WO1994002479A1 - Nouveaux diazabicycloalcenes et procedes de prepararation - Google Patents

Nouveaux diazabicycloalcenes et procedes de prepararation Download PDF

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Publication number
WO1994002479A1
WO1994002479A1 PCT/KR1993/000065 KR9300065W WO9402479A1 WO 1994002479 A1 WO1994002479 A1 WO 1994002479A1 KR 9300065 W KR9300065 W KR 9300065W WO 9402479 A1 WO9402479 A1 WO 9402479A1
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Prior art keywords
formula
compound
lower alkyl
diazabicyclo
amino
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PCT/KR1993/000065
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English (en)
Inventor
Wan Joo Kim
Tae Ho Park
Moon Hwan Kim
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Korea Research Institute Of Chemical Technology
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Publication date
Application filed by Korea Research Institute Of Chemical Technology filed Critical Korea Research Institute Of Chemical Technology
Priority to EP93916266A priority Critical patent/EP0650487A1/fr
Priority to AU45875/93A priority patent/AU663403B2/en
Priority to JP6504363A priority patent/JPH08509457A/ja
Publication of WO1994002479A1 publication Critical patent/WO1994002479A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel diazabicycloalkenes and processes for preparing these compounds.
  • the compounds of the present invention are useful as intermediates in the preparation of quinolone-type or ⁇ -lactam-type antibacterial agents.
  • the present invention also relates to novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof and to processes for preparing these compounds.
  • the present inventors have conducted extensive studies which have led to the synthesis of novel 2,8-diazabicyclo[4.3.0]non-5-ene and 2,7-diazabicyclo[3.3.0]oct- 4-ene, which can be introduced into a molecule of quinolone-type and ⁇ -lactam-type antibacterials as side-chain.
  • the present inventors have also invented processes for preparing these compounds.
  • the present invention relates to compounds of Formula (I) wherein
  • R 1 and R 5 each represent hydrogen, lower alkyl, or a conventional amino-protecting group
  • R 2 , R 3 and R 4 each represent hydrogen, lower alkyl or lower alkyl substituted by amino, hydroxyl or halogen;
  • n denotes an integer of 0 or 1.
  • the present invention also provides novel quinolone carboxylic acid derivatives of Formula (I-A):
  • R 1 , R 3 and R 4 are the same as defined above;
  • A is hydrogen or chlorine atom, or methyl or an amino group
  • B is a lower alkyl group, or a cyclopropyl or a phenyl group optionally substituted with a hlogen atom;
  • C is nitrogen atom, or a methyne group optionally substituted with a lower alkyl or a lower alkoxy group or a halogen atom, and their pharmaceutically acceptable salts.
  • An object of the present invention is to provide diazabicycloalkenes of
  • Formula (I) more particularly 2,8-diazabicyclo[4.3.0]non-5-ene and 2,7-diazabicyclo[3.3.0]oct-4-ene and their derivatives.
  • Another object of the present invention is to provide novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof which possess a broad spectrum of potent antibacterial activities against various microorganisms, and to provide processes for preparing these compounds.
  • lower alkyl used herein means a straight or branched C 1-5 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and t-butyl.
  • halogen used herein means chlorine, bromine and fluorine.
  • amino-protecting groups referred to herein include t-butoxycarbonyl, ethoxycarbonyl and benzyl groups.
  • Another object of the present invention is to provide processes for preparing these compounds. Processes for preparing compounds (I) of the present invention are illustrated hereinbelow.
  • R 1 , R 2 , and R 5 are as defined above, and R 6 represents lower alkyl or a conventional amino-protecting group, such as phenylmethyl, diphenylmethyl, triphenylmethyl and a substituted phenyl.
  • compounds of Formula (I) can be prepared by: (a) reacting a compound of Formula (II) with a primary amine of Formula R 6 NH 2 to give a compound of Formula (III); (b) acylating a compound of Formula (III) with a malonic acid derivative to give a compound of Formula (IV); (c) cyclizing a compound of Formula (IV) in the presence of a base; (d) decarboxylating a compound of Formula (V) in the presence of an acid to form a compound of Formula (VI); (e) reducing a compound of Formula (VI) with a reducing agent to give a compound of Formula (VII); (f) deblocking a compound of Formula (VII) to give a compound of Formula (VIII); (g) acylating a compound of Formula (VIII) to give a compound of Formula (IX); and (h) dehydrating a compound of Formula (IX).
  • the above process is explained in detail hereinbelow
  • step (a) the reaction of a compound of Formula (II) and an amine may be carried out in the absence or presence of a solvent such as ethanol, toluene or dimethylformamide (DMF) at a temperature between about 25°C and about 200°C, preferably between about 80°C and about 120°C to provide a compound of Formula (II) and an amine.
  • a solvent such as ethanol, toluene or dimethylformamide (DMF)
  • step (b) the acylation of a compound of Formula (III) with malonyl chloride is effected at a temperature below 0°C in the presence of an organic base such as triethylamine in a solvent such as methylene chloride or chloroform.
  • step (c) a compound of Formula (IV) is treated with a C 1-5 alkoxide in ethanol, toluene or a mixture thereof.
  • the preferred reaction temperature is about 10°C to about 100°C.
  • step (d) a compound of Formula (V) is treated with hydrochloric, hydrobromic or toluenesulfonic acids in water, methanol, ethanol or mixtures thereof and the resulting mixture is then heated under reflux until a compound of Formula (VI) is formed.
  • a compound of Formula (VI) is reduced with a reducing agent such as lithium aluminum hydride (LAH) and diborane in tetrahydrofuran (THF), methanol, ethyl ether or mixtures thereof to provide a compound of Formula (VII).
  • LAH lithium aluminum hydride
  • THF tetrahydrofuran
  • methanol ethyl ether or mixtures thereof
  • step (f) a compound of Formula (VII) is subjected to catalytic hydrogenation on a noble catalyst such as palladium or platinum to form a compound of Formula (VIII).
  • step (g) the amino group of a compound of Formula (VIII) is protected by a conventional acylation means to give a compound of Formula (IX).
  • step (h) a compound of Formula (IX) is reacted with methanesulfonyl chloride or toluenesulfonyl chloride in the presence of an organic base such as triethylamine or pyridine in a solvent such as methylene chloride, chloroform or ethyl ether to form the corresponding mesylate or tosylate, which is then heated under reflux in the presence of a base such as lower alkoxide, sodium hydride and 1 ,8-dia 2 abicyclo[5.4.0]undec-7-ene (DBU), or 1,5-diazabicyclo-[4.3.0]non-5-ene (DBN) in dimethylsulfoxide (DMSO), toluene or a mixture thereof.
  • an organic base such as triethylamine or pyridine
  • a solvent such as methylene chloride, chloroform or ethyl ether
  • a base such as lower alkoxide
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, X represents a leaving group such as halogen e.g., chlorine, bromine or lower alkoxycarbonyl e.g. , ethoxycarbonyl, and n denotes an integer of 0 or 1.
  • halogen e.g., chlorine, bromine or lower alkoxycarbonyl e.g. , ethoxycarbonyl
  • n denotes an integer of 0 or 1.
  • compounds of Formula (I) can be prepared by (i) condensing a compound of Formula (X) (J.
  • step (i) a condensation of a compound of Formula (X) with an alkylamine of Formula is effected in a solvent such as ethanol, benzene, or toluene at a temperature between about 70°C and about 130°C to form a compound of Formula (XI).
  • a solvent such as ethanol, benzene, or toluene at a temperature between about 70°C and about 130°C to form a compound of Formula (XI).
  • step (j) a compound of Formula (XI) is reduced either with a reducing agent such as sodium borohydride and sodium borocyanohydride or by catalytic hydrogenation on a noble catalyst such as palladium and platinum in a solvent such as methanol, ethanol, THF or mixtures thereof to give a compound of Formula (XII).
  • a reducing agent such as sodium borohydride and sodium borocyanohydride
  • a noble catalyst such as palladium and platinum in a solvent
  • solvent such as methanol, ethanol, THF or mixtures thereof
  • step (k) a compound of Formula (XII) is treated with metal magnesium to undergo a Grignard reaction or treated with sodium hydride or alkali metal alkoxide to form a bicyclic compound of Formula (XIII).
  • step (1) a compound of Formula (XIII) is treated with alkyl magnesium halide in a solvent such as ethyl ether and THF to provide a compound of Formula (XIV).
  • step (m) a compound of Formula (XIV) is dehydrated, followed by deblocking the amino protection group to give a diazabicyclo compound of Formula (I).
  • Intermediates represented by the above Formula (XIII) are novel compounds, and they may be prepared in accordance with Process (C) hereinbelow. Process (C)
  • diazabicycloketones of Formula (XIII) can be prepared by (n) condensing a compound of Formula (X) with a primary amine of Formula R 1 NH 2 to form an enamine of Formula (XV); (o) reducing an enamine of Formula (XV) to form the corresponding secondary amine of Formula (XVI); (p) alkylating the secondary amine of Formula (XVI) to form the corresponding tertiary amine of Formula (XVII); (q) cyclizing the tertiary amine of Formula (XVII).
  • step (n) a compound of Formula (X) is treated with a primary amine by procedures similar to those described in Process (B), step (i) above to provide a compound of Formula (XV).
  • step (o) a compound of Formula (XV) is reduced by procedures similar to those described in Process (B), Step (j) above to provide a compound of Formula (XVI).
  • step (p) a mixture of a compound of Formula (XVI) and an acrylate in a polar solvent such as ethanol or DMS is heated under reflux until a compound of Formula (XVII) is formed.
  • step (q) a compound of Formula (XVII) is treated according to procedures similar to those described in Process (B), step (k) above to form a compound of Formula (XIII).
  • the compounds (I) of the present invention were isolated and purified according to conventional methods such as a chromatography. Depending on the product, hexane and ethyl acetate in a retio ranging from 10: 1 to 1 :2 can be used as an eluent.
  • Quinolone compounds represented by formula (I-A) according to the present invention can be prepared by either process(D) or (E) set forth hereinafter.
  • quinolone compounds represented by formula (I-A) of the present invention can be prepared by reacting a compound of formula (II- A) with a compound of formula (III-A) in a solvent, preferably in the presence of an inorganic or organic base.
  • Solvents used in this process include water, a lower alkanol, acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide and a mixture thereof.
  • Inorganic bases used herein include calcium carbonate, potassium carbonate, and the like.
  • Organic bases used herein include 1 ,8-diazabicyclo[5.4.0]undec-7-ene(DBU), triethylamine, and the like.
  • the above reaction may be carried out at a temperature between about 20°C and about 200°C, preferably between about 60°C and about 130°C.
  • the reacting time is about 1 to about 24 hours.
  • R 1 , R 3 , R 4 , A, B, C and Y are the same as defined above; and R is hydrogen atom or a lower alkyl group.
  • the above Process (D) comprises the following four steps;
  • the compound of formula (V-A) can be prepared by reacting a compound of formula (I V-A) with a compound of formula (II- A).
  • the above reaction can be conducted in the presence of a solvent such as a lower alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture thereof, preferably in the presence of an inorganic base such as sodium hydroxide and sodium carbonate or an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylamine at a temperature ranging from about 0°C to the refulx temperature of the solvent employed.
  • a solvent such as a lower alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture thereof, preferably in the presence of an inorganic base such as sodium hydroxide and sodium carbonate or an organic base such as 1,8-diaza
  • Step (2) The compound of formula (VII-A) can be obtained by condensing with an amine compound of formula (VI-A) after a compound of formula (V-A) is heated under reflux with ethyl orthoformate and acetic anhydride.
  • the condensation reaction is preferably carried out with a solvent such as ethanol, dimethylsulfoxide, acetone, 1 ,4-dioxane or a mixture thereof at a temperature ranging from 0 to 50°C.
  • the compound of formula (VIII-A) can be obtained by cyclizing a compound of formula (VII-A); and said cyclization reaction is preferably carried out by employing a reaction solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture thereof, preferably in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium fluoride and potassium fluoride or an organic base such as triethylamine and pyridine at a temperature ranging from 0°C to the reflux temperature of the solvent employed.
  • a reaction solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture thereof, preferably in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium fluoride and potassium fluoride or an organic base such as triethylamine and pyridine at a temperature ranging from 0°C to the reflux temperature of
  • the compound of formula (I-A) can be prepared by hydrolyzing a compound of formula (VIII- A) obtained from Step (3) above.
  • the hydrolysis can be carried out by employing a conventional method such as acid or base treatment.
  • the compounds employed as starting materials in accordance with the present invention are commercially available and also can be obtained through known processes in the art.
  • the compound of formula (III-A) can be prepared by the process described in J. Med. Chem, 31, 503(1988) and Drug of the Future, 14, 931(1989); and the compound of formula (IV-A) by using the process described in Chem. Pharm. Bull., 38, 2472(1989).
  • the compound of formula (I-A) can be converted into their pharmaceutically acceptable salts by employing conventional methods.
  • the compound of formula (I-A) can be converted into the salt with an inorganic acid such as hydrochloric, sulfuric and phosphoric acids, or an organic acid such as methanesulfonic, lactic, oxalic and acetic acids, or a salt of an alkaline metal such as sodium and potassium.
  • an inorganic acid such as hydrochloric, sulfuric and phosphoric acids
  • an organic acid such as methanesulfonic, lactic, oxalic and acetic acids
  • a salt of an alkaline metal such as sodium and potassium.
  • Example 1 obtained from the above step 1) was treated according to the procedures similar to those described in step 2) of Example 1 to obtain N,N '-dibenzyl-3-methyl-5-oxo-2,8-diazabicyclo[4.3.0]non-5-ene, which was then treated according to the procedures similar to those described in steps 3) to 6) of Example 1 to yield 3. 14g of the desired compound.
  • 0.1G of methyl orange was added to a solution of 32g of the compound obtained from the above step 1) in 320ml of methanol-tetrahydrofuran.
  • the reaction mixture was cooled in ice-water bath, and then acidified with a 3N HCl-methanol solution until the solution became pink-colored.
  • 6g of sodium borocyanohydride in three portions were added, and a solution of 3N HCl-methanol was added to the reaction mixture until the pink-color of the solution no longer disappeared.
  • the reaction mixture was made alkaline with saturated aqueous sodium carbonate solution and then extracted with 500ml of ethyl ether.
  • Example 1 Preparation of 5-fluoromethyl-2,8-diazabicyclo[4.3.0.]non-5-ene dihydrochloride 1) Preparation of N,N -di(t-butoxycarbonyl)-5-fluoromethyl-2,8-diaza bicyclo[4.3.0.]non-5-ene
  • the reaction mixture was cooled, and washed with ethyl acetate.
  • the volume of the aqueous layer reduced to 50ml by vacuum distillation, and then, the pH of the mixture was adjusted to 7.6 by adding a 15 % aqueous sodium carbonate solution.
  • the aqueous solution was extracted twice with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, and then concentrated in vacuo.
  • the residue was chromatographed on a silica gel column to obtain 9.4 lg of the desired compound.
  • the minimal inhibitory concentration (MIC) of the compounds synthesized in Examples hereof was determined in accordance with the agar culture medium two-fold dilution method(Hoechst 345) by using a Mueller-Hinton agar. Hoechst standard strains were used as the in vitro antibacterial activity test strains. The strains having 10 7 CFU/ml were inoculated on the culture medium, and the growth of the strains was observed after incubating them at 37°C for 18 hours, in which ofloxacin, ciprofloxacin and spafloxacin were used as controls. The results of the MIC tests are shown in Table 1.
  • Streptococcus aureus SG 51 1 0.025 0.013 0.025 0.391 0.391 0.049
  • Streptococcus aureus 503 0.025 0.013 0.025 0.391 0.781 0.025

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à de nouveaux diazabicycloalcènes de la formule (I), dans laquelle R1 et R5 représentent chacun hydrogène, alkyle inférieur ou un groupe aminoprotecteur usuel; R2, R3 et R4 représentent chacun indépendamment hydrogène, alkyle inférieur, alkyle inférieur substitué par amino, hydroxyle ou halogène; et n représente un entier égal à 0 ou 1. La présente invention se rapporte également à de nouveaux dérivés d'acide carboxylique à base de quinolone, répondant à la formule (I-A), dans laquelle R1, R3 et R4 sont tels que définis ci-dessus; A représente un atome d'hydrogène ou de chlore, ou un groupe amino ou méthyle; B représente un groupe alkyle inférieur, ou un groupe cyclopropyle ou phényle éventuellement substitué par un atome d'halogène; et C représente un atome d'azote, ou un groupe méthyne éventuellement substitué par un groupe alcoxy inférieur ou alkyle inférieur ou un atome d'halogène. L'invention se rapporte en outre aux sels pharmaceutiquement acceptables de ces dérivés ainsi qu'à des procédés de préparation de ces composés.
PCT/KR1993/000065 1992-07-23 1993-07-23 Nouveaux diazabicycloalcenes et procedes de prepararation WO1994002479A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP93916266A EP0650487A1 (fr) 1992-07-23 1993-07-23 Nouveaux diazabicycloalcenes et procedes de prepararation
AU45875/93A AU663403B2 (en) 1992-07-23 1993-07-23 Novel diazabicycloalkenes and processes for the preparation thereof
JP6504363A JPH08509457A (ja) 1992-07-23 1993-07-23 新規ジアザビシクロアルケン類及びそれらの調製方法

Applications Claiming Priority (3)

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KR1992-13212 1992-07-23
KR1019920013212A KR960003611B1 (ko) 1992-07-23 1992-07-23 신규한 디아자비시클로 알켄 유도체 및 그의 제조방법
CN94100564A CN1105666A (zh) 1992-07-23 1994-01-22 新型二氮双环烯烃及其制备方法

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EP (1) EP0650487A1 (fr)
JP (1) JPH08509457A (fr)
KR (1) KR960003611B1 (fr)
CN (1) CN1105666A (fr)
AU (1) AU663403B2 (fr)
CA (1) CA2140453A1 (fr)
MX (1) MX9304445A (fr)
WO (1) WO1994002479A1 (fr)
ZA (1) ZA935346B (fr)

Cited By (1)

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Publication number Priority date Publication date Assignee Title
US5498615A (en) * 1993-04-24 1996-03-12 Korea Research Institute Of Chemical Technology Quinolone carboxylic acid derivatives and process for preparing the same

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DE3910663A1 (de) * 1989-04-03 1990-10-04 Bayer Ag 5-alkylchinoloncarbonsaeuren
EP0393424A2 (fr) * 1989-04-17 1990-10-24 Bayer Ag Procédé de préparation de 2,7-Diazabicyclo(3.3.O)octanes
DE4032090A1 (de) * 1990-02-13 1991-08-14 Bayer Ag Polycyclische 3-aryl-pyrrolidin-2,4-dion-derivate
DE4032560A1 (de) * 1990-10-13 1992-04-16 Bayer Ag 7-(2,7-diazabicyclo(3.3.0)octyl)-3-chinolon- und -naphtyridoncarbonsaeure-derivate
US5140033A (en) * 1989-04-03 1992-08-18 Bayer Aktiengesellschaft Antibacterial 5-alkylquinolonecarboxylic acids

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DE3906365A1 (de) * 1988-07-15 1990-01-18 Bayer Ag 7-(1-pyrrolidinyl)-3-chinolon- und -naphthyridoncarbonsaeure-derivate, verfahren sowie substituierte (oxa)diazabicyclooctane und -nonane als zwischenprodukte zu ihrer herstellung, und sie enthaltende antibakterielle mittel und futterzusatzstoffe
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US5140033A (en) * 1989-04-03 1992-08-18 Bayer Aktiengesellschaft Antibacterial 5-alkylquinolonecarboxylic acids
EP0393424A2 (fr) * 1989-04-17 1990-10-24 Bayer Ag Procédé de préparation de 2,7-Diazabicyclo(3.3.O)octanes
DE4032090A1 (de) * 1990-02-13 1991-08-14 Bayer Ag Polycyclische 3-aryl-pyrrolidin-2,4-dion-derivate
DE4032560A1 (de) * 1990-10-13 1992-04-16 Bayer Ag 7-(2,7-diazabicyclo(3.3.0)octyl)-3-chinolon- und -naphtyridoncarbonsaeure-derivate

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Title
CHEMICAL ABSTRACTS, Vol. 117, No. 3, issued July 20, 1992 (Columbus, Ohio, USA) V.N. PSHENICHNYI, "Synthesis and Stereochemistry of Substituted 12-Hydroxy-8,16-Diazagona-1,3,5(10)-Triene- 17-Ones", page 759, column 1, the Abstract No. 26904g, Vestsi Akad. Navuk Belarusi, Ser. Khim. Navuk 1992 , (1), 84-8 (Russ). *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5498615A (en) * 1993-04-24 1996-03-12 Korea Research Institute Of Chemical Technology Quinolone carboxylic acid derivatives and process for preparing the same

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KR940002242A (ko) 1994-02-17
AU4587593A (en) 1994-02-14
EP0650487A1 (fr) 1995-05-03
AU663403B2 (en) 1995-10-05
CA2140453A1 (fr) 1994-02-03
JPH08509457A (ja) 1996-10-08
CN1105666A (zh) 1995-07-26
MX9304445A (es) 1994-04-29
ZA935346B (en) 1994-02-14
KR960003611B1 (ko) 1996-03-20

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