# US 7,411,093 B2 · Aminocycloalkanes as DPP-IV inhibitors

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- Number: US 7,411,093 B2
- Document ID: US7411093B2
- Status: Granted
- Kind: B2
- Application number: 11/302,067
- Filed: 2005-12-13
- Published: 2006-06-22
- Granted: 2008-08-12
- Earliest claimed: 2004-12-20
- Assignees: Hoffman-La Roche Inc.
- Inventors: Markus Boehringer; Daniel Hunziker; Bernd Kuhn; Bernd Michael Loeffler; Hans Peter Marty; Patrizio Mattei; Robert Narquizian
- Web page: https://patentgrep.com/patent/US7411093B2

## CPC

- C07C 211/35: containing only non-condensed rings
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 207/27: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D 207/325: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to compounds of formula (I) wherein R1 is 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, particularly non-insulin dependent diabetes mellitus, and impaired glucose tolerance.

## Claims

### Claim 1

A compound according to formula (I):
wherein:
R1 is selected from
R2, R3, R4, R5 and R6 are each independently selected from hydrogen, lower alkyl, halogenated lower alkyl or halogen; provided that R2, R3, R4, R5 and R6 are not all hydrogen;
R7 is lower alkyl;
R8 is lower alkyl;
X is >C═O or >SO2;
R9 R11 are hydrogen or together form a double bond;
R10 and R12 are independently selected from hydrogen or lower alkyl;
m is 1 or 2;
n is 0, 1, or 2;
and pharmaceutically acceptable salts thereof,
with the further proviso that the following compounds are excluded
2-(m-tolyl)-cyclohexylamine, 2-(p-tolyl)-cyclohexylamine, 2-(o-tolyl)-cyclohexylamine, 2-(2-chlorophenyl)-cyclohexylamine, 2-(3-chlorophenyl)-cyclohexylamine, 2-(p-chlorophenyl)-cyclohexylamine, 2-(2-bromophenyl)-cyclohexylamine, 2-(o-tolyl)-cyclopentylamine, 2-(p-tolyl)-cyclopentylamine,
2-(4-chlorophenyl)-cyclopentylamine, 2-(3,5-ditluorophenyl)-cyclopentylamine, 2-(3-fluorophenyl)-cyclopentylamine, 2-(4-fluorophenyl)-cyclopentylamine,
2-(4-bromophenyl)-cyclopentylamine,
2-(4-tert-butylphenyl)-cyclopentylamine, and
2-(3,4-difluorophenyl)-cyclopentylamine.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1 is
and wherein R2, R3, R4, R5 and R6 are each independently selected from hydrogen, lower alkyl, halogenated lower alkyl, lower alkoxy or halogen; provided that R2, R3, R4, R5 and R6 are not all hydrogen.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R1 is
and wherein R7 is lower alkyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R1 is
and wherein R8 is lower alkyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R1 is
X is >C═O or >SO2;
R9 and R11 are hydrogen or together form a double bond;
R10 and R12 are independently selected from hydrogen or lower alkyl and
m is 1 or 2.

### Claim 6 (depends on 1)

The compound according to claim 1 selected from
(trans)-2-m-tolyl-cyclohexylamine,
(cis)-2-m-tolyl-cyclohexylamine,
(trans)-2-o-tolyl-cyclohexylamine,
(cis)-2-o-tolyl-cyclohexylamine,
(trans)-2-(2-methoxy-phenyl)-cyclohexylamine,
(trans)-2-(2,5-dichloro-phenyl)-cyclohexylamine,
(cis)-2-(2,5-dichloro-phenyl)-cyclohexylamine,
(trans)-2-(2,4-dimethyl-phenyl)-cyclohexylamine,
(cis)-2-(3-bromo-phenyl)-cyclohexylamine,
(trans)-2-(3-bromo-phenyl)-cyclohexylamine,
(trans)-2-(2-fluoro-5-methyl-phenyl)-cyclohexylamine,
(cis)-2-(5-methyl-thiophen-2-yl)-cyclohexylamine,
(trans)-2-(5-methyl-thiophen-2-yl)-cyclohexylamine,
(cis)-2-(2,4-dichloro-phenyl)-cyclohexylamine,
(trans)-2-(2,4-dichloro-phenyl)-cyclohexylamine,
(cis)-2-(3-fluoro-phenyl)-cyclohexylamine,
(trans)-2-(2-chloro-phenyl)-cyclohexylamine,
(trans)-2-(2,5-dimethyl-phenyl)-cyclohexylamine,
(cis/trans)-2-(2-fluoro-phenyl)-cyclohexylamine,
(trans)-2-(2-fluoro-phenyl)-cyclohexylamine,
(cis)-2-(3-chloro-phenyl)-cyclohexylamine,
(trans)-2-(3-chloro-phenyl)-cyclohexylamine,
(cis)-2-(2,5-dichloro-phenyl)-cycloheptylamine,
(trans)-2-(2,5-dichloro-phenyl)-cycloheptylamine,
(cis)-2-(2,5-dichloro-phenyl)-cyclopentylamine,
(trans)-2-(3-methyl-pyrrol-1-yl)-cyclohexylamine,
(trans)-2-(3-ethyl-pyrrol-1-yl)-cyclohexylamine,
(trans)-2-(1,1-dioxo-[1,2]thiazinan-2-yl)-cyclohexylamine,
(trans)-1-(2-amino-cyclohexyl)-5,6-dihydro-1H-pyridin-2-one,
(trans)-1-(2-amino-cyclohexyl)-4-methyl-1,5-dihydro-pyrrol-2-one,
(trans)-1-(2-amino-cyclohexyl)-4-methyl-5,6-dihydro-1H-pyridin-2-one,
(trans)-1-(2-amino-cyclohexyl)-piperidin-2-one,
(trans)-1-(2-amino-cyclohexyl)-4-methyl-pyrrolidin-2-one, and
pharmaceutically acceptable salts thereof.

### Claim 7 (depends on 1)

A process for manufacturing a compound according to claim 1, comprising the steps of:
a) a reductive amination of a ketone of formula II
wherein R1 and n are as defined in claim 1, or
b) a deprotection of a carbamic acid ester of formula III
wherein R1 and n are as defined in claim 1 and Rp is an amino protecting group.

### Claim 8

A pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula I
wherein
R1 is selected from
R2, R3, R4, R5 and R6 are each independently selected from hydrogen, lower alkyl, halogenated lower alkyl, lower alkoxy or halogen; provided that R2, R3, R4, R5 and R6 are not all hydrogen;
R7 is lower alkyl;
R8 is lower alkyl;
X is >C═O or >SO2;
R9 and R11 are hydrogen or together form a double bond;
R10 and R12 are independently selected from hydrogen or lower alkyl;
m is 1 or 2; and
n is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof;
and a pharmaceutically acceptable carrier and/or adjuvant.

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

A method for the treatment of diseases which are associated with DPP-IV, comprising the step of administering a compound according to claim 1 to a human being or animal in need thereof.

### Claim 11 (depends on 10)

The method according to claim 10, wherein said disease is non-insulin dependent diabetes mellitus, impaired glucose tolerance, obesity, metabolic syndrome or β-cell protection.