Title: Therapeutic uses of tri-aryl acid derivatives
Abstract: The use of triaryl acid derivatives of formula (I) ##STR1##
and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR receptor.
Patent Number: 7,005,440 Issued on 02/28/2006 to Jayyosi, et al.
| Inventors:
|
Jayyosi; Zaid (Flemington, NJ);
McGeehan; Gerard M. (Chester Springs, PA);
Kelley; Michael F. (West Chester, PA);
Labaudiniere; Richard F. (Collegeville, PA);
Zhang; Litao (Kennett Square, PA);
Groneberg; Robert D. (Boulder, CO);
McGarry; Daniel G. (King of Prussia, PA);
Caulfield; Thomas J. (Paris, FR);
Minnich; Anne (Flemington, NJ);
Bobko; Mark (Exton, PA);
Morris; Robert (Wayne, PA)
|
| Assignee:
|
Aventis Pharma Deutschland GmbH (Frankfurt am Main, DE)
|
| Appl. No.:
|
724496 |
| Filed:
|
November 28, 2000 |
| Current U.S. Class: |
514/375; 514/279; 514/247; 514/248; 548/217; 544/242; 544/249 |
| Current Intern'l Class: |
A01N 43/76 (20060101) |
| Field of Search: |
548/236,217
514/374,252.01,824,866,375,279,247,248
544/242,249
|
References Cited [Referenced By]
U.S. Patent Documents
| 4920131 | Apr., 1990 | Huang et al.
| |
| 5051427 | Sep., 1991 | Huang et al.
| |
| 5508408 | Apr., 1996 | von Sprecher et al.
| |
| 6376512 | Apr., 2002 | Jayyosi et al.
| |
| Foreign Patent Documents |
| 0 643 045 | Mar., 1995 | EP.
| |
| WO 89/0430/3 | May., 1989 | WO.
| |
| WO 89/0529/4 | Jun., 1989 | WO.
| |
| WO 89/1262/9 | Dec., 1989 | WO.
| |
| WO 92/2253/3 | Dec., 1992 | WO.
| |
| WO 97/2433/1 | Jul., 1997 | WO.
| |
| WO 97/2785/7 | Aug., 1997 | WO.
| |
| WO 97/2814/9 | Aug., 1997 | WO.
| |
| WO 97/3190/7 | Sep., 1997 | WO.
| |
| WO 9731907 | Sep., 1997 | WO.
| |
| WO 98/2797/4 | Jul., 1998 | WO.
| |
| WO 99/0735/7 | Feb., 1999 | WO.
| |
| WO 99/0850/1 | Feb., 1999 | WO.
| |
| WO 99/2027/5 | Apr., 1999 | WO.
| |
| WO 00/6488/8 | Nov., 2000 | WO.
| |
Other References
Co-pending U.S. Appl. No. 09/490,897, filed on Jan. 27, 2000.
Co-pending U.S. Appl. No. 09/622,649, filed on Sep. 14, 2000.
|
Primary Examiner: Wilson; James O.
Assistant Examiner: Fedowitz; Matthew L.
Attorney, Agent or Firm: Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of International Application No. PCT/US00/11490,
filed on Apr. 28, 2000, which application, in turn, claims priority from U.S. Provisional
Application No. 60/131,454, filed on Apr. 28, 1999.
Claims
What is claimed is:
1. A compound of formula I
##STR215##
wherein:
##STR216##
is quinoxalinyl, quinazolinyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,
benzofuranyl, benzothiophenyl, oxazolyl, thiazolyl, oxadiazolyl, isoxazolyl, imidazolyl,
pyrazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,
which is optionally substituted by one or more ring system substituents;
##STR217##
and
##STR218##
are, independently, aryl, which are optionally substituted by one or more ring
system substituents;
A is —O—, —S—, —SO—, —SO
2—,
—NR
13—, —C(O)—, —N(R
14)C(O)—,
—C(O)N(R
5)—, —N(R
14)C(O)N(R
15)—,
—C(R
14)═N—, a chemical bond,
##STR219##
B is —O—, —S—, —SO—, —SO
2—,
ethynylene, —C(O)—, —N(R
18)C(O)—, or —C(O)NR
18—;
D is —O—, —S—, —NR
19—, a chemical
bond, ethynylene, —N(R
20)C(O)—, —C(O)—, or
—C(O)N(R
20)—;
E is a chemical bond or an ethylene group;
a is 0-4;
b is 0-4;
c is 0-4;
d is 0-5;
e is 0-4;
f is 0-6;
g is 1-4;
h is 1-4;
R
1, R
3, R
5, R
7, R
9, and
R
11, are independently hydrogen, halogen, alkyl, carboxyl, alkoxycarbonyl
or aralkyl;
R
2, R
4, R
6, R
8, R
10 and
R
12, are independently —(CH
2)
q—X;
q is 0-3;
X is hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carboxyl, alkoxycarbonyl,
tetrazolyl, acyl, acylHNSO
2—, —SR
23, Y
1Y
2N—
or Y
3Y
4NCO—;
Y
1 and Y
2 are independently hydrogen, alkyl, aryl, aralkyl
or heteroaralkyl, or one of Y
1 and Y
2 is hydrogen or alkyl
and the other of Y
1 and Y
2 is acyl or aroyl;
Y
3 and Y
4 are independently hydrogen, alkyl, aryl, aralkyl
or heteroaralkyl;
Z is R
21O
2C—, R
21OC—, cyclo-imide,
—CN, R
21O
2SHNCO—, R
21O
2SHN—,
(R
21)
2NCO—, R
21O—2,4-thiazolidinedionyl,
or tetrazolyl; and
R
21 is hydrogen, alkyl, aryl, cycloalkyl, or aralkyl;
R
13, R
19 and R
23 are independently R
22OC—,
R
22NHOC—, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,
heteroaralkyl, or aralkyl;
R
14, R
15, R
16, R
18 and R
20 are
independently hydrogen, alkyl, aralkyl, carbonyl, or alkoxycarbonyl;
or R
14, and R
15 taken together with the carbon and nitrogen
atoms through which they are linked form a 5 or 6-membered azaheterocyclyl group; and
R
22 is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,
heteroaralkyl, or aralkyl; or
a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof
or a solvate thereof;
wherein
"alkyl," when used to designate an alkyl group per se or when used as an alkyl
component of any other group, is an aliphatic hydrocarbon group which is straight
or branched having 1 to about 20 carbon atoms and is optionally substituted by
one or more alkyl group substituents;
"aryl" is an aromatic monocyclic or multicyclic ring system of about 6 to about
14 carbon atoms, which is optionally substituted by one or more ring system substituents;
"heteroaryl" is an aromatic monocyclic or multicyclic ring system of about 5
to about 14 carbon atoms, in which at least one of the carbon atoms in the ring
system is replaced by nitrogen, oxygen or sulfur, which is optionally substituted
by one or more ring system substituents;
"heterocyclyl" is a non-aromatic saturated monocyclic or multicyclic ring system
of 3 to about 10 carbon atoms, in which at least one of the carbon atoms in the
ring system is replaced by nitrogen, oxygen or sulfur, which is optionally substituted
by one or more ring system substituents;
"heteroaralkyl" is a heteroaryl-alkyl group, wherein the heteroaryl and alkyl
groups are as defined above;
an "alkyl group substituent" is halo, carboxy, cycloalkyl, cycloalkenyl, heterocyclyl,
heterocyclenyl, aryl, alkoxy, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl,
or Y
1Y
2NCO—, wherein Y
1 and Y
2 are
independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or Y
1 and
Y
2 taken together with the nitrogen atom to which Y
1 and
Y
2 are attached form heterocyclyl wherein the substituents may contain
further alkyl group substituents or ring system substituents as recited herein; and
a "ring system substituent" is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
aralkyl, heteroaralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,
nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl,
alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl,
fused cycloalkenyl, fused heterocyclyl, fused heterocyclenyl, arylazo, heteroarylazo,
R
aR
bN—, R
cR
dNCO—, R
cO
2CN—,
or R
cR
dNSO
2— wherein R
a and R
b
are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or one
of R
a and R
b is hydrogen or alkyl and the other of R
a
and R
b is aroyl or heteroaroyl, and R
c and R
d
are independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,
heterocyclyl, heterocyclenyl, aralkyl or heteroaralkyl and, where the ring is cycloalkyl,
cycloalkenyl, heterocyclyl or heterocyclenyl, the ring system substituent may also
include methylene, oxo and thioxo on carbon atoms thereof
wherein the substituents may contain further alkyl group substituents or ring
system substituents as recited herein.
2. A compound according to claim 1 wherein
##STR220##
is optionally substituted quinoxalinyl, quinazolinyl, benzoxazolyl, benzimidazolyl,
benzothiazolyl, oxazolyl, thiazolyl, oxadiazolyl, isoxazolyl, imidazolyl, pyrazolyl,
thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
3. A compound according to claim 1 wherein a=1, 2 or 3; R
1 and R
2
are hydrogen; A is —O—; and b=0.
4. A compound according to claim 1 wherein c=0 or 1; R
5 and R
6
are hydrogen; B is —O—; and d=0 or 1.
5. A compound according to claim 1 wherein e=0; f=0 or 1; D and E is a chemical
bond; Z is tetrazolyl, NH
2CO— or —CO
2R
21;
and R
21 is hydrogen or lower alkyl.
6. A compound according to claim 1 wherein e=0; f=0 or 1; D is —O—
or a chemical bond; E is a chemical bond; and Z is tetrazolyl, NH
2CO—
or —CO
2R
21;
and R
21 is hydrogen or lower alkyl.
7. A compound according to claim 1 wherein
##STR221##
is an unsubstituted quinozalin-2-yl, 3-substituted quinozalin-2-yl, 6-substituted
quinozalin-2-yl or 3,6-disubstituted quinozalin-2-yl; unsubstituted quinazolin-2-yl,
4-substituted quinazolin-2-yl or 6-substituted quinazolin-2-yl; 2-substituted-oxazol-4-yl
or 2,5 disubstituted-oxazol-4-yl; 4-substituted oxazol-2-yl or 4,5-disubstituted-oxazol-2-yl;
2-substituted thiazol-4-yl or 2,5-disubstituted thiazol-4-yl; 4-substituted thiazol-2-yl
or 4,5-disubstituted-thiazol-2-yl; 5-substituted-[1,2,4]oxadiazol-3-yl; 3-substituted-[1,2,4]oxadiazol-5-yl;
5-substituted-imidazol-2-yl or 3,5-disubstituted-imidazol-2-yl; 2-substituted-imidazol-5-yl
or 2,3-disubstituted-imidazol-5-yl; 3-substituted-isoxazol-5-yl; 5-substituted-isoxazol-3-yl;
5-substituted-[1,2,4] thiadiazol-3-yl; 3-substituted-[1,2,4]-thiadiazol-5-yl; 2-substituted-[1,3,4]-thiadiazol-5-yl;
2-substituted-[1,3,4]-oxadiazol-5-yl; 1-substituted-pyrazol-3-yl; 3-substituted-pyrazol-5-yl;
3-substituted-[1,2,4]-triazol-5-yl; 1-substituted-[1,2,4]-triazol-3-yl; 3-substituted
pyridin-2-yl, 5-substituted pyridin-2-yl, 6-substituted pyridin-2-yl or 3,5-disubstituted
pyridin-2-yl; 3-substituted pyrazin-2-yl, 5-substituted pyrazin-2-yl, 6-substituted
pyrazin-2-yl or 3,5 disubstituted-pyrazin-2-yl; 5-substituted pyrimidin-2-yl or
6-substituted-pyrimidin-2-yl; 6-substituted-pyridazin-3-yl or 4,6-disubstituted-pyridazin-3-yl;
unsubstituted-benzothiazol-2-yl or 5-substituted-benzothiazol-2-yl; unsubstituted
benzoxazol-2yl or 5-substituted-benzoxazol-2yl; unsubstituted-benzimidazol-2-yl
or 5-substituted-benzimidazol-2-yl; unsubstituted-thiophen-2-yl, 3-substituted-thiophen-2-yl,
6-substituted-thiophen-2-yl or 3,6-disubstituted-thiophen-2-yl; unsubstituted-benzofuran-2-y,
3-substituted-benzofuran-2-yl, 6-substituted-benzofuran-2-yl or 3,6-disubstituted-benzofuran-2-yl;
3-substituted-benzofuran-6-yl or 3,7-disubstituted-benzofuran-6-yl.
8. A compound according to claim 7 wherein
##STR222##
is substituted by a substituent selected from the group consisting of phenyl,
substituted-phenyl, thienyl, substituted thienyl, cycloalkyl, straight or branched
lower alkyl, fluoro, chloro, alkoxy, aralkyloxy, trifluoromethyl and trifluoromethyloxy.
9. A compound according to claim 1 wherein R
1 and R
2 are
hydrogen; a=1; A is —O—; and b=0.
10. A compound of formula (Ia)
##STR223##
wherein:
##STR224##
is quinoxalinyl, quinazolinyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,
benzofuranyl, benzothiophenyl, oxazolyl, thiazolyl, oxadiazolyl, isoxazolyl, imidazolyl,
pyrazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,
which is optionally substituted by one or more ring system substituents;
##STR225##
is aryl, which is optionally substituted by one or more ring system substituents;
A is —O—, —S—, —SO—, —SO
2—,
—NR
13—, —C(O)—, —N(R
14)C(O)—,
—C(O)N(R
15)—, —N(R
14)C(O)N(R
15)—,
—C(R
14)═N—, a chemical bond,
##STR226##
B is —O—, —S—, —SO—, —SO
2—,
ethynylene, —C(O)—, —N(R
18)C(O)—, or —C(O)NR
18—;
D is —O—, —S—, —NR
19—, a chemical
bond, ethynylene, —N(R
20)C(O)—, —C(O)—, or —C(O)N(R
20)—;
E is a chemical bond or an ethylene group;
a is 0-4;
b is 0-4;
c is 0-4;
d is 0-5;
e is 0-4;
f is 0-6;
g is 1-4;
h is 1-4;
R
1, R
3, R
5, R
7, R
9, and
R
11, are independently hydrogen, halogen, alkyl, carboxyl, alkoxycarbonyl
or aralkyl;
R
2, R
4, R
6, R
8, R
10 and
R
12, are independently —(CH
2)
q—X;
q is 0-3;
X is hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carboxyl, alkoxycarbonyl,
tetrazolyl, acyl, acylHNSO
2—, —SR
23, Y
1Y
2N—
or Y
3Y
4NCO—;
Y
1 and Y
2 are independently hydrogen, alkyl, aryl, aralkyl
or heteroaralkyl, or one of Y
1 and Y
2 is hydrogen or alkyl
and the other of Y
1 and Y
2 is acyl or aroyl;
Y
3 and Y
4 are independently hydrogen, alkyl, aryl, aralkyl
or heteroaralkyl;
Z is R
21O
2C—, R
21OC—, cyclo-imide,
—CN, R
21O
2SHNCO—, R
21O
2SHN—,
(R
21)
2NCO—, R
21O-2,4-thiazolidinedionyl,
or tetrazolyl;
R′ and R" are, independently, hydrogen or ring system substituents;
R
21 is hydrogen, alkyl, aryl, cycloalkyl, or aralkyl;
R
13, R
19 and R
23 are independently R
22OC—,
R
22NHOC—, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,
heteroaralkyl, or aralkyl;
R
14, R
15, R
16, R
18 and R
20 are
independently hydrogen, alkyl, aralkyl, carbonyl, or alkoxycarbonyl;
or R
14, and R
15 taken together with the carbon and nitrogen
atoms through which they are linked form a 5 or 6-membered azaheterocyclyl group; and
R
22 is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,
heteroaralkyl, or aralkyl; or
a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof
or a solvate thereof;
wherein
"alkyl," when used to designate an alkyl group per se or when used as an alkyl
component of any other group, is an aliphatic hydrocarbon group which is straight
or branched having 1 to about 20 carbon atoms and is optionally substituted by
one or more alkyl group substituents;
"aryl" is an aromatic monocyclic or multicyclic ring system of about 6 to about
14 carbon atoms, which is optionally substituted by one or more ring system substituents;
"heteroaryl" is an aromatic monocyclic or multicyclic ring system of about 5
to about 14 carbon atoms, in which at least one of the carbon atoms in the ring
system is replaced by nitrogen, oxygen or sulfur, which is optionally substituted
by one or more ring system substituents;
"heterocyclyl" is a non-aromatic saturated monocyclic or multicyclic ring system
of 3 to about 1.0 carbon atoms, in which at least one of the carbon atoms in the
ring system is replaced by nitrogen, oxygen or sulfur, which is optionally substituted
by one or more ring system substituents;
"heteroaralkyl" is a heteroaryl-alkyl group, wherein the heteroaryl and alkyl
groups are as defined above;
an "alkyl group substituent" is halo, carboxy, cycloalkyl, cycloalkenyl, heterocyclyl,
heterocyclenyl, aryl, alkoxy, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl,
or Y
1Y
2NCO—, wherein Y
1 and Y
2 are
independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or Y
1 and
Y
2 taken together with the nitrogen atom to which Y
1 and
Y
2 are attached form heterocyclyl
wherein the substituents may contain further alkyl group substituents or ring
system substituents as recited herein; and
a "ring system substituent" is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
aralkyl, heteroaralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,
nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl,
alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl,
fused cycloalkenyl, fused heterocyclyl, fused heterocyclenyl, arylazo, heteroarylazo,
R
aR
bN—, R
cR
dNCO—, R
cO
2CN—,
or R
cR
dNSO
2— wherein R
a and R
b
are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or one
of R
a and R
b is hydrogen or alkyl and the other of R
a
and R
b is aroyl or heteroaroyl, and R
c and R
d
are independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,
heterocyclyl, heterocyclenyl, aralkyl or heteroaralkyl and, where the ring is cycloalkyl,
cycloalkenyl, heterocyclyl or heterocyclenyl, the ring system substituent may also
include methylene, oxo and thioxo on carbon atoms thereof
wherein the substituents may contain further alkyl group substituents or ring
system substituents as recited herein.
11. A compound according to claim 10 wherein
a=1 or 2;
A is —O—;
b=0;
R
1, R
2, R
7 and R
8 are independently
hydrogen;
##STR227##
is optionally substituted phenyl;
c=0;
B is —O—;
d=1;
e=0;
f=0;
D and E are a chemical bond;
R′ is hydrogen, halo or benzyloxy;
R" is lower alkyl;
Z is —CO
2H.
12. A compound according to claim 10 wherein:
a=1;
A is —O—;
b=0;
c=0-1;
B is —O—;
d=0 or 1, wherein c+d=1 or 2;
e=0;
f=0;
D and E are a chemical bond;
R′ is hydrogen, aralkoxy, or halo;
R" is lower alkyl;
Z is —CO
2H.
13. A compound according to claim 10 wherein:
a=1;
A is —O—;
b=0;
c=0;
B is —O—;
d=1;
e=0;
f=0;
D and E are a chemical bond;
R′ is hydrogen;
R" is lower alkyl;
Z is —CO
2H.
14. A compound according to claim 10 wherein:
a=1;
A is —O—;
b=0;
c=0;
B is —O—;
d=1;
e=0;
f=0;
D and E are a chemical bond;
R′ is hydrogen;
R" is methyl;
Z is —CO
2H.
15. A compound according to claim 10 wherein:
##STR228##
is optionally substituted quinoxalinyl, quinazolinyl, benzoxazolyl, benzimidazolyl,
benzothiazolyl, oxazolyl, thiazolyl, oxadiazolyl, isoxazolyl, imidazolyl, pyrazolyl,
thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
##STR229##
is optionally substituted phenyl;
a=1;
A is —O—;
b=0;
c=0;
B is —O—;
d=1;
e=0;
f=0;
D and E are a chemical bond;
R′ is hydrogen;
R" is lower alkyl;
Z is CO
2H.
16. A pharmaceutical composition comprising a pharmaceutically acceptable amount
of the compound according to claim 1 and a pharmaceutically acceptable carrier.
17. A method of treating a patient suffering from a physiological disorder capable
of being modulated by a compound according to claim 1 having PPAR ligand binding
activity, comprising administering to the patient a pharmaceutically effective
amount of the compound, or a pharmaceutically acceptable salt thereof.
18. A method according to claim 17 wherein the physiological disorder is associated
with a physiological detrimental blood level of insulin, glucose, free fatty acids
(FFA), or triglycerides.
19. The method according to claim 18, wherein the physiological disorder is hyperglycemia.
20. The method according to claim 19, wherein the hyperglycemia is diabetes.
21. The method according to claim 19, wherein the hyperglycemia is Type II diabetes.
22. The method according to claim 18, wherein the physiological disorder is hyperinsulinism.
23. The method according to claim 22, wherein the hyperinsulinism is Syndrome X.
24. The method according to claim 18, wherein the physiological disorder is insulin resistance.
25. The method according to claim 18, wherein the physiological disorder is a
cardiovascular condition.
26. The method according to claim 25, wherein the cardiovascular condition is atherosclerosis.
27. The method according to claim 18, wherein the physiological disorder is hyperlipidemia.
28. The method according to claim 18, wherein the physiological disorder is hypertension.
29. The method according to claim 18, wherein the physiological disorder is an
eating disorder.
30. The method according to claim 17 wherein the mediating is agonistic.
31. The method according to claim 17 wherein the mediating is antagonistic.
32. A method for mediating the activity of PPAR-γ receptor comprising contacting
said PPAR-γ receptor with a compound of according to claim 1.
33. A pharmaceutical composition comprising a pharmaceutically acceptable amount
of the compound according to claim 10 and a pharmaceutically acceptable carrier.
34. A method of treating a patient suffering from a physiological disorder capable
of being modulated by a compound according to claim 10 having PPAR ligand binding
activity, comprising administering to the patient a pharmaceutically effective
amount of the compound, or a pharmaceutically acceptable salt thereof.
35. A method according to claim 34 wherein the physiological disorder is associated
with a physiological detrimental blood level of insulin, glucose, free fatty acids
(FFA), or triglycerides.
36. The method according to claim 34, wherein the physiological disorder is hyperglycemia.
37. The method according to claim 36, wherein the hyperglycemia is diabetes.
38. The method according to claim 36, wherein the hyperglycemia is Type II diabetes.
39. The method according to claim 34, wherein the physiological disorder is hyperinsulinism.
40. The method according to claim 39, wherein the hyperinsulinism is Syndrome X.
41. The method according to claim 34, wherein the physiological disorder is insulin resistance.
42. The method according to claim 34, wherein the physiological disorder is a
cardiovascular disorder.
43. The method according to claim 42, wherein the cardiovascular disorder is atherosclerosis.
44. The method according to claim 34, wherein the physiological disorder is hyperlipidemia.
45. The method according to claim 34, wherein the physiological disorder is hypertension.
46. The method according to claim 34, wherein the physiological disorder is an
eating disorder.
47. The method according to claim 34 wherein the mediating is agonistic.
48. The method according to claim 34 wherein the mediating is antagonistic.
49. A method for mediating the activity of PPAR receptor comprising contacting
said PPAR receptor with a compound of according to claim 10.
50. A compound as claimed in claim 1, wherein the optional ring system substituents
for Ar I are selected from the group consisting of phenyl, substituted-phenyl,
thienyl, substituted thienyl, cycloalkyl, straight or branched lower alkyl, fluoro,
chloro, alkoxy, aralkyloxy, trifluoromethyl and trifluoromethyloxy.
51. A compound as claimed in claim 11, wherein R" is methyl.
52. A compound as claimed in claim 12, wherein R" is methyl.
53. A compound as claimed in claim 1, wherein the compound is
##STR230##
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
54. A compound as claimed in claim 1, wherein the compound is
##STR231##
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
55. A compound as claimed in claim 1, wherein the compound is
##STR232##
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
56. A compound as claimed in claim 1, wherein the compound is
##STR233##
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Description
BACKGROUND OF THE INVENTION
This invention is directed to the use of triaryl acid derivatives and their
pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor
binders of this invention are useful as agonists or antagonists of the PPAR receptor.
FIELD OF THE INVENTION
Peroxisome proliferator-activated receptors (PPAR) can be subdivided into
three subtypes, namely: PPARα, PPARδ, and PPARγ. These are encoded
by different genes (Motojima, Cell Structure and Function, 18:267-277, 1993). Moreover,
2 isoforms of PPARγ also exist, PPARγ
1, and γ
2.
These 2 proteins differ in their NH
2-terminal-30 amino acids and are
the result of alternative promoter usage and differential mRNA splicing (Vidal-Puig,
Jimenez, Linan, Lowell, Hamann, Hu, Spiegelman, Flier, Moller, J. Clin. Invest.,
97:2553-2561, 1996).
Biological processes modulated by PPAR are those modulated by receptors,
or receptor 24 combinations, which are responsive to the PPAR receptor ligands
described herein. These processes include, for example, plasma lipid transport
and fatty acid catabolism, regulation of insulin sensitivity and blood glucose
levels, which are involved in hypoglycemia/hyperinsulinism (resulting from, for
example, abnormal pancreatic beta cell function, insulin secreting tumors and/or
autoimmune hypoglycemia due to autoantibodies to insulin, the insulin receptor,
or autoantibodies that are stimulatory to pancreatic beta cells), macrophage differentiation
which lead to the formation of atherosclerotic plaques, inflammatory response,
carcinogenesis, hyperplasia or adipocyte differentiation.
Obesity is an excessive accumulation of adipose tissue. Recent work in this
area indicates that PPARγ plays a central role in the adipocyte gene expression
and differentiation. Excess adipose tissue is associated with the development of
serious medical conditions, for example, non-insulin-dependent diabetes mellitus
(NIDDM), hypertension, coronary artery disease, hyperlipidemia and certain malignancies.
The adipocyte may also influence glucose homeostasis through the production of
tumor necrosis factor α (TNFα) and other molecules.
Non-insulin-dependent diabetes mellitus (NIDDM), or Type II
diabetes, is the more common form of diabetes, with 90-95% of hyperglycemic patients
experiencing this form of the disease. In NIDDM there appears to be a reduction
in the pancreatic β-cell mass, several distinct defects in insulin secretion
or a decrease in tissue sensitivity to insulin. The symptoms of this form of diabetes
include fatigue, frequent urination, thirst, blurred vision, frequent infections
and slow healing of sores, diabetic nerve damage and renal disease.
Resistance to the metabolic actions of insulin is one of the key features
of non-insulin dependent diabetes (NIDDM). Insulin resistance is characterised
by impaired uptake and utilization of glucose in insulin-sensitive target organs,
for example, adipocytes and skeletal muscle, and by impaired inhibition of hepatic
glucose output. The functional insulin deficiency and the failure of insulin to
supress hepatic glucose output results in fasting hyperglycemia. Pancreatic β-cells
compensate for the insulin resistance by secreting increased levels of insulin.
However, the β-cells are unable to maintain this high output of insulin,
and, eventually, the glucose-induced insulin secretion falls, leading to the deterioration
of glucose homeostasis and to the subsequent development of overt diabetes.
Hyperinsulinemia is also linked to insulin resistance, hypertriglyceridaemia
and increased plasma concentration of low density lipoproteins. The association
of insulin resistance and hyperinsulinemia with these metabolic disorders has been
termed "Syndrome X" and has been strongly linked to an increased risk of hypertension
and coronary artery disease.
Metformin is known in the art to be used in the treatment of diabetes in
humans (U.S. Pat. No. 3,174,901). Metformin acts primarily to decrease liver glucose
production. Troglitazone®) is known to work primarily on enhancing the ability
of skeletal muscle to respond to insulin and take up glucose. It is known that
combination therapy comprising metformin and troglitazone can be used in the treatment
of abnormalities associated with diabetes (DDT 3:79-88, 1998).
PPARγ activators, in particular Troglitazone®, have been found
to convert cancerous tissue to normal cells in liposarcoma, a tumor of fat (PNAS
96:3951-3956, 1999). Furthermore, it has been suggested that PPAR γ activators
may be useful in the treatment of breast and colon cancer (PNAS 95:8806-8811, 1998,
Nature Medicine 4:1046-1052, 1998).
Moreover, PPARγ activators, for example Troglitazone®, have
been implicated in the treatment of polycystic ovary syndrome (PCO). This is a
syndrome in women that is characterized by chronic anovulation and hyperandrogenism.
Women with this syndrome often have insulin resistance and an increased risk for
the development of noninsulin-dependent diabetes mellitus. (Dunaif, Scott, Finegood,
Quintana, Whitcomb, J. Clin. Endocrinol. Metab., 81:3299, 1996.
Furthermore, PPARγ activators have recently been discovered to
increase the production of progesterone and inhibit steroidogenesis in granulosa
cell cultures and therefore may be useful in the treatment of climacteric. (U.S.
Pat. No. 5,814,647 Urban et al. Sep. 29, 1998; B. Lohrke et al. Journal of Edocrinology,
159, 429-39, 1998). Climacteric is defined as the syndrome of endocrine, somatic
and psychological changes occurring at the termination of the reproductive period
in the female.
Peroxisomes are cellular organelles which play a role in controlling
the redox potential and oxidative stress of cells by metabolizing a variety of
substrates such as hydrogen peroxide. There are a number of disorders associated
with oxidative stress. For example, inflammatory response to tissue injury, pathogenesis
of emphysema, ischemia-associated organ injury (shock), doxorubicin-induced cardiac
injury, drug-induced hepatotoxicity, atherosclerosis, and hyperoxic lung injuries,
are each associated with the production of reactive oxygen species and a change
in the reductive capacity of the cell. Therefore, it is envisaged that PPARα
activators, among other things, regulate the redox potential and oxidative stress
in cells, would be effective in the treatment of these disorders (Poynter et al,
J. Biol. Chem. 273, 32833-41, 1998).
It has also been discovered that PPARα agonists inhibit NFΛB-mediated
transcription thereby modulating various inflammatory responses such as the inducible
nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) enzyme pathways (Pineda-Torra,
I. T al, 1999, Curr. Opinion in Lipidology, 10,151-9) and thus can be used in the
therapeutic intervention of a wide variety of inflammatory diseases and other pathologies
(Colville-Nash, et al., Journal of Immunology, 161, 978-84, 1998; Staels et al,
Nature, 393, 790-3, 1998).
Peroxisome proliferators activate PPAR, which in turn, acts as a transcription
factor, and causes differentiation, cell growth and proliferation of peroxisomes.
PPAR activators are also thought to play a role in hyperplasia and carcinogenesis
as well as altering the enzymatic capability of animal cells, such as rodent cells,
but these PPAR activators appear to have minimal negative effects in human cells
(Green, Biochem. Pharm. 43(3):393, 1992). Activation of PPAR results in the rapid
increase of gamma glutamyl transpeptidase and catalase.
PPARα is activated by a number of medium and long-chain fatty acids
and is involved in stimulating β-oxidation of fatty acids in tissues such
as liver, heart, skeletal muscle, and brown adipose tissue (Isseman and Green,
supra; Beck et al., Proc. R. Soc. Lond. 247:83-87, 1992; Gottlicher et al., Proc.
Natl. Acad. Sci. USA 89:4653-4657, 1992). Pharmacological PPARα activators,
for example fenofibrate, clofibrate, genfibrozil, and bezafibrate, are also involved
in substantial reduction in plasma triglycerides along with moderate reduction
in LDL cholesterol, and they are used particularly for the treatment of hypertriglyceridemia,
hyperlipidemia and obesity. PPARα is also known to be involved in inflammatory
disorders. (Schoonjans, K., Current Opionion in Lipidology, 8, 159-66, 1997).
The human nuclear receptor PPARδ has been cloned from a human osteosarcoma
cell cDNA library and is fully described in A. Schmidt et al., Molecular Endocrinology,
6:1634-1641 (1992), the contents of which are hereby incorporated herein by reference.
It should be noted that PPARδ is also referred to in the literature as PPARβ
and as NUC1, and each of these names refers to the same receptor. For example,
in A. Schmidt et al., Molecular Endocrinology, 6: pp. 1634-1641, 1992, the receptor
is referred to as NUC1. PPARδ is observed in both embryo and adult tissues.
This receptor has been reported to be involved in regulating the expression of
some fat-specific genes, and plays a role in the adipogenic process (Amri, E. et
al., J. Biol. Chem. 270, 2367-71, 1995).
Atherosclerotic disease is known to be caused by a number of factors,
for example, hypertension, diabetes, low levels of high density lipoprotein (HDL),
and high levels of low density lipoprotein (LDL). In addition to risk reduction
via effects on plasma lipid concentrations and other risk factors, PPARα
agonists exert direct atheroprotective effects (Frick, M. H., et al. 1997. Circulation
96:2137-2143, de Faire, et al. 1997. Cardiovasc. Drugs Ther. 11 Suppl 1:257-63:257-263).
It has recently been discovered that PPARδ agonists are useful in raising
HDL levels and therefore useful in treating atherosclerotic diseases. (Leibowitz
et al.; WO/9728149). Atherosclerotic diseases include vascular disease, coronary
heart disease, cerebrovascular disease and peripheral vessel disease. Coronary
heart disease includes CHD death, myocardial infarction, and coronary revascularization.
Cerebrovascular disease includes ischemic or hemorrhagic stroke and transient ischemic attacks.
PPARγ subtypes are involved in activating adipocyte differentiation,
and are not involved in stimulating peroxisome proliferation in the liver. Activation
of PPARγ is implicated in adipocyte differentiation through the activation
of adipocyte-specific gene expression (Lehmann, Moore, Smith-Oliver, Wilkison,
Willson, Kliewer, J. Biol. Chem., 270:12953-12956, 1995). The DNA sequences for
the PPARγ receptors are described in Elbrecht et al., BBRC 224;431437 (1996).
Although peroxisome proliferators, including fibrates and fatty acids, activate
the transcriptional activity of PPAR's, only prostaglandin J
2 derivatives
such as the arachidonic acid metabolite 15-deoxy-delta
12, 14-prostaglandin
J
2 (15d-PGJ
2) have been identified as natural ligands specific
for the PPARγ subtype, which also binds thiazolidinediones. This prostaglandin
activates PPARγ-dependent adipogenesis, but activates PPARα only at
high concentrations (Forman, Tontonoz, Chen, Brun, Spiegelman, Evans, Cell, 83:803-812,
1995; Kliewer, Lenhard, Wilson, Patel, Morris, Lehman, Cell, 83:813-819, 1995).
This is further evidence that the PPAR family subtypes are distinct from one another
in their pharmacological response to ligands.
It has been suggested that compounds activating both PPARα and PPARγ
should be potent hypotriglyceridemic drugs, which could be used in the treatment
of dyslipidemia associated with atherosclerosis, non-insulin dependent diabetes
mellitus, Syndrome X,. (Staels, B. et al., Curr. Pharm. Des., 3 (1), 1-14 (1997))
and familial combined hyperlipidemia (FCH). Syndrome X is the syndrome characterized
by an initial insulin resistant state, generating hyperinsulinaemia, dyslipidaemia
and impaired glucose tolerance, which can progress to non-insulin dependent diabetes
mellitus (Type II diabetes), characterized by hyperglycemia. FCH is characterized
by hypercholesterolemia and hypertriglyceridemia within the same patient and family.
The present invention is directed to a series of compounds that are useful in
modulating PPAR receptors, as well as to a number of other pharmaceutical uses
associated therewith.
SUMMARY OF THE INVENTION
This invention provides new aromatic compounds and pharmaceutical compositions
prepared therewith that are PPAR ligand receptor binders, and which are useful
as agonists or antagonists of the PPAR receptors. The invention also includes the
discovery of new uses for previously known compounds.
The compounds for use according to the invention, including the new compounds
of the present invention, are of Formula I
##STR2##
wherein:
##STR3##
are independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl,
fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl,
fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl;
A is —O—, —S—, —SO—, —SO2—,
—NR13—, —C(O)—, —N(R14)C(O)—,
—C(O)N(R15)—, —N(R14)C(O)N(R15)—,
—C(R14)═N—,
##STR4##
##STR5##
B is —O—, —S—, —SO—, —SO2—,
—NR17—, a chemical bond, ethynylene, —C(O)—,
—N(R18)C(O)—, or —C(O)N(R18—;
D is —O—, —S—, —NR19—, a
chemical bond, ethynylene, —C(O)—, —N(R20)C(O)—,
or —C(O)N(R20)—;
E is a chemical bond or an ethylene group;
a is 0-4;
b is 0-4;
c is 0-4;
d is 0-5;
e is 0-4;
f is 0-6;
g is 1-4;
h is 1-4;
R1, R3, R5, R7, R9,
and R11, are independently hydrogen, halogen, alkyl, carboxyl, alkoxycarbonyl
or aralkyl;
R2, R4, R6, R8, R10
and R12, are independently —(CH2)q—X;
q is 0-3;
X is hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy,
carboxyl, alkoxycarbonyl, tetrazolyl, acyl, acylHNSO2—, —SR23,
Y1Y2N— or Y3Y4NCO—;
Y1 and Y2 are independently hydrogen, alkyl, aryl,
aralkyl or heteroaralkyl, or one of Y1 and Y2 is hydrogen
or alkyl and the other of Y1 and Y2 is acyl or aroyl;
Y3 and Y4 are independently hydrogen, alkyl, aryl,
aralkyl or heteroaralkyl;
Z is R21O2C—, R21,OC—, cyclo-imide,
—CN, R21O2SHNCO—, R21O2SHN—,
(R21)2NCO—, R21O—2,4-thiazolidinedionyl,
or tetrazolyl; and
R19 and R21, are independently hydrogen, alkyl, aryl,
cycloalkyl, or aralkyl;
R13, R17, R19 and R23 are independently
R22OC—, R22NHOC—, hydrogen, alkyl, aryl, heteroaryl,
cycloalkyl, heterocyclyl, heteroaralkyl, or aralkyl;
R14, R15, R16, R18 and R20
are independently hydrogen, alkyl, aralkyl, carbonyl, or alkoxycarbonyl;
or R14, and R15 taken together with the carbon and
nitrogen atoms through which they are linked form a 5 or 6-membered azaheterocyclyl
group; or
when a is 24, then vicinal R1 radicals taken together with the
carbon atoms to which the R1 radicals are linked form an ethylene group; or
when b is 2-4, then vicinal R3 radicals taken together with the
carbon atoms to which the R3 radicals are linked form an ethylene group; or
- when c is 2-4, then vicinal R5 radicals taken together with
the carbon atoms to which the R5 radicals are linked form an ethylene
group; or
when d is 2-5, then vicinal R7 radicals taken together with the
carbon atoms to which the R7 radicals are linked form an ethylene group; or
when e is 2-4, then vicinal R9 radicals taken together with the
carbon atoms to which the R9 radicals are linked form an ethylene group; or
when f is 2-6, then vicinal R11 radicals taken together with
the carbon atoms to which the R11 radicals are linked form an ethylene
group; and
R22 is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,
heteroaralkyl, or aralkyl; or
a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof
or a solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
As employed above and throughout the disclosure, the following terms, unless
otherwise
indicated, shall be understood to have the following meanings:
Definitions
In the present specification, the term "compounds for use according to the invention",
and equivalent expressions, are meant to embrace compounds of general Formula (I)
as hereinbefore described, which expression includes the prodrugs, the pharmaceutically
acceptable salts, and the solvates, e.g. hydrates, where the context so permits.
Similarly, reference to intermediates, whether or not they themselves are claimed,
is meant to embrace their salts, and solvates, where the context so permits. For
the sake of clarity, particular instances when the context so permits are sometimes
indicated in the text, but these instances are purely illustrative and it is not
intended to exclude other instances when the context so permits.
"Prodrug" means a compound which is convertible in vivo by metabolic means
(e.g. by hydrolysis) to a compound of Formula (I), including N-oxides thereof.
For example an ester of a compound of Formula (I) containing a hydroxy group may
be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester
of a compound of Formula (I) containing a carboxy group may be convertible by hydrolysis
in vivo to the parent molecule.
"Patient" includes both human and other mammals.
"Chemical bond" means a direct single bond between atoms.
"Acyl" means an H—CO— or alkyl-CO— group wherein the alkyl
group is as herein described. Preferred acyls contain a lower alkyl. Exemplary
acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
"Alkenyl" means an aliphatic hydrocarbon group containing a carbon—carbon
double bond and which may be a straight or branched chain having about 2 to about
15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon
atoms in the chain and more preferably about 2 to about 4 carbon atoms in the chain.
Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl
are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about
4 carbon atoms in the chain, which may be straight or branched. The alkenyl group
is optionally substituted by one or more halo groups. Exemplary alkenyl groups
include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl,
heptenyl, octenyl and decenyl.
"Alkoxy" means an alkyl —O— group wherein the alkyl group is
as herein described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy and heptoxy.
"Alkoxycarbonyl" means an alkyl-O—CO— group, wherein
the alkyl group is as herein defined. Exemplary alkoxycarbonyl groups include methoxycarbonyl,
ethoxycarbonyl, or t-butyloxycarbonyl.
"Alkyl" means an aliphatic hydrocarbon group which may be a straight or branched
chain having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups
have 1 to about 13 carbon atoms in the chain. Branched means that one or more lower
alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.
"Lower alkyl" means that there are about 1 to about 4 carbon atoms in the chain,
which may be straight or branched. The alkyl is optionally substituted with one
or more "alkyl group substituents" which may be the same or different, and include
halo, carboxy, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, alkoxy,
alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, Y
1Y
2
NCO—, wherein Y
1 and Y
2 are independently hydrogen,
alkyl, aryl, aralkyl or heteroaralkyl, or —Y
1 and Y
2 taken
together with the nitrogen atom to which Y and Y
2 are attached form
heterocyclyl. Exemplary alkyl groups include methyl, trifluoromethyl, ethyl, n-propyl,
i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. Preferably, the alkyl group
substituent is selected from acyl, halo, carboxy, carboxymethyl, methoxycarbonylethyl,
benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl and alkoxycarbonyl.
"Alkylsulfinyl" means an alkyl-SO— group wherein the alkyl
group is as defined above. Preferred groups are those wherein the alkyl group is
lower alkyl.
"Alkylsulfonyl" means an alkyl-SO
2-group wherein the alkyl
group is as defined above. Preferred groups are those wherein the alkyl group is
lower alkyl.
"Alkylthio" means an alkyl-S— group wherein the alkyl group is
as defined above. Exemplary alkylthio groups include methylthio, ethylthio, i-propylthio
and heptylthio.
"Aralkoxy" means an aralkyl-O— group wherein the aralkyl group is
as defined herein. Exemplary aralkoxy groups include benzyloxy and 1- and 2-naphthalenemethoxy.
"Aralkoxycarbonyl" means an aralkyl-O—CO— group wherein
the aralkyl group is as defined herein. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
"Aralkyl" means an aryl-alkyl-group wherein the aryl and alkyl groups are
as defined herein. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl
groups include benzyl, 2-phenethyl and naphthalenemethyl.
"Aralkylsulfonyl" means an aralkyl-SO
2— group
wherein the aralkyl group is as defined herein.
"Aralkylsulfinyl" means an aralkyl-SO— group wherein the
aralkyl group is as defined herein.
"Aralkylthio" means an aralkyl-S— group wherein the aralkyl group
is as defined herein. An exemplary aralkylthio group is benzylthio.
"Aroyl" means an aryl-CO— group wherein the aryl group is as defined
herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system of about 6
to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms. The aryl
is optionally substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Exemplary aryl groups include
phenyl, naphthyl, substituted phenyl, and substituted naphthyl.
"Aryldiazo" means an aryl-diazo-group wherein the aryl and diazo groups
are as defined herein.
"Fused arylcycloalkenyl" means a fused aryl and cycloalkenyl as defined herein.
Preferred fused arylcycloalkenyls are those wherein the aryl thereof is phenyl
and the cycloalkenyl consists of about 5 to about 6 ring atoms. A fused arylcycloalkenyl
group may be bonded to the rest of the compound through any atom of the fused system
capable of such bondage. The fused arylcycloalkenyl may be optionally substituted
by one or more ring system substituents, wherein the "ring system substituent"
is as defined herein. Exemplary fused arylcycloalkenyl groups include 1,2-dihydronaphthylenyl;
indenyl; 1,4-naphthoquinonyl, and the like.
"Fused arylcycloalkyl" means a fused aryl and cycloalkyl as defined herein.
Preferred fused arylcycloalkyls are those wherein the aryl thereof is phenyl and
the cycloalkyl consists of about 5 to about 6 ring atoms. A fused arylcycloalkyl
group may be bonded to the rest of the compound through any atom of the fused system
capable of such bonding. The fused arylcycloalkyl may be optionally substituted
by one or more ring system substituents, wherein the "ring system substituent"
is as defined herein. Exemplary fused arylcycloalkyl and substituted fused arylcycloalkyl
groups include 1,2,3,4-tetrahydronaphthyl; 1,4-dimethyl-2,3-dihydronaphthyl; 2,3-dihydro-1,4-naphthoquinonyl,
α-tetralonyl, tetralonyl and the like.
"Fused arylheterocyclenyl" means a fused aryl and heterocyclenyl wherein the
aryl and heterocyclenyl groups are as defined herein. Preferred fused arylheterocyclenyl
groups are those wherein the aryl thereof is phenyl and the heterocyclenyl consists
of about 5 to about 6 ring atoms. A fused arylheterocyclenyl group may be bonded
to the rest of the compound through any atom of the fused system capable of such
bonding. The designation of aza, oxa or thia as a prefix before the heterocyclenyl
portion of the fused arylheterocyclenyl means that a nitrogen, oxygen or sulfur
atom respectively, is present as a ring atom. The fused arylheterocyclenyl may
be optionally substituted by one or more ring system substituents, wherein the
"ring system substituent" is as defined herein. The nitrogen atom of a fused arylheterocyclenyl
may be a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclenyl
portion of the fused arylheterocyclenyl is also optionally oxidized to the corresponding
N-oxide, S-oxide or S,S-dioxide. Exemplary fused arylheterocyclenyl and substituted
fused arylheterocyclenyl groups include 3H-indolinyl, 2(1H)quinolinonyl, 4-oxo-1,4-dihydroquinolinyl,
2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl,
1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, chromonyl, 3,4-dihydroisoquinoxalinyl,
4(3H)quinazolinonyl, 4H-chromen-2yl, and the like. Preferably, 2(1H)quinolinonyl,
1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, or 4-(3H)quinazolinonyl.
"Fused arylheterocyclyl" means a fused aryl and heterocyclyl wherein the aryl
and heterocyclyl groups are as defined herein. Preferred fused arylheterocyclyls
are those wherein the aryl thereof is phenyl and the heterocyclyl consists of about
5 to about 6 ring atoms. A fused arylheterocyclyl may be bonded to the rest of
the compound through any atom of the fused system capable of such bonding. The
designation of aza, oxa or thia as a prefix before the heterocyclyl portion of
the fused arylheterocyclyl means that a nitrogen, oxygen or sulphur atom respectively
is present as a ring atom. The fused arylheterocyclyl group may be optionally substituted
by one or more ring system substituents, wherein the "ring system substituent"
is as defined herein. The nitrogen atom of a fused arylheterocyclyl may be a basic
nitrogen atom. The nitrogen or sulphur atom of the heterocyclyl portion of the
fused arylheterocyclyl is also optionally oxidized to the corresponding N-oxide,
S-oxide or S,S-dioxide. Exemplary fused arylheterocyclyl and substituted fused
arylheterocyclyl groups include indolinyl, o-benzoic sulfimidyl, 4-chromanonyl,
oxindole, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1H-2,3-dihydroisoindol-2-yl,
2,3-dihydrobenz[f]isoindol-2-yl, 1,2,3,4-tetrahydrobenz[g]isoquinolin-2-yl, chromanyl,
isochromanonyl, 2,3-dihydrochromonyl, 1,4-benzodioxan, 1,2,3,4-tetrahydroquinoxalinyl,
and the like. Preferably, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl,
and 1,2,3,4-tetrahydroquinolinyl.
"Aryloxy" means an aryl-O— group wherein the aryl group is as defined
herein. Exemplary groups include phenoxy and 2-naphthyloxy.
"Aryloxycarbonyl" means an aryl-O—CO— group wherein
the aryl group is as defined herein. Exemplary aryloxycarbonyl groups include phenoxycarbonyl
and naphthoxycarbonyl.
"Arylsulfonyl" means an aryl-SO
2— group wherein the
aryl group is as defined herein.
"Arylsulfinyl" means an aryl-SO— group wherein the aryl group
is as defined herein.
"Arylthio" means an aryl-S— group wherein the aryl group is as defined
herein. Exemplary arylthio groups include phenylthio and naphthylthio.
"Carbamoyl" is an NH
2—CO— group.
"Carboxy" means a HO(O)C— (carboxylic acid) group.
"Compounds of the invention," and equivalent expressions, are meant to
embrace compounds of general Formula (I) as hereinbefore described, which expression
includes the prodrugs, the pharmaceutically acceptable salts, and the solvates,
e.g. hydrates, where the context so permits. Similarly, reference to intermediates,
whether or not they themselves are claimed, is meant to embrace their salts, and
solvates, where the context so permits. For the sake of clarity, particular instances
when the context so permits are sometimes indicated in the text, but these instances
are purely illustrative and it is not intended to exclude other instances when
the context so permits.
"Cycloalkoxy" means an cycloalkyl-O— group wherein the cycloalkyl
group is as defined herein. Exemplary cycloalkoxy groups include cyclopentyloxy
and cyclohexyloxy.
"Cycloalkenyl" means a non-aromatic mono- or multicyclic ring system
of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms,
and which contains at least one carbon—carbon double bond. Preferred ring
sizes of rings of the ring system include about 5 to about 6 ring atoms. The cycloalkenyl
is optionally substitute
