Patent GB-970440-A (GB)
Title: Anti-inflammatory compositions comprising steroids and indole derivatives
IPC: C07D209/28
Filed: 1962-08-02
Abstract: a -(2-Methyl-5-lower alkoxy-3-indolyl)-lower fatty acid derivatives and the corresponding 5-lower alkyl compounds of the general formula <FORM:0970440/C1/1> wherein A represents -CH2- or <FORM:0970440/C1/2> , R is a hydrogen atom or a methyl radical, R2 is a C1-5 alkyl or C1-5 alkoxy radical, Y is a hydrogen atom, a C1-5 alkyl radical or an equivalent of a metal, and R1 is a hydrogen, chlorine, bromine or fluorine atom or a C1-5 alkyl, mercapto, methylmercapto, methoxy, hydroxy, cyano, trifluoromethyl, nitro, acyl or amino radical, and, when R1 is a chlorine, bromine or fluorine atom, one or more such atoms are attached to the ring, may be prepared by reacting an aralkyl or aroyl halide with the sodium derivative of an a -(2-methyl-5-substituted-3-indolyl)-lower aliphatic acid ester of the general formula <FORM:0970440/C1/3> (where R is a hydrogen atom or a methyl radical, R2 is a C1-5 alkyl or alkoxy radical and Y is a C1-5 alkyl radical and, if desired, converting the resulting ester into the free acid or a salt thereof.  Specific examples relating to the preparation of such compounds and intermediates are as follows: (A) Ethyl-a -(2-methyl-5-methoxy-3-indolyl)-propionate; Ethyl-a -(2,5-dimethyl-3-indolyl)-propionate and the corresponding acetates are prepared by reacting the appropriately substituted phenylhydrazine with ethyl-a -methyl-laevulinate or ethyl laevulinate. They may be saponified to the corresponding free acids by treatment with sodium hydroxide. (B) a -(1-p-Chlorobenzyl-2-methyl-5-methoxy-3-indolyl)-propionic acid is prepared by reacting ethyl-a -(2-methyl-5-methoxy-3-indolyl)-propionate with p-chlorobenzyl chloride in the presence of sodium hydride to give ethyl-a -(1-p-chlorobenzyl -2-methyl-5-methoxy-3-indolyl)-propionate which is saponified to the free acid.  The corresponding acetic acid derivative is similarly prepared from its acetate ester and from ethyl-a -(2,5-dimethyl-3-indolyl)-propionate there may be similarly obtained ethyl-a -(1-p-chlorobenzyl-2,5-dimethyl-3-indolyl)-propionate and the free acid. (C) a -(1-p-Methylthiobenzyl-2-methyl-5-methoxy -3-indolyl)-propionic acid is prepared by reacting thioanisole with chloromethyl methyl ether to give p-methylthiobenzyl chloride which is reacted with ethyl-a -(2-methyl-5-methoxy-3-indolyl)-propionate to give ethyl a -(1-p-methylthiobenzyl-2-methyl-5-methoxy-3-indolyl)-propionate which may be saponified to the free acid which may be converted to the sodium or aluminium salts. The corresponding (1-p-methylthiobenzyl-2-methyl-5-methoxy-3-indolyl)-acetate and the free acid may be similarly prepared from ethyl (2-methyl-5-methoxy-3-indolyl)-acetate.  (D) a -(2-Methyl-5-methoxy-3-indolyl)-propionic anhydride is prepared by treating 2-methyl-5-methoxy-3-indolyl-a -propionic acid with dicyclohexylcarbodiimide and is converted to t-butyl a -(2-methyl-5-methoxy-3-indolyl)-propionate by treatment with t-butyl alcohol and zinc chloride.  Treatment of this t-butyl ester with p-methylthiobenzoyl chloride or p-chlorobenzoyl chloride yields t-butyl a -(1-p-methylthiobenzoyl-2-methyl-5-methoxy-3-indolyl)-propionate or the corresponding 1-p-chlorobenzoyl compound both of which may be converted to the free acids by heating to 215 DEG C. under nitrogen. By similar reactions and commencing with 2-methyl-5-methoxy-3-indolyl acetic acid, there are produced (a) 2-methyl-5-methoxy-3-indolyl acetic anhydride, (b) t-butyl 2-methyl-5-methoxy-3-indolyl acetate, (c) t-butyl (1 - p - chlorobenzoyl - 2 - methyl -5- methoxy-3-indolyl)-acetate and, (d) the corresponding free acid. Racemic forms of compounds produced as above may be resolved by the method described in Specification 957,990.ALSO:Pharmaceutical anti-inflammatory compositions comprise an anti-inflammatory steroid compound and a compound of the general formula <FORM:0970440/A5-A6/1> wherein A is > CH2 or > C = O, R is a hydrogen atom of a methyl radical, Y is a hydrogen atom or a methyl radical, Y is a hydrogen atom or a lower (C1-5) alkyl radical or a metal (e.g. Na, K, Al, Mg), R2 is a C1-5 alkyl or C1-5 alkoxy radical and R1 is a hydrogen, chlorine, fluorine or bromine atom or a C1-5 alkyl, mercapto, methyl mercapto, methoxy, hydroxy, cyano, trifluoromethyl, nitro, acyl or amino radical.  When R1 is halogen, one or more such atoms may be attached to the benzene ring.  Specified steroids are cortisone, hydrocortisone, prednisone, prednisolone, dexamethasone, triamcinolone, D 6-dexamethasone, 6a -methyl prednisolone, 6a -fluoro dexamethasone, 16b -methyl-9a -fluoro-prednisolone and 9a -chloro-16a -methyl prednisolone.  They may be in forms suitable for oral, parenteral and topical application, e.g. a tablet, capsule, syrup, elixir, cream, ointmennt, jelly, sterile and non-sterile solutions and suspensions which may comprise conventional pharmaceutical excipients.  Specification 957,990 is referred to.