US 2010/0063120 A1 · Imidazolidine Derivatives, Uses Therefor, Preparation Thereof and Compositions Comprising Such

Abstract

Compounds of formula (I): wherein X is O or S, R1 is acyl, aldehyde, cycloalkyl, an optionally substituted alkyl, alkenyl or alkynyl, R2 is H. alkyl, hydroxyalkyl, haloalkyl, alkenyl, or alkynyl; substituted alkyl; alkylcarbonyl; R3 and R4 are H, halogen, alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, hydroxyalkyl, haloalkyl, haloalkenyl, or haloalkynyl; or R3 and R4 form an, optionally aromatic or heterocyclic, optionally substituted ring, R5 is H, halogen, trifluoromethyl, —CN, or —NO2; not all of R3, R4, and R5 being H, R6 and R9 are H, halogen, OH; alkyl. hydroxyalkyl, alkoxyl, thioalkyl, haloalkyl, alkenyl, or alkynyl; R7 and R8 are H, halogen, OH, SH; alkoxyl or alkylthio optionally substituted by OH and/or halogen; one of R7 and R8 not being H or halogen; or one of R7 and R8 is a pharmaceutically acceptable ester or thioester grouping, or R6 is C1-3-alkyl or, together with either R1 or R2, represents C1-3 alkylene or alkenylene linking group, optionally substituted by methyl, trifluoromethyl, OH, or halogen, and pharmaceutically acceptable salts and esters thereof, are useful as selective androgen modulators.

Claims46

Dependent claims

(canceled)

A compound of formula (I):

wherein
X is O or S,
R1 represents acyl, aldehyde, cycloalkyl group or is a straight or branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, haloalkyl, haloalkenyl, or haloalkynyl group;
alkylsulphonyl;
arylsulphonyl optionally substituted by one or more substituents, which may be the same or different, selected from the group b as defined below;
alkylenedioxy groups;
alkoxycarbonyl;
aralkoxycarbonyl;
aryloxycarbonyl;
alkoxycarbonylalkyl;
aralkoxycarbonylalkyl;
aryloxycarbonylalkyl;
trifluoromethyl;
a straight or branched alkyl group substituted with an aryl group, a cycloalkyl or heterocyclyl group, alkoxy, alkoxy-substituted alkoxy, alkylthio and the oxidised sulphoxide and sulphone forms thereof, alkylenedioxy groups;
cyano, amino, alkylamino, aralkylamino, arylamino, dialkylamino, diaralkylamino, diarylamino, acylamino, trifluoromethylcarbonylamino, fluoroalkylcarbonylamino, diacylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or oxo group;
and wherein any cycloalkyl or heterocyclyl groups or any aryl component is mono- or bi-cyclic and is optionally substituted by one or more substituents, which may be the same or different, selected from the group b, wherein the group b consists of:
halogen atoms;
hydroxyl;
aldehyde groups;
straight and branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, haloalkyl, haloalkenyl, and haloalkynyl groups;
straight and branched alkoxyl groups;
straight and branched thioalkyl and alkylthio groups;
alkoxycarbonyl;
hydroxycarbonylalkyl;
alkoxycarbonylalkyl;
perfluoroalkyl;
perfluoroalkoxy;
—CN;
acyl;
amino, alkylamino, dialkylamino, acylamino groups;
alkyl groups substituted with an amino, alkylamino, dialkylamino, acylamino, or diacylamino group;
CONH2;
alkylamido groups;
alkylthio and the oxidised sulphoxide and sulphone forms thereof;
alkylenedioxy groups;
and sulphonamide or alkylsulphonamide groups;
R2 represents a hydrogen atom, a straight or branched alkyl group, hydroxyalkyl, haloalkyl, alkenyl, or alkynyl group;
alkoxy- or alkenyloxy-substituted alkyl;
alkylcarbonyl;
alkoxycarbonylalkyl;
or trifluoromethyl group;
R3 and R4, which may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, trifluoromethyl, a straight or branched alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, haloalkenyl, or haloalkynyl group;
a straight or branched alkoxyl group;
or a straight or branched alkylthio group, or R3 and R4, together, represent an, optionally aromatic or heterocyclic, ring having the carbons to which they are attached forming a part of said ring, and being optionally further substituted by substituents b,
R5 represents a hydrogen atom, a halogen atom, trifluoromethyl, —CN, or an —NO2 group;
provided that not all of R3, R4, and R5 represents H,
R6 and R9 are the same or different, and each represents hydrogen, halogen, hydroxyl;
a straight or branched alkyl group, hydroxyalkyl, haloalkyl, alkenyl, or alkynyl group;
a straight or branched alkoxyl group;
or a straight or branched thioalkyl group;
R7 and R8 are the same or different, and each represents hydrogen, halogen, hydroxyl, sulphydryl;
a straight and branched alkoxyl group optionally substituted by one or more hydroxyl groups and/or halogen atoms;
a straight or branched alkylthio group optionally substituted by one or more hydroxyl groups and/or halogen atoms;
and wherein at least one of R7 and R8 is a hydroxyl;
a sulphydryl;
a straight or branched alkoxyl group;
a straight or branched alkylthio group;
or a group —OR10 or —SR10, representing a pharmaceutically acceptable ester or thioester grouping, respectively,
or R7, R8 and R9 are as defined, and R6 is C1-3-alkyl or, together with either R1 or R2, represents a methylene, ethylene, ethenylene, propylene, or propenylene linking group, optionally substituted by one or more methyl, trifluoromethyl, hydroxyl or halogen atoms,
and wherein any alkyl components contain from 1 to 6 carbon atoms, unless otherwise specified, and any alkenyl or alkynyl components contain from 2 to 6 carbon atoms, and are optionally substituted by at least one halogen atom or hydroxy group, and wherein any aryl component is optionally a heteroaryl group,
provided that, when X is O, R1 is alkyl, and R2 is hydrogen, then at least one of R7 and R8 is a hydroxyl, a sulphydryl, or a group —OR10 or —SR10, wherein R10 is as defined,
and pharmaceutically acceptable salts and esters thereof.

59 more elements

A compound selected from:

1-(3,4-dichlorophenyl)-4-(4-hydroxyphenyl)-3-methylimidazolidine-2,5-dione,
1-(3,4-dichlorophenyl)-4-(4-hydroxyphenyl)-3-(2-propenyl)imidazolidine-2,5-dione,
4-[2,5-dioxo-4-(4-hydroxyphenyl)-3-(2-propynyl)imidazolidin-1-yl]-2-trifluoromethylbenzonitrile,
4-[3,4-dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile,
4-[2,5-dioxo-4-(4-hydroxyphenyl)-4-methyl-3-(2-propynyl)-imidazolidin-1-yl]-2-trifluoromethylbenzonitrile,
4-[4-(4-hydroxyphenyl)-4-methyl-5-oxo-3-(2-propenyl)-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile,
2-chloro-4-[3,4-dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-3-methylbenzonitrile,
4-[3,4-dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-methoxybenzonitrile,
(R)-4-[3,4-dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-trifluoromethylbenzonitrile,
1-(3,4-dichlorophenyl)-4-hydroxymethyl-4-(4-hydroxyphenyl)-3-methyl-imidazolidine-2,5-dione,
4-[4-hydroxymethyl-4-(4-hydroxyphenyl)-3-methyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile,
4-[4-fluoromethyl-4-(4-hydroxyphenyl)-3-methyl-2,5-dioxoimidazolidin. 1-yl]-2-trifluoromethylbenzonitrile,
4-[3-(2-butynyl)-4-(4-hydroxyphenyl)-4-methyl-2,5-dioxo-imidazolidin 1-yl]-2-trifluoromethyl-benzonitrile,
4-[4-(4-hydroxyphenyl)-3-methoxymethyl-4-methyl-2,5-dioxoimudazolidin-1-yl]-2-trifluoromethylbenzonitrile,
4-[1-(3,4-dichlorophenyl)-2,5-dioxo-3-methylimidazolidin-4-yl]phenyl-N,N-dimethylcarbamate,
3-[1-(3,4-dichlorophenyl)-2,5-dioxo-3-methylimidazolidin-4-yl]phenyl-N,N-dimethylcarbamate,
4-[1-(3,4-dichlorophenyl)-2,5-dioxo-3-methylimidazolidin-4-yl]phenyl acetate,
(R)-4-[3,4-dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-methoxybenzonitrile,
(R)-4-[4-fluoromethyl-4-(4-hydroxyphenyl)-3-methyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile,
4-[2,5-dioxo-4-(4-hydroxyphenyl)-3-methoxymethyl-4-methylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, and
(R)-4-[2,5-dioxo-4-(4-hydroxyphenyl)-3-methoxymethyl-4-methylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile.

18 more elements

A method of treatment of a condition characterized by decreased androgen receptor activity, comprising administering to a subject a therapeutically effective amount of a compound of formula (I):

wherein
X is O or S,
R1 represents acyl, aldehyde, cycloalkyl group or is a straight or branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, haloalkyl, haloalkenyl, or haloalkynyl group;
alkylsulphonyl;
arylsulphonyl optionally substituted by one or more substituents, which may be the same or different, selected from the group b as defined below;
alkylenedioxy groups;
alkoxycarbonyl;
aralkoxycarbonyl;
aryloxycarbonyl;
alkoxycarbonylalkyl;
aralkoxycarbonylalkyl;
aryloxycarbonylalkyl;
trifluoromethyl;
a straight or branched alkyl group substituted with an aryl group, a cycloalkyl or heterocyclyl group, alkoxy, alkoxy-substituted alkoxy, alkylthio and the oxidised sulphoxide and sulphone forms thereof, alkylenedioxy groups;
cyano, amino, alkylamino, aralkylamino, arylamino, dialkylamino, diaralkylamino, diarylamino, acylamino, trifluoromethylcarbonylamino, fluoroalkylcarbonylamino, diacylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or oxo group;
and wherein any cycloalkyl or heterocyclyl groups or any aryl component is mono- or bi-cyclic and is optionally substituted by one or more substituents, which may be the same or different, selected from the group b, wherein the group b consists of:
halogen atoms;
hydroxyl;
aldehyde groups;
straight and branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, haloalkyl, haloalkenyl, and haloalkynyl groups;
straight and branched alkoxyl groups;
straight and branched thioalkyl and alkylthio groups;
alkoxycarbonyl;
hydroxycarbonylalkyl;
alkoxycarbonylalkyl;
perfluoroalkyl;
perfluoroalkoxy;
—CN;
acyl;
amino, alkylamino, dialkylamino, acylamino groups;
alkyl groups substituted with an amino, alkylamino, dialkylamino, acylamino, or diacylamino group;
CONH2;
alkylamido groups;
alkylthio and the oxidised sulphoxide and sulphone forms thereof;
alkylenedioxy groups;
and sulphonamide or alkylsulphonamide groups;
R2 represents a hydrogen atom, a straight or branched alkyl group, hydroxyalkyl, haloalkyl, alkenyl, or alkynyl group;
alkoxy- or alkenyloxy-substituted alkyl;
alkylcarbonyl;
alkoxycarbonylalkyl;
or trifluoromethyl group;
R3 and R4, which may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, trifluoromethyl, a straight or branched alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, haloalkenyl, or haloalkynyl group;
a straight or branched alkoxyl group;
or a straight or branched alkylthio group, or R3 and R4, together, represent an, optionally aromatic or heterocyclic, ring having the carbons to which they are attached forming a part of said ring, and being optionally further substituted by substituents b,
R5 represents a hydrogen atom, a halogen atom, trifluoromethyl, —CN, or an —NO2 group;
provided that not all of R3, R4, and R5 represents H,
R6 and R9 are the same or different, and each represents hydrogen, halogen, hydroxyl;
a straight or branched alkyl group, hydroxyalkyl, haloalkyl, alkenyl, or alkynyl group;
a straight or branched alkoxyl group;
or a straight or branched thioalkyl group;
R7 and R8 are the same or different, and each represents hydrogen, halogen, hydroxyl, sulphydryl;
a straight and branched alkoxyl group optionally substituted by one or more hydroxyl groups and/or halogen atoms;
a straight or branched alkylthio group optionally substituted by one or more hydroxyl groups and/or halogen atoms;
and wherein at least one of R7 and R8 is a hydroxyl;
a straight or branched alkoxyl group;
a straight or branched alkylthio group;
or a group —OR10 or —SR10, representing a pharmaceutically acceptable ester or thioester grouping, respectively, or R7, R8 and R9 are as defined, and R6 is C1-3-alkyl or, together with either R1 or R2, represents a methylene, ethylene, ethenylene, propylene, or propenylene linking group, optionally substituted by one or more methyl, trifluoromethyl, hydroxyl or halogen atoms,
and wherein any alkyl components contain from 1 to 6 carbon atoms, unless otherwise specified, and any alkenyl or alkynyl components contain from 2 to 6 carbon atoms, and are optionally substituted by at least one halogen atom or hydroxy group, and wherein any aryl component is optionally a heteroaryl group,
and pharmaceutically acceptable salts and esters thereof.

56 more elements

Dependencies are inferred from the claim text.

Imidazolidine Derivatives, Uses Therefor, Preparation Thereof and Compositions Comprising Such

Life of this patent

Imidazolidine Derivatives, Uses Therefor, Preparation Thereof and Compositions Comprising Such

Life of this patent

Abstract

Claims46