Sumitomo Chemical Company, Limited

Kozo Shimago

Hisao Tobiki

Takenari Nakagome

Hirotada Yamada

Toshiaki Komatsu

Yasuko Eda

Hiroshi Noguchi

Akio Izawa

Norihiko Tanno

Iwao Nakatsuka

Shigeru Okano

Kenji Irie

Kosaku Okamura

Naohito Ohashi

Kikuo Ishizumi

Takaharu Ikeda

Kousaku Okamura

Kaoru Maeshima

Takeo Takahashi

Norithiko Tanno

Toyozo Katsura

Yasushi Taira

A process for preparing an optically active cis-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione of the formula: ##STR1## wherein an asterisk (*) indicates an asymmetric carbon, Bzl represents a benzyl group and the 3a- and 6a-positions take the cis-configuration, which comprises reducing selectively an optically active cis-imidazolidinedicarboxylic acid monoester of the formula: ##STR2## wherein R is a C.sub.1 -C.sub.6 alkyl group and Bzl is as defined above with a reducing agent at either one of the carboxyl group and the alkoxycarbonyl group in the said monoester, followed by cyclization.

Preparation of optically active

A process for preparing biotin, characterized in that a compound of the formula: ##STR1## wherein R.sup.1 and R.sup.2 are each hydrogen or benzyl and R.sup.3 is hydrogen or carboxyl, with the proviso that R.sup.1 and R.sup.2 are not simultaneously hydrogen, or a mixture of two or more different compounds of the formula [I] is heated in the presence of an alkanesulfonic acid.

Process for preparing biotin

A process for preparing an optically active cis-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione of the formula: ##STR1## wherein an asterisk (*) indicates an asymmetric carbon, Bzl represents a benzyl group and the 3a- and 6a-positions take the cis-configuration, which comprises reducing selectively an optically active cis-imidazolidinedicarboxylic acid monoester of the formula: ##STR2## wherein R is a C.sub.1 -C.sub.6 alkyl group and Bzl is as defined above with a reducing agent at either one of the carboxyl group and the alkoxycarbonyl group in the said monoester, followed by cyclization, the said monoester being the one obtainable by hydrolysis of a cis-imidazolidinedicarboxylic acid diester of the formula: ##STR3## wherein R and Bzl are each as defined above with an enzymatic material having a capability of hydrolyzing the ester group in the said diester.

Intermediates to optically active

A cephalosporin derivative of the formula (I), ##STR1## wherein A is a mono- or polycyclic heteroaromatic ring, which contains at least one nitrogen atom as a hetero atom and which may be substituted with one or more substituents; R is a phenyl group substituted with at least one substituent selected from the group consisting of an amino group, a hydroxy group, a ureido group and a hydroxymethyl group; and X is an --OCOCH.sub.3 group or an --S-Het group in which Het is a 5- or 6-membered heterocyclic ring containing one to four hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms which may be substituted with one or more substituents, and the non-toxic pharmaceutically acceptable salts thereof which are useful as an antimicrobial and prepared by the reaction of a compound of the formula (II),

N-acylamino-.alpha.-arylacetamido cephalosporins

N-acylamino-alpha-arylacetamido cephalosporins and antibacterial

A cephalosporin derivative of formula (I): ##STR1## wherein X is an --OCOCH.sub.3 group or an --S--Het group in which Het is a 5- or 6-membered heterocyclic ring containing one to four hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, which may be substituted with one or more substituents, and the non-toxic pharmaceutically acceptable salts thereof which are useful as an antimicrobial material and which are prepared by the reaction of a compound of formula (II): ##STR2## or a reactive derivative thereof, with a compound of formula (III): ##STR3## wherein X is as defined above, or a derivative thereof.

7-(.alpha.-(4-Hydroxy-1,5-naphthyridine-3-carbonamido)-.alpha.-ph

A cephalosporin derivative of formula (I): ##STR1## wherein X is an --OCOCH.sub.3 group or an -S-Het group in which Het is a 5- or 6-membered heterocyclic ring containing one to four hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, which may be substituted with one or more substituents, and the non-toxic pharmaceutically acceptable salts thereof which are useful as an antimicrobial material and which are prepared by the reaction of a compound of formula (II): ##STR2## or a reactive derivative thereof, with a compound of formula (III): ##STR3## wherein X is as defined above, or a derivative thereof.

7-(.alpha.-(4

A penicillin of the formula: ##STR1## (i.e. 6-[D-2-(3-hydroxypyridazine-4-carbonamido)-2-(p-hydroxyphenyl)acetamido]pe nicillanic acid), which is valuable as an antibacterial agent, a nutritional supplement in animal feeds and a therapeutic agent in poultry and mammals including man and is especially useful in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria.

Novel penicillin, and its preparation and use

A penicillin of the formula: ##STR1## wherein ##STR2## is a six-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as the hetero atom, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl, R.sub.1 and R.sub.2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmercapto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano or R.sub.1 and R.sub.2 may link together to form a lower alkylene chain which may be substituted with an oxo group, and Z is phenyl, hydroxyphenyl, lower alkyl, cyclohexadienyl, thienyl or isothiazolyl, which is prepared by reacting a compound of the formula: ##STR3## wherein Z is as defined above or its derivative with a carboxylic acid of the formula: ##STR4## wherein ##STR5## and R.sub.2 are each as defined above or its reactive derivative, if necessary, followed by hydrolysis or acylation of the resulting product and/or elimination of any protective group and which is useful as an antimicrobial agent against various gram-positive and gram-negative bacteria including Pseudomonas.

Penicillins

Penicillins of the formula: ##STR1## wherein R is an unsubstituted phenyl group or a substituted phenyl group having one or more hydroxyl groups or a cyclohexadienyl group and A represents a monocyclic or polycyclic nitrogen-containing heterocyclic aromatic ring, which are useful as antimicrobial agents having a broad antimicrobial spectrum against gram-positive and gram-negative bacteria including Pseudomonas and can be produced advantageously from the phenacyl ester of 6-aminopenicillanic acid through a series of steps.

Penicillins and their preparation

Novel penicillins of the formula: ##STR1## wherein the ring A is a benzene ring or a 5 or 6-membered heteroaromatic ring containing one or two nitrogen atoms as the hetero atom, on which one or more of lower alkyl, lower alkoxy, lower alkylthio, lower haloalkyl, lower alkylenedioxy halogen, hydroxyl, nitro, free or protected amino, lower alkylamino, di(lower)alkylamino and lower alkanoylamino may be present, Z is a nitrogen atom or a methylene group, X is an oxygen atom or a sulfur atom, Y is a hydrogen atom, a lower alkoxycarbonyl group or a lower alkanoyl group, R.sub.1 is a free or protected hydroxyl group and R.sub.2 and R.sub.3 are each a hydrogen atom or a halogen atom, and their non-toxic pharmaceutically acceptable salts, and their preparation.

Novel penicillins and their preparation

Novel penicillins of the formula ##SPC1## Wherein ##EQU1## represents a substituted or unsubstituted benzene or nitrogen atom-containing heteroaromatic ring which may be substituted, ##EQU2## represents a pyridine, pyrazine or pyridazine ring, X represents an oxygen or sulfur atom, Y represents a hydrogen atom or a loer alkoxycarbonyl or lower alkanoyl group, and R.sub.1, R.sub.2 and R.sub.3 are each a hydrogen or halogen atom or a nitro, lower alkylamino, di(lower)alkylamino, aine, lower alkoxycarbonylamino, lower alkanoylamino, amino(lower)alkyl, lower alkyl, lower alkoxy, hydroxyl, sulfamoyl, trifluoromethyl, lower alkylthio or lower alkylsulfonyl group, excluding the cases where all of R.sub.1, R.sub.2 and R.sub.3 are hydrogen atoms and where R.sub.1 is a hydroxyl group and R.sub.2 and R.sub.3 are each a hydrogen or halogen atom, and their nontoxic, pharmaceutically acceptable salts, which can be prepared by reacting a carboxylic acid of the formula: ##EQU3## wherein ##EQU4## X and Y are each as defined above or its reactive derivative with a compound of the formula: ##SPC2## Wherein R.sub.1, R.sub.2 and R.sub.3 are each as defined above or its reactive derivative, and are ueful as antimicrobial agents against gram-positive and gram-negative bacteria including Pseudomonas.

Penicillins substituted with heterocyclic and substituted phenyl groups

Novel penicillins of the formula: ##SPC1## Wherein the ring A is a benzene ring or a 5 or 6-membered heteroaromatic ring containing one or two nitrogen atoms as the hetero atom, on which one or more of lower alkyl, lower alkoxy, lower alkylthio, lower haloalkyl, lower alkylenedioxy, halogen, hydroxyl, nitro, free or protected amino, lower alkylamino, di(lower)alkylamino and lower alkanoylamino may be present, Z is a nitrogen atom or a methylene group, X is an oxygen atom or a sulfur atom, Y is a hydrogen atom, a lower alkoxycarbonyl group or a lower alkanoyl group, R.sub.1 is a free or protected hydroxyl group and R.sub.2 and R.sub.3 are each a hydrogen atom or a halogen atom, and their non-toxic pharmaceutically acceptable salts, and their preparation.

Naphthyridine-3-carboxamido-benzylpenicillins and salts thereof

A penicillin of the formula: ##SPC1## Wherein A is a substituted or unsubstituted condensed aromatic carbocyclic or heterocyclic ring, R is hydrogen or lower alkyl, X is oxygen or sulfur, Y is hydrogen, lower alkyl, lower alkanoyl or lower alkoxycarbonyl and Z is phenyl or thienyl which can be produced by reacting 6-aminopenicillanic acid or its ester with a carboxylic acid of the formula: ##SPC2## Wherein A, R, X, Y and Z are each as defined above or its reactive derivative. The said penicillin and its non-toxic salts have a broad antimicrobial spectrum against various gram-positive and gram-negative bacteria, and they exhibit characteristically a strong antimicrobial activity against Pseudomonas.

Penicillins substituted with heterocyclic groups

Penicillins of the formula: ##SPC1## Wherein R is an unsubstituted phenyl group or a substituted phenyl group having one or more hydroxyl groups or a cyclohexadienyl group and A represents a monocyclic or polycyclic nitrogen-containing heterocyclic aromatic ring, which are useful as antimicrobial agents having a broad antimicrobial spectrum against gram-positive and gram-negative bacteria including Pseudomonas and can be produced advantageously from the phenacyl ester of 6-aminopenicillanic acid through a series of steps.

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Takarazuka, Japan

Kozo Shimago