PC33846A
1
CLAIMS
1. A compound of the formula (I):
(I)
wherein:
R1 is either a phenyl group optionally substituted by one or two substituents each independently selected from F, Cl, Br, CN, C1-4 alkyl, C1-4 alkylthio, C1-4 alkoxy, fluoro-C1-6 alkyl and fluoro-C1-6 alkoxy, or is a C3-6 cycloalkyl group;
X represents a direct link, NH, or O;
Z is selected from ;
R2is H or C1-6 alkyl optionally substituted with from 1 to 3 fluorine atoms;
R3is C1-6 alkyl optionally substituted with from 1 to 3 fluorine atoms;
Ar is an aromatic group consisting of 1, 2 or 3 aromatic rings, which aromatic rings are each independently selected from phenyl and a 5- or 6- membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, and which aromatic rings, if there are 2 or more, can be fused and/or linked by one or more covalent bond(s), and which aromatic rings are optionally substituted by 1, 2 or 3 substitutents each independently selected from F, Cl, CN, OH, C1-6 alkyl, C1-6 alkylthio, fluoro-C1-6 alkyl, fluoro-C1-6 alkylthio,fluoro-C1-6 alkoxy, C1-6 alkoxy, SO2R4, NR5R6, NHSO2R7, SO2NR8R9, CONR10R11 and NHCOR12;
R4 and R7 are each independently C1-6 alkyl optionally substituted by from 1 to 3 fluorine atoms;
R5, R6, R8, R9, R10, R11 and R12 are each independently H or C1-6 alkyl optionally substituted by from 1 to 3 fluorine atoms;
or a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof.
2.A compound as claimed in claim 1 which is a compound of formula (Ia)
(Ia)
or a compound of formula (Ib)
(Ib)
wherein R1, X, Ar and Zare as defined in claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
3. A compound as claimed in claim 1 or 2 wherein R1 is a phenyl group optionally substituted by one or two substituents each independently selected from F, Cl, C1-4 alkyl and C1-4 alkoxy, or is a C3-6 cycloalkyl group.
4. A compound as claimed in claim 3 wherein R1 is cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-ethoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl or 4-methylphenyl.
5. A compound as claimed in claim 4 wherein R1 is 4-methoxyphenyl or 4-fluorophenyl.
6. A compound as claimed inany one of claims 1 to 5 wherein X represents a direct link.
7.A compound as claimed in any one of claims 1 to 6wherein Z is
.
8.A compound as claimed in any one of claims 1 to 7 wherein Z is –COOH.
.
9.A compound as claimed in any one of claims 1 to 8 wherein Ar is an aromatic group consisting of 1, 2 or 3 aromatic rings, which aromatic rings are each independently selected from phenyl and a 5- or 6- membered heteroaromatic ring comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms; and which aromatic rings, if there are 2 or more, can be fused and/or linked by one or more covalent bond(s), and which aromatic rings are optionally substituted by 1, 2 or 3 substitutents each independently selected from F, Cl, CN, OH, C1-6 alkyl, C1-6 alkylthio, fluoro-C1-6 alkyl, fluoro-C1-6 alkylthio, fluoro-C1-6 alkoxy, C1-6 alkoxy, SO2R4, NR5R6, NHSO2R7, SO2NR8R9, CONR10R11 and NHCOR12.
10.A compound as claimed in any one of claims 1 to 9 whereinAr is phenyl,naphthyl, biphenyl, pyridinylphenyl, pyrimidinylphenyl, phenylpyridinyl, phenylpyrimidinyl, phenylpyrazinyl or pyrazinylphenyl, each optionally substituted by 1, 2 or 3 substituents each independently selected from F, Cl, CN, OH, C1-6 alkyl, C1-6 alkylthio, fluoro-C1-6 alkyl, fluoro-C1-6 alkylthio, fluoro-C1-6 alkoxy, C1-6 alkoxy, SO2R4, NR5R6, NHSO2R7, SO2NR8R9, CONR10R11 and NHCOR12.
11.A compound as claimed in any one of claims 1 to 10 whereinAr isphenyl, naphthyl, biphenyl, pyridinylphenyl, pyrimidinylphenyl, phenylpyridinyl, phenylpyrimidinyl, phenylpyrazinyl or pyrazinylphenyl, each optionally substituted by 1, 2 or 3 substituents each independently selected from F, Cl, CN, -CONH2and C1-6 alkoxy.
12.A compound as claimed in any one of claims 1 to 11 whereinAr is
2,3-difluorophenyl, 3-chloro-4-fluorophenyl,
4-(4-cyanophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(5-chloropyridin-2-yl)phenyl, 4-(5-cyanopyridin-2-yl)phenyl, 4-(5-chloropyrimidin-2-yl)phenyl, 4-(5-cyanopyrimidin-2-yl)phenyl, 4-(5-fluoropyrimidin-2-yl)phenyl, 4-(5-aminocarbonylpyrimidin-2-yl)phenyl,
2-(4-chlorophenyl)pyridin-5-yl, 2-(4-fluorophenyl)pyridin-5-yl, 2-(4-cyanophenyl)pyridin-5-yl,
2-(4-chlorophenyl)pyrimidin-5-yl,
5-(4-chlorophenyl)pyrazin-2-yl or 5-(4-fluorophenyl)pyrazin-2-yl.
13.A compound as claimed in claim 1 or 2 selected from:
3-{[(4'-cyanobiphenyl-4-yl)oxy]methyl}-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid (R1= 4-fluorophenyl, X= direct link, Z= -COOH, Ar= 4-(4-cyanophenyl)phenyl);
3-{[(4'-cyanobiphenyl-4-yl)oxy]methyl}-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (R1= 4-methoxyphenyl, X= direct link, Z= -COOH, Ar= 4-(4-cyanophenyl)phenyl);
3-{[4-(5-chloropyrimidin-2-yl)phenoxy]methyl}-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid (R1= 4-fluorophenyl, X= direct link, Z= -COOH, Ar= 4-(5-chloropyrimidin-2-yl)phenyl);
1-(4-chlorobenzoyl)-3-{[4-(5-chloropyridin-2-yl)phenoxy]methyl}pyrrolidine-3-carboxylic acid (R1= 4-chlorophenyl, X= direct link, Z= -COOH, Ar= 4-(5-chloropyridin-2-yl)phenyl);
1-(4-chlorobenzoyl)-3-({[6-(4-chlorophenyl)pyridin-3-yl]oxy}methyl)pyrrolidine-3-carboxylic acid (R1= 4-chlorophenyl, X= direct link, Z= -COOH, Ar= 2-(4-chlorophenyl)pyridin-5-yl);
3-{[4-(5-chloropyrimidin-2-yl)phenoxy]methyl}-1-(2-methoxybenzoyl)pyrrolidine-3-carboxylic acid (R1= 2-methoxyphenyl, X= direct link, Z= -COOH, Ar=4-(5-chloropyrimidin-2-yl)phenyl);
3-({[2-(4-chlorophenyl)pyrimidin-5-yl]oxy}methyl)-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid (R1= 4-fluorophenyl, X= direct link, Z= -COOH, Ar= 2-(4-chlorophenyl)pyrimidin-5-yl);
3-{[4-(5-cyanopyridin-2-yl)phenoxy]methyl}-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid (R1= 4-fluorophenyl, X= direct link, Z= -COOH, Ar=4-(5-cyanopyridin-2-yl)phenyl);
3-{[4-(5-chloropyrimidin-2-yl)phenoxy]methyl}-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (R1= 4-methoxyphenyl, X= direct link, Z= -COOH, Ar=4-(5-chloropyrimidin-2-yl)phenyl);
3-({[6-(4-chlorophenyl)pyridin-3-yl]oxy}methyl)-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid (R1= 4-fluorophenyl, X= direct link, Z= -COOH, Ar=2-(4-chlorophenyl)pyridin-5-yl);
3-({[6-(4-chlorophenyl)pyridin-3-yl]oxy}methyl)-1-(2-methoxybenzoyl)pyrrolidine-3-carboxylic acid (R1= 2-methoxyphenyl, X= direct link, Z= -COOH, Ar=2-(4-chlorophenyl)pyridin-5-yl):
or a pharmaceutically acceptable salt, solvate or prodrug of any thereof.
14. A pharmaceutical composition including a compound as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof, and a pharmaceutically acceptable excipient, diluent, carrier or adjuvant.
15.A compound as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof, for use as a medicament.
16. A compound as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof, for use in the treatment of a disease or disorder which would benefit from, or is mediated by, EP2 receptor antagonism.
17. A compound as claimed inclaim16, wherein the disease or disorder is endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), chronic pelvic pain syndrome, polycystic kidney disease or polycystic ovarian syndrome.
18.Use of a compound as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof, in the manufacture of a medicament forthe treatment of a disease or disorder which would benefit from, or is mediated by, EP2 receptor antagonism.
19.Use according to claim 18,wherein the disease or disorder is endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), chronic pelvic pain syndrome, polycystic kidney disease or polycystic ovarian syndrome.
20.A method of treatment of a a disease or disorder which would benefit from, or is mediated by, EP2 receptor antagonism in a mammal, comprising administering to said mammala therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof.
21.A method according to claim 20, wherein the disease or disorder is endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), chronic pelvic pain syndrome, polycystic kidney disease or polycystic ovarian syndrome.
22.A compound of formula:
(II)
wherein R1, X and Z are as defined in claim 1 and LG is a leaving group such as Cl, Br, I, mesyloxy and tosyloxy.
23.A combination of a compound as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof, and another therapeutically active entity.