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Claims for Patent: 4,179,507

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Claims 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.
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