Patent GB-928491-A (GB)
Title: í¸-steroids and process for the preparation thereof
IPC: A61K31/295
Filed: 1960-10-05
Abstract: The invention comprises steroids of the general formula <FORM:0928491/IV(a)/1> wherein Y represents an alkyl or alkylene group containing 10 to 12 carbon atoms, R represents an alkyl or hydroxyalkyl group containing 2 to 4 carbon atoms or a corresponding acylated hydroxyalkyl group, and A represents a di (hydroxyalkyl) amino, piperidino, morpholino, thiamorpholino, pyrrolidino, N-methylpiperazino, N-(2-hydroxyethyl)-piperazino, N-(2-haloethyl)-piperazino, di (haloalkyl) amino, phthalimido or isoindolino radical, and the acid addition and quaternary ammonium salts thereof, and the preparation of the said steroids by:-  (a) reacting a steroid compound of the formula <FORM:0928491/IV(a)/2> wherein X represents a halogen, R1 represents an alkyl or hydroxyalkyl radical containing 2 to 4 carbon atoms, and Y has the above significance, with a di (hydroxyalkyl) amine, piperidine, morpholine, thiamorpholine, N-methyl-piperazine, N-(2-hydroxyethyl)-piperazine, isoindoline, alkali metal phthalimide or pyrrolidine,  (b) if desired, acylating the hydroxy group of R when the acyl derivatives are desired,  (c) if desired, reducing the phthalimido group to an isoindolino group, e.g. with lithium aluminium hydride  (d) and, if desired, when A is di (haloalkyl) amino, treating the di (hydroxyalkyl) amino compound of steps (a) or (b) with a halogenating agent, preferably a chlorinating agent,  (e) and forming the acid addition and quaternary ammonium salts of said steroids when desired.  The invention also comprises steroids of the general formula <FORM:0928491/IV(a)/3> wherein A represents a di (C1 to C4 alkyl) amino, di (hydroxyalkyl) amino, di (haloalkyl) amino, piperidino, morpholino, pyrrolidino, thiamorpholino, N-methyl-piperazino, N-(2-hydroxyethyl)-piperazino or N-(2-haloethyl) piperazino radical, n is 2, 3 or 4, and Y represents a group of the formula <FORM:0928491/IV(a)/4> or <FORM:0928491/IV(a)/5> and acid addition and quaternary salts thereof.  The acid addition salt may be a hydrochloride, hydrobromide, thymosulphonate, maleate, succinate or citrate, and the quaternanry salt may be a methiodide, ethiodide, methobromide, or methosulphate.  Some of the compounds of the third general formula above may be prepared by the following reaction scheme <FORM:0928491/IV(a)/6> where n is 2, 3 or 4, Y represents a group of one of the formulae immediately above, X represents a halogen and A has the significance immediately above except that it does not represent a di (haloalkyl) amino or an N-(2-haloethyl)-piperazino radical. The first step in this process is preferably carried out in the presence of pyridine, and the second amination step is preferably carried out by heating.  Alternatively, the tosyl ester in the above reaction scheme can be etherified with the required aminoalkanol of the formula A(CH2)nOH wherein n is 2, 3 or 4 and A has the significance immediately above.  The steroid basic ethers may also be prepared by the method exemplified in the following reaction scheme <FORM:0928491/IV(a)/7> wherein R2NH provides the radical represented by the symbol A in the first general formula above.  In the first step of this process it is preferable to use stannic chloride as the condensation catalyst although other acid catalysts may be used, for example, sulphuric acid, aluminium chloride or boron trifluoride.  Epichlorohydrin may also be used in the condensation reaction but it is preferred to use epibromohydrin. When the symbol A is a di (haloalkyl) amino or an N-(2-haloethyl) piperazino radical, the final product may be obtained by halogenating the corresponding compound wherein the symbol A is a di (hydroxyalkyl) amino or an N-(2-hydroxyethyl) piperazino radical, for example, with phosphorus oxyhalide or thionyl halide.  Therapeutic compositions, having antiinflammatory activity, contain as the active ingredient steroids of the first and third general formulae above. The compositions may be administered parenterally or topically.  Some of the active ingredients are capable of depressing the cholesterol level in blood and reducing the clotting time in blood.