Yamanouchi Pharmaceutical Company Ltd.

Akio Koda

Yukiyasu Murakami

Ichiro Isaka

Masuo Murakami

Noriaki Nagano

Tadao Shibanuma

Atsuki Yamazaki

Kohji Nakano

Ryuichiro Hara

Teruya Kashiwagi

Kohzi Nakano

Kozo Takahashi

Masaru Iwanami

Isao Souzu

Teruaki Ozasa

Kuniichiro Yano

Norio Kawahara

Hidefumi Matsui

Hiroshi Horiguchi

Khozi Nakano

Teruya Ashiwagi

Isao Souzo

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

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 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.

Cephalosporin compounds

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 oxofuryl ester derivatives of 6-(.alpha.-amino-phenylacetamido)penicillanic acid, 7-(.alpha.-aminophenylacetamido)-cephalosporanic acid, or 7-(.alpha. -aminophenylacetamide)desacetoxycephalosporanic acid represented by the general formula ##SPC1## Wherein A represents ##SPC2## Wherein R.sup.1 and R.sup.2, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, said R.sup.1 and R.sup.2 may form together a 1,3-butadienylene group, R.sup.3 represents a hydrogen atom or an acetoxy group, and Means a single bond or a double bond, and acid addition salts of them. When those compounds are orally administered, they are readily absorbed by the intestines and show antibacterial activity by splitting their ester bonds. The rate of absorption of the compounds by the intestines are higher and the toxic property of them is less than those of known compounds similar to the above compounds.

Novel oxofuryl ester derivatives of penicillin and cephalosporin

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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Tokyo, Japan

Akio Koda