The Ring System Is 4-aza-bicyclo(3.2.0)heptane (including Unsaturated) And Has Sulfur Bonded Directly At The 2-position Patents (Class 540/350)
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Patent number: 5712267Abstract: Compounds of formula (I): ##STR1## wherein R.sup.1x is hydrogen or methyl, R.sup.2x is hydrogen optionally substituted aliphatic hydrocarbon or acylimidoyl, R.sup.3x is hydrogen or an ester group, and Q.sup.x is cyclic or acyclic nitrogen-containing group. The compounds are potent antibiotics which are resistant to dehydropeptidase I, and are thus useful for the treatment of many microbial infections.Type: GrantFiled: June 6, 1995Date of Patent: January 27, 1998Assignee: Sankyo Company,. LimitedInventors: Isao Kawamoto, Rokuro Endo, Masao Miyauchi, Katsuya Ishikawa, Eiji Nakayama, Hiroshi Yasuda, Satoshi Ohya, Yukio Utsui, Katsuhiko Watanabe
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Patent number: 5707987Abstract: A compound of the formula: ##STR1## wherein R.sup.1 is a hydrogen atom or a lower alkyl group, R.sup.2 is a hydrogen atom or a negative charge, R.sup.3 is a hydrogen atom or a lower alkyl group, Ar is a phenyl group, a naphthyl group or a group of: ##STR2## (wherein each of A.sub.4 and A.sub.5 is a single bond, --NHSO.sub.2 -- or the like, and Het is a pyrrolinyl group, a 1,4-diazabicyclo?2.2.2!octanyl group or the like which may be substituted with a hydroxyl group, a carbamoyl lower alkyl group or the like) which may be substituted with a lower alkyl group, a lower alkylsulfamoyl group or the like which may be substituted with a hydroxyl group, a di-lower alkylsulfonyl group or the like; a hydroxyl group; a di-lower alkylsulfamoyl group or the like, each of A.sub.1, A.sub.2 and A.sub.Type: GrantFiled: August 23, 1996Date of Patent: January 13, 1998Assignee: Banyu Pharmaceutical Co., Ltd.Inventors: Susumu Nakagawa, Hiroshi Fukatsu, Ryosuke Ushijima
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Patent number: 5681951Abstract: A process for preparing a compound of formula (I'): ##STR1## comprising reacting a compound of formula (II'): ##STR2## with a compound of formula (III'):A'SH (III')wherein the reaction of the compound of formula (II') and the compound of formula (III') are carried out in the presence of a salt of a metal of Group II or III of the Periodic Table of Elements, wherein A' is an alkyl, aryl, aralkyl or heterocyclic, R.sup.1' is hydrogen or a carboxy protecting group, R.sup.2' and R.sup.3' can be hydrogen or alkyl, X' can be sulfur, k' is 1 or 2 and R.sup.4' is alkyl, alkenyl, aryl, aralkyl, cycloalkyl or heterocyclic.Type: GrantFiled: June 2, 1995Date of Patent: October 28, 1997Assignee: Sankyo Company, LimitedInventors: Koichi Hirai, Yuji Iwano, Takahide Nishi, Akira Yoshida, Kozo Oda, Hiroo Koyama
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Patent number: 5679790Abstract: Novel carbapenem compounds, (1R,5S,6S)-2-?1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-?(R)-1-hydroxyeth yl!-1-methyl-carbapen-2-em-3-carboxyic acid derivatives.These carbapenem compounds are represented by the following formula having a beta-coordinated methyl group introduced at the 1-position and a ?1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio group introduced at the 2-position. ##STR1## In the formula, R is hydrogen; lower alkyl group which is unsubstituted or substituted by hydroxy, lower alkoxy or lower alkoxy-lower alkoxy group; group --COOR.sup.1 (R.sup.1 is hydrogen or lower alkyl group); or group --CONR.sup.2 R.sup.3 (R.sup.2 and R.sup.3 are, independently each other, hydrogen or lower alkyl), andY is carboxy, --COO.sup..crclbar. or protected carboxy.These compounds are useful antibiotics for prevention and treatment of bacterial infections.Type: GrantFiled: April 12, 1996Date of Patent: October 21, 1997Assignee: Lederle (Japan), Ltd.Inventors: Takao Abe, Takeshi Isoda, Chisato Sato, Ado Mihira, Satoshi Tamai, Toshio Kumagai
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Patent number: 5672701Abstract: Compounds of the formula ##STR1## wherein A is an unsubstituted or hydroxy-substituted straight or branched C.sub.1-10 alkylene group or a straight or branched C.sub.1-10 alkylene group having an intervening heteroatom selected from oxygen, sulfur and nitrogen;R.sup.2 is hydroxy, halogen, C.sub.1-4 alkoxy, nitrile, azido, a quaternary ammonio group, --NR.sup.5 R.sup.6, ##STR2## azetidinyl, or a 5- or 6-membered heterocyclic group selected from heteroaromatic and heteroalicyclic joined through a carbon atom thereof;or a non-toxic pharmaceutically acceptable salt thereof, are novel antimicrobial agents which are useful in the treatment of infectious disease in humans and other animals. Novel intermediates and processes for their preparation are also disclosed.Type: GrantFiled: January 26, 1995Date of Patent: September 30, 1997Assignee: Bristol-Myers Squibb CompanyInventors: Alain Martel, Carol Bachand, Marcel Menard
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Patent number: 5659043Abstract: This invention relates to 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine represented by the following formula and its acid addition salts ##STR1## and to the production process therefor. The above compounds are useful as intermediates for preparing carbapenem compounds, which have strong antibacterial activity, with convenience and high yield.Type: GrantFiled: December 12, 1995Date of Patent: August 19, 1997Assignee: Lederle (Japan) Ltd.Inventors: Kazuhiko Hayashi, Chisato Sato, Satoshi Tamai
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Patent number: 5652233Abstract: The present invention relates to carbapenems and provides a compound of the formula (I): ##STR1## or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is hydrogen or C.sub.1-4 alkyl;R.sup.4 and R.sup.5 are the same or different and are selected from hydrogen, halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, C.sub.1-4 alkylaminosulphonyl, di-C.sub.1-4 -alkylaminosulphonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N-C.sub.1-4 alkyl)amino, C.sub.1-4 alkanesulphonamido and C.sub.1-4 alkylS(O)n- wherein n is zero, one or two:with the proviso that there is no hydroxy or carboxy substituent in a position ortho to the link to --NR.sup.3 --.Type: GrantFiled: June 5, 1995Date of Patent: July 29, 1997Assignee: Zeneca LimitedInventors: Michael John Betts, Gareth Morse Davies, Michael Lingard Swain
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Patent number: 5641770Abstract: The present invention relates to 2-(2-substituted pyrrolidin-4-yl)-thio-carbapenem derivatives and pharmaceutically acceptable salts thereof, to a process for preparing the derivatives, an intermediate compound for preparing the derivatives, an antibacterial composition containing the derivatives, and use of the derivatives as an antibacterial agent.Type: GrantFiled: July 21, 1995Date of Patent: June 24, 1997Assignee: Chong Kun Dang Corp.Inventors: Hyo Sung Kwak, Chong Ryul Lee, Sang Choon Lee, Hong Woo Lee, Hoi Choo Son, Eung Nam Kim, Kyeong Bok Min
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Patent number: 5629419Abstract: An improved process for preparing a 4-mercaptopyrrolidine compound [I]: ##STR1## wherein R is H, lower alkyl or lower alkanoyl, R.sup.1 is H or SH-protecting group, and X is O or S, which comprises reacting halogenobutyric acid compound [VI], or a salt thereof, with amine compound [VII], or a salt thereof, and if necessary, followed by thiocarbonylating the product and/or removing the protecting group, said 4-mercaptopyrrolidine compound [I] being useful as intermediate for carbapenem antibacterial agents.Type: GrantFiled: November 8, 1995Date of Patent: May 13, 1997Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Hiroshi Ohmizu, Masahiko Seki, Takeshi Yamanaka
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Patent number: 5614624Abstract: A compound of the formula ##STR1## in which: R.sup.1' is hydrogen or a carboxy-protecting group;R.sup.41' is hydrogen or a hydroxy-protecting group;R.sup.42' is a C.sub.1 -C.sub.6 alkyl, a C.sub.1 -C.sub.6 alkoxy, a halogen, an aryl or an aryloxy; R.sup.43' is hydrogen, a C.sub.1 -C.sub.6 alkyl, a C.sub.1 -C.sub.6 alkoxy, a hydroxy, a halogen, a cyano, a nitro or a group of the formula --NR.sup.8' R.sup.9', where R.sup.8' and R.sup.9' are independently selected from the group consisting of hydrogen, amino-protecting groups, C.sub.1 -C.sub.6 alkyl groups and phenyl groups, or R.sup.8' and R.sup.9' together represent a group --(CH.sub.2).sub.q '--O.sub.r '--(CH.sub.2).sub.s '--, where q' and s' are independently 0 or an integer of from 1 to 5 and r' is 0 or 1, provided that (q'+s') is an integer of at least 2; R.sup.45' and R.sup.46' are independently selected from the group consisting of C.sub.1 -C.sub.6 alkyl groups and aryl groups, or R.sup.45' and R.sup.46' together represent a group --(CH.sub.2).sub.Type: GrantFiled: June 2, 1995Date of Patent: March 25, 1997Assignee: Sankyo Company, LimitedInventors: Koichi Hirai, Yuji Iwano, Takahide Nishi, Akira Yoshida, Kozo Oda, Hiroo Koyama
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Patent number: 5608056Abstract: A compound of the formula: ##STR1## in which R.sup.1 is carboxy or protected carboxy,R.sup.2 is 1-hydroxyethyl,R.sup.3 is methyl,R.sup.4 is optionally substituted pyridyl(lower)alkyl, optionally N-substituted 2-oxopiperazin-1-yl-(lower)alkyl, optionally substituted imidazol-1-yl(C.sub.2 -C.sub.3)alkyl, optionally substituted imidazol-5-yl-(lower)alkyl, optionally substituted imidazol-2-yl-(lower)alkyl, optionally substituted pyrazol-4-(or 5-)yl(lower)alkyl, optionally substituted pyrazol-1-ylethyl, optionally substituted triazolyl(lower)alkyl, optionally substituted pyrimidinyl(lower)alkyl, optionally substituted dihydropyrimidinyl(lower)alkyl, or optionally substituted (2,3-dihydroimidazo-[1,2-b]pyrazol-1-yl)ethyl, andR.sup.5 is hydrogen or imino-protective group,and pharmaceutically acceptable salts thereof, which have antimicrobial activity.Type: GrantFiled: September 21, 1994Date of Patent: March 4, 1997Assignee: Fujisawa Pharmaceutical Co., Ltd.Inventors: Masayoshi Murata, Hideo Tsutsumi, Keiji Matsuda, Kohji Hattori, Takashi Nakajima
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Patent number: 5602118Abstract: Carbapenem antibiotic compounds of the general formula: ##STR1## wherein the moiety ##STR2## is a 4, 5 or 6 membered mono, di- or tri- substituted oxygen or sulfur containing ring; wherein Z is oxygen, sulfur, sulfoxide and sulfone, pharmaceutical compositions thereof useful for the treatment of bacterial infections, processes for preparing the compounds and new intermediates useful in the process.Type: GrantFiled: January 26, 1994Date of Patent: February 11, 1997Assignee: American Cyanamid CompanyInventors: Yang-I Lin, Panayota Bitha, Subas Sakya, Timothy W. Strohmeyer, Karen Bush, Carl B. Ziegler, Gregg B. Feigelson
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Patent number: 5587474Abstract: A method for removing substituted or unsubstituted allyl group from .beta.-lactam compound having substituted or unsubstituted allyl group-protecting carboxyl group, which comprises treating said .beta.-lactam compound with palladium catalyst in the presence of allyl-scavenger in aqueous organic solvent, by which the substituted or unsubstituted group can be easily and effectively removed under moderate conditions so that the desired compound can be obtained in high yield at low cost.Type: GrantFiled: June 17, 1993Date of Patent: December 24, 1996Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Kazuhiko Kondo, Hiroshi Horikawa, Tameo Iwasaki
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Patent number: 5583218Abstract: Carbapenem derivatives of formula (I): ##STR1## wherein (a) R.sub.1 is a hydrogen atom, an alkyl group of from 1 to 6 carbon atoms, a hydroxy-lower alkyl group or a protected hydroxy-lower alkyl group of from 1 to 6 carbon atoms in its alkyl moiety, (b) COOR.sub.2 is a carboxyl group, a carboxylate anion or a protected carboxyl group, (c) R.sub.3 is an alkyl group of from 1 to 6 carbon atoms and (d) R.sub.4 is a substituted or unsubstituted heterobicyclic group of formula (II): ##STR2## in which the partial structure ##STR3## is a 5- or 6-membered, saturated or unsaturated, nitrogen-containing heterocycle containing 1 to 4 hereto atoms each selected from the group consisting of oxygen, sulfur and nitrogen, at least one hetero atom being nitrogen, and is which R.sub.5 and R.sub.6 each is a hydrogen atom or an appropriate substituent, any isomeric form thereof, and pharmacologically acceptable salts thereof are potent and stable antimicrobial agents.Type: GrantFiled: February 13, 1996Date of Patent: December 10, 1996Assignee: Daiichi Pharmaceutical Co., Ltd.Inventors: Makoto Takemura, Toshiyuki Nishi, Hiroshi Susaki, Youhei Ishida, Hiroko Koda, Takeshi Hayano
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Patent number: 5578722Abstract: Novel and effective process for preparing a carbapenem compound of the formula (III): ##STR1## wherein R.sub.1 and R.sub.2 are each H or lower alkyl, R.sub.3 is lower alkyl, R.sub.4 is a protecting group, L is substituted or unsubstituted arylsulfonyloxy, lower alkanesulfonyloxy, halogeno-lower alkanesulfonyloxy, di-lower alkylphosphoryloxy, etc., and X is H or protected hydroxy, which comprises reacting a .beta.-lactam compound (I) with an acetic acid ester derivative (II), in the presence of base, followed by treating the product with an active esterifying agent for a hydroxy group, said compound (III) being useful as intermediate in preparing 1.beta.-alkylcarbapenem compounds having antibacterial activity.Type: GrantFiled: March 20, 1995Date of Patent: November 26, 1996Assignee: Sumitomo Pharmaceuticals Co., Ltd.Inventors: Makoto Sunagawa, Haruki Matsumura
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Patent number: 5571805Abstract: The present invention relates to carbapenems and provides a compound of the formula (I) ##STR1## wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxyethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is hydrogen or C.sub.1-4 alkyl;P is of the formula (IA), (IB) or (IC) ##STR2## and in the formula (IB) the naphthyl group may be bonded to the nitrogen of the linking carbamoyl group at either ring; Z is carboxy, sulfonic acid, sulfinic acid, C.sub.1-4 alkanamidosulfonyl (--SO.sub.2 NHCOC.sub.1-3 alkyl), benzamidosulfonyl, C.sub.1-4 alkylsulfonylcarbamoyl (--CONHSO.sub.2 C.sub.1-4 alkyl), phenylsulfonylcarbamoyl, C.sub.1-4 alkoxy carbamoyl, hydroxycarbamoyl, sulfoamino, N--C.sub.1-4 alkanesulfonamido, cyanocarbamoyl, cyanosulfamoyl, tetrazol-5-yl, 3-hydroxyisoxazol-4-yl and 3-hydroxyisoxazol-5-yl;and P is optionally further substituted provided that when P is of the formula (IA) or (IC), Z is not carboxy;or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.Type: GrantFiled: September 8, 1994Date of Patent: November 5, 1996Assignee: Zeneca LimitedInventors: Frederic H. Jung, Alain M. Bertrandie, Ronald H. B. Galt
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Patent number: 5559224Abstract: Carbapenem derivatives which may be utilized as antibiotics and which show strong antibacterial activity against various bacterial strains including Pseudomonas aeruginosa. The compounds containing the derivatives are quite safe and are also stable against hydrolases such as dehyropeptidase (DHP).Type: GrantFiled: May 5, 1995Date of Patent: September 24, 1996Assignee: Daiichi Pharmaceutical Co., Ltd.Inventors: Toshiyuki Nishi, Hiroko Koda, Kazuyuki Sugita, Yohhei Ishida, Makoto Takemura, Takeshi Hayano
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Patent number: 5554606Abstract: The present invention provides a compound of the formula (I) ##STR1## wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 and R.sup.4 are ortho with respect to one another wherein R.sup.3 and R.sup.4 are independently hydroxy or in vivo hydrolyzable esters thereof; the benzene ring being optionally further substituted; or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.Type: GrantFiled: October 26, 1994Date of Patent: September 10, 1996Assignee: Zeneca LimitedInventors: Michael J. Betts, Gloria A. Breault
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Patent number: 5550121Abstract: A compound of the formula: ##STR1## wherein R.sup.1 is a hydrogen atom or a methyl group, R.sup.2 is a hydrogen atom or a negative charge, R.sup.3 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, an N-lower alkylamino group, an N,N-di-lower alkylamino group, a lower alkanoylamino group, an aroylamino group, a (lower alkylsulfonyl)amino group, a sulfamoylamino group, a cyano group, a nitro group, a group of --COOR.sup.4 (wherein R.sup.4 is a hydrogen atom or a lower alkyl group) or a group of --CON(R.sup.5)R.sup.6 (wherein each of R.sup.5 and R.sup.6 which may be the same or different, is a hydrogen atom or a lower alkyl group, or R.sup.5 and R.sup.Type: GrantFiled: September 27, 1994Date of Patent: August 27, 1996Assignee: Banyu Pharmaceutical Co., Ltd.Inventors: Susumu Nakagawa, Shinji Kato, Satoshi Murase, Osamu Okamoto, Ryuji Mitomo, Katsumi Yamamoto, Koji Yamada, Hiroshi Fukatsu
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Patent number: 5547667Abstract: Conjugates of general formula 1:[A--O--W--Z].sub.a --T 1wherein the moiety A--O-- is the residue of drug of formula A--O--H in which --O--H is a primary or secondary hydroxyl group; a is an integer of from 1 to 30; W is a group of general formula 2: ##STR1## wherein b is an integer of from 1 to 4, B represents a C.sub.1 -C.sub.3 alkylene group and R.sub.1 and R.sub.2 each independently represent hydrogen, halogen, alkyl, phenyl or substituted phenyl; Z is a spacer group and T is a carrier moiety.Type: GrantFiled: October 25, 1994Date of Patent: August 20, 1996Assignee: Farmitalia Carlo Erba S.r.l.Inventors: Francesco Angelucci, Laura Bersani, Michele Caruso, Marina Ripamonti, Daniela Ruggieri, Antonino Suarato
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Patent number: 5541178Abstract: A carbapenem compound of the formula (I) ##STR1## wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is hydrogen or C.sub.1-4 alkyl;R.sup.4 is hydroxy or carboxy;and the phenyl ring is optionally further substituted by one or two substituents selected from halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, trifluoromethyl, C.sub.1-4 alkoxycarbonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino sulphonic acid, C.sub.1-4 alkylS(O).sub.n --(wherein n is 0-2), N-C.sub.1-4 alkanesulphonamido, C.sub.1-4 alkanoylamino and C.sub.1-4 alkanoyl(N-C.sub.1-4 alkyl)amino:provided that the phenyl ring is substituted by at least one carboxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.Type: GrantFiled: October 6, 1993Date of Patent: July 30, 1996Assignee: Zeneca LimitedInventors: Michael J. Betts, Michael L. Swain
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Patent number: 5539102Abstract: The method for producing a sulfamide according to the present invention includes the step of reacting an alcohol and an oxycarbonylsulfamide compound in the presence of a trivalent phosphorus compound and an azodicarboxylic acid derivative. In one embodiment, the sulfamide is represented by Formula I, the alcohol is represented by Formula II, and the oxycarbonylsulfamide compound is represented by Formula III:R.sup.3 NHSO.sub.2 NR.sup.1 R.sup.2 (I)wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, and alkyl substituted with the heterocyclic group, respectively, said heterocyclic group being selected from the group consisting of pyranosyl, furanosyl, piperidinyl, pyrrolidinyl, an azetidinone ring, a cephem ring, a penem ring, and a carbapenem ring; R.sup.Type: GrantFiled: February 18, 1993Date of Patent: July 23, 1996Assignee: Shionogi Seiyaku Kabushiki KaishaInventors: Yuji Sendo, Makoto Kii, Yasuhiro Nishitani, Tadashi Irie, Yutaka Nishino
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Patent number: 5534510Abstract: Novel carbapenem compounds, (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyeth yl]-1-methyl-carbapen-2-em-3 -carboxyic acid derivatives.These carbapenem compounds are represented by the following formula having a beta-coordinated methyl group introduced at the 1-position and a [1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio group introduced at the 2-position. ##STR1## In the formula, R is hydrogen; lower alkyl group which is unsubstituted or substituted by hydroxy, lower alkoxy or lower alkoxy-lower alkoxy group; group --COOR.sup.1 (R.sup.1 is hydrogen or lower alkyl group); or group --CONR.sup.2 R.sup.3 (R.sup.2 and R.sup.3 are, independently each other, hydrogen or lower alkyl), andY is carboxy, --COO.sup..crclbar. or protected carboxy.These compounds are useful antibiotics for prevention and treatment of bacterial infections.Type: GrantFiled: June 29, 1994Date of Patent: July 9, 1996Assignee: Lederle (Japan), Ltd.Inventors: Takao Abe, Takeshi Isoda, Chisato Sato, Ado Mihira, Satoshi Tamai, Toshio Kumagai
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Patent number: 5527793Abstract: The present invention relates to carbapenems and provides a compound of the formula (I) ##STR1## wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is hydrogen or C.sub.1-4 alkyl;A is a 5-membered heteroaryl ring containing one nitrogen atom and up to two additional heteroatoms selected from nitrogen, oxygen and sulphur; and is bonded to the nitrogen of the linking carbamoyl group by a carbon atom in the ring, is substituted with the carboxy group on a carbon atom in the ring and is optionally further substituted on a carbon atom in the ring; andin any ring --NH--, H is optionally replaced by C.sub.1-4 alkyl; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. Processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them are also described.Type: GrantFiled: July 7, 1993Date of Patent: June 18, 1996Assignee: Zeneca LimitedInventors: Frederic H. Jung, Jean J. Lohmann
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Patent number: 5527791Abstract: The present invention provides a compound of the formula: ##STR1## or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:A is a group of the formula (IA) or (IB): ##STR2## R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl; R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 and R.sup.4 are the same or different and are a variety of substituents X is alkanediyl containing 1-6 carbon atoms optionally interrupted by O, S(O).sub.x (wherein x is zero, one or two), --CONR.sup.5 -- or --NR.sup.5 -- or wherein R.sup.5 is hydrogen or C.sub.1-4 alkyl;or X is alkenediyl containing 1-6 carbon atoms optionally interrupted by O, S(O).sub.x or --NR.sup.5 --.Type: GrantFiled: September 21, 1993Date of Patent: June 18, 1996Assignee: Zeneca LimitedInventors: Michael J. Betts, Gareth M. Davies, Frederic H. Jung
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Patent number: 5519015Abstract: The present invention relates to carbapenems and provides a compound of the formula (I) ##STR1## wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is hydrogen or C.sub.1-4 alkyl; and the thienyl ring is optionally further substitued by one or two substituents selected from halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, trifluoromethyl, C.sub.1-4 alkoxycarbonyl, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, sulfonic acid, C.sub.1-4 alkylS(O).sub.n -- (wherein n is 0-2), C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N-C.sub.1-4 alkyl)amino, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl and N-C.sub.1-4 alkanesulfonamido; or by a tetramethylene group attached to adjacent carbon atoms on the thienyl ring; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.Type: GrantFiled: November 26, 1993Date of Patent: May 21, 1996Assignee: Zeneca LimitedInventor: Frederic H. Jung
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Patent number: 5496816Abstract: Carbapenems of the formula: ##STR1## are disclosed as useful antibacterial agents. Pharmaceutical compositions and methods of use are also disclosed.Type: GrantFiled: December 20, 1994Date of Patent: March 5, 1996Assignee: Merck & Co., Inc.Inventors: Timothy A. Blizzard, Ronald W. Ratcliffe, Sherman T. Waddell, Sandra P. Szumiloski, Robert R. Wilkening, Kenneth J. Wildonger
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Process for preparing optically active 4-mercapto-2-pyrrolidone derivative and intermediate therefor
Patent number: 5495012Abstract: A process for preparing an optically active 4-mercapto-2-pyrrolidone derivative of the formula [I]: ##STR1## wherein R.sup.1 is a hydrogen atom or a protecting group and R.sup.2 is a hydrogen atom or a protecting group, which comprises subjecting racemic 4-amino-3-mercaptobutyric acid or a salt thereof to optical resolution by using 1-(trichlorophenyl)ethanesulfonic acid, followed by subjecting the product to cyclization reaction after protecting the functional groups thereof, if necessary, and further optionally removing the protecting groups therefrom. The present process is industrially advantageous than conventional processes for preparing optically active 4-mercapto-2-pyrrolidone derivatives which are useful as an intermediate for various medicines such as carbapenem antibacterial agents.Type: GrantFiled: March 24, 1995Date of Patent: February 27, 1996Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Tameo Iwasaki, Kazuhiko Kondo, Tadashi Nakatani, Ryuzo Yoshioka -
Patent number: 5493018Abstract: This invention relates to the synthesis of a bicyclic ketoester compound of the formula 1 obtained by cyclizing a diazo compound of formula 2: in the presence of a rhodium catalyst. ##STR1## By adding an effective amount of a Lewis acid to the cyclization reaction, the reaction selectively produces the 1-beta methyl isomer, and epimerization of the 1-beta methyl compound to the 1-alpha isomer is minimized.Type: GrantFiled: January 25, 1994Date of Patent: February 20, 1996Assignee: Merck & Co., Inc.Inventors: Thomas Meng-Han Liu, Joseph E. Lynch, Ralph P. Volante
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Patent number: 5478820Abstract: The present invention relates to carbapenems and provides a compound of the formula (I): ##STR1## or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is hydrogen or C.sub.1-4 alkyl;R.sup.4 and R.sup.5 are the same or different and are selected from hydrogen, halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, C.sub.1-4 alkylaminosulphonyl, di-C.sub.1-4 alkylaminosulphonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N-C.sub.1-4 alkyl)amino, C.sub.1-4 alkanesulphonamido and C.sub.1-4 alkylS(O).sub.n -- wherein n is zero, one or two:with the proviso that there is no hydroxy or carboxy substituent in a position ortho to the --NR.sup.2 --.Type: GrantFiled: October 4, 1993Date of Patent: December 26, 1995Assignee: Zeneca Ltd.Inventors: Michael J. Betts, Gareth M. Davies, Michael L. Swain
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Patent number: 5463046Abstract: The present invention relates to new 1-.beta.-methyl-2-thiolic carbapenem derivatives represented by the following general formula (I) and producing method thereof. ##STR1## The above-mentioned compound is very stable against DHP-1 enzyme due to effective shielding of carbapenem ring structually and is highly effective in both gram-positive and gram-negative microorganism, especially has a remarkable effect on the Pseudomonas aeruginosa known as a disease germ having strong resistance.Type: GrantFiled: November 19, 1993Date of Patent: October 31, 1995Assignees: Dong Kook Pharmaceutical Co., Ltd., Ki-Beom KwonInventors: Jung H. Cho, Chang H. Oh, Ki H. Nam
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Patent number: 5449672Abstract: A compound of the formula: ##STR1## wherein R.sup.1 is a hydrogen atom or a methyl group, R.sup.2 is a hydrogen atom or a negative charge, X is a group of --N(R.sup.3)R.sup.4 (wherein R.sup.3 is a lower alkyl group, and R.sup.4 is a hydrogen atom or a lower alkyl group) or a group of --N.sup.+ (R.sup.5)(R.sup.6)R.sup.7 (wherein each of R.sup.5, R.sup.6 and R.sup.7 which may be the same or different, is a lower alkyl group), and n is an integer of from 2 to 4; or a pharmaceutically acceptable salt or ester thereof.Type: GrantFiled: August 12, 1994Date of Patent: September 12, 1995Assignee: Banyu Pharmaceutical Co., Ltd.Inventors: Susumu Nakagawa, Shinji Kato, Satoshi Murase, Osamu Okamoto, Ryuji Mitomo, Katsumi Yamamoto, Koji Yamada, Hiroshi Fukatsu
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Patent number: 5447925Abstract: The present invention provides a compound of the formula (I) ##STR1## wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;n is zero or an integer 1 to 4; andP is a benzene ring substituted by groups R.sup.3 and R.sup.4 which are ortho with respect to one another wherein R.sup.3 and R.sup.4 are independently hydroxy or in vivo hydrolysable esters thereof;or P is a group of the formula (II) or (III) ##STR2## wherein M is oxygen or a group NR.sup.5 wherein R.sup.5 is hydrogen or C.sub.1-4 alkyl;ring P being optionally further substituted;or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.Type: GrantFiled: October 6, 1993Date of Patent: September 5, 1995Assignees: Imperial Chemical Industries PLC, ICI Pharma S.A.Inventors: Michael J. Betts, Gloria A. Breault
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Patent number: 5444057Abstract: The present invention relates to carbapenems and provides a compound of the formula (I) ##STR1## wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is hydrogen or C.sub.1-4 alkyl;and the pyridyl group is bonded to the nitrogen of the linking carbamoyl group by a carbon atom, is substituted with the carboxy group on a carbon atom and is optionally substituted on one or two pyridyl ring carbon atoms; or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof. Processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them.Type: GrantFiled: September 15, 1994Date of Patent: August 22, 1995Assignee: Zeneca LimitedInventor: Frederic H. Jung
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Patent number: 5441949Abstract: The present invention relates to carbapenems and provides a compound of the formula (I) ##STR1## wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is hydrogen or C.sub.1-4 alkyl;P.sup.1 is of the formula: ##STR2## and one or two of A,B,C,D,E,F,G and H, are nitrogen and the remainder are CH; and P is bonded to the nitrogen of the linking carbamoyl group by a carbon atom, in either ring, is substituted by the carboxy group on a carbon atom, in either ring, and is optionally further substituted, by up to three substitutents, on a carbon atom, in either ring; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. Processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them are also described.Type: GrantFiled: September 16, 1994Date of Patent: August 15, 1995Assignee: Zeneca LimitedInventors: Frederic H. Jung, Jean-Claude Arnould
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Patent number: 5442055Abstract: There is disclosed an azetidinone compound of the formula [I]: ##STR1## wherein Ring B is a benzene ring which may have substituent(s), R.sup.1 is a hydroxy-substituted lower alkyl group which may have substituent(s), X is oxygen atom and the like, Y is oxygen atom and the like, and Z is a methylene group which may have substituent(s), which is useful as a synthetic intermediate of the 1.beta.-methylcarbapenem-type antibacterial agent.Type: GrantFiled: November 5, 1993Date of Patent: August 15, 1995Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Tameo Iwasaki, Kazuhiko Kondo
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Patent number: 5438054Abstract: Carbapenem compounds of formula I and their pharmaceutically acceptable salts and esters are provided: ##STR1## wherein R, R.sup.1, R.sup.2, R.sup.3, p, q and r are as defined herein, which are useful as antibacterial agents.Type: GrantFiled: March 9, 1994Date of Patent: August 1, 1995Assignee: Banyu Pharmaceutical Co., Ltd.Inventors: Susumu Nakagawa, Norikazu Ohtake, Fumio Nakano, Koji Yamada, Ryosuke Ushijima, Satoshi Murase, Hiroshi Fukatsu
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Patent number: 5424069Abstract: A method of crystallizing (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio- 6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate (hereinafter simply referred to as L-627), which is characterized by maintaining an aqueous solution of L-627 at temperatures ranging from the eutectic temperature of the solution to temperatures lower than 0.degree. C.The method provides some advantages that loss of L-627 accompanied by crystallization is less, number of steps in the preparation of vial formulations is less and maintenance of these steps under sterile and dust-free conditions can be performed easily, dispensation of the drug can be conducted with quantitative accuracy, and the crystals dissolve in a solvent promptly at the time of use.Type: GrantFiled: November 30, 1993Date of Patent: June 13, 1995Assignee: Takeda Chemical Industries, Ltd.Inventors: Masayoshi Kaneko, Shigeo Yabuno
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Patent number: 5424306Abstract: A storage stable form of the pivaloyloxymethyl ester of the carbapenem derivative known as (1R, 5S, 6S)-2-[(4R)-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-c arbapen-2-em-3-carboxylic acid in crystalline form.Type: GrantFiled: November 12, 1993Date of Patent: June 13, 1995Assignee: Sankyo Company, LimitedInventors: Isao Kawamoto, Masao Miyauchi, Roruro Endo
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Patent number: 5420119Abstract: Carbapenem compounds of formula (I): ##STR1## [in which: A is a fully saturated heterocyclic group, of which at least one ring atom is nitrogen; R.sup.1 is hydrogen or methyl; R.sup.2 is hydrogen or alkyl; R.sup.3 is hydrogen or a negative ion; Q is: (i) --B--N.sup.+ R.sup.8 R.sup.9 R.sup.10, where R.sup.8, R.sup.9 and R.sup.10 are alkenyl, alkynyl or optionally substituted alkyl, and B is alkylene or alkylidene; (ii) a heterocyclic group of which one ring atom is a >N.sup.+ R.sup.11 R.sup.12, where R.sup.11 and R.sup.12 are alkenyl, alkynyl or optionally substituted alkyl; (iii) alkyl substituted by a heterocyclic group as defined in (ii) above; or (iv) alkyl substituted by an aromatic heterocyclic group, of which one ring atom is ##STR2## or R.sup.2 and Q, and the nitrogen to which they are attached, form a group of formula (II): ##STR3## where m and n are 1, 2 or 3; R.sup.6 is optionally substituted alkyl; and R.sup.Type: GrantFiled: October 27, 1993Date of Patent: May 30, 1995Assignee: Sankyo Company, LimitedInventors: Isao Kawamoto, Masao Miyauchi, Eiji Nakayama, Rokuro Endo, Satoshi Ohya, Yukio Utsui
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Patent number: 5420122Abstract: Novel 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and processes for their preparation are disclosed. These novel compounds have antimicrobial activity, and are useful as a medicament in the treatment of infectious diseases in human beings and animals.Type: GrantFiled: April 14, 1992Date of Patent: May 30, 1995Assignee: Fujisawa Pharmaceutical Co., Ltd.Inventors: Masayoshi Murata, Hideo Tsutsumi, Keiji Matsuda, Kohji Hattori, Takashi Nakajima
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Patent number: 5414081Abstract: Disclosed is a process for preparing a .beta.-lactam compound represented by the formula: ##STR1## wherein R.sup.1 represents a hydroxy-substituted lower alkyl group or an amino group each of which may be protected; R.sup.2 represents hydrogen atom or an ester residue; X represents a methylene group which may be substituted by a lower alkyl group, sulfur atom or a group represented by the formula: --A--CH.sub.2 -- where A represents sulfur atom, oxygen atom or methylene group; and W represents an active ester residue of hydroxyl group, or a salt thereof, which comprises the steps of treating a 1-aza-3-thia-bicycloalkane compound represented by the formula: ##STR2## wherein R.sup.1, R.sup.2 and X have the same meanings as defined above, or a salt thereof with a base in the presence of a desulfurizing agent and then reacting the resulting compound with an active esterifying agent of hydroxyl group.Type: GrantFiled: February 17, 1993Date of Patent: May 9, 1995Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Hiroshi Horikawa, Kazuhiko Kondo, Tameo Iwasaki
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Patent number: 5407931Abstract: The invention relates to heterocyclic derivatives having antibacterial activity, to processes for their preparation, to compositions containing them, and to their medicinal uses.Type: GrantFiled: September 7, 1990Date of Patent: April 18, 1995Assignee: Glaxo S.p.A.Inventors: Bruno Tamburini, Alcide Perboni, Tino Rossi, Daniele Donati, Daniele Andreotti, Giovanni Gaviraghi, Roberto Carlesso, Claudio Bismara
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Patent number: 5387578Abstract: Conjugate of general formula 1:[A--O--W-Z].sub.a -T 1wherein the moity A--O--is the residue of drug of formula A--O--H in which --O--H is a primary or secondary hydroxyl group; a is an integer of from 1 to 30; W is a group of general formula 2: ##STR1## wherein b is an integer of from 1 to 4, B represents a C.sub.1 -C.sub.3 alkylene group and R.sub.1 and R.sub.2 each independently represent hydrogen, halogen, alkyl, phenyl or substituted phenyl; Z is a spacer group and T is a carrier moiety.Type: GrantFiled: April 3, 1992Date of Patent: February 7, 1995Assignee: Farmitalia Carlo Erba S.r.l.Inventors: Francesco Angelucci, Laura Bersani, Michele Caruso, Marina Ripamonti, Daniela Ruggieri, Antonino Suarato
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Patent number: 5374720Abstract: A compound of the formula: ##STR1## wherein R is a hydrogen atom or a methyl group, R.sup.1 is a hydrogen atom or a negative charge, each of R.sup.2 and R.sup.3 which may be the same or different, is a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a formimidoyl group, an acetoimidoyl group, --COOR.sup.4, --CON(R.sup.5)R.sup.6, --N(R.sup.5)R.sup.6, --CH.sub.2 COOR.sup.4, --CH.sub.2 N(R.sup.5)R.sup.6 or --CH.sub.2 CON(R.sup.5)R.sup.6 (wherein R.sup.4 is a hydrogen atom or a lower alkyl group, each of R.sup.5 and R.sup.6 which may be the same or different, is a hydrogen atom or a lower alkyl group, or R.sup.5 and R.sup.6 form together with the adjacent nitrogen atom a heterocyclic group selected from the group consisting of an aziridinyl group, an azetidinyl group, a pyrrolidinyl group and a piperidyl group), A is .dbd.NR.sup.7, .dbd.N.sup.+ (R.sup.7)R.sup.8, wherein each of R.sup.7 and R.sup.Type: GrantFiled: October 21, 1991Date of Patent: December 20, 1994Assignee: Banyu Pharmaceutical Co., Ltd.Inventors: Susumu Nakagawa, Norikazu Ohtake, Fumio Nakano, Koji Yamada, Ryosuke Ushijima, Satoshi Murase, Hiroshi Fukatsu
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Patent number: 5373002Abstract: A compound of the formula: ##STR1## wherein R is a hydrogen atom or a methyl group, R.sup.1 is a hydrogen atom or a negative charge, R.sup.2 is a lower alkyl group, a lower alkyl group substituted with a hydroxyl group or --COOR.sup.3 (wherein R.sup.3 is a hydrogen atom or a lower alkyl group), A is .dbd.NH, .dbd.NR.sup.4 or .dbd.N(R.sup.4)R.sup.5 (wherein each of R.sup.4 and R.sup.5 which may be the same or different, is a lower alkyl group or a lower alkyl group substituted with a hydroxyl group), p is an integer of from 0 to 3, and each of q and r which may be the same or different, is an integer of from 0 to 5, provided that q and r are not simultaneously 0 and q +r.ltoreq.6; or a pharmaceutically acceptable salt or ester thereof.Type: GrantFiled: September 25, 1992Date of Patent: December 13, 1994Assignee: Banyu Pharmaceutical Co., Ltd.Inventors: Susumu Nakagawa, Norikazu Ohtake, Fumio Nakano, Koji Yamada, Ryosuke Ushijima, Satoshi Murase, Hiroshi Fukatsu
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Patent number: 5360904Abstract: A process for preparing penem esters by reacting ##STR1## wherein R.sub.1 is a hydroxy protecting group and X is a C.sub.1 -C.sub.10 alkyl or aryl group, with ##STR2## wherein R.sub.2 is hydrogen or a C.sub.1 -C.sub.6 alkyl group in the presence of an anhydrous organic solvent, condensing the product with ##STR3## wherein X is a halogen atom or a --OCOOR.sub.3 group and then cyclizing.Type: GrantFiled: September 21, 1992Date of Patent: November 1, 1994Assignee: Farmitalia Carlo Erba S r lInventors: Angelo Bedeschi, Walter Cabri, Marcello Marchi, Ettore Perrone
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Patent number: 5360798Abstract: An antibacterial aminooxypyrrolidinylthiocarbapenem I, its production from the corresponding carbapenem V and thiol VI, its pharmaceutical formulation, and its use or combating bacteria are presented. ##STR1## (wherein R is optionally substituted amino; R.sup.1 is hydrogen or 1C to 5C alkyl; R.sup.2 is hydrogen or a conventional hydroxy protective group; R.sup.3 is hydrogen or an imino protective group or imino substituent; R.sup.4 is 1C to 5C alkylene; and R.sup.5 is hydrogen or a conventional carboxy protective group; X is a leaving group; R.sup.6 is hydrogen or a thiol protective group; and wavy lines each shows a bond in R or S configuration).Type: GrantFiled: June 10, 1992Date of Patent: November 1, 1994Assignee: Shionogi Seiyaku Kabushiki KaishaInventors: Yuji Sendo, Kii Makoto
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Patent number: 5359059Abstract: Process for preparing carbapenem derivative of the formula [I], which comprises subjecting azetidinone compound of the formula [II] to intramolecular cyclization reaction together with elimination reaction of the group of --SR.sup.4, followed by re-adding said group of --SR.sup.4 to the 2-position of the carbapenem skeleton of the intramolecularly cyclized compound, which is industrially useful as process for preparing carbapenem antimicrobials or synthetic intermediate therefor. ##STR1## wherein R.sup.1 is protected or unprotected hydroxy-substituted lower alkyl group, R.sup.2 is hydrogen atom or ester residue, R.sup.3 is hydrogen atom or lower alkyl group, and the group of --SR.sup.4 is group which can be used as substituent at 2-position of the carbapenem antimicrobials.Type: GrantFiled: August 2, 1993Date of Patent: October 25, 1994Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Tameo Iwasaki, Kazuhiko Kondo, Hiroshi Horikawa
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Patent number: RE34960Abstract: Compounds of formula (I): ##STR1## .[.[.]. wherein: R.sup.1 .[.represents a hydrogen atom, an alkyl group, an alkoxy group or various substituted alkyl groups.]. .Iadd.is hydroxyethyl; .Iaddend.R.sup.2 represents a group of formula ##STR2## in which ##STR3## .[.represents an alicyclic amine group having from 4 to 8 ring atoms, optionally having a single double bond, optionally containing an additional hetero-atom and optionally having an oxo group on the ring;.]. .Iadd.is a 3-pyrrolidinyl group; .Iaddend.X represents a hydrogen atom.[.; an alkyl group, an alkoxy group, an alkylthio group, an alkylsulphinyl group, an alkylsulphonyl group, a hydroxy group, a halogen atom or various substituted alkyl groups.].;Y represents .[.a hydrogen atom, an alkyl group, an aliphatic acyl group or an acylimidoyl.]. .Iadd.an acetylimidoyl .Iaddend.group; andR.sup.3 represents a carboxy group or a protected carboxy group.[.].].Type: GrantFiled: May 20, 1987Date of Patent: May 30, 1995Assignee: Sankyo Company, LimitedInventors: Tetsuo Miyadera, Yukio Sugimura, Toshihiko Hashimoto, Teruo Tanaka, Kimio Iino, Tomoyuki Shibata, Shinichi Sugawara