Takeda Chemical Industries, Inc.

Taiiti Okada

Akira Morimoto

Michihiko Ochiai

Yoshihiro Matsushita

Kenji Kawakita

Osami Aki

Osamu Aki

Yasuaki Abe

Toru Ishida

Provided is a process for preparing a cephem compound of the formula: ##STR1## wherein R.sup.3 is hydrogen or methoxy, R.sup.4 is hydrogen or a residue of a nucleophilic compound, R.sup.5 is hydroxyl or a protected hydroxyl, and R.sup.8 is hydrogen or halogen, or a pharmaceutically acceptable salt or ester thereof, which comprises introducing an acyl group of the formula: ##STR2## wherein R.sup.5 and R.sup.8 are as defined above into the amino group of the molecule of the formula: ##STR3## wherein R.sup.3 and R.sup.4 are as defined above or a salt or ester thereof.

Methods for the manufacture of cephems

Broad spectrum antibiotics are provided which are compounds of the formula: ##STR1## wherein R.sup.4 is a residue of a nucleophilic compound and R.sup.5 is hydroxyl or protected hydroxyl; or a pharmaceutically acceptable salt or ester thereof.

Cephem compounds

An improved industrial process for producing a compound of the general formula: ##STR1## wherein R is an alkyl group having 1 to 4 carbon atoms which comprises reacting a compound of the general formula: ##STR2## wherein R is as defined above with nitrous acid in a mixed solvent of water and a water-insoluble or slightly soluble organic solvent.

Process for producing nitrophenol compound

Broad spectrum antibiotics are provided which are compounds of the formula: ##STR1## wherein -W-R is a residue of a nucleophilic compound and R.sup.5 is hydroxyl or protected hydroxyl, or a pharmaceutically acceptable salt or 4-carboxy ester which is the alkoxymethyl, .alpha.-alkoxyethyl, .alpha.-alkoxy-.alpha.-substituted methyl, alkylthiomethyl, acyloxymethyl or .alpha.-acyloxy-.alpha.-substituted methyl ester thereof.

A method for producing a compound of the formula: ##STR1## [wherein R.sup.1 and R.sup.2 each stand for a lower alkyl group; n denotes an integer of 0 to 21; X stands for hydrogen atom or an optionally protected hydroxyl group; and Y stands for an optionally protected hydroxyl group], which comprises reducing an ester compound of the formula: ##STR2## [wherein R.sup.1, R.sup.2, n, X and Y are of the same meaning as defined above, and R.sup.3 stands for a lower alkyl group ] with a mixture of sodium borohydride and aluminum chloride. This method give the desired compound in a high yield, and is advantageous from the industrial point of view.

Reduction of carboxylic esters

Novel cephem compounds of the formula: ##STR1## wherein R.sup.4 is a residue of a nucleophilic compound selected from hydroxyl, mercapto, cyano, azido, amino, carbamoyloxy, carbamoylthio and thiocarbamoyloxy, said group being unsubstituted or substituted by alkyl of up to three carbons, and R.sup.5 is hydroxyl or lower alkoxy, or a pharmaceutically acceptable ester thereof, have strong antibiotic properties against a wide variety of microorganisms.

Thiazolylacetamido cephalosporin compounds

3-Tertiary ammoniomethyl-7-beta-[alpha-(hydroxy or protected hydroxy)imino-alpha-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, pharmaceutically acceptable salt or 4-carboxy ester is provided which is a broad spectrum antibiotic.

Thiazolylacetamido cephalosphorin compounds

The present invention is directed to a compound having antibacterial activity of the formula ##STR1## wherein R.sup.1 represents amino, protected amino, hydroxy or protected hydroxy;

Thiazolylacetamido cephalosporin type compounds

Novel cephem compounds of the formula; ##STR1## wherein R.sup.1 represents amino or hydroxyl group which may be protected, R.sup.2 represents amino or hydroxyl group or a group convertible into these groups, R.sup.3 represents hydrogen or methoxy group or a group convertible into methoxy group, R.sup.4 represents hydrogen or a residue of a nucleophilic compound and R.sup.8 represents hydrogen or a halogen, or a pharmaceutically acceptable salt or ester thereof, have strong antibiotic properties against a wide variety of microorganisms including gram-positive bacteria as well as gram-negative ones, especially by oral administration and can be used as therapeutic agent for various bacterial infections of animals including human beings.

Thiazolylacetamido compounds

.alpha.-Alkoxyimino-.beta.-oxo-.gamma.-Bromobutyric acid

Novel cephem compounds of the formula; ##STR1## wherein R.sup.1 represents amino or hydroxyl group which may be protected, R.sup.2 represents amino or hydroxyl group or a group convertible into these groups, R.sup.3 represents hydrogen or methoxy group or a group convertible into methoxy group, R.sup.4 represents hydrogen or a residue of a nucleophilic compound and R.sup.8 represents hydrogen or a halogen, or a pharmaceutically acceptable salt or ester thereof, have strong antibiotic properties against a wide variety of microorganisms including gram-positive bacteria as well as gram-negative ones, especially by oral administration and can be used as therapeutic agent for various bacterial infections of animals including human beings. Also disclosed are novel thiazolylacetic acid compounds of the formula: ##STR2## wherein R.sup.1 represents amino, protected amino, hydroxyl or protected hydroxyl, R.sup.2 represents amino, protected amino, hydroxyl, protected hydroxyl or the group ##STR3## represents a group of the formula ##STR4## wherein R.sup.5 represents hydroxyl or lower alkoxy and R.sup.8 represents hydrogen or a halogen, or a salt, an ester or a reactive derivative thereof, and to processed for preparing these compounds. These latter compounds are useful as intermediates in the preparation of the novel cephem compounds.

A compound of the formula: ##STR1## wherein R.sup.2 is hydrogen or a halogen and R.sup.3 stands for methyl, acetoxymethyl, carbamoyloxymethyl, an alkoxymethyl, an alkylthiomethyl, 2-carboxy-1-ethenyl, or a heterocyclic thiomethyl, or a pharmaceutically acceptable salt thereof, is found to have a broad antimicrobial spectrum and, in particular, effective against Gram-negative bacteria including Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescense as well as Gram-positive ones including antibiotic resistant strains. Thus, these compounds may be used for antimicrobial agents in therapeutical purposes.

7-Methoxycephalosporin derivatives

Cephem and penam compounds having a partial structure of formula (II): ##STR1## wherein R.sup.1 and R.sup.2, respectively, represent a hydrocarbon group which is attached to P, either directly or through an oxygen atom, and which may optionally be substituted, and R.sup.3 is a hydrocarbon residue, are useful as intermediates for synthetic penicillins and cephalosporins, which in turn are useful as antibiotics or intermediates for some other synthetic penicillins and cephalosporins having antibiotic activity. To the 6- or 7-amino group of these penam or cephem compounds an objective acyl group can be introduced to give 6- or 7-acyl amino compound in a good yield, without isomerization of 6.alpha.-or 7.alpha.-substituent OR.sup.3 of the penam or cephem compounds.

7.beta.-Phosphoramido-7.alpha.-methoxycephalosporanic acid derivatives

A compound of the formula: ##STR1## wherein R.sup.1 stands for a halogenoethoxycarbonylamino and R.sup.2 stands for hydrogen or a halogen, is an important intermediate for producing a cephalosporin derivative of the formula: ##STR2## wherein R.sup.3 stands for methyl, acetoxymethyl, carbamoyloxymethyl, an alkoxymethyl, an alkylthiomethyl, 2-carboxy-1-ethenyl, or a heterocyclic thiomethyl, R.sup.5 stands for hydrogen or methoxy and R.sup.2 has the same meaning as defined before, which is active against various pathogenic microorganisms even at a low concentration.

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Kyoto, Japan

Taiiti Okada