Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-20
1997-06-10
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514318, 514339, 514415, 544310, 544316, 546193, 546194, 546201, 548504, 548505, A61K 3140, C07D40112
Patent
active
056375930
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage Application of PCT/EP93/03563 filed Dec. 14, 1993 which published as WO 94/14770 on Jul. 7, 1994.
The present invention relates to novel tryptamine analogues, processes and intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular for the treatment and/or prophylaxis of disorders characterised by excessive vasodilatation, such as migraine and portal hypertension.
WO-A-93/11106 published after the priority date of the present application describes indole derivatives as serotonin (5HT.sub.1) agonists. The generic disclosure of this document overlaps with the present application in describing compounds of structure (I) as hereinafter described wherein: substituted by up to 3 groups selected from halo, C.sub.1-4 alkyl, CO.sub.2 R.sup.9, NHCOR.sup.9, CONR.sup.10 R.sup.11, SO.sub.2 NR.sup.10 R.sup.11, NHSO.sub.2 R.sup.12, NO.sub.2, NR.sup.10 R.sup.11, NHCONH.sub.2 or CN, ##STR2##
WO-A-93/11106 also specifically discloses as Example 1G a compound wherein R.sup.1 is 3-CF.sub.3 -2-pyridyl, A.sup.1 A.sup.2 is NH, R.sup.2 is hydrogen and R.sup.3 is CH.sub.2 CH.sub.2 NMe.sub.2.
The present invention provides, in a first aspect, a compound of structure (I): ##STR3## in which A.sup.1 is O, S(O).sub.n in which n is 0,1 or 2, NR, CH.sub.2, or CH(OH); ring; --CH.dbd.NNHC(NH)NH.sub.2 or ##STR4## R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-4 alkyl; R.sup.6 and R.sup.7 are the same or different and are each hydrogen or C.sub.1-4 alkyl or together with the nitrogen atom to which they are attached form a ring;
Suitably A.sup.1 is O, S, NR or CH.sub.2.
Suitably A.sup.2 is a bond or CH.sub.2.
Suitably R.sup.1 is an optionally substituted 6- or 10-membered aryl ring such as phenyl or naphthyl.
Suitably R.sup.1 is an optionally substituted 6- to 10-membered heteroaryl ring containing from 1 to 4 nitrogen atoms. Examples of such heteroaryl rings include pyridine, pyridazine, pyrimidine, pyrazine, triazine, quinoline, or quinazoline. Particular examples are pyridine, pyridazine, pyrimidine, pyrazine and quinoline.
The heteroaryl ring can be linked to A.sup.1 A.sup.2 via a carbon or nitrogen atom of the heteroaryl ring.
Suitably R.sup.1 is unsubstituted or substituted by up to 3 groups selected from halo, C.sub.1-4 alkyl, hydroxy, oxo, C.sub.1-4 alkoxy, --CO.sub.2 R.sup.9, --NHCOR.sup.9, --CONR.sup.10 R.sup.11, --SO.sub.2 NR.sup.10 R.sup.11, --NHSO.sub.2 R.sup.12, NO.sub.2, --NR.sup.10 R.sup.11, --NHCONH.sub.2, CN, CF.sub.3 or CF.sub.3 O wherein R.sup.9 to R.sup.11 are independently hydrogen or C.sub.1-4 alkyl and R.sup.12 is C.sub.1-4 alkyl.
Suitably, R.sup.2 is hydrogen, halogen, C.sub.1-4 alkyl, CN, NO.sub.2 or CF.sub.3. Preferably R.sup.2 is hydrogen or halogen, in particular hydrogen or chlorine.
Suitably R.sup.3 is C(R.sup.4)(R.sup.5)CH.sub.2 NR.sup.6 R.sup.7, or --CH.dbd.NNHC(NH)NH.sub.2.
Suitably, R.sup.4 and R.sup.5 are hydrogen or C.sub.1-4 alkyl. Preferably R.sup.4 and R.sup.5 are both hydrogen or methyl.
Suitably, R.sup.6 and R.sup.7 are the same or different and are each hydrogen or C.sub.1-4 alkyl or together with the nitrogen atom to which they are attached form a ring. Preferably R.sup.6 and R.sup.7 are both hydrogen or methyl.
Suitable rings formed by R.sup.6 and R.sup.7 together with the nitrogen atom to which they are attached include for, example, 5- or 6-membered rings such as pyrrolidino and piperidino rings.
Suitably R.sup.3 is a group ##STR5##
Examples of C.sub.1-4 alkyl groups (alone or as part of another group, e.g. C.sub.1-4 alkoxy) include methyl, ethyl, propyl or butyl which can be straight chain or branched.
Examples of halo groups include fluoro, bromo, chloro or iodo.
Particular compounds of structure (I) include: 1-amino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane,
Pharmaceutically acceptable acid addition salts of the compounds of structure (I) include, for example, those formed with inorganic acids e.g. hydrochloric, sulphuric, methanesulphonic or phosphoric acids and organic acids e.
REFERENCES:
patent: 5245046 (1993-09-01), Youngdale et al.
patent: 5401854 (1995-03-01), Haffer et al.
Chem Abs, vol. 106, No. 13, 30 Mar. 1987, 98661w, Mukhomorov V.K. `Influence of electronic and steric interactions on the radioprotective properties of indolylalkylamines`.
J. Med. Chem. vol. 36, No. 11, 28 May 1993, pp. 1529-1538, L.J. Street et al. `Synthesis and serotonergic activity of 5-(oxadiazolyl)tryptamines: potent agonists for 5-HT1D receptors`.
Porter Roderick A.
Ward John G.
Haley Jacqueline
King William T.
Lentz Edward T.
SmithKline Beecham Plc
Stein-Fernandez Nora
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