IP Library › Granted Patent US 9,371,282

Granted Patent B2

US 9,371,282 · App. 14/275,879 · Granted Jun 21, 2016

Somatostatin receptor subtype 4 (SSTR4) agonists

Inventors: Riccardo Giovannini (Verona, IT); Yunhai Cui (Biberach an der Riss, DE); Henri Doods (Warthausen, DE); Marco Ferrara (San Donato, IT); Stefan Just (Biberach an der Riss, DE); Raimund Kuelzer (Mittelbiberach, DE); Iain Lingard (Monza, IT); Rocco Mazzaferro (San Giuliano, IT); Klaus Rudolf (Warthausen, DE)

Assignee: Centrexion Therapeutics Corporation

C07D209/52 C07D401/12 C07D403/12 C07D405/12 C07D413/12 C07D417/12 C07D471/04 C07D487/04

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Quick Facts

Patent No.: US 9,371,282
App. No.: 14/275,879
Granted: Jun 21, 2016
Kind: B2

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Abstract

3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid amide derivatives which are agonists of somatostatin receptor subtype 4 (SSTR4), useful for preventing or treating medical disorders related to SSTR4.

Claims (83)

1. A compound of the formula (I)

wherein

A is selected from the group consisting of H and C 1-6 -alkyl;

R 1 and R 2 are independently selected from the group consisting of H, C 1-6 -alkyl and C 3-6 -cycloalkyl, wherein at least one of R 1 or R 2 is C 1-6 -alkyl or C 3-6 -cycloalkyl, wherein the C 1-6 -alkyl or the C 3-6 -cycloalkyl is optionally substituted with halogens or MeO—, or

wherein R 1 and R 2 together form a 2- to 5-membered alkylene-bridge optionally substituted with halogens incorporating 0 to 2 heteroatoms independently selected from the group consisting of N, O and S;

W is selected from the group consisting of a mono- or bicyclic aryl, a mono- or bicyclic heteroaryl, a mono- or bicyclic heterocyclyl and a mono- or bicyclic cycloalkyl,

wherein each of these ring systems are optionally substituted with one or more R 3 , and wherein the heteroaryl comprises up to 4 heteroatoms and one or two 5- or 6-membered ring(s);

R 3 is independently selected from the group consisting of

C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkyl-O—, benzyl, halogen, HO—, NC—, mono- or bicyclic heteroaryl, and 5- or 6-membered monocyclic heterocyclyl containing one heteroatom selected from the group consisting of N, O or S(O) r , wherein the heteroaryl contains up to 4 heteroatoms and one or two 5- or 6-membered rings(s) and r is 0, 1 or 2,

wherein the C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkyl-O—, benzyl, heteroaryl and the heterocyclyl are optionally substituted with halogens, HO—, acetyl, C 1-6 -alkyl-O—, oxo, R 4 —S(O) 2 —, with R 4 being aryl, C 3-6 -cycloalkyl and/or C 1-6 -alkyl; and

Y is selected from the group consisting of a bond, —CH 2 —, —CH 2 CH 2 —, and —CH 2 O—;

or a salt thereof.

2. A compound according to claim 1 , wherein A is H.

3. A compound according to claim 1 , wherein

W is selected from the group consisting of a

mono- or bicyclic aryl, a mono- or bicyclic heteroaryl and a mono- or bicyclic heterocyclyl,

wherein each of these ring systems are optionally substituted with one or more R 3 , and wherein the heteroaryl comprises up to 4 heteroatoms and one or two 5- or 6-membered ring(s).

4. A compound according to claim 1 , wherein

W is selected from the group consisting of

wherein each of these ring systems are optionally substituted with one or more R 3 .

5. A compound according to claim 1 , wherein

W is selected from the group consisting of

wherein each of these ring systems are optionally substituted with one or more R 3 .

6. A compound according to claim 1 , wherein

W is selected from the group consisting of

wherein each of these ring systems are optionally substituted with one or more R 3 .

7. A compound according to claim 1 , wherein R 3 is selected from the group consisting of C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkyl-O—, halogen, and NC—,

wherein, in case R 3 is connected to N-atoms of W, R 3 is selected from the group consisting of C 1-3 -alkyl and C 3-6 -cycloalkyl,

wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, and the C 1-3 -alkyl-O-substituents are optionally substituted with halogens.

8. A compound according to claim 1 , wherein R 3 is selected from the group consisting of H 3 C—, F— and F 3 C—, wherein, in case R 3 is connected to N-atoms of W, R 3 is H 3 C—.

9. A compound according to claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of H and C 1-3 -alkyl optionally substituted with halogens, wherein at least one of R 1 or R 2 is independently C 1-3 alkyl optionally substituted with halogens, or wherein R 1 and R 2 together form a 2- to 5-membered alkylene-bridge optionally substituted with halogens incorporating 0 to 2 heteroatoms independently selected from the group consisting of N, O or S.

10. A compound according to claim 1 , wherein R 1 and R 2 are both H 3 C—.

11. A compound according to claim 1 , wherein Y is selected from the group consisting of a bond, —CH 2 CH 2 — and —CH 2 O—.

12. A compound according to claim 1 , wherein Y is selected from the group consisting of a bond and —CH 2 O—.

13. A compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a salt of any of the above compounds.

14. A pharmaceutical composition containing a compound according to claim 1 together with a pharmaceutically acceptable carrier.

15. A method for the treatment of pain which comprises administering to a host suffering from pain a therapeutically effective amount of a compound according to claim 1 .

16. The compound according to claim 1 , wherein the compound is