Shionogi Company Limited

Shionogi Seiyaku Kabushiki Kaisha

Susumu Kamata

Nobuhiro Haga

Kaoru Seno

Sanji Hagishita

Mitsuaki Ohtani

Fumihiko Watanabe

Tatsuo Tsuri

Kenji Kawada

Takeaki Matsui

Wataru Nagata

Masayuki Narisada

Saichi Matsumoto

Tadahiko Tsushima

Tadashi Yoshida

Yoshimi Kawamura

Koichi Matsumoto

Shigeru Matsutani

Bunji Kageyama

Shigeo Yagi

Toshiyuki Kamigauchi

Hirokuni Jyoyama

Kimio Takahashi

Morio Kishi

Toshihiko Okada

Takeshi Shiota

Ryuji Sakazaki

Yasunobu Ishihara

Masanao Inagaki

Toshiro Konoike

Tadadiko Tsushima

Yasushi Murakami

Sanji Hagashita

Novel antibiotic stalobacins H-1 and I-1 having physico-chemical properties as shown in Table 4 are provided, which are excellent antibiotics showing marked effects on Gram-positive bacteria.

Antibiotic stalobacins

Benzodiazepine derivative

Carbamoylmethylurea derivatives

A selective and high-yield method is described for producing stereoisomeric benzylidene derivatives of the formula III: ##STR1## wherein R.sup.1 and R.sup.2 each independently is lower alkyl, lower alkoxy or halogen; Y is SO.sub.2, SO or CO; --A-- is optionally substituted lower alkylene; --B-- is --CH.sub.2 -- or --O--; or --A-- and --B-- taken together may form optionally substituted phenylene or optionally substituted lower alkenylene; and R is hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkoxy, hydroxy, optionally substituted aryl, optionally substituted arylalkyl; optionally substituted arylalkyloxy, heterocyclic ring or N-protecting groups, which comprises reacting a compound of the formula I: ##STR2## wherein R.sup.1 and R.sup.2 are as defined above and X is lower alkoxy or halogen with a compound of the formula II: ##STR3## wherein Y, --A--, --B-- and R are as defined above in the presence of a base.

Method for producing benzylidene derivatives

Novel antibiotic stalobacins A to I having physico-chemical properties as shown in Tables 1 to 4 are provided, which are excellent antibiotics showing marked effects on Gram-positive bacteria.

The present invention relates to novel 3-benzylidene-1-carbamoyl-2-pyrroridone analogues having advantage anti-inflammatory activities, which is represented by the formula: ##STR1## wherein R.sup.1 and R.sup.2 each is independently hydrogen, alkyl, alkoxy, or halogen; R.sup.3 is hydrogen or acyl; R.sup.4 is hydrogen, alkyl, hydroxy, alkoxy, cyano, or halogen; R.sup.5 and R.sup.6 each is independently hydrogen, alkyl, aryl, aralkyl, heterocyclic group, substituted or unsubstituted amino, or OR.sup.7 wherein R.sup.7 is hydrogen, alkyl, aryl, acyl, or aralkyl, or taken together with the adjacent nitrogen atom may form heterocyclic group which may contain N, O, and/or S, and X and Y each is independently O, S, substituted or unsubstituted imino, or substituted or unsubstituted methylene. In more detail, the present invention provides an anti-inflammatory agent which is useful for the treatment of chronic inflammation and has little side effect, e.g., stomach disease.

3-benzylidene-1-carbamoyl-2-pyrrolidone analogues

3-benzylidene-1-carbamoyl-2-pyrrolidone compounds useful as

Lipid derivatives represented by the formula: ##STR1## wherein R.sub.1 is alkyl or alkylcarbamoyl; R.sub.2 is lower alkyloxy, lower alkylcarbamoyloxy, lower alkylcarbonylamino, lower alkyloxycarbonylamino, lower alkylureido, lower alkyloxymethyl, lower alkylcarbonylmethyl, cyanomethyl, heterocyclic group, or heterocyclyloxy; R.sub.2 ' is hydrogen or R.sub.2 and R.sub.2 ' taken together with R.sub.2 form --O(CH.sub.2).sub.m -- wherein m is an integer of 1 to 5; R.sub.3, R.sub.4, and R.sub.5 each is hydrogen or lower alkyl or two or three of R.sub.3, R.sub.4, and R.sub.5 taken together with the adjacent nitrogen atom form cyclic ammonio; R.sub.6 is hydrogen or lower alkylcarbonyl; X.sup.- is a counter anion; Y is oxygen or sulfur; and n is an integer of 1 to 10, being useful as PAF antagonists, e.g., as antithrombotic, antivasoconstricting, antibronchoconstricting agent or antitumor agent.

Lipid derivatives

Lipid derivatives represented by the formula: ##STR1## wherein R.sub.1 is alkyl or alkylcarbamoyl; R.sub.2 is lower alkyloxy, lower alkylcarbamoyloxy, lower alkylcarbonylamino, lower alkyloxycarbonylamino, lower alkylureido, lower alkyloxymethyl, lower alkylcarbonylmethyl, cyanomethyl, heterocyclic group, or he0 terocyclyloxy; R.sub.2 ' is hydrogen or R.sub.2 and R.sub.2 ' taken together form --O(CH.sub.2).sub.m -- wherein m is an integer of 1 to 5; R.sub.3, R.sub.4, and R.sub.5 each is hydrogen or lower alkyl or two or three of R.sub.3, R.sub.4, and R.sub.5 taken together with the adjacent nitrogen atom form cyclic ammonio; R.sub.6 is hydrogen or lower alkylcarbonyl; X.sup.- is a counter anion; Y is oxygen or sulfur; and n is an integer of 1 to 10, being useful as PAF antagonists, e.g., as antithrombotic, antivasoconstricting, antibronchoconstricting agent or antitumor agent.

There are provided compounds of the formula: ##STR1## wherein R.sub.1 is a hydrogen or C.sub.1 -C.sub.5 alkyl; R.sub.2 is an C.sub.1 -C.sub.10 alkyl, aryl, aralkyl, or pyridyl, where the aryl, aralkyl, or pyridyl are unsubstituted or are substituted by C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkoxy, nitro, hydroxy, carboxy, amino, C.sub.1 -C.sub.5 alkylamino, C.sub.1 -C.sub.5 dialkyamino whose two alkyl groups may be different from each other, C.sub.2 -C.sub.3 alkanoylamino, or halogen and X is an C.sub.1 -C.sub.7 alkylene, C.sub.2 -C.sub.7 alkenylene, --CH(F)CH.dbd.CH(CH.sub.2).sub.3 --, --(CH.sub.2).sub.3 --S--(CH.sub.2).sub.2 --, --(CH.sub.2).sub.2 --S--(CH.sub.2).sub.3 --, --C.sub.6 H.sub.4 -O--CH.sub.2 -- or --CH.sub.2 CH.dbd.CH--m--C.sub.6 H.sub.4 --, or their pharmaceutically accepatble salts. The compounds are useful as antithrombotic, anti-vasconstricting and anti-bronchoconstricting drugs.

6-oxa and thiabicyclo [3.1.0.] compounds

There are provided compounds of the formula: ##STR1## wherein R.sub.1 is a hydrogen or C.sub.1 -C.sub.5 alkyl; R.sub.2 is an C.sub.1 -C.sub.10 alkyl, aryl, aralkyl, or pyridyl, where the aryl, aralkyl, or pyridyl are unsubstituted or are substituted by C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkoxy, nitro, hydroxy, carboxy, amino, C.sub.1 -C.sub.5 alkylamino, C.sub.1 -C.sub.5 dialkylamino whose two alkyl groups may be different from each other, C.sub.2 -C.sub.3 alkanoylamino, or halogen and X is an C.sub.1 -C.sub.7 alkylene, C.sub.2 -C.sub.7 alkenylene, --CH(F)CH.dbd.CH(CH.sub.2).sub.3 --, --(CH.sub.2).sub.3 --S--(CH.sub.2).sub.2 --, --CH.sub.2).sub.2 --S--(CH.sub.2).sub.3 --, --C.sub.6 H.sub.4 --O--CH.sub.2 --or --CH.sub.2 CH.dbd.CH--m--C.sub.6 H.sub.4 --, or their pharmaceutically acceptable salts. The compounds are useful as antithrombotic, anti-vasoconstricting and anti-bronchoconstricting drugs.

Bicyclo (2.2.1.) hept-exo-2-yl and bicyclo (2.2.2.) oct-endo-2-yl

Bicyclic sulfonamido derivatives represented by the formula: ##STR1## wherein R.sub.1 is a hydrogen or lower alkyl; R.sub.2 is an alkyl, substituted or unsubstituted arly, aralkyl or hetelocycle; R.sub.3 is hydrogen or methyl; X is an alkylene or alkenylene which may be substituted by a fluorine atom or atoms and may contain an oxygen, sulfur and/or phenylene in the chain; Y is straight or branched alkylene or alkeneylene, oxygen, or sulfur; m is 0 or 1; and n is 0, 1 or 2, or their salt, said derivatives being useful as antithrombotic, anti-vasoconstricting, and anti-bronchoconstricting drugs.

Bicyclic sulfonamide derivatives

Bicyclic sulfonamido derivatives represented by the formula: ##STR1## wherein R.sub.1 is a hydrogen or lower alkyl; R.sub.2 is an alkyl, substituted or unsubstituted aryl, aralkyl or hetelocycle; R.sub.3 is a hydrogen or methyl; X is an alkylene or alkenylene which may be substituted by a fluorine atom or atoms and may contain an oxygen, sulfur and/or phenylene in the chain; Y is straight or branched alkylene or alkenylene oxygen, or sulfur; m is 0 or 1; and n is 0, 1 or 2, or their salt, said derivatives being useful as antithrombotic, anti-vasoconstricting, and anti-bronchoconstricting drugs.

7-oxabicyclo[2.2.1] heptane sulfonamide derivatives

Bicyclic sulfonamido derivatives represented by the formula: ##STR1## wherein R.sub.1 is a hydrogen or lower alkyl; R.sub.2 is an alkyl, substituted or unsubstituted aryl, aralkyl or heterocycle; R.sub.3 is a hydrogen or methyl; X is an alkylene or alkenylene which may be substituted by a fluorine atom or atoms an may contain an oxygen, sulfur and/or phenylene in the chain; Y is straight or branched alkylene or alkenylene, oxygen, or sulfur; m is 0 or 1; and n is 0, 1 or 2, or their salt, said derivatives being useful as antithrombotic, anti-vasoconstricting, and anti-bronchoconstricting drugs.

Highly selective and high yield process for producing antitumor agent 1-phthalidyl-5-fluorouracil derivatives of formula (I) which comprises reacting a phthalidyl compound (II) with an amine (III) to yield the quaternary ammonium salts (IV), and reacting the latter with 5-fluorouracil. ##STR1## [wherein X is leaving group; ##STR2## is triethylamine, N-methylmorpholine, N-ethylmorpholine, and the like; R.sup.4 and R.sup.5 each is hydrogen, trialkylsilyloxy, alkoxy, nitro, cyano, carboxy, or alkoxycarbonyl].

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Hyogo, Japan

Susumu Kamata