Prodrugs of [4 [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(1H-pyrrolo-pyridin-yl)-methanones and synthesis thereof
View Patent ↗The present invention relates to substituted 2-amino-N-(4-fluoro-3-{1-[1-(alkyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamides (compounds of formula I) compositions thereof, and their use in the treatment of inflammatory diseases.
1. A compound of formula (I):
wherein,
X and Y are selected from the group consisting of hydrogen, methyl, fluoro, chloro, trifluoromethyl, methoxy, trifluoromethoxy, morpholin-4-yl-methanone such that not two of the substituents are hydrogen at the same time;
R 1 is H, lower alkyl or substituted alkyl;
R 2 is selected from the group consisting of hydrogen and natural and unnatural amino acids; or
an N-oxide of said compound, a pharmaceutically acceptable salt of said compound, a solvate of said compound or a hydrate of said compound.
2. A compound according to claim 1 wherein R 2 is selected from the group consisting of hydrogen and —C(O)CH(CH(CH 3 ) 2 )NH 2 .
3. A compound according to claim 2 in which X is —OCF 3 .
4. A compound according to claim 2 in which X is morpholin-4-yl-methanone.
5. A compound according to claim 1 in which R 1 is isopropyl.
6. A compound according to claim 1 which is selected from the group consisting of:
(S)-2-Amino-N-[(4-fluoro-3-{1-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-benzylcarbamoyl)-methyl]-3-methyl-butyramide hydrochloride,
(S)-2-Amino-N-(4-fluoro-3-{1-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-3-methyl-butyramide hydrochloride,
(R)-2-Amino-N-(4-fluoro-3-{1-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-3-methyl-butyramide hydrochloride,
(S)-2-Amino-N-(4-fluoro-3-{1-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-3-methyl-butyramide hydrochloride,
(S)-2-Amino-N-[(4-fluoro-3-{1-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indole-3-carbonyl]-piperidin-4-yl}-benzylcarbamoyl)-methyl]-3-methyl-butyramide hydrochloride,
(R)-2-Amino-N-(4-fluoro-3-{1-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-3-methyl-butyramide hydrochloride, and
(S)-2-Amino-N—[(S)-1-(4-fluoro-3-{1-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indole-3-carbonyl]-piperidin-4-yl}-benzylcarbamoyl)-2-methyl-propyl]-3-methyl-butyramide hydrochloride.
7. A pharmaceutical composition comprising a compound according to claim 1 in a pharmaceutically acceptable carrier.