Patent EA-003458-B1 (EA)
Title: Enhancement of oxazolidinone antibacterial agents activity by using arginine derivatives
Inventor: BAHANON MICHAEL JOHN
IPC: C07D413/10
Filed: 1999-05-13
Abstract: 1. A method for treating gram-negative organisms infections in mammal which comprises administration of an effective amount of an oxazolidinone antibacterial agent and an arginine derivative of formula A wherein R<1> is a) aryl, optionally substituted with C1-4alkyl, C1-4alkoxy, C1-4alkylthio, halo, or -NH2, b) -(CH2)1-aryl, in which aryl is substituted with C1-4alkyl, C1-4alkoxy, C1-4alkylthio, halo, or -NH2, or c) thienyl, furyl, pyridyl, benzofuranyl, or benzothienyl; Z is R2, or -CHWR2; R2 is a) aryl, optionally substituted with one or two C1-4alkyl, C1-4alkoxy, C1-4alkylthio, halo, -NH2, C1-4alkylamino, C1-4dialkylamino, or -NHOH, b) C1-4alkyl, optionally substituted with fluoro, c) C1-4alkoxy, d) C1-4alkylthio, e) halo, or f) thienyl, furanyl, or pyridyl; W is H, -NH2, C1-4 alkylamino, C1-4 dialkylamino, halo, hydroxyl, C1-4 alkoxy, C1-4 alkylthio, or azaheterocycle; aryl is phenyl, or naphthyl; azaheterocycle is n-morpholinyl, n-piperazinyl, n-pyrrolidinyl, n-imidazolyl, n-pyrrolyl, n-pyrazolyl, n-triazolyl, or n-tetrazolyl; i is 0, 1, or 2; and pharmaceutically acceptable salts, wherein the oxazolidinone antibacterial agent is compounds of structure B wherein R1 is methyl, ethyl, cyclopropyl, or dichloromethyl; R2 is hydrogen or fluoro; and Het is a 6-membered saturated heterocyclic moiety having one to two atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms. 2. The method of claim 1 wherein the oxazolidinone antibacterial agent is a compound of structures I, II, III, IV or V. 3. The method of claim 1 wherein the oxazolidinone antibacterial agent is a compound of structure II. 4. The method of claim 1 wherein the arginine derivative of formula A is L-phenylalanyl-L-arginyl-(-naphthylamide. 5. The method of claim 1 wherein the oxazolidinone antibacterial agent and the arginine derivative of formula A are administered in a ratio of 10 (the oxazolidinone antibacterial agent) : 0.01 (the arginine derivative of formula A). 6. The method of claim 1 wherein the oxazolidinone antibacterial agent and the arginine derivative of formula A are administered in a ratio of 1: 1. 7. The method of claim 1 wherein the effective amount of oxazolidinone antibacterial agent is from about 0.1 to about 100 mg/kg of body weight/day. 8. The method of claim 1 wherein the effective amount of oxazolidinone antibacterial agent is from about 3 to about 50 mg/kg of body weight/day. 9. The method of claim 1 wherein the amount of the arginine derivative of formula A is from about 0.01 to about 100 mg/kg of body weight/day. 10. The method of claim 1 wherein the amount of the arginine derivative of formula A is from about 0.3 to about 50 mg/kg of body weigh/day. 11. The method of claim 1 wherein the oxazolidinone antibacterial agent and the arginine derivative of formula A are administered simultaneously. 12. The method of claim 1 wherein the arginine derivative of formula A is administrated about one to four hours before the oxazolidinone antibacterial agent is administered. 13. The method of claim 1 wherein the effective amount of an oxazolidinone antibacterial agent and an arginine derivative of formula A are administered orally, parenterally, transdermally or topically. 14. The method of claim 1 wherein the gram-negative organisms are aerobic gram-negative organisms. 15. The method of claim 15 wherein the aerobic gram-negative organism is E. coli, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, or Klebsiella pneumoniae. 16. A composition for treating gram-negative organisms infections in mammal which comprises an oxazolidinone antibacterial agent of formula B, an arginine derivative of formula A and a pharmaceutically acceptable carrier. 17. The composition of claim 16 wherein the oxazolidinone antibacterial agent is compounds of structures I, II, III, IV or V. 18. The composition of claim 17 wherein the arginine derivative of formula A is L-phenylalanyl-Larginyl-(-naphthylamide.