Patent GB-762256-A (GB)
Title: Tertiary-amino-substituted compounds of the tropane and granatanine series
Filed: 1954-09-09
Abstract: The invention comprises: (a) compounds of the general formul <FORM:0762256/IV(b)/1> and <FORM:0762256/IV(b)/2> wherein Y represents NH, N-(lower-alkyl), N-(lower-alkanoyl), N-(mono-carbocyclic aroyl), N - (lower - alkylcarbamyl), N - (lower - alkenylcarbamyl), N - (mono - carbocyclic arylcarbamyl), N - (lower - alkylthiocarbamyl), N-(lower - alkenylthiocarbamyl), N - (mono-carbocyclic arylthiocarbamyl), O or S, n is an integer from 2 to 6, m is 1 or 2, R represents a lower-alkyl, mono-carbocyclic aryl-lower-alkyl or mono-carbocyclic aryl group, and N=B represents a di-lower-alkylamino, 1-pyrrolidyl, 1-piperidyl, 4-morpholinyl or mono-carbocyclic aryl-lower-alkylamino group (Y and N=B being attached to different carbon atoms of the CnH2n bridge, the mono-carbocyclic aryl groups in all cases including phenyl or phenyl substituted by halogen or by lower-alkyl, loweralkoxy or methylenedioxy groups, and the qualification "lower" denoting that the groups in question contain 1-6 carbon atoms), and their acid addition and quaternary ammonium salts; (b) the preparation of compounds of formula I in which Y is NH by condensing a compound of the formula <FORM:0762256/IV(b)/3> with a tertiary-amino lower-alkylamine H2N-CnH2n-N=B and reducing the unsaturated compound so formed; (c) the preparation of compounds of formula I in which Y is N-acyl (as defined above) by treating the products of (b) with an acylating agent (e.g. an acid, acid anhydride, acid halide, isocyanate or isothiocyanate); (d) the preparation of compounds of formula I in which Y is N-(lower-alkyl) by reducing compounds in which Y is N-(lower-alkanoyl) by means of lithium aluminium hydride; (e) the preparation of compounds of formula I in which Y is N(CH3) (except those in which n=2 and N=B is a mono-carbocyclic aryl-lower-alkylamino group) or of compounds of formula I(a) by heating the products of (b) with formaldehyde and formic acid; (f) the preparation of compounds of formula I in which Y is O or S by reacting a compound of the formula <FORM:0762256/IV(b)/4> with a compound of the formula X1-CnH2n-N=B, where one of X and X1 represents halogen and the other OM or SM, M being an alkali metal. Processes (b) and (f) may be followed by treatment of the resulting base with an acid or a quaternizing agent.  The reduction step in process (b) may be effected simultaneously with the condensation, by catalytic hydrogenation, or subsequently thereto, either by catalytic hydrogenation, yielding almost exclusively the stereoisomer corresponding to the normal tropane series, or chemically (e.g. with sodium and a lower alkanol), yielding a mixture of stereoisomers, which can be separated by fractional crystallization of their N-(substituted thiocarbamyl) derivatives. Examples illustrate various combinations of the following meanings of the symbols in formul  I and I(a): Y=NH, N(CH3), O, S, N(CSNHC6H5), N(CSNHCH2CH= CH2), N(CSNHC2H5), N(CSNHC6H4OC2H5-4), N(COCH3), N(C2H5), N(COCH2CH3), N(C3H7), N(COCH2CH2CH3), N(C4H9) and N(CHO); m = 1 and 2; n = 2, 3 and 4; R = CH3,C6H5CH2, 4-CH3OC6H4CH2, 2,3-(CH3O)2C6H3CH2, 3,4-CH2O2C6H3CH2, 2- and 4-ClC6H4CH2 and C6H5; N = B = N(C2H5)2, N(CH3)2, NC5H10, NC4H8, NC4H8O, N(CH3)(C6H5) and N(C2H5) (C6H5); lower-alkyl in I(a) = CH3 and C2H5.  Salts are prepared in some cases by treatment of the bases with hydrochloric, hydrobromic, picric and perchloric acids, methyl bromide and iodide and ethyl iodide (others being listed).  The products (especially the quaternary ammonium salts) are useful as ganglionic blocking agents.  Starting materials. Ketones of formula III are prepared by condensing succinic or glutaric dialdehyde with a primary amine (H2NR) and an acetone dicarboxylic acid ester, followed by hydrolysis and decarboxylation. The succinic dialdehyde is conveniently prepared in situ by acid treatment of 2 : 5-diethoxytetrahydrofuran and the glutaric dialdehyde by heating its dioxime with sodium nitrite in hydrochloric acid.  The preparation of 8-benzylnortropanone is described in detail. Alcoholates and halides of formula V (X = OM or halogen) are obtainable by reducing the keto group in compounds III and converting the resulting OH group to OM or replacing it by halogen.