Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-07-26
1997-03-18
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514323, 514411, 540602, 546200, 548448, A61K 3140, C07D20988
Patent
active
056123310
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/03628, filed Dec. 16, 1993.
The present invention relates to novel tetrahydrocarbazole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, in particular for the treatment of migraine.
U.S. Pat. Nos. 4,257,952, 4,172,834, 4,062,864 and 3,959,309 describe a broad class of 3-amino and 3-(substituted amino) tetrahydrocarbazoles having a variety of substituents at the 5,6,7 and/or 8 positions, including inter alia the group --CONR.sub.2 R.sub.3 wherein R.sub.2 and R.sub.3 are hydrogen, lower alkyl or together with the nitrogen atom form a heterocyclic ring. Such compounds are said to have analgetic, psychotropic and antihistaminic properties.
International Application No WO 93/00086 describes 3-amino and 3-(substituted amino) tetrahydrocarbazoles substituted at the 6-position of the tetrahydrocarbazole ring by a substituent selected from 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 ; and R.sup.5 and R.sup.6 represent hydrogen or C.sub.1-6 alkyl, or together with the nitrogen atom form a ring. The compounds are said to be 5-HT.sub.1-like agonists.
We have now found novel tetrahydrocarbazole derivatives having affinity for 5-HT.sub.1 -like receptors.
The present invention provides in a first aspect a compound of formula (I): ##STR2## wherein R.sup.1 represents halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, NO.sub.2, --NR.sup.4 R.sup.5, R.sup.4 R.sup.5 NCO(CH.sub.2).sub.m --, R.sup.4 R.sup.5 NSO.sub.2 (CH.sub.2).sub.m --, R.sup.6 CONH(CH.sub.2).sub.m -- or R.sup.7 SO.sub.2 NH(CH.sub.2).sub.m --; alkyl or NR.sup.4 R.sup.5 represents a 5- to 7-membered heterocyclic ring; or benzyl or --NR.sup.2 R.sup.3 represents a pyrrolidino, piperidino or hexahydroazepino ring; and chain wherein the double bond is not adjacent the nitrogen atom;
In the compounds of formula (I) a halogen atom may be a fluorine, chlorine, bromine or iodine atom. An alkyl or alkylene group or moiety may have a straight or branched chain. A C.sub.1-4 alkyl group may be for example methyl, ethyl, n-propyl, n-butyl or any branched isomer thereof such as isopropyl, or t-butyl, and a C.sub.5-6 alkyl group may for example include n-pentyl, or n-hexyl or any branched isomer thereof such as sec-pentyl.
When --NR.sup.4 R.sup.5 represents a heterocyclic ring this is preferably a 5- to 7-membered saturated heterocyclic ring which may optionally contain a further heteroatom selected from oxygen, sulphur or nitrogen. Suitable rings thus include pyrrolidino, piperidino, piperazino and morpholino. It will be appreciated that when the ring includes a further nitrogen atom this will carry a hydrogen atom or a suitable substituent group such as a C.sub.1-4 alkyl group.
The group A preferably represents a C.sub.1-4 alkylene chain or a C.sub.3-4 alkenylene chain. Most preferably A represents --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 -- or --CH.dbd.CHCH.sub.2 --.
n may be for example from zero to 3; preferably n is zero or 1.
R.sup.1 preferably represents halogen e.g. bromo or chloro, C.sub.1-4 alkoxy e.g. methoxy, NO.sub.2, --NR.sup.4 R.sup.5, R.sup.4 R.sup.5 NSO.sub.2 (CH.sub.2).sub.m --, or R.sup.7 SO.sub.2 NH(CH.sub.2).sub.m -- where R.sup.4, R.sup.5, R.sup.7 and m are as defined above. Preferably R.sup.4 and R.sup.5 independently represent hydrogen or methyl. R.sup.7 preferably represents methyl. m preferably represents zero.
Most preferably n is zero, or n is 1 and R.sup.1 represents C.sub.1-4 alkoxy e.g. methoxy.
R.sup.2 and R.sup.3 each preferably represent hydrogen, methyl or ethyl. Most preferably NR.sup.2 R.sup.3 is --NH.sub.2.
It will be appreciated that for use in medicine a salt of formula (I) should be a physiologically acceptable salt. Suitable physiologically acceptable sal
REFERENCES:
patent: 4257952 (1981-03-01), Mooradian
J. Med Chem, vol. 36, No. 13, Jun. 1993, pp. 1918-1919, F.D.King et al: `3-Amino -6-carboxamido-1,2,3,4-tetrahydrocarbazole: a conformationally restricted analogue of 5-carboxamidotryptamine with selectivity for the serotonin 5-HT1D receptor`.
Porter Roderick A.
Vimal Mythily
King William T.
Lentz Edward T.
Raymond Richard L.
SmithKline Beecham Plc
Stein-Fernandez Nora
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