US 7,605,289 B2Granted

Benzamide derivatives and uses related thereto

AssigneeAmgen Inc.

InventorsJay P. Powers, Michael Degraffenreid, Xiao He, Lisa Julian, Dustin L. McMinn, Daqing Sun, Yosup Rew, Xuelei Yan

Life of this patent

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Abstract

Benzamide derivatives of formula I and II, and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof, and pharmaceutical compositions comprising the same, are described and have therapeutic utility, particularly in the treatment of diabetes, obesity, and related conditions and disorders: wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are defined as provided herein.

Claims42

Dependent claims

A compound having formula (I):

or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:
R1 is a member selected from the group consisting of —OH, halogen and (C1-C6)haloalkyl;
R2 and R3 are members independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl and (C3-C8)cycloalkyl, wherein no more than two of R1, R2 and R3 are halogen;
R4 is a member selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl and (C3-C8)cycloalkyl;
R5 is selected from the group consisting of halogen, —CN, —NO2, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy, (C3-C8)heterocycloalkyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR″, —OC(O)R′, —C(O)N(R′)2, —S(O)R″, —SO2R″, —SO2N(R′)2, —N(R′)2, —NR′C(O)R′, —NR′SO2R″, —X—C(O)R′, —X—C(O)OR′, —X—NR′C(O)OR″, —X—OR″, —X—OC(O)R′, —X—C(O)N(R′)2, —X—S(O)R″, —X—SO2R″, —X—SO2N(R′)2, —X—N(R′)2 and —X—NR′C(O)R′;
R6 is selected from the group consisting of halogen, —CN, —NO2, methyl, ethyl, straight or branched butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, straight or branched octyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy, (C3-C8)heterocycloalkyl(C1-C6)alkyl, aryl, heteroaryl(C1-C6)alkyl, aryl(C1-C6)alkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR″, —OC(O)R′, —C(O)N(R′)2, —S(O)R″, —SO2R″, —SO2N(R′)2, —N(R′)2, —NR′C(O)R′, —NR′SO2R″, —X—C(O)R″, —X—C(O)OR″, —X—NR′C(O)OR″, —X—OR″, —X—OC(O)R′, —X—C(O)N(R′)2, —X—S(O)R″, —X—SO2R″, —X—SO2N(R′)2, —X—N(R′)2 and —X—NR′C(O)R′;
any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from the group consisting of halogen, —CN, —NO2, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)2, —S(O)R″, —SO2R″, —SO2N(R′)2, —N(R′)2, —NR′C(O)R′ and —NR′SO2R″;
X is a branched or straight chain (C1-C8)alkylene group;
each occurrence of R′ is independently H or an unsubstituted member selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, aryl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)heterocycloalkyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl(C1-C6)alkyl, or two R′ groups, when attached to the same nitrogen atom, can be combined with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl group;
and
each occurrence of R″ is independently an unsubstituted member selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, aryl, (C3-C8)cycloalkyl(C1-C6)alkyl, heterocyclyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl or aryl(C1-C6)alkyl;
with the proviso that when R1 is —OH, then R2 and R3 are not both CF3.

9 more elements

A compound having the formula (II):

wherein
R7 is a member selected from the group consisting of —OH, halogen and (C1-C6)haloalkyl;
R8 and R9 are members independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl and (C3-C8)cycloalkyl, wherein no more than two of R7, R8 and R9 are halogen;
R10 is a member selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl and (C3-C8)cycloalkyl;
R11 and R12 are each members independently selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy, (C3-C8)heterocycloalkyl(C1-C6)alkyl, aryl, heteroaryl(C1-C6)alkyl, aryl(C1-C6)alkyl;
wherein R11 and R12, together with the nitrogen to which they are attached may combine to form a five to fourteen-membered ring heterocycloalkyl containing from 1 to 4 heteroatoms independently selected from nitrogen and sulfur;
any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from the group consisting of halogen, —CN, —NO2, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)heterocycloalkyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl(C1-C6)alkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)2, —S(O)R″, —SO2R″, —SO2N(R′)2, —N(R′)2, —NR′C(O)R′, —NR′SO2R″, —X—C(O)R′, —X—C(O)OR′, —X—NR′C(O)OR″, —X—OR″, —X—OC(O)R′, —X—C(O)N(R′)2, —X—S(O)R″, —X—SO2R″, —X—SO2N(R′)2, —X—N(R′)2 and —X—NR′C(O)R′;
wherein any alkyl or alkylene group is optionally substituted by up to three substitutes selected from the groups consisting of —OR′, ═O, —NR′R″, -halo, —OC(O)R′, —CO2R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO2R′, —NR′SO2NR′R″, —SO2R′, —SO2NR′R″, —NR″SO2R′—CN and —NO2;
X is a branched or straight chain (C1-C8)alkylene group;
each occurrence of R′ is independently H or an unsubstituted member selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, aryl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)heterocycloalkyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl(C1-C6)alkyl, or two R′ groups, when attached to the same nitrogen atom, can be combined with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl group;
and
each occurrence of R″ is independently an unsubstituted member selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, aryl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)heterocycloalkyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl or aryl(C1-C6)alkyl;
with the provisos that:
(a) when R7 is —OH, then R8 and R9 are not both CF3, and
(b) said compound is not
4-(1-ethyl-1-hydroxypropyl)-N,N-bis(1-methylethyl)-benzamide, or
4-(1-hydroxy-1-methylphenyl)-N-[1-[3-[6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl]phenyl]ethyl]-N-[(4-methylsulfonyl)phenyl]-benzamide,
or a pharmaceutically acceptable salt or stereoisomer thereof.

15 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/448,986Filed 8 Jun 2006 · us provisional application
Priority: 17 Jun 2005
Published: US 2006/0293392 A128 Dec 2006
Granted: 20 Oct 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification58 codes

C07D 277/28
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms: radicals substituted by…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics

Family

Application60/691,244Us provisional application · filed 17 Jun 2005
US 2006/0293392 A1Pre-grant publication · published 28 Dec 2006
US 7,605,289 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound having formula (I):

or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:
R1 is a member selected from the group consisting of —OH, halogen and (C1-C6)haloalkyl;
R2 and R3 are members independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl and (C3-C8)cycloalkyl, wherein no more than two of R1, R2 and R3 are halogen;
R4 is a member selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl and (C3-C8)cycloalkyl;
R5 is selected from the group consisting of halogen, —CN, —NO2, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy, (C3-C8)heterocycloalkyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR″, —OC(O)R′, —C(O)N(R′)2, —S(O)R″, —SO2R″, —SO2N(R′)2, —N(R′)2, —NR′C(O)R′, —NR′SO2R″, —X—C(O)R′, —X—C(O)OR′, —X—NR′C(O)OR″, —X—OR″, —X—OC(O)R′, —X—C(O)N(R′)2, —X—S(O)R″, —X—SO2R″, —X—SO2N(R′)2, —X—N(R′)2 and —X—NR′C(O)R′;
R6 is selected from the group consisting of halogen, —CN, —NO2, methyl, ethyl, straight or branched butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, straight or branched octyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy, (C3-C8)heterocycloalkyl(C1-C6)alkyl, aryl, heteroaryl(C1-C6)alkyl, aryl(C1-C6)alkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR″, —OC(O)R′, —C(O)N(R′)2, —S(O)R″, —SO2R″, —SO2N(R′)2, —N(R′)2, —NR′C(O)R′, —NR′SO2R″, —X—C(O)R″, —X—C(O)OR″, —X—NR′C(O)OR″, —X—OR″, —X—OC(O)R′, —X—C(O)N(R′)2, —X—S(O)R″, —X—SO2R″, —X—SO2N(R′)2, —X—N(R′)2 and —X—NR′C(O)R′;
any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from the group consisting of halogen, —CN, —NO2, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)2, —S(O)R″, —SO2R″, —SO2N(R′)2, —N(R′)2, —NR′C(O)R′ and —NR′SO2R″;
X is a branched or straight chain (C1-C8)alkylene group;
each occurrence of R′ is independently H or an unsubstituted member selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, aryl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)heterocycloalkyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl(C1-C6)alkyl, or two R′ groups, when attached to the same nitrogen atom, can be combined with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl group;
and
each occurrence of R″ is independently an unsubstituted member selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C6)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, aryl, (C3-C8)cycloalkyl(C1-C6)alkyl, heterocyclyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl or aryl(C1-C6)alkyl;
with the proviso that when R1 is —OH, then R2 and R3 are not both CF3.

9 more elements

Facts

Application

11/448,986Filed 8 Jun 2006 · us provisional application

Priority

17 Jun 2005

Published

US 2006/0293392 A128 Dec 2006

Granted

20 Oct 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification58 codes

C07D 277/28
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms: radicals substituted by…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics