Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-04-07
2000-06-13
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514253, 514292, 546 86, 544126, 544361, A61K 31437, C07D47104
Patent
active
060750219
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is 1H-pyrido[3,4-b]indole-4-carboxamide derivatives, their preparation and their application in therapeutics.
The compounds of the invention correspond to the general formula (I) ##STR2## in which X represents a hydrogen or halogen atom or a (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy, trifluoromethyl or phenylmethoxy group, cyclopropyl or phenylmethyl group, substituted by a methoxy group, or a phenyl(C.sub.1 -C.sub.3)alkyl group optionally substituted on the phenyl ring by a halogen atom or a methyl or methoxy group, or a cyclohexylmethyl group, or a thienylmethyl group, or a pyridinylmethyl group, or a phenyl group optionally substituted by one or more halogen atoms or a (C.sub.1 -C.sub.3)alkyl' or (C.sub.1 -C.sub.3)alkoxy group, or a pyridinyl group, or a 5-methyl-1,2-oxazolyl group, or a 5-methyl-1,3,4-thiadiazolyl group, or a naphthyl group, hydrogen atom, a (C.sub.1 -C.sub.3)alkyl group, a 2-methoxyethyl group, a hydroxy(C.sub.2 -C.sub.4)alkyl group, a carboxy-(C.sub.1 -C.sub.3)alkyl group, a (C.sub.1 -C.sub.3)alkoxycarbonyl(C.sub.1 -C.sub.3)alkyl group or a phenyl(C.sub.1 -C.sub.3)alkyl group, or else together form, with the nitrogen atom which carries them, either a pyrrolidinyl group optionally substituted by a hydroxyl, ethoxy, methoxycarbonyl or methoxymethyl group, or a piperidinyl group, or a morpholinyl group, or a 4-methylpiperazinyl group, or an azetidinyl group, or a thiazolidinyl group, and double.
Depending on the nature of this bond, a compound according to the invention can optionally exist in the form of a pure optical isomer or of a mixture of such isomers.
The preferred compounds are those in the general formula of which X is in the 6 position and represents a fluorine atom, R.sub.1 represents a methyl group, R.sub.2 represents a phenyl group, R.sub.3 represents a methyl group and R.sub.4 represents an ethyl group or else R.sub.3 and R.sub.4 form, with the nitrogen atom which carries them, a pyrrolidinyl ring.
The compounds of general formula (I) can be prepared by processes illustrated in the following schemes.
According to Scheme 1, the starting compound corresponds to the general formula (II), in which X is as defined above and R.sub.1 is as defined above; when R.sub.1 represents hydrogen, it is possible, if desired, to carry out an alkylation in order to produce a compound of general formula (II) in which R.sub.1 represents a (C.sub.1 -C.sub.3)alkyl group. The compound of general formula (II) is thus reacted with ethyl pyruvate of formula (III), in acidic medium, for example in the presence of gaseous hydrochloric acid in ethanol or in the presence of sulphuric acid or of boron trifluoride etherate in acetic acid, between room temperature and the reflux temperature, in order to obtain the diester of general formula (IV).
The latter is then treated in ethanol at the reflux temperature with an amine of general formula R.sub.2 NH.sub.2, in which R.sub.2 is as defined above. An ester of general formula (V) is obtained, which is converted to the corresponding acid, of general formula (VI), by hydrolysis in basic medium.
This acid is then converted to the primary, secondary or tertiary amide of general formula (I') by reaction with an amine of general formula HNR.sub.3 R.sub.4, in which R.sub.3 and R.sub.4 are as defined above, either through the imidazolide obtained by reaction with N,N'-carbonyldiimidazole or ##STR3## through the acid chloride.
In the compound of general formula (I') thus obtained, the bond between the 3 and 4 positions is a single bond. If it is desired to prepare a compound in which this bond is a double bond, a compound of general formula (I') is oxidized by means of 2,3-dichloro-5,6-dicyanocyclohexa-2,5-diene-1,4-dione or of 3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione, in a solvent such as toluene or dichloromethane, between room temperature and the reflux temperature, in order to obtain the corresponding compound, in the structure of which the bond between the carbon atoms in the 3 and 4 positions is double, whic
REFERENCES:
C. Herdeis et al., "Synthesis and Serotonin-Receptor Activity of Substituted 1-Oxo-1,2,3,4-tetrahydro-.beta.-carbolines", Zeitschrift Fur Naturforschung, Teil B: Anorganische Chemie, Organische Chemie, vol. 42B, pp. 785-790, (1987).
Evanno Yannick
George Pascal
LeGalloudec Odette
Maloizel Christian
Sevrin Mireille
Powers Fiona T.
Synthelabo
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