instant invention. The term CETP inhibitor refers to compounds that
inhibit the cholesteryl ester transfer protein (CETP) mediated
transport of various cholesteryl esters and triglycerides from HDL
to LDL and VLDL. A variety of these compounds are described and
referenced below; however, other CETP inhibitors will be known to
those skilled in the art. U.S. Pat. No. 5,512,548 discloses certain
polypeptide derivatives having activity as CETP inhibitors, while
certain CETP-inhibitory rosenonolactone derivatives and
phosphate-containing analogs of cholesteryl ester are disclosed in
J. Antibiot, 49(8): 815-816 (1996), and Bioorg. Med. Chem. Lett.;
6:1951-1954 (1996), respectively.
[0834] Preferred CETP inhibitors that can be used in combination
with a compound of the present invention include those described
below in U.S. patent application Ser. No. 09/391,152, filed Sep. 7,
1999.
[0835] [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0836] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0837] [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid 2-hydroxy-ethyl ester;
[0838] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester;
[0839] [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester;
[0840] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid propyl ester; and
[0841] [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid propyl ester,
[0842] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0843] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester;
[0844] [2S,4S]
2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amin-
o]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester;
[0845] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid tert-butyl ester;
[0846] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0847] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0848] [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0849] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0850] [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid 2-hydroxy-ethyl ester;
[0851] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester;
[0852] [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester;
[0853] [2S,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid propyl ester; and
[0854] [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid propyl ester, and pharmaceutically acceptable salts and
prodrugs thereof and salts of the prodrugs.
[0855] Any ACAT inhibitor can serve as an additional compound in
the combination therapy aspect of this invention. The term ACAT
inhibitor refers to a compound that inhibits the intracellular
esterification of dietary cholesterol by the enzyme acyl CoA:
cholesterol acyltransferase. Such inhibition may be determined
readily by one of skill in the art according to standard assays,
such as the method of Heider et al. described in Journal of Lipid
Research., 24:1127 (1983). A variety of these compounds are
described and referenced below; however, other ACAT inhibitors will
be known to those skilled in the art. U.S. Pat. No. 5,510,379
discloses certain carboxysulfonates, while WO 96/26948 and WO
96/10559 both disclose urea derivatives having ACAT inhibitory
activity.
[0856] Any compound having activity as a squalene synthetase
inhibitor can serve as an additional compound in the combination
therapy aspect of the instant invention. The term squalene
synthetase inhibitor refers to compounds that inhibit the
condensation of two molecules of farnesylpyrophosphate to form
squalene, a reaction that is catalyzed by the enzyme squalene
synthetase. Such inhibition is readily determined by those skilled
in the art according to standard methodology (Methods of
Enzymology, 15:393-454 (1969); and Methods of Enzymology, 110:
359-373 (1985); and references cited therein). A summary of
squalene synthetase inhibitors has been complied in Curr. Op. Ther.
Patents, 861-4, (1993). European patent application publication
Number 0 567 026 A1 discloses certain 4,1-benzoxazepine derivatives
as squalene synthetase inhibitors and their use in the treatment of
hypercholesterolemia and as fungicides. European patent application
publication Number 0 645 378 A1 discloses certain seven- or
eight-membered heterocycles as squalene synthetase inhibitors and
their use in the treatment and prevention hypercholesterolemia and
fungal infections. European patent application publication Number 0
645 377 A1 discloses certain benzoxazepine derivatives as squalene
synthetase inhibitors useful for the treatment of
hypercholesterolemia or coronary sclerosis. European patent
application publication Number 0 611 749 Al discloses certain
substituted amic acid derivatives useful for the treatment of
arteriosclerosis. European patent application publication Number 0
705 607 A2 discloses certain condensed seven- or eight-membered
heterocyclic compounds useful as antihypertriglyceridemic agents.
PCT publication WO 96/09827 discloses certain combinations of
cholesterol absorption inhibitors and cholesterol biosynthesis
inhibitors including benzoxazepine derivatives and benzothiazepine
derivatives. European patent application publication Number 0 701
725 A1 discloses a process for preparing certain optically-active
compounds, including benzoxazepine derivatives, having plasma
cholesterol and triglyceride lowering activities.
[0857] Other compounds that are marketed for hyperlipidemia,
including hypercholesterolemia, and which are intended to help
prevent or treat atherosclerosis, include bile acid sequestrants,
such as Colestid.RTM., LoCholest.RTM. and Questran.RTM.; and fibric
acid derivatives, such as Atromid.RTM., Lopid.RTM., and
Tricor.RTM.. These compounds can also be used in combination with a
compound of the present invention.
[0858] It is also contemplated that the compounds of the present
invention be administered with a lipase inhibitor and/or a
glucosidase inhibitor, which are typically used in the treatment of
conditions resulting from the presence of excess triglycerides,
free fatty acids, cholesterol, cholesterol esters or glucose
including, inter alia, obesity, hyperlipidemia,
hyperlipoproteinemia, Syndrome X, and the like.
[0859] In a combination with a compound of the present invention,
any lipase inhibitor or glucosidase inhibitor may be employed.
Preferred lipase inhibitors comprise gastric or pancreatic lipase
inhibitors. Preferred glucosidase inhibitors comprise amylase
inhibitors.
[0860] A lipase inhibitor is a compound that inhibits the metabolic
cleavage of dietary triglycerides into free fatty acids and
monoglycerides. Under normal physiological conditions, lipolysis
occurs via a two-step process that involves acylation of an
activated serine moiety of the lipase enzyme. This leads to the
production of a fatty acid-lipase hemiacetal intermediate, which is
then cleaved to release a diglyceride. Following further
deacylation, the lipase-fatty acid intermediate is cleaved,
resulting in free lipase, a monoglyceride and a fatty acid. The
resultant free fatty acids and monoglycerides are incorporated into
bile acid-phospholipid micelles, which are subsequently absorbed at
the level of the brush border of the small intestine. The micelles
eventually enter the peripheral circulation as chylomicrons.
Accordingly, compounds, including lipase inhibitors that
selectively limit or inhibit the absorption of ingested fat
precursors are useful in the treatment of conditions including
obesity, hyperlipidemia, hyperlipoproteinemia, Syndrome X, and the
like.
[0861] Pancreatic lipase mediates the metabolic cleavage of fatty
acids from triglycerides at the 1- and 3-carbon positions. The
primary site of the metabolism of ingested fats is in the duodenum
and proximal jejunum by pancreatic lipase, which is usually
secreted in vast excess of the amounts necessary for the breakdown
of fats in the upper small intestine. Because pancreatic lipase is
the primary enzyme required for the absorption of dietary
triglycerides, inhibitors have utility in the treatment of obesity
and the other related conditions.
[0862] Gastric lipase is an immunologically distinct lipase that is
responsible for approximately 10 to 40% of the digestion of dietary
fats. Gastric lipase is secreted in response to mechanical
stimulation, ingestion of food, the presence of a fatty meal or by
sympathetic agents. Gastric lipolysis of ingested fats is of
physiological importance in the provision of fatty acids needed to
trigger pancreatic lipase activity in the intestine and is also of
importance for fat absorption in a variety of physiological and
pathological conditions associated with pancreatic insufficiency.
See, for example, C. K. Abrams, et al., Gastroenterology, 92, 125
(1987).
[0863] A variety of lipase inhibitors are known to one of ordinary
skill in the art. However, in the practice of the methods,
pharmaceutical compositions, and kits of the instant invention,
generally preferred lipase inhibitors are those inhibitors that are
selected from the group consisting of lipstatin,
tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176,
valilactone, esterastin, ebelactone A, ebelactone B and RHC
80267.
[0864] The pancreatic lipase inhibitors lipstatin, 2S, 3S, 5S, 7Z,
10Z)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-7,
10-hexadecanoic acid lactone, and tetrahydrolipstatin (orlistat),
2S, 3S,
5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoi-
c acid lactone, and the variously substituted N-formylleucine
derivatives and stereoisomers thereof, are disclosed in U.S. Pat.
No. 4,598,089.
[0865] The pancreatic lipase inhibitor FL-386,
1-[4-(2-methylpropyl)cycloh-
exyl]-2-[(phenylsulfonyl)oxy]-ethanone, and the variously
substituted sulfonate derivatives related thereto, are disclosed in
U.S. Pat. No. 4,452,813.
[0866] The pancreatic lipase inhibitor WAY-121898,
4-phenoxyphenyl-4-methy- lpiperidin-1-yl-carboxylate, and the
various carbamate esters and pharmaceutically acceptable salts
related thereto, are disclosed in U.S. Pat. Nos. 5,512,565;
5,391,571 and 5,602,151.
[0867] The lipase inhibitor Bay-N-3176,
N-3-trifluoromethylphenyl-N'-3-chl-
oro-4'-trifluoromethylphenylurea, and the various urea derivatives
related thereto, are disclosed in U.S. Pat. No. 4,405,644.
[0868] The pancreatic lipase inhibitor valilactone, and a process
for the preparation thereof by the microbial cultivation of
Actinomycetes strain MG147-CF2, are disclosed in Kitahara, et al.,
J. Antibiotics, 40 (11), 1647-1650 (1987).
[0869] The lipase inhibitor esteracin, and certain processes for
the preparation thereof by the microbial cultivation of
Streptomyces strain ATCC 31336, are disclosed in U.S. Pat. Nos.
4,189,438 and 4,242,453.
[0870] The pancreatic lipase inhibitors ebelactone A and ebelactone
B, and a process for the preparation thereof by the microbial
cultivation of Actinomycetes strain MG7-G1, are disclosed in
Umezawa, et al., J. Antibiotics, 33, 1594-1596 (1980). The use of
ebelactones A and B in the suppression of monoglyceride formation
is disclosed in Japanese Kokai 08-143457, published Jun. 4,
1996.
[0871] The lipase inhibitor RHC 80267,
cyclo-O,O'-[(1,6-hexanediyl)-bis-(i- minocarbonyl)]dioxime, and the
various bis(iminocarbonyl)dioximes related thereto may be prepared
as described in Petersen et al., Liebig's Annalen, 562, 205-229
(1949). The ability of RHC 80267 to inhibit the activity of
myocardial lipoprotein lipase is disclosed in Carroll et al.,
Lipids, 27, pp. 305-307 (1992) and Chuang et al., J. Mol. Cell
Cardiol., 22, 1009-1016 (1990).
[0872] A glucosidase inhibitor inhibits the enzymatic hydrolysis of
complex carbohydrates by glycoside hydrolases, for example amylase
or maltase, into bioavailable simple sugars, for example, glucose.
The rapid metabolic action of glucosidases, particularly following
the intake of high levels of carbohydrates, results in a state of
alimentary hyperglycemia which, in adipose or diabetic subjects,
leads to enhanced secretion of insulin, increased fat synthesis and
a reduction in fat degradation. Following such hyperglycemias,
hypoglycemia frequently occurs, due to the augmented levels of
insulin present. Additionally, it is known that both hypoglycemias
and chyme remaining in the stomach promotes the production of
gastric juice, which initiates or favors the development of
gastritis or duodenal ulcers. Accordingly, glucosidase inhibitors
are known to have utility in accelerating the passage of
carbohydrates through the stomach and inhibiting the absorption of
glucose from the intestine. Furthermore, the conversion of
carbohydrates into lipids of the fatty tissue and the subsequent
incorporation of alimentary fat into fatty tissue deposits is
accordingly reduced or delayed, with the concomitant benefit of
reducing or preventing the deleterious abnormalities resulting
therefrom.
[0873] In combination with a compound of the present invention, any
glucosidase inhibitor may be employed; however, a generally
preferred glucosidase inhibitor comprises an amylase inhibitor. An
amylase inhibitor is a glucosidase inhibitor that inhibits the
enzymatic degradation of starch or glycogen into maltose. The
inhibition of such enzymatic degradation is beneficial in reducing
amounts of bioavailable sugars, including glucose and maltose, and
the concomitant deleterious conditions resulting therefrom.
[0874] A variety of glucosidase and amylase inhibitors are known to
one of ordinary skill in the art. However, in the practice of the
methods, pharmaceutical compositions and kits of the instant
invention, generally preferred glucosidase inhibitors are those
inhibitors that are selected from the group consisting of acarbose,
adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose,
tendamistate, AI-3688, trestatin, pradimicin-Q and salbostatin.
[0875] The glucosidase inhibitor acarbose,
O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-
-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]-.alpha.-gluco-
pyranosyl-(1.fwdarw.4)--O-.alpha.-D-glucopyranosyl-(1.fwdarw.4)-D-glucose,
the various amino sugar derivatives related thereto and a process
for the preparation thereof by the microbial cultivation of
Actinoplanes strains SE 50 (CBS 961.70), SB 18 (CBS 957.70), SE 82
(CBS 615.71), SE 50/13 (614.71) and SE 50/110 (674.73) are
disclosed in U.S. Pat. Nos. 4,062,950 and 4,174,439
respectively.
[0876] The glucosidase inhibitor adiposine, consisting of adiposine
forms 1 and 2, is disclosed in U.S. Pat. No. 4,254,256.
Additionally, a process for the preparation and purification of
adiposine is disclosed in Namiki et al., J Antiobiotics, 35,
1234-1236 (1982).
[0877] The glucosidase inhibitor voglibose,
3,4-dideoxy-4-[[2-hydroxy-1-(h-
ydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositol, and
the various N-substituted pseudo-aminosugars related thereto, are
disclosed in U.S. Pat. No. 4,701,559.
[0878] The glucosidase inhibitor miglitol,
(2R,3R,4R,5S)-1-(2-hydroxyethyl-
)-2-(hydroxymethyl)-3,4,5-piperidinetriol, and the various
3,4,5-trihydroxypiperidines related thereto, are disclosed in U.S.
Pat. No. 4,639,436.
[0879] The glucosidase inhibitor emiglitate, ethyl
p-[2-[(2R,3R,4R,5S)-3,4-
,5-trihydroxy-2-(hydroxymethyl)piperidino]ethoxy]-benzoate, the
various derivatives related thereto and pharmaceutically acceptable
acid addition salts thereof, are disclosed in U.S. Pat. No.
5,192,772.
[0880] The glucosidase inhibitor MDL-25637,
2,6-dideoxy-7-O-.beta.-D-gluco-
pyrano-syl-2,6-imino-D-glycero-L-gluco-heptitol, the various
homodisaccharides related thereto and the pharmaceutically
acceptable acid addition salts thereof, are disclosed in U.S. Pat.
No. 4,634,765.
[0881] The glucosidase inhibitor camiglibose, methyl
6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-.a-
lpha.-D-glucopyranoside sesquihydrate, the deoxy-nojirimycin
derivatives related thereto, the various pharmaceutically
acceptable salts thereof and synthetic methods for the preparation
thereof, are disclosed in U.S. Pat. Nos. 5,157,116 and
5,504,078.
[0882] The amylase inhibitor tendamistat, the various cyclic
peptides related thereto and processes for the preparation thereof
by the microbial cultivation of Streptomyces tendae strains 4158 or
HAG 1226, are disclosed in U.S. Pat. No. 4,451,455.
[0883] The amylase inhibitor AI-3688, the various cyclic
polypeptides related thereto, and a process for the preparation
thereof by the microbial cultivation of Streptomyces aureofaciens
strain FH 1656, are disclosed in U.S. Pat. No. 4,623,714.
[0884] The amylase inhibitor trestatin, consisting of a mixture of
trestatin A, trestatin B and trestatin C, the various
trehalose-containing aminosugars related thereto and a process for
the preparation thereof by the microbial cultivation of
Streptomyces dimorphogenes strains NR-320-OM7HB and NR-320-OM7HBS,
are disclosed in U.S. Pat. No. 4,273,765.
[0885] The glucosidase inhibitor pradimicin-Q and a process for the
preparation thereof by the microbial cultivation of Actinomadura
verrucospora strains R103-3 or A10102, are disclosed in U.S. Pat.
Nos. 5,091,418 and 5,217,877 respectively.
[0886] The glycosidase inhibitor salbostatin, the various
pseudosaccharides related thereto, the various pharmaceutically
acceptable salts thereof and a process for the preparation thereof
by the microbial cultivation of Streptomyces albus strain ATCC
21838, are disclosed in U.S. Pat. No. 5,091,524.
[0887] Preferred lipase inhibitors comprise compounds selected from
the group consisting of lipstatin, tetrahydrolipstatin, FL-386,
WAY-121898, Bay-n-3176, valilactone, esteracin, ebelactone A,
ebelactone B, RHC 80267, stereoisomers thereof, and
pharmaceutically acceptable salts of said compounds and
stereoisomers. The compound tetrahydrolipstatin is especially
preferred.
[0888] Preferred glucosidase inhibitors comprise compounds selected
from the group consisting of acarbose, adiposine, voglibose,
miglitol, emiglitate, MDL-25637, camiglibose, pradimicin-Q, and
salbostatin. An especially preferred glucosidase inhibitor is
acarbose. Especially preferred glucosidase inhibitors further
comprise amylase inhibitors that are selected from the group
consisting of tendamistate, Al-3688 and trestatin.
[0889] In another aspect of the present invention, the compounds of
Formula I can be used in combination with an additional
anti-obesity agent. The additional anti-obesity agent is preferably
selected from the group consisting of a .beta..sub.3-adrenergic
receptor agonist, a cholecystokinin-A agonist, a monoamine reuptake
inhibitor, a sympathomimetic agent, a serotoninergic agent, a
dopamine agonist, a melanocyte-stimulating hormone receptor agonist
or mimetic, a melanocyte-stimulating hormone receptor analog, a
cannabinoid receptor antagonist, a melanin concentrating hormone
antagonist, leptin, a leptin analog, a leptin receptor agonist, a
galanin antagonist, a lipase inhibitor, a bombesin agonist, a
neuropeptide-Y antagonist, a thyromimetic agent,
dehydroepiandrosterone or an analog thereof, a glucocorticoid
receptor agonist or antagonist, an orexin receptor antagonist, a
urocortin binding protein antagonist, a glucagon-like peptide-1
receptor agonist, and a ciliary neurotrophic factor.
[0890] Especially preferred anti-obesity agents comprise those
compounds selected from the group consisting of sibutramine,
fenfluramine, dexfenfluramine, bromocriptine, phentermine,
ephedrine, leptin, phenylpropanolamine
[0891] pseudoephedrine,
{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylam-
ino)ethoxy]phenyl}acetic acid,
{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxy-
ethylamino)ethoxy]phenyl}benzoic acid,
{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-
-hydroxyethylamino)ethoxy]phenyl}propionic acid, and
{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenoxy}acet-
ic acid.
[0892] The compounds of the present invention can also be used in
combination with an antihypertensive agent. Examples of presently
marketed products containing antihypertensive agents include
calcium channel blockers, such as Cardizem.RTM., Adalat.RTM.,
Calan.RTM., Cardene.RTM., Covera.RTM., Dilacor.RTM., DynaCirc.RTM.,
Procardia XL.RTM., Sular.RTM., Tiazac.RTM., Vascor.RTM.,
Verelan.RTM., Isoptin.RTM., Nimotop.RTM., Norvasc.RTM., and
Plendil.RTM.; angiotensin converting enzyme (ACE) inhibitors, such
as Accupril.RTM., Altace.RTM., Captopril.RTM., Lotensin.RTM.,
Mavik.RTM., Monopril.RTM., Prinivil.RTM., Univasc.RTM.,
Vasotec.RTM. and Zestril.RTM.. In addition, diuretics and
combinations of the above antihypertensive agents have been
employed and are contemplated to be used in combination with a
compound of the present invention.
[0893] The compounds of the present invention can also be used in
combination with an antidepressant. Examples of marketed
antidepressants that can be used in combination with a compound of
the present invention include monoamine oxidase inhibitors such as
Nardil.RTM. and Parnate.RTM.; selective seratonin reuptake
inhibitors, such as Paxil.RTM., Prozac.RTM., and Zoloft.RTM.;
triclyclics, such as Asendin.RTM., Elavil.RTM., Etrafon.RTM.,
Limbitrol.RTM., Norpramin.RTM. Pamelor.RTM., Sinequan.RTM.,
Surmontil.RTM., Tofranil.RTM., Triavil.RTM., and Vivactil.RTM..
Additional compounds that are used to treat depression and that can
be used in combination with a compound of the present invention
include Desyrel.RTM., Effexor.RTM., Remeron.RTM., Serzone.RTM., and
Wellbutrin.RTM..
[0894] The compounds of the present invention can also be used in
combination with a compound useful to treat osteoporosis. Examples
of marketed products containing active agents that can be used in
combination with a compound of the present invention include
biphosphonates such as Fosamax.RTM. and hormonal agents such as
calcitonin and estrogens. In addition, Evista.RTM. may be used in
combination with a compound of the present invention.
[0895] The compounds of the present invention are administered to a
patient in a therapeutically effective amount. The compounds can be
administered alone or as part of a pharmaceutically acceptable
composition. In addition, the compounds or compositions can be
administered all at once, as for example, by a bolus injection,
multiple times, such as by a series of tablets, or delivered
substantially uniformly over a period of time, as for example,
using transdermal delivery. It is also noted that the dose of the
compound can be varied over time.
[0896] In addition, the compounds of the present invention can be
administered alone, in combination with other compounds of the
present invention, or with other pharmaceutically active compounds.
The other pharmaceutically active compounds can be intended to
treat the same disease or condition as the compounds of the present
invention or a different disease or condition. If the patient is to
receive or is receiving multiple pharmaceutically active compounds,
the compounds can be administered simultaneously, or sequentially
in any order. For example, in the case of tablets, the active
compounds may be found in one tablet or in separate tablets, which
can be administered at once or sequentially. In addition, it should
be recognized that the compositions may be different forms. For
example, one or more compounds may be delivered via a tablet, while
another is administered via injection or orally as a syrup. All
combinations, delivery methods and administration sequences are
contemplated.
[0897] Since one aspect of the present invention contemplates the
treatment of the disease/conditions with a combination of
pharmaceutically active agents that may be administered separately,
the invention further relates to combining separate pharmaceutical
compositions in kit form. The kit comprises two separate
pharmaceutical compositions: a compound of the present invention, a
prodrug thereof, or a salt of such compound or prodrug; and an
additional pharmaceutically active compound. The kit comprises a
container for containing the separate compositions, such as a
divided bottle or a divided foil packet. Additional examples of
containers include syringes, boxes, bags, and the like. Typically,
the kit comprises directions for the administration of the separate
components. The kit form is particularly advantageous when the
separate components are preferably administered in different dosage
forms (e.g., oral and parenteral), are administered at different
dosage intervals, or when titration of the individual components of
the combination is desired by the prescribing physician.
[0898] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed via said opening.
[0899] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen that
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card,
e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . .
Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a
single tablet or capsule or several pills or capsules to be taken
on a given day. Also, a daily dose of compounds of the present
invention can consist of one tablet or capsule, while a daily dose
of the second compound can consist of several tablets or capsules
and vice versa. The memory aid should reflect this and aid in
correct administration of the active agents.
[0900] In another specific embodiment of the invention, a dispenser
designed to dispense the daily doses one at a time in the order of
their intended use is provided. Preferably, the dispenser is
equipped with a memory-aid, so as to further facilitate compliance
with the regimen. An example of such a memory-aid is a mechanical
counter which indicates the number of daily doses that has been
dispensed. Another example of such a memory-aid is a
battery-powered micro-chip memory coupled with a liquid crystal
readout, or audible reminder signal which, for example, reads out
the date that the last daily dose has been taken and/or reminds one
when the next dose is to be taken.
[0901] The compounds of the present invention and other
pharmaceutically active agents, if desired, can be administered to
a patient either orally, rectally, parenterally, (for example,
intravenously, intramuscularly, or subcutaneously)
intracisternally, intravaginally, intraperitoneally,
intravesically, locally (for example, powders, ointments or drops),
or as a buccal or nasal spray.
[0902] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions, or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles include water, ethanol, polyols (propylene
glycol, polyethylene glycol, glycerol, and the like), suitable
mixtures thereof, vegetable oils (such as olive oil) and injectable
organic esters such as ethyl oleate. Proper fluidity can be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0903] These compositions may also contain adjuvants such as
preserving, wetting, emulsifying, and dispersing agents. Prevention
of microorganism contamination of the compositions can be
accomplished with various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the
like. It may also be desirable to include isotonic agents, for
example, sugars, sodium chloride, and the like. Prolonged
absorption of injectable pharmaceutical compositions can be brought
about by the use of agents capable of delaying absorption, for
example, aluminum monostearate and gelatin.
[0904] Solid dosage forms for oral administration include capsules,
tablets, powders, and granules. In such solid dosage forms, the
active compound is admixed with at least one inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, mannitol, and silicic acid; (b) binders, as for
example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for
example, glycerol; (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain complex silicates, and sodium carbonate; (e) solution
retarders, as for example, paraffin; (f) absorption accelerators,
as for example, quaternary ammonium compounds; (g) wetting agents,
as for example, cetyl alcohol and glycerol monostearate; (h)
adsorbents, as for example, kaolin and bentonite; and/or (i)
lubricants, as for example, talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, or
mixtures thereof. In the case of capsules and tablets, the dosage
forms may also comprise buffering agents.
[0905] Solid compositions of a similar type may also be used as
fillers in soft or hard filled gelatin capsules using such
excipients as lactose or milk sugar, as well as high molecular
weight polyethylene glycols, and the like.
[0906] Solid dosage forms such as tablets, dragees, capsules, and
granules can be prepared with coatings and shells, such as enteric
coatings and others well known in the art. They may also contain
opacifying agents, and can also be of such composition that they
release the active compound or compounds in a delayed manner.
Examples of embedding compositions that can be used are polymeric
substances and waxes. The active compounds can also be in
micro-encapsulated form, if appropriate, with one or more of the
above-mentioned excipients.
[0907] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the active compounds, the
liquid dosage form may contain inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents and
emulsifiers, as for example, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in
particular, cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan, or
mixtures of these substances, and the like.
[0908] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0909] Suspensions, in addition to the active compound, may contain
suspending agents, as for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, or mixtures of these substances, and the like.
[0910] Compositions for rectal or vaginal administration are
preferably suppositories, which can be prepared by mixing a
compound of the present invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or
a suppository wax, which are solid at ordinary room temperature,
but liquid at body temperature, and therefore, melt in the rectum
or vaginal cavity and release the active component.
[0911] Dosage forms for topical administration of a compound of the
present invention include ointments, powders, sprays and inhalants.
The active compound or compounds are admixed under sterile
condition with a physiologically acceptable carrier, and any
preservatives, buffers, or propellants that may be required.
Opthalmic formulations, eye ointments, powders, and solutions are
also contemplated as being within the scope of this invention.
[0912] The compounds of the present invention can be administered
to a patient at dosage levels in the range of about 0.7 to about
7,000 mg per day. For a normal adult human having a body weight of
about 70 kg, a dosage in the range of about 0.01 to about 100 mg
per kilogram body weight is typically sufficient. The specific
dosage and dosage range that can be used depends on a number of
factors, including the requirements of the patient, the severity of
the condition or disease being treated, and the pharmacological
activity of the compound being administered. The determination of
dosage ranges and optimal dosages for a particular patient is well
within the ordinary skill in the art in view of this disclosure. It
is also noted that the compounds of the present invention can be
used in sustained release, controlled release, and delayed release
formulations, which are well known in the art.
[0913] The following paragraphs describe exemplary formulations,
dosages, etc. useful for non-human animals. The administration of a
compound of the present invention can be effected orally or
non-orally, for example by injection. An amount of a compound of
the present invention is administered such that an effective dose
is received, generally a daily dose which, when administered orally
to an animal is usually between 0.01 and 100 mg/kg of body weight,
preferably between 0.1 and 50 mg/kg of body weight. Conveniently,
the compound can be carried in the drinking water so that a
therapeutic dosage of the compound is ingested with the daily water
supply. The compound can be directly metered into drinking water,
preferably in the form of a liquid, water-soluble concentrate (such
as an aqueous solution of a water soluble salt). Conveniently, the
compound can also be added directly to the feed, as such, or in the
form of an animal feed supplement, also referred to as a premix or
concentrate. A premix or concentrate of the compound in a carrier
is more commonly employed for the inclusion of the agent in the
feed. Suitable carriers are liquid or solid, as desired, such as
water, various meals such as alfalfa meal, soybean meal, cottonseed
oil meal, linseed oil meal, corncob meal and corn meal, molasses,
urea, bone meal, and mineral mixes such as are commonly employed in
poultry feeds. A particularly effective carrier is the respective
animal feed itself; that is, a small portion of such feed. The
carrier facilitates uniform distribution of the compound in the
finished feed with which the premix is blended. It is important
that the compound be thoroughly blended into the premix and,
subsequently, the feed. In this respect, the compound may be
dispersed or dissolved in a suitable oily vehicle such as soybean
oil, corn oil, cottonseed oil, and the like, or in a volatile
organic solvent and then blended with the carrier. It will be
appreciated that the proportions of compound in the concentrate are
capable of wide variation since the amount of active compound in
the finished feed may be adjusted by blending the appropriate
proportion of premix with the feed to obtain a desired level of
compound.
[0914] High potency concentrates may be blended by the feed
manufacturer with proteinaceous carrier such as soybean oil meal
and other meals, as described above, to produce concentrated
supplements, which are suitable for direct feeding to animals. In
such instances, the animals are permitted to consume the usual
diet. Alternatively, such concentrated supplements may be added
directly to the feed to produce a nutritionally balanced, finished
feed containing a therapeutically effective level of a compound of
the present invention. The mixtures are thoroughly blended by
standard procedures, such as in a twin shell blender, to ensure
homogeneity.
[0915] If the supplement is used as a top dressing for the feed, it
likewise helps to ensure uniformity of distribution of the compound
across the top of the dressed feed.
[0916] Preferred medicated swine, cattle, sheep and goat feeds
generally contain from about 1 to about 400 grams of a compound of
the present invention per ton of feed, the optimum amount for these
animals usually being about 50 to about 300 grams per ton of
feed.
[0917] Preferred poultry and domestic pet feeds usually contain
about 1 to about 400 grams and preferably about 10 to about 400
grams of a compound of the present invention per ton of feed.
[0918] For parenteral administration in animals, the compounds of
the present invention may be prepared in the form of a paste or a
pellet and administered as an implant, usually under the skin of
the head or ear of the animal.
[0919] In general, parenteral administration involves injection of
a sufficient amount of a compound of the present invention to
provide the animal with about 0.01 to about 100 mg/kg of body
weight per day of the active ingredient. The preferred dosage for
poultry, swine, cattle, sheep, goats and domestic pets is in the
range of from about 0.1 to about 50 mg/kg/day.
[0920] Paste formulations can be prepared by dispersing a compound
of the present invention in pharmaceutically acceptable oil such as
peanut oil, sesame oil, corn oil or the like.
[0921] Pellets containing an effective amount of a compound of the
present invention can be prepared by admixing a compound of the
present invention with a diluent such as carbowax, carnauba wax,
and the like, and a lubricant, such as magnesium or calcium
stearate, can be added to improve the pelleting process.
[0922] It is, of course, recognized that more than one pellet may
be administered to an animal to achieve the desired dose level.
Moreover, it has been found that implants may also be made
periodically during the animal treatment period in order to
maintain the proper active agent level in the animal's body.
[0923] The terms pharmaceutically acceptable salts, esters, amides,
or prodrugs means the carboxylate salts, amino acid addition salts,
esters, amides, and prodrugs of a compound that are, within the
scope of sound medical judgment, suitable for use with patients
without undue toxicity, irritation, allergic response, and the
like, commensurate with a reasonable benefivrisk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible.
[0924] The term "salts" refers to inorganic and organic salts of a
compound of the present invention. These salts can be prepared in
situ during the final isolation and purification of a compound, or
by separately reacting a compound with a suitable organic or
inorganic acid and isolating the salt thus formed. Representative
salts include the hydrobromide, hydrochloride, sulfate, bisulfate,
nitrate, acetate, oxalate, besylate, palmitiate, stearate, laurate,
borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,
fumarate, succinate, tartrate, naphthylate, mesylate,
glucoheptonate, lactobionate, and laurylsulphonate salts, and the
like. These may include cations based on the alkali and alkaline
earth metals, such as sodium, lithium, potassium, calcium,
magnesium, and the like, as well as non-toxic ammonium, quaternary
ammonium, and amine cations including, but not limited to,
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, ethylamine, and the
like. See, for example, S.M. Berge, et al., "Pharmaceutical Salts,"
J Pharm Sci, 66:1-19 (1977).
[0925] Examples of pharmaceutically acceptable, non-toxic esters of
a compound of the present invention, if applicable, include
C.sub.1-C.sub.8alkyl esters. Acceptable esters also include
C.sub.5-C.sub.7cycloalkyl esters, as well as arylalkyl esters such
as benzyl. C.sub.1-C.sub.4 alkyl esters are preferred. Esters of a
compound of the present invention may be prepared according to
methods that are well known in the art.
[0926] Examples of pharmaceutically acceptable non-toxic amides of
a compound of the present invention include amides derived from
ammonia, primary C.sub.1-C.sub.8alkyl amines, and secondary
C.sub.1-C.sub.8dialkyl amines. In the case of secondary amines, the
amine may also be in the form of a 5 or 6 membered heterocycloalkyl
group containing at least one nitrogen atom. Amides derived from
ammonia, C.sub.1-C.sub.3 primary alkyl amines, and C.sub.1-C.sub.2
dialkyl secondary amines are preferred. Amides of a compound of the
present invention may be prepared according to methods well known
to those skilled in the art.
[0927] The term "prodrug" means a compound that is transformed in
vivo to yield a compound of the present invention. The
transformation may occur by various mechanisms, such as through
hydrolysis in blood. A discussion of the use of prodrugs is
provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery
Systems," Vol. 14 of the A. C. S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987.
[0928] For example, if a compound of the present invention contains
a carboxylic acid functional group, a prodrug can comprise an ester
formed by the replacement of the hydrogen atom of the acid group
with a group such as (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0929] Similarly, if a compound of the present invention comprises
an alcohol functional group, a prodrug can be formed by the
replacement of the hydrogen atom of the alcohol group with a group
such as (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl- ,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxyc- arbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkan-
oyl, arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacy- l, where each a-aminoacyl group
is independently selected from the naturally occurring L-amino
acids, P(O)(OH).sub.2, --P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or
glycosyl (the radical resulting from the removal of a hydroxyl
group of the hemiacetal form of a carbohydrate).
[0930] If a compound of the present invention comprises an amine
functional group, a prodrug can be formed by the replacement of a
hydrogen atom in the amine group with a group such as R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
((C.sub.1-C.sub.1-0)alkyl, (C.sub.3-C.sub.7)cycloalkyl, benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl-natural .alpha.-aminoacyl, --C(OH)C(O)OY wherein
(Y is H, (C.sub.1-C.sub.6)alkyl or benzyl), --C(OYO)Y.sub.1 wherein
Y.sub.0 is (C.sub.1-C.sub.4) alkyl and Y.sub.1 is
((C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sub.2)Y.sub.3
wherein Y.sub.2 is H or methyl and Y.sub.3 is mono-N-- or
di-N,N--(C.sub.1-C.sub.- 6)alkylamino, morpholino, piperidin-1-yl
or pyrrolidin-1-yl.
[0931] A compound of the present invention may contain asymmetric
or chiral centers, and therefore, exist in different stereoisomeric
forms. It is contemplated that all stereoisomeric forms of a
compound as well as mixtures thereof, including racemic mixtures,
form part of the present invention. In addition, the present
invention contemplates all geometric and positional isomers. For
example, if a compound contains a double bond, both the cis and
trans forms, as well as mixtures, are contemplated.
[0932] Diasteromeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as by chromatography and/or fractional crystallization. Enantiomers
can be separated by converting the enantiomeric mixture into a
diasteromeric mixture by reaction with an appropriate optically
active compound (e.g., alcohol), separating the diastereomers and
converting (e.g., hydrolyzing) the individual diastereomers to the
corresponding pure enantiomers. Also, some of the compounds of this
invention may be atropisomers (e.g., substituted biaryls) and are
considered as part of this invention.
[0933] A compound of the present invention may exist in unsolvated
as well as solvated forms with pharmaceutically acceptable solvents
such as water, ethanol, and the like. The present invention
contemplates and encompasses both the solvated and unsolvated
forms.
[0934] It is also possible that a compound of the present invention
may exits in different tautomeric forms. All tautomers of a
compound of the present invention are contemplated. For example,
all of the tautomeric forms of the imidazole moiety are included in
this invention. Also, for example, all keto-enol or imine-enamine
forms of the compounds are included in this invention.
[0935] Those skilled in the art will recognize that the compound
names contained herein may be based on a particular tautomer of a
compound. While the name for only a particular tautomer may be
used, it is intended that all tautomers are encompassed by the name
of the particular tautomer and all tautomers are considered part of
the present invention.
[0936] It is also intended that the invention disclosed herein
encompass compounds that are synthesized in vitro using laboratory
techniques, such as those well known to synthetic chemists; or
synthesized using in vivo techniques, such as through metabolism,
fermentation, digestion, and the like. It is also contemplated that
a compound of the present invention may be synthesized using a
combination of in vitro and in vivo techniques.
[0937] The present invention also includes isotopically-labelled
compounds, which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, 13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively. Compounds of the present invention,
prodrugs thereof, and pharmaceutically acceptable salts of said
compounds or of said prodrugs which contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of this invention. Certain isotopically-labelled compounds of the
present invention, for example those into which radioactive
isotopes such as .sup.3H and .sup.14C are incorporated, are useful
in compound and/or substrate tissue distribution assays. Tritiated,
i.e., .sup.3H, and carbon-.sup.14, i.e., .sup.14C, isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, may afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
Formula I of this invention and prodrugs thereof can generally be
prepared by carrying out the procedures disclosed in the Schemes
and/or in the Examples below, by substituting a readily available
isotopically labelled reagent for a non-isotopically labelled
reagent.
[0938] The compounds of the present invention can be generally
prepared as follows:
[0939] Preparation of the 3'-substituted or unsubstituted
tetrazoles 1-3 is illustrated in Scheme 1. The intermediate 1 for
preparation of the tetrazoles of the present invention can be
synthesized by coupling a 4-cyanophenol 1b with a bis-aryl iodonium
tetrafluoroborate 1c at room temperature in an organic solvent such
as dichloromethane, in the presence of a copper catalyst such as
copper bronze and a base such as triethylamine (TEA). The
4-cyanophenol 1b is prepared by reacting a 4-bromophenol 1a, which
are known in the art, with copper cyanide in dimethylformamide
(DMF) at reflux temperature. Preparation of the bis-aryl iodoniurn
tetrafluoroborate 1c can be carried out from a known anisole
according to the procedure described in the J. Med. Chem, 38,
695-707, (1995). The tetrazole 1-2 is prepared by reacting the
cyano compound 1 with sodium azide and ammonium chloride in DMF at
reflux temperature followed by HCl work up. The tetrazole 1-2 is
demethylated using a suitable boron trihalide such as boron
trichloride or boron tribromide, in an organic solvent such as
chloroform, to afford the hydroxy tetrazole 1-3.
[0940] The 3'-sulfonamides are prepared as shown in Scheme 2.
Treatment of the compound 1 with neat chlorosulfonic acid at about
0.degree. C. to about room temperature gives the
3'-chlorosulfonylated compound 2-1. The compound 2-1 is reacted
with a primary amine in a solvent such as dichloromethane,
tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH) or
acetonitrile, in the presence of a base such as TEA or
diisopropylethylamine, to afford the compound 2-2. Likewise, the
compound 2-3 can be prepared by reacting 2-1 with a secondary amine
under similar conditions. Alternatively, the compound 2-3 may be
prepared by alkylation of the compound 2-2. A preferred alkylation
method uses a suitable alkylating agent such as an alkyl halide, in
the presence of a base such as sodium hydride, in an organic
solvent such as THF. The compound 2-2 is demethylated using boron
tribromide in chloroform. The demethylated compound is then
converted to the tetrazole 2-4 by reacting with sodium azide and
ammonium chloride in DMF at elevated temperature. Likewise, the
tetrazole 2-5 can be prepared from the compound 2-3 via
demethylation and tetrazole formation under similar conditions.
[0941] Formation of the 3'-carboxamides is carried out as described
in Scheme 3. Treatment of 1 with hexamethylenetetramine at
65.degree. C. in trifluoroacetic acid (TFA) gives the 3'-aldehyde
3-1. Oxidation of 3-1 provides the carboxylic acid 3-2. Preferred
oxidation methods include Jones oxidation (chromic acid/aqueous
sulfuric acid) and those employing sodium hypochlorite (buffered
aqueous NaClO, and 2-methyl-2-butene in t-butanol/THF). The
carboxylic acid 3-2 can be converted to the carboxamide 3-3 or 3-4
according to methods analogous to those known in the art. For
example, employment of an acid chloride activated ester, or mixed
anhydride of 3-2 with a primary or secondary amine in a dried
aprotic solvent such as dichloromethane, THF, dimethylether (DME)
or diethylether (DEE), in the presence of a base such as TEA,
dimethylaminopyridine or pyridine. Also, the carboxylic acid 3-2
can be reacted with N-hydroxysuccinimide, dicyclohexylcarbodimmide,
and an amine in the presence of a base such as TEA in
1,2-dimethoxyethane. Alternatively, the compound 3-3 can be
converted to the compound 3-4 by alkylation. A preferred alkylation
method uses an alkylating agent such as an alkyl halide, in the
presence of a base such as sodium hydride, in an organic solvent
such as THF. The compound 3-3 is converted to the tetrazole 3-5 via
demethylation and tetrazole formation by procedures analogous to
those described in Scheme 2. Likewise, the compound 3-6 is prepared
from the compound 3-4 via demethylation and tetrazole formation. It
is noted that the tetrazole can be formed first followed by
demethylation.
[0942] The aminotetrazoles 4-4 are prepared as shown in Scheme 4.
The intermediate 4 can be synthesized according to methods
analogous to those known in the art. For example, by coupling
4-nitrophenol with bis-aryl iodonium tetrafluoroborate at room
temperature in the presence of a copper catalyst and TEA in
dichloromethane (J. Med. Chem, 38, 695-707, (1995). An alternative
method for preparing 4 is by coupling a 4-halonitrobenzene such as
4-iodonitrobenzene, 4-bromonitrobenzene or 4-chloronitrobenzene
with an appropriate 4-methoxyphenol at 120.degree. C. in the
presence of a suitable base such as potassium carbonate or
potassium t-butoxide, in a polar solvent such as dimethylsulfoxide
(DMSO) or N-methylpyrrolidone. A third method for preparing 4 is by
coupling a 4-methoxyphenylboronic acid with a 4-nitrophenol in the
presence of copper (II) acetate and a base such as TEA, pyridine or
a mixture of TEA and pyridine according to the procedure described
in Tetrahedron Lett., 39, 2933-2936, 2937-2940, (1998).
Hydrogenation of 4 in the presence of 10% Pd/C gives the aniline
4-1. The aniline 4-1 is reacted with cyanogen bromide in the
presence of sodium acetate in a mixture of acetic acid and water to
give the cyanamide 4-2. Treatment of the cyanamide 4-2 with sodium
azide in the presence of ammonium chloride in DMF at elevated
temperature gives the aminotetrazole 4-3. Demethylation of 4-3 with
boron tribromide affords the hydroxy tetrazole 4-4.
[0943] Preparation of aminotetrazoles containing 3'-sulfonamides is
illustrated in Scheme 5. The compound 5 is reacted with neat
chlorosulfonic acid at 0.degree. C. to room temperature to give the
3'-chlorosulfonylated compound 5-1. The compound 5-1 is reacted
with a primary amine in a solvent such as dichloromethane, THF or
acetonitrile, in the presence of a base such as TEA or
diisopropylethylamine, to afford the secondary sufonamide 5-2.
Alternatively, the compound 5-1 can be converted to the tertiary
sulfonamide 5-3 using a secondary amine under similar conditions.
In addition, the compound 5-3 may be prepared by alkylation of the
compound 5-2. A preferred alkylation method uses an alkylating
agent such as an alkyl halide, in the presence of a base such as
sodium hydride, in an organic solvent such as THF. The compound 5-2
is converted to the cyanamide 5-4 via demethylation, hydrogenation
and cyanamide formation by procedures analogous to those described
in and Scheme 4. The cyanamide 5-4 is reacted with sodium azide and
ammonium chloride in DMF to give the aminotetrazole 5-6. Similarly,
the compound 5-7 is prepared from the compound 5-3 via
demethylation, hydrogenation, cyanamide formation and then
tetrazole formation.
[0944] Preparation of aminotetrazoles containing 3'-carboxamides
can be carried out as outlined in Scheme 6. The compound 5 can be
converted to the aldehyde 6-1 according to methods known in the
art. For example, the compound 5 can be reacted with
hexamethylenetetramine at 65.degree. C. in TFA to give the
3'-aldehyde 6-1. Oxidation of 6-1 provides the carboxylic acid 6-2.
Preferred oxidation methods include Jones oxidation (chromic
acid/aqueous sulfuric acid) and methods employing sodium
hypochlorite (buffered aqueous NaClO, and 2-methyl-2-butene in
t-butanol/THF). The carboxylic acid 6-2 can be converted to the
carboxamide 6-3 or 6-4 according to methods analogous to those
known in the art. For example, employment of an acid chloride,
activated ester, or mixed anhydride of 6-2 with a primary or
secondary amine in a dried aprotic solvent such as dichloromethane,
THF, DME, in the presence of a base such as TEA,
dimethylaminopyridine or pyridine can be used to make a
carboxamide. Also, the carboxylic acid 6-2 can be reacted with
N-hydroxysuccinimide, dicyclohexylcarbodiimide, and an amine in the
presence of a base such as TEA in 1,2-dimethoxyethane.
Alternatively, the compound 6-3 can be converted to the compound
6-4 by alkylation. A preferred alkylation method uses a suitable
alkylating agent such as an alkyl halide, in the presence of a base
such as sodium hydride, in an organic solvent such as THF. The
compound 6-3 is converted to the aminotetrazole 6-5 via
demethylation, hydrogenation, cyanamide formation and tetrazole
formation by standard procedures analogous to those described in
Scheme 4. Likewise, the compound 6-6 can be prepared from the
compound 64 via demethylation, hydrogenation, cyanamide formation
and tetrazole formation.
[0945] Preparation of the alkylsulfones 7-3 is illustrated in
Scheme 7. The compound 5 is reacted with chlorosulfonic acid
followed by reduction with sodium sulfite in H.sub.2O in the
presence of a base such as sodium bicarbonate, or NaOH to afford
the sulfinic acid 7-1. Alkylation of the sulfinic acid 7-1 with
alkyl halide in the presence of a base such as sodium bicarbonate,
NaOH, sodium hydride, sodium methoxide, and potassium t-butoxide
gives the alkyl sulfone 7-2. The compound 7-2 can be converted to
the aminotetrazole 7-3 via demethylation, hydrogenation, cyanamide
formation and tetrazole formation.
[0946] Preparation of the 3'-aryl sulfones is outlined in Scheme 8.
Treatment of 5 with arylsulfonic acid in the presence of a
dehydrating agent, preferably P.sub.2O.sub.5 in methanesulfonic
acid [Eaton's reagent] or polyphosphoric acid at elevated
temperature gives the sulfone 8-1. The compound 8-1 can be
converted to the aminotetrazole 8-2 via demethylation,
hydrogenation, cyanamide formation and tetrazole formation.
[0947] The benzyltetrazoles 9-6 are prepared as shown in Scheme 9.
The diaryl ether 9-2 is obtained by coupling of bis-aryl iodonium
tetrafluoroborate Ic with the phenol 9-1 in the presence of copper
bronze and triethyl amine in dichloromethane. Reduction of 9-2 with
diisobutylaluminum hydride (DIBAL) in dichloromethane affords the
benzyl alcohol 9-3. Treatment of 9-3 with
dibromotriphenylphosphorane in acetonitrile gives the benzyl
bromide 9-4. Reaction of the bromide 9-4 with copper cyanide in DMF
at 140.degree. C. yields the benzyl cyanide 9-5. The
benzyltetrazole 9-6 can be obtained from 9-5 via demethylation and
tetrazole formation. 16 17 18 19 20 21 22 23
EXAMPLES
[0948] The examples presented below are intended to illustrate
particular embodiments of the invention and are not intended to
limit the scope of the specification, including the claims, in any
manner.
[0949] The following abbreviations or acronyms may be used in this
application
1 RT room temperature NMR nuclear magnetic resonance TLC thin layer
chromatography MS mass spectrometry APCI- atmospheric pressure
chemical ionization, negative ion mode Calc Calculated Equiv
equivalent(s) MeOH methanol APCI+ atmospheric pressure chemical
ionization, positive ion mode THF tetrahydrofuran EtOAc ethyl
acetate Et ethyl Me methyl
Example 1
4-[2,6-Dimethyl-4-(2H-Tetrazol-5-yl)-Phenoxy]-2-Isopropyl-Phenol
[0950] Step A-Preparation of
4-Hydroxy-3,5-Dimethyl-Benzonitrile
[0951] To a solution of 4-bromo-2,6-dimethyl-phenol (1.0 g, 5.0
mmol) (Aldrich Chemical Co., Milwaukee, Wis.) in 8 ml of
N,N-dimethylformamide at room temperature (RT) was added copper (I)
cyanide (0.67 g, 7.5 mmol), and the reaction mixture was refluxed
for 7 hours. The mixture was then cooled to RT and filtered. The
filtrate was poured into 50 ml of water and extracted with ethyl
acetate (3.times.50 ml). The combined organic layers were washed
with water (3.times.50 ml), dried, and concentrated. The residue
was purified by preparative TLC (dichloromethane) to afford the
title product of Step A. NMR (400 MHz, CDCl.sub.3) .delta. 7.28 (s,
2H), 5.26 (br s, 1H), 2.27 (s, 6H).
[0952] Step B-Preparation of
4-(3-Isopropyl-4-Methoxy-Phenoxy)-3,5-Dimethy- l-Benzonitrile
[0953] To a solution of bis-(3-isopropyl-4-methoxy-phenyl)-iodonium
tetrafluoroborate (3.03 g, 5.9 mmol) and copper bronze (0.5 g, 7.9
mmol) in 8 ml of dichloromethane cooled to 0.degree. C. was added
dropwise a solution of 4-hydroxy-3,5-dimethyl-benzonitrile (0.58 g,
3.9 mmol) and triethylamine (0.61 ml, 4.4 mmol) in 6 ml of
dichloromethane. The reaction mixture was stirred for 6 days at RT,
then filtered through Celite.RTM. and concentrated. The residue was
purified by preparative TLC (hexanes:dichloromethane 1:4) to afford
the title product of Step B. NMR (400 MHz, CDCl.sub.3) .delta. 7.40
(s, 2H), 6.74 (d, 1H), 6.67 (d, 1H), 6.21 (dd, 1H), 3.77 (s, 3H),
3.27 (p, 1H), 2.15 (s, 6H), 1.17 (d, 3H).
[0954] Step C-Preparation of
5-[4-(3-Isopropyl-4-Methoxy-Phenoxy]-3,5-Dime-
thyl-Phenyl]-2H-Tetrazole
[0955] To a solution of
4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-ben- zonitrile (37
mg, 0.13 mmol ) in 0.5 ml of N,N-dimethylformamide at RT was added
sodium azide (9.0 mg, 0.14 mmol) and ammonium chloride (7.4 mg,
0.14 mmol). The mixture was refluxed for 20 hours, then poured into
ice/water and acidified with 2N HCl to pH 2. The white solid was
collected by filtration and dried in vacuo. The title product of
Step C was used in the next step without purification. MS
(APCI.sup.-) Calc.: 338.4, Found: 337.3 (M-1).
[0956] Step D-Preparation of
4-[2,6-Dimethyl-4-(2H-Tetrazol-5-yl)-Phenoxy]-
-2-Isopropyl-Phenol
[0957] To a solution of
5-[4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl--
phenyl]-2H-tetrazole (26 mg, 0.077 mmol) in 6 ml of chloroform at
RT was added boron tribromide (1 M in dichloromethane, 0.12 ml,
0.12 mmol). The reaction was stirred for 20 hours at RT, then
additional boron tribromide (1 M in dichloromethane, 0.3 ml) was
added, and the reaction was stirred at RT for 6 hours. Water (10
ml) was added, and the reaction was stirred for 1 hour at RT, then
extracted with ethyl acetate (3.times.15 ml), dried, and
concentrated. The white solid residue was triturated with
dichloromethane (2.times.0.3 ml) and dried in vacuo to afford the
title product of Example 1. MS (APCI--) Calc.: 324.4, Found: 323.3
(M-1).
[0958] EXAMPLE 1-1 was prepared in an analogous manner to the
sequence of reactions described for EXAMPLE 1 with the noted
changes.
Example 1-1
[0959]
4-[2,6-Dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-isopropyl-phenol,
MS (APCI.sup.-) Calc.: 364.0, Found: 363.2 (M-1).
[0960] 3,5-dichloro-4-hydroyxbenzonitrile was used in place of
4-hydroxy-3,5-dimethylbenzonitrile in Step B.
Example 2
4-[2,6-Dichloro-4-(2H-Tetrazol-5-yl)-Phenoxy]-2-(Pyrrolidine-1-Sulfonyl)-P-
henol
[0961] Step A-Preparation of
3,5-Dichloro-4-[4-Methoxy-3-(Pyrrolidine-1-Su-
lfonyl)-Phenoxy]-Benzonitrile
[0962] To 3,5-dichloro-4-(4-methoxy-phenoxy)-benzonitrile (70 mg,
0.238 mmol) was added chlorosulfonic acid (0.6 ml, 9.0 mmol)
dropwise at RT. The resulting solution was stirred for 1 hour at
RT, then added dropwise to ice. The mixture was extracted with
dichloromethane (3.times.10 ml), and the combined organic phases
were dried and concentrated. The residue was dissolved in
dichloromethane (2 ml) and pyrrolidine (40 .mu.1,0.48 mmol) and
triethylamine (80 .mu., 0.57 mmol) were added. The solution was
stirred at RT for 1 hour, then concentrated. The residue was
purified by preparative TLC (ethyl acetate:hexanes 1:1) to afford
the title product of Step A. MS (APCI+) CaIc.: 426.0, Found: 427.0
(M+1).
[0963] Step B-Preparation of
3,5-Dichloro-4-[4-Hydroxy-3-(Pyrrolidine-1-Su-
lfonyl)-Phenoxy]-Benzonitrile
[0964] To a solution of
3,5-dichloro-4-[4-methoxy-3-(pyrrolidine-1-sulfony-
l)-phenoxy]-benzonitrile (30 mg, 0.070 mmol) in 2 ml of
dichloromethane at RT was added boron tribromide (1 M in
dichloromethane, 0.386 ml, 0.39 mmol). The reaction mixture was
stirred for 1 hour at RT. Water (10 ml) was added, and the reaction
was stirred for 20 minutes at RT, then extracted with ethyl acetate
(2.times.10 ml) and dichloromethane (1.times.10 ml). The combined
organic phases were dried, and concentrated. The title product of
Step B was used in the next step without purification. MS (APCI+)
Calc.: 412.0, Found: 413.1 (M+1).
[0965] Step C-Preparation of
4-[2,6-Dichloro-4-(2H-Tetrazol-5-yl)-Phenoxy]-
-2-(Pyrrolidine-1-Sulfonyl)-Phenol
[0966]
4-[2,6-Dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(pyrrolidine-1-sulf-
onyl)-phenol was prepared from
3,5-dichloro-4-[4-hydroxy-3-(pyrrolidine-1--
sulfonyl)-phenoxy]-benzonitrile according to a procedure analogous
to that described in EXAMPLE 1, Step C. Sodium azide (4.0 equiv)
and ammonium chloride (4.0 equiv) were used, and the reaction was
heated to 143.degree. C. for 40 hours. After the reaction had been
acidified and the crude product collected by filtration, the solid
was dissolved in MeOH, filtered, and the filtrate was concentrated.
The residue was purified by preparative TLC
(methanol:water:chloroform=19:1:47) to afford the title product of
Example 2. MS (APCI.sup.-) Calc.: 455.0, Found: 454.2 (M-1).
[0967] EXAMPLES 2-1 to 2-4 were prepared in an analogous manner to
the sequence of reactions described for EXAMPLE 2 with the noted
changes .
Example 2-1
4-[2,6-Dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(piperidine-1-sulfonyl)-ph-
enol, MS (APCI.sup.-) Calc.: 469.1 Found: 468.1 (M-1).
[0968] Piperidine (2.0 equiv) was substituted for pyrrolidine in
Step A.
Example 2-2
4-[2,6-Dichloro-4-(2H-Tetrazol-5-yl)-Phenoxy]-2-(3,3-Dimethyl-Piperidine-1-
-Sulfonyl)-Phenol, MS (APCI--) Calc.: 497.1, Found: 496.2
(M-1).
[0969] 3,3-Dimethylpiperidine (2.0 equiv) was substittued for
pyrrolidine in Step A.
Example 2-3
N-Cyclopropyl-5-[2,6-Dichloro-4-(2H-Tetrazol-5-yl)-Phenoxy]-2-Hydroxy-Benz-
enesulfonamide, MS (APCI.sup.-) Calc.: 441.0 Found: 440.0
(M-1).
[0970] Cyclopropylamine (1.5 equiv) was substituted for pyrrolidine
in Step A.
Example 2-4
5-[2,6-Dichloro-4-(2H-Tetrazol-5-yl)-Phenoxy]-2-Hydroxy-N,N-Dimethyl-Benze-
nesulfonamide, MS (APCI.sup.-) Calc.: 429.0 Found: 428.1 (M-1).
[0971] Dimethylamine (2.0M in THF [3.5 equiv]) was substituted for
pyrrolidine in Step A.
Example 3
{5-[2,6-Dichloro-4-(1H-Tetrazol-5-yl)-Phenoxy1-2-Hydroxy-Phenyl}-Piperidin-
-1-yl-Methanone
[0972] Step A-Preparation of
3,5-Dichloro-4-(3-Formyl-4-Methoxy-Phenoxy)-B- enzonitrile
[0973] A solution of
3,5-dichloro-4-(4-methoxy-phenoxy)-benzonitrile (500 mg, 1.7 mmol)
and hexamethylenetetramine (357 mg, 2.5 mmol) in trifluoroacetic
acid (5 ml) was stirred for 4 hours at 75.degree. C. The mixture
was cooled to RT, and the excess trifluoroacetic acid was removed
in vacuo. The oily residue was diluted with 10 ml water, and the
resulting suspension was stirred for 1 hour, then neutralized with
saturated aqueous NaHCO.sub.3. The mixture was then extracted with
ethyl acetate (2.times.20 ml), and the combined organic phases were
washed with saturated aqueous NaHCO.sub.3 (1.times.25 ml), brine
(1.times.25 ml), dried over anhydrous Na.sub.2SO.sub.4, filtered,
and concentrated in vacuo to give a brown foam. The residue was
triturated in ethyl ether with a minimal amount of dichloromethane
to produce a precipitate, which was removed by filtration and
washed with ether. The filtrate (with the ether washings) was
concentrated to give the desired title product of Step A, which was
used in the next step without purification. MS (APCI+) Calc.:
320.9, Found: 322.1 (M+1).
[0974] Step B-Preparation of
5-(2,6-Dichloro-4-Cyano-Phenoxy)-2-Methoxy-Be- nzoic Acid
[0975] To a solution of
3,5-dichloro-4-(4-methoxy-phenoxy)-benzonitrile (100 mg, 0.31 mmol)
in acetone (1.5 ml) at RT was added Jones reagent (30 drops) with
stirring until a red color persisted. The solution was stirred 1
hour, then quenched with isopropanol (1 ml). The reaction was
filtered through Celite.RTM., and the filtrate was basified with an
aqueous solution of 1 N NaOH and the organic solvent was removed in
vacuo. The aqueous mixture was washed with diethyl ether
(2.times.15 ml), and the combined organic phases were then
back-extracted with 1N NaOH (1.times.15 ml). All of the aqueous
layers were combined and acidified with concentrated HCl to give a
turbid solution. This aqueous mixture was extracted with ethyl
acetate (3.times.20 ml), and the combined organic phases were dried
over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The
title product of Step B was used in the next step without
purification. MS (APCI-) Calc.: 337.2, Found: 336.1 (M-1).
[0976] Step C-Preparation of
3,5-Dichloro-4-[4-Methoxy-3-(Piperidine-1-Car-
bonyl)-Phenoxy]-Benzonitrile
[0977] A solution of
3,5-dichloro-4-(3-formyl-4-methoxy-phenoxy)-benzonitr- ile (85 mg,
0.25 mmol) and thionyl chloride (92 .mu.1,1.26 mmol) in
tetrahydrofuran (2.5 ml) was refluxed for 1 hour. THF and excess
thionyl chloride was then removed under reduced pressure, and the
residue was dissolved in dichloromethane (2.5 ml) and piperidine
(30 .mu.1,0.30 mmol) and N,N-diisopropylethylamine (88 .mu.l, 0.50
mmol) were added. The solution was stirred at RT for 1 hour, then
concentrated. The product was purified by preparative TLC (diethyl
ether:dichloromethane 1:9) to afford the title product of Step C.
MS (APCI+) Calc.: 404.0, Found: 405.1 (M+1).
[0978] Step D-Preparation of
3,5-Dichloro-4-[4-Hydroxy-3-(Piperidine-1-Car-
bonyl)-Phenoxy]-Benzonitrile
[0979]
3,5-Dichloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-benzon-
itrile was prepared from
3,5-dichloro-4-[4-methoxy-3-(piperidine-1-carbony-
l)-phenoxy]-benzonitrile according to a procedure analogous to that
described in EXAMPLE 2, Step B. Boron tribromide (1 M in
dichloromethane, 2.0 equiv) was used. After water addition, the
mixture was stirred for 30 minutes at RT, then basified with
aqueous saturated sodium bicarbonate solution, and extracted with
dichloromethane (3.times.10 ml). The combined organic phases were
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated.
The title product of Step E was used in the next step without
purification.) MS (APCI+) CaIc.: 390.0, Found: 391.1 (M+1).
[0980] Step E-Preparation of
{5-[2,6-Dichloro-4-(1H-Tetrazol-5-yl)-Phenoxy-
]-2-Hydroxy-Phenyl}-Piperidin-1-yl-Methanone
[0981]
{5-[2,6-Dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydroxy-phenyl}-pi-
peridin-1-yl-methanone was prepared from
3,5-dichloro-4-[4-hydroxy-3-(pipe-
ridine-1-carbonyl)-phenoxy]-benzonitrile according to a procedure
analogous to that described in EXAMPLE 1, Step C. Sodium azide (2.0
equiv) and ammonium chloride (2.0 equiv) were used initially, and
the reaction mixture was heated to reflux for 2 hours, after which
additional sodium azide (2.0 equiv) was added, and the reaction was
heated to reflux for 20 hours. After the reaction had been
acidified and the crude product collected by filtration, then
purified by preparative TLC
[0982] (methanol:water:dichloromethane 20:3:77) to afford the title
product of Example 3. MS (APCI+) Calc.: 433.0, Found: 434.1
(M+1).
[0983] EXAMPLES 3-1 to 3-4 were prepared in an analogous manner to
the sequence of reactions described for EXAMPLE 3 with the noted
changes.
Example 3-1
N-Cyclobutyl-5-[2,6-Dichloro-4-(1H-Tetrazol-5-yl)-Phenoxy]-2-Hydroxy-Benza-
mide, MS (APCI-) Calc.: 419.0, Found: 418.1 (M-1).
[0984] Cyclobutylamine (1.0 equiv) was substituted for piperidine
in Step C.
Example 3-2
N-Cyclohexyl-5-[2,6-Dichloro-4-(1H-Tetrazol-5-yl)-Phenoxy]-2-Hydroxy-Benza-
mide, MS (APCI.sup.-) Calc.: 447.0, Found: 446.2 (M-1).
[0985] Cyclohexylamine (1.0 equiv) was substituted for piperidine
in Step C.
Example 3-3
{5-[2,6-Dichloro-4-(1H-Tetrazol-5-yl)-Phenoxy]-2-Hydroxy-phenyl}-pyrrolidi-
n-1-yl-methanone, MS (APCI.sup.-) Calc.: 419.0, Found: 418.0
(M-1).
[0986] Pyrrolidine (1.0 equiv) was substituted for piperidine in
Step C.
Example 3-4
N-Bicyclo[2.2.1]Hept-2-yl-5-8
2,6-Dichloro-4-(1H-Tetrazol-5-yl)-Phenoxy]-2- -Hydroxy-Benzamide,
MS (APCI.sup.-) Calc.: 459.0, Found: 458.1 (M-1).
[0987] Exo-2-aminonorbornane (1.0 equiv) was substituted for
piperidine in Step C.
Example 4
4-[2.6-Dimethyl-4-(1H-Tetrazol-5-Ylamino)-Phenoxy]-2-Isopropyl-Phenol
[0988] Step A-Preparation of
4-(3-Isopropyl-4-Methoxy-Phenoxy)-3,5-Dimethy- l-Phenylamine
[0989] To
4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (3.2 g,
10.1 mmol) in a mixture of ethyl acetate (10 ml) and ethanol (50
ml) was added catalyst 10% Pd/C (0.32 g). The mixture was
hydrogenated under 40 psi at RT for 16 hours. The mixture was
filtered through Celite.RTM. and concentrated. The title product of
Step A was obtained by recrystallization from
dichloromethane/hexanes. MS (APCI+) Calc.: 285.4, Found: 286.2
(M+1).
[0990] Step B-Preparation of
4-(3-Isopropyl-4-Methoxy-Phenoxy)-3,5-Dimethy-
l-Phenyl-Cyanamide
[0991] To a solution of
4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phe- nylamine (100
mg, 0.35 mmol), acetic acid (1 ml), and water (1 ml) cooled to
0.degree. C. was added sodium acetate (43 mg, 0.53 mmol), and the
mixture was stirred for 10 minutes until dissolved. Cyanogen
bromide (45 mg, 0.42 mmol) was added, and the reaction mixture was
allowed to slowly warm to RT and stirred for 18 hours. The mixture
was then diluted with water (15 ml) and extracted with ethyl
acetate (3.times.10 ml). The combined organic phases were washed
with aqueous saturated sodium bicarbonate solution (3.times.20 ml),
brine (20 ml), then dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by preparative
TLC (ethyl acetate:hexanes 2:3) to afford the title product of Step
B. MS (APCI.sup.-) Calc.: 310.4, Found: 309.2 (M-1).
[0992] Step C-Preparation of
[4-(3-Isopropyl-4-Methoxy-Phenoxy)-3,5-Dimeth-
yl-Phenyl]-(1H-Tetrazol-5-yl)-Amine
[0993]
[4-(3-Isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-(1H-tetrazo-
l-5-yl)-amine was prepared from
4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dime- thyl-phenyl-cyanamide
according to a procedure analogous to that described in EXAMPLE 1,
Step C. Sodium azide (1.2 equiv) and ammonium chloride (10.0 equiv)
were used, and the reaction was heated to 165.degree. C. for 5
hours. After the reaction had been acidified, the mixture was
extracted with ethyl acetate (3.times.10 ml). The combined organic
extracts were washed with 1 N HCl (3.times.50 ml) and brine
(1.times.50 ml). The organic phase was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by preparative TLC (methanol:water:dichloromethane 10:0.5:
89.5) to afford the title product of Step C. MS (APCI+) Calc.:
353.4, Found: 354.1 (M+1).
[0994] Step D-Preparation of
4-[2,6-Dimethyl-4-(1H-Tetrazol-5-Ylamino)-Phe-
noxy]-2-Isopropyl-Phenol
[0995]
4-[2,6-Dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-isopropyl-phen-
ol was prepared from
[4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-pheny-
l]-(1H-tetrazol-5-yl)-amine according to a procedure analogous to
that described in EXAMPLE 2, Step B. Boron tribromide (1 M in
dichloromethane, 8.0 equiv) was used. After water addition, the
mixture was extracted with ethyl acetate (3.times.10 ml). The
combined organic phases were dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by preparative
TLC (methanol:water:dichloromethane 25:3:72) to afford the title
product of Example 4. MS (APCI+) Calc.: 339.4, Found: 340.1
(M+1).
Example 5
5-[2-Chloro-6-Methyl-4-(1H-Tetrazol-5-Ylamino)-Phenoxy]-N-Cycloproyl-2-Hyd-
roxy-Benzenesulfonamide
[0996] Step A-Preparation of
5-(2-Chloro-6-Methyl-4-Nitro-Phenoxy)-2-Metho- xy-Benzenesulfonyl
Chloride
[0997] To a stirred solution of chlorosulfonic acid (17.3 g, 148
mmol, 8.7 equiv) cooled to 0.degree. C. was slowly added
4-(4-methoxy-phenoxy)-3-ch- loro-5-methyl-nitrobenzene (5.0 g, 17
mmol). The solution was warmed to RT and stirred for 1 hour, then
quenched by the dropwise addition into ice water (about 500 ml).
The mixture was then extracted with ethyl acetate (4.times.100 ml),
and the combined organic extracts were washed with saturated
aqueous NaHCO.sub.3 (2.times.100 ml) and brine (1.times.100 ml).
The aqueous phases were combined and back-extracted twice with
ethyl acetate. All of the organic phases were combined and dried
over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The
title product of Step A was used in the next step without
purification. MS (APCI.sup.-) Calc.: 392.2, Found: 372.1
(M-sulfonic acid -1).
[0998] Step B-Preparation of
5-(2-Chloro-6-Methyl-4-Nitro-Phenoxy)-N-Cyclo-
propyl-2-Methoxy-Benzenesulfonamide
[0999] To a solution of
5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-methoxy-be- nzenesulfonyl
chloride (5.61 g, 14.3 mmol) in dichloromethane (100 ml) at RT was
added dropwise a solution of cyclopropylamine (1.22 g, 21.4 mmol)
and N,N-diisopropylethylamine (5.55 g, 42.9 mmol) in
dichloromethane (30 ml) over 15 minutes. The reaction mixture was
stirred for 1 hour at RT, then quenched with aqueous 1 N HCl (100
ml). The organic phase was separated, and the aqueous phase was
extracted with dichloromethane (2.times.100 ml). All of the organic
phases were combined and extracted twice with aqueous 1 N HCl, then
three times with saturated aqueous NaHCO.sub.3. The aqueous acidic
washes and the aqueous basic washes were combined, respectively,
and back-extracted with ethyl acetate (2.times.50 ml). All of these
organic phases were combined with the previously combined organic
phases and dried over anhydrous Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography (ethyl ether:dichloromethane 0.5:99.5) to afford the
title product of Step B. MS (APCI.sup.-) Calc.: 412.3, Found: 411.1
(M-1).
[1000] Step C-Preparation of
5-(2-Chloro-6-Methyl-4-Nitro-Phenoxy)-N-Cyclo-
propyl-2-Hydroxy-Benzenesulfonamide
[1001]
5-(2-Chloro-6-methyl-4-nitro-phenoxy)-N-cyclopropyl-2-hydroxy-benze-
nesulfonamide was prepared from
5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-me-
thoxy-benzenesulfonamide according to a procedure analogous to that
described in EXAMPLE 2, Step B. Boron tribromide (1 M in
dichloromethane, 2.0 equiv) was used. After water addition, the
mixture was extracted with dichloromethane (3.times.50 ml). The
combined organic phases were dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated. The title product of Step C was used in
the next step without purification. MS (APCI.sup.-) Calc.: 398.3,
Found: 397.2 (M-1).
[1002] Step D-Preparation of
5-(4-Amino-2-Chloro-6-Methyl-Phenoxy)-N-Cyclo-
propyl-2-Hydroxy-Benzenesulfonamide
[1003]
5-(4-Amino-2-chloro-6-methyl-phenoxy)-N-cyclopropyl-2-hydroxy-benze-
nesulfonamide was prepared from
5-(2-chloro-6-methyl-4-nitro-phenoxy)-N-cy-
clopropyl-2-hydroxy-benzenesulfonamide according to the procedure
described in EXAMPLE 4, Step A. The reaction mixture was
hydrogenated for 2.5 hours. Then the mixture was filtered through
Celite.RTM. and concentrated, and the title product of Step D was
used in the next step without purification.) MS (APCI.sup.-) Calc.:
368.3, Found: 367.2 (M-1).
[1004] Step E-Preparation of
5-(2-Chloro-4-Cyanoamino-6-Methyl-Phenoxy)-N--
Cyclopropyl-2-Hydroxy-Benzenesulfonamide
[1005]
5-(2-Chloro-4-cyanoamino-6-methyl-phenoxy)-N-cyclopropyl-2-hydroxy--
benzenesulfonamide was prepared from
5-(4-amino-2-chloro-6-methyl-phenoxy)-
-N-cyclopropyl-2-hydroxy-benzenesulfonamide according to the
procedure described in EXAMPLE 4, Step B. The crude residue was
purified by preparative TLC (methanol:dichloromethane 4:96) to
afford the title product of Step E. MS (APCI.sup.-) Calc.: 393.2,
Found: 392.0 (M-1).
[1006] Step F-Preparation of
5-[2-Chloro-6-Methyl-4-(1H-Tetrazol-5-Ylamino-
)-Phenoxy]-N-Cyclopropyl-2-Hydroxy-Benzenesulfonamide
[1007]
5-[2-Chloro-6-methyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-N-cycloprop-
yl-2-hydroxy-benzenesulfon-amide was prepared from
5-[2-chloro-4-cyanoamin-
o-6-methyl-phenoxy]-N-cyclopropyl-2-hydroxy-benzenesulfonamide
according to a procedure analogous to that described in EXAMPLE 1,
Step C. Sodium azide (1.2 equiv) and ammonium chloride (10 equiv)
were used, and the reaction was heated to 165.degree. C. for 3
hours. After the reaction had been acidified, the aqueous mixture
was washed with ethyl acetate (3.times.10 ml). The combined organic
extracts were extracted with aqueous 1 N HCl (3.times.50 ml), and
brine (50 ml). The organic phase was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by preparative TLC (methanol:water:dichloromethane
25:3:72) to afford the title product of Example 5. MS (APCI+)
Calc.: 436.1, Found: 436.9 (M+1).
[1008] EXAMPLE 5-1 was prepared in an analogous manner to the
sequence of reactions described for EXAMPLE 5 with the noted
changes.
Example 5-1
N-Cyclopropyl-5-[2,6-Dichloro-4-(1H-Tetrazol-5-Ylamino)-Phenoxy]-2-Hydroxy-
-Benzenesulfonamide, MS (APCI+) Calc.: 456.0, Found: 457.3
(M+1).
[1009] 4-(4-methoxy-phenoxy)-3,5-dichloronitrobenzene was
substituted for 4-(4-methoxy-phenoxy)-3-chloro-5-methylnitrobenzene
in Step A.
Example 6
N-Cyclobutyl-5-[2,6-Dimethyl-4-(1H-Tetrazol-5-Ylamino)-Phenoxy]-2-Hydroxy--
N-Methyl-Benzamide
[1010] Step A-Preparation of
5-(2,6-Dimethyl-4-Nitro-Phenoxy)-2-Methoxy-Be- nzaldehyde
[1011] To a solution of
4-(4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (7.0 g, 25.6 mmol)
dissolved in trifluoroacetic acid (60 ml) at RT was added
hexamethylenetetramine (5.75 g, 41.0 mmol), and the solution was
heated to 75.degree. C. and stirred for 6 hours. The reaction
mixture was then concentrated to dryness, and the residue was taken
up in water (150 ml) and stirred at RT for 20 hours. The mixture
was then extracted with a 10% solution of methanol/dichloromethane
(4.times.50 ml) and ethyl acetate (1.times.75 ml). All of the
organic phases were combined, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was then
triturated with ethyl ether, cooled to 0.degree. C., and the title
product of Step A was collected by filtration. MS (APCI.sup.-)
Calc.: 301.3, Found: 300 (M-1).
[1012] Step B-Preparation of
5-(2,6-Dimethyl-4-Nitro-Phenoxy)-2-Methoxy-Be- nzoic Acid
[1013] To a solution of
5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-benzald- ehyde (6.56 g,
21.8 mmol) in tetrahydrofuran (31 ml) was added t-butyl alcohol
(215 ml), then 2-methyl-2-butene (27.5 ml, 327 mmol). To this
mixture was added dropwise a solution of NaClO.sub.2 (17.8 g, 196
mmol) dissolved in aqueous KH.sub.2PO.sub.4 buffer (254 ml of a
0.6M solution, 153 mmol), and the reaction mixture was stirred at
RT for 16 hours. An aqueous saturated solution of
Na.sub.2S.sub.2O.sub.3 (100 ml) was then added, the mixture was
stirred for 30 minutes at room temperature, then extracted with
ethyl acetate (3.times.300 ml). The combined organic phases were
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated.
The remaining t-butyl alcohol was azeotroped with hexanes. The
title product of Step B was used in the next step without
purification. MS (APCI.sup.-) Calc.: 317.3, Found: 316.3 (M-1).
[1014] Step C-Preparation of
N-Cyclobutyl-5-(2,6-Dimethyl-4-Nitro-Phenoxy)-
-2-Methoxy-Benzamide
[1015] To a cooled solution of
5-(2,6-Dimethyl-4-nitro-phenoxy)-2-methoxy-- benzoic acid (2.6 g,
8.2 mmol) in THF (80 ml) at 0.degree. C. was added
N-methylmorpholine (1.7 g, 16.5 mmol) and isobutylchloroformate
(1.7 g, 12.3 mmol). After stirring at 0.degree. C. for 45 minutes,
cyclobutyl amine (1.2 g, 16.5 mmol) was added. The resulting
mixture was stirred at 0.degree. C. for 15 minutes, then at room
temperature for 2 hours. The solution was concentrated in vacuo,
and the residue was partitioned between ethyl acetate (75 ml) and 1
N HCl (75 ml). The EtOAc extract was washed with 1 N HCl
(2.times.75 ml). The combined aqueous washings were extracted with
EtOAc (2.times.50 ml). The combined organic extracts were dried
over sodium sulfate and concentrated. The title product of Step C
was purified by chromatography to give an off-white solid. MS
(APCI.sup.-) Calc.: 370.4, Found: 369.1 (M-1).
[1016] Step D-Preparation of
N-Cyclobutyl-5-(2,6-Dimethyl-4-Nitro-Phenoxy)-
-2-Methoxy-N-Methyl-Benzamide
[1017] To a solution of
N-cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2-me- thoxy-benzamide
(125 mg, 0.34 mmol) in N,N-dimethylformamide (4.0 ml) cooled to
0.degree. C. was added NaH (20 mg, 0.84 mmol), and the reaction was
stirred for 15 minutes at 0.degree. C. Methyl iodide (0.10 ml, 1.7
mmol) was added, and the reaction mixture was stirred for 18 hours
at room temperature. An aqueous solution of 1N HCl (50 ml) was
added, and the mixture was extracted with ethyl acetate (3.times.15
ml). The combined organic phases were dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by preparative TLC (ethyl acetate:hexanes=3:2) to afford
the title product of Step D. MS (APCI.sup.+) Calc.: 384.4, Found:
385.2 (M+1).
[1018] Step E-Preparation of
N-Cyclobutyl-5-(2,6-Dimethyl-4-Nitro-Phenoxy)-
-2-Hydroxy-N-Methyl-Benzamide
[1019]
N-Cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2-hydroxy-N-methyl-be-
nzamide was prepared from
N-cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2--
methoxy-N-methyl-benzamide according to a procedure analogous to
that described in EXAMPLE 2, Step B. Boron tribromide (1 M in
dichloromethane, 2.0 equiv) was used After water addition, the
mixture was extracted with dichloromethane (3.times.10 ml). The
combined organic phases were dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated. The title product of Step E was used in
the next step without purification. MS (APCI.sup.+) Calc.: 370.4,
Found: 371.1 (M+1).
[1020] Step F-Preparation of
5-(4-Amino-2,6-Dimethyl-Phenoxy)-N-Cyclobutyl-
-2-Hydroxy-N-Methyl-Benzamide
[1021]
5-(4-Amino-2,6-dimethyl-phenoxy)-N-cyclobutyl-2-hydroxy-N-methyl-be-
nzamide was prepared from
N-cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2--
hydroxy-N-methyl-benzamide according to a procedure analogous to
that described in EXAMPLE 4, Step A. Methanol was used instead of
ethanol as a co-solvent. The reaction mixture was hydrogenated for
2 hours. Then, the mixture was filtered through Celite.RTM. and
concentrated, and the title product of Step F was used in the next
step without purification. MS (APCI.sup.+) Calc.: 340.4, Found:
341.1 (M+1).
[1022] Step G-Preparation of
5-(4-Cyanoamino-2,6-Dimethyl-Phenoxy)-N-Cyclo-
butyl-2-Hydroxy-N-Methyl-Benzamide
[1023]
5-(4-Cyanoamino-2,6-dimethyl-phenoxy)-N-cyclobutyl-2-hydroxy-N-meth-
yl-benzamide was prepared from
5-(4-amino-2,6-dimethyl-phenoxy)-N-cyclobut-
yl-2-hydroxy-N-methyl-benzamide according to a procedure analogous
to that described in EXAMPLE 4, Step B. Upon work-up, the reaction
mixture was diluted with 1 N HCl (10 ml) and extracted with ethyl
acetate (3.times.10 ml). The combined organic phases were washed
with 1 N HCl (3.times.40 ml), brine (40 ml), then dried over
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The residue
was purified by preparative TLC (ethyl acetate:hexanes 4:1) to
afford the title product of Step G. MS (APCI.sup.+) Calc.: 365.4,
Found: 366.1 (M+1).
[1024] Step H-Preparation of
N-Cyclobutyl-5-[2,6-Dimethyl-4-(1H-Tetrazol-5-
-Ylamino)-Phenoxy]-2-Hydroxy-N-Methyl-Benzamide
[1025]
N-Cyclobutyl-5-[2,6-dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-h-
ydroxy-N-methyl-benzamide was prepared from
5-(4-cyanoamino-2,6-dimethyl-p-
henoxy)-N-cyclobutyl-2-hydroxy-N-methyl-benzamide according to a
procedure analogous to that described in EXAMPLE 1, Step C. Sodium
azide (1.2 equiv) and ammonium chloride (10 equiv) were used, and
the reaction was heated to 165.degree. C. for 5 hours. After the
reaction had been acidified, the aqueous mixture was washed with
ethyl acetate (3.times.10 ml). The combined organic extracts were
extracted with aqueous 1 N HCl (3.times.50 ml), and brine (50 ml).
The organic phase was dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by preparative
TLC (methanol:water:dichloromethane 15:1.5:83.5) to afford the
title product of Example 6. MS (APCI.sup.+) Calc.: 408.5, Found:
409.2 (M+1).
Example 7
2-Cyclopropylmethanesulfonyl-4-[2,6-Dimethyl-4-(1H-Tetrazol-5-Ylamino)-Phe-
noxy]-Phenol
[1026] Step A-Preparation of
5-(2,6-Dimethyl-4-Nitro-Phenoxy)-2-Methoxy-Be- nzenesulfinic
Acid
[1027] To a solution of chlorosulfonic acid (2.4 ml, 36.6 mmol)
cooled to 0.degree. C. was slowly added
4-(4-methoxy-phenoxy)-3,5-dimethyl-nitroben- zene (2.00 g, 7.3
mmol). The reaction was stirred at RT for 3 hours, then the mixture
was added dropwise to ice-water (150 ml). The mixture was extracted
with ethyl acetate (3.times.100 ml), and the combined organic
phases were extracted with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated. To the residue was
added NaHCO.sub.3 (3.69 g, 43.9 mmol), Na.sub.2SO.sub.3 (2.78 g,
22.0 mmol), and water (25 ml). The mixture was heated to reflux for
3 hours, then cooled to RT. The mixture was acidified carefully
with concentrated HCl, and then extracted with ethyl acetate
(3.times.50 ml). The combined organic phases were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and
concentrated. The title product of Step A was used in the next step
without further purification. MS (APCI.sup.-) Calc.: 337.4, Found:
336.1 (M-1).
[1028] Step B-Preparation of
5-(2,6-Dimethyl-4-Nitro-Phenoxy)-2-Methoxy-Cy-
clopropylmethanesulfonylbenzene
[1029] 5-(2,6-Dimethyl-4-nitro-phenoxy)-2-methoxy-benzenesulfinic
acid (1.88 g, 5.57 mmol) was dissolved in a solution of NaOH (0.22
g, 5.57 mmol, 1.0 equiv) in ethanol (25 ml).
Bromomethyl-cyclopropane (3.76 g, 27.9 mmol, 5.0 equiv) was added,
and the solution was heated to reflux for 6 h, with periodic
addition of aqueous 32% NaOH solution to maintain basicity. The
mixture was then cooled to RT and acidified with aqueous 1 N HCl
solution. The mixture was then diluted with water (100 ml) and
extracted with ethyl acetate (3.times.50 ml). The combined organic
phases were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel chromatography (ethyl acetate:hexanes
grading to 40:60) to afford the title product of Step B. MS
(APCI.sup.-) Calc.: 391.4, Found: 390.2 (M-1).
[1030] Step C-Preparation of
2-Cyclopropylmethanesulfonyl-4-(2,6-Dimethyl--
4-Nitro-Phenoxy)-Phenol
[1031]
2-Cyclopropylmethanesulfonyl-4-(2,6-dimethyl-4-nitro-phenoxy)-pheno-
l was prepared from
5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-cyclopropyl-
methanesulfonylbenzene according to a procedure analogous to that
described in EXAMPLE 2, Step B. Boron tribromide (1 M in
dichloromethane, 2.0 equiv) was used. After 30 minutes, ice water
(50 ml) was added to quench the reaction, and the mixture was
extracted with dichloromethane (3.times.25 ml). The combined
organic phases were dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was dissolved in ethyl
acetate/methanol and stirred with activated carbon, then filtered
through Celite.RTM. and concentrated. The title product of Step C
was used in the next step without further purification. MS
(APCI.sup.-) Calc.: 377.4, Found: 376.1 (M-1).
[1032] Step D-Preparation of
4-(4-Amino-2,6-Dimethyl-Phenoxy)-2-Cyclopropy-
lmethanesulfonyl-Phenol
[1033]
4-(4-Amino-2,6-dimethyl-phenoxy)-2-cyclopropylmethanesulfonyl-pheno-
l was prepared from
2-cyclopropylmethanesulfonyl-4-(2,6-dimethyl-4-nitro-p-
henoxy)-phenol according to a procedure analogous to that described
in EXAMPLE 4, Step A. Methanol was used instead of ethanol as a
co-solvent. Reaction mixture was hydrogenated for 3 hours. After
the mixture was filtered through Celite.RTM. and concentrated, the
title product of Step D was used in the next step without
purification. MS (APCI.sup.-) Calc.: 347.4, Found: 346.0 (M-1).
[1034] Step E-Preparation of
4-(3-Cyclopropylmethanesulfonyl-4-Hydroxy-Phe-
noxy)-3,5-Dimethyl-Phenyl-Cyanamide
[1035]
4-(3-Cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phe-
nyl-cyanamide was prepared from
4-(4-amino-2,6-dimethyl-phenoxy)-2-cyclopr-
opylmethanesulfonyl-phenol according to a procedure analogous to
that described in EXAMPLE 4, Step B. During work-up, the combined
organic phases were washed with 1 N HCl (2.times.50 ml) instead of
aqueous saturated sodium bicarbonate solution. The residue was
purified by preparative TLC (methanol:dichloromethane 4:96) to
afford the title product of Step E. MS (APCI.sup.-) Calc.: 372.4,
Found: 371.4 (M-1).
[1036] Step F-Preparation of
2-Cyclopropylmethanesulfonyl-4-[2,6-Dimethyl--
4-(1H-Tetrazol-5-Ylamino)-Phenoxy]-Phenol
[1037]
2-Cyclopropylmethanesulfonyl-4-[2,6-dimethyl-4-(1H-tetrazol-5-ylami-
no)-phenoxy]-phenol was prepared from
4-(3-cyclopropylmethanesulfonyl-4-hy-
droxy-phenoxy)-3,5-dimethyl-phenyl-cyanamide according to a
procedure analogous to that described in EXAMPLE 1, Step C. Sodium
azide (1.5 equiv) and ammonium chloride (10 equiv) were used, and
the reaction was heated to 140.degree. C. for 20 hours. After the
reaction had been acidified, the aqueous mixture was extracted with
ethyl acetate (3.times.10 ml). The combined organic extracts were
washed with aqueous 1 N HCl (3.times.50 ml), and brine (50 ml). The
organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified by preparative TLC
(methanol:water:dichloromethane =15:1.5:83.5) to afford the title
product of Example 7. MS (APCI.sup.-) Calc.: 415.1, Found: 413.8
(M-1).
[1038] The following compounds can also be made procedures
analogous to those set forth above:
[1039]
2-cyclobutylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamin-
o)-phenoxy]-phenol;
[1040]
2-cyclobutylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazol-5-ylami-
no)-phenoxy]-phenol;
[1041]
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-cyclobuty-
lmethanesulfonyl-phenol;
[1042]
2-cyclopentylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylami-
no)-phenoxy]-phenol;
[1043]
2-cyclopentylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazol-5-ylam-
ino)-phenoxy]-phenol;
[1044]
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-cyclopent-
ylmethanesulfonyl-phenol;
[1045]
2-cyclohexylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamin-
o)-phenoxy]-phenol;
[1046]
2-cyclohexylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazol-5-ylami-
no)-phenoxy]-phenol;
[1047]
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-cyclohexy-
lmethanesulfonyl-phenol;
[1048]
4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-benz-
enesulfonyl)-phenol;
[1049]
4-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-benz-
enesulfonyl)-phenol; and
[1050]
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-
-benzenesulfonyl)-phenol.
Biological Assays
[1051] The utility of the compounds of the present invention can be
evidenced by activity in at least one of the assays described
below.
Assay 1
[1052] Oxygen Consumption
[1053] As would be appreciated by those skilled in the relevant
art, during increased energy expenditure, animals generally consume
more oxygen. In addition, metabolic fuels such as, for example,
glucose and fatty acids, are oxidized to CO.sub.2 and H.sub.2O with
the concomitant evolution of heat, commonly referred to in the art
as thermogenesis. Thus, the measurement of oxygen consumption in
animals, including humans and companion animals, is an indirect
measure of thermogenesis. Indirect calorimetry is commonly used in
animals, e.g., humans, by those skilled in the relevant art to
measure such energy expenditures.
[1054] Those skilled in the art understand that increased energy
expenditure and the concomitant burning of metabolic fuels
resulting in the production of heat may be efficacious with respect
to the treatment of, e.g., obesity. As is well known by those
skilled in the art, thyroid hormones affect cardiac functioning,
for example, by causing an increase in the heart rate and,
accordingly, an increase in oxygen consumption with concomitant
heat production.
[1055] The ability of compounds of the present invention to
generate a thermogenic response may be demonstrated according to
the following protocol.
[1056] A. Experimental.
[1057] This in vivo screen is designed to evaluate the efficacy and
cardiac effects of compounds that are tissue-selective thyroid
hormone agonists. The efficacy endpoints measured are whole body
oxygen consumption and the activity of liver mitochondrial
alpha-glycerophosphate dehydrogenase ("mGPDH"). The cardiac
endpoints that are measured are heart weight and heart mGPDH
activity. The protocol involves: (a) dosing fatty Zucker rats for
about 6 days, (b) measuring oxygen consumption and (c) harvesting
tissue for preparation of mitochondria and subsequent assaying of
enzyme activity thereby.
[1058] B. Preparation of Rats.
[1059] Male fatty Zucker rats having a body weight range of from
about 400 g to about 500 g are housed for from about 3 to about 7
days in individual cages under standard laboratory conditions prior
to the initiation of the study.
[1060] A compound of Formula I, or a pharmaceutically acceptable
salt or prodrug or salt of the prodrug of a compound of Formula I,
vehichle, or T.sub.3 sodium salt, is administered by oral gavage as
a single daily dose given between about 3 p.m. to about 6 p.m. for
about 6 days. A compound of Formula I, or a pharmaceutically
acceptable salt or prodrug or salt of the prodrug of a compound of
Formula I, or T.sub.3 sodium salt is dissolved in a suitably small
volume of about 1 N NaOH and then brought up to a suitable volume
with about 0.01 N NaOH containing about 0.25% of methyl cellulose
(10:1, 0.01N NaOH/MC:1N NaOH). The dosing volume is about 1 ml.
[1061] C. Oxygen Consumption.
[1062] About 1 day after the last dose of the compound is
administered, oxygen consumption is measured using an open circuit,
indirect calorimeter (Oxymax, Columbus Instruments, Columbus, Ohio.
43204). The Oxymax gas sensors are calibrated with N.sub.2 gas and
a gas mixture (about 0.5% of CO.sub.2, about 20.5% of O.sub.2,
about 79% of N.sub.2) before each experiment.
[1063] The subject rats are removed from their home cages and their
body weights recorded. The rats are placed into the sealed chambers
(43.times.43.times.10 cm) of the Oxymax, the chambers are placed in
the activity monitors, and the air flow rate through the chambers
is then set at from about 1.6 l/min to about 1.7 l/min.
[1064] The Oxymax software then calculates the oxygen consumption
(ml/kg/h) by the rats based on the flow rate of air through the
chambers and the difference in oxygen content at the inlet and
output ports. The activity monitors have 15 infrared light beams
spaced about one inch apart on each axis, and ambulatory activity
is recorded when two consecutive beams are broken, and the results
are recorded as counts.
[1065] Oxygen consumption and ambulatory activity are measured
about every 10 minutes for from about 5 hours to about 6.5 hours.
Resting oxygen consumption is calculated on individual rats by
averaging the values excluding the first 5 values and the values
obtained during time periods where ambulatory activity exceeds
about 100 counts.
Assay 2
[1066] Binding to Thyroid Hormone Receptors
[1067] The ability of a compounds of the present invention, ("the
test thyromimetic compounds"), to bind to thyroid hormone receptors
can be demonstrated in the following protocol.
[1068] A. Preparation of Insect Cell Nuclear Extracts
[1069] High Five cell pellets (BTI--TN-5B1-4, catalog number
B855-02, Invitrogen.RTM., Carlsbad, Calif.) obtained about 48 hours
after infection with baculovirus (GibcoBRL.RTM., Gaithersburg, Md.)
expressing either human TR.alpha. or TR.beta. are suspended in ice
cold Sample Buffer (10 mM Tris, pH 8.0; 1 mM MgCl.sub.2; 1 mM DTT;
0.05% Tween 20; 1 mM 4-(2-aminoethyl)-benzenesulfonylfluoride; 25
pg/ml leupeptin). After about 10 minutes incubation on ice, the
suspension is homogenized by 20 strokes with a Dounce homogenizer
(VWR.RTM. Scientific Products, West Chester, Pa.) and centrifuged
at 800.times. g for about 15 minutes at 4.degree. C. The pellet
(nuclei) is suspended in a hypertonic buffer (0.4 M KCl; 10 mM
Tris, pH 8.0; 1 mM MgCl.sub.2; 1 mM DTT; 0.05% Tween 20) and
incubated for about 30 min on ice. The suspension is centrifuged at
100,000.times.g for about 30 minutes at 4.degree. C. The
supernatant (nuclear extract) is stored in 0.5 ml aliquots at
-80.degree. C.
[1070] B. Binding Assay
[1071] Competition binding assays to measure the interaction of the
test thyromimetic compounds with thyroid hormone receptor .alpha.1
and .beta.1 (TR.alpha. and TR.beta.) are carried out according to
the following protocol.
[1072] Solutions of test thyromimetic compounds (final compound
concentration of 20 mM) are prepared using 100% DMSO as a solvent.
Each compound is serially diluted in an assay buffer (5 mM
Tris-HCl, pH 8.0; 50 mM NaCl; 2 mM EDTA; 10% (v/v) glycerol; 1 mM
DTT, "assay buffer") containing 0.4 nM .sup.1251-T.sub.3 (specific
activity of about 2200 Ci/mmol) to yield solutions that vary in
compound concentration from about 10 pM to about 0.1 nM.
[1073] High Five insect cell nuclear extract containing either
TR.alpha. or TR.beta. is diluted to a total protein concentration
of 0.0075 mg/ml using the assay buffer as diluent.
[1074] One volume (100 .mu.l) of each thyromimetic compound
dilution (containing 0.4 nM .sup.1251-T3) is combined with an equal
volume (100 .mu.l) of diluted nuclear extract containing TR.alpha.1
or TR.beta.1, and incubated at RT for about 90 min. A one hundred
and fifty .mu.l sample of the binding reaction is removed and
placed into a 96-well filter plate (Millipore.RTM., Bedford, Mass.)
that has been pre-washed with ice-cold assay buffer. The plate is
subjected to vacuum filtration using a filtration manifold
(Millipore.RTM.). Each well is washed five times by the addition of
200 .mu.l, of ice-cold assay buffer and subsequent vacuum
filtration. The plate is removed from the vacuum filtration
manifold, the bottom of the plate is briefly dried on paper towels,
then 25 .mu.l of Wallac.RTM. (EG&G Wallac.RTM., Gaithersburg,
Md.) Optiphase Supermix scintillation cocktail is added to each
well and the top of the plate is covered with plastic sealing tape
(Microplate Press-on Adhesive Sealing Film, Packard.RTM. Instrument
Co., Inc., Downers Grove, Ill.) and the radioactivity is
quantitated using a Wallac.RTM. Microbeta 96-Well plate
scintillation counter.
* * * * *