Cephalosporin compounds

Details Cephalosporin compounds Cephalosporin compounds

1995-01-23

1997-09-02

Ford, John M.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

540225, P07D50136

Patent

active

056633319

DESCRIPTION:

BRIEF SUMMARY
This application is a 35 USC .sctn.371 of PCT/KR93/0005, filed Jan. 16, 1993.


FIELD OF THE INVENTION

The present invention relates to new cephalosporin compounds of the formula (I), particularly 3-position of cephem rings substituted with new thione compounds and pharmaceutically acceptable salts thereof, which have broad antibacterial activities against both Gram-positive and Gram-negative bacteria.


SUMMARY OF THE INVENTION

An objective of the present invention is to provide new antibiotic cephalosporin compounds of the formula(I) or pharmaceutically acceptable salts thereof ##STR2## wherein R.sub.1 is a C.sub.1-4 alkyl (preferably ethyl or ethyl), C.sub.3-4 alkenyl(preferably allyl), C.sub.3-4 alkynyl (preferably propargyl) group or --C(R.sup.a)(R.sup.b)CO.sub.2 H(preferably --C(CH.sub.3).sub.2 CO.sub.2 H or --CH.sub.2 CO.sub.2 H), wherein R.sup.a and R.sup.b, same or different, are a hydrogen atom or a C.sub.1-4 alkyl group; alkenyl (preferably allyl), C.sub.3-4 cycloalkyl (preferably cyclopropyl)group or carboxyalkyl (preferably --CH.sub.2 CO.sub.2 H)group; nitrogen atom(s) (preferably piperazine, alkylpiperazine-substituted with C.sub.1-4 alkyl at N-- or 2-position of piperazine, imidazole-substituted or unsubstituted with C.sub.1-4 alkyl);


DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formula(I) can be prepared by reacting the compounds of the formular(II) with the new thione compounds of the formular (III), as follows: ##STR3## wherein R.sub.1 is a methyl, allyl, propargyl group or --C(CH.sub.3).sub.2 CO.sub.2 H;
In the preparation of the objective compounds(I), the compounds of the formula(III) are used preferably in an amount of from 1 to 2 equivalent(s) based on 1 equivalent of the compounds of the formula(II). The reaction for introducing the compounds(lII) into the 3-position of compound(II) to prepare compounds(I) is carried out in the presence of a solvent such as water, N,N-dimethylformamide, dimethylsulfoxide, or a mixed agueous solvent of water. An appropriate water-miscible solvent is acetonitrile or acetone.
Also, the reaction may be carried out at 40.degree. C. to 100.degree. C., preferably 60.degree. C. to 80.degree. C.
To stabilize reaction products and their intermediates, one or more salts selected from the group consisting of sodium iodide and potassium iodide can be used as stabilizing agents.
On the other hand, the separation and purification of the compounds(I) can be carried out using a known method such as recrystallization, column chromatography over silica gel or ion-exchange chromatography.
The new thione compounds of the formula(III) can be prepared from quinolone compounds which prepared by known method, as follows: ##STR4## wherein R.sub.2 is a methyl cyclopropyl, ethyl or allyl group;
The compounds of the formula(IV) can be prepared by reacting quinolone compounds, sodium borohydride with p-toluenesulfonic acid in the polar solvent, preferably alcohol.
The compounds of the formula(V) can be prepared by reacting the compounds of the formular(IV) with p-chloranil in the polar solvent, preferably 1,4-dioxane at 50.degree. C. to 100.degree. C.
Also, the compounds of the formula(VI) can be prepared by reacting the compounds of the formular(V) with phosphorus pentasulfide in the polar solvent, preferably acetonitrile, and the new thione compounds of the formula(III) can be prepared by substitution of 5- or 6-membered heterocyclic compounds-containing 1 or 2 nitrogen atom(s)(preferably piperazine, alkylpiperazine-substituted with C.sub.1-4 alkyl at N-- or 2-position of piperazine, imidazole-substituted or unsubstituted with C.sub.1-4 alkyl) at the 7-position of compounds(VI).
In case R.sub.4 is a carboxylic acid, the compounds of the formula(III) can be prepared from the compounds of the formula(VII) which prepared by known method, as follows: ##STR5## wherein R.sub.2 is a cyclopropyl;
The compounds of the formula(VIII) can be prepared by reacting with the compounds of the formular(VII) and phosphorus pentasulfide in the polar solvent, preferably acetonit

REFERENCES:
patent: 4785090 (1988-11-01), Tsuruoka et al.

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