WO1996028454A1 - Composes imidazothiazole - Google Patents
Composes imidazothiazole Download PDFInfo
- Publication number
- WO1996028454A1 WO1996028454A1 PCT/JP1996/000626 JP9600626W WO9628454A1 WO 1996028454 A1 WO1996028454 A1 WO 1996028454A1 JP 9600626 W JP9600626 W JP 9600626W WO 9628454 A1 WO9628454 A1 WO 9628454A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- pharmacologically acceptable
- acceptable salt
- imidazo
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a novel imidazothiazol compound having an effect of overcoming an anticancer drug resistance or an effect of enhancing an anticancer agent effect, and particularly to a tetrahydromidomidazobenzothiazole or imidazobenzothiabul compound.
- JP-A-2-400383, JP-A-2-24081, JP-B-6-92391, JP-B6-92441 Japanese Patent Application Laid-Open Nos. 5-117172 and 5-138221 describe that 1,4-dihydroxypyridine compounds have an action to overcome the anticancer drug shochu. Recently, it has been reported that quinoline or indole derivatives have a similar anticancer drug resistance overcoming action (Japanese Patent Application Laid-Open No. 4-239893, Japanese Patent Application Laid-Open No. 5-6554). (See No. 87) o
- the present inventors have synthesized many tetrahydromidazobenzothiabool or imidazobenzothiabul compounds, and have extensively screened these compounds to determine whether or not they have the combined effect with anticancer drugs.
- the imidazothiazole compound represented by the following formula (A) has the effect of significantly increasing the sensitivity of cancer cells to anticancer drugs, particularly the sensitivity of cancer cells that have acquired resistance to anticancer drugs. I went. Furthermore, these compounds showed an effect of extending the survival time of a tumor-bearing animal when used in combination with an anticancer agent, and were further found to have low toxicity, thereby completing the present invention. That is, according to the present invention, formula (A):
- R represents also good Fuweniru or naphthyl group optionally having a substituent
- R 2 represents a Ashiru group, and binding of the two ... line section or absent present co this And a pharmacologically acceptable salt thereof, and an anticancer drug-resistance overcoming agent and an enhancing anticancer agent effect comprising the compound or a pharmacologically acceptable salt thereof as an active ingredient.
- An agent is provided.
- the compound represented by the formula (A) specifically includes both compounds represented by the following formulas (I) and (II).
- the phenyl group or the naphthyl group which may have a substituent of R and is a nitro group.
- a lower alkyl group having 1 to 3 carbon atoms such as a halogen atom, a methoxy group, an ethoxy group or the like; a lower alkyl group having 1 to 3 carbon atoms such as a methyl group or an ethyl group; a dialkylamino group such as a dimethylamino group or a getylamino group. Examples thereof include a phenyl group and a naphthyl group which may be substituted with a group or a phenyl group.
- a preferable group of R is a nitro group, a fluoro group, a methoxy group, a dimethylamino group or a phenyl group, which may be substituted with a phenyl group or a naphthyl group.
- R 2 examples include an acyl group.
- the acyl group include a benzoyl group and a pyridylcarboxy group which may have a substituent such as a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group such as a methoxy group and an ethoxy group.
- a benzyl group, a pyridylcarbonyl group, or a lower alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, etc.
- a piperidylcarbonyl group substituted by a benzyl group or the like specifically, a benzoyl group, a 3-pyridylcarbonyl group, an N-methyl-3-piperidylcarbonyl group, an N-propyl-3- 3-piperidylcarbonyl group, an N- Isopropyl-13-piperidylcarbonyl group, N-benzyl-3-piperidylcarbonyl group and the like can be mentioned.
- Pharmaceutically acceptable salts of the compounds of formula (I) or (II) include, for example, inorganic acid salts formed from hydrochloric acid, hydrobromic acid, sulfuric acid, bisulfite, phosphoric acid, etc., and formic acid, Organic acid salts formed from acetic acid, cunic acid, fumaric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, metalsulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc. Can be mentioned.
- the imidavtiavl compound represented by the formula (I) or ( ⁇ ) provided by the present invention can be produced according to a well-known method.
- the method of producing the imidazothiabool compound represented by the formula (I) is shown below as an example. That is, first, by reacting a compound represented by the following formula (I) with dimethylformamide and phosphorus chlorinated (Vilsmeier-Haack reaction), a compound represented by the formula (IV) is obtained. To produce aldehydes. Next, the obtained aldehyde represented by the formula (IV) and the acid hydrazide represented by the formula (V) are reacted under acidic conditions (Method A) under the conditions of force, basic conditions. It can be produced by reacting (method B).
- the starting compounds used in these production methods are known compounds that can be easily obtained, or can be easily produced by those skilled in the art as needed.
- the compound of the formula (I) obtained by these methods can be prepared by known treatment means (for example, it can be isolated and purified by extraction, chromatography, recrystallization, etc.).
- the compound of the formula (II) can be produced by the same method as described above except that a compound in which R, is substituted at the 2-position of imidazo [2,11b] benzothiazol is used as a starting compound.
- the compound according to the present invention exhibits an effect of enhancing the effect of an anticancer agent, further exhibits an effect of overcoming an antiadhesive resistance to an adriamycin-resistant cancer and a pink-listin-resistant cancer, and shows the survival time of a cancer-bearing animal in combination with an anticancer agent. It is useful as an anticancer drug resistance overcoming agent or an anticancer agent effect enhancer because it has a prolonged action.
- Oral dosage forms include, for example, tablets, granules, capsules, pills, powders, and liquids
- parenteral dosage forms include, for example, injections, suppositories, and the like. .
- These preparations can be prepared according to a conventional method using the compound of the present invention or a pharmacologically acceptable salt thereof and a usual preparation carrier.
- excipients such as lactose, glucose, corn starch, and sucrose
- disintegrants such as calcium carboxymethylcellulose and hydroxypropyl cellulose; calcium stearate; and stearic acid
- Lubricants such as magnesium, talc, polyethylene glycol and hardened oil
- binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin, and gum arabic
- glycerin ethylene glycol
- the desired dosage form can be prepared using a wetting agent such as coal, and other surfactants and flavoring agents as required.
- a diluent such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, tragarant gum, etc. Buffers, preservatives, flavors, coloring agents and the like can be used.
- the dosage unit is the compound of the present invention per adult, and when administered orally, 5 to 100 mg / day. It is preferably administered in the range of 5 to 200 mg, and in the case of parenteral administration, in the range of 1 to 500 mg, preferably 1 to 200 mg per day, each in 1 to 3 divided doses per day.
- the desired therapeutic effect can be expected.
- lactose and corn sugar are mixed until uniform, a 5 W / V% ethanol solution of hydroxypropyl cellulose is added and kneaded and granulated. After passing through a 16-mesh sieve and sieving, the tablets were compressed in a conventional manner to give tablets having a weight of 130 mg per tablet, a diameter of 7 mm, and a drug content of 25 mg.
- the culture solution was Eagle's MEM medium (Nissui Pharmaceutical) containing 10% fetal calf serum (Flow Laboratories) and 0.292 mg / ml L-glutamine (Flow Laboratories). Manufactured by the company.
- the following tests were conducted on the combination of the test compound with doxorubicin (adriamycin, ADM), an anticancer drug, to overcome the anticancer drug resistance and enhance the anticancer drug effect.
- each test cell Suspend each test cell in the culture medium, and adjust the cell density to about 200 cells / ml. Dispense 2 ml of this cell suspension into a Petri dish and place it in a carbon dioxide incubator (5% CO 2 , 95% air). Incubate in C for 24 hours. Thereafter, add 5 to 10 p.1 each of the ADM aqueous solution of the specified concentration and the dimethyl sulfoxide (DMSO) solution of the test compound at the specified concentration, and continue the culture for 7 days. After completion of the culture, the cells were fixed with a medium, stained with Giemsa, the number of colonies in each petri dish was counted, and a volume response curve was prepared. From this, the ADM concentration ( LD5e ) at 50 % cell viability was calculated, and the anticancer drug resistance overcoming effect and the anticancer drug effect enhancing effect were determined.
- DMSO dimethyl sulfoxide
- VCR vincristine
- VCR + compound 1 0.69 3.3
- VCR + compound 2 0.30 1.6
- VCR vincristine
- Anticancer drug resistance overcoming effect • X 1 0 0
- VCR + compound 14 ⁇ represents a combined group of VCR (100 ug / kg) and compound 14 (10 mg / kg).
- Test method The compound of the present invention was suspended in 0.5% carboxymethylcellulose sodium (CMC—Na) containing 0.1% Tween 80, and the standard ratio was 1 Z 2 from 2000 mgZkg. Up to 125 mg / kg, from 125 mg / kg up to a common ratio of 1 Z2, 3 up to 3 mgZkg, 3 animals died per group Mice were administered intraperitoneally until no further cases were seen. The survival of the animals was observed up to 7 days after administration, and the LD 50 value was calculated by the area method of Van Der Wearder. The test results are shown below.
- the imidazobenzothiazole and tetrahydromidabbenzothiazole compounds according to the present invention enhance their effects when used in combination with an anticancer agent.
- the effect is particularly remarkable for clones that have acquired resistance to anticancer drugs.
- VJ-300 cells which are multidrug-resistant clones of KB cells derived from human nasopharyngeal carcinoma, have a value of 30% compared to cells that have not acquired resistance to anticancer drugs. 6.
- the same effect (50% resistant cancer cell viability) cannot be obtained unless a 6-fold concentration of the anticancer agent is used, whereas the compound 5 (1 ug / ml) of the present invention shows 1 The same effect is obtained at twice the concentration.
- the compound of the present invention has low toxicity and is effective in both in vitro and in vivo tests, and thus is useful as an anticancer drug resistance overcoming agent or an anticancer agent effect enhancer.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96906003A EP0816366A4 (en) | 1995-03-13 | 1996-03-13 | IMIDAZOTHIAZOL COMPOUNDS |
US08/913,276 US5919799A (en) | 1995-03-13 | 1996-03-13 | Imidazothiazole compound |
JP52746896A JP3178843B2 (ja) | 1995-03-13 | 1996-03-13 | イミダゾチアゾール化合物 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7/79330 | 1995-03-13 | ||
JP7933095 | 1995-03-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996028454A1 true WO1996028454A1 (fr) | 1996-09-19 |
Family
ID=13686882
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1996/000626 WO1996028454A1 (fr) | 1995-03-13 | 1996-03-13 | Composes imidazothiazole |
Country Status (5)
Country | Link |
---|---|
US (1) | US5919799A (ja) |
EP (1) | EP0816366A4 (ja) |
JP (1) | JP3178843B2 (ja) |
CA (1) | CA2215197A1 (ja) |
WO (1) | WO1996028454A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6593353B1 (en) | 1999-01-29 | 2003-07-15 | Board Of Trustees Of The University Of Illinois | p53 inhibitors and therapeutic use of the same |
JP2012521435A (ja) * | 2009-03-23 | 2012-09-13 | アムビト ビオスシエンセス コルポラチオン | 併用療法を用いた治療方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL2001892T3 (pl) | 2006-03-17 | 2013-09-30 | Ambit Biosciences Corp | Imidazolotiazolowe związki do leczenia chorób proliferacyjnych |
FR2910895B1 (fr) * | 2006-12-29 | 2010-08-27 | Biopharmed | "derives d'imino-tetrahydrobenzotriazoles ayant des proprietes anti-migratoires de metastases met dependantes" |
MX2010002295A (es) | 2007-09-19 | 2010-03-22 | Ambit Biosciences Corp | Formas solidas que comprenden n-(5-ter-butil-isoxazol-3-il)-n´-{4- [7-(2-morfolin-4-il-etoxi) imidazo [2,1-b]-[1,3] benzotiazol-2-il] fenil} urea, composiciones de las mismas, y usos de las mismas. |
EP2305688A1 (en) * | 2009-09-28 | 2011-04-06 | Université de la Méditerranée - Aix-Marseille II | Novel aminoacids derivatives, their process of preparation and their therapeutical uses as MET inhibitors |
CN108558910B (zh) * | 2018-05-11 | 2020-09-01 | 西南大学 | 席夫碱类咪唑并苯并噻唑化合物及其制备方法和应用 |
CN110172068A (zh) * | 2019-06-05 | 2019-08-27 | 河南龙湖生物技术有限公司 | 具有抗肿瘤活性的苯并噻唑类化合物及其制备方法和应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS56138196A (en) * | 1980-03-29 | 1981-10-28 | Yamanouchi Pharmaceut Co Ltd | Imidazo (2,1-b)benzothiazole derivative |
FR2699920A1 (fr) * | 1992-12-24 | 1994-07-01 | Synthelabo | Dérivés d'imidazo [2,1-b] benzothiazole-3-acétamide, leur préparation et leur application en thérapeutique. |
Family Cites Families (23)
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AU421744B2 (en) * | 1967-08-24 | 1972-02-24 | I. C. I. Australia Limited | Chemical process |
FR2463774A1 (fr) * | 1979-08-21 | 1981-02-27 | Yamanouchi Pharma Co Ltd | Derives du 2-phenylimidazo(2,1-b)benzothiazole |
JPS5740492A (en) * | 1980-08-22 | 1982-03-06 | Yamanouchi Pharmaceut Co Ltd | Novel 2-phenylimidazo 2,1-b benzothiazole derivative |
JPS57149288A (en) * | 1981-03-12 | 1982-09-14 | Yamanouchi Pharmaceut Co Ltd | Imidazo(2,1-b)benzothiazole derivative |
JPS6329341A (ja) * | 1986-07-22 | 1988-02-08 | Matsushita Electric Ind Co Ltd | 情報担体デイスク |
JPS63152116A (ja) * | 1986-12-17 | 1988-06-24 | Hitachi Ltd | シリコン系アモルフアス合金膜の形成方法 |
JPS63152117A (ja) * | 1986-12-17 | 1988-06-24 | Toshiba Corp | 多結晶シリコン薄膜の製造装置 |
JPH01127823A (ja) * | 1987-11-12 | 1989-05-19 | Rinnai Corp | 暖房機 |
JPH01127822A (ja) * | 1987-11-13 | 1989-05-19 | Toshiba Corp | 乾燥機付マルチ給湯機 |
JP2678768B2 (ja) * | 1988-06-22 | 1997-11-17 | 日研化学株式会社 | テトラヒドロイミダゾ[2,1−b]ベンゾチアゾール誘導体及び該化合物を有効成分とする抗潰瘍剤 |
JP2726999B2 (ja) * | 1988-06-22 | 1998-03-11 | 日研化学株式会社 | イミダゾ[2,1−b]ベンゾチアゾール誘導体及び該化合物を有効成分とする抗潰瘍剤 |
JP2678786B2 (ja) * | 1989-03-14 | 1997-11-17 | 日研化学株式会社 | 1,4―ジヒドロピリジン誘導体 |
JP2640245B2 (ja) * | 1988-07-28 | 1997-08-13 | 日研化学株式会社 | 1,4−ジヒドロピリジン誘導体 |
JP2850376B2 (ja) * | 1988-08-02 | 1999-01-27 | 日産化学工業株式会社 | 抗癌剤薬効増強剤 |
CA1334752C (en) * | 1988-08-02 | 1995-03-14 | Ryozo Sakoda | Drug effect-enhancing agent for antitumor drug |
JP2804276B2 (ja) * | 1988-12-28 | 1998-09-24 | 日研化学株式会社 | イミダゾ[2,1―b]チアゾール類 |
JP2579701B2 (ja) * | 1991-01-17 | 1997-02-12 | 三井東圧化学株式会社 | 新規キノリン誘導体およびそれを有効成分として含有する制癌剤効果増強剤 |
JPH05117235A (ja) * | 1991-04-26 | 1993-05-14 | Ajinomoto Co Inc | 新規1,4−ジヒドロピリジン誘導体及びそれを含有する癌耐性克服剤 |
EP0524055A1 (fr) * | 1991-07-19 | 1993-01-20 | Synthelabo | Dérivés d'imidazo[2,1-b]benzothiazole-3-acétamide, leur préparation et leur application en thérapeutique |
JP2773994B2 (ja) * | 1991-09-10 | 1998-07-09 | 新日本製鐵株式会社 | コークス炉の原料炭装入方法 |
JP3201006B2 (ja) * | 1992-09-04 | 2001-08-20 | ソニー株式会社 | ディスクカートリッジの収納ケース |
JP3052223B2 (ja) * | 1992-09-11 | 2000-06-12 | 片岡物産株式会社 | ゴミ箱 |
JP2699920B2 (ja) * | 1995-03-23 | 1998-01-19 | 日本電気株式会社 | 多層印刷配線板の製造方法 |
-
1996
- 1996-03-13 EP EP96906003A patent/EP0816366A4/en not_active Withdrawn
- 1996-03-13 US US08/913,276 patent/US5919799A/en not_active Expired - Fee Related
- 1996-03-13 CA CA002215197A patent/CA2215197A1/en not_active Abandoned
- 1996-03-13 WO PCT/JP1996/000626 patent/WO1996028454A1/ja not_active Application Discontinuation
- 1996-03-13 JP JP52746896A patent/JP3178843B2/ja not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS56138196A (en) * | 1980-03-29 | 1981-10-28 | Yamanouchi Pharmaceut Co Ltd | Imidazo (2,1-b)benzothiazole derivative |
FR2699920A1 (fr) * | 1992-12-24 | 1994-07-01 | Synthelabo | Dérivés d'imidazo [2,1-b] benzothiazole-3-acétamide, leur préparation et leur application en thérapeutique. |
Non-Patent Citations (1)
Title |
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See also references of EP0816366A4 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6593353B1 (en) | 1999-01-29 | 2003-07-15 | Board Of Trustees Of The University Of Illinois | p53 inhibitors and therapeutic use of the same |
US6982277B2 (en) | 1999-01-29 | 2006-01-03 | The Board Of Trutees Of The University Of Illinois | P53 inhibitors and therapeutic use of the same |
US7008956B2 (en) | 1999-01-29 | 2006-03-07 | The Board Of Trustees Of The University Of Illinois | p53 inhibitors and therapeutic use of the same |
US7012087B2 (en) | 1999-01-29 | 2006-03-14 | The Board Of Trustees Of The University Of Illinois | p53 inhibitors and therapeutic use of the same |
JP2012521435A (ja) * | 2009-03-23 | 2012-09-13 | アムビト ビオスシエンセス コルポラチオン | 併用療法を用いた治療方法 |
JP2015212268A (ja) * | 2009-03-23 | 2015-11-26 | アムビト ビオスシエンセス コルポラチオン | 併用療法を用いた治療方法 |
Also Published As
Publication number | Publication date |
---|---|
CA2215197A1 (en) | 1996-09-19 |
EP0816366A4 (en) | 1998-07-08 |
JP3178843B2 (ja) | 2001-06-25 |
EP0816366A1 (en) | 1998-01-07 |
US5919799A (en) | 1999-07-06 |
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