7-Acylamino-3-substituted cephalosporanic acid derivatives, processes for their preparation and pharmaceutical compositions containing them

Claim 2

A compound of the formula: in which R 1 is a group of the formula: wherein R 4 is lower alkyl and R 5 is amino or a protected amino group, R 2 is lower alkoxymethyl, lower alkylthiomethyl or lower alkenylthiomethyl, R 3 is carboxy or a protected carboxy group, and A is lower alkylene which may have a substituent selected from the groups consisting of amino, a protected amino group, hydroxy, oxo and a group of the formula: =N~OR 6 , wherein R 6 is hydrogen, lower alkenyl, lower alkynyl, lower alkyl, or lower alkyl substituted by one or more substituent(s) selected from carboxy, a protected carboxy group, amino, a protected amino group and a heterocyclic group, and a pharmaceutically acceptable salt thereof.

Claim 3

A compound of claim 1, in which the formula: R 1- A- is a group of the formula: in which R 1 is a group of the formula: wherein R 5 is amino or acylamino, R 6 is lower alkyl, carboxy(lower)alkyl or esterified carbox y( l ower)alkyl, and R is carboxy or an esterified carboxy group.

Claim 4

A compound of claim 2, which is syn isomer.

Claim 5

A compound of claim 3, in which R 5 is amino.

Claim 6

A compound of claim 4, in which R 2 is lower alkoxymethyl or lower alkylthiomethyl, R 3 is carboxy, and R 6 is lower alkyl or carboxy(lower)alkyl.

Claim 7

A compound of claim 5, which is selected from the group consisting of: 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid or its hydrochloride, and 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyimino- acetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid.

Claim 8

A compound of claim 1, in which R 1 is a group of the formula: wherein R 5 is amino or acylamino, A is methylene, aminomethylene, acylaminomethylene, hydroxymethylene or carbonyl, and R 3 is carboxy or an esterified carboxy group.

Claim 9

A compound of claim 7, in which R 5 is amino.

Claim 10

A compound of claim 8, in which R 2 is lower alkylthiomethyl, and R 3 is carboxy.

Claim 11

A compound of claim 9, which is selected from the group consisting of: 7-[2-(2-aminothiazol-4-yl)acetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)glycinamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)glycolamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid and 7-[2-(2-aminothiazol-4-yl)glyoxylamido]-3-methyl- ' thiomethyl-3-cephem-4-carboxylic acid.

Claim 12

A compound of claim 1, in which R 1 is a group of the formula: : wherein R 4 is as defined in claim 1, A is aminomethylene or acylaminomethylene, and R 3 is carboxy or an esterified carboxy group.

Claim 13

A compound of claim 11, in which R 1 is a group of the formula: wherein R 4 is as defined above.

Claim 14

A compound of claim 12, in which R 3 is carboxy.

Claim 15

A compound of claim 13, which is selected from the group consisting of: 7-[2-(3-methanesulfonamidophenyl)glycinamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid, 7-[2-(3-methanesulfonamidophenyl)glycinamido]-3-ethylthiomethyl-3-cephem-4-carboxylic acid, 7-[2-(3-methanesulfonamidophenyl)glycinamido]-3-methoxymethyl-3-cephem-4-carboxylic acid and 7-[2-(3-methanesulfonamidophenyl)glycinamido]-3- allylthiomethyl-3-cephem-4-carboxylic acid or its trifluoroacetate.

Claim 16

A process for preparing a compound of the formula: in which R 1 is a group of the formula: wherein R 4 is lower alkyl and R 5 is amino or a protected amino group, R 2 is lower alkoxymethyl, lower alkylthiomethyl or lower alkenylthiomethyl, R 3 is carboxy or a protected carboxy group and A is lower alkylene which may have a substituent selected from the groups consisting of amino, a protected amino group, hydroxy, oxo and a group of the formula: =N~OR 6 , wherein R 6 is hydrogen, lower alkenyl, lower alkynyl, lower alkyl, or lower alkyl substituted by one or more substituent(s) selected from carboxy, a protected carboxy group, amino, a protected amino group and a heterocyclic group, and pharmaceutically acceptable salt thereof, which comprises (1) reacting a compound of the formula: in which R 2 and R 3 are each as defined above, or its reactive derivative at the amino group or a salt thereof with a compound of the formula: in which R 1 and A are each as defined above, or its reactive derivative at the carboxy group or a salt thereof to give a compound of the formula: in which R 1 , R 2 , R 3 and A are each as defined above, or a salt thereof; or (2) subjecting a compound of the formula: in which A 1 is lower alkylene having a protected amino group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof to removal reaction of the amino-protective group to give a compound of the formula: in which A 2 is lower alkylene having an amino group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (3) subjecting a compound of the formula: in which is a group of the formula: wherein R 8 is a protected amino group, and R 2 , R 3 and A are each as defined above, or a salt thereof to removal reaction of the amino-protective group to give a compound of the formula: in which is a group of the formula: and R 2 , R 3 and A are each as defined above, or a salt thereof; or (4) subjecting a compound of the formula: in which Ra is a protected carboxy group, and R 1 , R and A are each as defined above, or a salt thereof to removal reaction of the carboxy-protective group to give a compound of the formula: in which R 1 , R 2 and A are each as defined above, or a salt thereof; or (5) introducing a carboxy-protective group into a compound of the formula: in which R 1 , R 2 and A are each as defined above, or a salt thereof to give a compound of the formula: in which R 1 , R 2 , and A are each as defined above, or a salt thereof; or (6) reducing a compound of the formula: in which A3 is lower alkylene having an oxo group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof to give a compound of the formula: in which A4 is lower alkylene having a hydroxy group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (7) reacting a compound of the formula: in which A 5 is lower alkylene which may have a group of the formula: =N~OR6, wherein R 6 is as defined above, X 1 is halogen, and R 2 and R 3 are each as defined above, or a salt thereof with a compound of the formula: in which R 5 is as defined above, to give a compound of the formula: in which R 2 , R 3 , R 5 and A 5 are each as defined above, or a salt thereof; or (8) subjecting a compound of the formula: in which A is lower alkylene having a group of the formula: =N~O , wherein is lower alkyl substituted by a protected carboxy group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof to removal reaction of the carboxy-protective group to give a compound of the formula: in which A 7 is lower alkylene having a group of the formula: wherein is lower alkyl sustituted by carboxy, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (9) subjecting a compound of the formula: in which is lower alkoxycarbonyl substituted by protected amino and protected carboxy groups, and R 1 , R 2 and A are each as defined above, or a salt thereof to removal reaction of the amino- and carboxy-protective groups to give a compound of the formula: in which is lower alkoxycarbonyl substituted by amino and carboxy, and R l , R 2 and A are each as defined above, or a salt thereof, or (10) subjecting a compound of the formula: in which A 8 is lower alkylene having a group of the formula:=N~O , wherein is lower alkoxycarbonyl(lower)alkyl substituted by protected amino and protected carboxy groups or lower alkyl substituted by protected amino and protected carboxy groups, and R 1 , R2 and R 3 are each as defined above, or a salt thereof to removal reaction of the amino- and carboxy-protective groups to give a compound of the formula: in which A 9 is lower alkylene having a group of the formula: =N~O , wherein is lower alkoxycarbonyl(lower)-alkyl substituted by amino and carboxy or lower alkyl substituted by amino and carboxy, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (11) introducing a carboxy-protective group into a compound of the formula: in which R 1 , R 2 , R 3 and A 7 are each as defined above, or a salt thereof to give a compound of the formula: in which R 1 , R 2 , R 3 and A 6 are each as defined above, or a salt thereof; or (12) reacting a compound of the formula: in which A 10 is lower alkylene having a group of the formula: =N~O , wherein is lower alkyl substituted bv a group of the formula : ,and R 1 , R 2 and R 3 are each as defined above, or a salt thereof with a compound of the formula: in which R 7 is lower alkyl, to give a compound of the formula: in which A 11 is lower alkylene having a 6 group of the formula: =N~O , wherein is lower alkyl substituted by a group of the formula: wherein R 7 is as defined above, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (13) reacting a compound of the formula: in which R 1 , R 2 and A 11 are each as defined above, or a salt thereof with a base to give a compound of the formula: in which A 12 is lower alkylene having a group of the formula: =N~O , wherein is lower alkyl substituted by a cation of the formula: wherein R 7 is as defined above, and R1 and R Z are each as defined above, or a salt thereof.

Claim 17

A process for preparing a compound of the formula: in which R 1 is a group of the formula: wherein R 4 is lower alkyl and R 5 is amino or a protected amino group, R 2 is lower alkoxymethyl, lower alkylthiomethyl or lower alkenylthiomethyl, R 3 is carboxy or a protected carboxy group and A is lower alkylene which may have a substituent selected from the groups consisting of amino, a protected amino group, hydroxy, oxo and a group of the formula: =N~OR 6 , wherein R 6 is hydrogen, lower alkenyl, lower alkynyl, lower alkyl, or lower alkyl substituted by one or more substituent(s) selected from carboxy, a protected carboxy group, amino, a protected amino group and a heterocyclic group, and pharmaceutically acceptable salt thereof, which comprises (1) reacting a compound of the formula: in which R 2 and R 3 are each as defined above, or its reactive derivative at the amino group or a salt thereof with a compound of the formula: in which R 1 and A are each as defined above, or its reactive derivative at the carboxy group or a salt thereof to give a compound of the formula: in which R 1 , R 2 , R 3 and A are each as defined above, or a salt thereof; or (2) subjecting a compound of the formula: in which A 1 is lower alkylene having a protected amino group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof to removal reaction of the amino-protective group to give a compound of the formula: in which A 2 is lower alkylene having an amino group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (3) subjecting a compound of the formula: in which is a group of the formula: wherein R 8 is a protected amino group, and R 2 , R 3 and A are each as defined above, or a salt thereof to removal reaction of the amino-protective group to give a compound of the formula: in which is a group of the formula: and R 2 , R 3 and A are each as defined above, or a salt thereof; or (4) subjecting a compound of the formula: in which Ra is a protected carboxy group, and R 1 , R and A are each as defined above, or a salt thereof to removal reaction of the carboxy-protective group to give a compound of the formula: in which R 1 , R 2 and A are each as defined above, or a salt thereof; or (5) introducing a carboxy-protective group into a compound of the formula: in which R 1 , R 2 and A are each as defined above, or a salt thereof to give a compound of the formula: in which R 1 , R 2 , and A are each as defined above, or a salt thereof; or (6) reducing a compound of the formula: in which A3 is lower alkylene having an oxo group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof to give a compound of the formula: in which A4 is lower alkylene having a hydroxy group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (7) reacting a compound of the formula: in which A 5 is lower alkylene which may have a group of the formula: =N~OR6, wherein R 6 is as defined above, X 1 is halogen, and R 2 and R 3 are each as defined above, or a salt thereof with a compound of the formula: in which R 5 is as defined above, to give a compound of the formula: in which R 2 , R 3 , R 5 and A 5 are each as defined above, or a salt thereof; or (8) subjecting a compound of the formula: in which A is lower alkylene having a group of the formula: =N~O , wherein is lower alkyl substituted by a protected carboxy group, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof to removal reaction of the carboxy-protective group to give a compound of the formula: in which A 7 is lower alkylene having a group of the formula: wherein is lower alkyl sustituted by carboxy, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (9) subjecting a compound of the formula: in which is lower alkoxycarbonyl substituted by protected amino and protected carboxy groups, and R 1 , R 2 and A are each as defined above, or a salt thereof to removal reaction of the amino- and carboxy-protective groups to give a compound of the formula: in which is lower alkoxycarbonyl substituted by amino and carboxy, and R l , R 2 and A are each as defined above, or a salt thereof, or (10) subjecting a compound of the formula: in which A 8 is lower alkylene having a group of the formula:=N~O , wherein is lower alkoxycarbonyl(lower)alkyl substituted by protected amino and protected carboxy groups or lower alkyl substituted by protected amino and protected carboxy groups, and R 1 , R2 and R 3 are each as defined above, or a salt thereof to removal reaction of the amino- and carboxy-protective groups to give a compound of the formula: in which A 9 is lower alkylene having a group of the formula: =N~O , wherein is lower alkoxycarbonyl(lower)-alkyl substituted by amino and carboxy or lower alkyl substituted by amino and carboxy, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (11) introducing a carboxy-protective group into a compound of the formula: in which R 1 , R 2 , R 3 and A 7 are each as defined above, or a salt thereof to give a compound of the formula: in which R 1 , R 2 , R 3 and A 6 are each as defined above, or a salt thereof; or (12) reacting a compound of the formula: in which A 10 is lower alkylene having a group of the formula: =N~O , wherein is lower alkyl substituted bv a group of the formula : ,and R 1 , R 2 and R 3 are each as defined above, or a salt thereof with a compound of the formula: in which R 7 is lower alkyl, to give a compound of the formula: in which A 11 is lower alkylene having a 6 group of the formula: =N~O , wherein is lower alkyl substituted by a group of the formula: wherein R 7 is as defined above, and R 1 , R 2 and R 3 are each as defined above, or a salt thereof; or (13) reacting a compound of the formula: in which R 1 , R 2 and A 11 are each as defined above, or a salt thereof with a base to give a compound of the formula: in which A 12 is lower alkylene having a group of the formula: =N~O , wherein is lower alkyl substituted by a cation of the formula: wherein R 7 is as defined above, and R1 and R Z are each as defined above, or a salt thereof.

Claim 18

A pharmaceutical composition comprising, as active ingredients, the compounds of the claim 1, in admixture with pharmaceutically acceptable carriers.

Claim 19

A method for treating an infectious disease caused by pathogenic microorganisms, which comprises administering a compound of the claim 1 to infected human being and animals.

Claim 20

A compound of the formula: in which R A is amino or a protected amino group, R b ' is lower alkenyl, X is -S- or -SO-, and R 3 is carboxy or a protected carboxy group, and a salt thereof.

Claim 21

A compound of the formula: in which R A is amino or a protected amino group, R b ' is lower alkenyl, X is -S- or -SO-, and R 3 is carboxy or a protected carboxy group, and a salt thereof.

Claim 22

L9. A process for preparing a compound of the formula: in which R A is amino or a protected amino group, R b ' is lower alkenyl, X is -S- or -SO-, and R 3 is carboxy or a protected carboxy group, and a salt thereof, which comprises (1) reacting a compound of the formula: in which R a is a protected amino group, Y' is a conventional group which is capable to be replaced by the residue (-SR b' ) of the compound of the formula: HS-R b' , in which R b' is as defined above, and R 3 is as defined above, or a salt thereof with a compound of the formula: in which R b' is as defined above, or its reactive derivative at the mercapto group to give a compound of the formula: in which R a , R b' and R 3 are each as defined above, or a salt thereof; or (2) reducing a compound of the formula: in which R a , R b' and R 3 are each as defined above, or a salt thereof to give a compound of the formula: in which R a , R b' and R 3 are each as defined above, or a salt thereof; or (3) subjecting a compound of the formula: in which R a , R b' and R 3 are each as defined above, or a salt thereof to removal reaction of the amino-protective group to give a compound of the formula: in which R b' and R 3 are each as defined above, or a salt thereof.

Claim 23

L9. A process for preparing a compound of the formula: in which R A is amino or a protected amino group, R b ' is lower alkenyl, X is -S- or -SO-, and R 3 is carboxy or a protected carboxy group, and a salt thereof, which comprises (1) reacting a compound of the formula: in which R a is a protected amino group, Y' is a conventional group which is capable to be replaced by the residue (-SR b' ) of the compound of the formula: HS-R b' , in which R b' is as defined above, and R 3 is as defined above, or a salt thereof with a compound of the formula: in which R b' is as defined above, or its reactive derivative at the mercapto group to give a compound of the formula: in which R a , R b' and R 3 are each as defined above, or a salt thereof; or (2) reducing a compound of the formula: in which R a , R b' and R 3 are each as defined above, or a salt thereof to give a compound of the formula: in which R a , R b' and R 3 are each as defined above, or a salt thereof; or (3) subjecting a compound of the formula: in which R a , R b' and R 3 are each as defined above, or a salt thereof to removal reaction of the amino-protective group to give a compound of the formula: in which R b' and R 3 are each as defined above, or a salt thereof.