Tricyclic compounds as modulators of TNF-α synthesis and as PDE4 inhibitors

Patent metadata

Field	Value
Publication number	US-9163022-B2
Application number	US-201414477302-A
Country	US
Kind code	B2
Filing date	Sep 4, 2014
Priority date	Jan 25, 2008
Publication date	Oct 20, 2015
Grant date	Oct 20, 2015

Abstract

The present invention relates to chemical compounds of Formula (I) are as herein defined, pharmaceutical compositions, and methods of use in the treatment of conditions or disorders mediated by TNF-α or by PDE4, including but not limited to rheumatoid arthritis.

First claim

We claim:

1. A method of treating rheumatoid arthritis comprising administering to a human a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
A 1 is O or S;
A 2 is O or S;
U is N;
V is C—(CH 2 ) v R V ;
W is C—(CH 2 ) w R W ;
X is C—(CH 2 ) x R X ;
Y is C—(CH 2 ) y R Y ;
Z is C—(CH 2 ) z R Z ;
R 1 is —(CH 2 ) q R Q ;
R 2 is —(CH 2 ) s R S ;
wherein
each of q, s, w, x, y, and z individually is 0, 1, 2, 3, or 4;
v is zero;
R Q is selected from the group consisting of:
alkyl,
cycloalkyl,
phenyl,
benzyl,
tetrahydrofuranyl,
tetrahydropyranyl,
pyrrolidinyl,
piperidinyl, and
—OR 8 , wherein
the cycloalkyl is optionally substituted with one or more R c ;
the phenyl and benzyl are each independently optionally substituted with one or more R a ; and
the tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl are each independently optionally substituted with one or more R hc ;

R V is chloro or —OCH 3 ;
each of R S , R W , R X , R Y , and R Z is independently selected from the group consisting of
alkyl;
alkenyl;
alkynyl;
aryl;
aryl substituted with one or more R a ;
azido;
cyano;
cycloalkyl;
cycloalkyl substituted with one or more R c ;
fused cycloalkylaryl substituted with one or more R f1 ;
fused arylcycloalkyl substituted with one or more R f2 ;
fused heterocyclyaryl substituted with one or more R f3 ;
fused arylheterocyclyl substituted with one or more R f4 ;
fused cycloalkylheteroaryl substituted with one or more R f5 ;
fused heteroarylcycloalkyl substituted with one or more R f6 ;
fused heterocyclylheteroaryl substituted with one or more R f7 ;
halogen;
haloalkyl;
heterocyclyl;
heterocyclyl substituted with one or more R hc ;
heteroaryl;
heteroaryl substituted with one or more R ha ;
hydrogen;
—NR 3 R 4 ;
—C(O)NR 3 R 4 ;
—C(O)R 5 ;
—C(O) 2 R 6 ;
—S(O) n R 7 ;
—OR 8 ; and
nitro;
wherein
each of R 3 and R 4 is independently selected from the group consisting of H, acyl, alkyl, alkoxy, alkoxyalkyl, alkylsulfonyl, aryl, cycloalkyl, heterocyclyl and heteroaryl;
j is 0, 1, or 2;
each R 5 , R 6 , R 7 , and R 8 is independently selected from the group consisting of
 hydrogen;
 alkyl;
 alkenyl;
 alkynyl;
 alkoxy;
 aryl;
 aryl substituted with one or more R a ;
 cycloalkyl;
 cycloalkyl substituted with one or more R c ;
 halogen;
 haloalkyl;
 heterocyclyl;
 heterocyclyl substituted with one or more R hc ;
 heteroaryl; and
 heteroaryl substituted with one or more R ha ;
 wherein each of R a , R c , R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , R f7 , R hc and R ha is independently selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, amide, amino, aryl, cyano, cycloalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, nitro, —C(O)OR 9 , —SO 2 R 10 , —SR 11 , —C(O)R 12 , —C(O)NR 13 , —NH—SO 2 —R 14 , —SO 2 —NR 15 R 16 , and —SO 2 —CH 2 —SO 2 —CH 3 ; and wherein
 each of R 9 , R 10 , R 11 , R 12 , R 13 R 14 , R 15 , and R 16 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl.

2. The method of claim 1 , wherein A 1 and A 2 are each O.

3. The method of claim 1 , wherein R X is halogen or hydrogen and x is zero.

4. The method of claim 1 , wherein R 1 is cycloalkyl or cycloalkyl substituted with one or more R c .

5. The method of claim 4 , wherein the cycloalkyl is cyclopentyl or cyclohexyl substituted with one or more R c .

6. The method of claim 1 , wherein R S is selected from the group consisting of
hydrogen,
alkyl,
cycloalkyl,
phenyl,
benzyl,
furanyl,
thiophenyl,
isoxazolyl,
benzodioxolyl, and
indanyl,
—C(O)R 5 ,
—C(O) 2 R 6 , and
—OR 8 , wherein
the cycloalkyl is optionally substituted with one or more R c ;
the phenyl and benzyl are each independently optionally substituted with one or more R a ; and
the furanyl, thiophenyl, isoxazolyl, benzodioxolyl, and indanyl, are each independently optionally substituted with one or more R ha .

7. The method of claim 6 , wherein R 2 is phenyl substituted with one or more R a , and R a is halogen.

8. The method of claim 7 , wherein R 2 is 3-chlorophenyl.

9. The method of claim 8 , wherein R 1 is a 4-substituted cyclohexyl group.

10. The method of claim 9 , wherein R 1 is trans-4-cyclohexanecarboxylic acid.

11. The method of claim 10 , wherein the compound is in the form of a hydrochloric acid salt.

12. The method of claim 1 , wherein the compound is 1-cyclopentyl-7-methoxy-3-(4-methyl-thiophen-2-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound is 1-cyclopentyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the compound is 3-(3-chloro-phenyl)-1-(1-methane-sulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]-quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the compound is trans-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido-[5,4-c]quinolin-1-yl]-cyclohexanecarboxylic acid or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound is 3-(3-chloro-phenyl)-1-((R)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the compound is 3-(3-chloro-phenyl)-1-((S)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is 3-(3-chloro-phenyl)-1-(1-ethanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido-[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the compound is N-{4-[(S)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-trans-cyclohexyl}-methanesulfonamide or a pharmaceutically acceptable salt thereof.

Assignees

• High Point Pharmaceuticals Llc
• Vtv Therapeutics Llc

Inventors

• Mjalli Adnan M M
• Gaddam Bapu
• Polisetti Dharma Rao
• Kostura Matthew J
• Guzel Mustafa

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title