US 2006/0040906 A1Published application

Piperazine urea derivatives as melanocortin-4 receptor agonists

AssigneeMerck & Co., Inc.

InventorsRaman Bakshi, Ravi Nargund, Brenda Palucki, Min Park, Zhixiong Ye

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Abstract

Certain novel piperazine urea derivatives are agonists of the human melanocortin-4 receptor (MC-4R) and, in particular, are receptor-subtype selective agonists of MC-4R. They are useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity and diabetes.

Claims38

Dependent claims

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof;
wherein
m is 1 or 2;
each p is independently 0, 1, or 2;
each n is independently 0, 1, or 2;
R1 is selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CHR12)n—C3-6 cycloalkyl,
(CHR12)n—O(CHR12)aryl,
(CHR12)n-aryl, and
(CHR12)n-heteroaryl;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
R3, R4, R5, R6, R7, R8, R9, and R10 are each independently selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)nC3-6 cycloalkyl,
(CH2)n-heteroaryl, and
(CH2)n-heterocyclyl;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
or R3 and R5 and the carbon atoms to which they are attached form a 5- to 7-membered ring;
or R3 and R9 and the carbon atoms to which they are attached form a 5- to 7-membered ring;
or R5 and R7 and the carbon atoms to which they are attached form a 5- to 7-membered ring;
or R7 and R9 and the carbon atoms to which they are attached form a 5- to 7-membered ring;
R2 is selected from the group consisting of
hydrogen,
C2-6 alkenyl,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)nC3-6 cycloalkyl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl,
(CH2)1-2OR12,
(CH2)1-2CO2R12,
(CH2)1-2CONR12R12,
CH2C≡CH, and
CH2CHF2;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
or R2 and R3 and the carbonoms to which they are attached form a 5- to 7-membered ring;
or R3 and R4 and the carbon atom to which they are attached form a 3- to 6-membered spirocyclic ring;
R11 is selected from the group consisting of
hydrogen,
C1-6 alkyl,
(CH2)n-phenyl,
(CH2)n-naphthyl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl,
(CH2)nC3-7 cycloalkyl,
halogen,
OR12,
(CH2)nN(R12)2,
(CH2)nC≡N,
(CH2)nCO2R12,
NO2,
(CH2)nNR12SO2R12,
(CH2)nSO2N(R12)2,
(CH2)nS(O)pR1 2,
(CH2)nNR12C(O)N(R12)2,
(CH2)nC(O)N(R12)2,
(CH2)nNR12C(O)R12,
(CH2)nNR12CO2R12,
O(CH2)nC(O)N(R12)2,
CF3,
CH2CF3,
OCF3, and
OCH2CF3;
wherein phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl 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 methylene (CH2) carbon atom in R11 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
or two substituents when on the same methylene (CH2) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
each R12 is independently selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)n-phenyl,
(CH2)n-naphthyl,
(CH2)n-heteroaryl, and
(CH2)nC3-7 cycloalkyl;
wherein any methylene (CH2) carbon atom in R12 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
or two R12 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC1-4 alkyl;
each R13 is independently selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl, and
(CH2)nC3-7 cycloalkyl;
wherein alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, hydroxy,
C1-3 alkoxy, C1-3 alkylthio, carboxy, C1-4 alkyloxycarbonyl, amino,
C1-4 alkylamino, and di(C1-4 alkylamino);
or two R13 groups together with the atoms to which they are attached form a 5- to 8-membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR12, NBoc, and NCbz;
X is selected from the group consisting of
C1-8 alkyl,
(CH2)nC3-8 cycloalkyl,
(CH2)n-phenyl,
(CH2)n-naphthyl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl,
(CH2)nC═N,
(CH2)nCON(R13R13),
(CH2)nCO2R13,
(CH2)nCOR13,
(CH2)nNR13C(O)R13,
(CH2)nNR13CO2R13,
(CH2)nNR13C(O)N(R13)2,
(CH2)nNR13SO2R13,
(CH2)nS(O)pR13,
(CH2)nSO2N(R13)(R13),
(CH2)nOR13,
(CH2)nOC(O)R13,
(CH2)nOC(O)OR13,
(CH2)nOC(O)N(R13)2,
(CH2)nN(R13)(R13), and
(CH2)nNR13SO2N(R13)(R13);
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
and wherein any methylene (CH2) carbon atom in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
and
Y is selected from the group consisting of
hydrogen,
C1-8 alkyl,
C2-6 alkenyl,
(CH2)nC3-8 cycloalkyl,
(CH2)n-phenyl,
(CH2)n-naphthyl,
(CH2)n-heteroaryl, and
(CH2)n-heterocyclyl;
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
and wherein any methylene (CH2) carbon atom in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl.

129 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/526,178Filed 5 Sep 2003
Priority: 11 Sep 2002
Published: 23 Feb 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/00
Drugs for disorders of the metabolism

Family

Application60/409,879Us provisional application · filed 11 Sep 2002
US 7,414,057 B2Related patent
US 2006/0040906 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
m is 1 or 2;
each p is independently 0, 1, or 2;
each n is independently 0, 1, or 2;
R1 is selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CHR12)n—C3-6 cycloalkyl,
(CHR12)n—O(CHR12)aryl,
(CHR12)n-aryl, and
(CHR12)n-heteroaryl;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
R3, R4, R5, R6, R7, R8, R9, and R10 are each independently selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)nC3-6 cycloalkyl,
(CH2)n-heteroaryl, and
(CH2)n-heterocyclyl;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
or R3 and R5 and the carbon atoms to which they are attached form a 5- to 7-membered ring;
or R3 and R9 and the carbon atoms to which they are attached form a 5- to 7-membered ring;
or R5 and R7 and the carbon atoms to which they are attached form a 5- to 7-membered ring;
or R7 and R9 and the carbon atoms to which they are attached form a 5- to 7-membered ring;
R2 is selected from the group consisting of
hydrogen,
C2-6 alkenyl,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)nC3-6 cycloalkyl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl,
(CH2)1-2OR12,
(CH2)1-2CO2R12,
(CH2)1-2CONR12R12,
CH2C≡CH, and
CH2CHF2;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
or R2 and R3 and the carbonoms to which they are attached form a 5- to 7-membered ring;
or R3 and R4 and the carbon atom to which they are attached form a 3- to 6-membered spirocyclic ring;
R11 is selected from the group consisting of
hydrogen,
C1-6 alkyl,
(CH2)n-phenyl,
(CH2)n-naphthyl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl,
(CH2)nC3-7 cycloalkyl,
halogen,
OR12,
(CH2)nN(R12)2,
(CH2)nC≡N,
(CH2)nCO2R12,
NO2,
(CH2)nNR12SO2R12,
(CH2)nSO2N(R12)2,
(CH2)nS(O)pR1 2,
(CH2)nNR12C(O)N(R12)2,
(CH2)nC(O)N(R12)2,
(CH2)nNR12C(O)R12,
(CH2)nNR12CO2R12,
O(CH2)nC(O)N(R12)2,
CF3,
CH2CF3,
OCF3, and
OCH2CF3;
wherein phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl 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 methylene (CH2) carbon atom in R11 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
or two substituents when on the same methylene (CH2) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
each R12 is independently selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)n-phenyl,
(CH2)n-naphthyl,
(CH2)n-heteroaryl, and
(CH2)nC3-7 cycloalkyl;
wherein any methylene (CH2) carbon atom in R12 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
or two R12 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC1-4 alkyl;
each R13 is independently selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl, and
(CH2)nC3-7 cycloalkyl;
wherein alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, hydroxy,
C1-3 alkoxy, C1-3 alkylthio, carboxy, C1-4 alkyloxycarbonyl, amino,
C1-4 alkylamino, and di(C1-4 alkylamino);
or two R13 groups together with the atoms to which they are attached form a 5- to 8-membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR12, NBoc, and NCbz;
X is selected from the group consisting of
C1-8 alkyl,
(CH2)nC3-8 cycloalkyl,
(CH2)n-phenyl,
(CH2)n-naphthyl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl,
(CH2)nC═N,
(CH2)nCON(R13R13),
(CH2)nCO2R13,
(CH2)nCOR13,
(CH2)nNR13C(O)R13,
(CH2)nNR13CO2R13,
(CH2)nNR13C(O)N(R13)2,
(CH2)nNR13SO2R13,
(CH2)nS(O)pR13,
(CH2)nSO2N(R13)(R13),
(CH2)nOR13,
(CH2)nOC(O)R13,
(CH2)nOC(O)OR13,
(CH2)nOC(O)N(R13)2,
(CH2)nN(R13)(R13), and
(CH2)nNR13SO2N(R13)(R13);
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
and wherein any methylene (CH2) carbon atom in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
and
Y is selected from the group consisting of
hydrogen,
C1-8 alkyl,
C2-6 alkenyl,
(CH2)nC3-8 cycloalkyl,
(CH2)n-phenyl,
(CH2)n-naphthyl,
(CH2)n-heteroaryl, and
(CH2)n-heterocyclyl;
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R11;
alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R11 and oxo;
and wherein any methylene (CH2) carbon atom in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl.

129 more elements

Facts

Application

10/526,178Filed 5 Sep 2003

Priority

11 Sep 2002

Published

23 Feb 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/00
Drugs for disorders of the metabolism