Quinolone inotropic agents

Claim 2

A quinolone of the formula:- or a pharmaceutically acceptable salt thereof, wherein "Het" is an optionally substituted 5-membered monocyclic aromatic heterocyclic group containing at least one nitrogen atom in the aromatic ring and attached by a nitrogen atom of said ring to the 5-, 6-, 7- or 8-position of said quinolone; R, which is attached to the 5-, 6-, 7- or 8-position, is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, CF3, halo, cyano or hydroxymethyl; and the dashed line between the 3- and 4-positions represents an optional bond.

Claim 3

A compound as claimed in claim 1, wherein "Het" is a pyrrolyl, imidazolyl, pyrazolyl, triazolyl or tetrazolyl group, said groups being optionally substituted by up to 3 substituents each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkox y, hydroxy, halo, CF 3 , cyano, hydroxymethyl, (C 1 -C 4 alkoxy)carbonyl, nitro, -CONR 1 R 2 and -NR 1 R 2 wherein R 1 and R are each independently H or C 1 -C 4 alkyl.

Claim 4

A compound as claimed in claim 1 or 2 wherein R is H, C 1 -C 4 alkyl, CF 3 or halo.

Claim 5

A compound as claimed in claim 1 wherein (a) "Het" is attached to the 6-position of the quinolone and is an imidazolyl, pyrazolyl, triazolyl or tetrazolyl group, said groups being optionally substituted by up to 3 substituents each independently selected from C 1 -C 4 alkyl, CF 3 , N0 2 , NH 2 , CN and halo, and (b) R is attached to the 8-position of the quinolone and is H, C 1 -C 4 alkyl, CF 3 or halo.

Claim 6

A compound as claimed in claim 4 wherein (a) "Het" is an imidazol-1-yl, 2-methylimidazol-1-yl, 4-methylimidazol-l-yl, 5-methylimidazol-1-yl, 1,2,4-triazol-1-yl, 2,4-dimethylimidazol-1-yl, pyrazol-1-yl, 4-trifluoromethylimidazol-1-yl, tetrazol-1-yl, 3,5-dimethyl-1,2,4-triazol-1-yl, 3,5-dimethyl-1,2,4-triazol-4-yl, tetrazol-2-yl, 1,2,4-triazol-4-yl, 2,4-dimethyl-5-nitroimidazol-1-yl, 5-nitro-4-methylimidazol-1-yl, 5-amino-2,4-dimethylimidazol-1-yl, 5-bromo-2,4-dimethyl- imidazol-1-yl, 5-iodo-2,4-dimethyl- imidazol-1-yl or 5-cyano-2,4-dimethylimidazol-1-yl group, and (b) R is H, CH 3 , CF 3 or Br.

Claim 7

A compound as claimed in any one of the preceding claims wherein there is a double bond in the 3,4-position of the quinolone.

Claim 8

A compound as claimed in claim 5 wherein (a) "Het" is a 2,4-dimethylimidazol-1-yl, 2,4-dimethyl-5-nitroimidazol-1-yl, tetrazol-1-yl or 1,2,4-triazol-4-yl group, (b) R is CH 3 , and (c) there is a double bond between the 3- and 4-positions of the quinolone.

Claim 9

A compound as claimed in claim 1 wherein (a) Het is a pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl group, said groups being optionally substituted by up to 3 substituents each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkox y, hydroxy, halo, CF 3 , cyano, hydroxymethyl, (C 1 -C 4 alkoxy)carbonyl, -CONR 1 R 2 and -NR 1 R 2 wherein R 1 and R are each independently H or C 1 -C 4 alkyl, and (b) R is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, CF 3 or halo.

Claim 10

A pharmaceutical composition comprising a compound of the formula (I) as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

Claim 11

A compound of the formula (I) as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in medicine.

Claim 12

A compound of the formula:- wherein "Het" and R are as defined in claim 1.

Claim 13

A compound of the formula:- . or an acid addition salt thereof, where R and Het, which are attached to the 3-, 4-, 5- or 6-positions, are as defined in claim 1, and Q is a leaving group.

Claim 14

A compound as claimed in claim 12 wherein Q is a C 1 -C 4 alkoxy group.

Claim 15

CLAIMS For the Contracting State: AT 1. A process for preparing a 2-(lH)-quinolone of the formula:- or a pharmaceutically acceptable salt thereof, wherein "Het" is an optionally substituted 5-membered monocyclic aromatic heterocyclic group containing at least one nitrogen atom in the aromatic ring and attached by a nitrogen atom to the 5-, 6-, 7- or 8- position of said quinolone; R, which is attached to the 5-, 6-, 7- or 8- position, is hydrogen, C 1 -C 4 alkyl, C 1 - C 4 alkoxy, hydroxy, CF 3 , halo, cyano or hydroxymethyl; and the dashed line between the 3- and 4- positions represents an optional bond, characterised by cyclising a compound (or acid addition salt thereof) of the formula:- wherein "Het" and R, which are attached to the 3-, 4-, 5- or 6- positions of the benzene ring, are as defined above, and Q is a leaving group, thereby producing a compound of the formula:- said process being followed by, optionally, one or more of the following steps:- (a) reduction of a compound of the formula (IA) so as to produce the corresponding 3,4-dihydro derivative; (b) nitration of a compound of the formula (I) so as to produce the corresponding compound having a nitro substituent on the group "Het"; (c) reduction of a nitro substituent on the group "Het" of a compound of the formula (I) so as to produce the corresponding amino-substituted compound; (d) halogenation of a compound of the formula (I) so as to introduce a halo-substituent either on the group "Het", or in the 8-position of the quinolone group; . (e) conversion of a compound of the formula (I) in which "Het" is amino-substituted into a compound in which "Het" is cyano-substituted by the Sandmeyer reaction; (f) conversion of a compound of the formula (I) in which "Het" is substituted by Br or I, into a compound in which "Het" is substituted by cyano by reaction with a metal cyanide; and (g) conversion of a compound of the formula (I) into a pharmaceutically acceptable salt.

Claim 16

A process according to claim 1, characterised in that the cyclisation is carried out with concentrated sulphuric acid.

Claim 17

A process according to claim 1 or 2, characterised in that Q is C l- C 4 alkox y .

Claim 18

A process for preparing a compound of the formula (I) as defined in claim 1 wherein "Het" is a 1,2,4-triazol-4-yl group and R is as defined in claim 1, or a pharmaceutically acceptable salt thereof, characterised by reacting a compound of the formula:- with 1,2-diformylhydrazine, thereby producing a compound of the formula:- said process being followed by, optionally, one or more of steps (a) to (g) as defined in claim 1.

Claim 19

A process for preparing a compound of the formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, characterised by demethylating a compound of the formula:- wherein "Het" and R are as defined in claim 1, thereby producing a compound of the formula:- said process being followed by, optionally, one or more of steps (a) to (g) as defined in claim 1.

Claim 20

A process according to claim 5, characterised in that the demethylation is carried out with aqueous mineral acid.

Claim 21

A process according to claim 6, characterised in that the demethylation is carried out with aqueous HC1 or aqueous HBr.

Claim 22

A process for preparing a compound of the formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, characterised by cyclising a compound of the formula:- where R and "Het" are as defined in claim 1, with hydrochloric acid, thereby producing a compound of the formula:- said process being followed by, optionally, one or more of steps (a) to (g) as defined in claim 1.

Claim 23

A process for preparing a 3,4-dihydro-2-(lH)quinolone of the formula (I) as defined in claim 1, characterised by hydrogenating a compound of the formula:- where "Het" and R are as defined in claim 1, so as to produce a compound of the formula:- followed by cyclising the compound (VI) by heating in an organic solvent thereby producing a compound of the formula:- said process being followed by, optionally, one or more of steps (b) to (g) as defined in claim 1.

Claim 24

A process for preparing a compound of the formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, characterised by reacting a compound of the formula:- with a Wittig reagent of the formula:- where M is an alkali metal, thereby producing a compound of the formula:- said process being followed by, optionally, one or more of steps (a) to (g) as defined in claim 1.

Claim 25

A process according to any one of the preceding claims, characterised in that R is H, C 1 -C 4 alkyl, CF 3 or halo.

Claim 26

A process according to any one of claims 1 to 3 and 5 to 10, characterised in that "Het" is a pyrrolyl, imidazolyl, pyrazolyl, triazolyl or tetrazolyl group, said groups being optionally substituted by up to 3 substituents each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halo, CF 3 , cyano, hydroxymethyl, (C 1 -C 4 alkoxy)carbonyl, nitro, -CONR 1 R 2 and - NR 1 R 2 wherein R 1 and R are each independently H or C 1 -C 4 alkyl.

Claim 27

A process according to claim 12, characterised in that (a) "Het" is attached to the 6-position of the quinolone and is an imidazolyl, pyrazolyl, triazolyl or tetrazolyl group, said groups being optionally substituted by up to 3 substituents each independently selected from C 1 -C 4 alkyl, CF 3 , N0 2 , NH 2 , CN and halo and (b) R is attached to the 8-position of the quinolone and is H, C 1 -C 4 alkyl, CF 3 or halo.

Claim 28

A process according to claim 13, characterised in that (a) "Het" is an imidazol-1-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1,2,4-triazol-1-yl, 2,4-dimethylimidazol-1-yl, pyrazol-1-yl, 4-trifluoromethyl- imidazol-1-yl, tetrazol-1-yl, 3,5-dimethyl-1,2,4-triazol-1-yl, 3,5-dimethyl-1,2,4-triazol-4-yl, tetrazol-2-yl, 1,2,4-triazol-4-yl, 2,4-dimethyl-5-nitroimidazol-1-yl, 5-nitro-4-methylimidazol-1-yl, 5-amino-2,4-dimethyl- imidazol-1-yl, 5-bromo-2,4-dimethyl- imidazol-1-yl, 5-iodo-2,4-dimethylimidazol-l-yl or 5-cyano-2,4-dimethylimidazol-1-yl group, and (b) R is H, CH 3 , CF 3 or Br.

Claim 29

A process according to any one of the preceding claims, characterised in that a compound having a double bond between the 3- and 4-positions is produced.

Claim 30

A process according to claim 14, characterised in that (a) "Het" is a 2,4-dimethylimidazol-1-yl, 2,4-dimethyl-5-nitroimidazol-1-yl, tetrazol-1 - yl or 1,2,4-triazol-4-yl group, (b) R is CH3, and (c) there is a double bond between the 3- and 4-positions of the quinolone.

Claim 31

A process according to any one of claims 1 to 3, characterised in that (a) Het is a pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl group, said groups being optionally substituted by up to 3 substituents each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halo, CF 3 , cyano, hydroxymethyl, (C 1 -C 4 alkoxy)carbonyl, -CONR 1 R 2 and -NR 1 R 2 wherein R 1 and R 2 are each independently H or C 1 -C 4 alkyl, and (b) R is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, CF 3 or halo, said process being followed by, optionally, step (a) and/or (g) as defined in claim 1.

Claim 32

A process for preparing a pharmaceutical composition, characterised by preparing a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof by a process as claimed in any one of the preceding claims, followed by mixing the thus-produced product with a pharmaceutically acceptable diluent or carrier.

Claim 33

A process for preparing a pharmaceutical composition, characterised by mixing a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable diluent or carrier.