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Claims for Patent: 4,297,351

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Claims for Patent: 4,297,351

Title: Method of manufacture and use of improved 2.beta., 16.beta.-piperidino androstanes
Abstract:New and pharmacologically useful pharmaceutically acceptable acid addition salts are disclosed for the 16.beta.-monoquaternary ammonium derivatives of either the 2.beta., 16.beta.-bis-piperdino-3.alpha., 17.beta.-dihydroxy-5.alpha.-androstane 3.alpha., 17.beta.-di-lower aliphatic esters or the 2.beta., 16.beta.-bis-piperidino-3.alpha.-hydroxy-5.alpha.-androstane-3.alpha.-lowe r aliphatic esters, which salts are surprisingly relatively stable in aqueous solutions, so that they provide stable aqueous injection preparations.
Inventor(s): Carlyle; Ian C. (Hamilton, GB6), Sleigh; Thomas (Wishaw, GB6), Savage; David S. (Glasgow, GB6)
Assignee: Akzona Incorporated (Asheville, NC)
Application Number:06/194,942
Patent Claims: 1. A method for the preparation of a pharmaceutically acceptable acid addition salt of the 16.beta.-mono-quaternary ammonium derivative of either a 3.alpha.,17.beta.-di-lower aliphatic ester of 2.beta.,16.beta.-dipiperidino-3.alpha.,17.beta.-dihydroxy-5.alpha.-androst ane or a 3.alpha.-lower aliphatic ester of 2.beta.,16.beta.-dipiperidino-3.alpha.-hydroxy-5.alpha.-androstane comprising

adding a pharmaceutically acceptable acid to the 16.beta.-mono-quaternary ammonium derivative of either a 3.alpha.,17.beta.-di-lower aliphatic ester of 2.beta.,16.beta.-dipiperidino-3.alpha.,17.beta.-dihydroxy-5.alpha.-androst ane or a 3.alpha.-lower aliphatic ester of 2.beta.,16.beta.-dipiperidino-3.alpha.-hydroxy-5.alpha.-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 comprises

using as said neuromuscular blocking agent an effective amount of a pharmaceutically acceptable acid addition salt of the 16.beta.-mono-quaternary ammonium derivative of either a 3.alpha.,17.alpha.-di-lower aliphatic ester of 2.beta.,16.beta.-dipiperidino-3.alpha.,17.beta.-dihydroxy-5.alpha.-androst ane or a 3.alpha.-lower aliphatic ester of 2.beta.,16.beta.-dipiperidino-3.alpha.-hydroxy-5.alpha.-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 --OR.sub.2 ;

(b) R.sub.1 and R.sub.2 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..crclbar. represents a pharmaceutically acceptable organic or inorganic anion.

5. The method of claim 4, wherein at least one of R.sub.1 and R.sub.2 is acetyl.

6. The method of claim 5, wherein A.sup..crclbar. 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 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide hydrochloride.

9. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha.-proprionate 17.beta.-acetate 16.beta.N-methobromide hydrochloride.

10. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.-ol 3.alpha.-acetate 16.beta.N-methobromide hydrochloride.

11. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.-ol 3.alpha.-acetate 16.beta.N-allylobromide hydrochloride.

12. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.-ol 3.alpha.-acetate 16.beta.N-propargylobromide hydrochloride.

13. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane 3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide hydrobromide.

14. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha.-butyrate 17.beta.-acetate 16.beta.N-methobromide hydrobromide.

15. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide maleate.

16. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol, 3.alpha.-butyrate 17.beta.-acetate 16.beta.N-methobromide maleate.

17. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide citrate.

18. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha.-propionate 17.beta.-acetate 16.beta.N-methobromide citrate.

19. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide phosphate.

20. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha. pivalate 17.beta.-acetate 16.beta.N-methobromide phosphate.

21. The method of claim 1, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha. pivalate 17.beta.-acetate 16.beta.N-methobromide tartrate.

22. The method of claim 1, wherein said acid addition salt has the formula: ##STR3## (a) R represents H or the moiety --OR.sub.2 ; (b) R.sub.1 and R.sub.2 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..crclbar. and X.sup..crclbar. each represents a pharmaceutically acceptable organic or inorganic anion.

23. The method of claim 22 wherein X.sup..crclbar. and A.sup..crclbar. 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 --OR.sub.2 ;

(b) R.sub.1 and R.sub.2 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..crclbar. represents a pharmaceutically acceptable organic or inorganic anion.

26. The method of claim 25, wherein at least one of R.sub.1 and R.sub.2 is acetyl.

27. The method of claim 26, wherein A.sup..crclbar. 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 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide hydrochloride.

30. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha.-proprionate 17.beta.-acetate 16.beta.N-methobromide hydrochloride.

31. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.-ol 3.alpha.-acetate 16.beta.N-methobromide hydrochloride.

32. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.-ol 3.alpha.-acetate 16.beta.N-allylobromide hydrochloride.

33. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.-ol 3.alpha.-acetate 16.beta.N-propargylobromide hydrochloride.

34. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane 3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide hydrobromide.

35. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha.-butyrate 17.beta.-acetate 16.beta.N-methobromide hydrobromide.

36. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide maleate.

37. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha.-butyrate 17.beta.-acetate 16.beta.N-methobromide maleate.

38. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide citrate.

39. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha.-propionate 17.beta.-acetate 16.beta.N-methobromide citrate.

40. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol diacetate 16.beta.N-methobromide phosphate.

41. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha. pivalate 17.beta.-acetate 16.beta.N-methobromide phosphate.

42. The method of claim 2, wherein the acid addition salt is 2.beta.,16.beta.-dipiperidino-5.alpha.-androstane-3.alpha.,17.beta.-diol 3.alpha. pivalate 17.beta.-acetate 16.beta.N-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 --OR.sub.2 ;

(b) R.sub.1 and R.sub.2 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..crclbar. and X.sup..crclbar. each represents a pharmaceutically acceptable organic or inorganic anion.

44. The method of claim 43 wherein X.sup..crclbar. and A.sup..crclbar. are identical.
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