Process of preparing enantiomers of carbazole derivatives

Details Process of preparing enantiomers of carbazole derivatives Process of preparing enantiomers of carbazole derivatives

1995-07-18

1997-04-08

Ramsuer, Robert W.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D20988

Patent

active

056189478

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to certain tetrahydrocarbazole derivatives, in particular their enantiomeric forms, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, in particular the treatment of migraine.
International Patent Application WO93/00086 describes compounds of the formula: ##STR2## and salts thereof for use in the treatment of conditions wherein a 5-HT.sub.1 -like agonist is indicated, in particular migraine.
In the above compounds R.sup.1 represents hydrogen, halogen, trifluoromethyl, nitro, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, arylC.sub.1-6 alkoxy, --CO.sub.2 R.sup.4, --(CH.sub.2).sub.n CN,-- (CH.sub.2).sub.n CONR.sup.5 R.sup.6, --(CH.sub.2).sub.n SO.sub.2 NR.sup.5 R.sup.6, C.sub.1-6 alkanoylamino(CH.sub.2).sub.n, or C.sub.1-6 alkylsulphonylamino(CH.sub.2).sub.n ; R.sup.4 represents hydrogen, C.sub.1-6 alkyl or arylC.sub.1-6 alkyl; R.sup.5 and R.sup.6 each independently represent hydrogen, or C.sub.1-6 alkyl, or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form a ring; n represents 0, 1 or 2; and R.sup.2 and R.sup.3 each independently represent hydrogen, C.sub.1-6 alkyl or benzyl or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexahydroazepino ring. The carbon atom to which the group NR.sup.2 R.sup.3 is attached (i.e. at position 3 of the terrahydrocarbazole ring) is an asymmetric carbon atom and hence the compounds exist as optically active enantiomers.
WO93/00086 describes inter alia the preparation of the above compounds wherein R.sup.1 is --C(O)NH.sub.2, one of R.sup.2 and R.sup.3 is hydrogen and the other is methyl or ethyl, viz: 6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole (as the hydrochloride salt) and 6-carboxamido-3-N-ethylamino-1,2,3,4-tetrahydrocarbazole (as the oxalate salt). Both compounds were obtained only as mixtures of enantiomers.
We have now isolated the individual isomers of the above compounds. Thus, in a first aspect the present invention provides the (+) and (-) enantiomers of a compound of formula (I): ##STR3## wherein R.sup.1 is methyl or ethyl, or a salt thereof.
In accordance with convention the (+) and (-) designations indicate the direction of rotation of plane-polarised light by the compounds. The prefix (+) indicates that the isomer is dextrorotatory (also designated d) and the prefix (-) indicates the levorotatory isomer (also designated 1). The R and S designations denote the absolute configuration as determined by X-ray crystallography.
The individual compounds of formula (I) provided by the invention may be named as: A) B) C) D)
Salts, solvates and hydrates of the above named compounds are also within the scope of the present invention.
It will be appreciated that for use in medicine a physiologically acceptable salt should be employed. Suitable physiologically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts such as those formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric or phosphoric acids and organic acids e.g. succinic, tartaric, malonic, citric, maleic, acetic, fumaric or methanesulphonic acid. Other non-physiologically acceptable salts e.g. oxalates may be used for example in the isolation of enantiomers of formula (I), and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of enantiomers of formula (I) and their salts.
Acids which have more than one carboxyl group e.g. succinic, tartaric, malonic or citric acids may correspondingly react with more than one molecule of an enantiomer (I), for example succinic acid may react with either one or two molecules of (I) to form either a 1:1 salt (succinate) or a 2:1 salt (hemi-succinate). All such salt forms are encompassed by the present invention; in general the 1:1 salt form is preferred.
Specific salts according to the present invention include: (+)-tartrate salt (1:1), (-)-tartrate salt (1:1), (2:1), methanesu

REFERENCES:
patent: 4257952 (1981-03-01), Mooradian
Hacksell et al., "Chirality in drug research and design", Trends in Biotechnology, vol. 11, pp. 73-74 (1993).
Ariends, "Nonchiral, homochiral and composite chiral drugs", Trends in Pharmacological Sciences, vol. 14, pp. 68-75 (1993).

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