IL33986A - Substituted thiazolium salts,their preparation and pharmaceutical compositions containing them - Google Patents

Description

Substituted thiazolium their preparation and pharmaceutical containing TEE FOUNDATION LIMITED 2 This invention relates to quaternary ammonium orally ingestible their synthesis compositions containing and their use as therapeutic The present invention provides compounds of formula phenyl group wherein R is alkyl or is a substituted by one groups selected from halogen fluorine and alkyl having 1 to 4 carbon and alkoxy having 1 to 4 carbon Z is or and is the anion of a pharmaceutically acceptable The compounds of formula have been found active against parasitic especially although the compounds also have activity against other nematodes such as Thus they have been found active against Syphacia in a screening organism for the human vermicularis both organisms having similar they have activity against Aspiculuris tetraptera in Most the compounds have high doses together with their good low gives them a high therapeutic The compounds in which Z is biphenylyl are particularly Other preferred compounds are those in which Z is the alkoxy having 1 to 6 carbon that is to When R is an alkyl it has to 6 carbon that is methyl to When R is a such as halogen fluorine and alk having 1 to 4 carbon atoms to or alkoxy having 1 to 4 carbon atoms to When Z is the alkoxy has 1 to 6 carbon atoms to Examples of particularly valuable compounds of formula thiazole thiazole vinyl thiazole vinyl thiazole vinyl thiazole thiazole thiazole thiazole 2 thiazole thiazole 2 vinyl thiazole vinyl thiazole thiazole vinyl and vinyl methiodide Unless otherwise references in the tion and claims to pyrrylvinylthiazolium salts of formula mean salts of a pharmaceutically acceptable The compounds of formula may be made by any method known for preparing compounds of an analogous chemical they may be prepared by the reaction of a thiazolium compound of the formula with an aldehyde of the formula wherein R and X are as defined The reaction is preferably carried out in the presence of a basic catalyst such as but other bases of comparable or greater basic strength may be for amines or an alkali metal hydroxide or an The reaction is conveniently carried out in the in which the reactants may be dissolved or suspended in a finely divided The liquid medium for the reaction is preferably a lower alcohol containing such as methanol or or may be some other polar medium not reactive to the reactants such as dimethyl sulphoxide or The reaction is preferably conducted at a temperature from to the boiling point of the action mixture The intermediate 2 salts of formula may be prepared by the following sequence of the last step providing for the quaternisation of the of formula by a methyl derivative H2NC where the symbol Z has the meanings given and A is a nucleophilic group or for bromine or or a or The compounds of formula may also be prepared by the reaction of a phenacyl derivative of formula with a of formula wherein and A are as defined This reaction proceeds via an intermediate of formula wherein Z and R are as defined and this thioimidate if may be isolated and then converted to a compound of formula as described The compounds of formula are formed by the reaction of the phenacyl derivative of formula and the thioamide of formula under conditions which convert the thioimidate mediate to a compound of formula In heating the or reacting them in the presence of an will tend to form the compounds of formula A temperature O of to 150 C is conveniently employed to effect a rapid conversion to the compounds of formula The acid may be a mineral acid such as hydrochloric or hydrobromic acid and preferably corresponds to the nucleophilic group or atom A which provides the anion X of formula The reaction is preferably performed in the presence of a polar liquid for a lower alkanol such as ethanol or or a The optimum reaction conditions for forming the compounds of formula vary according to the nature of the thioimidate the group A and the liquid medium The thioimidates of formula and their acid addition salts may themselves be converted to the compounds of formula by treatment with an preferably a mineral for hydrochloric or hydrobromic which should preferably correspond to the thioimidate if and to the desired thiazolium salt of formula The acid addition salts of the thioimidates of formula may also be converted to the compounds of formula by heating the preferably the hydrochloric or acid addition The reaction is preferably conducted in a polar liquid for a lower such as butanol conveniently at a temperature of The activity against nematodes of the compounds of formula resides in the and the nature of the anion X is unimportant providing that the salt is ceutically Examples of suitable salts are the sulphates and alkyl The methosulphate and salts are preferred since they can be conveniently introduced in the quaternisation step by the use of methyl sulphate and methyl The bromide salts may be preapred by the use of methyl Other salts may be prepared by conventional for by replacing the anion by double decomposition of either the 2 salt or the For the chloride salts may be prepared from the iodide salts by shaking the latter with silver chloride in alkanolic and the chloride and bromide salts may be converted to the iodide salts by reaction with potassium iodide either before or after their isolation from the reaction For the treatment of nematode infections in the compounds of formula are by oral pharmaceutical compositions comprising the compounds and an acceptable carrier For administration of the compounds of formula in dry solid they may be presented as capsules or in a gelatin containing the desired amount of the compound distributed in such carriers as are usually The compositions are prepared in general by intimately and uniformly mixing the active ingredient with the carrier which may comprise one or more disintegrating agents and Boluses and tablets may be compounded by technique well known in the for by compression on a tabletting The tablets may be formed so as to disintegrate or to provide a prolonged or delayed or to provide a predetermined release of the active ingredient at successive The tablets also may be Capsules are readily prepared by combining the active ingredient with any desired excipient and filling into the The compounds of formula may also be administered in a liquid preparation or as a component of the feed of the Liquid preparations may comprise a suspension or solution of the active ingredient in water or in a vegetable or mineral oil or an emulsion The liquid carrier itself may consist of one or more for liquid bacteriostats sweeteners colouring dispersing suspending agents and emulsifiers The normal unit dose range for the compounds of formula is from 5 to 100 body weight of the animal being The preferred unit dose range is 5 to 25 ether and there was obtained thiazole After purification by digesting with hot this compound had a melting point of To a mixture of thiazole methiode and in methanol was added piperidine The reaction mixture was heated on a steam bath for 3 An orange condensation product was formed within a few The longer heating period was employed because of the relative insolubility of both the starting compound and the in order to ensure nearly complete transformation of this insoluble reactant into the insoluble After filtration and washing with methanol and thiazole methiodide was After further digestions with hot methanol an orange product melting at was was prepared as Aniline acetonylacetone and glacial acetic acid were mixed and heated for a half to one hour on a steam Upon cooling white crystals formed which were recrystallised from ethanol to give 2 to 33 melting at 51 to To chilled in an ice phosphorus oxychloride was gradually To this cooled 2 phenylpyrrole was added carefully and the action mixture was removed from the ice bath and was heated for 2 hours at The mixture was then poured on to one hundred to two hundred grams of The aqueous ice mixture was basified to ph 11 with aqueous sodium hydroxide and gave white crystals of the aldehyde This was collected and recrystallised from ethanol giving 18 grams yield of purified melting point Example 2 By the method of Example 1 the following compounds were thiazole methiodide thiazole methiodide thiazole methiodide methiodide methiodide thiazole methiodide thiazole methiodide vinyl thiazole methiodide r 2 thiazole methiodide 2 thiazole methiodide 2 vinyl 2 vinyl thiazole methiodide biphenylylthiazole methiodide vinyl thiazole methiodide methiodide vinyl methiodide methiodide Example 3 bromide A solution of chloroacetmethyla ide and and triphenylphosphine in benzene was heated in a bath at for 24 The solid was collected and washed with This triphenylphosphonium chloride had To a stirred solution of this phosphonium salt and 2 g in methanol was added slowly a solution of sodium methoxide prepared by dissolving sodium in methanol The mixture was stirred for a further 1 hour at room water was added and most of the methanol was The residual mixture was extracted with and the ether extract was washed with dried allowed to The resulting acrylomethylamide formed colourless prisms of a hydrate which on drying gave the anhydrous The foregoing amide was dissolved in pyridine phosphorus pentasulphide was added and the mixture was refluxed with mechanical stirring for 30 The mixture was poured into water and the insoluble oil was extracted with and the extract was dried and The residue was purified by chromatography on alumina in chloroform solution to give as a yellow glassy material A solution of the thioamide and bromide in acetone was refluxed for 2 The bright yellow solid which had come out of solution was This acrylothioimidate hydrobromide had unchanged by recrystallisation from The above thioimidate hydrobromide was heated on the with hydrobromic acid of for 25 The cooled mixture was diluted with water and neutralised by addition of sodium hydroxide solid was collected and recrystallised from ethanol to give light brown of 2 vinyl thiazolium Treatment of a methanolic solution of the bromide with aqueous potassium iodide gave the corresponding Example 4 2 bromophenylthiazollum From 2 and carbamoylmethyltriphenylphosphonium chloride under the conditions described in Example was prepared acrylomethylamide which crystallised from methanol in colourless By treatment with phosphorus pentasulphide in pyridine solution as described in Example the amide was converted to 2 acrylothiomethylamide crystallising from methanol in bright yellow A solution of this thioamide and phenacyl bromide in acetone was boiled under The yellow solid which soon came out of solution was collected after 1 and recrystallised from methanol to give deep yellow of acrylothioimidate hydrobromide This thioimidate hydrobromide in methanol and hydrobromic acid of was boiled for 15 On the solution deposited deep yellow prisms of 2 vinyl l thiazolium The corresponding prepared from the bromide using potassium iodide had A solution of 2 thiomethylamide and bromide in ethanol containing hydrobromic acid of was refluxed for The dark solution was methanol to give deep yellow of bro ophenyl thiazolium Example 5 thiazolium iodide Phosphorus oxvchloride was added to formamide with external ice 37 was then added gradually over to minutes to the which was then allowed to warm o up to room temperature and was finally heated at 100 for 2 After the mixture was poured onto ice 300 and basified to pH 11 with aqueous sodium The product separated as solid which was recrystallized from The above aldehyde thiazole methiodide methanol and piperidine were heated on a steam bath for 2 An insoluble product was formed and was collected by filtration from the cooled after recrystallization from Analysis for Calculated Found Example By a process similar to that used thiazole methiodide and gave after Analysis for Calculated Found Similarly from methiodide was obtained thiazolium after recrystallization from Analysis for Calculated Found 15a Example 7 and 2 to 3 of acetic acid were mixed and heated for 2 at Upon cooling the reaction mixture After two recrystallizations from methanol 37 of crystals were obtained melting at Phosphorus oxychloride 16 was added gradually over 5 minutes with ice cooling to dimethylformamide While still cooling dimethylpyrrole was added and the mixture was heated for 2 at The reaction mixture was of ice water was added and the solution was made basic pH with aqueous sodium hydroxide The precipitated as a grey white This was collected by washed with much cold and after recrystallization methyl alcohol gave the purified product which melted at 15b A mixture of thiazole methiodide carboxaldehyde methanol and piperidine was heated for 2 at After cooling the orange condensation product was collected by and washed first with then with Further digestion of the product with hot methanol followed by and washing with methanol and ether gave the orange product melting at Example 8 iodide A mixture containing methiodide carboxaldehyde methanol and piperidine was heated for 2 at Concentration of the methanol solution and cooling gave the yellow After recrystallization from a mixture the pure product was obtained and melted at In a similar fashion to the foregoing Examples there was successively prepared and o carboxaldehyde From this aldehyde there was then prepared by the method of the foregoing Examples thiazolium 15c Example 5 A tablet was made from the following ingredients methiodide as the 250 Lactose 100 Starch 50 Gelatin 8 Magnesium Stearate 5 Ingredients and half of were admixed and granulated with a solution of in aqueous The remainder of and the magnesium stearate were added to the dried granules and the mixture compressed to form Example 6 A paediatric suspension containing vinyl methiodide equivalent to 50 base in each 5 was prepared from the following ingredients methiodide equivalent to 50 Compound Tragacanth Powder Syrup Glycerin Methyl Hydroxybenzoate Purified water to A paste was prepared of and using and Ingredient was dissolved in the greater part of using and the solution used to dilute the paste previously The volume of the resultant suspension was adjusted using the rest of the purified insufficientOCRQuality

Claims (51)

I* - 17 - 33986/2 CLAIMS '

1. A pyrrylvinylthiazolium salt of the formula wherein R is alkyl having 1 to 6 carbon atoms or is a. phenyl group -optionally substituted by one or more groups selected from halogen (chlorine, bromine, fluorine and iodine), alkyl having 1 to 4 carbon ., atoms, and alkoxy having 1 to 4 carbon atoms; Z is phenyl, .ρ,-halophenyl p_-alkoxyphenyl wherein the alkoxy has 1 to 6 carbon atoms , biphenylyl,. p_-alkoxybiphenylyl wherein the alkoxy has 1 to 6 carbon atoms, or naphthyl; and X is the anion of a pharmaceutically acceptable acid.

2. A compound as claimed in claim 1 wherein Z is phenyl, p_-halophenyl or £-alkoxyphenyl wherein the alkoxy has 1 to 6 carbon atoms, R is a phenyl group or .is an alkyl group, having 1 to 6 carbon atoms , and X is a pharmaceutically acceptable anion of an acid.

3. A compound as claimed in claim 1 wherein Z is biphenylyl or p_-alkoxy biphenylyl wherein the alkoxy has 1 to 6 carbon atoms, R is a phenyl group or is ari alkyl group having 1 to 6 carbon atoms , and X is a pharmaceutically acceptable anion of an acid. . . 4

4. A compound as -claimed in claim 1 wherein Z is naphthyl, I R is a phenyl group or is an alkyl group having 1 to 6 carbon atoms, and X is a pharmaceutically acceptable anion of an acid.

5. A compound as claimed in claim 1 wherein R is a phenyl B 216 "A"

6. A compound as claimed in claim 1 wherein X is the anion of a hydrogen halide acid.

7. A compound as claimed in claim 1 wherein X is the methosulphate anion or the p_-toluenesulphonate anion.

8. A salt of the 2-{ β- (l-n-butyl-2 , 5-dimethyl-3-pyrryl) vinyl} -3-methyl-4- (p_-bromophenyl) thiazole cation.

9. A salt of the 2-{ 3- (l-n-butyl-2 ,5-dimethyl-3-pyrryl) vinyl}-3-methyl-4- (p_-methoxypheny1) thiazole cation

10. A salt of the 2-{ 3- (l-n-butyl-2 , 5-dimethyl-3-pyrryl) Vinyl} -3-methyl-4- (p_-chlorophenyl) thiazole cation.

11. A salt of the 2-{ β- (l-n-butyl-2 , 5-dimethyl-3-pyrryl) vinyl} -3-methyl-4-phenylthiazole cation.

12. A salt of the 2-{ 3- (l-n-amyl-2 , 5-dimethy1-3-pyrryl) vinyl} -3-methyl-4-phenylthiazole cation .

13. A salt of the 2-{ 3- (l-n-amyl-2 , 5-dimethyl-3-pyrryl ) vinyl} 3-methyl-4- (£-chlorophenyl) thiazole cation.

14. A salt of the 2-{ 3- (l-phenyl-2 , 5-dimethyl-3-pyrryl) vinyl}-3-methyl-4- (£-bromophenyl) thiazole cation.

15. A salt of the 2-{ β- (l-n-amyl-2 ,5-dimethyl-3-pyrryl) vinyl}-3-methyl-4- (p_-bromophenyl ) thiazole cation.

16. A salt of the 2- { 3- (1 , 2 , 5-trimethyl-3-pyrryl) vinyl}-3-methy1-4- (£-bromophenyl) thiazole cation. .

17. A salt of the 2-{β- (1 , 2 , 5-trimethyl-3-pyrryl) vinyl}-3-methyl-4- (£-chlorophenyl) thiazole cation.

18. A salt of the 2- { - (1 , 2 , 5-trimethyl-3-pyrryl) vinyl }-3-methy1-4-3-naphthylthiazole cation.

19. A salt of the 2-{ 3- (1 , 2 , 5-trimethyl-3-pyrryl) vinyl}-3-methyl-4-£-biphen^¾ylthiazole cation .

20. A salt of the 2-{ 3- (l-£-chlorophenyl-2 ,5- dimethyl-3-pyrryl) vinyl }-3-methyl-4-£-biphenylylthiazole cation . B 2.16 "A"

21. A salt of the 2-{ 3- (l-phenyl-2 , 5-dimethyl-3-pyrryl) vinyl }-3-methyl-4-p_-biphenylylthiazole cation .

22. A salt of the 2-{ g- (l-ethyl-2 , 5-dimethyl-3-pyrryl) vinyl}-3-methyl-4-p_-biphenylylthiazole cation .

23. A salt of the 2-{ g- (l-phenyl-2 , 5-dimethyl-3-pyrryl) vinyl } -3-methy1-4-phenylthiazole cation .

24. A salt of the 2-{ g- (l-ethyl-2 , 5-dimethyl-3-pyrryl ) vinyl } -3-methy1-4-phenylthiazole cation .

25. A salt of the 2- { g- (1 , 2 , 5-trimethyl-3-pyrryl) vinyl } -3-methyl-4-phenylthiazole cation.

26. The halide salt of a thiazolium cation claimed in any of claims 8 to 25.

27. The iodide salt of a thiazolium cation claimed in any of claims 8 to 25,

28. The bromide salt of a thiazolium cation claimed in any of claims 8 to 25.

29. A method of preparing a pyrrylvinylthiazolium salt claimed in any of claims 1 to 28 comprising the reaction of a thiazolium compound of the formula wherein R, Z and X are defined in any of claims 1 to 28, an< the optional conversion of the salt into the salt of another acid. B 216 "A

30. A method as claimed in claim 29 wherein the reaction is effected in the presence of a basic catalyst.

31. A method as claimed in claim 30 wherein the basic catalyst is piperidine.

32. A method as claimed in claim 30 wherein the basic catalyst is pyrrolidine or N-methylpyrrolidine .

33. A method as claimed in claim 30 wherein the basic catalyst is an alkoxide or an alkali metal hydroxide.

34. A method as claimed in any of claims 29 to 33 wherein the reaction is effected in the presence of a polar liquid medium.

35. A method as claimed in claim 34 wherein the polar liquid medium is a lower alcohol such as methanol or ethanol

36. A method as claimed in claim 34 wherein the polar liquid medium is dimethyl sulphoxide or sulfolane.

37. A method as claimed in any of claims 29 to 36 wherein the reaction is effected at the reflux temperature of the reaction mixture.

38. A method as claimed in claim 29 wherein a 2 , 3-dimethyl-4-p_-biphenylylthiazolium salt is reacted with l-phenyl-2 , 5-dimethylpyrrole-3-carboxaldehyde in methanol in the presence of piperidine.

39. A method of preparing a pyrrylvinylthiazolium salt claimed in any of claims 1 to 28 comprising the ring closure of a thioimidate of formula R B 216 "A" or an acid addition salt thereof wherein Z and R are defined in any of claims 1 to 28, and the optional conversion of the salt into the salt of another acid.

40. A method as claimed in claim 39 wherein the thioimidate is formed in situ by the reaction between a thioamide of formula CH- - HN and a phenacyl derivative of formula Z - C0.CH2A wherein R and Z are defined in any of claims 1 to 28 and A is a nucleophilic group or atom.

41. A method as claimed in claim 40 wherein the nucleophilic group or atom A corresponds to the anion X of the desired pyrrylvinylthiazolium salt.

42. A method as claimed in claim 41 wherein A is an atom of chlorine, bromine or iodine, or is the methosulphate or the £-toluenesulphonate group.

43. A method as claimed in claim 39 wherein the thioimidate is present as its hydrogen chloride or hydrogen bromide acid addition salt.

44. A method as claimed in any of claims 39 to 43 wherein the reaction is conducted at a temperature of from 80° to 150°C.

45. A method as claimed in any of claims 39 to 44 wherein the reaction. is conducted in the presence of an acid.

46. A method as claimed in claim 45 wherein the acid is a mineral acid.

47. A method as claimed in claim 45 wherein the acid corresponds to the anion X of the desired pyrrylvinylthiazolium B 216 "A" *

48. A method as claimed in claim 46 wherein the acid is hydrochloric or hydrobromic acid.

49. A method as claimed in any of claims 39 to 48 wherein the reaction is conducted in the presence of a polar liquid medium.

50. A method as claimed in claim 49 wherein the polar liquid medium is a lower alcohol such as ethanol or butanol.

51. A method as claimed in claim 39 wherein the ring closure is effected of p_-phenylphenacyl- -methyl-3- (2 , 5-dimethyl-l-phenylpyrrol-3-yl) acrylothioimidate or of an acid addition salt thereof.

52. A pyrrylvinylthiazolium salt as defined in any of claims 1 to 28 when prepared by a method claimed in any of claims 29 to 51. MJC/RM/17.2.70 - 23 - 33986/ 5 - A*1 orally ingestible pharmaceutical composition comprising a pyrrylvinylthiazolium salt as claimed in any of Claims 1 to 28 in association with an acceptable carrier therefor.

54. A compositio as claimed in Claim 53 characterized in that the acceptable carrier is a solid.

55. A composition as claimed in Claim 53 characterized in that the acceptable carrier is a liquid.

56. A composition as claimed in any of Claims 53 to 55 in unit dose form.

57. - . ' tablet suitable for oral- administration comprising a pyrrylvinylthiazolium salt as claimed in any of Claims 1 to 28 and an acceptable carrier therefor.

58. ; A capsule suitable for Oral administration comprising a pyrrylvinylthiazolium salt as claimed in any of Claims 1 to 28 and an acceptable carrier therefor.

59. A suspension in a liquid carrier suitable for oral administration, of a pyrrylvinylthiazolium salt as claimed in any of Claims 1 to 28» 1 ·:: '■ ·■ .

60. A composition as claimed in any of Claims 53 to 59 characterised in th t the pyrrylvinylthiazolium salt is a 2-[ -(l-phen l-2, 5-«iiiaethyl-3-pyrryl)vinyl|«.3-methyl-4-£-bighenylylthiazolium salt.

61. A composition as claimed in Claim 60 characterised in that the pyrrylvinylthiazolium sal is a halide salt.

64. An orally ingestible pharmaceutical composition comprising a pyrrylvinylthiazolium salt as claimed in any of Claims 1 to 28 and an acceptable carrier therefor substantially as hereinbefore described with particular reference to Examples 5 and 6. 65· A nefchod of preparing an orally ingestible pharmaceutical composition comprising a pyrrylvinylthiazolium salt as claimed in any of Claims 1 to 28 and an acceptable carrier therefor substantially as hereinbefore described with particular reference to Examples 5 and 6.

66. method for the treatment of a nematode infection in a warm-blooded animal other tha man comprising the oral administration to the animal of a compound claimed in any of Claims 1 to 28. 3?e/rb