Yamanouchi Pharmaceutical Company Ltd.

Yukiyasu Murakami

Akio Koda

Noriaki Nagano

Tadao Shibanuma

Kohji Nakano

Ryuichiro Hara

Minoru Okada

Yasuo Isomura

Toichi Takenaka

Tadao Kojima

Atsuki Yamazaki

Ichiro Isaka

Hideki Arima

Kazuharu Tamazawa

Kiyoshi Takanobu

Masuo Murakami

Masaru Iwanami

Isao Souzu

Teruaki Ozasa

Teruya Kashiwagi

Kuniichiro Yano

Kohzi Nakano

Norio Kawahara

Isao Souzo

Khozi Nakano

Teruya Ashiwagi

A process is provided for producing diastereoisomer A or a pharmaceutically acceptable acid addition salt of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzylpyrrolidin-3-yl) ester 5-methyl ester which comprises subjecting a mixture of diastereoisomers A and B of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzylpyrrolidin-3-yl) ester 5-methyl ester to column chromatography using silica gel as a carrier and a mixture of ethyl acetate and acetic acid as an eluant, and then separating the acetate of diastereoisomer A from the eluate, or treating the acetate with a base, or further treating the resulting diastereoisomer A with a pharmaceutically acceptable acid.

Dihydropyridine-3, 5-dicarboxylic acid ester derivatives

A dextro-rotatory optical isomer of diastereoisomer A of (.+-.)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzylpyrrolidin-3-yl)ester 5-methyl ester is provided having the formula ##STR1## and wherein the melting point of the hydrochloride of the dextro-rotatory optical isomer is 223.degree. to 230.degree. C. (decomp.), or a pharmaceutically acceptable acid addition salt thereof.

Dihydropyridine-3,5-dicarboxylic acid ester derivatives

The diastereoisomer A of a dihydropyridine-3,5-dicarboxylic acid ester derivative is provided as well as its pharmaceutically acceptable acid addition salts. The invention further discloses a process for producing the compounds and their use as medicaments in imparting vasodilating activity.

Various 7-amino-3-substituted-methyl-3-cephem-4-carboxylic acids and lower alkylsily derivatives such as 7-amino-3-(2,3-cyclopenteno-1-pyridiniomethyl)-3-cephem-4 -carboxylic acid iodide and trimethylsilyl 7-trimethylsilylamino-3 -(5,6,7,8-tetrahydro-2-isoquinoliniomethyl)-3-cephem-4 -carboxylate iodide are valuable intermediates in the preparation of new and novel antibacterial agents. A new process for the preparation of these acids and the derivatives has been devised.

Amino-3-substituted-methyl-3-cephem-4-carboxylic acid and lower

Various 7-amino-3-substituted-methyl-3-cephem-4-carboxylic acids and lower alkylsilyl derivatives such as 7-amino-3-(2,3-cyclopenteno-1-pyridiniomethyl)-3-cephem-4-carboxylic acid iodide and trimethylsilyl 7-trimethyl-silylamino-3-(5,6,7,8-tetrahydro-2-isoquinoliniomethyl)-3-ceph em-4-carboxylate iodide are valuable intermediates in the preparation of new and novel antibacterial agents. A new process for the preparation of these acids and the derivatives has been devised.

Process for preparing 3-substituted-methyl-3-cephem derivatives

Novel cephalosporin compounds of the formula ##STR1## wherein the wavy line means syn-form and anti-form bonds, R.sup.1 represents a cyanomethyl group, a thiocarbamoylmethyl group or an aminothiazolylmethyl group, and A represents a unsubstituted or substituted pyridinio group; and salts thereof. These compounds have excellent antibacterial activities.

Cephalosporin compounds and salts thereof

Novel cephem compounds are provided having the formula: ##STR1## wherein R represents lower alkyl, which may be substituted with lower acyloxy, lower alkylthio or certain 5 or 6-membered heterocyclic ring-containing groups. The cephem compounds and salts thereof exhibit antibacterial activity to many pathogens. A process for producing the cephem compounds is also provided.

Cephem compounds

A cephalosporin derivative of the formula ##STR1## wherein R is a hydrogen atom, a lower alkyl group which may have been substituted or a carbamoyl group which may have been substituted; R.sub.1 is hydrogen atom or a methoxy group; R.sub.2 is a hydrogen atom, an acyloxy group, or a nitrogen-containing 5-membered heterocyclic thio group which may have been substituted; R.sub.3 is a free amino group or an amino group having a protective group; and R.sub.4 is a free carboxy group or a carboxy group having a protective group or the salts thereof. The compound of this invention has an excellent antibacterial activity against gram negative bacteria and gram positive bacteria.

Cephalosporin derivative and pharmaceutical composition

Cephalosporin compounds represented by the general formula ##STR1## wherein R represents a group shown by formula ##STR2## wherein R.sup.1 represents a hydrogen atom or a lower alkyl group of 1-3 carbon atoms and R.sup.2 represents a hydrogen atom, a lower alkyl group of 1-3 carbon atoms, a phenyl group which may be substituted by an amino or hydroxy group, a cyano group, a carboxy group, or a carboxymethyl group; said R.sup.1 and R.sup.2 may form a cycloalkylidene group of 4-6 carbon atoms together with the carbon atom to which they are bonded) or a group shown by formula --CH.sub.2 --R.sup.3 (wherein R.sup.3 represents a hydrogen atom, a halogenomethyl group, a carbamoyl group, a carboxymethyl group, .alpha.4-carboxy-3-hydroxyisothiazol-5-yl-thiomethyl group, or .alpha.2-carboxyphenylthiomethyl group); R' represents a group shown by formula ##STR3## (wherein R.sub.a represents a carboxy group, a cyano group, or a carbamoyl group which may be substituted by a lower alkyl group of 1-3 carbon atoms and R.sub.b represents a hydrogen atom or an amino group) or a group shown by formula ##STR4## (wherein R.sub.a and R.sub.b have the same significance as above); and the waveline .about. shows an anti-form or syn-form bond and the salts thereof. They possess excellent antibacterial activities against gram positive bacteria and gram negative bacteria, in particular, pseudomonas aeruginosa and are useful as anti-bacterial agents.

Cephalosporin compounds

Cephalosporin compounds shown by the general formula ##STR1## wherein R.sub.1 represents hydrogen atom or an amino group; R.sub.2 and R.sub.3, which may be the same or different, each represents hydrogen atom, a hydroxy group, an oxo group, a lower alkyl group, or a lower alkoxy group; R.sub.4 represents a hydrogen atom or a lower alkoxy group; R.sub.5 represents an acetoxy group or --S--R.sub.6 (wherein R.sub.6 represents a 5- or 6-membered nitrogen-containing heterocyclic group which can be substituted by a lower alkyl group or lower alkoxy group); and A represents a monocyclic or bicyclic heterocyclic ring containing one or two atoms selected from the group consisting of nitrogen, oxygen and a sulfur atom; and pharmaceutically acceptable nontoxic salts thereof. These compounds have excellent antimicrobial activity against various microorganisms including resistant bacteria and are used for the treatment of bacterial infections of animals including human beings.

The ampicillin derivatives represented by the general formula ##SPC1## Wherein R represents ##SPC2## Wherein R' represents a hydrogen atom, a methyl group, or an ethyl group and A and B each represents a hydrogen atom, a hydroxyl group, a methyl group, a methoxy group, a nitro group, or a halogen atom and further said B may combine with A on the carbon atom at the position to form ##SPC3## Group (where in Z represents --CH=N-- or --CH=CH-- and an R.sup.2 represents a hydrogen atom, a hydroxyl group, a phenyl group, a methyl group, an ethyl group, a methoxy group, an ethoxyl group, a methylthio group, a trifluoromethyl group, a halogen atom, a nitro group, an acetyl group, an acetamido group, a ethoxycarbonyloxy group, or a methylsulfonyl group and further R.sub.2 and ##SPC4## May form a thiazole, isothiazolo, pyrrolo, furo, or benzo fused ring which may be substituted by an oxo group, a methyl group, or an acetyl group) and the dotted line means an arbitrary double bond, ##SPC5## Wherein R.sup.3 and R.sup.4 each represents a hydrogen atom or a methyl group, ##SPC6## Wherein R.sup.5 represents a halogen atom, a methoxy group, a nitro group, or a hydroxyl group and R.sup.6 represents a hydrogen atom, a methoxy group, a halogen atom, a nitro group, or a hydroxyl group, or ##SPC7## Wherein R.sup.7 represents a hydrogen atom or a hydroxyl group, Y represents O or S, and the dotted line means an arbitrary double bond, said substituent group, being bonded to the ampicillin molecule through --CO-- at the 2-position, 3-position, 5-position or 6-position when the oxo group (+0) is at the 4-portion and being bonded to the ampicillin molecule through the --CO-- group at the 2-position, 4-position, or 5-position when the oxy group is at the 6-position, and salts of the ampicillin derivatives. Those compounds are valuable as antibacterial agents.

Ampicillin derivatives substituted by heterocyclic acyl group

The penicillin derivatives represented by the formula ##SPC1## Wherein ring A represents a 5- or 6-membered single or fused ring which may contain one or more nitrogen atoms, an oxygen atom, or a sulfur atom; R.sup.1, R.sup.2, and R.sup.3, which may be the same or different, each represents a hydrogen atom, a hydroxy group, a lower alkyl group, a nitro group, a halogen atom, or an oxo group; and B represents a p-hydroxyphenyl group or a 1,4-cyclohexadien -1-yl group, and their nontoxic pharmaceutically acceptable salts. The compounds are antibiotics having excellent antibacterial activity in particular with respect to the Pseudomonas genus.

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Saitama, Japan

Yukiyasu Murakami