4-aminopiperidine derivatives

• US 7,683,079 B2
• Filed: 12/14/2005
• Issued: 03/23/2010
• Est. Priority Date: 12/20/2004
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Luebbers, Thomas, Loeffler, Bernd Michael, Boehringer, Markus, Kuhn, Bernd, Hunziker, Daniel, Ricklin, Fabienne
• Primary Examiner(s): Dentz; Bernard
• Assistant Examiner(s): Gallis; David E
• Application Number:
  US11/300,206
• Publication Number:
  US 20060135561A1
• Time in Patent Office: 1,560 Days
• Field of Search: 546/192, 546/195, 546/194, 546/205, 546/207, 546/223, 514/317, 514/319, 514/326, 514/329
• US Class Current: 514/329
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 277/04 having no double bonds between ring members or between ring members and non-ring members

Abstract

The present invention relates to compounds of the formula (I)

wherein R¹ and R² are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, non-insulin dependent diabetes mellitus and/or impaired glucose tolerance, obesity, and/or metabolic syndrome or β-cell protection.

Claims

1. A compound of the formula I:

2. The compound according to claim 1, wherein R¹ is selected from the group consisting of phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;

and —

(CHR³)_m-phenyl, wherein m is 1 or 2 and with phenyl being unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy and wherein R³ is hydrogen.

3. The compound according to claim 1, wherein R¹ is selected from the group consisting of phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;

and —

(CHR³)_m-phenyl, wherein m is 1 or 2 and with phenyl being unsubstituted or mono-, di-, or trisubstituted by lower alkoxy and wherein R³ hydrogen.

4. The compound according to claim 1, wherein R¹ is phenyl mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy.

5. The compound according to claim 1, wherein R² is selected from the group consisting of phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.

6. The compound according to claim 1, wherein R² is phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, halogenalkyl, or lower alkoxy.

7. The compound according to claim 1, selected from (cis)-3-phenyl-1-phenethyl-piperidine-4-yl-amine, (trans)-3-phenyl-1-phenethyl-piperidine-4-yl-amine, (cis)-3-(3-chloro-phenyl)-1-phenethyl-piperidine-4-yl-amine, (cis/trans)-3-(3-chloro-phenyl)-1-benzyl-piperidine-4-yl-amine, (cis/trans)-3-(3-methyl-phenyl)-1-benzyl-piperidine-4-yl-amine, (cis)-3-(3-chloro-phenyl)-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-4-yl-amine, (cis)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride, (trans)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride, (cis/trans)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride, (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride, (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-p-tolyl-piperidine-4-yl-amine hydrochloride, (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-(3,4-dimethyl-phenyl)-piperidine-4-yl-amine hydrochloride, (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-piperidine-4-yl-amine hydrochloride, and pharmaceutically acceptable salts thereof

8. The compound according to claim 1, selected from (cis)-3-phenyl-1-phenethyl-piperidine-4-yl-amine, (cis)-3-(3-chloro-phenyl)-1-phenethyl-piperidine-4-yl-amine, (cis/trans)-3-(3-chloro-phenyl)-1-benzyl-piperidine-4-yl-amine, (cis/trans)-3-(3-methyl-phenyl)-1-benzyl-piperidine-4-yl-amine, (cis)-3-(3-chloro-phenyl)-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-4-yl-amine, (trans)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride, (cis/trans)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride, (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride, and pharmaceutically acceptable salts thereof.

9. The compound according to claim 1, selected from (cis)-3-(3-chloro-phenyl)-1-phenethyl-piperidine-4-yl-amine, (cis/trans)-3-(3-chloro-phenyl)-1-benzyl-piperidine-4-yl-amine, (cis/trans)-3-(3-chloro-phenyl)-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-4-yl-amine, (cis)-1-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride, and pharmaceutically acceptable salts thereof.

10. A process for the manufacture of compounds of formula I according to claim 1, comprising the steps of:

a) converting a compound of the formula

11. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier and/or adjuvant.