US 2007/0191433 A1Published application

Acylated piperidine derivatives as melanocortin 4-receptor agonists

AssigneeMerck & Co., Inc.

InventorsRaman Bakshi, James Dellureficio, Ravi Nargund

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Abstract

Certain novel N-acylated piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

Claims15

Dependent claims

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of:
(1) hydrogen,
(2) amidino,
(3) —C1-4 alkyliminoyl,
(4) —C1-8 alkyl,
(5) —(CH2)n—C3-7 cycloalkyl,
(6) —(CH2)nheterocycloalkyl,
(7) —(CH2)n-phenyl,
(8) —(CH2)n-naphthyl, and
(9) —(CH2)n-heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R3, and alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R3 and oxo;
R2 is selected from the group consisting of:
(1) phenyl,
(2) naphthyl, and
(3) heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R9;
each R3 is independently selected from the group consisting of:
(1) —C1-8 alkyl,
(2) —(CH2)n-phenyl,
(3) —(CH2)n-heteroaryl,
(4) —(CH2)nheterocycloalkyl,
(5) —(CH2)nC3-7 cycloalkyl,
(6) halogen,
(7) —OR8,
(8) —(CH2)nC═N,
(9) —(CH2)nN(R8)2,
(10) —(CH2)nC(O)N(R8)2,
(11) —(CH2)nC(O)NR8N(R8)2,
(12) —(CH2)nC(O)NR8NR8C(O)R8, and
(13) —(CH2)nCF3,
wherein phenyl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, and wherein any alkyl, cycloalkyl, heterocycloalkyl, and methylene (CH2) carbon atom in R3 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, or two R3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
R4 is selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6 alkyl,
(3) —OC1-6 alkyl, and
(4) —(CH2)nN(R8)C(O)R8;
R5 is selected from the group consisting of:
(1) —CF3,
(2) —C1-6 alkyl,
(3) —C2-8 alkenyl,
(4) —C2-8 alkynyl,
(5) —OC1-8 alkyl,
(6) —(CH2)nC3-7 cycloalkyl,
(7) —(CH2)nheterocycloalkyl,
(8) —(CH2)n-phenyl,
(9) —(CH2)n-naphthyl,
(10) —(CH2)n-heteroaryl, and
(11) —(CH2)nC3-7 bicycloalkyl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R3, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and bicycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R3 and oxo, and wherein any methylene (CH2) in R5 is unsubstituted or substituted with one to two substituents independently selected from
halogen, hydroxy, oxo, and C1-4 alkyl;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —OC1-6 alkyl;
R7 is selected from the group consisting of:
(1) —(CH2)nN(R8)2,
(2) —(CH2)nNR8C(O)R8,
(3) —(CH2)nOR8,
(4) —(CH2)nC═N,
(5) —(CH2)nC(O)OR8,
(6) —(CH2)nC(O)N(R8)2,
(7) —(CH2)nNR8C(O)N(R8)2,
(8) —(CH2)nNR8C(O)heteroaryl,
(9) —(CH2)nheteroaryl,
(10) —(CH2)nNR8S(O)pR8,
(11) —(CH2)nSR8, and
(12) —(CH2)nS(O)pR8,
wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from C1-4 alkyl;
and any methylene (CH2) in R7 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C1-4 alkyl, or two C1-4 alkyl substituents on any methylene (CH2) in R7 together with the atom to which they are attached form a 3, 4, 5, or 6-membered ring optionally containing an additional heteroatom selected from O, S, —NH, and —NC1-4 alkyl;
each R8 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-8 alkyl,
(3) —C2-8 alkenyl,
(4) —(CH2)nC3-7 cycloalkyl,
(5) —(CH2)nheterocycloalkyl,
(6) —(CH2)n-phenyl, and
(7) —(CH2)n-heteroaryl;
each R9 is independently selected from the group consisting of:
(1) —C1-8 alkyl,
(2) —C2-8 alkenyl,
(3) —(CH2)n-phenyl,
(4) —(CH2)n-naphthyl,
(5) —(CH2)n-heteroaryl,
(6) —(CH2)nheterocycloalkyl,
(7) —(CH2)nC3-7 cycloalkyl,
(8) halogen,
(9) —OR8,
(10) —(CH2)nC(O)R8,
(11) —(CH2)nOC(O)R8,
(12) —(CH2)nC(O)OR8,
(13) —(CH2)nC═N,
(14) NO2,
(15) —(CH2)nN(R8)2,
(16) —(CH2)nC(O)N(R8)2,
(17) —(CH2)nNR8C(O)R8,
(18) —(CH2)nNR8C(O)OR8,
(19) —(CH2)nNR8C(O)-heteroaryl,
(20) —(CH2)nNR8C(O)N(R8)2,
(21) —(CH2)nC(O)NR8N(R8)2,
(22) —(CH2)nC(O)NR8NR8C(O)R8,
(23) —(CH2)nNR8S(O)pR8,
(24) —(CH2)nS(O)pN(R8)2,
(25) —(CH2)n S(O)pR8,
(26) —O(CH2)nC(O)N(R8)2,
(27) —(CH2)nCF3, and
(28) —O(CH2)nCF3,
wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and any methylene (CH2) carbon atom in R9 are unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, or two R9 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
r is 1 or 2;
s is 0, 1 or 2;
n is 0, 1, 2, 3, or 4;
and
p is 0, 1, or 2.

110 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/632,000Filed 15 Jul 2005
Priority: 19 Jul 2004
Published: 16 Aug 2007
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 15/00
Drugs for genital or sexual disorders
A61P 15/10
Drugs for genital or sexual disorders ; Contraceptives: for impotence

Family

Application60/589,089Us provisional application · filed 19 Jul 2004
US 7,618,987 B2Related patent
US 2007/0191433 A1This patent

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

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Abstract

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of:
(1) hydrogen,
(2) amidino,
(3) —C1-4 alkyliminoyl,
(4) —C1-8 alkyl,
(5) —(CH2)n—C3-7 cycloalkyl,
(6) —(CH2)nheterocycloalkyl,
(7) —(CH2)n-phenyl,
(8) —(CH2)n-naphthyl, and
(9) —(CH2)n-heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R3, and alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R3 and oxo;
R2 is selected from the group consisting of:
(1) phenyl,
(2) naphthyl, and
(3) heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R9;
each R3 is independently selected from the group consisting of:
(1) —C1-8 alkyl,
(2) —(CH2)n-phenyl,
(3) —(CH2)n-heteroaryl,
(4) —(CH2)nheterocycloalkyl,
(5) —(CH2)nC3-7 cycloalkyl,
(6) halogen,
(7) —OR8,
(8) —(CH2)nC═N,
(9) —(CH2)nN(R8)2,
(10) —(CH2)nC(O)N(R8)2,
(11) —(CH2)nC(O)NR8N(R8)2,
(12) —(CH2)nC(O)NR8NR8C(O)R8, and
(13) —(CH2)nCF3,
wherein phenyl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, and wherein any alkyl, cycloalkyl, heterocycloalkyl, and methylene (CH2) carbon atom in R3 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, or two R3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
R4 is selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6 alkyl,
(3) —OC1-6 alkyl, and
(4) —(CH2)nN(R8)C(O)R8;
R5 is selected from the group consisting of:
(1) —CF3,
(2) —C1-6 alkyl,
(3) —C2-8 alkenyl,
(4) —C2-8 alkynyl,
(5) —OC1-8 alkyl,
(6) —(CH2)nC3-7 cycloalkyl,
(7) —(CH2)nheterocycloalkyl,
(8) —(CH2)n-phenyl,
(9) —(CH2)n-naphthyl,
(10) —(CH2)n-heteroaryl, and
(11) —(CH2)nC3-7 bicycloalkyl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R3, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and bicycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R3 and oxo, and wherein any methylene (CH2) in R5 is unsubstituted or substituted with one to two substituents independently selected from
halogen, hydroxy, oxo, and C1-4 alkyl;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —OC1-6 alkyl;
R7 is selected from the group consisting of:
(1) —(CH2)nN(R8)2,
(2) —(CH2)nNR8C(O)R8,
(3) —(CH2)nOR8,
(4) —(CH2)nC═N,
(5) —(CH2)nC(O)OR8,
(6) —(CH2)nC(O)N(R8)2,
(7) —(CH2)nNR8C(O)N(R8)2,
(8) —(CH2)nNR8C(O)heteroaryl,
(9) —(CH2)nheteroaryl,
(10) —(CH2)nNR8S(O)pR8,
(11) —(CH2)nSR8, and
(12) —(CH2)nS(O)pR8,
wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from C1-4 alkyl;
and any methylene (CH2) in R7 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C1-4 alkyl, or two C1-4 alkyl substituents on any methylene (CH2) in R7 together with the atom to which they are attached form a 3, 4, 5, or 6-membered ring optionally containing an additional heteroatom selected from O, S, —NH, and —NC1-4 alkyl;
each R8 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-8 alkyl,
(3) —C2-8 alkenyl,
(4) —(CH2)nC3-7 cycloalkyl,
(5) —(CH2)nheterocycloalkyl,
(6) —(CH2)n-phenyl, and
(7) —(CH2)n-heteroaryl;
each R9 is independently selected from the group consisting of:
(1) —C1-8 alkyl,
(2) —C2-8 alkenyl,
(3) —(CH2)n-phenyl,
(4) —(CH2)n-naphthyl,
(5) —(CH2)n-heteroaryl,
(6) —(CH2)nheterocycloalkyl,
(7) —(CH2)nC3-7 cycloalkyl,
(8) halogen,
(9) —OR8,
(10) —(CH2)nC(O)R8,
(11) —(CH2)nOC(O)R8,
(12) —(CH2)nC(O)OR8,
(13) —(CH2)nC═N,
(14) NO2,
(15) —(CH2)nN(R8)2,
(16) —(CH2)nC(O)N(R8)2,
(17) —(CH2)nNR8C(O)R8,
(18) —(CH2)nNR8C(O)OR8,
(19) —(CH2)nNR8C(O)-heteroaryl,
(20) —(CH2)nNR8C(O)N(R8)2,
(21) —(CH2)nC(O)NR8N(R8)2,
(22) —(CH2)nC(O)NR8NR8C(O)R8,
(23) —(CH2)nNR8S(O)pR8,
(24) —(CH2)nS(O)pN(R8)2,
(25) —(CH2)n S(O)pR8,
(26) —O(CH2)nC(O)N(R8)2,
(27) —(CH2)nCF3, and
(28) —O(CH2)nCF3,
wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and any methylene (CH2) carbon atom in R9 are unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, or two R9 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
r is 1 or 2;
s is 0, 1 or 2;
n is 0, 1, 2, 3, or 4;
and
p is 0, 1, or 2.

110 more elements

Facts

Application

11/632,000Filed 15 Jul 2005

Priority

19 Jul 2004

Published

16 Aug 2007

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 15/00
Drugs for genital or sexual disorders
A61P 15/10
Drugs for genital or sexual disorders ; Contraceptives: for impotence