# US 5,344,842 A · Thiosemicarbazone derivatives

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- Number: US 5,344,842 A
- Document ID: US5344842A
- Status: Granted
- Kind: A
- Application number: 08/066,815
- Filed: 1993-05-24
- Granted: 1994-09-06
- Earliest claimed: 1992-06-03
- Assignees: Ciba-Geigy Corporation
- Inventors: Martin Missbach
- Web page: https://patentgrep.com/patent/US5344842A

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 19/10: for osteoporosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 277/54: Nitrogen and either oxygen or sulfur atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to novel thiosemicarbazones of formula I ##STR1## wherein R.sub.1 is lower alkyl, lower alk-2-en-1-yl or lower alk-2-yn-1-yl, R.sub.2 and R.sub.3 independently of one another are hydrogen or lower alkyl, or R.sub.2 and R.sub.3 together are lower alkylidene, R.sub.4 is hydrogen, lower alkyl, lower alkoxy, aryl or aryl-lower alkyl, or the group --C(.dbd.O)--R.sub.6 wherein R.sub.6 is lower alkyl, aryl, heteroaryl, aryloxy, aryl-lower alkoxy or lower alk-2-en-1-yloxy, R.sub.5 is aryl, aryl-lower alkyl, unsaturated or saturated heterocyclyl-lower alkyl, lower alkoxycarbonyl-lower alkyl or the group --C(.dbd.O)--R.sub.7 wherein R.sub.7 is lower alkyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, heteroaryl, aryloxy, aryl-lower alkoxy or lower alk-2-en-1-yloxy, or, when R.sub.4 is other than hydrogen, R.sub.5 may also be lower alkyl, lower alk-2-en-1-yl or lower alk-2-yn-1-yl, and to the salts thereof, to processes for the preparation of the said compounds, to pharmaceutical compositions comprising them and to their use as active ingredients in medicaments.

## Claims

### Claim 1

A compound of formula I ##STR13## wherein R.sub.1 is lower alkyl, lower alk-2-en-1-yl or lower alk-2-yn-1-yl,
R.sub.2 and R.sub.3 independently of one another are hydrogen or lower alkyl, or R.sub.2 and R.sub.3 together are lower alkylidene,
R.sub.4 is hydrogen, lower alkyl, lower alkoxy, aryl, aryl-lower alkyl or the group --C(.dbd.O)--R.sub.6 wherein R.sub.6 is lower alkyl, aryl, heteroaryl, aryloxy, aryl-lower alkoxy or lower alk-2-en-1-yloxy,
R.sub.5 is aryl, aryl-lower alkyl, unsaturated or saturated heterocyclyl-lower alkyl, lower alkoxycarbonyl-lower alkyl or the group --C(.dbd.O)--R.sub.7 wherein R.sub.7 is lower alkyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, heteroaryl, aryloxy, aryl-lower alkoxy or lower alk-2-en-1-yloxy, or a salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 of formula I, wherein
R.sub.1 is C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.5 alk-2-en-1-yl or C.sub.3 -C.sub.5 alk-2-yn-1-yl,
R.sub.2 and R.sub.3 independently of one another are hydrogen, or identical C.sub.1 -C.sub.4 alkyl radicals or C.sub.1 -C.sub.4 alkylidene, and
R.sub.4 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.2 alkoxy, phenyl or phenyl-lower alkyl or the group --C(.dbd.O)--R.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.4 alkyl, phenyl, naphthyl, pyridyl, thienyl, pyrryl, furyl, phenoxy, phenyl-C.sub.1 -C.sub.4 alkoxy or C.sub.3 -C.sub.5 alk-2-en- 1-yloxy,
R.sub.5 is phenyl, naphthyl, phenyl-lower alkyl, pyridyl-, thienyl-, pyrryl- or furyl-, pyrrolidinyl-, tetrahydrofuranyl- or tetrahydropyranyl-lower alkyl or C.sub.1 -C.sub.4 alkoxycarbonylC.sub.1 -C.sub.4 alkyl or the group --C(.dbd.O)--R.sub.7 wherein R.sub.7 has the meaning of R.sub.6 as defined for R.sub.4 or is phenyl-lower alkyl or phenyl-lower alkenyl, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound according to claim 1 of formula I, wherein
R.sub.1 is C.sub.3 -C.sub.5 alk-2-en-1-yl, such as allyl or methallyl, or C.sub.3 -C.sub.5 alk-2-yn-1-yl, such as prop-2-yn-1-yl,
R.sub.2 and R.sub.3 are both hydrogen or identical C.sub.1 -C.sub.4 alkyl radicals, such as methyl groups,
R.sub.4 is hydrogen, C.sub.1 -C.sub.4 alkyl, such as methyl or ethyl, C.sub.1 -C.sub.2 alkoxy, such as methoxy or ethoxy, phenyl, phenyl-lower alkyl, such as benzyl or phenylethyl, or the group --C(.dbd.O)--R.sub.6 wherein R.sub.6 is a C.sub.1 -C.sub.4 alkyl group, such as the methyl group, phenyl, pyridyl, thienyl, phenoxy, benzyloxy or C.sub.3 -C.sub.5 alk-2-en-1-yloxy, such as allyloxy or methallyloxy, and
R.sub.5 is phenyl, phenyl-lower alkyl, such as benzyl, or phenylethyl, pyridyl-, thienyl-, pyrryl-, furyl-, pyrrolidinyl-, tetrahydrofuranyl, or tetrahydropyranyl-lower alkyl, such as pyridyl-, thienyl-, pyrrol- or furyl-, pyrrolidinyl-, tetrahydrofuranyl- or tetrahydrofuranyl-methyl or methoxycarbonylmethyl or -ethyl, or the group --C(.dbd.O)--R.sub.7 wherein R.sub.7 has the meaning of R.sub.6 as defined for R.sub.4 or is benzyl or phenylallyl, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound according to claim 1 of formula I, wherein
R.sub.1 is allyl or methallyl,
R.sub.2 and R.sub.3 are both hydrogen,
R.sub.4 is hydrogen, methyl or methoxy or the group --C(.dbd.O)--R.sub.6 wherein R.sup.6 is methyl, phenyl, phenoxy, benzyloxy or allyloxy and
R.sub.5 is phenyl, benzyl, pyridyl-, furyl- or tetrahydropyranyl-methyl or methoxycarbonylmethyl or the group --C(.dbd.O)--R.sub.7 wherein R.sub.7 has the meaning of R.sub.6 as defined for R.sub.4 or is benzyl or phenylallyl, or a pharmaceutically acceptable salt thereof.

### Claim 5

A compound selected from the group consisting of
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-phenyl-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-p-bromophenyl-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-p-fluorophenyl-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-pentafluorophenyl-thiosemicarbazo ne,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-tolyl-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-p-cyanophenyl-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-benzyl-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-(thiophene-2-methyl)-thiosemicarb azone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-(furan-2-methyl)-thiosemicarbazon e,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-(tetrahydrofuran-2-methyl)-thiose micarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-(2-picolyl)-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-phenylethyl-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-glycinyl ethyl ester thiosemicarbazone,
1(5,5-Dimethyl-3-methallyl-4-oxo-thiazolidin-2-ylidene)-4-glycinyl ethyl ester thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-(2,2-dimethoxyethyl)-thiosemicarb azone,
[1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-2,4-dimethyl-thiosemicarbazone,]
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-hydroxymethylphenyl-thiosemicarba zone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-(3,4-methylene-dioxyphen-1-yl)-th iosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-(propionic acidethyl ester-2-yl)-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-(2-methyl-propionyl)-thiosemicarb azone,
1-(5,5-Dimethyl-3-methallyl-4-oxo-thiazolidin-2-ylidene)-4-benzoyl-thiosemi carbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-(thiophene-2-carbonyl)-thiosemica rbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-phenylacetyl-thiosemicarbazone,
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-benzyloxycarbonyl-thiosemicarbazo ne,
[1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-2-acetyl-4-methyl-thiosemicarbazon e,]
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-p-hydroxyphenyl-thiosemicarbazone
[1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-2-benzoyl-4-methyl-thiosemicarbazo ne,]
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-allyloxycarbonyl-thiosemicarbazon e, and
1-(3-Allyl-4-oxo-thiazolidin-2-ylidene)-4-cinnamoyl-thiosemicarbazone, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

A composition for the treatment of a disease of the rheumatoid type comprising a rheumatoid type disease treating effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier therefor.

### Claim 7 (depends on 3)

A composition for the treatment of a disease of the rheumatoid type comprising a rheumatoid type disease treating effective amount of a compound of claim 3 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier therefor.

### Claim 8 (depends on 1)

A method of treating a disease of the rheumatoidtype in an animal in need thereof comprising administering to said animal a rheumatoid type disease treating effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 5)

A method of treating a disease of the rheumatoidtype in an animal in need thereof comprising administering to said animal a rheumatoid type disease treating effective amount of a compound of claim 5 or a pharmaceutically acceptable salt thereof.