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Claims for Patent: 7,129,232

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Claims for Patent: 7,129,232

Title:Cephem compounds
Abstract: The present invention relates to a compound of the formula [I]: ##STR00001## wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen or amino protecting group, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.3 is hydrogen or lower alkyl; R.sup.4 is ##STR00002## R.sup.5 is carboxy or protected carboxy; and R.sup.6 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): Ohki; Hidenori (Osaka, JP), Okuda; Shinya (Osaka, JP), Yamanaka; Toshio (Osaka, JP), Ohgaki; Masaru (Osaka, JP), Toda; Ayako (Osaka, JP), Kawabata; Kohji (Osaka, JP), Inoue; Satoshi (Takata-gun, JP), Misumi; Keiji (Takata-gun, JP), Itoh; Kenji (Takata-gun, JP), Satoh; Kenji (Takata-gun, JP)
Assignee: Astellas Pharma Inc. (Tokyo, JP) Wakunaga Pharmaceutical Co., Ltd (Osaka, JP)
Application Number:10/695,895
Patent Claims: 1. A compound of the formula [I]: ##STR00019## wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.3 is hydrogen or lower alkyl; R.sup.4 is ##STR00020## wherein A is ##STR00021## wherein X is O or NH, R.sup.7 is hydrogen, lower alkyl, aryl(lower)alkyl or acyl, R.sup.8 is hydrogen or hydroxy, R.sup.9 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; R.sup.5 is carboxy or an esterfied carboxy; and R.sup.6 is amino, aryl(lower)alkylamino or acylamino, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.3 is hydrogen; A is ##STR00022## wherein X is O or NH; R.sup.7 is hydrogen, aryl(lower)alkyl or acyl; R.sup.9 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 R.sup.8 is hydrogen, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.5 is carboxy or esterified carboxy; R.sup.6 is amino or acylamino; R.sup.7 is hydrogen, lower alkyl or acyl; and R.sup.9 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 R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.5 is carboxy or esterified carboxy; R.sup.6 is amino or acylamino; R.sup.7 is hydrogen or acyl; and R.sup.9 is amino or acylamino, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl, lower alkanoyl or lower alkoxycarbonyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.5 is carboxy or lower alkoxycarbonyl; R.sup.6 is amino, lower alkanoylamino or lower alkoxycarbonylamino; R.sup.7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and R.sup.9 is amino, lower alkanoylamino or lower alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.5 is carboxy; R.sup.6 is amino; R.sup.7 is hydrogen or lower alkanoyl; and R.sup.9 is amino, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein R.sup.4 is selected from the group consisting of --NH-A-(NH).sub.m--(CH.sub.2).sub.q--(CH.sub.2).sub.p--R.sup.14, ##STR00023## wherein R.sup.7, A, m, p and q are each as defined in claim 1, R.sup.14 is amino, mono or di(lower)alkylamino, aryl(lower)alkylamino or acylamino, R.sup.15 is guanidino or acyl guanidino, and R.sup.16 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 R.sup.4 is selected from the groups consisting of ##STR00024## wherein p is 0, 1 or 2, q is 0 or 1, R.sup.7 is hydrogen, aryl(lower)alkyl or acyl, and R.sup.9 is amino, aryl(lower)alkylamino or acylamino, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 wherein R.sup.7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and R.sup.9 is amino, lower alkanoylamino or lower alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 wherein R.sup.7 is hydrogen or lower alkanoyl; and R.sup.9 is amino, or a pharmaceutically acceptable salt thereof.

12. A process for preparing a compound of the formula [I]: ##STR00025## wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.3 is hydrogen or lower alkyl; R.sup.4 is ##STR00026## wherein A is ##STR00027## wherein X is O or NH, R.sup.7 is hydrogen, lower alkyl, aryl(lower)alkyl or acyl, R.sup.8 is hydrogen or hydroxy, R.sup.9 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; R.sup.5 is carboxy or an esterfied carboxy; and R.sup.6 is amino, aryl(lower)alkylamino or acylamino, or a salt thereof, which comprises (1) reacting a compound of the formula [II]: ##STR00028## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formula [III]: ##STR00029## wherein R.sup.5 and R.sup.6 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]: ##STR00030## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each as defined above, or a salt thereof, or (2) subjecting a compound of the formula [Ia]: ##STR00031## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8, A, k, m, n, p and q are each as defined above, and R.sup.9a 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]: ##STR00032## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8, A, k, m, n, p and q are each as defined above, and R.sup.9b 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]: ##STR00033## wherein R.sup.5 and R.sup.6 are each as defined above, R.sup.10 is an esterfied carboxy, and Y is a leaving group, or a salt thereof with a compound of the formula [VII]: ##STR00034## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each as defined above, or a salt thereof to give a compound of the formula [VIII]: ##STR00035## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.10 are each as defined above, and Z.sup.{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]: ##STR00036## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 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 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)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 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)acetamido]-3-[3-amino-4-(3-aminopropionamido)-2-methyl-1-pyrazolio]- methyl-3-cephem-4-carboxylate.

17. The compound of claim 1, which is 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)acetamido]-3-[3-amino-4-(aminoacetyl)amino-2-methyl-1-pyrazolio]met- hyl-3-cephem-4-carboxylic acid hydrogen sulfate.

18. The compound of claim 1, which is 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazol- io}methyl-3-cephem-4-carboxylic acid hydrogen sulfate.

19. The compound of claim 1, which is 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)acetamido]-3-(3-amino-4-guanidino-2-methyl-1-pyrazolio)methyl-3-cep- hem-4-carboxylic acid hydrogen sulfate.
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