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Details for Patent: 4,539,208

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Details for Patent: 4,539,208

Title: Combination of thienamycin-type antibiotics with dipeptidase inhibitors
Abstract:A novel antibacterial drug combination is provided, one component being a fused ring .beta.-lactam, such as thienamycin and its semi-synthetic derivatives, 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 .beta.-lactam compound are employed for 30 to 1 parts by weight of the inhibitor compound.
Inventor(s): Kahan; Frederick M. (Scotch Plains, NJ), Kropp; Helmut (Kenilworth, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Filing Date:Aug 10, 1981
Application Number:06/291,711
Claims:1. An antibacterial composition comprising a combination of thienamycin-type compound of the formula ##STR73## wherein X is CH.sub.2 or S; R.sup.2 is H; --S--C.sub.1 --C.sub.6 alkyl; --S--(CH.sub.2).sub.2 --NHR.sup.3 wherein R.sup.3 is H, acetyl, formimidoyl, or acetimidoyl; --S(O)--CH.dbd.CHNHCOCH.sub.3 ; or --S--CH.dbd.CHNHCOCH.sub.3 and R.sup.6 is H or ##STR74## wherein R.sup.7 is H, OH or sulfonyloxy and a dipeptidase (3.C.3.413.11) inhibitor compound of the following formula ##STR75## wherein R.sup.2 and R.sup.3 are hydrocarbon radicals in the range respectively of 3-10 and 1-15 carbon atoms; in either one of 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 alkyl amino group, including quaternary nitrogen groupings; or, there may be replacement by acid groups such as 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, the ratio of the thienamycin-type compound 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 thienamycin-type compound is thienamycin.

5. The composition of claim 1 in which the thienamycin-type compound is N-formimidoylthienamycin.

6. The composition of claim 1 in which the thienamycin-type compound is N-acetimidoylthienamycin.

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. An antibacterial composition comprising (A) N-formimidoylthienamycin and (B) 7-(L-2-amino-2-carboxyethylthio) 2-(2,2-dimethylcyclopropane-carboxamido) 2-heptenoic acid or its sodium, potassium, calcium or magnesium salt form, wherein the weight ratio of (A):(B) is about 1.1.

30. The method for treating bacterial infections which comprises administering to an animal either separately or together an antibacterially effective amount of the composition of claim 1.

31. The method of claim 30 in which the thienamycin-type compound is N-formimidoylthienamycin.

32. The method of claim 30 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.

33. The method for treating bacterial infections which comprises administering to an animal an antibacterially effective amount of a thienamycin-type compound of claim 1 and, either separately or together, from 3-200 mg/kg daily of a dipeptidase inhibitor compound of claim 1.

34. The method of claim 33 wherein the dipeptidase inhibitor compound is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2 -heptenoic acid.
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