Cephalosporins

Details Cephalosporins Cephalosporins

1997-07-21

2001-11-06

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S194000, C548S195000, C548S196000

Reexamination Certificate

active

06313305

ABSTRACT:

STATE OF THE ART
Related prior art includes EP application No. 0,266,060 and U.S. Pat. Nos. 4,486,586 and 5,075,298.
OBJECTS OF THE INVENTION
It is an object of the invention to provide the novel compounds of formula I and their non-toxic, pharmaceutically acceptable acid addition salts and a process and intermediates for their preparation.
It is another object of the invention to provide novel anti-bacterial compositions and a novel method of combatting bacterial infections in warm-blooded animals.
These and other objects and advantages of the invention will become obvious from the following detailed description.
THE INVENTION
The novel compounds of the invention are the syn isomer in (R) or (S) form or a mixture thereof of a compound of the formula
syn isomer, in the (R) or (S) form or in the form of an (R,S) mixture, in the form of an internal salt or their salts with organic or mineral acids wherein R
7
is selected from the group consisting of
R′
1
is selected from the group consisting of alkyl of 1 to 4 carbon atoms, —CN, carboxy and alkoxy carboxyl of 1 to 4 alkoxy carbon atoms, R
1
, R
2
, R
3
and R
5
are individually selected from the group consisting of hydrogen, halogen, hydroxy, alkyl of 1 to 4 carbon atoms optionally substituted with at least one member of the group consisting of halogen, alkoxy and alkylthio of 1 to 4 carbon atoms, —NO
2
, —CN, —NH
2
, mono- and dialkylamino of 1 to 4 carbon atoms, carbamoyl, (alkylamino) carbonyl of 2 t o 5 carbon atoms, (dialkylamino) carbonyl of 3 to 9 carbon atoms, carboxy, alkoxycarbonyl of 2 to 5 carbon atoms, acyloxy of 1 to 8 carbon atoms and
Rx and Ry are individually hydrogen or alkyl of 1 to 4 carbon atoms, R
4
is —OH or acyloxy of 1 to 8 carbon atoms, A and A′ are individually selected from the group consisting of hydrogen, an equivalent of an alkali metal or alkaline earth metal, magnesium, ammonium and an organic amine, or one or two of —COOA or —COOA′ are —CO
2
−
, the wavy line means —CH
2
R
6
can be in the E or Z position, R
6
in the quaternary ammonium form is selected from the group consisting of
X is selected from the group consisting of —CH
2
—, —NH—, —O— and —S—, Q, J, Y, T, U, V, W and Z are individually ═N— or —CH═, each of cyclics containing 1 to 5 heteroatoms of which at least one is ═N— and optionally substituted by at least one R or R′, R and R′ are individually selected from the group consisting of halogen, alkyl and alkoxy of 1 to 4 carbon atoms, halogen, —CN, —COOQ
1
, —CONQ
1
Q
2
, —NQ
1
Q
2
, —SO
2
NQ
1
Q
2
, —CSNH
2
, —NHCOQ
1
, —CH═NOH, —CH═N—O—Q
1
, —CH
2
CN and —CH
2
—S—Q
1
, Q
1
and Q
2
are individually hydrogen or alkyl of 1 to 4 carbon atoms, P
1
, P
2
and P
3
are individually alkyl of 1 to 4 carbon atoms optionally substituted with a substituent of R or R′ or P
1
and P
2
taken together with the nitrogen to which they are attached form a 5 or 6 ring heterocyclic with the proviso that when R
3
is —OH or alkoxy of 1 to 8 carbon atoms, at least one of R
1
, R
2
and R
5
is other than hydrogen.
Examples of alkyl and alkoxy of 1 to 4 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy. Examples of alkylthio of 1 to 4 carbon atoms are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio and tert.-butylthio.
Examples of alkylamino of 1 to 4 carbon atoms are methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec.-butylamino and tert.-butylamino while examples of dialkylamino of 2 to 8 carbon atoms are dimethylamino, diethylamino, diproplylamino, diisopropylamino, dibutylamino, diisobutylamino, ethyl methylamino, propyl methylamino, butyl methylamino and propyl ethylamino.
Examples of (alkylamino) carbonyl of 2 to 5 carbon atoms are (methylamino) carbonyl, (ethylamino) carbonyl, (propylamino) carbonyl, (isopropylamino) carbonyl and (butylamino) carbonyl. Examples of alkoxycarbonyl of 2 to 5 carbon atoms are methoxycarbonyl and ethoxycarbonyl. Examples of (dialkylamino) carbonyl or 3 to 9 carbon atoms are (dimethylamino) carbonyl, (diethylamino) carbonyl, (dipropylamino) carbonyl.
Examples of acyloxy of 1 to 8 carbon atoms are acetoxy, propionyloxy and benzoyloxy while examples of halogen are fluorine, chlorine, bromine or iodine.
When P
1
and P
2
form a heterocycle with the nitrogen atom to which they are attached, it may be pyrrolidine, morpholine or piperidine. When R
4
is acyloxy, it is preferably acetoxy, propionyloxy or benzoyloxy.
Among the values of A′ and A are an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium and organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris[(hydroxymethyl)-amino]-methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine and N-methylglucamine.
The products of formula I can also appear in the form of a pure internal salt, in salified form or in a combined form with the acids of the solution. Among the acids with which the products of formula I can be salified include acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid.
In the invention, more preferably A′ is hydrogen and CO2A is CO
2
−
.
The expression in the form of quaternary ammonium indicates that R
6
is linked by one of the nitrogen atoms that it contains. Preferably R
6
is one of the following:
Prefered compounds are those wherein:
R
6
is quinolinium, isoquinolinium, 4-(methylthio)-pyridinium, thieno-[2,3-b]pyridinium, imidazo(1,2-a)pyridinium or 6,7-dihydro-5H-pyridinium, those in which R
3
and R
4
individually are hydroxy and those in which R
2
and R
5
are chlorine or fluorine, those in which R
1
and R
2
are fluorine and those in which R
2
is methoxy and one of R
1
or R
5
is chlorine and those wherein R′
1
is —CH, —COOH or alkoxycarbonyl.
Specific compounds of the invention are the internal salt of (6R-(3-(E) 6&agr;, 7&bgr;(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl) imidazo(1,2-a)pyridinium,
the internal salt of (6R-(3-(E) 6&agr;, 7&bgr;(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0)oct-2-en-3-yl)-2-propenyl)-imidazo)pyridinium,
the internal salt of (6R-(3-(E) 6&agr;, 7&bgr;(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2-chloro-4,5-dihydroxy-3-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium,
the internal salt of (6R-(3-(E) 6&agr;, 7&bgr;(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyridinium,
the internal salt of (6R-(3-(E) 6&agr;, 7&bgr;(Z(S*))))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3,4-dihydroxy-5-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium,
the internal salt of [6R-[3(E), 6&agr;, 7&bgr;(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(2-chloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium (R) or (S) or an (R+S) mixture,
the internal salt of [6R-(3(E), 6&agr;, 7&bgr;(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(3-cyano-4,5-dihydroxy-phenyl)-methoxy]-imino)-acetamido

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