Nippon Kayaku Kabushiki Kaisha

Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai

Other

Rinzo Nishizawa

Hamao Umezawa

Takaaki Aoyagi

Tetsushi Saino

Tadashi Shirai

Tomio Takeuchi

Masao Suzuki

Masao Yoshida

Katsutoshi Takahashi

Teruya Nakamura

Tomohisa Takita

Shigeru Aoki

Yoshihisa Umeda

Yasuhisa Tashiro

Takashi Nagashima

Yukio Takei

The invention relates to Spergualin-related compounds of the formula: ##STR1## (wherein R.sub.1 is a lower alkylene group which may be substituted by a hydroxymethyl group; X is a hydrogen atom or a halogen atom; m and n are each 0 or an integer of 1 to 5) and salts thereof and a process for producing the same.

Spergualin-related compounds having a phenylene group as well as a

This invention relates to a novel spergualin-related compound and a process for the production thereof. The novel compound, which has a high antitumor activity, is represented by the general formula ##STR1## wherein R.sub.1 represents a hydrogen atom, hydroxyl group, or an aliphatic acyloxy group having 1 to 10 carbon atoms, R.sub.2 represents an amino acid residue (except for the residue of .alpha.-hydroxyglycine) formed by removing one hydrogen atom and hydroxyl group from respectively the .alpha.- or .omega.-amino group and the .alpha.-carboxyl group of an .alpha.- or .omega.-amino acid, said amino acid residue forming acid amide linkages with the adjacent carbonyl group and amino group, and m is an integer of 4 to 6.

Spergualin-related compounds and process for the preparation thereof

A novel process for producing 7-alkoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1-phthalazone, and its intermediates. 7-Alkoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1-phthalazone can be obtained by reacting substituted methylenetriphenylphosphorane with 3,5-dimethyl-4-alkoxycarbonylphthalic anhydride to obtain 6-alkoxycarbonyl-5,7-dimethyl-.DELTA..sup.3,.alpha. -substituted methylenephthalide, reacting the latter with hydrazine to obtain a phthalazone derivative, hydrolyzing the latter, halogenating the hydrolyzate to obtain 7-alkoxycarbonyl-6,8-dimethyl-4-(.alpha.-halogeno-.alpha.-substituted methyl)-1-phthalazone and then directly hydrolyzing and decarboxylating the latter or, when said 7-alkoxycarbonyl-6,8-dimethyl-4-(.alpha.-halogeno-.alpha.-substituted methyl)-1-phthalazone is 7-alkoxycarbonyl-6,8-dimethyl-1-phthalazone-4-.alpha.-halogenoacetic acid, reacting it with a carboxylic acid salt such as sodium acetate and simultaneously decarboxylating the acyloxylated compound and then hydrolyzing the decarboxylated product or firstly decarboxylating the 1-phthalazone-4-.alpha.-halogenoacetic acid derivative, reacting the decarboxylated product with said carboxylic acid salt and then hydrolyzing the reaction product or when said 7-alkoxycarbonyl-6,8-dimethyl-4-(.alpha.-halogeno-.alpha.-substituted methyl)-1-phthalazone is 7-alkoxycarbonyl-4-(.alpha.-carbamoyl-.alpha.-halogenomethyl-6,8-dimethyl- 1-phthalazone, reacting it with said carboxylic acid salt and then hydrolyzing and decarboxylating the acyloxylated compound simultaneously.

Intermediates of

A process for producing threo-3-amino-2-hydroxybutanoylaminoacetic acids comprises the steps of allowing to react a starting compound represented by the general formula: ##STR1## wherein R.sub.1 represents a naphthyl or a group of the formula: ##STR2## in which R.sub.6 and R.sub.7 represent individually hydrogen, halogen, amino or a protected amino, hydroxy or a protected hydroxy, a lower alkoxy or a lower alkyl and R.sub.2 represents a protected amino, with a starting compound represented by the general formula: ##STR3## wherein R.sub.3 represents hydrogen or an ester residue, to obtain threo-3-protected amino-2-hydroxy-4-oxobutanoic acid or its ester represented by the general formula: ##STR4## wherein R.sub.1, R.sub.2 and R.sub.3 have the same meanings as above, and then reducing the same into threo-3-protected amino-2-hydroxybutanoic acid or its ester represented by the general formula: ##STR5## wherein R.sub.1, R.sub.2 and R.sub.3 have the same meanings as above, and further converting the above compound into 3-amino-2-hydroxybutanoic acid represented by the general formula: ##STR6## wherein R.sub.2 ' represents amino or a protected amino, thereafter condensing the same, in a conventional manner for forming a peptide coupling, with a compound represented by the general formula: ##STR7## wherein R.sub.4 represents an alkyl having 3-4 carbon atom or 3-guanidinopropyl, while previously protecting as required those groups not relevant to the reaction, and removing the protecting groups for the functional groups to produce threo-3-amino-2-hydroxybutanoylaminoacetic acids represented by the general formula: ##STR8## wherein R.sub.1 and R.sub.4 have the same meanings as above. This invention also provides the compounds represented by the general formula (III) as novel intermediates for the above aimed compounds and a process for producing the intermediates.

Process for producing threo-3-amino-2-hydroxy-butanoyl-aminoacetic acids

Threo-3-protected amino-2-hydroxy-4-oxobutanoic acid or its esters represented by the formula: ##STR1## wherein R.sub.1 represents naphthyl or a group of the formula ##STR2## in which R.sub.6 and R.sub.7 represent individually hydrogen, halogen, amino, an amino protected with acyl, lower alkyloxycarbonyl or carbamoyl, hydroxy or protected with acyl, lower alkyloxycarbonyl or carbamoyl, lower alkoxy, lower alkyl or phenyl group; R.sub.2 represents an amine protected with acyl, lower alkyloxycarbonyl or carbamoyl; and R.sub.3 represents hydrogen, lower alkyl having 1 to 6 carbon atoms or benzyl.

Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids,

A novel process for producing 7-alkoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1-phthalazone, and its intermediates. 7-Alkoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1-phthalazone can be obtained by reacting substituted methylenetriphenylphosphorane with 3,5-dimethyl-4-alkoxycarbonylphthalic anhydride to obtain 6-alkoxycarbonyl-5,7-dimethyl-.DELTA..sup.3,.alpha. -substituted methylenephthalide, reacting the latter with hydrazine to obtain a phthalazone derivative, hydrolyzing the latter, halogenating the hydrolyzate to obtain 7-alkoxycarbonyl-6,8-dimethyl-4-(.alpha.-halogeno-.alpha.-substituted methyl)-1-phthalazone and then directly hydrolyzing and decarboxylating the latter or, when said 7-alkoxycarbonyl-6,8-dimethyl-4-(.alpha.-halogeno-.alpha.-substituted methyl)-1-phthalazone is 7-alkoxycarbonyl-6,8-dimethyl-1-phthalazone-4-.alpha.-halogenoacetic acid, reacting it with a carboxylic acid salt such as sodium acetate and simultaneously decarboxylating the acyloxylated compound and then hydrolyzing the decarboxylated product or firstly decarboxylating the 1-phthalazone-4-.alpha.-halogenoacetic acid derivative, reacting the decarboxylated product with said carboxylic acid salt and then hydrolyzing the reaction product or when said 7-alkoxycarbonyl-6,8-dimethyl-4-(.alpha.-halogeno-.alpha.-substituted methyl)-1-phthalazone is 7-alkoxycarbonyl-4-(.alpha.-carbamoyl-.alpha.-halogenomethyl)-6,8-dimethyl -1-phthalazone, reacting it with said carboxylic acid salt and then hydrolyzing and decarboxylating the acyloxylated compound simultaneously.

Process for producing

Bestatin, which is [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine, and related compounds which inhibit aminopeptidase B, leucino aminopeptidase and Bleomycin hydrolase, enhance the anti-tumor effect of Bleomycin and exhibit an antifertility effect were synthesized and tested.

Bestatin

Two optically active amino acid-mandelic acid complexes are obtained by interacting in a solvent under pH conditions of 1.0-4.0 an amino acid expressed by a general formula ##STR1## (in which R represents a methyl group, an ethyl group or a methylthioethyl group) and mandelic acid, one of the acids being an optically active substance and the other being a racemic modification, and optically resolving the resulting complexes into two diastereoisomers by using solubility difference therebetween. The optically active complexes are each decomposed by means of an acid, a strongly acidic ion-exchange resin, or a weakly basis ion-exchange resin to obtain optically active amino acids or optically active mandelic acid.

Process for preparing optically active amino acid or mandelic acid

Two optically active amino acid-mandelic acid complexes are obtained by reacting in a solvent under pH conditions of 1.0-4.0, an amino acid expressed by a general formula ##STR1## (in which R represents a methyl group, an ethyl group or a methylthioethyl group) and mandelic acid, one of the acids being an optically active substance and the other being a racemic modification, and optically resolving the resulting complexes into two diastereomers by using a solubility difference therebetween. The optically active complexes are each decomposed by means of an acid, a strongly acidic ion-exchange resin, or a weakly basic ion-exchange resin to obtain optically active amino acids or optically active mandelic acid.

Growing community of inventors

Tokyo, Japan

Rinzo Nishizawa