Claims
- 1. A compound of the formula ##STR39## wherein X is ##STR40## R is hydrogen or a carboxylic acid protecting group; R.sub.1 is an acyl group;
- R.sub.2 is hydrogen or lower alkoxy; and
- R.sub.3 is of the formula, ##STR41## wherein R.sub.4, R.sub.4' and R.sub.4" are independently hydrogen or ##STR42## wherein R.sub.200 is straight or branched lower alkyl, A and B are halogen, a, b, x, y and z are independently zero (upon which a hydrogen atom is present at that ring position) or 1 except that at least two of x, y and z are always 1, and m is zero or an integer from 1 to 8.
- 2. A compound as in claim 1 wherein m is zero or 1.
- 3. A compound as in claim 1 wherein R.sub.4, R.sub.4' and R.sub.4" are independently hydrogen or ##STR43##
- 4. A compound as in claim 1 wherein A and B are chlorine.
- 5. A compound as in claim 1 wherein R is hydrogen.
- 6. A compound as in claim 1 wherein X is ##STR44##
- 7. A compound as in claim 1 wherein X is ##STR45##
- 8. A compound as in claim 1 wherein X is ##STR46##
- 9. A compound as in claim 1 wherein X is ##STR47##
- 10. A compound as in claim 1 wherein acyl group R.sub.1 is an aliphatic group of the formula ##STR48## wherein R.sub.5 is selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohexadienyl, or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanomethylthio groups.
- 11. A compound as in claim 1 wherein acyl group R.sub.1 is a carbocyclic aromatic group selected from the group consisting of ##STR49## wherein n is 0, 1, 2 or 3; R.sub.6, R.sub.7, and R.sub.8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and R.sub.90 is selected from the group consisting of amino, acylamino, hydroxyl, a carboxyl salt, protected carboxy, azido and a sulfo salt.
- 12. A compound as in claim 1 wherein acyl group R.sub.1 is a heteroaromatic group selected from the group consisting of ##STR50## wherein n is 0, 1, 2 or 3; R.sub.90 is selected from the group consisting of amino, acylamino, hydroxyl, a carboxyl salt, protected carboxy, azido and a sulfo salt; and R.sup.101 is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, the heterocyclic ring being substituted with halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms.
- 13. A compound as in claim 1 wherein acyl group R.sub.1 is a substituted acetyl group of the formula ##STR51## wherein R.sub.111 is alkyl, hydroxyalkyl or an aromatic group of the formula ##STR52## wherein R.sub.6, R.sub.7 and R.sub.8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminomethyl, or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, the heterocyclic ring being substituted with halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, and R.sub.120 is alkyl or substituted alkyl, the substituted alkyl group being substituted with one or more halogen, cyano, nitro, amino or mercapto groups.
- 14. A compound as in claim 1 wherein acyl group R.sub.1 is an (acylamino) substituted acetyl group of the formula ##STR53## wherein R.sub.111 is alkyl, hydroxyalkyl or an aromatic group of the formula ##STR54## wherein R.sub.6, R.sub.7 and R.sub.8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminomethyl, or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, the heterocyclic ring being substituted with halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, and R.sub.140 is ##STR55## (where R.sub.6, R.sub.7 and R.sub.8 are as previously defined and n is 0, 1, 2 or 3), hydrogen, lower alkyl, lower alkyl substituted with halo, trifluoromethyl, amino and cyano, amino alkylamino, dialkylamino, (cyanoalkyl)amino, hydrazino, alkyl hydrazino, aryl hydrazino and acyl hydrazino.
- 15. A compound as in claim 1 wherein acyl group R.sub.1 is a (substituted acylimino) substituted acetyl group having the formula ##STR56## wherein R.sub.111 is alkyl, hydroxyalkyl or an aromatic group of the formula ##STR57## wherein R.sub.6, R.sub.7 and R.sub.8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminomethyl, or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, the heterocyclic ring being substituted with halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, and R.sub.140 is ##STR58## (wherein R.sub.6, R.sub.7 and R.sub.8 are as defined above and n is 0, 1, 2 or 3), hydrogen, lower alkyl, lower alkyl substituted with halo, trifluoromethyl, amino and cyano, amino, alkylamino, dialkylamino, (cyanoalkyl) amino, hydrazino, alkyl hydrazino, aryl hydrazino and acyl hydrazino, and R.sub.22 and R.sub.23 are independently selected from the group consisting of hydrogen and lower alkyl, or R.sub.22 and R.sub.23 taken together with the carbon atom to which they are attached form a C.sub.3 -C.sub.7 carbocyclic ring.
- 16. A compound as in claim 1 wherein acyl group R.sub.1 is a substituted acetyl group of the formula ##STR59## wherein R.sub.111 is alkyl, hydroxyalkyl or an aromatic group of the formula ##STR60## wherein R.sub.6, R.sub.7 and R.sub.8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminomethyl, or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, the heterocyclic ring being substituted with halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, and R.sub.15 is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e., --N.dbd.CHR.sub.11 wherein R.sub.111 is as defined above), ##STR61## (wherein R.sub.16 is hydrogen, alkyl or halogen substituted alkyl), aromatic group (as defined by R.sub.111 above), alkyl or substituted alkyl, the substituted alkyl group being substituted with one or more halogen, cyano, nitro, amino or mercapto groups.
- 17. A compound as in claim 1 wherein acyl group R.sub.1 is of the formula ##STR62## wherein R.sub.101 is an unsubstituted or substituted 5, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms wherein the heterocyclic ring is substituted by halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkoxy and R.sub.130 is hydrogen, lower alkyl, C.sub.3 -C.sub.7 cycloalkyl and substituted lower alkyl wherein the lower alkyl is substituted with one or more halogen, cyano, nitro, amino, mercapto, lower alkylthio, carboxyl (including salts thereof), amido, lower alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, diloweralkoxyphosphinyl carboxyl lower alkyl or carboxyl-3,7-cycloalkyl.
- 18. A compound as in claim 17 wherein acyl group R.sub.101 is of the formula ##STR63## wherein R.sub.20 is hydrogen or an amino protecting group, and R.sub.130 is hydrogen, lower alkyl or a group of the formula ##STR64## wherein R.sub.22 and R.sub.23 are selected from the group consisting of hydrogen and lower alkyl or taken together with the carbon atom to which they are attached form a C.sub.3 -C.sub.7 carbocyclic ring, and Q is hydroxy or NHR.sub.19 where R.sub.19 is hydrogen or lower alkyl, amino, alkyl amino, aryl amino or acyl amino.
- 19. A compound as in claim 18 wherein R.sub.20 is hydrogen or triphenylmethyl.
- 20. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[(3,4-dihydroxyphenyl)carbonyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid monosodium salt.
- 21. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-[[[2-amino-4-thiazolyl][(2-amino-2-oxoethoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 22. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-7-[[[(2-amino-4-thiazolyl)[1-carboxyl-1-methyl ethoxy]imino]acetyl]amino]-3-[[(3,4-dihydroxybenzoyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium salt.
- 23. A compound as in claim 1, which is [6R-[6 alpha,7 beta(R*)]]-7-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-3-[[[(3,4-dihydroxy) benzoyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid monosodium salt.
- 24. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[(3,4-bis(acetyloxy)benzoyl)]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 25. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[(2,3-dihydroxyphenyl)carbonyl]oxy]methyl]-8-oxo-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 26. A compound as in claim 1, which is [6R-trans)-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 27. A compound as in claim 1, which is (6R-trans)-7-amino-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester monohydrochloride.
- 28. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-3-[[[3,4,5-tris(acetyloxy)benzoyl]oxy]methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 29. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[2-(3,4-dihydroxyphenyl)-1-oxoethy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 30. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt.
- 31. A compound as in claim 1, which is (6R-trans)-7-amino-3-[[[3,4-bis(acetyloxy)benzoyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester monohydrochloride.
- 32. A compound as in claim 1, which is [6R-[6 alpha,7 beta(S)*)]]-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 33. A compound as in claim 1, which is [6R-cis)-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 34. A compound as in claim 1, which is [6R-cis)-3-[[(3,4-dihydroxybenzoyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 35. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[(3,4bis(acetyloxy)-2,5-dichlorobenzoyl)]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 36. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-3-[[[[[3,4-bis(acetyloxy)phenyl]amino]carbonyl]oxy]methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 37. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-3-[[[[[3,4-bis(acetyloxy)phenyl]amino]carbonyl]oxy]methyl]-7[[[[2-amino-[2-amino-2-oxoethoxy]imino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 38. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[(3,4-dihydroxybenzoyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 39. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[(3,4-bis(acetyloxy)benzoyl)]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 40. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-3-[[(3,4-bis(acetyloxy)benzoyl)]amino]methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 41. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)]]-3-[[[(3,4-dihydroxy)benzoyl]amino]methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 42. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)[[-7-[[[2-amino-[(2-amino-2-oxoethoxy)imino]-4-thiazolyl]acetyl]amino]-3-[[(3,4-dihydroxybenzoyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 43. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)[[-7-[[[2-amino[(2-amino-2-oxoethoxy)imino]-4-thiazolyl]acetyl]amino]-3-[[(3,4-dihydroxybenzoyl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt.
- 44. A compound as in claim 1, which is [6R-[6 alpha,7 beta(Z)[[-7-[[2-amino-4-thiazolyl)[(carboxymethoxy)imino]acetyl]amino]-3-[[3,4-dihydroxybenzoyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium salt.
- 45. A compound as in claim 1, which is (6R-trans)-7-[[(2-amino-4-thiazolyl)[[1-(aminocarbonyl)-1-methylethoxy]imino]-acetyl]amino]-3-[[(3,4-dihydroxy-benzoyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid monosodium salt.
CROSS-REFERENCE TO RELATED APPLICATION
This is a continuation-in-part of application Ser. No. 07/062,928, filed Jun. 16, 1987, now abandoned.
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Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
62928 |
Jun 1987 |
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