Compounds
The invention relates to substituted phenoxyacetic acids (I) as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
in which:
X is halogen, cyano, nitro, S(O) n R 6 (wherein n is 0, 1 or 2) or C 1-4 -alkyl which is substituted by one or more halogen atoms;
Y is hydrogen;
Z is phenyl or naphthyl each of which is substituted by one or more substituents independently selected from halogen, CN, OH, SH, nitro, COR 9 , CO 2 R 6 , SO 2 R 9 , OR 9 , SR 9 , SOR 9 , SO 2 NR 10 R 11 , CONR 10 R 11 , NR 10 R 11 , NHSO 2 R 9 , NR 9 SO 2 R 9 , NR 6 CO 2 R 6 , NHCOR 9 , NR 9 COR 9 , NR 6 CONR 4 R 5 , NR 6 SO 2 NR 4 R 5 , aryl, heteroaryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl or C 1-6 alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, C 3 -C 7 cycloalkyl, OR 6 , NR 6 R 7 , S(O) n R 6 (wherein n is 0, 1 or 2), CONR 6 R 7 , NR 6 COR 7 , SO 2 NR 6 R 7 and NR 6 SO 2 R 7 ;
R 1 and R 2 independently represent a hydrogen atom, halogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl or a C 1-6 alkyl group, the latter four groups being optionally substituted by one or more substituents independently selected from halogen,
C 3 -C 7 cycloalkyl, NR 6 R 7 , OR 6 , S(O) n R 6 (wherein n is 0, 1 or 2);
or
R 1 and R 2 together can form a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR 6 and itself optionally substituted by one or more C 1 -C 3 alkyl or halogen;
R 3 represents C 3 -C 7 cycloalkyl or C 1-6 alkyl which may be optionally substituted by one or more substituents independently selected from halogen, C 3 -C 7 cycloalkyl, OR 6 and NR 6 R 7 , S(O) n R 6 (wherein n is 0, 1 or 2), CONR 6 R 7 , NR 6 COR 7 , SO 2 NR 6 R 7 and NR 6 SO 2 R 7 ;
R 4 and R 5 independently represent hydrogen, C 3 -C 7 cycloalkyl or C 1-6 alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C 3 -C 7 cycloalkyl, OR 6 and NR 6 R 7 , S(O) n R 6 (wherein n is 0, 1 or 2), CONR 6 R 7 , NR 6 COR 7 , SO 2 NR 6 R 7 and NR 6 SO 2 R 7 ;
or
R 4 and R 5 together with the nitrogen atom to which they are attached can form a 3-8 membered saturated heterocylic ring optionally containing one or more atoms selected from 0, S(O) n (wherein n is 0, 1 or 2), NR 8 , and itself optionally substituted by halogen or C 1-3 alkyl;
R 6 and R 7 independently represents a hydrogen atom or C 1 -C 6 alkyl;
R 8 is hydrogen, C 1-4 alkyl, —COC 1 -C 4 alkyl, CO 2 C 1 -C 4 alkyl or CONR 6 C 1 -C 4 alkyl;
R 9 represents aryl, heteroaryl, C 3 -C 7 cycloalkyl or C 1-6 alkyl, the latter two groups may be optionally substituted by one or more substituents independently selected from halogen, C 3 -C 7 cycloalkyl, aryl, heteroaryl OR 6 and NR 6 R 7 , S(O) n R 6 (wherein n is 0, 1 or 2), CONR 6 R 7 , NR 6 COR 7 , SO 2 NR 6 R 7 and NR 6 SO 2 R 7 ;
R 10 and R 11 independently represent aryl or heteroaryl, hydrogen, C 3 -C 7 cycloalkyl or C 1-6 alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C 3 -C 7 cycloalkyl, aryl, heteroaryl, OR 6 and NR 6 R 7 , S(O) n R 6 (wherein n is 0, 1 or 2), CONR 6 R 7 , NR 6 COR 7 , SO 2 NR 6 R 7 and NR 6 SO 2 R 7 ;
or
R 10 and R 11 together with the nitrogen atom to which they are attached can form a 3-8 membered saturated heterocylic ring optionally containing one or more atoms selected from O, S(O) n (wherein n is 0, 1 or 2), NR 8 , and itself optionally substituted by halogen or C 1 -C 3 alkyl.
2. A compound according to claim 1 in which X is halogen, cyano, nitro, S(O) n R 6 or C 1-4 alkyl which is substituted by one or more halogen atoms.
3. A compound according to claim 1 in which X is trifluoromethyl, nitro, cyano or halogen.
4. A compound according to claim 1 in which Z is phenyl, which is substituted with one or more substituents as defined in claim 1 .
5. A compound according to claim 1 in which both R 1 and R 2 are hydrogen or one is hydrogen and the other is methyl or ethyl or both are methyl.
6. A compound according to claim 1 selected from:
{[5-Chloro-4′-(ethylthio)biphenyl-2-yl]oxy}acetic acid,
{[5-Chloro-4′-(ethylsulfonyl)biphenyl-2-yl]oxy}acetic acid,
[(4′,5-Dichlorobiphenyl-2-yl)oxy]acetic acid,
[(5-Chloro-4′-cyanobiphenyl-2-yl)oxy]acetic acid,
[(5-Chloro-4′-methoxybiphenyl-2-yl)oxy]acetic acid,
[(5-Chloro-3′,4′-dimethoxybiphenyl-2-yl)oxy]acetic acid,
2′-(Carboxymethoxy)-5′-chlorobiphenyl-4-carboxylic acid,
{[5-Chloro-4′-(methylsulfonyl)biphenyl-2-yl]oxy}acetic acid,
{[5-Chloro-4′-(ethylsulfonyl)-2′-methylbiphenyl-2-yl]oxy}acetic acid,
{[4′-(Methylthio)-5-(trifluoromethyl)biphenyl-2-yl]oxy}acetic acid,
{[4′-(Methylsulfonyl)-5-(trifluoromethyl)biphenyl-2-yl]oxy}acetic acid,
{[4′-(Ethylsulfonyl)-2′-methyl-5-(trifluoromethyl)biphenyl-2-yl]oxy}acetic acid,
[[2′,5-Dichloro-4′-(ethylsulfonyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Chloro-4′-(ethylsulfonyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5-Chloro-4′-(ethylsulfonyl)-2′-fluoro[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-(Ethylsulfonyl)-2′-fluoro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5-Chloro-4′-(ethylsulfonyl)-2′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
2-[[5-Chloro-4′-(ethylsulfonyl)[1,1′-biphenyl]-2-yl]oxy]-propanoic acid,
2-[[4′-(Ethylsulfonyl)-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[[4′-(Ethylsulfonyl)-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(2R)-propanoic acid,
2-[[2′,5-Dichloro-4′-(ethylsulfonyl)[1,1′-biphenyl]-2-yl]oxy]-(25)-propanoic acid,
2-[[2′-Chloro-4′-(ethylsulfonyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(25)-propanoic acid,
2-[[4′-(Ethylsulfonyl)-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-2-methyl-propanoic acid,
2-[[4′-(Ethylsulfonyl)-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-butanoic acid,
[[4′-(Ethylsulfonyl)-5-fluoro-2′-methyl[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-(Ethylsulfonyl)-4,5-difluoro-2′-methyl[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-(Ethylsulfonyl)-3,5-difluoro-2′-methyl[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Amino-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Amino-2′-chloro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Chloro-4′-hydroxy-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Chloro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′,5-Bis(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5′-Fluoro-2′-methoxy-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5′-Cyano-2′-methoxy-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Chloro-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′,5′-Dimethyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5′-Chloro-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Fluoro-6′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Fluoro-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[[(Ethylamino)carbonyl]amino]-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Methyl-4′-[[(methylamino)carbonyl]amino]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[[(Cyclopropylamino)carbonyl]amino]-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Methyl-4′-[[(propylamino)carbonyl]amino]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′,4′-Dimethyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5′-Fluoro-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-(Aminocarbonyl)-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-Fluoro-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′,5′-Difluoro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5′-(Aminosulfonyl)-2′-chloro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Cyano-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Chloro-2′-fluoro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′,5′-Difluoro-4′-methoxy-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-fluoro-5′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Fluoro-4′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Methoxy-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-(Aminosulfonyl)-2′,5′-difluoro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Chloro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-(1-Methylethyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′,4′-Difluoro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Ethyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-Fluoro-5-(trifluoromethyl)[1,1′:4′,1″-terphenyl]-2-yl]oxy]acetic acid,
[[4′-(Trifluoromethoxy)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′,3′-Dichloro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-(1,1-Dimethylethyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[2-(6-Methoxy-2-naphthalenyl)-4-(trifluoromethyl)phenoxy]-acetic acid,
[[4′-(Ethylthio)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Acetyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5′-(Aminosulfonyl)-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-Cyano-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Methyl-5′-(methylsulfonyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
2′-(Carboxymethoxy)-5′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylic acid, 3-methyl ester,
2′-(Carboxymethoxy)-5′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid, 2-methyl ester,
[[5-(Trifluoromethyl)[1,1′:4′,1″-terphenyl]-2-yl]oxy]-acetic acid,
[[3′-Fluoro-2′,4′-dimethyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Nitro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-Chloro-2′-methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5-(Trifluoromethyl)[1,1′:3′,1″-terphenyl]-2-yl]oxy]-acetic acid,
2′-(Carboxymethoxy)-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid, 4-methyl ester,
[[4′-Nitro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5-(Trifluoromethyl)-3′-[(trifluoromethyl)thio][1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[5-(Trifluoromethyl)-4′-[(trifluoromethyl)thio][1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Fluoro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-Fluoro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-Methyl-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Fluoro-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[2′-Methoxy-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-Methoxy-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Methoxy-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-(Ethylsulfonyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[3′-Propoxy-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-Propoxy-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[2-(2-Amino-4-methyl-5-pyrimidinyl)-4-(trifluoromethyl)phenoxy]-acetic acid,
[[4′-Cyano-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′,5-Bis(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[2-(2-Naphthalenyl)-4-(trifluoromethyl)phenoxy]-acetic acid,
[[4′-(1-Pyrrolidinylsulfonyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[(Dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[[(Phenylmethyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[[(2,2,2-Trifluoroethyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[[(5-Methyl-2-thiazolyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[(Phenylamino)sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[(Diethylamino)sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[(Cyclopropylamino)sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-(Aminosulfonyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[(Methylamino)sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[[4′-[(4-Methyl-1-piperazinyl)sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-acetic acid,
[2-[4-Methyl-2-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]-acetic acid,
[[2′-Chloro-4′-[(methoxycarbonyl)amino]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]acetic acid
2-[[2′-Chloro-4′-(methylsulfonyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[[3′-Cyano-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[[4′-[(Dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[[2′-Chloro-4′-[(dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[[2′-Fluoro-4′-(methylsulfonyl)-5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
[[2′,5-Dichloro-4′-(methylsulfonyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
[[5-Chloro-4′-[(dimethylamino)sulfonyl][1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
[[2′,5-Dichloro-4′-[(dimethylamino)sulfonyl][1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
[(5-Chloro-3′-cyano[1,1′-biphenyl]-2-yl)oxy]-(2S)-propanoic acid,
[[5-Chloro-4′-[(dimethylamino)sulfonyl]-2′-fluoro[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
[[5-Chloro-4′-(4-morpholinylsulfonyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
[[5-Chloro-2′-fluoro-4′-(methylsulfonyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[[4′-(1-Azetidinylsulfonyl)-5-chloro[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[[5-Chloro-2′-methyl-4′-(1-pyrrolidinylcarbonyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[(2′,4′-Dichloro-5-cyano[1,1′-biphenyl]-2-yl)oxy]-(2S)-propanoic acid,
2-[[5-Cyano-2′-fluoro-4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[(3′-Cyano-5-fluoro[1,1′-biphenyl]-2-yl)oxy]-(2S)-propanoic acid, sodium salt,
2-[(2′,4′-Dichloro-5-fluoro[1,1′-biphenyl]-2-yl)oxy]-(2S)-propanoic acid, sodium salt,
2-[[2′-Chloro-5-fluoro-4′-(methylsulfonyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
2-[[2′-Chloro-5-fluoro-5′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
[[4′-(Methylsulfonyl)-2′,5-bis(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy]acetic acid, and
[(5-Chloro-3′-cyano[1,1′-biphenyl]-2-yl)oxy]-acetic acid,
and pharmaceutically acceptable salts thereof.
7. A method of treating asthma or rhinitis in a patient suffering from, or at risk of, asthma or rhinitis, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1 .
8. A compound according to claim 2 , in which Z is phenyl, which is substituted with one or more substituents as defined in claim 1 .
9. A compound according to claim 2 , in which both R 1 and R 2 are hydrogen or one is hydrogen and the other is methyl or ethyl or both are methyl.
10. A compound according to claim 3 , in which Z is phenyl, which is substituted with one or more substituents as defined in claim 1 .
11. A compound according to claim 3 , in which both R 1 and R 2 are hydrogen or one is hydrogen and the other is methyl or ethyl or both are methyl.