JP3264388B2 - Drugs against drug-resistant pathogenic microorganisms - Google Patents
Drugs against drug-resistant pathogenic microorganismsInfo
- Publication number
- JP3264388B2 JP3264388B2 JP34861492A JP34861492A JP3264388B2 JP 3264388 B2 JP3264388 B2 JP 3264388B2 JP 34861492 A JP34861492 A JP 34861492A JP 34861492 A JP34861492 A JP 34861492A JP 3264388 B2 JP3264388 B2 JP 3264388B2
- Authority
- JP
- Japan
- Prior art keywords
- agent
- drug
- resistant
- pathogenic microorganisms
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Quinoline Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は、抗病原微生物剤に耐性
を示す病原微生物の薬剤に対する感受性回復剤及びこれ
を含む医薬品に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an agent for restoring the susceptibility of a pathogenic microorganism which exhibits resistance to an anti-pathogenic microorganism, to a drug containing the same.
【０００２】[0002]
【従来の技術】ペニシリンに始まる抗生物質の登場によ
り、微生物による感染症の脅威は著しく減少したかに見
えた。しかし、今日新聞紙上をにぎわせているように、
メチリシン耐性の黄色ブドウ状球菌（ＭＲＳＡ）に代表
される耐性病原菌の登場は、抗生物質等による感染症治
療に大きな影を投げかけている。BACKGROUND OF THE INVENTION With the advent of antibiotics beginning with penicillin, the threat of microbial infections appears to have been significantly reduced. However, like today's newspapers,
The emergence of resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), has cast a huge shadow on the treatment of infectious diseases with antibiotics and the like.
【０００３】これら耐性病原菌に対する治療としては、
主として、多種の治療薬の複合使用が行われている。例
えば、メチリシン耐性黄色ブドウ状球菌に対してはフォ
スフォマイシンとキノロン系抗生物質の併用などが行わ
れている。しかし、耐性獲得による病原微生物の治療薬
に対する感受性低下は著しく、併用による効果も治療へ
の寄与は小さい。硫酸アルベカシンやバンコマイシンと
言った新規薬物も耐性菌の出現は時間の問題と言われて
おり、これら耐性病原微生物による疾病に対しては打つ
手がないのが現状である。[0003] As treatment for these resistant pathogens,
Primarily, there is a combined use of various therapeutic agents. For example, a combination of fosfomycin and a quinolone antibiotic is used for metilicin-resistant Staphylococcus aureus. However, the sensitivity of the pathogenic microorganism to the therapeutic agent is significantly reduced due to the acquisition of resistance, and the effect of the combination also contributes little to the treatment. It is said that the emergence of resistant bacteria of new drugs such as arbekacin sulfate and vancomycin is a matter of time, and there is no way to deal with diseases caused by these resistant pathogenic microorganisms.
【０００４】[0004]
【発明が解決しようとする課題】上記の如く薬物耐性微
生物による疾病の問題は人類の存亡がかかった重大な問
題であり、治療法のないこれら疾病に対して治療薬を提
供することは全人類的見地において意義深い。As described above, the problem of diseases caused by drug-resistant microorganisms is a serious problem that has caused the survival of human beings, and providing a therapeutic agent for these diseases for which there is no cure has been proposed by all human beings. Significant in terms of perspective.
【０００５】従って、本発明は抗生物質、抗マラリア剤
等の治療薬に耐性を示す病原微生物による疾病に対し、
従来の治療薬と併用することによりその治療効果を高め
ることのできる、薬剤耐性に対する感受性回復剤を提供
することを目的とする。Accordingly, the present invention provides a method for treating diseases caused by pathogenic microorganisms that are resistant to therapeutic agents such as antibiotics and antimalarials.
An object of the present invention is to provide an agent for restoring susceptibility to drug resistance, which can enhance its therapeutic effect by being used in combination with a conventional therapeutic agent.
【０００６】[0006]
【課題を解決するための手段】本発明者らは、かかる実
状に鑑み鋭意研究を行った結果、特定のピペラジン誘導
体が、耐性を獲得した黄色ブドウ状球菌、大腸菌、マラ
リア原虫、スピロヘータ等の病原微生物の抗生物質、抗
原虫剤等の病原微生物剤に対する感受性を復帰せしめる
作用を持つことを見いだし、本発明を完成した。Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of the above circumstances, and as a result, it has been found that a specific piperazine derivative has acquired resistance to pathogens such as Staphylococcus aureus, Escherichia coli, malaria parasites, spirochetes and the like. The present inventors have found that they have the effect of restoring the sensitivity of microorganisms to pathogenic microbial agents such as antibiotics and antiprotozoal agents, and completed the present invention.
【０００７】すなわち、本発明は、次の一般式（１）で
表わされる化合物からなるメチシリン耐性黄色ブドウ状
球菌に対する薬剤感受性回復剤に係るものである。That is, the present invention relates to an agent for restoring drug sensitivity to methicillin-resistant Staphylococcus aureus, comprising a compound represented by the following general formula (1).
【０００８】[0008]
【化２】 Embedded image
【０００９】（式中、Ｘは酸素原子、硫黄原子又は基−
ＮＨ−を示し、Ｒ1は水素原子又はハロゲン原子を示
す）Wherein X is an oxygen atom, a sulfur atom or a group
NH— and R 1 represents a hydrogen atom or a halogen atom)
【００１０】化合物（１）の性状は、置換基の種類や数
により異なるが、アモルファスないしは白色から淡黄色
の結晶で、概ねジメチルスルホキシド、クロロホルム、
メタノールなどの有機溶剤に溶け、水には溶けにくい傾
向にある。The properties of the compound (1) vary depending on the type and number of the substituents, but are amorphous or white to pale yellow crystals, and are generally dimethylsulfoxide, chloroform,
It tends to be soluble in organic solvents such as methanol and hardly soluble in water.
【００１１】化合物（１）の具体例としては、例えば以
下に示すものが挙げられる。 （ａ）１−［４−（ジベンゾ［ａ，ｄ］シクロヘプタン
−１−イル）−１−ピペラジニル］−３−（２−クロロ
−５−キノリル）オキシプロパン−２−オール （ｂ）１−［４−（ジベンゾ［ａ，ｄ］シクロヘプタン
−１−イル）−１−ピペラジニル］−３−（８−キノリ
ル）アミノプロパン−２−オール （ｃ）１−［４−（ジベンゾ［ａ，ｄ］シクロヘプタン
−１−イル）−１−ピペラジニル］−３−（５−キノリ
ル）オキシプロパン−２−オール （ｄ）１−［４−（ジベンゾ［ａ，ｄ］シクロヘプタン
−１−イル）−１−ピペラジニル］−３−（８−キノリ
ル）オキシプロパン−２−オール （ｅ）１−［４−（ジベンゾ［ａ，ｄ］シクロヘプタン
−１−イル）−１−ピペラジニル］−３−（５−クロロ
−８−キノリル）オキシプロパン−２−オール （ｆ）１−［４−（ジベンゾ［ａ，ｄ］シクロヘプタン
−１−イル）−１−ピペラジニル］−３−（５−キノリ
ル）チオプロパン−２−オール （ｇ）１−［４−（ジベンゾ［ａ，ｄ］シクロヘプタン
−１−イル）−１−ピペラジニル］−３−（８−キノリ
ル）アミノプロパン−２−オールSpecific examples of the compound (1) include the following. (A) 1- [4- (dibenzo [a, d] cycloheptane-1-yl) -1-piperazinyl] -3- (2-chloro-5-quinolyl) oxypropan-2-ol (b) 1- [4- (Dibenzo [a, d] cycloheptane-1-yl) -1-piperazinyl] -3- (8-quinolyl) aminopropan-2-ol (c) 1- [4- (dibenzo [a, d ] Cycloheptane-1-yl) -1-piperazinyl] -3- (5-quinolyl) oxypropan-2-ol (d) 1- [4- (dibenzo [a, d] cycloheptane-1-yl)- 1-piperazinyl] -3- (8-quinolyl) oxypropan-2-ol (e) 1- [4- (dibenzo [a, d] cycloheptan-1-yl) -1-piperazinyl] -3- (5 -Chloro-8-quinolyl) oxypropane- 2-ol (f) 1- [4- (dibenzo [a, d] cycloheptan-1-yl) -1-piperazinyl] -3- (5-quinolyl) thiopropan-2-ol (g) 1- [4 -(Dibenzo [a, d] cycloheptane-1-yl) -1-piperazinyl] -3- (8-quinolyl) aminopropan-2-ol
【００１２】これらの化合物（１）は何れも既知の化合
物であり、例えば以下に示す反応式に従って容易に合成
でき、カラムクロマトグラフィー、再結晶等の通常の手
段で精製することができる。All of these compounds (1) are known compounds and can be easily synthesized, for example, according to the following reaction formula, and can be purified by ordinary means such as column chromatography and recrystallization.
【００１３】[0013]
【化３】 Embedded image
【００１４】すなわち、キノリン類（２）、エピクロル
ヒドリン（３）及び水酸化ナトリウムを、ジクロロメタ
ンと水の混合溶媒中で臭化テトラブチルアンモニウムを
触媒として室温で約２４時間反応させ、有機相を分離し
て減圧濃縮後カラムクロマトグラフィーで精製すること
によりエポキシ付加体（４）が得られる。次いでエポキ
シ付加体（４）と１−（ジベンゾ［ａ，ｄ］シクロヘプ
タン−１−イル）ピペラジン（５）を、エタノール中無
触媒で室温にて約４８時間反応させ、溶媒を減圧留去後
カラムクロマトグラフィーで精製することにより化合物
（１）が得られる。That is, quinolines (2), epichlorohydrin (3) and sodium hydroxide are reacted in a mixed solvent of dichloromethane and water with tetrabutylammonium bromide as a catalyst at room temperature for about 24 hours to separate the organic phase. After concentration under reduced pressure and purification by column chromatography, the epoxy adduct (4) is obtained. Next, the epoxy adduct (4) and 1- (dibenzo [a, d] cycloheptane-1-yl) piperazine (5) are reacted in ethanol without a catalyst at room temperature for about 48 hours. Compound (1) is obtained by purification by column chromatography.
【００１５】このようにして得られた化合物（１）は、
後記実施例に示すように薬剤に対する耐性を獲得した黄
色ブドウ状球菌やマラリア原虫など薬剤耐性病原微生物
に対して、優れた感受性回復作用を示し、従来の治療薬
と同時に使用した場合、従来の治療薬の効果を著しく増
強させ、かつ、安全性も高いため薬剤耐性微生物による
疾病の治療薬として有用である。The compound (1) thus obtained is
As shown in Examples below, it shows excellent susceptibility-restoring action against drug-resistant pathogenic microorganisms such as Staphylococcus aureus and malaria parasite that have acquired drug resistance, and when used simultaneously with conventional therapeutic agents, Since the effect of the drug is significantly enhanced and the safety is high, it is useful as a therapeutic drug for diseases caused by drug-resistant microorganisms.
【００１６】化合物（１）を薬剤耐性病原微生物の薬剤
に対する感受性回復剤として使用する場合、その投与量
は患者の年齢、体重、性別、投与方法、体調、病状等に
より異なるが、成人一日当たり経口投与の場合１０〜２
０００mg、非経口投与の場合５〜１０００mgが適当であ
る。また、薬剤耐性病原微生物による疾病の治療薬とし
て使用する場合は、上記と同様の量の化合物（１）を通
常の用法・用量の治療薬と併用する。When the compound (1) is used as an agent for restoring the susceptibility of a drug-resistant pathogenic microorganism to a drug, its dosage varies depending on the age, weight, sex, administration method, physical condition, medical condition, etc. of the patient, but is preferably administered orally per day per adult. 10-2 for administration
2,000 mg is suitable for parenteral administration, and 5-1000 mg for parenteral administration. When used as a therapeutic drug for a disease caused by drug-resistant pathogenic microorganisms, the same amount of compound (1) as described above is used in combination with a therapeutic drug in the usual usage and dosage.
【００１７】本発明の感受性回復剤又は治療薬は、通常
の方法で錠剤、顆粒剤、散剤、カプセル剤、懸濁剤、注
射剤、坐剤等の種々の剤形とすることができる。固型製
剤の場合、化合物（１）に賦形剤、更に必要に応じて結
合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤、増量剤、
被覆剤、糖衣剤などを加え、常法により錠剤、顆粒剤、
散剤、カプセル剤、坐剤とすることができる。注射剤の
場合、本発明化合物（１）を注射用生理食塩水等の水性
担体に溶解、分散又は乳化して注射液とするか、又は用
事溶解用の粉末とすることができる。注射剤の投与方法
としては、静脈内投与、動脈内投与、門脈内投与、腹腔
内投与、皮下投与、病巣内直接投与が挙げられる。The sensitivity-restoring or therapeutic agent of the present invention can be made into various dosage forms such as tablets, granules, powders, capsules, suspensions, injections, suppositories and the like in a usual manner. In the case of a solid preparation, compound (1) may contain an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a bulking agent,
Add coatings, sugar coatings, etc., tablets, granules,
Powders, capsules and suppositories can be prepared. In the case of an injection, the compound (1) of the present invention can be dissolved, dispersed or emulsified in an aqueous carrier such as physiological saline for injection to give an injection solution or a powder for business dissolution. Examples of the method of administering the injection include intravenous administration, intraarterial administration, intraportal administration, intraperitoneal administration, subcutaneous administration, and direct intralesional administration.
【００１８】本発明の感受性回復剤と共に用いられる抗
病原微生物剤としては特に限定されず、臨床上用いられ
ているものであればいずれでもよいが、例えばキニー
ネ、クロロキン、メフロキン、プリマキン等の抗マラリ
ア剤、ペニシリン、テトラサイクリン、セファロスポリ
ン、クロラムフェニコール等の抗生物質が挙げられる。The antipathogenic microbial agent used together with the sensitizing agent of the present invention is not particularly limited, and may be any clinically used one. For example, antimicrobial agents such as quinine, chloroquine, mefloquine and primaquine may be used. Antibiotics such as malaria drugs, penicillins, tetracyclines, cephalosporins, chloramphenicol and the like can be mentioned.
【００１９】[0019]
【実施例】以下、実施例を挙げて更に詳細に説明する
が、本発明はこれらに限定されるものではない。EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
【００２０】実施例１ ＭＲＳＡに対する作用 実験的に黄色ブドウ状球菌にメチシリン耐性をもたせた
実験変異株３株及び臨床より分離されたメチシリン耐性
黄色ブドウ状球菌臨床分離株３株について、化合物の存
在下及び非存在下での各種抗生物質のＭＩＣを測定する
ことにより、化合物（１）のＭＲＳＡに対する作用を検
討した。被験菌を感受性測定用ブイヨンに接種し、３７
℃、２４時間前培養した後菌数が１０6個／mlになるよ
うに調整した菌液を、改良ミュラー・ヒントン培地に接
種した。化合物（１）をＤＭＳＯ １mlに溶解し、最終
濃度が１００μg ／mlになるように調整し、培地に加え
た。ネガティブコントロールにはＤＭＳＯ １mlのみを
用いた。各種抗生物質は最高濃度（最終濃度として）の
ものを調製し、２倍希釈で順次調整し、完全に菌の発育
が阻止された最低濃度をもってＭＩＣとした。判定は接
種後４２℃、２４時間培養した後行った。各種抗生物質
の最高濃度は次のとおりとした。 メチシリン：８００μg ／ml，セフメタゾール：１００
μg ／ml，エリスロマイシン：４００μg ／ml，カナマ
イシン：４００μg ／ml，フォスフォマイシン：４００
μg ／ml，ノルフロキサシン：４００μg ／ml この結果を表１〜２に示す。表１〜２から明らかなよう
に、化合物（１）は、いずれも有意にＭＲＳＡの薬剤感
受性を回復した。Example 1 Action on MRSA In the presence of the compound, three experimental mutant strains having experimentally imparted methicillin resistance to Staphylococcus aureus and three clinical isolates of methicillin-resistant Staphylococcus aureus isolated from clinical sites were used. The effect of compound (1) on MRSA was examined by measuring the MIC of various antibiotics and in the absence of the antibiotic. The test strain was inoculated into a susceptibility measurement broth and 37
After pre-cultivation at 24 ° C. for 24 hours, a bacterial solution adjusted to a bacterial count of 10 6 cells / ml was inoculated into the improved Muller Hinton medium. Compound (1) was dissolved in 1 ml of DMSO, adjusted to a final concentration of 100 μg / ml, and added to the medium. As a negative control, only 1 ml of DMSO was used. Various antibiotics were prepared at the highest concentration (as the final concentration) and adjusted sequentially by two-fold dilution, and the MIC was defined as the lowest concentration at which the growth of the bacteria was completely inhibited. The determination was performed after culturing at 42 ° C. for 24 hours after inoculation. The maximum concentrations of various antibiotics were as follows. Methicillin: 800 μg / ml, cefmetazole: 100
μg / ml, erythromycin: 400 μg / ml, kanamycin: 400 μg / ml, fosfomycin: 400
μg / ml, norfloxacin: 400 μg / ml The results are shown in Tables 1-2. As is clear from Tables 1 and 2, all of the compound (1) significantly recovered the drug sensitivity of MRSA.
【００２１】[0021]
【表１】 [Table 1]
【００２２】[0022]
【表２】 [Table 2]
【００２３】[0023]
【００２４】[0024]
【００２５】実施例３ 急性毒性 ５〜６週齢のＩＣＲ系マウス（体重２０〜２５ｇ）を用
い、化合物（ａ）、（ｂ）及び（ｅ）の腹腔内投与にお
ける急性毒性試験を行った。試料は化合物１０mgを１ml
の０．１％ＣＭＣ溶液に均一に分散させて調製した。観
察は投与後１４日間行った。最大投与量は１０００mg／
kgとした。この結果、ＬＤ50値はいずれも１０００mg／
kg以上であり、いずれも高い安全性を示した。Example 3 Acute Toxicity Acute toxicity test was performed on intraperitoneal administration of Compounds (a), (b) and (e) using 5-6 week old ICR mice (body weight 20-25 g). Sample is 1 mg of compound 10 mg
In a 0.1% CMC solution. The observation was performed for 14 days after the administration. The maximum dose is 1000mg /
kg. As a result, the LD 50 value was 1000 mg /
kg or more, all of which showed high safety.
【００２６】[0026]
【発明の効果】本発明の薬剤に対する感受性回復剤は優
れた感受性回復作用を有し、抗生物質や抗原虫剤と共に
用いると薬剤耐性病原微生物に対して優れた抗菌・抗原
虫効果を示すため、クロロキン耐性マラリア、ＭＲＳＡ
等の生命を著しく脅かす疾病の治療に極めて有用であ
り、数億人に達すると思われるこれらの疾病の患者の治
療において極めて有意義である。EFFECTS OF THE INVENTION The agent for restoring susceptibility to the drug of the present invention has an excellent susceptibility restoring effect, and exhibits excellent antibacterial and antiprotozoal effects against drug-resistant pathogenic microorganisms when used together with antibiotics and antiprotozoal agents. Chloroquine resistant malaria, MRSA
It is extremely useful in the treatment of severely life-threatening diseases such as these, and is of great significance in treating patients with these diseases, which are expected to reach hundreds of millions.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ // Ｃ０７Ｄ 215/20 Ｃ０７Ｄ 215/20 215/26 215/26 215/30 215/30 215/38 215/38 215/40 215/40 217/02 217/02 217/20 217/20 (56)参考文献 特開 平３−101662（ＪＰ，Ａ) 特開 平４−230376（ＪＰ，Ａ) 特表 平２−500979（ＪＰ，Ａ) 国際公開92／18131（ＷＯ，Ａ１) (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/496 A61K 31/70 A61K 45/00 C07D 215/20 C07D 215/26 C07D 215/30 C07D 215/38 C07D 215/40 C07D 217/02 C07D 217/20 ＣＡ（ＳＴＮ) ＣＡＯＬＤ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification code FI // C07D 215/20 C07D 215/20 215/26 215/26 215/30 215/30 215/38 215/38 215/40 215 / 40 217/02 217/02 217/20 217/20 (56) References JP-A-3-101662 (JP, A) JP-A-4-230376 (JP, A) JP-T2-500979 (JP, A) A) WO 92/18131 (WO, A1) (58) Fields investigated (Int. Cl. 7 , DB name) A61K 31/496 A61K 31/70 A61K 45/00 C07D 215/20 C07D 215/26 C07D 215 / 30 C07D 215/38 C07D 215/40 C07D 217/02 C07D 217/20 CA (STN) CAOLD (STN) REGISTRY (STN)
Claims (2)
らなるメチシリン耐性黄色ブドウ状球菌に対する薬剤感
受性回復剤。 【化１】 （式中、Ｘは酸素原子、硫黄原子又は基−ＮＨ−を示
し、Ｒ1は水素原子又はハロゲン原子を示す）An agent for restoring drug sensitivity to methicillin-resistant Staphylococcus aureus, comprising a compound represented by the following general formula (1): Embedded image (In the formula, X represents an oxygen atom, a sulfur atom or a group —NH—, and R 1 represents a hydrogen atom or a halogen atom.)
ン、セフメタゾール、エリスロマイシン、カナマイシ
ン、フォスフォマイシン又はノルフロキサシンである請
求項１記載の薬剤感受性回復剤。2. The agent according to claim 1, wherein the agent that restores sensitivity is methicillin, cefmetazole, erythromycin, kanamycin, fosfomycin or norfloxacin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34861492A JP3264388B2 (en) | 1992-12-28 | 1992-12-28 | Drugs against drug-resistant pathogenic microorganisms |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34861492A JP3264388B2 (en) | 1992-12-28 | 1992-12-28 | Drugs against drug-resistant pathogenic microorganisms |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06199669A JPH06199669A (en) | 1994-07-19 |
| JP3264388B2 true JP3264388B2 (en) | 2002-03-11 |
Family
ID=18398194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP34861492A Expired - Fee Related JP3264388B2 (en) | 1992-12-28 | 1992-12-28 | Drugs against drug-resistant pathogenic microorganisms |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3264388B2 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999061021A1 (en) * | 1998-05-26 | 1999-12-02 | Shionogi & Co., Ltd. | Drug-sensitivity recovering agents for resistant pathogenic microorganisms |
| JP2000072749A (en) * | 1998-08-24 | 2000-03-07 | Mitsui Chemicals Inc | Apoptosis inducer using quinoline derivative |
| EP1336608A4 (en) * | 2000-11-22 | 2009-03-25 | Pola Chem Ind Inc | Dibenzosberanyl piperazine derivatives and drug-resistance overcoming agents containing the derivatives |
| WO2002056884A2 (en) * | 2001-01-22 | 2002-07-25 | Schering Corporation | Treatment of malaria with farnesyl protein transferase inhibitors |
| WO2002080895A2 (en) * | 2001-04-06 | 2002-10-17 | Schering Corporation | Treatment of malaria with farsenyl protein transferase inhibitors |
| WO2012086006A1 (en) | 2010-12-20 | 2012-06-28 | トヨタ自動車株式会社 | Fuel injection valve |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992018131A1 (en) | 1991-04-19 | 1992-10-29 | Cba International, Inc. | Method for potentiating primary drugs in treating multidrug resistant cells |
-
1992
- 1992-12-28 JP JP34861492A patent/JP3264388B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992018131A1 (en) | 1991-04-19 | 1992-10-29 | Cba International, Inc. | Method for potentiating primary drugs in treating multidrug resistant cells |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06199669A (en) | 1994-07-19 |
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