IP Library › Granted Patent US 9,790,211
Granted Patent B2
US 9,790,211 · App. 14/777,925 · Granted Oct 17, 2017

5-amino-quinoline-8-carboxamide derivatives as 5-HT4 receptor agonists

Inventors: Ramakrishna Nirogi (Andhra Pradesh, IN); Anil Karbhari Shinde (Andhra Pradesh, IN); Venkateswarlu Jasti (Andhra Pradesh, IN)
Assignee: Suven Life Sciences Limited
C07D405/14C07D401/12G01N33/558G01N33/57426G01N2333/82G01N2800/52
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Quick Facts
Patent No.
US 9,790,211
App. No.
14/777,925
Granted
Oct 17, 2017
Kind
B2
Abstract

The present invention relates to novel quinoline compounds of formula (I), and their pharmaceutically acceptable salts and process for their preparation. The compounds of formula (I) are useful in the treatment of various disorders that are related to 5-HT 4 receptor agonists.

Claims (159)

1. A compound of the general formula (I):

or a pharmaceutically acceptable salt thereof,

wherein,

“X” is halogen;

“ ” is a bond represents racemic mixture, R-enantiomer, S-enantiomer, exo isomer, endo isomer or achiral;

is

R 1 is hydrogen, hydroxy or fluoro;

R 2 is hydrogen, hydroxy or fluoro;

R 3 is

R 5 is fluoro, hydroxy or methoxy;

m is 0 or 1 , both inclusive.

2. A compound selected from:

(a) a compound of formula (Ia):

or a pharmaceutically acceptable salt thereof,

wherein,

“X” is halogen;

“ ” is a bond represents a racemic mixture, R-enantiomer, S-enantiomer, exo isomer, endo isomer or achiral;

is

R 1 is hydrogen, hydroxy or fluoro;

“m” is 0 or 1, both inclusive;

R 2 is hydroxy or fluoro;

R 3 is

 and

R 5 is fluoro, hydroxy or methoxy;

(b) a compound of formula (Ib-1):

or a pharmaceutically acceptable salt thereof,

wherein,

“X” is halogen;

“ ” is a bond which represents a racemic mixture, R-enantiomer, S-enantiomer, exo isomer, endo isomer or achiral;

R 1 is hydrogen, hydroxy or fluoro;

“m” is 0 or 1, both inclusive; and

“-------” represents a bond or no bond;

(c) a compound of formula (Ib-2):

or a pharmaceutically acceptable salt thereof,

wherein,

“X” is halogen;

“ ” is a bond which represents a racemic mixture, R-enantiomer, S-enantiomer, exo isomer, endo isomer or achiral;

R 1 is hydrogen, hydroxy or fluoro;

“m” is 0 or 1, both inclusive; and

“-------” represents a bond or no bond;

(d) compound of formula (Id-1):

or a pharmaceutically acceptable salt thereof,

wherein,

“X” is halogen:

“ ” is a bond which represents a racemic mixture, R-enantiomer, S-enantiomer, exo isomer, endo isomer or achiral;

R 1 is hydrogen, hydroxy or fluoro;

“m” is 0 or 1, both inclusive; and

“-------” represents a bond or no bond;

(e) a compound of formula (Id-2):

or a pharmaceutically acceptable salt thereof,

wherein,

“X” is halogen;

“ ” is a bond which represents a racemic mixture, R-enantiomer, S-enantiomer, exo isomer, endo isomer or achiral;

R 1 is hydrogen, hydroxy or fluoro;

“m” is 0 or 1, both inclusive; and

“-------” represents a bond or no bond.

3. The compound according to claim 1 , which is selected from the group consisting of:

5-amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide hemifumarate;

5-amino-6-chloro-N-{[3-tetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl] quinoline-8-carboxamide;

(R,S) 5-Amino-6-chloro-N-{[1-(tetrahydro-3-furanylmethyl)-4-piperidinyl]methyl}quinoline-8-carboximide L(+)-tartarate;

(R,S) 5-Amino-6-chloro-N-{[1-(tetrahydro-2-furanylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[3-(tetrahydro-3-furanylmethyl-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide;

5-Amino-6-fluoro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-3-pyrrolidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)tartarate;

(Exo)5-Amino-6-chloro-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide;

5-Amino-6-bromo-N{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(>)-tartarate;

5-Amino-6-bromo-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(tetrahydro-2-furanylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-fluoro-N-{[3-(tetrahydro-2H-pyran-4-yl methyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

(R,S)5-Amino-6-chloro-N-{[4-fluoro-1-(tetrahydro-3-furanylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-hydroxy-1-(tetrahydro-2H-pyran-4-yl methyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)tartarate;

5-Amino-6-chloro-N-[1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl] quinoline-8-carboxyamide;

5-Amino-6-chloro-N-{[1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxyamide;

5-Amino-6-Chloro-N-{[4-fluoro-1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-fluoro-N-{1-(1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-hydroxy-1-(4-hydroxy tetrahydro-2H-pyran-4-yl methyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(4-fluorotetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide hydrochloride;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide fumarate;

5-Amino-6-chloro-N-{[3-(2-hydroxy-2-methyl propyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-fluoro-N-{[1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-fluoro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-fluoro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-bromo-N-{[1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-bromo-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(4-fluoro-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[3-(2-fluoro-2-methyl propyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-fluoro-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[1-(2-methoxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-fluoro-N-{[1-(2-methoxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-bromo-N-{[1-(2-methoxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-methoxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-fluoro-N-{[4-fluoro-1-(2-methoxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide; and

5-Amino-6-bromo-N-{[4-fluoro-1-(2-methoxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide.

4. The compound according to claim 1 , which is selected from the group consisting of:

5-Amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide hemifumarate;

5-Amino-6-chloro-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl] quinoline-8-carboxamide;

(R,S) 5-Amino-6-chloro-N-{[1-(tetrahydro-3-furanylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

(R,S) 5-Amino-6-chloro-N-{[1-(tetrahydro-2-furanylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[3-(tetrahydro-3-furanylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide;

5-Amino-6-fluoro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-3-pyrrolidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

(Exo) 5-Amino-6-chloro-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide;

5-Amino-6-bromo-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-bromo-N-{[3-(tetrahydro-2H-pyran-4-yl methyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-B-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(tetrahydro-2-furanylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)tartarate;

5-Amino-6-fluoro-N-{[3-(tetrahydro-2H-pyran-4-yl methyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidin]methyl}quinoline-8-carboxamide L(+)-tartarate;

(R,S) 5-Amino-6-chloro-N-{[4-fluoro-1-(tetrahydro-3-furanylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-hydroxy-1-(tetrahydro-2H-pyran-4-yl methyl)-4-piperidinyl]methyl} quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(4-hydroxytetrahydro-2H-pyran-4-yl methyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-[1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[3-(4=hydroxytetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[1-(4-fluoro-1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)tartarate;

5-Amino-6-fluoro-N-{1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperazinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-hydroxy-1-(4-hydroxy tetrahydro-2H-pyran-4-yl methyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(4-fluorotetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide hydrochloride;

5-Amino-6-chloro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide fumarate;

5-Amino-6-chloro-N-{[3-(2-hydroxy-2-methyl propyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-fluoro-N-{[1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-fluoro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide;

5-Amino-6-fluoro-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate;

5-Amino-6-bromo-N-{[1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate; and

5-Amino-6-bromo-N-{[4-fluoro-1-(2-hydroxy-2-methyl propyl)-4-piperidinyl]methyl}quinoline-8-carboxamide L(+)-tartarate.

5. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

6. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable excipient.

7. A pharmaceutical composition comprising a compound according to claim 3 and a pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising a compound according to claim 4 and a pharmaceutically acceptable excipient.

9. A method of treating Alzheimer's disease, comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or pharmaceutically acceptable salt thereof.

10. A method of treating Alzheimer's disease, comprising administering to a patient in need thereof an effective amount of a compound of claim 2 or pharmaceutically acceptable salt thereof.

11. A method of treating Alzheimer's disease, comprising administering to a patient in need thereof an effective amount of a compound of claim 3 or pharmaceutically acceptable salt thereof.

12. A method of treating Alzheimer's disease, comprising administering to a patient in need thereof an effective amount, of a compound of claim 4 or pharmaceutically acceptable salt thereof.

13. A method of treating schizophrenia comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or pharmaceutically acceptable salt therof.

14. A method of treating constipation comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or pharmaceutically acceptable salt thereof.

15. A method of treating schizophrenia comprising administering to a patient in need thereof an effective amount of a compound of claim 2 or pharmaceutically acceptable salt thereof.

16. A method of treating constipation comprising administering to a patient in need thereof an effective amount of a compound of claim 2 or pharmaceutically acceptable salt thereof.

17. A method of treating schizophrenia comprising administering to a patient in need thereof an effective amount of a compound of claim 3 or pharmaceutically acceptable salt thereof.

18. A method of treating constipation compirising administering to a patient in need thereof an effective amount of a compound of claim 3 or pharmaceutically acceptable salt thereof.

19. A method of treating schizophrenia comprising administering to a patient in need thereof an effective amount of a compound of claim 4 or pharmaceutically acceptable salt thereof.

20. A method of treating constipation comprising administering to a patient in need thereof an effective amount of a compound of claim 4 or pharmaceutically acceptable salt thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 8, 2015
From: NIROGI, RAMAKRISHNA; SHINDE, ANIL KARBHARI; JASTI, VENKATESWARLU
To: SUVEN LIFE SCIENCES LIMITED
Reel/Frame 036756/0239 →
Priority Claims (1)
IN 1199/CHE/2013 · Mar 20, 2013 · national
Continuity (1)
Related Publication 20160280694A1 · Sep 29, 2016