Claims for Patent: 7,129,232

Summary for Patent: 7,129,232

Title:	Cephem compounds
Abstract:	The present invention relates to a compound of the formula [I]: wherein R1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R2 is hydrogen or amino protecting group, or R1 and R2 are bonded together and form lower alkylene or lower alkenylene; R3 is hydrogen or lower alkyl; R4 is R5 is carboxy or protected carboxy; and R6 is amino or protected amino, or a pharmaceutically acceptable salt thereof, a process for preparing a compound of the formula [I], and a pharmaceutical composition comprising a compound of the formula [I] in admixture with a pharmaceutically acceptable carrier.
Inventor(s):	Hidenori Ohki, Shinya Okuda, Toshio Yamanaka, Masaru Ohgaki, Ayako Toda, Kohji Kawabata, Satoshi Inoue, Keiji Misumi, Kenji Itoh, Kenji Satoh
Assignee:	Wakunaga Pharmaceutical Co Ltd, Astellas Pharma Inc
Application Number:	US10/695,895
Patent Claims:	1. A compound of the formula [I]: wherein R1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R2 is hydrogen, aryl(lower)alkyl or acyl, or R1 and R2 are bonded together and form lower alkylene or lower alkenylene; R3 is hydrogen or lower alkyl; R4 is wherein A is wherein X is O or NH, R7 is hydrogen, lower alkyl, aryl(lower)alkyl or acyl, R8 is hydrogen or hydroxy, R9 is amino, mono or di(lower)alkylamino, aryl(lower)alkylamino, acyl amino, guanidino, acyl guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino, aryl(lower)alkylamino or acylaminio, k, m, n and q are independently 0 or 1, and p is 0, 1, 2 or 3; R5 is carboxy or an esterfied carboxy; and R6 is amino, aryl(lower)alkylamino or acylamino, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein R1 is lower alkyl or hydroxy(lower)alkyl, and R2 is hydrogen, aryl(lower)alkyl or acyl, or R1 and R2 are bonded together and form lower alkylene; R3 is hydrogen; A is wherein X is O or NH; R7 is hydrogen, aryl(lower)alkyl or acyl; R9 is amino, aryl(lower)alkylamino or acylamino; and p is 0, 1 or 2, or a pharmaceutically, acceptable salt thereof. 3. The compound of claim 2 wherein R8 is hydrogen, or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1 wherein R1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R2 is hydrogen, aryl(lower)alkyl or acyl, or R1 and R2 are bonded together and form lower alkylene or lower alkenylene; R5 is carboxy or esterified carboxy; R6 is amino or acylamino; R7 is hydrogen, lower alkyl or acyl; and R9 is amino, mono or di(lower)alkylamino, acylamino, guanidino, acylguanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino or acylamino, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 4 wherein R1 is lower alkyl or hydroxy(lower)alkyl, and R2 is hydrogen, aryl(lower)alkyl or acyl, or R1 and R2 are bonded together and form lower alkylene; R5 is carboxy or esterified carboxy; R6 is amino or acylamino; R7 is hydrogen or acyl; and R9 is amino or acylamino, or a pharmaceutically acceptable salt thereof. 6. The compound of claim 5 wherein R1 is lower alkyl or hydroxy(lower)alkyl, and R2 is hydrogen, aryl(lower)alkyl, lower alkanoyl or lower alkoxycarbonyl, or R1 and R2 are bonded together and form lower alkylene; R5 is carboxy or lower alkoxycarbonyl; R6 is amino, lower alkanoylamino or lower alkoxycarbonylamino; R7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and R9 is amino, lower alkanoylamino or lower alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof. 7. The compound of claim 6 wherein R1 is lower alkyl or hydroxy(lower)alkyl, and R2 is hydrogen, or R1 and R2 are bonded together and form lower alkylene; R5 is carboxy; R6 is amino; R7 is hydrogen or lower alkanoyl; and R9 is amino, or a pharmaceutically acceptable salt thereof. 8. The compound of claim 1 wherein R4 is selected from the group consisting of —NH-A-(NH)m—(CH2)q—(CH2)p—R14, wherein R7, A, m, p and q are each as defined in claim 1, R14 is amino, mono or di(lower)alkylamino, aryl(lower)alkylamino or acylamino, R15 is guanidino or acyl guanidino, and R16 is saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino, aryl(lower)alkylamino or acylamino, or a pharmaceutically acceptable salt thereof. 9. The compound of claim 1 wherein R4 is selected from the groups consisting of wherein p is 0, 1 or 2, q is 0 or 1, R7 is hydrogen, aryl(lower)alkyl or acyl, and R9 is amino, aryl(lower)alkylamino or acylamino, or a pharmaceutically acceptable salt thereof. 10. The compound of claim 9 wherein R7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and R9 is amino, lower alkanoylamino or lower alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof. 11. The compound of claim 10 wherein R7 is hydrogen or lower alkanoyl; and R9 is amino, or a pharmaceutically acceptable salt thereof. 12. A process for preparing a compound of the formula [I]: wherein R1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R2 is hydrogen, aryl(lower)alkyl or acyl, or R1 and R2 are bonded together and form lower alkylene or lower alkenylene; R3 is hydrogen or lower alkyl; R4 is wherein A is wherein X is O or NH, R7 is hydrogen, lower alkyl, aryl(lower)alkyl or acyl, R8 is hydrogen or hydroxy, R9 is amino, mono or di(lower)alkylamino, aryl(lower)alkylamino, acyl amino, guanidino, acyl guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino, aryl(lower)alkylamino or acylamino, k, m, n and q are independently 0 or 1, and p is 0, 1, 2 or 3; R5 is carboxy or an esterfied carboxy; and R6 is amino, aryl(lower)alkylamino or acylamino, or a salt thereof, which comprises (1) reacting a compound of the formula [II]: wherein R1, R2, R3 and R4 are each as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formula [III]: wherein R5 and R6 are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof to give a compound of the formula [I]: wherein R1, R2, R3, R4, R5 and R6 are each as defined above, or a salt thereof, or (2) subjecting a compound of the formula [Ia]: wherein R1, R2, R3, R5, R6, R7, R8, A, k, m, n, p and q are each as defined above, and R9a is, aryl(lower)alkylamino or acylamino, acylguanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms substituted by aryl(lower)alkylamino or acylamino, or a salt thereof to elimination reaction of a protecting group on the amino to give a compound of the formula [Ib]: wherein R1, R2, R3, R5, R6, R7, R8, A, k, m, n, p and q are each as defined above, and R9b is amino, guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms substituted by amino, or a salt thereof, or (3) reacting a compound of the formula [VI]: wherein R5 and R6 are each as defined above, R10 is an esterfied carboxy, and Y is a leaving group, or a salt thereof with a compound of the formula [VII]: wherein R1, R2, R3 and R4 are each as defined above, or a salt thereof to give a compound of the formula [VIII]: wherein R1, R2, R3, R4, R5, R6 and R10 are each as defined above, and Z{circle around (−)} is an anion, or a salt thereof, and subjecting the compound of the formula [VIII] or a salt thereof to elimination reaction of the group protecting the esterfied carboxy, to give a compound of the formula [I]: wherein R1, R2, R3, R4, R5 and R6 are each as defined above, or a salt thereof. 13. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier. 14. A method for treating a bacterial infection comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals. 15. The compound of claim 1, which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[7-(3-aminopropionamido)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate. 16. The compound of claim 1, which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-(3-aminopropionamido)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate. 17. The compound of claim 1, which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-(aminoacetyl)amino-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylic acid hydrogen sulfate. 18. The compound of claim 1, which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylic acid hydrogen sulfate. 19. The compound of claim 1, which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-amino-4-guanidino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylic acid hydrogen sulfate.