Claims for Patent: 4,179,507

Summary for Patent: 4,179,507

Title:	Quarternary ammonium compounds
Abstract:	Compounds of formula (I): ##STR1## wherein Z.sup.1 and Z.sup.2 are the same or different and each represents a methylenedioxy substituent, or up to three methoxy substituents; R.sup.2 and R.sup.3 are the same or different and each is alkyl having 1-3 carbon atoms, prop-2-enyl or prop-2-ynyl; R.sup.4 and R.sup.5 are the same or different and each is a benzyl or phenethyl group wherein the phenyl ring is optionally substituted by one or more of halogen, alkoxy having 1 to 3 carbon atoms and methylenedioxy; A and B are the same or different and each is an alkylene radical containing 1,2, or 3 carbon atoms; L is an alkylene chain having from 2 to 12 carbon atoms or is a group --L.sup.1.0.L.sup.2 -- wherein each of L.sup.1 and L.sup.2 is alkylene having at least two carbon atoms and taken together L.sup.1 and L.sup.2 having up to 11 carbon atoms; and X.sup.- is an anion; may be used to effect neuromuscular paralysis in mammals.
Inventor(s):	Stenlake; John B. (Glasgow, GB6), Waigh; Roger D. (Wilmslow, GB2), Dewar; George H. (Bath, GB2), Urwin; John (South Shields, GB2), Dhar; Nirmal C. (Glasgow, GB6)
Assignee:	Burroughs Wellcome Co. (Research Triangle Park, NC)
Application Number:	05/749,174
Patent Claims:	1. A compound of formula ##STR14## wherein Z.sup.1 and Z.sup.2 are the same or different and each represents a methylenedioxy substituent, or up to three methoxy substituents: R.sup.2 and R.sup.3 are the same or different and each is alkyl having 1-3 carbon atoms, prop-2-enyl or prop-2-ynyl; R.sup.4 and R.sup.5 are the same or different and each is a benzyl or phenethyl group wherein the phenyl ring is unsubstituted or is substituted by one or more of halogen, alkoxy having 1 to 3 carbon atoms and methylenedioxy; A and B are the same or different and each is an alkylene radical containing 1, 2 or 3 carbon atoms; L is an alkylene chain having from 2 to 12 carbon atoms or is a group--L.sup.1.0.L.sup.2 --wherein each of L.sup.1 and L.sup.2 is alkylene having at least two carbon atoms and taken together L.sup.1 and L.sup.2 have upto 11 carbon atoms; and X.sup.- is an anion. 2. A compound as claimed in claim 1 wherein each of A and B is--CH.sub.2.CH.sub.2 --, each of R.sup.2 and R.sup.3 is methyl, each of R.sup.4 and R.sup.5 is mono-, di- or tri- methyoxybenzyl, each of Z.sup.1 and Z.sup.2 is 6,7-dimethoxy and L is alkylene having 2 to 8 carbon atoms. 3. A compound as claimed in claim 1 which is N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropap averinium di-iodide. 4. A compound as claimed in claim 1 wherein L is straight pentylene. 5. A compound as claimed in claim 1 wherein each of R.sup.4 and R.sup.5 is 3,4-dimethoxybenzyl. 6. A compound as claimed in claim 1 wherein X.sup.- is a pharmaceutically acceptable anion. 7. A compound as claimed in claim 1 wherein the compound has a solubility in water at room temperature of 20mg/ml or more. 8. A compound as claimed in claim 1 wherein X.sup.- is chloride, bromide, iodide, sulphonate, methanesulphonate, benzenesulphonate, p-toluenesulphonate, nitrobenzenesulphonate, naphthalenesulphonate, or tartrate. 9. A compound as claimed in claim 1 wherein X.sup.- is the anion of an organic acid. 10. A compound as claimed in claim 1 wherein X.sup.- is benzenesulphonate, p-toluenesulphonate, naphthalene-1-sulphonate or naphthalene-2-sulphonate. 11. A compound as claimed in claim 1 which is a N,N'-dimethyl-N,N'-7-methyl-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetr ahydropapaverinium, N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-(1',2',3',4'-t etrahydro-6',7'-dimethoxy-1-[2-(3",4"-dimethoxyphenyl)ethyl]isoquinolinium) N,N'-dimethyl-N,N'-4,8-dioxa-3,9-dioxoundecylene-1,11-bis-tetrahydropapaver inium, N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis-[1',2',3',4'-tetrah ydro-6',7'-dimethoxy-1-(3",4",5"-trimethoxybenzyl)isoquinolinium], N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis[1',2',3',4'-tetrahy dro-6',7'-dimethoxy -1-(2-bromo-4",5"-dimethoxybenzyl)isoquinolinium, N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis[1',2',3',4'-tetrahy dro-6',7'-dimethoxy-1-(3",4"-methylenedioxybenzyl)isoquinolinium, N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis[1',2',3',4'-tetrahy dro-6',7'-dimethoxy-1-(3",4"-dichlorobenzyl)isoquinolinium, N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis[1',2',3',4'-tetrahy dro-6',7'-dimethoxy-1-(2",5"-dimethoxybenzyl)isoquinolinium], N,N'-dimethyl-N,N'-4,13-dioxa-3,14-dioxohexadecylene-1,16-bis-tetrahydropap averinium, N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis-(.+-.)-tetrahydropa paverinium, N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis-(.+-.)-tetrahydropa paverinium, N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis-[1',2',3',4'-tetrah ydro-1'-(3",4"-dimethoxybenzyl)-6',7'-methylenedioxyisoquinolinium], N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis[1',2',3',4'-te trahydro-1'-(3",4"-dimethoxybenzyl)-6',7'-methylenedioxyisoquinolinium], N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis(1',2',3',4'-tetrahy dro-6',7'-dimethoxy-1'-benzylisoquinolinium, N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10bis[1',2',3',4'-tetrahyd ro-6',7'-dimethoxy-1'-(4"-methoxybenzyl)isoquinolinium], N,N'-dimethyl-N,N'-4,7,10-trioxa-3,11-dioxotridecylene-1,13 -bis-tetrahydropapaverinium, meso-N,N'-dimethyl-N,N'-4,7-dioxa-3,8-dioxodecylene-1,10-bis-tetrahydropapa verinium, or N,N'-dimethyl-N,N'-5,9-dioxa-4,10-dioxotridecylene-1,13bis-tetrahydropapave rinium salt. 12. A compound as claimed in claim 1 which is a N,N'-dimethyl-N,N'-4,9-dioxa-3,10-dioxododecylene-1,12-bis-(.+-.)-tetrahydr opapaverinium, or N,N'-dimethyl-N,N'-4,12-dioxa-3,13-dioxopentadecylene-1,15-bis-tetrahydropa paverinium salt. 13. A compound as claimed in claim 1 which is a N,N'-dimethyl-N,N'-4,11-dioxa-3,12-dioxotetradecylene-1,14-bis-tetrahydropa paverinium salt. 14. A compound as claimed in claim 1 which is a N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropapa verinium, N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-bis-D-(-)-tetrahydropap averinium, o N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-L-(+)-tetrahyd ropapaverinium or meso N,N'-dimethyl-N,N'-4,10-dioxo-3,11-tridecylene-1,13-bis-tetrahydropapverin ium salt. 15. A compound as claimed in 1 wherein the compound is in the form of a substantially dry powder. 16. A pharmaceutical composition comprising a compound of formula (I) ##STR15## in amount sufficient to effect neuromuscular paralysis wherein Z.sup.1 and Z.sup.2 are the same or different and each represents a methylenedioxy substituent, or up to three methoxy substituents; R.sup.2 and R.sup.3 are the same or different and each is alkyl having 1-3 carbon atoms, prop-2-enyl or prop-2-ynyl; R.sup.4 and R.sup.5 are the same or different and each is a benzyl or phenethyl group wherein the phenyl ring is optionally substituted by one or more of halogen, alkoxy having 1 to 3 carbon atoms and methylenedioxy; A and B are the same or different and each is an alkylene radical containing 1, 2 or 3 carbon atoms; L is an alkylene chain having from 2 to 12 carbon atoms or is a group--L.sup.1.O.L.sup.2 --wherein each of L.sup.1 and L.sup.2 is alkylene having at least two carbon atoms and taken together L.sup.1 and L.sup.2 have upto 11 carbon atoms; and X.sup.- is a pharmaceutically acceptable anion; in association with a pharmaceutically acceptable carrier. 17. A composition as claimed in claim 16 wherein in formula (I) each of A and B is--CH.sub.2,CH.sub.2 --, each of R.sup.2 and R.sup.3 is methyl, each of R.sup.4 and R.sup.5 is mono-, di- or tri- methoxybenzyl, each of Z.sup.1 and Z.sup.2 is 6,7-dimethoxy and L is alkylene having 2 to 8 carbon atoms. 18. A composition as claimed in claim 16 wherein in formula (I) each of R.sup.4 and R.sup.5 is 3,4-dimethoxybenzyl and L is straight butylene or pentylene. 19. A composition as claimed in claim 16 wherein the compound is N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropap averinium dibesylate. 20. A composition as claimed in claim 16 wherein the compound is N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropap averinium di-iodide. 21. A composition as claimed in claim 16 in the form of an injectable solution. 22. A composition as claimed in claim 16 comprising from 5 to 50 mg of a compound of formula (I) per milliliter. 23. A composition as claimed in claim 16 in the form of a unit dose comprising from 40 to 60 mg of a compound of formula (I). 24. A method of inducing neuromuscular paralysis in a mammal comprising the systemic administration to said mammal of an effective neuromuscular paralysing amount of a compound of formula (I) ##STR16## wherein Z.sup.1 and Z.sup.2 are the same or different and each represents a methylenedioxy substituent, or up to three methoxy substituents; R.sup.2 and R.sup.3 are the same or different and each is alkyl having 1-3 carbon atoms, prop-2-enyl or prop-2-ynyl; R.sup.4 and R.sup.5 are the same or different and each is a benzyl or phenethyl group wherein the phenyl ring is optionally substituted by one or more of halogen, alkoxy having 1 to 3 carbon atoms and methylenedioxy; A and B are the same or different and each is an alkylene radical containing 1, 2 or 3 carbon atoms; L is an alkylene chain having from 2 to 12 carbon atoms or is a group--L.sup.1.O.L.sup.2 --wherein each of L.sup.1 and L.sup.2 has at least two carbon atoms and taken together L.sup.1 and L.sup.2 have up to eleven carbon atoms; and X.sup.- is a pharmaceutically acceptable anion; in association with a pharmaceutically acceptable carrier. 25. A method as claimed in claim 24 wherein in formula (I) each of A and B is--CH.sub.2.CH.sub.2 --, each of R.sup.2 and R.sup.3 is methyl, each of R.sup.4 and R.sup.5 is mono- , di- or tri- methoxybenzyl, each of Z.sup.1 and Z.sup.2 is 6,7-dimethoxy and L is alkylene having 2 to 8 carbon atoms. 26. A method as claimed in claim 24 wherein formula (I) each of R.sup.4 and R.sup.5 is 3,4-dimethoxybenzyl and L is straight butylene or pentylene. 27. A method as claimed in claim 24 wherein the compound is N,N'-dimethyl-N,N'-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropapaveri nium di-iodide. 28. A method as claimed in claim 24 wherein--the compound of formula (I) is a N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropap averinium salt. 29. A method as claimed in claim 24 wherein the mammal is man. 30. A method as claimed in claim 24 wherein intravenous, subcutaneous or intramuscular administration is employed. 31. A method as claimed in claim 24 wherein the compound of formula (I) is administered at a dose of from 0.1 to 4.0 mg per kg bodyweight of said mammal. 32. A method as claimed in claim 31 wherein the dose is from 0.25 to 1.0 mg/kg. 33. A compound of formula (III) ##STR17## wherein Z.sup.1 and Z.sup.2 are the same or different and each represents a methylenedioxy substituent, or up to three methoxy substituents; R.sup.4 and R.sup.5 are the same or different and each is a benzyl or phenethyl group wherein the phenyl ring is unsubstituted or substituted by one or more of halogen, alkoxy having 1 to 3 carbon atoms and methylenedioxy; A and B are the same or different and each is an alkylene radical containing 1, 2 or 3 carbon atoms; and L is an alkylene chain having 2 to 12 carbon atoms or is a group--L.sup.1.O.L.sup.2 --wherein each of L.sup.1 and L.sup.2 is alkylene having at least two carbon atoms and taken together L.sup.1 and L.sup.2 having up to 11 carbon atoms; or the corresponding dioxalate salt thereof. 34. A compound of formula (IX) wherein L is an alkylene chain having from 2 to 12 carbon atoms or is a group--L.sup.1.O.L.sup.2 --wherein each of L.sup.1 and L.sup.2 is alkylene having at least two carbon atoms and taken together L.sup.1 and L.sup.2 having up to 11 carbon atoms; G and G.sup.2 are the same or different and each is a group--C(J.sup.1).dbd.CHJ.sup.2 or a reactive ester derivative of the group--J.OH wherein J is alkylene having 1 to 3 carbon atoms, one of J.sup.1 and J.sup.2 is hydrogen and the other of J.sup.1 and J.sup.2 is hydrogen or methyl. or G is a group as defined above and G.sup.2 is a group ##STR18## wherein Z.sup.2 represents a methylenedioxy substituent, or up to three methoxy substituents; R.sup.5 is a benzyl or phenethyl group wherein the phenyl ring is unsubstituted or substituted by one or more of halogen, alkoxy having 1 to 3 carbon atoms and methylenedioxy; and B is an alkylene radical containing 1, 2 to 3 carbon atoms. 35. N,N'-Dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,1 3-bis-tetrahydropapaverinium dibesylate. 36. N,N'-Dimethyl-N,N'-4,10-dioxa-3,11-d ioxotridecylene-1,13-bis-tetrahydropapaverinium ditosylate. 37. N,N'-Dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,1 3-bis-tetrahydropapaverinium dinaph-1-sylate. 38. N,N'-Dimethyl-N,N'-4,10-dioxa-3,11-dioxot ridecylene-1,13-bis-tetrahydropapaverinium dinaph-2-sylate. 39. N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,1 3-bis-tetrahydropapaverinium dimesylate. 40. The composition of claim 16 in which the compound is N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropap averinium dimesylate. 41. The method of claim 24 in which the compound is N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropap averinium dimesylate. 42. Pharmaceutically acceptable salt of the N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropap averinium cation. 43. A method as claimed in claim 24 in which the compound is N,N'-dimethyl-N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropap averinium dibesylate.