Pyrazolopyridazine antihypertensives

Claim 2

A compound of the formula ##STR18## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R 1 is halogen, carboxyl, lower alkoxycarbonyl, hydroxyaminocarbonyl, mercapto, lower alkanoylthio or aryl-(lower alkylthio)-, R 2 is hydroxy, lower alkoxy or amino, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 4 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R 1 wherein A and R 1 are as described above and the broken line denotes an optional carbon-carbon bond which can be present only when B is carbonyl, or a salt of a compound of formula I, wherein R 1 is carboxy and/or R 2 is hydroxy, with a pharmaceutically acceptable base.

Claim 3

A compound in accordance with claim 1, wherein B is carbonyl.

Claim 4

A compound in accordance with claim 2, wherein R 1 is mercapto.

Claim 5

A compound in accordance with claim 3, wherein R 2 is hydroxy.

Claim 6

A compound in accordance with claim 4, wherein R 3 is hydrogen.

Claim 7

A compound in accordance with claims 1, 2, 3, 4 or 5 wherein R 4 is hydrogen or lower alkyl, or aryl-(lower alkyl)-.

Claim 8

A compound in accordance with claim 1, wherein B is carbonyl, R 1 is mercapto, R 2 is hydroxy, R 3 is hydrogen and R 4 is hydrogen, methyl, ethyl or benzyl.

Claim 9

A compound in accordance with claim 1, 2,3,5,8-Tetrahydro-2-(2-mercaptoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid.

Claim 10

A compound selected from the group consisting of Hexahydro 2-mercaptomethyl-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, hexahydro 2-(2-mercaptoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, hexahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid and hexahydro 2,2-bis(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid.

Claim 11

A compound selected from the group consisting of Hexahydro 2-mercaptomethyl-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, hexahydro 2-(2-mercaptoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, hexahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid and hexahydro 2,2-bis(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid.

Claim 12

A compound selected from the group consisting of 2-Ethyl-hexahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 2-benzyl-2,3,5,8-tetrahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 2-ethyl-2,3,5,8-tetrahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, hexahydro-2-mercaptomethyl-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid and hexahydro-2-(2-mercaptoethyl)-2-methyl-3-oxo-1H-pyrazolo[1,2-a]pyridazino-5-carboxylic acid.

Claim 13

A compound selected from the group consisting of 2-Ethyl-hexahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 2-benzyl-2,3,5,8-tetrahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 2-ethyl-2,3,5,8-tetrahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, hexahydro-2-mercaptomethyl-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid and hexahydro-2-(2-mercaptoethyl)-2-methyl-3-oxo-1H-pyrazolo[1,2-a]pyridazino-5-carboxylic acid.

Claim 14

A compound selected from the group consisting of Diethyl 5-tert-butoxycarbonyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-2,2-diacetate, tert.butyl 2,2-bis(2-ethoxycarbonylethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2,2-bis(acetylthiomethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2,2-bis(2-acetylthioethyl)hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2-(2-acetylthioethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2-acetylthiomethyl-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl-2-(2-acetylthioethyl)-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2-(3-acetylthiopropyl)hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, diethyl 5-carboxy-hexahydro-1,3-dioxo-1H-pyrazolo-[1,2-a]pyridazine-2,2-diacetate, 5-carboxy-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-2,2-diacetic acid, 2-(2-acetylthioethyl)-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 2-(3-acetylthiopropyl)-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, methyl 2,3,5,8-tetrahydro-2-(2-iodoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and methyl 2-(2-acetylthioethyl)-2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate.

Claim 15

A compound selected from the group consisting of Diethyl 5-tert-butoxycarbonyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-2,2-diacetate, tert.butyl 2,2-bis(2-ethoxycarbonylethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2,2-bis(acetylthiomethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2,2-bis(2-acetylthioethyl)hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2-(2-acetylthioethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2-acetylthiomethyl-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl-2-(2-acetylthioethyl)-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2-(3-acetylthiopropyl)hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, diethyl 5-carboxy-hexahydro-1,3-dioxo-1H-pyrazolo-[1,2-a]pyridazine-2,2-diacetate, 5-carboxy-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-2,2-diacetic acid, 2-(2-acetylthioethyl)-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 2-(3-acetylthiopropyl)-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, methyl 2,3,5,8-tetrahydro-2-(2-iodoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and methyl 2-(2-acetylthioethyl)-2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate.

Claim 16

A compound selected from the group consisting of Tert.butyl 2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, 2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, methyl 2-(2-acetylthioethyl)-2-benzyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, methyl 2-ethyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, methyl 2-(2-acetylthioethyl)-2-ethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl hexahydro-2-[(N-hydroxycarbamoyl)methyl]-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, hexahydro-2-[(N-hydroxycarbamoyl)methyl]-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, tert.butyl 2-bromomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid and tert.butyl hexahydro-2-(2-acetylthioethyl)-2-methyl-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate.

Claim 17

A compound selected from the group consisting of Tert.butyl 2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, 2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, methyl 2-(2-acetylthioethyl)-2-benzyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, methyl 2-ethyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, methyl 2-(2-acetylthioethyl)-2-ethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl hexahydro-2-[(N-hydroxycarbamoyl)methyl]-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, hexahydro-2-[(N-hydroxycarbamoyl)methyl]-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, tert.butyl 2-bromomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, tert.butyl 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid and tert.butyl hexahydro-2-(2-acetylthioethyl)-2-methyl-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate.

Claim 18

A compound of the formula ##STR19## wherein R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 20 lower alkoxy and R 40 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-.

Claim 19

A compound of the formula ##STR19## wherein R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 20 lower alkoxy and R 40 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-.

Claim 20

A compound of the formula ##STR20## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R 2 hydroxy, lower alkoxy or amino, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 5 is hydroxy, R 41 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R 5 in which A and R 5 are as described above and the broken line denotes an optional carbon-carbon bond which can be present only when B is carbonyl.

Claim 21

A compound of the formula ##STR20## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R 2 hydroxy, lower alkoxy or amino, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 5 is hydroxy, R 41 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R 5 in which A and R 5 are as described above and the broken line denotes an optional carbon-carbon bond which can be present only when B is carbonyl.

Claim 24

A compound of the formula ##STR22## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R 2 is hydroxy, lower alkoxy or amino, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 6 is lower alkylsulfonyloxy or arylsulfonyloxy, R 43 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R 6 in which A and R 6 are as described above and the broken line denotes an optional carbon-carbon bond which can be present only when B is carbonyl.

Claim 25

A compound of the formula ##STR22## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R 2 is hydroxy, lower alkoxy or amino, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 6 is lower alkylsulfonyloxy or arylsulfonyloxy, R 43 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R 6 in which A and R 6 are as described above and the broken line denotes an optional carbon-carbon bond which can be present only when B is carbonyl.

Claim 26

A compound of the formula ##STR23## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R 2 is hydroxy, lower alkoxy or amino, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 8 is aryloxycarbonyl, R 44 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or group of the formula -A-R 8 in which A and R 8 are as described above and the broken line denotes an optional carbon-carbon bond which can be present only when B is carbonyl.

Claim 27

A compound of the formula ##STR23## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R 2 is hydroxy, lower alkoxy or amino, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 8 is aryloxycarbonyl, R 44 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or group of the formula -A-R 8 in which A and R 8 are as described above and the broken line denotes an optional carbon-carbon bond which can be present only when B is carbonyl.

Claim 28

A compound of the formula ##STR24## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, R 20 is lower alkoxy, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, Z is benzyloxycarbonyl and R 45 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-Z in which A and Z are as described above.

Claim 29

A compound of the formula ##STR24## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, R 20 is lower alkoxy, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, Z is benzyloxycarbonyl and R 45 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-Z in which A and Z are as described above.

Claim 30

A pharmaceutical composition for controlling or preventing hypertension comprising an effective amount of a compound of the formula ##STR25## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R 1 is halogen, carboxyl, lower alkoxycarbonyl, hydroxyaminocarbonyl, mercapto, lower alkanoylthio or aryl-(lower alkylthio)-R 2 is hydroxy, lower alkoxy or amino, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 4 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R 1 wherein A and R 1 are as described above and the brokenline denotes an optional carbon-carbon bond which can be present only when B is carbonyl, or a salt of a compound of formula I, wherein R 1 carboxy and/or R 2 hydroxy, with a pharmaceutically acceptable base, and a pharmaceutical carrier material.

Claim 31

A pharmaceutical composition for controlling or preventing hypertension comprising an effective amount of a compound of the formula ##STR25## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R 1 is halogen, carboxyl, lower alkoxycarbonyl, hydroxyaminocarbonyl, mercapto, lower alkanoylthio or aryl-(lower alkylthio)-R 2 is hydroxy, lower alkoxy or amino, R 3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R 4 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R 1 wherein A and R 1 are as described above and the brokenline denotes an optional carbon-carbon bond which can be present only when B is carbonyl, or a salt of a compound of formula I, wherein R 1 carboxy and/or R 2 hydroxy, with a pharmaceutically acceptable base, and a pharmaceutical carrier material.