IP Library › Granted Patent US 8,828,987

Granted Patent B2

US 8,828,987 · App. 13/992,258 · Granted Sep 9, 2014

Pyridine amide derivatives as EP4 receptor antagonists

Inventors: Manuela Borriello (Monza, IT); Lucio Rovati (Monza, IT); Luigi Piero Stasi (Monza, IT); Benedetta Buzzi (Meda, IT); Fabrizio Colace (Monza, IT)

Assignee: Rottapharm Biotech S.R.L.

C07D413/14 C07D401/04 C07D401/14

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Quick Facts

Patent No.: US 8,828,987
App. No.: 13/992,258
Granted: Sep 9, 2014
Kind: B2

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Abstract

The invention relates pyridine amide derivative of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently hydrogen, linear o branched (C1-C3)alkyl or joined together they form a cyclopropyl ring; R is independently selected from the group consisting of halogens and trifluoromethyl and p is 1, 2 or 3; A is C or N; E is a group of formula (B) or (C), wherein B is C(O)OH, C(O)O(C1-C3)alkyl, and C is selected from the group consisting of formula (I) m is 1,2 or 3, n is 0 or 1, W is —O—, —O(C1-C3 alkyl)-; —(C1-C3 alkyl)O—; —C(O)—; —C(═N—O(C1-C3 alkyl))-; —NH— or —NH(C1-C3alkyl)-; Ar is phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, —NH(C1-C3alkyl)-; —N(C1-C3alkyl)(C1-C3alkyl)-, a from 5 to 7 membered heterocyclic ring containing one nitrogen atom which is covalently bonded to Ar and optionally containing one or two heteroatoms selected from N, O and S; and a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from S, O e N, such heteroaromatic ring being substituted with one or two substituents selected from the group consisting of (C1-C3)alkyl, (C3-C5)cycloalkyloxy, (C1-C3)alkylcarbonyl. The compounds of the invention could be used for manufacturing a medicament for the treatment of pathologies which require the use of an antagonist of the EP4 receptor, such as the treatment of acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, endometriosis and migraine.

Claims (186)

1. A pyridine amide derivative of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 and R 2 are independently hydrogen, linear or branched (C1-C3)alkyl or joined together they form a cyclopropyl ring;

R is independently selected from the group consisting of halogens and trifluoromethyl and p is 1, 2 or 3;

A is C or N;

E is a group of formula (B) or (C), wherein

B is C(O)OH, C(O)O(C1-C3)alkyl, and

C is selected from the group consisting of:

m is 1, 2 or 3,

n is 0 or 1,

W is —O—, —O(C1-C3 alkyl)-; —(C1-C3 alkyl)O—; —C(O)—; —C(═N—O(C1-C3 alkyl))-; —NH— or —NH(C1-C3alkyl)-;

Ar is either (1) phenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, trifluoromethyl, trifluoromethoxy, methyl, —NH(C1-C3alkyl)-, —N(C1-C3alkyl)(C1-C3alkyl)-, a 5 to 7 membered heterocyclic ring containing one nitrogen atom which is covalently bonded to said phenyl and, optionally, containing one or two additional heteroatoms selected from N, O and S; or (2) a 5 or 6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from the group consisting of: S, O and N, such heteroaromatic ring being substituted with one or two substituents selected from the group consisting of: (C1-C3)alkyl, (C3-C5)cycloalkyloxy, and (C1-C3)alkylcarbonyl.

2. The pyridine amide derivative according to claim 1 , wherein p is 1 and R is one selected from the group consisting of: halogen and trifluoromethyl.

3. The pyridine amide derivative according to claim 2 , wherein p is 1 and R chlorine.

4. The pyridine amide derivative according to claim 1 , wherein R 1 and R 2 are at least one selected from the group consisting of: hydrogen, methyl and a cyclopropane ring.

5. The pyridine amide derivative according to claim 4 , wherein R 1 and R 2 form together a cyclopropane ring.

6. The pyridine amide derivative according to claim 1 , wherein the pyridine amide derivative of Formula (I) is a compound of Formula (Ia), in which E is COOH and A is C:

wherein Rp, R 1 , R 2 , W, Ar, m and have the same meaning as per Formula (I).

7. The pyridine amide derivative according to claim 6 , wherein m is 1 or 2.

8. The pyridine amide derivative according to claim 6 , wherein n is 0 and W is a bond.

9. The pyridine amide derivative according to claim 6 , wherein W is at least one selected from the group consisting: of O, NH and N(C1-C3)alkyl.

10. The pyridine amide derivative according to claim 6 , wherein Ar is phenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, trifluoromethyl, trifluoromethoxy, methyl, —NH(C1-C3alkyl)-, —N(C1-C3alkyl)(C1-C3alkyl)-, a from 5 to 7 membered heterocyclic ring containing one nitrogen atom, which is covalently bonded to said phenyl, and, optionally, containing one or two additional heteroatoms selected from the group consisting of: N, O and S.

11. The pyridine amide derivative according to claim 10 , wherein Ar is phenyl substituted with fluorine.

12. The pyridine amide derivative according to claim 6 , wherein Ar is a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from the group consisting of: S, O and N, such ring being substituted with one or two substituents selected from the group consisting of (C1-C3)alkyl, (C3-C5)cycloalkyloxy, and (C1-C3)alkylcarbonyl.

13. The pyridine amide derivative according to claim 12 , wherein Ar is pyridine.

14. The pyridine amide derivative according to claim 1 , wherein the pyridine amide derivative of Formula (I) is a compound of Formula (Ib), where E is B:

15. The pyridine amide derivative according to claim 14 , wherein m is 1 or 2.

16. The pyridine amide derivative according to claim 14 , wherein n is 0 and W is a bond.

17. The pyridine amide derivative according to claim 14 , wherein W is selected from the group consisting of: O, NH and N(C1-C3)alkyl.

18. The pyridine amide derivative according to claim 14 , wherein Ar is phenyl, optionally substituted with one or more halogen atoms, trifluoromethyl, trifluoromethoxy, methyl, —NH(C1-C3alkyl)-, —N(C1-C3alkyl)(C1-C3alkyl)-, a 5 to 7 membered heterocyclic ring containing one nitrogen atom, which is covalently bonded to said phenyl, and, optionally, containing one or two additional heteroatoms selected from the group consisting of: N, O and S.

19. The pyridine amide derivative according to claim 18 , wherein Ar is phenyl substituted with said halogen atom.

20. The pyridine amide derivative according to claim 14 , wherein Ar is a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from the group consisting of: S, O and N, such ring being substituted with one or two substituents selected from the group consisting of: (C1-C3)alkyl, (C3-C5)cycloalkyloxy, and (C1-C3)alkylcarbonyl.

21. The pyridine amide derivative according to claim 20 , wherein Ar is pyridine.

22. The pyridine amide derivative according to claim 1 , wherein the derivative of Formula (I) is selected from the group consisting of:

4-(1-(5-chloro-2-(2-phenylpyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (racemic mixture)

4-(1-(5-chloro-2-(2-phenylpyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (enantiomer 1)

4-(1-(5-chloro-2-(2-phenylpyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (enantiomer 2)

4-(1-(5-chloro-2-(3-phenylpyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid

4-(1-(5-chloro-2-(3-phenylpyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (enantiomer 1)

4-(1-(5-chloro-2-(3-phenylpyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (enantiomer 2)

4-(1-(2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinamido)cyclopropyl)benzoic acid (racemic mixture)

4-(1-(2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinamido)cyclopropyl)benzoic acid (enantiomer 1)

4-(1-(2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinamido)cyclopropyl)benzoic acid (enantiomer 2)

4-(1-(5-chloro-2-(3-phenoxyazetidin-1-yl)nicotinamido)cyclopropyl)benzoic acid

(S)-4-(1-(5-chloro-2-(3-(4-fluorophenoxy)azetidin-1-yl)nicotinamido)ethyl)benzoic acid

(S)-4-(1-(5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinamido)ethyl)benzoic acid

4-(1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid

4-(1-(5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid

4-(1-(5-chloro-2-(3-(4-fluorophenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid

4-(1-(5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid

4-(1-(5-chloro-2-(3-(4-fluoro-3-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid

4-(1-(5-chloro-2-(3-(3-(trifluoromethoxy)phenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid

4-(1-(5-chloro-2-(3-(2,4-difluorophenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid

4-(1-(5-chloro-2-(3-(3,4-difluorophenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid

4-(1-(5-chloro-2-(3-(3-(piperazin-1-yl)phenoxy)azetidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid

4-((5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinamido)methyl)benzoic acid

6-((5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinamido)methyl)nicotinic acid

4-(1-(5-chloro-2-(3-(3-fluorobenzoyl)azetidin-1-yl)nicotinamido)cyclopropyl)benzoic acid

4-(1-(5-chloro-2-(3-((3-fluorophenyl)(methoxyimino)methyl)azetidin-1-yl)-nicotinamido)cyclopropyl)benzoic acid (isomeric mixture)

4-(1-(5-chloro-2-(3-(3-fluorophenyl)-3-hydroxyazetidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid

4-(1-(5-chloro-2-(3-(4-fluorophenyl)-3-hydroxyazetidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid

4-(1-(5-chloro-2-(3-((4-fluorophenoxy)methyl)azetidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid

4-(1-(5-chloro-2-(3-((3-(trifluoromethyl)phenyl)amino)azetidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(5-chloro-2-(3-((3-fluorophenyl)amino)azetidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(5-chloro-2-(3-((4-fluorophenyl)amino)azetidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid

4-(1-(5-chloro-2-(3-((4-fluoro-2-methylphenyl)amino)azetidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(5-chloro-2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(5-chloro-2-(3-((2-methyl-4-(trifluoromethyl)phenyl)amino)azetidin-1-yl)-nicotinamido)cyclopropyl)benzoic acid

4-(1-(5-chloro-2-(3-((4-fluoro-2-methylphenyl)(methyl)amino)azetidin-1-yl)-nicotinamido)cyclopropyl)benzoic acid

4-(1-(2-(3-(3-fluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(2-(3-(4-fluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(2-(3-(4-chlorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(2-(3-(3-chlorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(2-(3-(4-fluoro-3-(trifluoromethyl)phenoxy)azetidin-1-yl)-5-(trifluoromethyl)-nicotinamido)cyclopropyl)benzoic acid

4-(1-(2-(3-(3-(trifluoromethoxy)phenoxy)azetidin-1-yl)-5-(trifluoromethyl)-nicotinamido)cyclopropyl)benzoic acid

4-(1-(2-(3-(2,4-difluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(2-(3-(3,4-difluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(2-(3-((5-methylisoxazol-3-yl)oxy)azetidin-1-yl)-5-(trifluoromethyl)-nicotinamido)cyclopropyl)benzoic acid

4-(1-(5-(trifluoromethyl)-2-(3-((6-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)nicotinamido)cyclopropyl)benzoic acid

4-(1-(2-(3-((5-fluoropyrimidin-2-yl)oxy)azetidin-1-yl)-5-(trifluoromethyl)-nicotinamido)cyclopropyl)benzoic acid

4-(1-(2-(3-((3-fluorophenyl)amino)azetidin-1-yl)-5-(trifluoromethyl)-nicotinamido)cyclopropyl)benzoic acid

4-(1-(2-(3-((4-fluorophenyl)amino)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(2-(3-((4-fluoro-2-methylphenyl)amino)azetidin-1-yl)-5-(trifluoromethyl)-nicotinamido)cyclopropyl)benzoic acid

4-(1-(2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)-5-(trifluoromethyl)-nicotinamido)cyclopropyl)benzoic acid

4-(1-(5-fluoro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)benzoic acid

4-(1-(5-fluoro-2-(3-(3-chlorophenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid

4-(1-(5-fluoro-2-(3-(3-(trifluoromethoxy)phenoxy)azetidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(5-fluoro-2-(3-((4-fluoro-2-methylphenyl)amino)azetidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid

4-((1S)-1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)-ethyl)benzoic acid

4-((1S)-1-(5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)-ethyl)benzoic acid

4-((1S)-1-(5-chloro-2-(3-(4-fluorophenoxy)pyrrolidin-1-yl)nicotinamido)-ethyl)benzoic acid

4-(1-(5-chloro-2-(3-phenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (racemic mixture)

4-(1-(5-chloro-2-(3-phenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (enantiomer 1)

4-(1-(5-chloro-2-(3-phenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (enantiomer 2)

4-(1-(5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid (racemic mixture)

4-(1-(5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid (enantiomer 1)

4-(1-(5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid (enantiomer 2)

4-(1-(5-chloro-2-(3-(4-fluorophenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid (racemic mixture)

4-(1-(5-chloro-2-(3-(4-fluorophenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid (enantiomer 1)

4-(1-(5-chloro-2-(3-(4-fluorophenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid (enantiomer 2)

4-(1-(5-chloro-2-(3-(3-fluorophenoxy)pyrrolidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid (racemic mixture)

4-(1-(5-chloro-2-(3-(3-fluorophenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid (enantiomer 1)

4-(1-(5-chloro-2-(3-(3-fluorophenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)-benzoic acid (enantiomer 2)

4-(1-(5-chloro-2-(3-(m-tolyloxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid

4-(1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid (racemic mixture)

4-(1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid (enantiomer 1)

4-(1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid (enantiomer 2)

4-(1-(5-chloro-2-(3-((3-fluorophenoxy)methyl)pyrrolidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid

4(R)-4-(1-(5-chloro-2-(2-((3-fluorophenoxy)methyl)pyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoic acid

4(S)-4-(1-(5-chloro-2-(2-((3-fluorophenoxy)methyl)pyrrolidin-1-yl)nicotinamido)-cyclopropyl)benzoic acid

4-(1-(5-chloro-2-(3-((3-fluorophenoxy)methyl)piperidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid

(R)-4-(1-(5-chloro-2-(3-(3-fluorophenoxy)pyrrolidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid

(S)-4-(1-(5-chloro-2-(3-(3-fluorophenoxy)pyrrolidin-1-yl)nicotinamido)cyclo-propyl)benzoic acid, and

N-(1-(4-(1H-tetrazol-5-yl)phenyl)cyclopropyl)-5-chloro-2-(3-(3-fluorophenoxy)-azetidin-1-yl)nicotinamide.

23. The pyridine amide derivative according to claim 22 , wherein the derivative of Formula (I) is selected from the group consisting of: