Claims for Patent: 4,297,351

Summary for Patent: 4,297,351

Title:	Method of manufacture and use of improved 2β, 16β-piperidino androstanes
Abstract:	New and pharmacologically useful pharmaceutically acceptable acid addition salts are disclosed for the 16β-monoquaternary ammonium derivatives of either the 2β, 16β-bis-piperdino-3α, 17β-dihydroxy-5α-androstane 3α, 17β-di-lower aliphatic esters or the 2β, 16β-bis-piperidino-3α-hydroxy-5α-androstane-3α-lower aliphatic esters, which salts are surprisingly relatively stable in aqueous solutions, so that they provide stable aqueous injection preparations.
Inventor(s):	Ian C. Carlyle, Thomas Sleigh, David S. Savage
Assignee:	Akzona Inc
Application Number:	US06/194,942
Patent Claims:	1. A method for the preparation of a pharmaceutically acceptable acid addition salt of the 16β-mono-quaternary ammonium derivative of either a 3α,17β-di-lower aliphatic ester of 2β,16β-dipiperidino-3α,17β-dihydroxy-5α-androstane or a 3α-lower aliphatic ester of 2β,16β-dipiperidino-3α-hydroxy-5α-androstane comprisingadding a pharmaceutically acceptable acid to the 16β-mono-quaternary ammonium derivative of either a 3α,17β-di-lower aliphatic ester of 2β,16β-dipiperidino-3α,17β-dihydroxy-5α-androstane or a 3α-lower aliphatic ester of 2β,16β-dipiperidino-3α-hydroxy-5α-androstane in a suitable solvent. 2. In the method for the administration of a neuromuscular blocking agent by injection to a surgical patient, the improvement which comprisesusing as said neuromuscular blocking agent an effective amount of a pharmaceutically acceptable acid addition salt of the 16β-mono-quaternary ammonium derivative of either a 3α,17α-di-lower aliphatic ester of 2β,16β-dipiperidino-3α,17β-dihydroxy-5α-androstane or a 3α-lower aliphatic ester of 2β,16β-dipiperidino-3α-hydroxy-5α-androstane. 3. The method of claim 1, wherein the acid addition salt is derived from one of the acids selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, acetic acid, propionic acid, butyric acid, caproic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, tartaric acid, malic acid, pyruvic acid, lactic acid, and citric acid. 4. The method of claim 1, wherein said acid addition salt is an acid addition salt of a compound of the formula ##STR2## wherein: (a) Represents H or the moiety --OR2 ;(b) R1 and R2 each represent an unsubstituted acyl group derived from a lower aliphatic carboxylic acid of one to about six carbons; (c) ALK is an alkyl, alkenyl or alkynyl group of one to about four carbon atoms; and (d) A.sup.⊖ represents a pharmaceutically acceptable organic or inorganic anion. 5. The method of claim 4, wherein at least one of R1 and R2 is acetyl. 6. The method of claim 5, wherein A.sup.⊖ is selected from the group consisting of methyl sulfate, p-toluene sulfonate, chloride, bromide, and iodide. 7. The method of claim 4, wherein ALK is methyl. 8. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol diacetate 16βN-methobromide hydrochloride. 9. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α-proprionate 17β-acetate 16βN-methobromide hydrochloride. 10. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α-ol 3α-acetate 16βN-methobromide hydrochloride. 11. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α-ol 3α-acetate 16βN-allylobromide hydrochloride. 12. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α-ol 3α-acetate 16βN-propargylobromide hydrochloride. 13. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane 3α,17β-diol diacetate 16βN-methobromide hydrobromide. 14. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α-butyrate 17β-acetate 16βN-methobromide hydrobromide. 15. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol diacetate 16βN-methobromide maleate. 16. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol, 3α-butyrate 17β-acetate 16βN-methobromide maleate. 17. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol diacetate 16βN-methobromide citrate. 18. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α-propionate 17β-acetate 16βN-methobromide citrate. 19. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol diacetate 16βN-methobromide phosphate. 20. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α pivalate 17β-acetate 16βN-methobromide phosphate. 21. The method of claim 1, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α pivalate 17β-acetate 16βN-methobromide tartrate. 22. The method of claim 1, wherein said acid addition salt has the formula: ##STR3## (a) R represents H or the moiety --OR2 ; (b) R1 and R2 each represent an unsubstituted acyl group derived from a lower aliphatic carboxylic acid of one to about six carbons;(c) ALK is an alkyl, alkenyl, or alkynyl group of one to about four carbon atoms; and (d) A.sup.⊖ and X.sup.⊖ each represents a pharmaceutically acceptable organic or inorganic anion. 23. The method of claim 22 wherein X.sup.⊖ and A.sup.⊖ are identical. 24. The method of claim 2, wherein the acid addition salt is derived from one of the acids selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, acetic acid, propionic acid, butyric acid, caproic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, tartaric acid, malic acid, pyruvic acid, lactic acid, and citric acid. 25. The method of claim 2, wherein said acid addition salt is an acid addition salt of a compound of the formula ##STR4## wherein: (a) R represents H or the moiety --OR2 ;(b) R1 and R2 each represent an unsubstituted acyl group derived from a lower aliphatic carboxylic acid of one to about six carbons; (c) ALK is an alkyl, alkenyl or alkynyl group of one to about four carbon atoms; and (d) A.sup.⊖ represents a pharmaceutically acceptable organic or inorganic anion. 26. The method of claim 25, wherein at least one of R1 and R2 is acetyl. 27. The method of claim 26, wherein A.sup.⊖ is selected from the group consisting of methyl sulfate, p-toluene sulfonate, chloride, bromide, and iodide. 28. The method of claim 25, wherein ALK is methyl. 29. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol diacetate 16βN-methobromide hydrochloride. 30. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α-proprionate 17β-acetate 16βN-methobromide hydrochloride. 31. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α-ol 3α-acetate 16βN-methobromide hydrochloride. 32. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α-ol 3α-acetate 16βN-allylobromide hydrochloride. 33. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α-ol 3α-acetate 16βN-propargylobromide hydrochloride. 34. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane 3α,17β-diol diacetate 16βN-methobromide hydrobromide. 35. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α-butyrate 17β-acetate 16βN-methobromide hydrobromide. 36. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol diacetate 16βN-methobromide maleate. 37. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α-butyrate 17β-acetate 16βN-methobromide maleate. 38. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol diacetate 16βN-methobromide citrate. 39. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α-propionate 17β-acetate 16βN-methobromide citrate. 40. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol diacetate 16βN-methobromide phosphate. 41. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α pivalate 17β-acetate 16βN-methobromide phosphate. 42. The method of claim 2, wherein the acid addition salt is 2β,16β-dipiperidino-5α-androstane-3α,17β-diol 3α pivalate 17β-acetate 16βN-methobromide tartrate. 43. The method of claim 2, wherein said acid addition salt has the formula ##STR5## wherein: (a) R represents H or the moiety --OR2 ;(b) R1 and R2 each represent an unsubstituted acyl group derived from a lower aliphatic carboxylic acid of one to about six carbons; (c) ALK is an alkyl, alkenyl, or alkynyl group of one to about four carbon atoms; and (d) A.sup.⊖ and X.sup.⊖ each represents a pharmaceutically acceptable organic or inorganic anion. 44. The method of claim 43 wherein X.sup.⊖ and A.sup.⊖ are identical.