Imidazolidine derivatives, uses therefor, preparation thereof and compositions comprising such
Compounds of formula (I): wherein X is O or S, R 1 is acyl, aldehyde, cycloalkyl, an optionally substituted alkyl, alkenyl or alkynyl, R 2 is H, alkyl, hydroxyalkyl, haloalkyl, alkenyl, or alkynyl; substituted alkyl; alkylcarbonyl; R 3 and R 4 are H, halogen, alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, hydroxyalkyl, haloalkyl, haloalkenyl, or haloalkynyl; or R 3 and R 4 form an, optionally aromatic or heterocyclic, optionally substituted ring, R 5 is H, halogen, trifluoromethyl, —CN, or —NO 2 ; not all of R 3 , R 4 , and R 5 being H, R 6 and R 9 are H, halogen, OH; alkyl, hydroxyalkyl, alkoxyl, thioalkyl, haloalkyl, alkenyl, or alkynyl; R 7 and R 8 are H, halogen, OH, SH; alkoxyl or alkylthio optionally substituted by OH and/or halogen; one of R 7 and R 8 not being H or halogen; or one of R 7 and R 8 is a pharmaceutically acceptable ester or thioester grouping, or R 6 is C 1-3 -alkyl or, together with either R 1 or R 2 , represents C 1-3 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.
1. A compound of formula (I):
wherein
X is O or S,
R 1 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; CONH 2 ; alkylamido groups; alkylthio and the oxidised sulphoxide and sulphone forms thereof; alkylenedioxy groups; and sulphonamide or alkylsulphonamide groups;
R 2 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;
R 3 and R 4 , 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 R 3 and R 4 , 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,
R 5 represents a hydrogen atom, a halogen atom, trifluoromethyl, —CN, or an —NO 2 group; provided that not all of R 3 , R 4 , and R 5 represents H,
R 6 and R 9 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;
R 7 and R 8 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 R 7 and R 8 is a hydroxyl; a sulphydryl; a straight or branched alkoxyl group; a straight or branched alkylthio group;
or R 7 , R 8 and R 9 are as defined, and R 6 is C 1-3 -alkyl or, together with either R 1 or R 2 , 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, R 1 is alkyl, and R 2 is hydrogen, then at least one of R 7 and R 8 is a hydroxyl, or a sulphydryl,
and pharmaceutically acceptable salts and esters thereof.
2. A compound according to claim 1 , wherein
R 1 represents acyl, aldehyde, cycloalkyl group or is a straight or branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, haloalkyl, haloalkenyl, or haloalkynyl group; 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, 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 as defined, and
R 3 and R 4 , which may be the same or different, each represents a hydrogen atom, a halogen atom, 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 R 3 and R 4 , 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.
3. A compound according to claim 2 , wherein X is O.
4. A compound according to claim 2 , wherein R 2 is a hydrogen atom, a straight or branched alkyl group, hydroxyalkyl, haloalkyl, or trifluoromethyl group.
5. A compound according to claim 2 , wherein one of R 7 and R 8 is a hydroxyl.
6. A compound according to claim 5 , wherein R 8 is —OH.
7. A compound according to claim 2 , wherein R 4 is halogen, trifluoromethyl, or a straight or branched alkyl or alkoxyl group.
8. A compound according to claim 2 , wherein R 5 is halogen, —NO 2 , or —CN.
9. A compound according to claim 2 , wherein R 4 is trifluoromethyl and R 5 is —CN.
10. 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-methyl-benzonitrile,
4-[3,4-dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-methoxy-benzonitrile,
(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-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile,
(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.
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to claim 1 .
12. The pharmaceutical composition of claim 11 , wherein the carrier is selected from a parenteral carrier, an oral carrier and a topical carrier.
13. A method of treatment of a condition selected from cachexia, osteoporosis, sarcopenia, a decline in libido and/or sexual dysfunction, and prostate cancer and/or hyperplasia, comprising administering to a subject a therapeutically effective amount of a compound of formula (I):
wherein
X is O or S,
R 1 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; CONH 2 ; alkylamido groups; alkylthio and the oxidised sulphoxide and sulphone forms thereof; alkylenedioxy groups; and sulphonamide or alkylsulphonamide groups;
R 2 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;
R 3 and R 4 , 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 R 3 and R 4 , 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,
R 5 represents a hydrogen atom, a halogen atom, trifluoromethyl, —CN, or an —NO 2 group; provided that not all of R 3 , R 4 , and R 5 represents H,
R 6 and R 9 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;
R 7 and R 8 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 R 7 and R 8 is a hydroxyl; a straight or branched alkoxyl group; a straight or branched alkylthio group;
or R 7 , R 8 and R 9 are as defined, and R 6 is C 1-3 -alkyl or, together with either R 1 or R 2 , 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.
14. The method according to claim 13 , wherein the condition is selected from cachexia, osteoporosis, sarcopenia, a decline in libido and/or sexual dysfunction.
15. The method according to claim 13 , wherein the condition is selected from prostate cancer and/or hyperplasia.
16. A method according to claim 13 , for the therapy of muscle loss induced by chronic treatment with glucocorticoids.
17. A method of treatment of cachexia, osteoporosis, sarcopenia, a decline in libido and/or sexual dysfunction, comprising administering to a subject, a therapeutically effective amount of a compound as recited in claim 13 .
18. A method of treatment of prostate cancer and/or hyperplasia, comprising administering to a subject, a therapeutically effective amount of a compound as recited in claim 13 .
19. A method of treatment of a disease associated with cachexia, osteoporosis, sarcopenia, a decline in libido and/or sexual dysfunction, and prostate cancer and/or hyperplasia, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition according to claim 11 .