# US 4,399,136 A · Pyrazolopyridazine antihypertensives

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- Number: US 4,399,136 A
- Document ID: US4399136A
- Status: Granted
- Kind: A
- Application number: 06/272,351
- Filed: 1981-06-10
- Granted: 1983-08-16
- Earliest claimed: 1980-06-13
- Assignees: Hoffmann-La Roche Inc.
- Inventors: Cedric H. Hassall; Geoffrey Lawton; Christopher J. Moody
- Web page: https://patentgrep.com/patent/US4399136A

## CPC

- C07D 487/04: Ortho-condensed systems
- C07D 237/04: having less than three double bonds between ring members or between ring members and non-ring members
- C07D 491/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of the formula ##STR1## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R.sup.1 is halogen, carboxyl, lower alkoxycarbonyl, hydroxyaminocarbonyl, mercapto, lower alkanoylthio or aryl(lower alkylthio)--, R.sup.2 is hydroxy, lower alkoxy or amino, R.sup.3 is hydrogen, lower alkyl, aryl or aryl(lower alkyl)--, R.sup.4 is hydrogen, lower alkyl, aryl, aryl-(lower alkyl)-- or a group of the formula --A-R.sup.1 wherein A and R.sup.1 are as described above and the broken line denotes an optional carbon-carbon bond which can be present only when B is carbonyl, and salts of the acids of formula I with pharmaceutically acceptable bases, a process for the manufacture thereof and pharmaceutical preparations containing same, are described. The compounds of formula I and their salts are useful as antihypertensive agents.

## Claims

### Claim 1

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.sup.1 is halogen, carboxyl, lower alkoxycarbonyl, hydroxyaminocarbonyl, mercapto, lower alkanoylthio or aryl-(lower alkylthio)-, R.sup.2 is hydroxy, lower alkoxy or amino, R.sup.3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R.sup.4 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R.sup.1 wherein A and R.sup.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.sup.1 is carboxy and/or R.sup.2 is hydroxy, with a pharmaceutically acceptable base.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 2)

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

### Claim 4 (depends on 3)

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

### Claim 5 (depends on 4)

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

### Claim 6 (depends on 1, 2, 3, 4, 5)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1, 2, 3, 5, 8)

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 9

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

### Claim 10

A compound selected from the group consisting of
2-Ethyl-hexahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazin e-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 11

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]pyrid azine-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-c arboxylate,
tert.butyl 2-acetylthiomethyl-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazi ne-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]pyrid azine-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]pyrida zine-5-carboxylic acid,
2-(3-acetylthiopropyl)-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyrid azine-5-carboxylic acid,
methyl 2,3,5,8-tetrahydro-2-(2-iodoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]py ridazine-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 12

A compound selected from the group consisting of
Tert.butyl 2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyrida zine-5-carboxylate,
2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridaz ine-5-carboxylic acid,
methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]py ridazine-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]pyr idazine-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-carboxyl ate,
2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxyli c acid and
tert.butyl hexahydro-2-(2-acetylthioethyl)-2-methyl-3-oxo-1H-pyrazolo[1,2-a]pyridazin e-5-carboxylate.

### Claim 13

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

### Claim 14

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.sup.2 hydroxy, lower alkoxy or amino, R.sup.3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R.sup.5 is hydroxy, R.sup.41 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R.sup.5 in which A and R.sup.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 15

A method of controlling or preventing hypertension which comprises administering to a host requiring such treatment a pharmaceutical composition containing an effective amount of a compound of the formula ##STR21## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, B is carbonyl or methylene, R.sup.1 is halogen, carboxyl, lower alkoxycarbonyl, hydroxyaminocarbonyl, mercapto, lower alkanoylthio or aryl-(lower alkylthio)-, R.sup.2 is hydroxy, lower alkoxy or amino, R.sup.3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R.sup.4 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R.sup.1 wherein A and R.sup.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 1, wherein R.sup.1 is carboxy and/or R.sup.2 is hydroxy, with a pharmaceutically acceptable base.

### Claim 16

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.sup.2 is hydroxy, lower alkoxy or amino, R.sup.3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R.sup.6 is lower alkylsulfonyloxy or arylsulfonyloxy, R.sup.43 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R.sup.6 in which A and R.sup.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 17

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.sup.2 is hydroxy, lower alkoxy or amino, R.sup.3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R.sup.8 is aryloxycarbonyl, R.sup.44 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or group of the formula -A-R.sup.8 in which A and R.sup.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 18

A compound of the formula ##STR24## wherein A is methylene, ethylene or propylene which may be substituted by lower alkyl, R.sup.20 is lower alkoxy, R.sup.3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, Z is benzyloxycarbonyl and R.sup.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 19

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.sup.1 is halogen, carboxyl, lower alkoxycarbonyl, hydroxyaminocarbonyl, mercapto, lower alkanoylthio or aryl-(lower alkylthio)-R.sup.2 is hydroxy, lower alkoxy or amino, R.sup.3 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)-, R.sup.4 is hydrogen, lower alkyl, aryl or aryl-(lower alkyl)- or a group of the formula -A-R.sup.1 wherein A and R.sup.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.sup.1 carboxy and/or R.sup.2 hydroxy, with a pharmaceutically acceptable base, and a pharmaceutical carrier material.