Shionogi Company Limited

Shionigi & Co., Ltd.

Hiromu Matsumura

Toshisada Yano

Masami Eigyo

Akira Matsushita

Hiroshi Hashizume

Masayuki Narisada

Wataru Nagata

Tsutomu Sugasawa

Teruji Tsuji

Fumihiko Watanabe

Tetsuo Okada

Makoto Adachi

Nobuhiro Ibii

Teruo Shiomi

Adachi Makoto

The compounds of the present invention relates to tetrahydropyridine derivatives and have high affinity and specificity to .sigma. receptors, whereby these are thought to be effective for some psychoses.

Tetrahydropyridine derivatives

A compound of the formula: ##STR1## wherein n is an integer of from 2 to 6; and p and q each is an integer of 0 or 1, excluding the case where p is 0 when q is 1; or a pharmaceutically acceptable acid addition salt thereof. This compound has a high affinity and specificity to .sigma. receptors, and is thought to be effective for treatment of some psychoses.

A compound of the formula (I): ##STR1## wherein X.sup.1 nd X.sup.2 each independently represents lower alkyl, lower alkoxy or halogen or a pharmaceutically acceptable salt thereof, which is useful as an active ingredient for a pharmaceutical composition for treating antidepressant or aftereffects of cerebrovascular impairments.

Piperidine derivatives and process for preparation thereof

The present invention relates to tetrahydropyridine derivatives which have high affinity and specificity to .sigma. receptors, whereby these compounds are thought to be effective for treatment of some psychoses.

A compound of the formula: ##STR1## wherein R.sup.1 is hydrogen, or C.sub.1 14 C.sub.6 alkyl; n is an integer of from 2 to 3; Z.sup.1 is phenyl, benzyl, or isoxazolyl and each is optionally substituted by a halogen, a methoxy, or a methyl group; Z.sup.2 is hydrogen, C.sub.1 -C.sub.5 alkyl, allyl, unsubstituted phenyl, or phenyl substituted by halogen, methyl, or methoxy; or

Carbamoylpyrrolidone derivatives and drugs for senile dementia

Teirahydropyridine derivatives

A compound of the formula: ##STR1## (wherein R is phenoxy optionally substituted by a halogen, methoxy, or methyl group, ##STR2## one of A and B is ##STR3## and the other is &gt;CH.sub.2 ;

A compound of the formula: ##STR1## (wherein R is phenoxy optionally substituted by a halogen, methoxy, or methyl group, ##STR2## one of A and B is ##STR3## and the other is &gt;CH.sub.2 : R.sup.1 is hydrogen or C.sub.1 -C.sub.5 alkyl; Z.sup.1 is phenyl, benzyl, or isoxazolyl each optionally substituted by a halogen, methoxy, or methyl group; Z.sup.2 is hydrogen, C.sub.1 -C.sub.5 alkyl, C.sub.2 -C.sub.5 alkenyl, or phenyl optionally mono-, di-, or tri-substituted by a halogen, methoxy, or methyl group; or Z.sup.1 and Z.sup.2 taken together with the adjacent nitrogen atom may form 5-membered heterocyclic group; Z.sup.3 is C.sub.1 -C.sub.5 hydroxyalkyl, di(C.sub.1 -C.sub.5 alkyl)sulfamoyl, 6-membered heterocyclic group, phenyl, benzyl, or phenylsulfonyl each phenyl moiety of the last three members being optionally substituted by a halogen, methoxy, or methyl group; Z.sup.4 is phenyl optionally substituted by a halogen, methoxy, or methyl group or 5- or 6-membered heterocyclic group which is optionally substituted by a halogen, methoxy, or methyl group and which can be optionally condensed with a benzene ring; Z.sup.5 is thienyl or phenyl each optionally substituted by a halogen, methoxy, or methyl group; Z.sup.6 is thienyl or phenyl each optionally substituted by a halogen, methoxy, or methyl group; m is an integer from 0 to 2; n is an integer from 2 to 3) or its pharmaceutical acceptable acid addition salt being useful as a drug for senile dementia, psychotropic, or antiamnesia agent is provided through several routes.

Carbamoylpyrolidone derivatives and drugs for senile dementia

A compound of the formula: ##STR1## wherein Y is ##STR2## R is hydrogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkanoyl, or C.sub.7 -C.sub.9 phenylalkyl, and X is hydrogen, C.sub.1 -C.sub.5 alkoxy, or halogen being useful for the treatment of senile dementia, psychoneurosis, and/or amnesia.

Pyrrolo(1,4)benzodiazepine derivatives

A compound of the formula: ##STR1## (wherein R is --SO.sub.2 R.sup.1 or --CONHR.sup.2 ; R.sup.1 is C.sub.1 -C.sub.5 alkyl, C.sub.8 -C.sub.12 phenylalkenyl, amino, dimethylamino, optionally substituted C.sub.8 -C.sub.12 aryl, or 5- or 6-membered heterocyclic group including at least one hetero atom selected from the group consisting of N, S, and O; R.sup.2 is amino, C.sub.1 -C.sub.8 alkylamino, C.sub.1 -C.sub.8 alkyl, or optionally substituted C.sub.8 -C.sub.12 aryl) or its pharmaceutically acceptable acid-addition salt, being useful as a drug for senile dementia, psychotropic, or antiamnesia agent is provided through several routes.

N-(2-oxpyrrolidin-1-yl-)acetyl)piperazine derivatives and drug for

A process for introducing thiocarboxylic ester at ortho-position of phenols or phenylamines which comprises reacting a phenyl compound having group or optionally substituted amino or cyclic amino group, of which at least one ortho-position is vacant, with C.sub.1 -C.sub.5 alkyl thiocyanate, C.sub.7 -C.sub.13 aralkyl thiocyanate or C.sub.6 -C.sub.12 aryl thiocyanate in the presence of a boron trihalide and hydrolyzing the resultant product under acidic conditions is provided, and said process is useful in the synthesis of medicinals, pesticides and dyes.

Process for introducing a thiocarboxylic ester group at the

A process for ortho-cyanation of phenols or phenylamines which comprises reacting a phenyl compound having hydroxy or optionally substituted amino or cyclic amino, of which ortho position is vacant, with trichloroacetonitrile, C.sub.1 -C.sub.5 alkyl thiocyanate or C.sub.6 -C.sub.12 aryl thiocyanate in the presence of a boron trihalide and treating the resultant product with an alkali is provided, and said process is useful in the synthesis of intermediates for medicinals or pesticides.

Process for ortho-cyanation of phenols or phenylamines

A useful intermediate for synthesizing penicillins or cephalosporins {i.e., 1-(2-protected amino-4-thiazolyl)propene-1,3-dicarboxylic acid half ester (VI)} is prepared by a process comprising (1) treating haloacetylmalonic acid ester (I) with thiourea to give 2-(2-amino-4-thiazolyl)malonic acid ester (II), (2) protecting the amino group of the latter to give 2-(2-protected amino-4-thiazolyl)malonic acid ester (III), (3) treating the product with haloalkenoic acid ester to give 1-(2-protected amino-4-thiazolyl)-2-propene-(1,1,3-tri or 1,1,3,3-tetra)carboxylic acid ester (IV), (4) hydrolyzing and decarboxylating the latter to give 1-(2-protected amino-4-thiazolyl)propene-1,3-dicarboxylic acid (V), and (5) treating the product with alcohol and a hemi-esterifying reagent to give the objective 1-(2-protected amino-4-thiazolyl)propene-1,3-dicarboxylic acid half ester (VI).

Thiazolylpropenedicarboxylic acid half esters and process for making

A 7.beta.-ureidoacetamido-7.alpha.-methoxy-3-[1-(2-hydroxyethyl)-1H-tetrazol -5-yl]thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid derivative represented by the following formula: ##STR1## wherein R is aryl or heteroaryl; R.sup.1 is hydrogen or alkyl optionally substituted by halogen or pyridinium; R.sup.2 is hydrogen or a hydroxy-protecting group; and R.sup.3 is hydrogen, a light metal, or a carboxy-protecting group.

Oxacephalosporin derivatives

A 7.beta.-ureidoacetamido-7.alpha.-methoxy-3-(1-carbamoylmethyl-1H-tetrazol- 5-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid derivative represented by the following formula: ##STR1## wherein Ar is phenyl, hydroxyphenyl, or thienyl and R is hydrogen, a light metal, or a carboxy-protecting group.

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Hyogo, Japan

Hiromu Matsumura