Oxadiazole derivatives as sphingosine 1-phosphate (S1P) receptor modulators
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.
1. A method of treating an immunosuppressant disorder associated with the sphingosine-1-phosphate receptor modulation, wherein the immunosuppressant disorder is selected from: rheumatoid arthritis, psoriasis, atherosclerosis, autoimmune uveitis, dry eye, inflammatory bowel diseases, atopic allergy, atopic dermatitis, contact dermatitis, multiple sclerosis, Sjogren's syndrome and organ transplant rejection, in a mammal in need thereof, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by Formula I 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 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 1 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. The method according to claim 1 , wherein said compound is represented by Formula I wherein:
A is C 6 aryl or heterocycle; and
B is C 6 aryl or C 3-8 cycloalkyl.
3. The method according to claim 1 , wherein said compound is represented by Formula I wherein:
4. The method according to claim 3 , wherein said compound is represented by Formula I 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 1 is CH 2 ;
L 2 is CHR 16 or direct bond; and
R 16 is H or C 1-6 alkyl.
5. The method according to claim 4 , wherein said compound is represented by Formula I 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. The method according to claim 1 , wherein said compound is represented by Formula I 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. The method according to claim 1 , wherein said compound is 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. The method according to claim 1 , wherein the pharmaceutical composition further comprises pharmaceutically acceptable adjuvants, diluents or carriers.
9. The method according to claim 1 , wherein the mammal is a human.