IP Library › Granted Patent US 8,497,254

Granted Patent B2

US 8,497,254 · App. 13/295,313 · Granted Jul 30, 2013

Oxadiazole derivatives as sphingosine 1-phosphate (S1P) receptor modulators

Inventors: Wenkui K. Fang (Irvine, CA); Liming Wang (Irvine, CA); Evelyn G. Corpuz (Irvine, CA); Ken Chow (Newport Coast, CA); Wha Bin Im (Irvine, CA)

Assignee: Allergan, Inc.

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,497,254
App. No.: 13/295,313
Granted: Jul 30, 2013
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates to novel oxadiazole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

Claims (110)

1. A compound is presented by Formula I, its enantiomers, diastereoisomers, hydrates, tautomers or a pharmaceutically acceptable salt thereof,

wherein:

A is C 6-10 aryl, heterocycle, C 3-8 cycloalkyl or C 3-8 cycloalkenyl;

B is C 6-10 aryl, heterocycle, C 3-8 cycloalkyl or C 3-8 cycloalkenyl;

R 1 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;

R 2 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;

R 3 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;

R 4 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;

R 5 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;

R 6 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;

R 7 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;

R 8 is independently halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;

L l is CH 2 ;

R 9 is O, S, C(O) or CH 2 ;

R 10 is H or C 1-8 alkyl;

L 2 is CHR 16 , O, S, NR 17 ,direct bond or —C(O)—;

R 11 is H, OPO 3 H 2 , carboxylic acid, PO 3 H 2 , C 1-8 alkyl, —S(O) 2 H, —P(O)MeOH, —P(O)(H)OH or OR 12 ;

R 12 is H or C 1-8 alkyl;

a is 0, 1 or 2;

b is 0 or 1;

c is 0, 1, 2 or 3;

R 13 is H, C 1-8 alkyl;

R 14 is H or C 1-8 alkyl; and

R 15 is H or C 1-8 alkyl;

R 16 is H, OH or C 1-8 alkyl; and

R 17 is H or C 1-8 alkyl;

with the proviso that the compound is not of structure

2. A compound according to claim 1 wherein:

A is C 6 aryl or heterocycle; and

B is C 8 aryl or C 3-8 cycloalkyl.

3. A compound according to claim 2 wherein:

4. A compound according to claim 1 wherein:

R 1 is H, halogen or —C 1-6 alkyl;

R 2 is H, halogen or —C 1-6 alkyl;

R 3 is H, halogen or —C 1-6 alkyl;

R 4 is H or C 1-6 alkyl,

R 5 is H or C 1-6 alkyl;

R 6 is H or C 1-6 alkyl;

R 7 is H or C 1-6 alkyl;

R 9 is C(O) or CH 2 ;

R 10 is H;

R 11 is OPO 3 H 2 , carboxylic acid or PO 3 H 2 ;

a is 0;

b is 0 or 1;

c is 0, 1, 2 or 3;

L l is CH 2 ;

L 2 is CHR 16 or direct bond; and

R 16 is H or C 1-6 alkyl.

5. A compound according to claim 1 wherein:

R 1 is H, fluoro, methyl or chloro;

R 2 is H, fluoro, methyl or chloro;

R 3 is H, fluoro, methyl or chloro;

R 4 is H or methyl;

R 5 is H or methyl;

R 6 is H or methyl;

R 7 is H or methyl;

R 9 is C(O) or CH 2 ;

R 10 is H;

R 11 is carboxylic acid or PO 3 H 2 ;

a is 0;

b is 0 or 1;

c is 0, 1, 2 or 3;

L 1 is CH 2 ;

L 2 is CHR 16 or direct bond; and

R 16 is H.

6. A compound according to claim 5 wherein:

R 1 is H, fluoro, methyl or chloro;

R 2 is H or chloro;

R 3 is H, fluoro, methyl or chloro;

R 4 is H;

R 5 is H or methyl;

R 6 is methyl;

R 7 is H or methyl;

R 9 is C(O) or CH 2 ;

R 10 is H;

R 11 is carboxylic acid or PO 3 H 2 ;

a is 0;

b is 0 or 1;

c is 0, 1 or 2;

L 1 is CH 2 ; and

L 2 is direct bond.

7. A compound according to claim 1 selected from:

3-[(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid;

{3-[(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid;

3-[(4-{5-[2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid;

{3-[(4-{5-[2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid;

3-[(4-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid;

3-(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-3-methylphenyl)propanoic acid

3-(4-{5-[1-(4-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-3-methylphenyl)propanoic acid;

3-(4-{5-[1-(3-chlorophenyl)-2-(3-methylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-3-methylphenyl)propanoic acid;

3-[(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzoyl)amino]propanoic acid;

3-[(4-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid;

{3-[(4-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid ;

3-{[4-(5-{2-(3,4-dimethylphenyl)-1-]3-(trifluoromethyl)phenyl]ethyl}-1,2,4-oxadiazol-3-yl)benzyl]amino}propanoic acid; and

3-[(4-{5-[2-(3,4-dimethylphenyl)-1-(3,5-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid.

8. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluents or carrier.

9. A pharmaceutical composition according to claim 8 wherein the compound is selected from: