IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0538767
(1983-10-03)
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우선권정보 |
GB-19750041897 (1975-10-13); GB-19760002629 (1976-01-23); GB-19760019000 (1976-05-08); GB-19760049570 (1976-11-27); GB-19760049569 (1976-11-27); GB-19760051808 (1976-12-11); GB-19770010116 (1977-03-10); GB-1977001 |
발명자
/ 주소 |
- Ponsford, Roger J.
- Howarth, Thomas T.
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출원인 / 주소 |
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대리인 / 주소 |
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인용정보 |
피인용 횟수 :
2 인용 특허 :
0 |
초록
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The compounds of the formula (II): ##STR## and salts and esters thereof wherein R is an inert ogranic group of up to 18 carbon atoms and are able to inhibit the action of various bacterial β-lactamases. Thus when a compound of the formula (II) or its salt or ester is used together with a penicillin
The compounds of the formula (II): ##STR## and salts and esters thereof wherein R is an inert ogranic group of up to 18 carbon atoms and are able to inhibit the action of various bacterial β-lactamases. Thus when a compound of the formula (II) or its salt or ester is used together with a penicillin or cephalosporin, the effectiveness of that penicillin or cephalosporin can be considerably enhanced. These novel synergysts can be prepared by etherification of an ester of clavulanic acid followed if desired by deesterification. The novel synergysts also possess antibacterial activity.
대표청구항
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1. A pharmaceutical composition for treating bacterial infections in humans and animals which comprises a synergistically effective amount of an ether of the formula (II): ##STR## or a pharmaceutically acceptable salt or a pharmaceutically acceptable este of a compound of the formula (V), wherein R
1. A pharmaceutical composition for treating bacterial infections in humans and animals which comprises a synergistically effective amount of an ether of the formula (II): ##STR## or a pharmaceutically acceptable salt or a pharmaceutically acceptable este of a compound of the formula (V), wherein R is a hydrocarbon of up to 18 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 1, OH, OCOR 1, COR 1, CO 2 R 1, NR 2 COR 1, NR 2 CO 2 R 1, SOR 1, SO 2 R 1, NH 2, NR 1 R 2, NO 2, CONR 1 R 2, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups, wherein R 1 is a hydrocarbon of up to 8 carbon atoms and R 2 is a hydrocarbon of up to 4 carbon atoms, or R is CR 4 R 5 R 6 wherein R 4 and R 5 are independently alkyl of up to 3 carbon atoms or phenyl unsubstituted or substituted by halogen or a group of the formula R 7 or OR 7 wherein R 7 is alkyl of up to 3 carbon atoms; and R 6 is hydrogen, alkyl of up to 3 carbon atoms or phenyl unsubstituted or substituted by halogen or a group of the formula R 8 or OR 8 wherein R 8 is alkyl of up to 3 carbon atoms, R 11 is a hydrocarbon of 1 to 8 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 12, OCOR 12, COR 12 or OH, or by halogen and one of said groups wherein R 12 is alkyl of 1 to 4 carbon atoms, and A is a group such that CO 2 A is a carboxylic acid moiety, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, and an antibacterially effective amount of a penicillin, in combination with a pharmaceutically acceptable carrier. 2. A composition according to claim 1 wherein the ether is of the formula (IIa): ##STR## or a pharmaceutically acceptable salt thereof wherein R is a hydrocarbon of up to 18 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 1, OH, OCOR 1, COR 1, CO 2 R 1, NR 2 COR 1, NR 2 CO 2 R 1, SOR 1, SO 2 R 1, NH 2, NR 1 R 2, NO 2, CONR 1 R 2, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups, wherein R 1 is a hydrocarbon of up to 8 carbon atoms and R 2 is a hydrocarbon of up to 4 carbon atoms; or is of the formula (IIb): ##STR## wherein A° is a group such that CO 2 A° is a pharmaceutically acceptable ester moiety and R is as above defined. 3. A composition according to claim 1 wherein R contains up to 7 carbon atoms. 4. A composition according to claim 1 wherein R is said hydrocarbon unsubstituted or substituted by halogen, a group of the formula OR 1, OCOR 1, CO 2 R 1, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups wherein R 1 is a hydrocarbon of up to 8 carbon atoms. 5. A composition according to claim 1 wherein R 1 is alkyl of 1 to 4 carbon atoms, phenyl or benzyl. 6. A composition according to claim 1 wherein one or both of R 1 and R 2 are methyl. 7. A composition according to claim 1 wherein R is CH 2 R 9 wherein R 9 is naphthyl, phenyl or phenyl substituted by halogen or a group R 10 or OR 10 wherein R 10 is alkyl of up to 3 carbon atoms. 8. A composition according to claim 1 wherein A is hydrogen or a sodium, potassium, calcium, magnesium, ammonium, monoalkyl ammonium, dialkyl ammonium, trialkyl ammonium or quaternary alkyl ammonium moiety of 1 to 6 carbon atoms in each alkyl moiety. 9. A composition according to claim 1 wherein the compound is in the form of the sodium, potassium or calcium salt. 10. A composition according to claim 1 wherein the compound is in the form of a pharmaceutically acceptable ester. 11. A composition according to claim 10 wherein the compound of the formula (II) is of the formula (III) or (IV): ##STR## wherein R is a hydrocarbon of up to 18 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 1, OH, OCOR 1, COR 1, NR 2 COR 1, NR 2 CO 2 R 1, SOR 1, SO 2 R 1, NH 2, NR 1 R 2, NO 2, CONR 1 R 2, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups, wherein R 1 is a hydrocarbon of up to 8 carbon atoms and R 2 is a hydrocarbon of up to 4 carbon atoms; A 1 is alkyl of 1 to 8 carbon atoms unsubstituted or substituted by halogen of a group of the formula OA 4, OCOA 4, SA 4 or SO 2 A 4 wherein A 4 is a hydrocarbon of up to 6 carbon atoms; A 2 is hydrogen, alkyl of up to 4 carbon atoms or phenyl unsubstituted or substituted by halogen or by a group A 5 or OA 5 wherein A 5 is alkyl of up to 6 carbon atoms; and A 3 is phenyl unsubstituted or substituted by halogen or by a group A 5 or OA 5 wherein A 5 is as above defined. 12. A composition according to claim 11 wherein A 1 is alkyl of 1 to 8 carbon atoms unsubstituted or substituted by a group of the formula OA 4 wherein A 4 is a hydrocarbon of up to 6 carbon atoms; A 2 is hydrogen; A 4 is methyl; and A 5 is methyl. 13. A composition according to claim 1 wherein the compound of the formula (II) is in the form of an ester wherein the ester moiety is the acetoxymethyl, α-acetoxyethyl, pivaloyloxymethyl, phthalidyl, ethoxycarbonyloxymethyl or ethoxycarbonyloxy ethyl ester. 14. A composition according to claim 1 wherein the compound of the formula (II) is in the form of the benzyl or p-methoxybenzyl ester. 15. A composition according to claim 1 wherein R 11 is alkylene of 1 to 4 carbon atoms, phenylene or alkylene of 1 to 2 carbon atoms substituted by phenyl or phenylene. 16. A composition according to claim 1 wherein R 11 is --CH 2 -- or --CH 2 CH 2 --. 17. A composition according to claim 1 wherein the compound of the formula (II) is of the formula (VI), (VII), (VIII), (IX), (X), (XIa) or (XIb): ##STR## or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof wherein R 12 is alkylene of 1 to 4 carbon atoms; R 13 is hydrogen or alkyl of 1 to 4 carbon atoms unsubstituted or substituted by phenyl; R 14 is a divalent hydrocarbon of 2 to 8 carbon atoms; R 15 is hydrogen or alkyl of 1 to 4 carbon atoms; R 16 is hydrogen, R 17, COR 17 or CO 2 R 17 wherein R 17 is alkyl of 1 to 4 carbon atoms unsubstituted or substituted by phenyl; A is a group such that CO 2 A is a carboxylic acid moiety or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof; R 18 is a moiety such that CH 2 R 18 is an inert hydrocarbon of up to 18 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 1, OH, OCOR 1, COR 1, CO 2 R 1, NR 2 COR 1 , NR 2 CO 2 R 1, SOR 1, SO 2 R 1, NH 2, NR 1 R 2, NO 2, COHR 1 R 2, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups wherein R 1 is a hydrocarbon of up to 8 carbon atoms and R 2 is a hydrocarbon of up to 4 carbon atoms; R 19 is alkyl of 1 to 4 carbon atoms or phenyl unsubstituted or substituted by a carboxylic acid group, a pharmaceutically acceptable carboxyl salt, a carboxylic acid alkyl ester moiety of 1 to 4 carbon atoms in the alkyl moiety or R 19 is a carboxylic acid group, a pharmaceutically acceptable carboxyl salt or a carboxylic acid alkyl ester of 1 to 4 carbon atoms in the alkyl ester moiety; R 20 is alkyl of 1 to 5 carbon atoms; A 1 is alkyl of 1 to 8 carbon atoms unsubstituted or substituted by halogen or a group of the formula OA 4, OCOA 4, SA 4 or SO 2 A 4 wherein A 4 is a hydrocarbon of up to 6 carbon atoms; A 2 is hydrogen, alkyl of up to 4 carbon atoms or phenyl unsubstituted or substituted by halogen or by a group A 5 or OA 5 wherein A 5 is alkyl of up to 6 carbon atoms; and A 3 is phenyl unsubstituted or substituted by halogen or by a group A 5 or OA 5 wherein A 5 is as above defined. 18. A composition according to claim 17 wherein R 12 is --CH 2 -- or --CH 2 CH 2 --; R 14 is alkylene or 2 to 4 carbon atoms, phenylene or alkylene of 2 to 4 carbon atoms substituted by phenyl or phenylene; R 20 is a group CH 2 R 21 wherein R 21 is hydrogen or alkyl of 1 to 4 carbon atoms. 19. A composition according to claim 17 wherein the compound of the formula (VI) is in the form of a pharmaceutically acceptable salt and the compound of the formula (IX) is in the form of the sodium, potassium or calcium salt. 20. A composition according to claim 18 wherein R 20 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl. 21. A composition according to claim 20 wherein R 20 is methyl or ethyl. 22. A composition according to claim 17 wherein the compound of the formula (XIa) is in the form of methoxymethyl ester. 23. A composition according to claim 1 wherein the penicillin is benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof. 24. A composition according to claim 1 wherein the compound is of the formula ##STR## wherein R 20 is methyl and the penicillin is amoxycillin. 25. A method of treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof a synergistically effective amount of an ether of the formula (II): ##STR## or a pharmaceutically acceptable salt or a pharmaceutically acceptable este of a compound of the formula (V), wherein R is a hydrocarbon of up to 18 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 1, OH, OCOR 1, COR 1, CO 2 R 1, NR 2 COR 1, NR 2 CO 2 R 1, SOR 1, SO 2 R 1, NH 2, NR 1 R 2, NO 2, CONR 1 R 2, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups, wherein R 1 is a hydrocarbon of up to 8 carbon atoms and R 2 is a hydrocarbon of up to 4 carbon atoms, or R is CR 4 R 5 R 6 wherein R 4 and R 5 are independently alkyl of up to 3 carbon atoms or phenyl unsubstituted or substituted by halogen or a group of the formula R 7 or OR 7 wherein R 7 is alkyl of up to 3 carbon atoms; and R 6 is hydrogen, alkyl of up to 3 carbon atoms or phenyl unsubstituted or substituted by halogen or a group of the formula R 8 or OR 8 wherein R 8 is alkyl of up to 3 carbon atoms, R 11 is a hydrocarbon of 1 to 8 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 12, OCOR 12, COR 12 or OH, or by halogen and one of said groups wherein R 12 is alkyl of 1 to 4 carbon atoms, and A is a group such that CO 2 A is a carboxylic acid moiety, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, and an antibacterially effective amount of a penicillin, in combination with a pharmaceutically acceptable carrier. 26. A method according to claim 25 wherein the ether is of the formula (IIa): ##STR## or a pharmaceutically acceptable salt thereof wherein R is a hydrocarbon of up to 18 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 1, OH, OCOR 1, COR 1, CO 2 R 1, NR 2 COR 1, NR 2 CO 2 R 1, SOR 1, SO 2 R 1, NH 2, NR 1 R 2, NO 2, CONR 1 R 2, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups, wherein R 1 is a hydrocarbon of up to 8 carbon atoms and R 2 is a hydrocarbon of up to 4 carbon atoms; or is of the formula (IIb): ##STR## wherein A° is a group such that CO 2 A° is a pharmaceutically acceptable ester moiety and R is as above defined. 27. A method according to claim 25 wherein R contains up to 7 carbon atoms. 28. A method according to claim 25 wherein R is said hydrocarbon unsubstituted or substituted by halogen, a group of the formula OR 1, OCOR 1, CO 2 R 1, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups wherein R 1 is a hydrocarbon of up to 8 carbon atoms. 29. A method according to claim 25 wherein R 1 is alkyl of 1 to 4 carbon atoms, phenyl or benzyl. 30. A method according to claim 25 wherein one or both of R 1 and R 2 are methyl. 31. A method according to claim 25 wherein R is CH 2 R 9 wherein R 9 is naphthyl, phenyl or phenyl substituted by halogen or a group R 10 or OR 10 wherein R 10 is alkyl of up to 3 carbon atoms. 32. A method according to claim 25 wherein A is hydrogen or a sodium, potassium, calcium, magnesium, ammonium, monoalkyl ammonium, dialkyl ammonium, trialkyl ammonium or quaternary alkyl ammonium moiety of 1 to 6 carbon atoms in each alkyl moiety. 33. A method according to claim 25 wherein the compound is in the form of the sodium, potassium or calcium salt. 34. A method according to claim 25 wherein the compound is in the form of a pharmaceutically acceptable ester. 35. A method according to claim 34 wherein the compound of the formula (II) is of the formula (III) or (IV): ##STR## wherein R is a hydrocarbon of up to 18 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 1, OH, OCOR 1, COR 1, NR 2 COR 1, NR 2 CO 2 R 1, SOR 1, SO 2 R 1, NH 2, NR 1 R 2, NO 2, CONR 1 R 2, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups, wherein R 1 is a hydrocarbon of up to 8 carbon atoms and R 2 is a hydrocarbon of up to 4 carbon atoms; A 1 is alkyl of 1 to 8 carbon atoms unsubstituted or substituted by halogen or a group of the formula OA 4, OCOA 4, SA 4 or SO 2 A 4 wherein A 4 is a hydrocarbon of up to 6 carbon atoms; A 2 is hydrogen, alkyl of up to 4 carbon atoms or phenyl unsubstituted or substituted by halogen or by a group A 5 or OA 5 wherein A 5 is alkyl of up to 6 carbon atoms; and A 3 is phenyl unsubstituted or substituted by halogen or by a group A 5 or OA 5 wherein A 5 is as above defined. 36. A method according to claim 35 wherein A 1 is alkyl of 1 to 8 carbon atoms unsubstituted or substituted by a group of the formula OA 4 wherein A 4 is a hydrocarbon of up to 6 carbon atoms; A 2 is hydrogen; A 4 is methyl; and A 5 is methyl. 37. A method according to claim 25 wherein the compound of the formula (II) is in the form of an ester wherein the ester moiety is the acetoxymethyl, α-acetoxyethyl, pivaloyloxymethyl, phthalidyl, ethoxycarbonyloxymethyl or ethoxycarbonyloxy ethyl ester. 38. A method according to claim 25 wherein the compound of the formula (II) is in the form of the benzyl or p-methoxybenzyl ester. 39. A method according to claim 25 wherein R 11 is alkylene of 1 to 4 carbon atoms, phenylene or alkylene of 1 to 2 carbon atoms substituted by phenyl or phenylene. 40. A method according to claim 25 wherein R 11 is --CH 2 -- or --CH 2 CH 2 --. 41. A method according to claim 25 wherein the compound of the formula (II) is of the formula (VI), (VII), (VIII), (IX), (X), (XIa) or (XIb): ##STR## or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof wherein R 12 is alkylene of 1 to 4 carbon atoms; R 13 is hydrogen or alkyl of 1 to 4 carbon atoms unsubstituted or substituted by phenyl; R 14 is a divalent hydrocarbon of 2 to 8 carbon atoms; R 15 is hydrogen or alkyl of 1 to 4 carbon atoms; R 16 is hydrogen, R 17, COR 17 or CO 2 R 17 wherein R 17 is alkyl of 1 to 4 carbon atoms unsubstituted or substituted by phenyl; A is a group such that CO 2 A is a carboxylic acid moiety or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof; R 18 is a moiety such that CH 2 R 18 is an inert hydrocarbon of up to 18 carbon atoms unsubstituted or substituted by halogen, a group of the formula OR 1, OH, OCOR 1, COR 1, CO 2 R 1, NR 2 COR 1 , NR 2 CO 2 R 1, SOR 1, SO 2 R 1, NH 2, NR 1 R 2, NO 2, COHR 1 R 2, carboxyl or a pharmaceutically acceptable salted carboxyl or by halogen and one of said groups wherein R 1 is a hydrocarbon of up to 8 carbon atoms and R 2 is a hydrocarbon of up to 4 carbon atoms; R 19 is alkyl of 1 to 4 carbon atoms or phenyl unsubstituted or substituted by a carboxylic acid group, a pharmaceutically acceptable carboxyl salt, a carboxylic acid alkyl ester moiety of 1 to 4 carbon atoms in the alkyl moiety or R 19 is a carboxylic acid group, a pharmaceutically acceptable carboxyl salt or a carboxylic acid alkyl ester of 1 to 4 carbon atoms in the alkyl ester moiety; R 20 is alkyl of 1 to 5 carbon atoms; A 1 is alkyl of 1 to 8 carbon atoms unsubstituted or substituted by halogen or a group of the formula OA 4, OCOA 4, SA 4 or SO 2 A 4 wherein A 4 is a hydrocarbon of up to 6 carbon atoms; A 2 is hydrogen, alkyl of up to 4 carbon atoms or phenyl unsubstituted or substituted by halogen or by a group A 5 or OA 5 wherein A 5 is alkyl of up to 6 carbon atoms; and A 3 is phenyl unsubstituted or substituted by halogen or by a group A 5 or OA 5 wherein A 5 is as above defined. 42. A method according to claim 41 wherein R 12 is --CH 2 -- or --CH 2 CH 2 --; R 14 is alkylene or 2 to 4 carbon atoms, phenylene or alkylene of 2 to 4 carbon atoms substituted by phenyl or phenylene; R 20 is a group CH 2 R 21 wherein R 21 is hydrogen or alkyl of 1 to 4 carbon atoms. 43. A method according to claim 41 wherein the compound of the formula (VI) is in the form of a pharmaceutically acceptable salt and the compound of the formula (IX) is in the form of the sodium, potassium or calcium salt. 44. A method according to claim 42 wherein R 20 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl. 45. A method according to claim 44 wherein R 20 is methyl or ethyl. 46. A method according to claim 41 wherein the compound of the formula (XIa) is in the form of methoxymethyl ester. 47. A method according to claim 25 wherein the penicillin is benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof. 48. A method according to claim 25 wherein the compound is of the formula ##STR## wherein R 20 is methyl and the penicillin is amoxycillin.
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