Patent GB-862370-A (GB)
Title: Steroid compounds and the preparation thereof
IPC: C07J41/00
Filed: 1957-07-04
Abstract: The invention comprises steroid compounds of the formula: <FORM:0862370/IV (b)/1> wherein R1 represents a hydrocortisone compound (minus its 21-hydroxyl group) said hydrocortisone compound being 14a -hydroxy-hydrocortisone, prednisolone or 14a -hydroxy-prednisolone or a 9a -fluoro derivative thereof, or 9a -fluoro-hydrocortisone, L represents -(CH2)n-, \C6H4, or -O-(CH2)n-, n represents a number from 1 to 6, each R represents a hydrogen atom, or an alkyl, hydroxylalkyl, aminoalkyl, aryl or aralkyl group containing up to 10 carbon atoms in each group, or all three R groups taken together with the nitrogen atom represent a morpholino, piperidino or piperazino group, and Z- is a pharmacologically acceptable anion, and the preparation thereof by reacting a steroid compound of the formula R1OH wherein R1 has the above significance with phosgene or a compound of the formula XY wherein X represents a halogen atom and Y represents a halogenated acyl group, and reacting the resulting 21-chloroformate or 21-halogenated acylate with the required amino alcohol or an amine respectively.  The amino acid ester product thus obtained being then, if desired, reacted with a salt forming agent for the introduction of the anion Z-.  Thus the compound of the formula R1OH may be reacted with a halogenated organic acyl halide in a liquid organic solvent, the product thus obtained is reacted with a liquid organic amine, and the amine ester is then reacted with a salt forming agent.  The group of the formula -NR3\sS may be of the following formula: <FORM:0862370/IV (b)/2> or <FORM:0862370/IV (b)/3> The pharmacologically acceptable anion may be derived from hydrochloric, hydrobromic, hydriodic, sulphuric, succinic or maleic acid.  In the Examples:-(1) prednisolone is reacted with chloracetyl chloride, and the resulting prednisolone chloroacetate is reacted with diethylamine to form prednisolone N,N-diethylaminoacetate which is converted into the corresponding hydrochloride salt; (2) prednisolone is reacted with phosgene to form prednisolone chloroformate and is then reacted with b -dimethylamino ethanol to form prednisolone b -dimethylaminoethylcarbonate which may be converted into the corresponding hydrobromide or methiodide salt; (3) 9a -fluorohydrocortisone is reacted with chloracetyl chloride to form the corresponding chloracetate and is then reacted with diethylamine to form 9a -fluoro-hydrocortisone N,N-diethylaminoacetate which may be converted into its corresponding hydrobromide salt; (4) N,N-diethylamino-acetate of 14a -hydroxy-prednisolone is prepared as in (1); and (5) 14a -hydroxy -hydrocortisone is reacted with chloracetyl chloride to form the corresponding chloracetate which is then reacted with trimethylamine to form 14a -hydroxy hydrocortisone dimethylaminoacetate methochloride.  Specification 814,000 is referred to.ALSO:A therapeutic composition comprises a steroid compound of the formula <FORM:0862370/VI/1> wherein R1 is a hydrocortisone compound minus its 21-hydroxyl group said hydrocortisone compound being 14a -hydroxyhydrocortisone, prednisolone or 14a -hydroxy-prednisolone or a 9a -fluoro derivative thereof or 9a -fluoro-hydro-cortisone, L represents -(CH2)n-, -C6H4-, or -O-(CH2)n-, n being a number from 1 to 6, each R represents a hydrogen atom or an alkyl, hydroxyalkyl, aminoalkyl, aryl or aralkyl group containing up to 10 carbon atoms in each group, or all three R groups taken together with the nitrogen atom represent a morpholino, piperidino or piperazino group, and Z-represents a pharmacologically acceptable anion, and a pharmaceutical carrier therefor.  The composition may be in the form of a salve, ointment or aqueous solution or suspension suitable for injection.  Sterile aqueous solutions made isotonic by the addition of glucose or saline or buffered with non-toxic buffers are useful for injection.  Small amounts of a chloro-butanol may be incorporated as a preservative.