Immunomodulator and anti-inflammatory compounds

Patent metadata

Field	Value
Publication number	US-9758474-B2
Application number	US-201414172707-A
Country	US
Kind code	B2
Filing date	Feb 4, 2014
Priority date	May 6, 2010
Publication date	Sep 12, 2017
Grant date	Sep 12, 2017

Abstract

The present invention provides dihydroorotate dehydrogenase inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders wherein the inhibition of Dihydroorotate dehydrogenase is known to show beneficial effect.

First claim

The invention claimed is:

1. A compound of formula (I)

or a tautomer, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or N-oxide thereof, wherein
Ring A including substituent R 1 is

Ring B, including X 1 , X 2 and X 3 is selected from

wherein Ring A and Ring B may each independently be optionally substituted by one or more R 4 and C* is attached to —NR—;
R is hydrogen;
L 1 and L 2 are absent;
Cy is selected from the group consisting of

each occurrence of R 4 is independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, —OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —C(═Y)—OR a , —C(═Y)—NR a R b , —S(═O) q —NR a R b , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, and substituted or unsubstituted cycloalkenyl;
each occurrence of R a and R b may be the same or different and are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, and —OR c (wherein R c is substituted or unsubstituted (C 1-6 )alkyl);
each occurrence of Y is independently selected from the group consisting of O, S and NR a ; and
each occurrence of q independently represents 0, 1 or 2

wherein the term substituted refers to substitution with any one or any combination of the following substituents which may be the same or different and are selected from hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), unsubstituted alkyl, unsubstituted alkoxy, halo-substituted alkoxy, unsubstituted alkenyl, unsubstituted (alkynyl, unsubstituted cycloalkyl, unsubstituted cycloalkenyl, unsubstituted cycloalkylalkyl, unsubstituted cycloalkenylalkyl, unsubstituted heterocyclic ring, unsubstituted heterocycicylalkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted heteroaryl, unsubstituted heteroarylalkyl, unsubstituted guanidine, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR y R z , —NR x COR y R z , —N(R x )SORy, —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x C(O)R y —, —NR x C(S)R y , —NR x C(S)NR y R z , —SONR x R y , —SO 2 NR x R y —, —OR x , —OR x C(O)NR y R z , —OR x C(O)OR y , —OC(O)R x , —OC(0)NR x R y , —RxNR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , —ONO 2 , wherein R x , R y and R z in each of the above groups can be hydrogen, unsubstituted alkyl, unsubstituted alkoxy, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted cycloalkenyl, unsubstituted cycloalkylalkyl, unsubstituted cycloalkenylalkyl, unsubstituted heterocyclic ring, heterocycicylalkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted heteroaryl, unsubstituted heteroarylalkyl.

2. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2 , further comprising one or more additional therapeutic agents selected from the group consisting of anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

4. A method of inhibiting dihydroorate dehydrogenase (DHODH) activity in a mammal comprising administering to the mammal a compound of claim 1 , wherein the compound inhibits DHODH activity in the mammal.

5. A compound selected from
2-(6-(3-Methoxyphenyl)pyridin-3-ylcarbamoyl)benzoic acid
2-(3′-Ethoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid
2-[3-Fluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid
2-[2′-Fluoro-3-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid
2-(3-fluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid
2-(3′-ethoxybiphenyl-4-ylcarbamoyl)benzoic acid
2-[3′-(ethylthio)-2,3,5,6-tetrafluorobiphenyl-4-ylcarbamoyl]benzoic acid
2-(2′-chloro-2-fluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid
2-(3-fluoro-3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid
2-(3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid
2-[3′-(ethylthio)-2-fluorobiphenyl-4-ylcarbamoyl]benzoic acid
2-(2′-chlorobiphenyl-4-ylcarbamoyl)benzoic acid
2-(3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid
2-[3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid
2-(3′-ethylbiphenyl-4-ylcarbamoyl)benzoic acid
2-(3′-butoxy-2,3,5,6-tetrafluorobiphenyl-4-ylcarbamoyl)benzoic acid
2-(3′-butoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid
2-(3′-cyclopropoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid
2-(3′-cyclopropoxybiphenyl-4-ylcarbamoyl)benzoic acid
2-(3′-butoxybiphenyl-4-ylcarbamoyl)benzoic acid
2-(3′-butoxy-2-fluorobiphenyl-4-ylcarbamoyl)benzoic acid
2-[2,6-Difluoro-4-(3-propyl-1H-indol-5-yl)phenylcarbamoyl]benzoic acid
2-[2-Chloro-4-(3-ethyl-1H-indol-5-yl)-6-fluorophenylcarbamoyl]benzoic acid

and pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition, comprising a compound of claim 5 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6 , further comprising one or more additional therapeutic agents selected from the group consisting of anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

8. A method of inhibiting DHODH activity in a mammal comprising administering to the mammal a compound of claim 5 , wherein the compound inhibits DHODH activity in the mammal.

Assignees

• Rhizen Pharmaceuticals Sa
• Incozen Therapeutics Pvt Ltd

Inventors

• Muthuppalaniappan Meyyappan
• Bhavar Prashant K
• Viswanadha Srikant
• Vakkalanka Swaroop K
• Merikapudi Gayatri S

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/08

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

• A61P37/06

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

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title