IL40050A

IL40050A - Compositions for treating microbial infections containing piperidine derivatives

Info

Publication number: IL40050A
Application number: IL40050A
Authority: IL
Original assignee: Wellcome Found
Priority date: 1971-08-05
Filing date: 1972-08-04
Publication date: 1976-02-29
Also published as: JPS6036409B2; NO139004C; CS172956B2; IE36867B1; FR2150733A1; JPS4828610A; IE36867L; HU170534B; GB1405246A; NO139004B; LU65857A1; NL7210719A; IT1057861B; FR2150733B1; BE787236A; IL40050A0; DE2238536C2; SE434337B; DE2238536A1

Claims

CLAIMS 1. A composition for testing or treating microbial systems or infections, comprising an effective potentiating amount of a potentiator which is a pteridine antagonist, determined as hereinbefore def-ined-j- which—itself inhibits the-enzyme hydroxymethyldihydropteridine pyrophosphokinase and has a sufficiently low toxicity to the mammalian and avian host, in combination with an effective amount of a competitor of jj-aminobenzoic acid or inhibitor of dihydrofolate reductase, or both, as hereinbefore defined.
2. A composition as claimed in Claim 1, in which the potentiator is a 2-amino-4-hydroxy-7 ,8-dihydropteridine compound. 3. composition as claimed in Claim 2, in which the pteridine compound is substituted on the 6th position through a carbon atom and is bisubstituted at the 7th position. 4. A composition as claimed in any one of the preceding claims, which comprises a compound of formula (I), or tautomeric forms thereof, or pharmaceutically acceptable salts thereof, 0 wherein R is an alkyl group, optionally substituted with a hydroxy group, with one or more halogen atoms or with an optionally substituted phenoxy group, and B?- and R^ are the same or different and each is an alkyl group or R^ and R^ together form a spirocycloalkyl ring system having 4 to 6 - 51 - 40050/2 carbon atoms outside the pteridine ring structure. 5. A composition as claimed in Claim 4, which comprises a compound of formula (I), wherein R is an alkyl or a hydroxy- alkyl group. 6. A composition as claimed in Claim 5» wherein the alkyl group is a methyl group. 7. A composition as claimed '.in Claim 4, which comprises a compound of formula (I), wherein R is a phenoxyalkyl group. 8. A composition as claimed in Claim 7, wherein the phenoxyalkyl group is a phenoxymethyl group. 9. A composition as claimed in either of Claims 7 and 8, which comprises a compound of formula (I), wherein the phenoxy group is substituted with one or more alkoxy, amino, alkyl or hydroxy groups or halogen atoms. 10. A composition as claimed in Claim 9, wherein the phenoxy group is mono- or dihalogeno substituted. 11. A composition as claimed in either of Claims 9 and 10, wherein the phenoxy group is substituted in the para position. 12. A composition as claimed in Claim 4, which comprises a compound of formula (I), wherein 3. is an alkyl group substituted with one or more halogen atoms. 13· A composition as claimed in Claim 12, wherein the alkyl ■ group is mono- or dihalogeno substituted. 4. A composition as claimed in any one of Claims 9 to 1J, wherein the halogen atoms are bromine atoms. 15· .A composition as claimed in any one of Claims 4 to 14, in 1 2 which H and H are both methyl groups. 16. composition as claimed in- any one of- Claims 4 to 14, in 1 -2 ■wnic xi and a are both ethyl groups. - - 40050/2 17· --- composition as claimed in . any o e ol' Claims \;o 14, ^ in which I?1 an H24" together form a spi ·οc c3.oalkvl group having to 6 -carbon atoms outside the pteridine ring sys eia. 18. · composition as claimed in Claim 4, in which · the compound cf formula (I) is 2-ainino--4- yGro:Q'-6-hydro:-:yLneth l- .7-dime hy1-7, c-dihydrop sridine . 19· A composition as claimed in Claim 4, in which the compound cf formula l) is -amino-4-l¾'dro:^-6-i.iethyl-7 , 7-aisethyl- , 8- dihycroptcridine .. 20. A composition as claimed in Claim 4, in which the' compound of formula (I) is 2-aminc\-4-hydroxy-6-bromomethyl-7, 7-dimethyl- 7.8-dihydropteridine . 21. A composition as claimed in Claim 4, in which the compound of formula (I) is 2-amino-^-¾i-droi-y-6-dibromomethyl-7 , -dimethyl 7, 8-dih dropteridine . 22. . A composition as claimed in Claim '4, in which the compound of formula (1) is 2-amino-4-hydroxy-6-hydroxymethyl-7 , 7-diethyl-7 , 8-dihydropteridine . 25. A composition as claimed in Claim 4, in which the compound of formula (I) is 2-amino-4-hydroxy-6-hydror^met! l-7-spiro-cyclohexyl-7,3-dihydropteridine . 24. A composition as claimed in any one of the preceding claims, comprising about 1 to 30 parts of each of the potentiator and the competitor, preferably 5 to 15 parts, or equivalent ■ amounts of salts thereof. 25. composition as claimed in any one of Claims 1 to 23, comprising about 1 to 30 parts of the potentiator, preferably 5 to 15 parts, and 1 part of the' inhibitor, or equivalent amounts cf salts thereof. 40050/2 26. A composition as claimed in Claim 24» comprising an effective potentiating amount of the potentiator which is a pterldine antagonist determined as hereinbefore defined, in combination with an effective amount of js-aminobenzoic acid or an inhibitor of dihydrofolate reductase, or both, as hereinbefore defined, comprising about 1 to JO parts of each of the potentiator and the competitor, preferably 5 to 15 parts, and one part of the inhibitor, or equivalent amounts of salts thereof. 27. A composition as claimed in any one of Claims 24 to 26 , in unit dosage form, comprising up to 750 mg, preferably about 200 mg, of the potentiator, 28· A composition as claimed in any one of Claims 24 to 26 and 27, in unit dosage form, comprising up to 15 mg, preferably about 200 mg, of the competitor. 29. A composition as claimed in any one of Claims 25 to 28, in unit dosage form, comprising up to 25 mg of the inhibitor. 30. A pharmaceutical formulation containin a composition as claimed in any one of the precedinggclaims, in combination with a pharmaceutically acceptable carrier. 31. A pharmaceutical formulation as claimed in Claim 0 in the liquid form, for use in the inhibition of the production of dihydrofolic acid by microorganisms, under in vifrrp or in, vivo conditions. 32. A pharmaceutical formulation as claimed in either of Claims 30 and 31 for external use, comprising 1 to 30 mg/ml of each of the potentiator and the competitor in a pharmaceutically acceptable solvent. 33· A pharmaceutical formulation as claimed in either of Claims 30 and 31 for external use, comprising 1 to 30 mg/ml of the 40050/2 34. pharmaceutical formulation as claimed in any one of Claims 30 to 33 for external use, comprising 1 to 30 mg/ml ( of each of the potentiator and the competitor and 0.03 to 1 mg/ml of the inhibitor in a pharmaceutically acceptable solvent. 35. An in vitro testing disc incorporating a pharmaceutical formulation as claimed in either of Claims 30 or 31, comprising about 10 to 100 yig/ml of the potentiator, 5 to 50 ug/ml of the competitor and 0.5 to 5 ^g/ml of the inhibitor in combination with a carrier. 36. A testing disc as claimed in Claim 35, wherein the carrier is a medium comprising a mixture of a aqueous infusion and papain digest of horse muscle. 37. pharmaceutical formulation as claimed in any one of Claims 30 to 34 presented in the form of a kit or separately packaged potentiator, inhibitor or competitor, with instructions to use them together in combination for the purpose of medical or vetinary treatment. 38. A pharmaceutical formulation for the testing or treatment of coccidial systems and infections, comprising an effective potentiating amount of potentiator as hereinbefore defined, in combination with a effective amount of a competitor or inhibitor, or both, as hereinbefore defined. 39., A pharmaceutical formulation as claimed in Claim 38, wherein the competitor is sulphaquinoxaline and the inhibitor is dia- veridine. 40. A pharmaceutical formulation as claimed in either of Claims 38 and 39, wherein the potentiator is 2-amino-4-hydroxy-6-hydro- xymeth l-7,7-dimethyl-7,8-dihydropteridine. 41. A pharmaceutical formulation as claimed in any one of Claims 38 to 40, comprising about 0.003 to 0.01 w/w of potentiator and about 0.001 to 0.006 w/w of sulpha uinoxaline. 40050/2 about 0.001 to 0.006$ w/w of diaveridine. 43. A pharmaceutical formulation as claimed in any one of Clai^ 38 to 42, comprising about 0.0005 to 0.025$ w/w of potentiator, preferably 0.001 to 0.009 w/w, and about 0.001 to 0.01 w/w of each of sulphaquinoxaline and diaveridine, preferably 0.0015 to 0.006 w/w. 44. A pharmaceutical formulation as claimed in any one of Claims 36, 39 and 43» in which the ooncentration ratio of sulphaquinoxaline to diaveridine is from 1:1 to 4:1. 45· A method of making a composition or pharmaceutical formul-l-!r >ont aa defined in any one f the preceding claims, in which the-*' effective amounts of the appropriate components are admixed and ' presented in a combined form. 46. A method of treating and preventing microbial infections, in animals, comprising the administration to the non-human host of a composition or pharmaceutical formulation, aa defined in any one of Claims 1 to 44. 47· A method as claimed in Claim 46, in which up to about 60 mg/kg of each of the potentiator and competitor are administered to the non-human host daily in several doses. 43. A method as claimed in Claim 46, in which up to about 60 mg/kg of the potentiator and up to about 7. mg/kg of the inhibitor are administered to the non-human host daily in several doses. 49· A method as claimed in any one of Claims 46 to 48, in which up to about 60 mg/kg of each of the potentiator and the competitor and up to about 7.5 mg/kg of the inhibitor are administered to the non-human host daily in several doses. - 56 - 40050/2 50. A method of inhibiting the production of dihydrofolic acid by microorganisms, which comprises contacting the microorganism with a composition or pharmaceutical formulation, as defined in any one of Claims 1 to 44· For the A^ica ts