Cyclic amine derivatives as EP
There is described a novel group of cyclic amine derivative compounds, having an EP 4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases. The present invention therefore relates to novel compounds which are selective antagonists of the EP 4 subtype of PGE 2 receptors with analgesic and antinflammatory activity, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.
1. A cyclic amine compound of Formula (I):
or a pharmaceutically acceptable salt or derivative thereof, wherein:
A is selected from the group consisting of
wherein
n=0, 1 or 2
m=0 or 1
R 1 and R 2 are independently hydrogen, linear or branched C 1-3 alkyl or are joined together to form a cyclopropyl ring;
R 3 is H or linear or branched C 1-3 alkyl R 4 and R 5 are independently hydrogen, fluorine, linear or branched C 1-3 alkyl or are joined together to form a cyclopropyl ring,
Ar is
phenyl having:
i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or
ii. in 3-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, provided that
ii.a. when A is B, both R 4 and R 5 are fluorine, linear or branched C 1-3 alkyl or joined together they form a cyclopropyl ring,
ii.b. A is C and m is 0
ii.c. A is D and m is 1,
a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or
a 6-membered heteroaromatic ring containing 1 to 3 N.
2. A cyclic amine compound of formula (I) according to claim 1 wherein Ar is phenyl having in 4 position one substituent selected from fluorine, cyano or trifluoromethyl.
3. A cyclic amine compound of formula (I) according to claim 2 wherein R 1 is hydrogen and R 2 is methyl or both R 1 and R 2 are fused together to form a cyclopropyl ring.
4. A cyclic amine compound according to claim 1 wherein A is B and is of the formula IB
and/or pharmaceutically acceptable derivatives or salts thereof, wherein
n=0, 1 or 2
R 1 and R 2 are independently hydrogen, linear o branched C 1-3 alkyl, or are joined together to form a cyclopropyl ring,
R 3 is H or linear or branched C 1-3 alkyl,
R 4 and R 5 are independently hydrogen, fluorine, linear or branched C 1-3 alkyl or are joined together to form a cyclopropyl ring,
Ar is
phenyl having:
i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or
ii. in 3-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, provided that both R 4 and R 5 are fluorine, linear or branched C 1-3 alkyl or are joined together to form a cyclopropyl ring,
a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or
a 6-membered heteroaromatic ring containing 1 to 3 N.
5. A cyclic amine compound of formula (IB) according to claim 4 wherein Ar is phenyl having in 4-position at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl.
6. A cyclic amine compound of formula (IB) according to claim 4 wherein R 1 and R 2 are methyl or are linked together to form a cyclopropyl ring.
7. A cyclic amine compound of formula (IB) according to anyone of claim 4 wherein R 3 is hydrogen.
8. A cyclic amine compound of formula (IB) according to claim 4 wherein R 4 and R 5 are independently selected from hydrogen, fluorine, methyl or are fused together to form a cyclopropyl ring.
9. A cyclic amine compound of formula (IB) according to claim 4 wherein n is 1 and R 4 and R 5 are independently selected from hydrogen, fluorine, methyl.
10. A cyclic amine compound of formula (IB) according to claim 4 wherein n is 2 and Ar is phenyl substituted in 4 position with at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl.
11. A cyclic amine compound of formula (IB) according to claim 4 wherein n is 2, both R 4 and R 5 are fluorine or are fused together to form a cyclopropyl ring.
12. A cyclic amine compound according to claim 1 wherein A is C and is of the formula IC
and/or pharmaceutically acceptable salts or derivatives thereof wherein
m=0 or 1
R 1 and R 2 are independently hydrogen, linear o branched C 1-3 alkyl, or joined together they form a cyclopropyl ring,
R 3 is H or linear or branched (C 1-3 ) alkyl,
Ar is
phenyl having
i) in 4-position halogen, cyano or trifluoromethyl, or
ii) in 3-position halogen, cyano, trifluoromethyl, provided that m is 0,
a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or
a 6-membered heteroaromatic ring containing 1 to 3 N.
13. A cyclic amine compound of formula (IC) according to claim 12 wherein Ar is phenyl having in 4-position at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl.
14. A cyclic amine compound of formula (IC) according to claim 12 wherein R 1 and R 2 are linked together to form a cyclopropyl ring.
15. A cyclic amine compound of formula (IC) according to claim 12 wherein R 3 is hydrogen or methyl.
16. A cyclic amine compound of formula (IC) according to claim 12 wherein m is 0 and Ar is phenyl substituted in 4 position with at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl.
17. A cyclic amine compound according to claim 1 wherein A is D and is of the formula (ID)
and/or pharmaceutically acceptable salts or derivatives thereof wherein
m=0 or 1
R 1 and R 2 are independently hydrogen, linear o branched C 1-3 alkyl, or joined together they form a cyclopropyl ring,
R 3 is H or linear or branched C 1-3 alkyl,
Ar is
phenyl having
i) in 4-position halogen, cyano or trifluoromethyl, or
ii) in 3-position halogen, cyano or trifluoromethyl provided that m is 1,
a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or
a 6-membered heteroaromatic ring containing 1 to 3 N.
18. A cyclic amine compound of formula (ID) according to claim 17 wherein Ar is phenyl having in 4-position fluorine, cyano or trifluoromethyl.
19. A cyclic amine compound of formula (ID) according to claim 17 wherein R 1 and R 2 are linked together to form a cyclopropyl ring.
20. A cyclic amine compound of formula (ID) according to claim 17 wherein R 3 is hydrogen or methyl.
21. A cyclic amine compound of formula (ID) according to claim 17 wherein m is 1 and Ar is phenyl substituted in 4 position with at least one substituent selected from the group consisting of: fluorine, chlorine, cyano and trifluoromethyl.
22. A cyclic amine compound according to claim 1 wherein A is E and is of the formula (IE)
and/or pharmaceutically acceptable salts or derivatives thereof wherein
R 1 and R 2 are independently hydrogen, linear o branched C 1-3 alkyl, or joined together they form a cyclopropyl ring,
R 3 is H or linear or branched C 1-3 alkyl,
Ar is
phenyl having in 3 or 4-position halogen, cyano or trifluoromethyl,
a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or
a 6-membered heteroaromatic ring containing 1 to 3 N.
23. A cyclic amine compound of formula (IE) according to claim 22 wherein Ar is phenyl having in 4-position at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl.
24. A cyclic amine compound of formula (IE) according to claim 22 wherein R 1 is hydrogen and R 2 is methyl or both R 1 and R 2 are linked together to form a cyclopropyl ring.
25. A cyclic amine compound of formula (IE) according to claim 22 wherein R 3 is hydrogen or methyl.
26. A compound according to claim 1 selected from the group consisting of:
lithium (R)-4-(1-(1-(4-(trifluoromethyl)benzyl)piperidine-2carboxamido)cyclo propyl)benzoate,
4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro [2.5]octane-5-carboxamido)cyclo propyl) benzoic acid carboxamido)cyclopropyl)benzoic acid,
4-((1S)-1-(6-(4-(trifluoromethyl)benzyI)-6-azaspiro[2.5]octane-5-carboxamido) ethyl)benzoic acid,
4-((1S)-1-(4,4-dimethyl-1-(4-trifluoromethyl)benzyl)piperidine-2-carboxamido) ethyl)benzoic acid,
4-((S)-1-((R)-4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoic acid,
(R)-4-(1-(4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido) cyclopropyl)benzoic acid,
4-(1-(4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclo propyl)benzoic acid,
4-(1-(4,4-difluoro-1-(3-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclo propyl)benzoic acid,
4-(1-(4,4-difluoro-1-(3-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclo -propyl)benzoic acid,
4-(1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4-carboxamido) cyclopropyl) benzoic acid,
4-(1-((3R)-2-(4-(trifluoromethyl) benzyl)-2-azabicyclo[4.1.0]heptane-3-carboxamido)cyclopropyl)benzoic acid,
4-((1 S)-1(3R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1.0]heptane-3-carboxamido)ethyl)benzoic acid,
lithium 4-((S)-1-((R)-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido) ethyl) benzoate,
4-(1-((1R,3R,5R)-2-(3-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoic acid, and 4-(1-((1R,3R,5R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxannido)cyclopropyl)benzoic acid.
27. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and/or excipient.
28. A method of treatment of at least one disorder selected from the group consisting of: acute and chronic pain, inflammatory pain, osteoarthritis and rheumatoid arthritis, wherein said method comprises:
identifying a subject patient suffering from acute and chronic pain, inflammatory pain, osteoarthritis and rheumatoid arthritis and any combinations of the foregoing; and
administering an effective amount of a compound of formula (I) according to claim 1 to the subject patient.