Abstract: 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.
Type:
Grant
Filed:
June 24, 1977
Date of Patent:
February 19, 1980
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Abstract: There is disclosed a process for preparing methoxymethyl 6-aminopenicillanate, its conversion to methoxymethyl amoxicillin and the use of the latter compound as an intermediate in the preparation of the methoxymethyl ester of p-hydroxyhetacillin which is the preferred product of this invention.
Abstract: The compounds of this invention represented by the following formula: ##STR1## (wherein R is hydrogen atom, an alkyl group having C.sub.1 to C.sub.4, a hydroxy group or a halogen atom) can be obtained by condensing the compounds represented by the following formula: ##STR2## wherein R is as defined above, X is hydrogen atom, and Y is hydrogen atom or an amino protecting group or reactive derivatives thereof with (S)-arginine according to a method commonly employed in the peptide chemistry.The peptides according to this invention have strong inhibitory activity against aminopeptidase B, can raise immunity of the organisms and prove useful for inhibiting transfer of cancer and relapse thereof. Also, when used jointly with Bleomycin which is an antitumor agent, they can greatly enhance the antitumor effect of said agent.
Type:
Grant
Filed:
September 15, 1978
Date of Patent:
January 22, 1980
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Abstract: Certain 7-acylamido-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxyl ic acids and their salts and easily hydrolyzed esters of the 4-carboxyl group were synthesized and found to be potent antibacterial agents which exhibited good aqueous solubility. In a preferred embodiment the 7-substituent was 2'-aminomethylphenylacetamido.
Type:
Grant
Filed:
August 5, 1976
Date of Patent:
January 8, 1980
Assignee:
Bristol-Myers Company
Inventors:
William J. Gottstein, Murray A. Kaplan, Alphonse P. Granatek
Abstract: Cephalosporins in a series having the formula ##STR1## wherein R.sup.1 is alkyl containing 1-4 carbon atoms or a nontoxic pharmaceutically acceptable salt thereof, were synthesized and found to be potent antibacterial agents especially when in the form of the syn isomers essentially free of the corresponding anti isomer.
Type:
Grant
Filed:
February 24, 1978
Date of Patent:
December 25, 1979
Assignee:
Bristol-Myers Company
Inventors:
Murray A. Kaplan, Alphonse P. Granatek, Solomon J. Nachfolger
Abstract: This invention provides the amino acid (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoic acid which is prepared by hydrolysis of bestatin. Bestatin is a chemical which inhibits aminopeptidase B, leucine aminopeptidase and bleomycin hydrolase, enhances the antitumor effect of bleomycin, has the chemical name [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine, has the following structure ##STR1## and is prepared by cultivating a strain of streptomyces which produces bestatin in a nutrient medium under aerobic conditions until substantial activity inhibitory to aminopeptidase B is imparted to said cultured medium and then recovering said bestatin from said cultured medium. A preferred strain is Streptomyces olivoreticuli FERM-P No. 2590 (A.T.C.C. 31159).
Type:
Grant
Filed:
August 19, 1977
Date of Patent:
December 18, 1979
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Abstract: Monosilver phosphanilate and disilver phosphanilate were prepared and found to be potent antibacterial agents, especially against strains of Pseudomonas, suitable for use in the topical therapy of burns.
Type:
Grant
Filed:
December 11, 1978
Date of Patent:
December 4, 1979
Assignee:
Bristol-Myers Company
Inventors:
Edmund S. Granatek, Frank D. Ruva, Frederick L. Grab
Abstract: Certain 7-acylamido-3-(1-carboxymethyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxy lic acids and their salts and easily hydrolyzed esters of the 4-carboxyl group were synthesized and found to be potent anti-bacterial agents which exhibited good aqueous solubilty. In a preferred embodiment the 7-substituent was D-.alpha.-hydroxyphenylcetamido.
Type:
Grant
Filed:
July 28, 1976
Date of Patent:
October 23, 1979
Assignee:
Bristol-Myers Company
Inventors:
William J. Gottstein, Murray A. Kaplan, Alphonse P. Granatek
Abstract: A clinically valuable antibiotic, 3',4'-dideoxykanamycin B is now produced by a reduced number of consecutive steps in an improved overall yield by new processes starting from kanamycin B via intermediate derivatives of kanamycin B in which all the five amino groups are protected with an unsubstituted or substituted benzyloxycarbonyl group and possibly the 2"-hydroxyl group may be protected with a lower alkylsufonyl, arylsulfonyl or aralkylsulfonyl group.
Type:
Grant
Filed:
November 14, 1977
Date of Patent:
October 2, 1979
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Abstract: The present invention relates to new physiologically active peptides, derivatives thereof and a process for preparation thereof. In particular, it relates to new tetrapeptides designated amastatins A.sub.1, A.sub.2, A.sub.3, B.sub.1 and B.sub.2 and derivatives thereof which have an inhibitory effect on aminopeptidase A and also show stimulation of antibody formation and to a process for preparation thereof by cultivating a strain belonging to the genus Streptomyces.
Type:
Grant
Filed:
June 16, 1978
Date of Patent:
September 11, 1979
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Inventors:
Hamao Umezawa, Takaaki Aoyagi, Tomio Takeuchi, Masa Hamada
Abstract: There is provided a process for recovering macromomycin (hereinafter referred to as MCR) which comprises adding coagulants or coagulants and neutralizers to a culture filtrate saturated with ammonium sulfate and collecting the resulting precipitate containing MCR in a high yield at low centrifugal force. From the precipitate obtained, MCR powders can be prepared according to the methods described in U.S. Pat. No. 3,595,954 and others.
Type:
Grant
Filed:
May 31, 1977
Date of Patent:
August 14, 1979
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Abstract: A novel, unique nucleoside, 3-.beta.-D-ribofuranosyl-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-7-o l, named isocoformycin, of the formula ##STR1## is provided by ring expansion of derivatives of 9-.beta.-D-ribofuranosyl-6-hydroxymethyl-1,6-dihydropurine. Isocoformycin markedly inhibits deaminating enzymes which inactivate formycin and adenine arabinoside (also known as ara-A and Vidarabine). Formycin and adenine arabinoside are used as antiviral and antitumor agents in mammals and birds and isocoformycin is advantageous to prolong the activity and effect of formycin and adenine arabinoside.
Type:
Grant
Filed:
December 9, 1977
Date of Patent:
August 7, 1979
Assignee:
Zaidan Hojin Biselbutsu Kagaku Kenkyu Kai
Abstract: A useful antibiotic, 3',4'-dideoxykanamycin B can be prepared in shortened steps and in an improved overall yield by a new process starting from kanamycin B via new intermediate derivatives of kanamycin B in which all the amino groups and possibly the 2"-hydroxyl group are protected with sulfonyl-type protecting groups selected from lower alkyl-, aryl- and aralkyl-sulfonyl groups.
Type:
Grant
Filed:
November 26, 1976
Date of Patent:
May 22, 1979
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Abstract: Certain 7-acylamido-3-(2-carboxyalkyl-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on- 6-ylthiomethyl)-3-cephem-4-carboxylic acids and their salts and easily hydrolyzed esters of the 4-carboxyl group were synthesized and found to be potent antibacterial agents which exhibited good aqueous solubility. A preferred embodiment was 7-[o-(methylaminomethyl)phenylacetamido]-3-(2-carboxyalkyl-2,3-dihydro-s-t riazolo[4,3-b]pyridazin-3-on-6-ylthiomethyl)-3-cephem-4-carboxylic acid.
Type:
Grant
Filed:
February 13, 1978
Date of Patent:
April 24, 1979
Assignee:
Bristol-Myers Company
Inventors:
Takayuki Naito, Jun Okumura, Hajime Kamachi, Seiji Iimura, Hideaki Hoshi, Masahisa Oka
Abstract: A number of 1N-(.alpha.-hydroxy-.omega.-aminoalkanoyl)-6'N-methyl-3',4'-dideoxykanamyc in B derivatives have been found to possess excellent antibacterial activity against most kanamycin susceptible and resistant organisms. In particular, 1N-(DL-isoseryl)-6'N-methyl-3',4'-dideoxykanamycin B, 1N-(L-isoseryl)-6'-N-methyl-3',4'-dideoxykanamycin B, 1N-(L-4-amino-2-hydroxybutyryl)-6'N-methyl-3',4'-dideoxykanamycin B and 1N-(L-5-amino-2-hydroxyvaleryl)-6'N-methyl-3',4'-dideoxykanamycin B, or an acid addition salt thereof possess these highly desirable attributes.
Type:
Grant
Filed:
December 29, 1977
Date of Patent:
April 3, 1979
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Abstract: 1-N-(L-4-amino-2-hydroxybutyryl) derivatives of kanamycin C, 3'-deoxykanamycin C and 3',4'-dideoxykanamycin C have been prepared which possess high antibacterial activity against a wide variety of drug-resistant bacteria. These new derivatives are prepared by reacting L-4-amino-2-hydroxybutyric acid or a functional equivalent thereof with the 1-amino group of kanamycin C, 3'-deoxykanamycin C or 3',4'-dideoxykanamycin C.
Type:
Grant
Filed:
September 19, 1977
Date of Patent:
February 20, 1979
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Abstract: 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxyamido)-.alpha.-phenyl (and p-hydroxyphenyl) acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acids were synthesized and found to have potent antibacterial activity in vitro especially against many strains of Pseudomonas aeruginosa.
Type:
Grant
Filed:
June 9, 1977
Date of Patent:
February 6, 1979
Assignee:
Bristol-Myers Company
Inventors:
Takayuki Naito, Jun Okumura, Masahisa Oka
Abstract: The present invention relates to new physiologically active peptides, derivatives thereof and a process for preparation thereof. In particular, it relates to new tetrapeptides designated amastatins A.sub.1, A.sub.2, A.sub.3, B.sub.1 and B.sub.2 and derivatives thereof which have an inhibitory effect on aminopeptidase A and also show stimulation of antibody formation and to a process for preparation thereof by cultivating a strain belonging to the genus Streptomyces.FIELD OF THE INVENTIONThe present invention relates to new physiologically active peptides, derivatives thereof and a process for preparation thereof. In particular, it relates to new tetrapeptides designated amastatins A.sub.1, A.sub.2, A.sub.3, B.sub.1 and B.sub.2 and derivatives thereof which have an inhibitory effect on aminopeptidase A and also show stimulation of antibody formation and to a process for preparation thereof by cultivating a strain belonging to the genus Streptomyces.
Type:
Grant
Filed:
September 19, 1977
Date of Patent:
November 21, 1978
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Inventors:
Hamao Umezawa, Takaaki Aoyagi, Tomio Takeuchi, Masa Hamada
Abstract: Kanamycin C, 3'-deoxykanamycin C and 3'4'-dideoxykanamycin C are obtained by a new process comprising treating the primary 6'-amino group of a tetra-N-protected derivative of kanamycin B, 3'-deoxykanamycin B and 3', 4'-dideoxykanamycin B with a nitrite to convert said amino group into hydroxyl group and then removing the protective groups. 3'-Deoxykanamycin C and 3', 4'-dideoxykanamycin C are new semi-synthetic aminoglycosidic antibiotics.
Type:
Grant
Filed:
May 23, 1977
Date of Patent:
October 17, 1978
Assignee:
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Abstract: A new synthetic route is provided for the production of 7-(2-aminomethylphenylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl )-3-cephem-4-carboxylic acid.