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Details for Patent: 5,856,321

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Details for Patent: 5,856,321

Title: Antibiotic compounds
Abstract:The present invention relates to carbapenems and provides a compound of the formula (I): ##STR1## or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl; R.sup.2 is hydrogen or C.sub.1-4 alkyl; R.sup.3 is hydrogen or C.sub.1-4 alkyl; R.sup.4 and R.sup.5 are the same or different and are selected from hydrogen, halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, C.sub.1-4 alkylaminosulphonyl, di-C.sub.1-4 -alkylaminosulphonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N--C.sub.1-4 alkyl)amino, C.sub.1-4 alkanesulphonamido and C.sub.1-4 alkylS(O).sub.n -- wherein n is zero, one or two: with the proviso that there is no hydroxy or carboxy substituent in a position ortho to the link to --NR.sup.3 --. Processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them.
Inventor(s): Betts; Michael John (Wilmslow, GB2), Davies; Gareth Morse (Macclesfield, GB2), Swain; Michael Lingard (Stockport, GB2)
Assignee: Zeneca Limited (London, GB)
Filing Date:Apr 03, 1997
Application Number:08/833,056
Claims:1. A process for preparing a compound of the formula (I) ##STR17## or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:

R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;

R.sup.2 is hydrogen or C.sub.1-4 alkyl;

R.sup.3 is hydrogen or C.sub.1-4 alkyl;

R.sup.4 and R.sup.5 are the same or different and are selected from hydrogen, halo, cyano, C.sub.14 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, C.sub.1-4 alkylaminosulphonyl, di-C.sub.1-4 -alkylaminosulphonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N--C.sub.1-4 alkyl)amino, C.sub.1-4 alkanesulphonamido and --S(O).sub.n C.sub.1-4 alkyl and wherein n is zero, one or two;

with the proviso that there is no hydroxy or carboxy substituent in a position ortho to the link to --NR.sup.3 -- which process comprises:

reacting a compound of formula (VI) with a compound of formula (VII): ##STR18## wherein R.sup.2, R.sup.4, and R.sup.5 are as defined above, R.sup.4 and R.sup.5 optionally being protected --COOR.sup.6 and --COOR.sup.7 are carboxy or protected carboxy; R.sup.8 is a group R.sup.3 as defined above, or an amino protecting group; R.sup.9 is hydrogen or an amino protecting group; and R.sup.10 is a group R.sup.1, as defined above, protected 1-hydroxyethyl or protected hydroxymethyl; and L is a leaving group;

and wherein any functional group is optionally protected and thereinafter optionally:

(i) removing any protecting groups;

(ii) forming a pharmaceutically acceptable salt; and

(iii) esterifying hydroxy and carboxy groups to form an in vivo hydrolysable ester.

2. A process for preparing a compound of the formula (I) ##STR19## or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:

R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;

R.sup.2 is hydrogen or C.sub.1-4 alkyl;

R.sup.3 is hydrogen or C.sub.1-4 alkyl;

R.sup.4 and R.sup.5 are the same or different and are selected from hydrogen, halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, C.sub.1-4 alkylaminosulphonyl, di-C.sub.1-4 -alkylaminosulphonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N--C.sub.1-4 alkyl)amino, C.sub.1-4 alkanesulphonamido and --S(O).sub.n C.sub.1-4 alkyl and wherein n is zero, one or two;

with the proviso that there is no hydroxy or carboxy substituent in a position ortho to the link to --NR.sup.3 --, which process comprises:

cyclising a compound of the formula (VIII): ##STR20## wherein R.sup.2, R.sup.4, and R.sup.5 are as defined above, R.sup.4 and R.sup.5 optionally being protected; --COOR.sup.6 and --COOR.sup.7 are carboxy or protected carboxy; R.sup.8 is a group R.sup.3 as defined above, or an amino protecting group; R.sup.9 is hydrogen or an amino protecting group; and R.sup.10 is a group R.sup.1, as defined above, protected 1-hydroxyethyl or protected hydroxymethyl; R.sup.11 -R.sup.13 are independently selected from C.sub.1-6 alkoxy, aryloxy, di-C.sub.1-6 alkylamino and diarylamino or any two of R.sup.11 -R.sup.13 represents o-phenylenedioxy; or one of R.sup.11 -R.sup.13 is C.sub.1-4 alkyl, allyl, benzyl or phenyl and the other two values are independently selected from C.sub.1-4 alkyl, trifluoromethyl or phenyl, wherein any phenyl group is optionally substituted with C.sub.1-3 alkyl or C.sub.1-3 alkoxy;

and wherein any functional group is optionally protected and thereinafter optionally:

(i) removing any protecting groups;

(ii) forming a pharmaceutically acceptable salt; and

(iii) esterifying hydroxy and carboxy groups to form an in vivo hydrolysable ester.

3. A process for preparing a compound of the formula (I) ##STR21## a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:

R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;

R.sup.2 is hydrogen or C.sub.1-4 alkyl;

R.sup.3 is hydrogen or C.sub.1-4 alkyl;

R.sup.4 and R.sup.5 are the same or different and are selected from hydrogen, halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, C.sub.1-4 alkylaminosulphonyl, di-C.sub.1-4 -alkylaminosulphonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N--C.sub.1-4 alkyl)amino, C.sub.1-4 alkanesulphonamido and --S(O).sub.n C.sub.1-4 alkyl and wherein n is zero, one or two;

with the proviso that there is no hydroxy or carboxy substituent in a position ortho to the link to --NR.sup.3 --, which process comprises:

deprotecting a compound of the formula (V): ##STR22## wherein R.sup.2, R.sup.4, and R.sup.5 are as defined above, R.sup.4 and R.sup.5 optionally being protected; --COOR.sup.6 and --COOR.sup.7 are carboxy or protected carboxy; R.sup.8 is a group R.sup.3 as defined above, or an amino protecting group; R.sup.9 is hydrogen or an amino protecting group; and R.sup.10 is a group R.sup.1, as defined above, protected 1-hydroxyethyl or protected hydroxymethyl; and

wherein at least one protecting group is present; and thereafter optionally;

(i) forming a pharmaceutically acceptable salt,

(ii) esterifying hydroxy and carboxy groups to form an in vivo hydrolysable ester.

4. The process according to any one of claims 1, 2 and 3, wherein R.sup.1 is 1-hydroxyethyl.

5. The process according to any one of claims 1, 2 and 3, wherein R.sup.2 is hydrogen or methyl.

6. The process according to any one of claims 1, 2 and 3, wherein R.sup.2 is methyl.

7. The process according to any one of claims 1, 2 and 3, wherein R.sup.3 is hydrogen.

8. The process according to any one of claims 1, 2 and 3, wherein the compound prepared has the structure of formula formula (IV): ##STR23##

9. The process according to claim 8 wherein R.sup.4 and R.sup.5 are the same or different and selected from hydrogen, fluoro, chloro, hydroxy, carboxy, cyano, nitro, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, trifluoromethyl, sulphonic acid, methylsulphinyl, methylsulphonyl, methanesulphonamido or acetamido.

10. The process according to claim 8 wherein at least one of R.sup.4 and R.sup.5 is hydrogen.

11. The process according to claim 8 wherein R.sup.4 is hydrogen, carboxy, fluoro, chloro, methyl, methoxy, cyano, sulphonic acid or methoxycarbonyl and R.sup.5 is hydrogen.

12. The process according to any one of claims 1, 2 and 3 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.

13. The process according to any one of claims 1, 2 and 3 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid.

14. The process according to any one of claims 1, 2 and 3 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid in the form of a monosodium salt.

15. The process according to any one of claims 1, 2 and 3 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid in the form of a disodium salt.

16. The process according to claim 1 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid in the form of a disodium salt which process comprises reacting (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidin -4-yl-thiol with allyl(1R,5R,6S,8R)-6-(1-hydroxyethyl)-1-methyl-2-diphenylphosphoryloxycarb apenem-3-carboxylate, and thereafter removing any protecting groups.

17. The process according to claim 1 in which the leaving group L is diphenylphosphoric ester (--OP(O)(OPh).sub.2).

18. The process according to claim 1 in which the reaction of compounds of formulae VI and VII is performed in the presence of the base diisopropylethylamine.

19. The process according to claim 1 in which the reaction of compounds of formulae VI and VII is performed at a temperature of between -25.degree. C. and ambient.

20. The process according to claim 1 in which the reaction of compounds of formulae VI and VII is performed at a temperature of -20.degree. C.

21. The process according to claim 1 in which the reaction of compounds of formulae VI and VII is performed at a temperature of -15.degree. C.

22. The process according to claim 1 in which the reaction of compounds of formulae VI and VII is performed in the organic solvent acetonitrile.

23. The process according to claim 1 in which the reaction of compounds of formulae VI and VII is performed in acetonitrile at -20.degree. C. in the presence of diisopropylethylamine.

24. The process according to claim 1 in which the reaction of compounds of formulae VI and VII is performed in acetonitrile at -15.degree. C. in the presence of diisopropylethylamine.

25. The process according to claim 1 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid in the form of a disodium salt which process comprises reacting (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl) pyrrolidin-4-yl-thiol with 4-nitrobenzyl(1R,5R,6S,8R)-6-(1-hydroxyethyl)-1-methyl-2-diphenylphosphory loxycarbapenem-3-carboxylate, and thereafter removing any protecting groups.

26. The process according to claim 2 wherein R.sup.11 -R.sup.13 are independently selected from methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, phenoxy, dimethylamino, diethylamino and diphenylamino or any two of R.sup.11 -R.sup.13 represent o-phenylenedioxy.

27. The process according to claim 2 wherein R.sup.11 -R.sup.15 each have the same value and are selected from methoxy, ethoxy, isopropoxy, n-butoxy and phenoxy.

28. The process according to claim 2 in which the cyclisation of the compound of formula VIII is performed at a temperature in the region of 60.degree.-15.degree. C.

29. The process according to claim 2 in which the cyclisation of the compound of formula VIII is performed in toluene, xylene or ethyl acetate.

30. The process according to claim 2 in which the cyclisation of the compound of formula VIII is performed in an atmosphere of nitrogen.

31. The process according to claim 2 in which the cyclisation of the compound of formula VIII is performed in the presence of a radical scavenger.

32. The process according to claim 2 in which the cyclisation of the compound of formula VIII is performed in the presence of hydroquinone.

33. The process according to claim 3 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid in the form of a disodium salt which process comprises deprotecting allyl (1R,5S,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(3-allyloxycarbonylphenylcar bamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxy late.

34. The process according to claim 3 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid in the form of a disodium salt which process comprises adding to a solution of allyl(1R,5S,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(3-allyloxycarbonylphen ylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-ca rboxylate and 2,2-dimethyl-1,3-dioxane-4,6-dione in a mixture of a dimethylformamide and tetrahydrofuran, under an argon atmosphere, tetrakis(triphenylphosphine)palladium, then gently warming the solution with protection from light and then adding sodium 2-ethylhexanoate in tetrahydrofuran and dimethyl sulfoxide.

35. The process according to claim 3 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid in the form of a disodium salt which process comprises deprotecting 4-nitrobenzyl(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-allyloxycarbonylphenylcarbamoyl )-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-met hylcarbapenem-3-carboxylate.

36. The process according to claim 3 wherein the compound prepared is (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid in the form of a disodium salt which process comprises adding to a solution of 4-nitrobenzyl(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-allyloxycarbonylphenylcarbamoyl )-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-met hylcarbapenem-3-carboxylate and Meldrum's acid in tetrahydrofuran, under an atmosphere of argon and with the exclusion of light, tetrakis(triphenylphosphine)palladium, then after stirring at ambient temperature, diluting with ethyl acetate, adding the mixture to a solution of sodium bicarbonate in distilled water, adding 10% Pd-charcoal and leaving in an atmosphere of hydrogen.

37. A process for preparing the compound (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid in the form of a disodium salt which process comprises reacting (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid with sodium 2-ethylhexanoate in tetrahydrofuran and dimethyl sulfoxide.
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