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Details for Patent: 4,880,793

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Details for Patent: 4,880,793

Title: Combination of thienamycin-type antibiotics with dipeptidase inhibitors
Abstract:A novel antibacterial drug combination is provided, one component being a 2-substituted penem, and the other component is a dipeptidase (E.C.3.4.13.11) inhibitor. The dual-component combination is formulated so that 1 to 3 parts by weight of the penem are employed for 30 to 1 parts by weight of the inhibitor compound.
Inventor(s): Kropp; Helmut (Kenilworth, NJ), Kahan; Frederick M. (Scotch Plains, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Filing Date:Mar 14, 1986
Application Number:06/840,532
Claims:1. An antibacterial composition comprising a combination of a penem having the following structure: ##STR79## wherein R is substituted or unsubstituted alkyl having 1 to 6 carbon atoms or --SR' wherein R' is substituted or unsubstituted:

phenyl or phenyl alkyl having 7-12 carbon atoms, heterocyclyl or heterocyclylalkyl wherein alkyl has 1-3 carbon atoms and the heterocyclic moiety has 1-4 hetero atoms selected from O, N, or S; and the easily removable or pharmaceutically acceptable salt or ester derivatives thereof; and a dipeptidase (E.C.3.4.13.11) inhibitor compound of the following formula: ##STR80## wherein R.sup.2 and R.sup.3 are hydrocarbon radicals in the range respectively of 3-10 and 1-15 carbon atoms; in these R.sup.2 or R.sup.3 hydrocarbon chains 1-6 hydrogens may be replaced by halogens or a nonterminal methylene may be replaced by oxygen or sulfur, including oxidized forms of the latter; additionally, a terminal hydrogen in R.sup.3 can also be replaced by hydroxyl or thiol, which may be acylated or carbamoylated; or the hydrogen can be replaced by amino, which may be derivatized as in an acylamino, ureido, amidino, guanidino, or alkyl or substituted amino group, including guaternary nitrogen groupings; or, there may be replacement by carboxylic, phosphonic or sulfonic acid groups or esters or amides thereof, or cyano; or combinations thereof, such as a terminal amino acid grouping; and R.sup.1 is hydrogen or lower alkyl (C.sub.1-6) or dialkylaminoalkyl, or a pharmaceutically acceptable cation, and the weight ratio of the penem to the dipeptidase inhibitor being within the range of about 1:3 to about 30:1.

2. The composition of claim 1 in which the combination is mixed with a pharmaceutical carrier.

3. The composition of claim 2 in which the carrier is adapted for injection.

4. The composition of claim 1 in which the penem is 2-ethylthio-6-(1-hydroxyethyl)-penem-2-em-3-carboxylic acid or sodium carboxylate.

5. The composition of claim 1 in which the penem is 2-pyridylthio-6-(1-hydroxyethyl)-pen-2-em-3-carboxylic acid or sodium carboxylate.

6. The composition of claim 1 in which the penem is 2-phenylthio-6-(1-hydroxyethyl)-pen-2-em-3-carboxylic acid or sodium carboxylate.

7. The composition of claim 1 in which R.sup.2 can be R.sup.4, wherein R.sup.4 is branched or cyclic hydrocarbon of 3-10 carbon atoms;

--R.sup.5 R.sup.6, wherein R.sup.5 is cycloalkyl of 3-6 carbon atoms and R.sup.6 is either 1 or 2 alkyl substituents which may be joined to form another ring on the cycloalkyl group or R.sup.6 is 1 or 2 chloro substituents; or

--R.sup.7 R.sup.8, wherein R.sup.7 is alkylene of 1-3 carbon atoms and R.sup.8 is cycloalkyl of 3-6 carbon atoms.

8. The composition of claim 1 in which R.sup.2 is straight, branched or cycloalkyl of 3-10 carbon atoms, providing the carbon adjacent to the carbonyl cannot be tertiary.

9. The composition of claim 1 in which R.sup.2 is

wherein R.sup.5 is cycloalkyl of 3-6 carbon atoms and R.sup.6 is either 1 or 2 alkyl substituents which may be joined to form another ring on the cycloalkyl group.

10. The composition of claim 1 in which R.sup.2 is

wherein R.sup.7 is an alkylene group of 1-3 carbon atoms and R.sup.8 is cycloalkyl of 3-6 carbon atoms.

11. The composition of claim 1 in which R.sup.2 is 2,2-dimethylcyclopropyl.

12. The composition of claim 1 in which R.sup.2 is 2,2-dichlorocyclopropyl.

13. The composition of claim 1 in which the dipeptidase inhibitor is Z-2-isovaleramido-2-butenoic acid.

14. The composition of claim 1 in which the dipeptidase inhibitor is Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-butenoic acid.

15. The composition of claim 1 in which the dipeptidase inhibitor is Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-pentenoic acid.

16. The composition of claim 1 in which the dipeptidase inhibitor is Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid.

17. The composition of claim 1 in which the dipeptidase inhibitor is Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid.

18. The composition of claim 1 in which the dipeptidase inhibitor is the 2-dimethylaminoethyl ester of Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid.

19. The composition of claim 1 in which the dipeptidase inhibitor is Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-[1-(phosphono)ethylamino]-2-oc tenoic acid.

20. The composition of claim 1 in which the dipeptidase inhibitor is Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-trimethylammonium-2-octenoic acid.

21. The composition of claim 1 in which the dipeptidase inhibitor is Z-2-(2,2-dichlorocyclopropanecarboxamido)-8-trimethylammonium-2-octenoic acid.

22. The composition of claim 1 in which the dipeptidase inhibitor is Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-guanidino, or amidino, or ureido-2-octenoic acid.

23. The composition of claim 1 in which the dipeptidase inhibitor is 6-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2 -hexenoic acid.

24. The composition of claim 1 in which the dipeptidase inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2 -heptenoic acid.

25. The composition of claim 1 in which one dipeptidase inhibitor is Z-8-[(carboxymethyl)methylamino]-2-(2,2-dimethylcyclopropane carboxamido)-2-octenoic acid.

26. The composition of claim 1 in which the dipeptidase inhibitor is Z-8-[(2-amino-2-oxoethyl)thio]-2-[(2,2-dimethylcyclopropane carboxamido)-2-oxoethyl)thio]-2-(2,2-dimethylcyclopropane carboxamido)-2-octenoic acid.

27. The composition of claim 1 in which the dipeptidase inhibitor is Z-8-cyano-2-(2,2-dimethylcyclopropane carboxamido)-2-octenoic acid.

28. The composition of claim 1 in which the dipeptidase inhibitor is Z-8-acetamido-2-(2,2-dimethylcyclopropane carboxamido)-2-octenoic acid.

29. The method of treating bacterial infections which comprises administering to an animal an antibacterially effective amount of a penem having the following structure: ##STR81## wherein R is substituted or unsubstituted alkyl having 1 to 6 carbon atoms, or --SR' wherein R' is substituted or unsubstituted: alkyl having 7-12 carbon atoms, heterocyclyl or heterocyclylalkyl wherein alkyl has 1-3 carbon atoms and the heterocyclic moiety has 1-4 hetero atoms selected from O, N, or S; and the easily removable or pharmaceutically acceptable salt or ester derivative thereof; and, either separately, or together, an amount of a dipeptidase (E.C.3.4.13.11) inhibitor of the following formula: ##STR82## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1, so that weight ratio of the penem to the inhibitor is within about 1:3 to about 30:1.

30. The method of claim 29 in which the penem is 2-ethylthio-6-(1-hydroxyethyl)-pen-2-em-3-carboxylic acid or sodium carboxylate.

31. The method of claim 29 in which the dipeptidase inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropane carboxamido)-2-heptenoic acid, or its sodium, potassium, calcium or magnesium salt form.

32. The method of claim 29 in which the dipeptidase inhibitor is .+-.Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid, or its sodium, potassium, calcium, or magnesium salt form.
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