1,3,5-trisubstituted 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity

A pharmaceutical composition comprising:

• at least one pharmaceutically acceptable carrier, at least one pharmaceutically acceptable auxiliary substance or a combination thereof, and
• an effective amount of at least one compound of formula (1), a tautomer, a stereoisomer, or an N-oxide thereof, or a salt or a hydrate of any of the foregoing:
• wherein:
• R1 and R2, which may be identical or different, are each chosen from
• phenyls, thienyls and pyridyls, optionally substituted with 1, 2 or 3 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, and
• naphthyl;
• X is chosen from (i) and (ii),
• wherein:
• R3 is chosen from hydrogen atoms and branched or linear C1-3 alkyl groups;
• R4 is chosen from
• branched or linear C1-8 alkyls and C3-8-cycloalkyl-C1-2-alkyl groups, branched or linear C1-8 alkoxys, C3-8 cycloalkyls, C5-10 bicycloalkyls, C6-10 tricycloalkyls, optionally comprising at least one heteroatom chosen from O, N, and S and optionally substituted with a group chosen from hydroxy groups, from 1 to 3 methyl groups, ethyl groups, and from 1 to 3 fluoro atoms,
• phenoxy, benzyl, phenethyl and phenylpropyl groups, optionally substituted on the phenyl ring with 1, 2 or 3 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
• pyridyl and thienyl groups, and
• NR5R6 wherein:
• R5 and R6, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group comprising from 4 to 10 ring atoms, wherein the heterocyclic group comprises one or two heteroatoms chosen from O, N, and S and wherein the heterocyclic group is optionally substituted with a group chosen from branched or linear C1-3 alkyls, phenyls, hydroxy, trifluoromethyl groups and fluoro atoms;
• or
• R3 and R4, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group comprising from 4 to 10 ring atoms, wherein the heterocyclic group comprises one or two heteroatoms chosen from O, N, and S and wherein the heterocyclic group is optionally substituted with a group chosen from branched or linear C1-3 alkyls, phenyls, hydroxy, trifluoromethyl groups and fluoro atoms
• R7 is chosen from
• benzyl, phenyl, thienyl and pyridyl groups, optionally substituted on the aromatic ring with 1, 2, 3 or 4 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, and acetyl,
• C1-8 branched or linear alkyls, C3-8 alkenyls, C3-10 cycloalkyls, C5-10 bicycloalkyls, C6-10 tricycloalkyls and C5-8 cycloalkenyls,
• naphthyl,
• amino groups, and
• C1-8 dialkylamino groups, C1-8 monoalkylamino groups and saturated or unsaturated, monocyclic or bicyclic, heterocyclic groups having 4 to 10 ring atoms, wherein the heterocyclic group comprises 1 or 2 nitrogen atoms and wherein the heterocyclic group optionally comprises 1heteroatom chosen from O and S and wherein the heterocyclic group is optionally substituted with anentity chosen from branched or linear C1-3 alkyls, phenyls, hydroxys, trifluoromethyls and fluoro atoms;
• R8 is chosen from hydrogen atoms and branched or linear C1-3 alkyls;
• R9 is chosen from
• hydrogen atoms and branched or linear C1-8 alkyls, C3-8 cycloalkyls and C2-10 heteroalkyls, optionally substituted with a group chosen from keto groups, trifluoromethyl groups and fluoro atoms,
• amino, hydroxy, phenoxy and benzyloxy groups
• branched or linear C1-8 alkoxy groups, optionally substituted with an entity chosen from hydroxy groups, trifluoromethyl groups and fluoro atoms,
• phenyl, benzyl, pyridyl, thienyl, pyridylmethyl and phenethyl groups wherein the aromatic rings are optionally substituted with 1, 2 or 3 of the substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, and
• NR10R11 with the proviso when R8 is chosen from a hydrogen atom or a methyl group, and wherein
• R10 and R11, which may be identical or different, are each chosen from C1-4 alkyls and C2-4 trifluoroalkyls or
• R10 and R11, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated heterocyclic group comprising from 4 to 8 ring atoms wherein the heterocyclic group comprises one or two atoms chosen from O, N, and S, and the heterocyclic group is optionally substituted with C1-2 alkyl groups;
• or
• R8 and R9, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group comprising from 4 to 10 ring atoms, wherein the heterocyclic group comprises one or two atoms chosen from O, N, and S, keto groups and —SO2— groups, wherein the heterocyclic group is optionally substituted with C1-2 alkyls, hydroxys, phenyls, methylaminos, dimethylaminos, azetidinyls, pyrrolidinyls, piperidinyls and hexahydro-1H-azepinyls.

The compounds of formula (XI)

• wherein R1 and R2, which may be identical or different, are each chosen from
• phenyls, thienyls and pyridyls, optionally substituted with 1, 2 or 3 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, and
• naphthyl;
• and
• R7 is chosen from
• benzyl, phenyl, thienyl and pyridyl groups, optionally substituted on the aromatic ring with 1, 2, 3 or 4 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
• C1-8 branched or linear alkyls, C3-8 alkenyls, C3-10 cycloalkyls, C5-10 bicycloalkyls, C6-10 tricycloalkyls and C5-8 cycloalkenyls,
• naphthyl,
• amino groups, and
• C1-8 dialkylamino groups, C1-8 monoalkylamino groups and saturated or unsaturated, monocyclic or bicyclic, heterocyclic groups having 4 to 10 ring atoms, wherein the heterocyclic group comprises 1 or 2 nitrogen atoms and wherein the heterocyclic group optionally comprises 1 heteroatom chosen from O and S and wherein the heterocyclic group is optionally substituted with anentity chosen from branched or linear C1-3 alkyls, phenyls, hydroxys, trifluoromethyls and fluoro atoms.

The compounds of formula (XII)

• wherein R1 and R2, which may be identical or different, are each chosen from
• phenyls, thienyls and pyridyls, optionally substituted with 1, 2 or 3 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, and
• naphthyl;
• and
• R7 is chosen from
• benzyl, phenyl, thienyl and pyridyl groups, optionally substituted on the aromatic ring with 1, 2, 3 or 4 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
• C1-8 branched or linear alkyls, C3-8 alkenyls, C3-10 cycloalkyls, C5-10 bicycloalkyls, C6-10 tricycloalkyls and C5-8 cycloalkenyls,
• naphthyl,
• amino groups, and
• C1-8 dialkylamino groups, C1-8 monoalkylamino groups and saturated or unsaturated, monocyclic or bicyclic, heterocyclic groups having 4 to 10 ring atoms, wherein the heterocyclic group comprises 1 or 2 nitrogen atoms and wherein the heterocyclic group optionally comprises 1 heteroatom chosen from O and S and wherein the heterocyclic group is optionally substituted with anentity chosen from branched or linear C1-3 alkyls, phenyls, hydroxys, trifluoromethyls and fluoro atoms;
• and
• wherein Z is chosen from Cl and Br atoms.

A method for preparing a medicament, comprising:

• combining an effective amount of at least one compound of formula (1), a tautomer, a stereoisomer, or N-oxide thereof, or a salt or hydrate of any of the foregoing:
• wherein:
• R1 and R2, which may be identical or different, are each chosen from
• phenyls, thienyls and pyridyls, optionally substituted with 1, 2 or 3 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, and
• naphthyl;
• X is chosen from (i) and (ii),
• wherein:
• R3 is chosen from hydrogen atoms and branched or linear C1-3 alkyl groups;
• R4 is chosen from
• branched or linear C1-8 alkyls and C3-8-cycloalkyl-C1-2-alkyl groups, branched or linear C1-8 alkoxys, C3-8 cycloalkyls, C5-10 bicycloalkyls, C6-10 tricycloalkyls, optionally comprising at least one heteroatom chosen from O, N, and S and optionally substituted with a group chosen from hydroxy groups, from 1 to 3 methyl groups, ethyl groups, and from 1 to 3 fluoro atoms,
• phenoxy, benzyl, phenethyl and phenylpropyl groups, optionally substituted on the phenyl ring with 1, 2 or 3 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
• pyridyl and thienyl groups, and
• NR5R6 wherein:
• R5 and R6, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group comprising from 4 to 10 ring atoms, wherein the heterocyclic group comprises one or two heteroatoms chosen from O, N, and S and wherein the heterocyclic group is optionally substituted with a group chosen from branched or linear C1-3 alkyls, phenyls, hydroxy, trifluoromethyl groups and fluoro atoms;
• or
• R3 and R4, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group comprising from 4 to 10 ring atoms, wherein the heterocyclic group comprises one or two heteroatoms chosen from O, N, and S and wherein the heterocyclic group is optionally substituted with a group chosen from branched or linear C1-3 alkyls, phenyls, hydroxy, trifluoromethyl groups and fluoro atoms;
• R7 is chosen from
• benzyl, phenyl, thienyl and pyridyl groups, optionally substituted on the aromatic ring with 1, 2, 3 or 4 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
• C1-8 branched or linear alkyls, C3-8 alkenyls, C3-10 cycloalkyls, C5-10 bicycloalkyls, C6-10 tricycloalkyls and C5-8 cycloalkenyls,
• naphthyl,
• amino groups, and
• C1-8 dialkylamino groups, C1-8 monoalkylamino groups and saturated or unsaturated, monocyclic or bicyclic, heterocyclic groups having 4 to 10 ring atoms, wherein the heterocyclic group comprises 1 or 2 nitrogen atoms and wherein the heterocyclic group optionally comprises 1heteroatom chosen from O and S and wherein the heterocyclic group is optionally substituted with anentity chosen from branched or linear C1-3 alkyls, phenyls, hydroxys, trifluoromethyls and fluoro atoms;
• R8 is chosen from hydrogen atoms and branched or linear C1-3 alkyls;
• R9 is chosen from
• hydrogen atoms and branched or linear C1-8 alkyls, C3-8 cycloalkyls and C2-10 heteroalkyls, optionally substituted with a group chosen from keto groups, trifluoromethyl groups and fluoro atoms,
• amino, hydroxy, phenoxy and benzyloxy groups
• branched or linear C1-8 alkoxy groups, optionally substituted with an entity chosen from hydroxy groups, trifluoromethyl groups and fluoro atoms,
• phenyl, benzyl, pyridyl, thienyl, pyridylmethyl and phenethyl groups wherein the aromatic rings are optionally substituted with 1, 2 or 3 of the substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, and
• NR10R11 with the proviso when R8 is chosen from a hydrogen atom or a methyl group, and wherein
• R10 and R11, which may be identical or different, are each chosen from C1-4 alkyls and C2-4 trifluoroalkyls or
• R10 and R11, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated heterocyclic group comprising from 4 to 8 ring atoms wherein the heterocyclic group comprises one or two atoms chosen from O, N, and S, and the heterocyclic group is optionally substituted with C1-2 alkyl groups;
• or
• R8 and R9, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group comprising from 4 to 10 ring atoms, wherein the heterocyclic group comprises one or two atoms chosen from O, N, and S, keto groups and —SO2— groups, wherein the heterocyclic group is optionally substituted with C1-2 alkyls, hydroxys, phenyls, methylaminos, dimethylaminos, azetidinyls, pyrrolidinyls, piperidinyls and hexahydro-1H-azepinyls;
• and at least one pharmaceutically acceptable carrier, at least one pharmaceutically acceptable auxiliary substance, or a combination thereof.

A method for treating eating disorders, obesity, juvenile obesity, and drug induced obesity in a patient in need thereof comprising:

• administering an effective amount of at least one compound of formula (1), a tautomer, a stereoisomer, or an N-oxide thereof, or a salt or a hydrate of any of the foregoing:
• wherein:
• R1 and R2, which may be identical or different, are each chosen from
• phenyls, thienyls and pyridyls, optionally substituted with 1, 2 or 3 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, and
• naphthyl;
• X is chosen from (i) and (ii),
• wherein:
• R3 is chosen from hydrogen atoms and branched or linear C1-3 alkyl groups;
• R4 is chosen from
• branched or linear C1-8 alkyls and C3-8-cycloalkyl-C1-2-alkyl groups, branched or linear C1-8 alkoxys, C3-8 cycloalkyls, C5-10 bicycloalkyls, C6-10 tricycloalkyls, optionally comprising at least one heteroatom chosen from O, N, and S and optionally substituted with a group chosen from hydroxy groups, from 1 to 3 methyl groups, ethyl groups, and from 1 to 3 fluoro atoms,
• phenoxy, benzyl, phenethyl and phenylpropyl groups, optionally substituted on the phenyl ring with 1, 2 or 3 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
• pyridyl and thienyl groups, and
• NR5R6 wherein:
• R5 and R6, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group comprising from 4 to 10 ring atoms, wherein the heterocyclic group comprises one or two heteroatoms chosen from O, N, and S and wherein the heterocyclic group is optionally substituted with a group chosen from branched or linear C1-3 alkyls, phenyls, hydroxy, trifluoromethyl groups and fluoro atoms;
• or
• R3 and R4, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group comprising from 4 to 10 ring atoms, wherein the heterocyclic group comprises one or two heteroatoms chosen from O, N, and S and wherein the heterocyclic group is optionally substituted with a group chosen from branched or linear C1-3 alkyls, phenyls, hydroxy, trifluoromethyl groups and fluoro atoms
• R7 is chosen from
• benzyl, phenyl, thienyl and pyridyl groups, optionally substituted on the aromatic ring with 1, 2, 3 or 4 substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
• C1-8 branched or linear alkyls, C3-8 alkenyls, C3-10 cycloalkyls, C5-10 bicycloalkyls, C6-10 tricycloalkyls and C5-8 cycloalkenyls,
• naphthyl,
• amino groups, and
• C1-8dialkylamino groups, C1-8 monoalkylamino groups and saturated or unsaturated, monocyclic or bicyclic, heterocyclic groups having 4 to 10 ring atoms, wherein the heterocyclic group comprises 1 or 2 nitrogen atoms and wherein the heterocyclic group optionally comprises 1 heteroatom chosen from O and S and wherein the heterocyclic group is optionally substituted with anentity chosen from branched or linear C1-3 alkyls, phenyls, hydroxys, trifluoromethyls and fluoro atoms;
• R8 is chosen from hydrogen atoms and branched or linear C1-3 alkyls;
• R9 is chosen from
• hydrogen atoms and branched or linear C1-8 alkyls, C3-8 cycloalkyls and C2-10 heteroalkyls, optionally substituted with a group chosen from keto groups, trifluoromethyl groups and fluoro atoms,
• amino, hydroxy, phenoxy and benzyloxy groups
• branched or linear C1-8 alkoxy groups, optionally substituted with an entity chosen from hydroxy groups, trifluoromethyl groups and fluoro atoms,
• phenyl, benzyl, pyridyl, thienyl, pyridylmethyl and phenethyl groups wherein the aromatic rings are optionally substituted with 1, 2 or 3 of the substituents Y, which may be identical or different, chosen from branched or linear C1-3-alkyls and alkoxys, phenyls, hydroxys, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, and
• NR10R11 with the proviso when R8 is chosen from a hydrogen atom or a methyl group, and wherein
• R10 and R11, which may be identical or different, are each chosen from C1-4 alkyls and C2-4 trifluoroalkyls or
• R10 and R11, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated heterocyclic group comprising from 4 to 8 ring atoms wherein the heterocyclic group comprises one or two atoms chosen from O, N, and S, and the heterocyclic group is optionally substituted with C1-2 alkyl groups;
• or
• R8 and R9, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group comprising from 4 to 10 ring atoms, wherein the heterocyclic group comprises one or two atoms chosen from O, N, and S, keto groups and —SO2— groups, wherein the heterocyclic group is optionally substituted with C1-2 alkyls, hydroxys, phenyls, methylaminos, dimethylaminos, azetidinyls, pyrrolidinyls, piperidinyls and hexahydro-1H-azepinyls.