Kabushiki Kaisha Yakult Honsha

Masahiko Mutai

Tadashi Miyasaka

Seigo Sawada

Kenichiro Nokata

Mitsuo Mada

Kiyohiro Shimada

Ryuichiro Tanaka

Toshizo Sakurai

Tsuneo Terashima

Koutaro Takamizawa

Hiroo Takayama

Kei Nakajima

Takashi Iijima

Yoichi Kobayashi

Keisuke Matsumoto

Yoshitaka Nagai

Teruo Yokokura

Tatsuhiko Kan

Tomoyuki Sako

Ikuo Kato

Yoshiko Sonoike

Hisao Hagiwara

Saeko Sawaki

Eiichi Sugino

Seizaburo Kobayashi

Nobuo Tsuchida

Shusei Takahashi

Takashi Nakao

Tokutaro Takahashi

Akio Kuroda

Sadao Ueyama

Isamu Kondo

Hiromi Ishiwa

Harue Shibahara

A botulinum toxin neutralizer comprising at least one fatty acid having the number of carbon atoms of at least 12. Such a fatty acid may be any of saturated fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, nonadecanoic acid, arachidic acid, and behenic acid or any of unsaturated fatty acids such as oleic acid. The toxin neutralizer acts as if it were an antagonistic receptor for botulinum toxin and, when encountering botulinum toxin in human body, directly combines with the toxin and disables the toxin from combining with the neuromuscular tissues of human body to prevent the outbreak of botulism. The toxin thus neutralized and affixed to the botulinum toxin neutralizer is excreted from the human body. The botulinum toxin neutralizer can be manufactured easily and economically from a naturally occurring glyceride and is thus far less costly then the known antitoxin of ganglioside GT1b produced from bovine brain.

Botulinum toxin neutralizer

A variety of chimeric plasmids each of which comprises (a) a tetracycline resistance gene (Tc) deriving from pAM.alpha.1, one of the plasmids retained by Streptococcus faecalis, (b) an ampicillin resistance gene (Amp) deriving from pACYC177, one of the vectors applicable to Escherichia coli and (c) either or both of origins, an origin (OripAM.alpha.1) deriving from the plasmid pAM.alpha.1 and an origin (Ori177) deriving from the vector pACYC177, the tetracycline resistance gene existing on each of which has the unique cleavage site for the restriction enzyme BalI on the entire DNA of the same plasmid and the ampicillin resistance gene existing on each of which has the unique cleavage sites for respective restriction enzymes BglI and PstI on the entire DNA on the same plasmid. There is also provided a chimeric plasmid vector containing (a) a tetracycline resistance gene region (Tc) derived from the plasmid pAM.alpha.1 of Streptococcus faecalis DS5 (ATCC14508), (b) an ampicillin resistance gene region (Amp) derived from the vector pACYC177 of E. coli, (c) a first DNA replication origin (OripAM.alpha.1) derived from the plasmid pAM.alpha.1, (d) a second DNA replication origin (Ori177) derived from the vector pACYC177, and (e) a polylinker region having recognition and cleavage sites for the restriction enzymes EcoRI at one terminal and HindIII at the other terminal of the polylinker DNA sequence.

Chimeric plasmids

A liquid food comprising polydextrose and oligosaccharides which are hard to digest and easy to ferment is provided. This liquid food has excellent effect for relieving constipation.

Liquid food for curing constipation: polydextrose and oligosaccharide

A botulinus toxin neutralizer comprising heat-treated fat globule membranes of animal milk or gangliosides isolated from fat globule membranes of animal milk. The neutralizer of the former nature is prepared from a material containing fat globules of animal milk by fractionating the material for separating the membranes of the fat globules from the rest of the material, and subjecting the separated fat globule membranes to heat treatment. The neutralizer of the former nature is prepared from a material containing fat globules by fractionating the material for separating the membranes of the fat globules from the rest of the material, and isolating gangliosides from the globule membranes.

Botulinus toxin neutralizer

New camptothecin derivatives possessing high anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R.sup.1 is a hydrogen atom, a halogen atom or an alkyl group with 1-4 carbon atoms and X is a chlorine atom or --NR.sup.2 R.sup.3 where R.sup.2 and R.sup.3 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted carbocyclic or heterocyclic group, with the proviso that when both R.sup.2 and R.sup.3 are the substituted or unsubstituted alkyl groups, they may be combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring which may be interrupted with --O--, --S-- and/or &gt;N--R.sup.4 in which R.sup.4 is a hydrogen atom, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted phenyl group and wherein the grouping --O--CO--X is bonded to a carbon atom located in any of the 9-, 10- and 11-positions in the ring A of camptothecin, as well as an ammonium salt or an alkali metal salt thereof. These new camptothecin derivatives are prepared by reacting a 7-R.sup.1 -camptothecin derivative having a hydroxyl group in any of the 9-, 10- and 11-positions on the ring A thereof with phosgen and then reacting, if necessary, the resultant 7-R.sup.1 -camptothecin derivative having a chlorocarbonyloxy group in the same position on the ring A thereof with an amine HNR.sup.2 R.sup.3 or by reacting a 7-R.sup.1 -camptothecin derivative having a hydroxyl group in any of the 9-, 10- and 11-positions on the ring A thereof with a carbamoyl chloride Cl-CONR.sup.2 R.sup.3.

Camptothecin derivatives and process for preparing same

New Camptothecin derivatives possessing high anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R.sup.1 stands for a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxy group or an acyloxy group, R.sup.2 for a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group, a carboxymethyl group or an acyloxymethyl group, and R.sup.3 for the grouping --XR' (where R' is a hydrogen atom, an alkyl group or an acyl group and X is an oxygen atom or a sulfur atom), a nitro group, an amino group, an alkylamino group, an acylamino group or a halogen atom, with the proviso that when both of R.sup.1 and R.sup.2 are hydrogen atoms, R.sup.3 should not be hydroxyl group, methoxy group or acetoxy group. These new camptothecin derivatives are prepared by treating a 5-R.sup.1 -7-R.sup.2 camptothecin derivative with a peroxidant and then reacting the resultant 5-R.sup.1 -7-R.sup.2 -camptothecin-1-oxide with an active hydrogen compound under irradiation of UV-rays or by catalytically hydrogenating the ring B of camptothecin in a solvent, treating the resultant tetrahydro product with an acylating agent, introducing nitro group into 10-position of the acylated product by the reaction with nitric acid, splitting off the acyl group in the 10-nitro product by hydrolysis and treating the hydrolyzed tetrahydro product with an oxidizing agent for dehydrogenation, and if desired, reducing the nitro group in the resultant product to amino group and modifying the amino group by N-alkylation, N-acylation or by diazotization followed by hydrolysis or Sandmeyer reaction, before or after the oxidation of the 10-nitro-tetrahydro product.

Photochemical process for preparing camptothecin derivatives

Novel coliform bacillus useful for industrial production of staphylokinase, a fibrinolytic enzyme, and process for the production of staphylokinase using said microbe are provided. The novel microbe comprises a recombinant DNA, carrying genetic information for the production of staphylokinase, said genetic information being DNA derived from a temperate phage DNA of Staphylococcus aureus.

Coliform bacillus having a gene for the production of staphylokinase and

New 5- and/or 7-substituted camptothecin-1-oxide derivatives possessing anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxy group or an acyloxy group and R' is a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group, an acyloxymethyl group or a carboxymethyl group, with the proviso that both of R and R' should not be hydrogen atoms. These 5- and/or 7-substituted camptothecin-1-oxide derivatives are prepared by treating the corresponding 5- and/or 7-substituted camptothecins with a peroxidant as an N-oxidizing reagent.

Camptothecin-1-oxide derivatives

New Camptothecin derivatives possessing high anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R.sup.1 is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxy group or an acyloxy group, R.sup.2 for a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group, a carboxymethyl group or an acyloxymethyl group, and R.sup.3 is the grouping --XR' (where R' is a hydrogen atom, an alkyl group or an acyl group and X is an oxygen atom or a sulfur atom), a nitro group, an amino group, an alkylamino group, an acylamino group or a halogen atom, with the proviso that when both of R.sup.1 and R.sup.2 are hydrogen atoms, R.sup.3 should not be a hydroxyl group, methoxy group or acetoxy group. These new camptothecin derivatives are prepared by treating a 5-R.sup.1 -7-R.sup.2 -camptothecin derivative with a peroxidant and then reacting the resultant 5-R.sup.1 -7-R.sup.2 -camptothecin-1-oxide with an active hydrogen compound under irradiation of UV-rays or by catalytically hydrogenating the ring B of camptothecin in a solvent, treating the resultant tetrahydro product with an acylating agent, introducing a nitro group into the 10-position of the acylated product by the reaction with nitric acid, splitting off the acyl group in the 10-nitro product by hydrolysis and treating the hydrolyzed tetrahydro product with an oxidizing agent for dehydrogenation, and if desired, reducing the nitro group in the resulting product to an amino group and modifying the amino group by N-alkylation, N-acylation or by diazotization followed by hydrolysis or the Sandmeyer reaction, before or after the oxidation of the 10-nitro-tetrahydro product.

This invention relates to a composition for promoting growth of Bifidobacteria containing as effective constituent an oligosaccharide represented by the general formula Gal-(gal).sub.n -Glc, wherein Gal denotes a galactose residue, Glc a glucose residue and n an integer of 1 to 4. This invention further relates to a method for manufacture of the material for promoting growth of Bifidobacteria characterized in that lactose or a lactose-containing material is treated with .beta.-galactosidase produced by Aspergillus oryzae.

Composition for promoting growth of bifidobacteria

New 7-substituted camptothecin derivatives possessing anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R stands for --CHO, --CH.sub.2 OR', --CH(OR').sub.2 or --CH.dbd.N--X where R' is a lower alkyl group with 1-6 carbon atoms or a phenylalkyl group with 1-3 carbon atoms in the alkylene moiety thereof, and X is a hydroxyl group or --NR.sup.1 R.sup.2 where R.sup.1 and R.sup.2 are the same or different and each represents a hydrogen atom or a lower alkyl group with 1-6 carbon atoms, or when R.sup.1 is hydrogen, R.sup.2 may be a lower alkyl group with 1-6 carbon atoms, a substituted or unsubstituted aryl group, a carbamoyl group, an acyl group, an aminoalkyl group or an amidino group, or when R.sup.1 is the lower alkyl group, R.sup.2 may be an aminoalkyl group, or R.sup.1 and R.sup.2 may be combined together with the nitrogen atom, to which R.sup.1 and R.sup.2 are bound, to form a heterocyclic group, and quaternary salts thereof. These 7-substituted camptothecin derivatives are prepared by treating 7-hydroxymethyl- or 7-dialkoxymethyl-camptothecin with a catinoid reagent, or treating 7-formyl- or 7-hydroxymethyl-camptothecin with an acid in the presence of a lower alkanol or phenylalkanol, or treating 7-formylcamptothecin or an acetal thereof with a nitrogen-containing carbonyl reagent and optionally treating the resulting product with a quaternating agent.

7-Substituted camptothecin derivatives

New camptothecin derivatives possessing either or both of high anti-tumor activity and slight toxicity, represented by the general formula: ##STR1## wherein X is H, CH.sub.2 OH, COOH, an alkyl group, an aralkyl group or the grouping CH.sub.2 OR.sup.1 or COOR.sup.2 wherein R.sup.1 is an alkyl group or an acyl group and R.sup.2 is a lower alkyl group, Y is H, OH or the grouping OR.sup.3 wherein R.sup.3 is a lower alkyl group or an acyl group, and Z is H or an acyl group, with the proviso that when X is CH.sub.2 OH, an alkyl group or an aralkyl group, both Y and Z are H, that when X is the grouping CH.sub.2 OR.sup.1 or COOR.sup.2, Y is H, that when Y is OH, both X and Z are H, and that when Y is the grouping OR.sup.3, X is H, and water-soluble alkali metal salts thereof. These camptothecin derivatives are prepared by treating camptothecin with sulfuric acid and a persulfate or with sulfuric acid and a peroxide, if necessary, with an organic compound corresponding to the organic moiety of the substituent to be introduced directly into camptothecin, in an aqueous medium in the presence or absence of a transition metal ion, and optionally treating the resultant products, if necessary, after oxidation of the introduced substituent, with an alkylating agent or an acylating agent.

Camptothecin derivatives

Immunostimulating agent for inhibiting tumors comprising Lactobacillus casei YIT 9018 and methods for treating and/or preventing tumor growth.

Antitumor agent containing Lactobacillus casei YIT 9018

Foods and drinks containing bifidobacteria are produced by inoculating and cultivating bifidobacteria or a mixture of bifidobacteria and lactic acid bacteria in a medium containing .alpha.-starch-transformed rice and bifidobacteria-fermentable sugars, and processing the resultant cultivated medium to produce foods and drinks containing bifidobacteria. The .alpha.-starch-transformed rice is produced by cooking rice. The medium for cultivating bifidobacteria may contain milk, and cultivating may be carried out under aerobic conditions.

Production of foods and drinks containing bifidobacteria

Foods and drinks containing bifidobacteria are prepared by growing in a milk medium under aerobic conditions a mixture of bifidobacteria containing a mutant strain of oxygen-resistant Bifidobacterium and a strain of obligatory anaerobic Bifidobacterium. Presence of the oxygen-resistant strain enables growing the obligatory anaerobic strain under aerobic conditions in a pure milk medium without added growth promoting substances.

Growing community of inventors

Tokyo, Japan

Masahiko Mutai