Dopamine-beta-hydroxylase inhibitors

Claim 2

A compound having the formula: wherein X is -H, -OH, halogen, C 1-4 alkyl, -CN, -N0 2 , -SO 2 NH 2 , -C0 2 H, -CONH 2 , -CHO, -CH 2 OH, -C F 3 , -OCH 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl or any accessible combination thereof up to four substituents; Y is -H, -OH, halogen, C 1-4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl; and R is -H or C 1-4 alkyl; and, n is 0-4, or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof, provided that when n is 0, Y is -OH and when n is 1-3, at least one of Y and X is not -H.

Claim 3

The compound of claim 1 wherein, Y is -H, R is -H, X is 3,5-difluoro and n is 1.

Claim 4

The compound of claim 1 wherein X is -H, Y is -OH, R is -H and n is 0-4; X is 3-OH, 3-Cl, 3-CH 3 , 3-Br, 3-F, 3-NO 2 , 3-CF 3 , 3,5-dichloro, 3,5-difluoro, 2,6-dichloro or 2,3,5,6-tetrafluoro, Y is -OH, R is -H and n is 1; X is -H, Y is -OH, R is -CH 3 and n is 3; X is -H, Y is -F, R is -H and n is 1; x is 3-Cl, Y is -Cl, R is -H and h is 1; X is 2,6-dichloro, 2-C1, 2,5-dichloro, 2,3-dichloro, 3-Cl, 3,5-dichloro, 3-F, 3,5-difluoro, Y is -H, R is - H and n is 1; X is -H, 3-Cl, 2-C1, 2,6-dichloro, Y is -Cl, R is -H and n is 1; X is 3,5-dichloro or 3,5-difluoro, Y is -H, R is -H and n is 3; or X is 3-OH, 2-CH, 2-OCH 3 , 3-OCH 3 or -H, Y is -H, R is -H and n is 1.

Claim 5

A pharmaceutical composition comprising a compound having the formula: wherein X is -H, -OH, halogen, C 1-4 alkyl, -CN, -NO 2 . -SO 2 NH 2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , -OCH 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, -CO 2 C 1-4 alkyl or any accessible combination thereof up to four substituents; Y is -H, -OH, halogen, C 1-4 alkyl, -CN, -NO 2 , -SO 2 H 2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl; and R is -H or C 1-4 alkyl; and, n is 0-4, or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof, provided that when n is 0, Y is -OH, and a suitable carrier.

Claim 6

The pharmaceutical composition of claim 4 wherein Y is -H, R is -H, X is 3,5-difluoro and n is 1.

Claim 7

The pharmaceutical composition of claim 4 wherein X is -H, Y is -OH, R is -H and n is 0-4; X is 3-OH, 3-C1, 3-CH 3 , 3-Br, 3-F, 3-NO 2 , 3-CF 3 , 3,5-dichloro, 3,5-difluoro, 2,6-dichloro or 2,3,5,6-tetrafluoro, Y is -OH, R is -H and n is 1; X is -H, Y is -OH, R is -CH 3 and n is 3; X is -H, Y is -F, R is -H and n is 1; X is 3-Cl, Y is -Cl, R is -H and n is 1; X is 2,6-dichloro, 2-Cl, 2,5-dichloro, 2,3-dichloro, 3-Cl, 3,5-dichloro, 3-F, 3,5-difluoro, Y is -H, R is -H and n is 1; X is -H, 3-Cl, 2-Cl, 2,6-dichloro, Y is -Cl, R is -H and n is 1; X is 3,5-dichloro or 3,5-difluoro, Y is -H, R is -H and n is 3; or X is 3-OH, 2-OH, 2-OCH 3 , 3-OCH 3 or -H, Y is -H, R is -H and n is 1.

Claim 8

A compound of formula, wherein X is -H, -OH, halogen, C 1-4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -C0 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , - OCH 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fiuoroalkyl, -CO2C 1-4 alkyl or any accessible combination thereof up to four substituents; Y is -H, -OH, halogen, C 1-4 alkyl, -CN, -N0 2 , -SO 2 NH 2 , -C0 2 H, -CONH 2 , -CHO, -CH 2 0H, -CF 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl; and R is -H or C 1-4 alkyl; and, n is 0-4, or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof for use as an active pharmaceutical substance.

Claim 9

A compound of claim 7 wherein Y is - H , R 1 is - H , X is 3,5-difluoro and n is 1 for use as an active pharmaceutical substance.

Claim 10

A compound of claim 7 wherein, X is -H, Y is -OH, R is -H and n is 0-4; X is 3-OH, 3-Cl, 3-CH 3 , 3-Br, 3-F, 3-NO 2 , 3-CF 3 , 3,5-dichloro, 3,5-difluoro, 2,6-dichloro or 2,3,5,6-tetrafluoro, Y is -OH, R is -H and n is 1; X is -H, Y is -OH, R is -CH 3 and n is 3; X is -H, Y is -F, R is -H and n is I; X is 3-Cl, Y is -Cl, R is -H and n is 1; X is 2,6-dichloro, 2-C1, 2,5-dichloro, 2,3-dichloro, 3-C1, 3,5-dichloro, 2,4,6-trichloro, 3-F, 3,5-difluoro, Y is -H, R is -H and n is 1; X is -H, 3-C1, 2-Cl, 2,6-dichloro, Y is -Cl, R is -H and n is 1; X is 3,5-dichloro or 3,5-difluoro, Y is -H, R is -H and n is 3; X is 3-OH, 2-OH, 2-OCH 3 , 2-OCH 3 or -H, Y is -H, R is -H and n is 1; or X is -H, Y is -H, R is -H and n is 0 for use as an active pharmaceutical substance.

Claim 11

A compound as claimed in any one of claims 7-9, for use in the inhibition of dopamine B-hydroxylase activity in mammals.

Claim 12

A compound having the formula: wherein Y 1 is -H, halogen, C 1-4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -C0 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , -OCH 3 , -SO 2 C 1-4 alkyl, -SO 2 c 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl; and X 1 is -H, halogen, C 1-4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , - OCH 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl or any accessible combination thereof up to four substituents; and n is 0-4, provided that when n is 0, Y 1 is -OCH 3 and when n is 1-3, at least one of Y and X is not -H.

Claim 13

A compound having the formula: wherein Y 1 is -OCH 3 ; X 1 is -H, halogen, C l-4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , -OCH 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl or any accessible combination thereof up to four substituents.

Claim 14

A process for preparing a compound of claim 1, which comprises: (a) reaction of a compound having the formula: wherein X 1 , Y 1 and n are as defined in claim 11 with acidic thiocyanate; or (b) where in the compound of claim 1, n is 0, cyclisation of a compound of formula: wherein Y 1 and X are as defined in claim 12, in the presence of an acid; and optionally alkylating the compound of claim 1 so formed where R is -H to a compound of claim 1 wherein R is C 1-4 alkyl and/or, where X 1 and/or Y 1 are -OCH 3 , optionally deprotecting the methoxy group(s) to prepare a compound of claim 1 wherein X and/or Y are -OH.

Claim 15

Claims for AT

Claim 16

A process for the preparation of a compound of formula, wherein X is -H, -OH, halogen, C 1-4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -C0 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , -OCH 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1- 4alkyl or any accessible combination thereof up to four substituents; Y is -H, -OH, halogen, C 1-4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 0H, -CF 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl; and R is -H or C 1-4 alkyl; and, n is 0-4, or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof, provided that when n is 0, Y .is -OH and when n is 1-3, at least one of Y and X is not -H, which comprises, (a) reacting a compound of formula, wherein Y 1 is Y but not -O H , and X 1 is X, but not -OH, and n is 0-4, with acidic thiocyanate; or, (b) where n is 0, cyclisation of a compound of formula, wherein Y 1 is -OCH 3 and X 1 is as defined in (a) above in the presence of an acid; and, optionally alkylating the compound so formed where R is -H, to a compound where R is C 1-4 alkyl, and/or, where X 1 and/or Y 1 are -OCH 3 , optionally deprotecting the methoxy group(s) to prepare a compound wherein X and/or Y are -OH.

Claim 17

A process for the preparation of a pharmaceutical composition which comprises combining a compound of structure, wherein X is -H, -OH, halogen, C 1-4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -C02H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , - OCH 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl or any accessible combination thereof up to four substituents; Y is -H, -OH, halogen, C l-4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -C0 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , -SO 2 C 1-4 alkyl, -SO 2 C 1-4 fluoroalkyl, or -CO 2 C 1-4 alkyl; and R is -H or C 1-4 alkyl; and, n is 0-4, or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier therefor.