GB1049789A - New thebaine derivatives and methods of preparing the same - Google Patents

Abstract

Novel thebaine compounds and the pharmaceutically acceptable acid addition salts and quaternary ammonium salts thereof, the free bases having the general formula <FORM:1049789/C2/1> wherein R1 is lower alkyl; R2 is hydrogen, lower alkyl, or an acyl group derived from a carboxylic acid having a maximum of 8 carbon atoms; R is (a) an unsaturated group of the general formula <FORM:1049789/C2/2> in which R3, R4 and R5 are each hydrogen, methyl or halogen; (b) a cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl group optionally substituted by one or more methyl groups; or (c) a propargyl group; and = represents an optional carbon-carbon bond, are prepared by one of the following methods: (a) by reacting a compound of the above formula (I) wherein R is hydrogen with a reactive halogen compound of the formula RX (where X = halogen) in the presence of an acid binding agent and optionally reacting a thebaine derivative in which R2 is hydrogen with an appropriate acyl halide or acid anhydride to give the compound in which R2 is an acyl group, (b) by reduction with lithium aluminium hydride of a compound in which R is COR1 where R1 is such that R1CH2\t is equivalent to R, (c) by treating a compound of the formula <FORM:1049789/C2/3> wherein R2 and R1 have the above meanings and R11 has the same meaning as R or represents hydrogen, with anhydrous p-toluenesulphonic acid optionally followed by reaction as in (a) above. The norcodeinone dimethyl ketal of the last general formula above is prepared by dehydrobromination of the 7-bromodihydro compound. Numerous methods of preparation of the above starting materials are described and the following intermediates are isolated: N-cyclopropylcarbonyldihydronorcodeinone, N - cyclopropylcarbonyl - D 6 - dihydronorthebaine, N - cyclopropylmethyl - D 6 - dihydronorthebaine, N - (t - butoxycarbonyl) - dihydronorcodeineone, N - (t - butoxycarbonyl) - D 6-dihydronorthebaine, 7 - bromo - N - (tbutoxycarbonyl) - dihydronorcodeineone dimethyl ketal, N - (t - butoxycarbonyl) - norcodeineone dimethyl ketal, N-(t-butoxycarbonyl)-northebaine, N - (trifluoroacetyl) - northebaine, northebaine, 7 - bromo - N - cyclopropylmethyldihydronorcodeinone dimethyl ketal, N-cyclopropylmethylnorcodeinone dimethyl ketal, N - (benzyloxycarbonyl) - dihydronorcodeinone, N - (benzyloxycarbonyl) - D 6 - dihydronorthebaine, D 6 - dihydronorthebaine, N - (cyclopropanecarbonyl) - dihydronormorphinone, N-(cyclopropanecarbonyl) - O - (N1,N1 - diethylcarbamyl) - dihydronormorphinone, N - (cyclopropanecarbonyl) - O - (N1,N1 - diethylcarbamyl) - D 6 - dihydronororipavine, N - (cyclobutanecarbonyl) - dihydronormorphinone, N-(cyclobutanecarbonyl) - O - (N1,N1 - diethylcarbamyl) - D 6 - dihydronororipavine, N - (cyclobutanecarbonyl) - dihydronormorphinone, N - (cyclobutanecarbonyl) - O - (N1,N1 - diethylcarbamyl) - dihydronormorphinone, N - (cyclobutanecarbonyl) - O - (N1,N1 - diethylcarbamyl)-D 6 - dihydronororipavine, 7 - bromodihydronorcodeinone dimethyl ketal, norcodeinone dimethyl ketal, N-allyl-norcodeinone dimethyl ketal, N1,N1 - diethylcarbamyl - dihydromorphinone, N - cyano - O - (N1,N1 - diethylcarbamyl) - dihydronormorphinone, O - (N1,N1-diethyl - carbamyl) - dihydronormorphinone, O - (N1,N1 - diethylcarbamyl) - N - (3,3 - dimethylallyl) - dihydronormorphinone, O - (N1,N1 - diethylcarbamyl) - N - (3,3 - dimethylallyl) - D 6 - dihydronororipavine, 7 - bromo-N - (cyclopropanecarbonyl) - O - (N1,N1 - diethylcarbamyl) - dihydronormorphinone dimethyl ketal, (N - cyclopropanecarbonyl)-O - (N1,N1 - diethylcarbmyl) - normorphinone dimethyl ketal, N - (cyclopropylmethyl)-normorphinone dimethyl ketal and O-acetyl-N-cyclopropylmethylnororipavine. Pharmaceutical compositions in conventional form for oral or parenteral administration comprise a compound of the first general formula above and the carrier therefore and are useful as analgesics and morphine antagonists.ALSO:A compound of formula <FORM:1049789/C3/1> is prepared by reaction of triethylsilane, tri-ethylamine and the corresponding N-benzyloxy-carbonyl-thebaine compound, in the presence of PdCl2.