Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-04-02
1998-05-12
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546113, 548467, A01N 4342, C07D47102, C07D20902
Patent
active
057505365
DESCRIPTION:
BRIEF SUMMARY
This is a 3H application of PCT/IB 94/00234 filed on Aug. 4, 1994.
The present invention refers to tropyl 7-azaindol-3-ylcarboxyamides of formula (I) ##STR3## wherein the symbol indicates that compounds (I) may have the configuration exo(or .beta.-) or endo(or .alpha.-) and -C.sub.4 alkyl; a C.sub.7 -C.sub.9 arylalkyl; a --(CH.sub.2).sub.n --(C.sub.3 -C.sub.7) cycloalkyl group wherein n is an number between 0 and 4; a C.sub.1 -C.sub.12 acyl group,
As C.sub.3 -C.sub.7 membered cycloaliphatic ring cyclopropyl, cyclopentyl and cyclohexyl are preferred.
As C.sub.7 -C.sub.9 arylalkyl the benzyl and the phenethyl radical are preferred.
As --(CH.sub.2)n---(C.sub.3 -C.sub.7) cycloalkyl group, the cyclopropylmethyl group is preferred.
As C.sub.1 -C.sub.12 acyl group the formyl group is preferred.
Among C.sub.1 -C.sub.4 alkyl radicals are preferred the methyl, ethyl and isopropyl radicals.
A further object of the invention is represented by the compounds of formula (I) wherein the aminotropyl group is protected by a suitable conventional protecting group among which is preferred the ter-butoxycarbonyl. Also included in the scope of the invention are the acid addition salts of the compounds (I) with suitable, non-toxic, pharmaceutically acceptable acids. Among these salts are cited the hydrochorides, hydrobromides, alkyl and arylsulfonates, succinates, tartrates and citrates.
The compounds of formula (I) are obtained by reaction of a tropylamine of formula (III): ##STR4## wherein the symbols R and have the above defined meaning, with an optionally activated azaindolyl-3-carboxylic acid (IV): ##STR5## wherein the symbol s, has the above mentioned meaning and T represents a hydroxy group or the residue of a carboxylic acid activating group. Preferred activating groups are those well known in the art such as, for example, chorine, bromine, azide, imidazolide, p-nitrophenoxy, 1-benzotriazole, N--O-succinimide, acyloxy and more specifically, pivaloyloxy, C1-C4 alkoxycarbonyloxy, such as, for example, C.sub.2 H.sub.5 OCO--O--, a dialkyl- or a dicycloalkyl-O-ureide. The carboxyamides of formula (I) are isolated from the reaction mixture as free bases or as addition compounds with a suitable mineral or organic acid. When the compounds of formula (IV) are used in their free acid form, the reaction is carried out in the presence of a condensing agent such as, for example, a carbodiimide, optionally in the presence of an activating agent such as, for example, hydroxybenzotriazole or hydroxysuccinimide, with the intermediate formation of dialkyl- or dicycloalkyl-O-ureides. Typical condensing agents are the dicyclohexyl- and the diisopropylcarbodiimide, carbodiimides soluble in an aqueous medium etc. Preferred reaction conditions are those which provide the use of equimolar amounts of the reagents, in inert solvents such as ethyl acetate, aromatic hydrocarbons such as benzene and toluene, cycloalkanes such as cyclohexane, dioxane, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, acetonitrile and the mixtures thereof, operating at a temperature between room temperature and the reflux temperature of the mixture, preferably at 50.degree.-60.degree. C.
The bicyclic tropylamines (III) are generally well known and also commercially available compounds. They may be prepared using methods known in the art; see for example, the method for the preparation of 3.alpha.-tropylamine of S. Archer et al., J. Amer. Chem. Soc., 79, 4194, 1957 and the method described for the preparation of 3.beta.-tropylamine R. Willstatter et al., Chem. Ber., 31, 1201, 1898, S. Archer et al., J. Amer. Chem. Soc., 80, 4677, 1858, and also A. Stoll et al., Helv. Chim. Acta 38, 559, 1955; further preparations of said tropylamines are described by P. Dostert et al., FR 2.449.570 (13 Aug. 1982) C.A. 98, 126444q (1983); P. Donatsch et al., DE 33 22754 (29 Dec. 1983); M. Langlois et al., FR 2.548.666 (11 Jan. 1985) C.A. 103, 123757e (1985); E. A. Watts PCT WO 85 00.170 (17 Jan. 1985) C.A. 103 123376e (1985); D. Lednicer et al., EP 147.044 (3 J
REFERENCES:
Kato et al., "Preparation of Pyrrolopyridine . . . ", Chemical Abstracts, vol. 116 (1992), p. 778, ABS #255499a.
Caplus Abstract of JP 4-21681, (1992).
M. Kato et al--preparation of pyrrolopyridine derivatives as 5-hydroxytryptamine (5-HT) antagonist--Chemical Abstracts--vol. 116, 1992.
Daffonchio Luisa
Mantovanini Marco
Melillo Gabriella
DOMPE ' SpA
Ngo Tamthom T.
Shah Mukund J.
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