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WO1996003393A1 - Compose de methine soluble dans l'eau et composition pharmaceutique utilisee dans le traitement du cancer contenant ce compose - Google Patents

Compose de methine soluble dans l'eau et composition pharmaceutique utilisee dans le traitement du cancer contenant ce compose Download PDF

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Publication number
WO1996003393A1
WO1996003393A1 PCT/JP1995/001408 JP9501408W WO9603393A1 WO 1996003393 A1 WO1996003393 A1 WO 1996003393A1 JP 9501408 W JP9501408 W JP 9501408W WO 9603393 A1 WO9603393 A1 WO 9603393A1
Authority
WO
WIPO (PCT)
Prior art keywords
ring
group
ion
carbon atoms
methine
Prior art date
Application number
PCT/JP1995/001408
Other languages
English (en)
Inventor
Noriaki Tatsuta
Akihiko Ikegawa
Masayuki Kawakami
Keizo Koya
Original Assignee
Fuji Photo Film Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US08/420,481 external-priority patent/US5599825A/en
Application filed by Fuji Photo Film Co., Ltd. filed Critical Fuji Photo Film Co., Ltd.
Priority to JP8505639A priority Critical patent/JPH10506878A/ja
Priority to EP95925127A priority patent/EP0772607A1/fr
Priority to AU29366/95A priority patent/AU678116B2/en
Publication of WO1996003393A1 publication Critical patent/WO1996003393A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/84—Naphthothiazoles

Definitions

  • Water-soluble methine compound and pharmaceutical composition for treatment of cancer comprising the same
  • the present invention relates to a methine compound useful as a photograhic material, medicine or the like, and to a pharmaceutical composition for treatment of cancer comprising the methine compound.
  • J. P. KOKAI Japanese Patent Unexamined Published Application
  • an object of the present invention is to provide a methine compound which falls in rhodacyanine dyes and which has a high solubility.
  • Another object of the present invention is to provide a good pharmaceutical composition for treatment of cancer.
  • Z 1 represents a non-metallic atomic group necessitated for forming a five-membered nitrogen-containing heterocyclic ring together with -N(R 1 )-C-
  • R 1 , R 2 and R 3 each represent an alkyl group and at least one of R 1 , R 2 and R 3 represents an alkyl group substituted with a polyethylene oxide group wherein one end of the polyalkylene oxide having a degree of polymerization of 2 to 6 is terminated with a hydrophobic group or substituted with a heterocyclic ring containing two or more oxygen atoms
  • Q represents an anion
  • k represents a numeral necessitated to control the charge in the molecule at zero
  • p represents 0 or 1
  • Y represents a methine group or
  • compositions for treatment of cancer which comprises a therapeutically effective amount of the methine compound and a pharmaceutically acceptable diluent and/or carrier.
  • Z 1 together with -N(R 1 )-C- represents a non-metallic atomic group necessitated for forming a thiazolidine ring, benzothiazoline ring, benzoxazoline ring, naphthothiazoline ring or naphthoxazoline ring
  • W 1 and W 2 each represent a hydrogen atom or they together form a non- metallic atomic group necessitated for forming a naphthalene condensed ring or benzene condensed ring
  • Q represents a halogen ion or organic acid anion
  • p represents 0 or 1
  • Y represents a methine group or nitrogen atom
  • R 1 , R, and R 5 each represent an alkyl group and at least one of R 1 , R 2 and R 1 has a substituent of the following formula Ill-a or Ill-b:
  • R 4 represents an alkyl group having 2 or less carbon atoms, m represents 3 or 4 and n represents 2 or 3.
  • the heterocyclic rings formed by Zi and -N(R 1 )-C- together are preferably thiazolidine ring, benzothiazoline ring, naphthothiazoline ring and nahthoxazoline ring. More preferred are benzothiazoline ring and naphthothiazoline ring. Among them, benzothiazoline ring is the most preferred.
  • the heterocyclic ring formed by Z 1 and -N(R 1 )-C- together may have a substituent. The substituent is preferably a halogen atom, alkyl group, alkoxy group, hydroxyl group or the like. The most preferred is methoxy group.
  • the condensed ring formed by W 1 and W 2 may have a substituent, which is preferably a halogen atom, alkyl group, alkoxy group, hydroxyl group or the like.
  • the alkyl groups represented by R 1 , R 2 and R 3 are preferably those having 1 to 5 carbon atoms, more preferably those having 1 to 3 carbon atoms .
  • Particularly preferred are ethylene oxide polymers .
  • the degree of polymerization is preferably 3 to 5 , particularly preferably 3 to 4.
  • the hydrophobic groups which terminate the polyalkylene oxide are preferably lower alkyl groups such as those having 1 to 3 carbon atoms.
  • the mode of the termination is, for example, an ether bond or ester bond.
  • Particularly preferred is the ether bond with an alkyl group having 1 to 3 carbon atoms, and most preferred is with methyl group.
  • Examples of the heterocyclic rings containing two or more oxygen atoms include dioxolane and dioxane. Particularly preferred are 1,3- dioxolanyl group and 1,3-dioxanyl group.
  • the alkyl group substituted with a polyalkylene oxide group having a degree of polymerization of 2 to 6 and terminated with a hydrophobic group or substituted with a heterocyclic ring containing two or more oxygen atoms is preferably R 3 .
  • the halogen ion or organic acid anion represented by Q is preferably an iodide ion, chloride ion or sulfonic acid ion. Among them, the chloride ion is more preferred.
  • Y is preferably a methine group, and p is preferably 0.
  • the methine compound of the present invention is usable as a spectral sensitizing dye or anticancer agent.
  • the methine compound of the present invention can be usually synthesized by a synthesis method described in U. S. Patent No. 2,388,963.
  • the methine compounds of the present invention are widely usable as spectral sensitizing dyes or medicines such as anticancer agents.
  • one of the methine compounds of the present invention is used as a medicine, it is usually administered, for example, by the following preferred method: the methine compound, dissolved in, for example, 5 % glucose solution or together with a suitable carrier or diluent, is injected into a vein, abdominal cavity, muscle or bladder.
  • the practical solubility suitable for the injection preparations is 0.1 to 1 % by weight.
  • compositions of this invention containing one or more compounds of the general formulas (I) to (II) described above can be effectively used to treat various types of cancer including melanomas, hepatomas, gliomas, neuroblastomas, sarcomas and carcinomas of the lung, colon, breast, bladder, ovary, testis, prostate, cervix, pancreas, stomach, small intestine and other organs.
  • compositions of this invention can contain one or more compounds of the general formulas (I) to (II) and a pharmaceutically acceptable diluent and/or carrier, and if desired, can further contain other therapeutic agents including conventional anti- tumor agents known in the art.
  • conventional anti-tumor agents which can be used include adriamycin, cisplatin, colchicine, CCNU (Lomastine), BCNU (Carmustine), Actinomycin D, 5- fluorouracil, thiotepa, cytosinearabinoside, cyclophosphamide, mitomycin C, and the like.
  • Suitable examples of the pharmaceutical carriers or diluents include glucose, sucrose, lactose, ethyl alcohol, glycerin, mannitol, sorbitol, pentaerythritol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, other polyethylene glycols, mono-, di- and triglycerides of saturated fatty acids such as glyceryl trilaurate, glyceryl monostearate, glyceryl tristearate and glyceryl distearate, pectin, starch, alginic acid, xylose, talc, lycopodium, oils and fats such as olive oil, peanut oil, castor oil, corn oil, wheat germ oil, sesame oil, cottonseed oil, sunflower seed oil and cod-liver oil, gelatin, lecithin, silica, cellulose, cellulose derivatives such as methyl
  • the pharmaceutically effective amount of the compound of the general formulas (I) to (II) and the mode or manner of administration will be dependent upon the nature of the cancer, the therapy sought, the severity of the disease, the degree of malignancy, the extent of metastatic spread, the tumor load, general health status, body weight, age, sex, and the genetic or racial background of the patient.
  • suitable modes of administration include intravenous, hypodermic, intraperitoneal, intramuscular or intravesicular injection or oral use in the form of, for example, a compound of the general formulas (I) to (II) in, e.g., a 5% glucose aqueous solution or with other appropriate carriers or diluents as described above.
  • a suitable therapeutically effective amount of a compound of the general formulas (I) to (II) in the composition is about 0.01% by weight to about 10% by weight, more generally 0.1% by weight to about 1%, based on the weight of the composition.
  • a suitable therapeutically effective amount of the compound of the general formulas (I) to (II) generally can range from 10 mg to 500 mg, more generally 100 mg to 200 mg, administered per day per 70 kg of body weight, in single or multiple doses, as determined appropriate for the therapy involved.
  • methine compounds of the present invention as photosensitive materials for photography or as medicines such as anticancer agent is expected, since they have a solubility in water or the like far higher than that of an analogous rhodacyanine dye.
  • the crude crystals thus obtained and 500 ml of methanol were fed into a 1l three-necked flask provided with a reflux condenser, and the resultant mixture was heated under reflux and stirring for 1 hour, and then cooled to 25oC.
  • the mixture thus obtained was suction- filtered, washed with 100 ml of methanol and dried.
  • reaction liquid After stirring the mixture at that temperature for 15 minutes, the reaction liquid was cooled to room temperature. 80 ml of ethyl acetate was added to the resultant mixture. The crystals thus formed were suction-filtered, washed with 50 ml of ethyl acetate and dried.
  • the reaction liquid was cooled to room temperature.
  • the crystals thus formed were suction-filtered and washed with 50 ml of ethyl acetate.
  • the crude crystals thus formed were dissolved in 50 ml of chloroform/methanol (1:1). 400 ml of ethyl acetate was added to the solution, and the crystals thus formed were suction-filtered.
  • the crystals thus obtained were dissolved in 100 ml of methanol/chloroform (4:1).
  • the solution was passed through a column filled with a strongly basic ion exchange resin (PA 318; a product of Mitsubishi Chemical Industries Ltd.) and eluted with methanol.
  • PA 318 a strongly basic ion exchange resin
  • the eluate was collected and then naturally filtered.
  • the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in methanol, and ethyl acetate was added to the solution to precipitate the crystals.
  • the crystals were suction-filtered, washed with ethyl acetate and dried at room temperature under reduced pressure to obtain the intended compound.
  • the resultant mixture was heated to 60 oC. 2 ml of triethylamine was added dropwise to the mixture. After stirring the mixture at that temperature for 5 minutes followed by addition of 150 ml of ethyl acetate, the reaction liquid was cooled to room temperature. The resultant crystals were suction-filtered and then washed with 50 ml of ethyl acetate.
  • Test 1 5 mg of a methine compound is fed into a test tube, to which 5 ml of ion-exchanged water is added, the resultant mixture is shaken at room temperature for 5 minutes, and the solubility thereof is macroscopically confirmed (1 mg/ml solution).
  • Test 2 5 mg of a methine compound is fed into a test tube, to which
  • the human colonic epithelial carcinoma cell lines LS174T there was used the established line by trypsinizing piece of LS174T obtained from the operating theatre of the original adenocarcinoma of colon in such that the piece becomes suitable for cultivation.
  • this cultured cells LS174T are hypodermically injected to a nude mouse, the cells can be easily grown in the body of the nude mouse as a moderately to sufficiently differentiated human colonic epithelial carcinoma.
  • the cells LS174T produce CEA in high level and can proliferate in hamster cheek pouches or immunodeprived mice, so that it has been proven that the cells LS174T have neoplastic properties.
  • mice Male, five weeks age) available from Charles River Japan Inc. were placed in an atmosphere having no pathogen. Tumors formed by the hypodermic injection of human colonic epithelial carcinoma cell lines LS174T into the mice were cut off under the aseptic condition, and the surrounding skin and connective tissue of the tumor tissues as well as the necrotic tissue located in the center of the tumor tissues were removed. The tumor tissues were cut in the form of 3-5 mm square, and the resulting one tissue was charged into a needle for transplantation to hypodermically transplant it into the mouse. The resulting mice were randomly divided into control group (six mice) and treating group (six mice). The intravenous administration of the pharmaceutical composition into the treating group started next day.
  • the amount and schedule of the administration were determined based on the experience, mainly the knowledge from the pretoxic-test data of LD 50 and LD 10. 5 % glucose solution or physiologic saline for injection was injected to the control group in the same amount as that to be intravenously injected to the treating group.
  • the pharmaceutical composition was dissolved in 5 % glucose solution or physiologic saline for injection in such that the amount of the pharmaceutical composition contained in the glucose solution or physiologic saline is 5 ml per one kg of weight of the mouse to be injected so as to prepare an injection liquid.
  • the proliferation of tumor in the control group reached exponential growth phase and the size of the tumor became detectable by touch with hand, i.e., generally three weeks after the transplantation, the experiment was stopped. Then the tumor of each mouse was cut off and the weight of the resulting tumor was measured by use of chemical balance. Regarding each group, tumor inhibition percentage between the treating group and control group was calculated. The results obtained are shown in Table 5.
  • LOX a human melanoma cell line, grown subcutaneously in nude mice was excised, trypsinized to yield a single cell suspension using a metal grid with a 4 mm mesh. Red blood cells were lysed by incubation with 0.17 molar ammonium chloride at 4 oC for 20 minutes. Five million viable trypan blue negative cells made up in 0.1 ml of Dulbecco modified Eagles' medium (DME) were injected into the peritoneal cavity of a male athymic Swiss nu/nu mouse. The control group and each treatment group consisted of 5 to 10 mice. Treatment was commenced the following day by intraperitoneal injection.
  • DME Dulbecco modified Eagles' medium
  • T/C is the ratio, expressed as a percentage of the mean survival age of the treated group to the mean survival age of the untreated control group.

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

Abstract

L'invention concerne des composés de méthine ayant la structure (1-13) ou (1-3), et leurs analogues. Ces composés de méthine ont une haute solubilité et sont utiles comme ingrédient actif dans une composition pharmaceutique destinée au traitement du cancer.
PCT/JP1995/001408 1994-07-21 1995-07-14 Compose de methine soluble dans l'eau et composition pharmaceutique utilisee dans le traitement du cancer contenant ce compose WO1996003393A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP8505639A JPH10506878A (ja) 1994-07-21 1995-07-14 水溶性メチン化合物及び該化合物を含有する癌治療用医薬組成物
EP95925127A EP0772607A1 (fr) 1994-07-21 1995-07-14 Compose de methine soluble dans l'eau et composition pharmaceutique utilisee dans le traitement du cancer contenant ce compose
AU29366/95A AU678116B2 (en) 1994-07-21 1995-07-14 Water-soluble methine compound and pharmaceutical composition for treatment of cancer comprising the same

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP16958294 1994-07-21
JP6/169582 1994-07-21
US08/420,481 1995-04-12
US08/420,481 US5599825A (en) 1994-07-21 1995-04-12 Water-soluble methine compound and pharmaceutical composition for treatment of cancer comprising the same

Publications (1)

Publication Number Publication Date
WO1996003393A1 true WO1996003393A1 (fr) 1996-02-08

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/001408 WO1996003393A1 (fr) 1994-07-21 1995-07-14 Compose de methine soluble dans l'eau et composition pharmaceutique utilisee dans le traitement du cancer contenant ce compose

Country Status (5)

Country Link
EP (1) EP0772607A1 (fr)
JP (1) JPH10506878A (fr)
AU (1) AU678116B2 (fr)
CA (1) CA2187445A1 (fr)
WO (1) WO1996003393A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1623981A4 (fr) * 2003-05-06 2008-07-23 Japan Science & Tech Agency Agent anti-leishmania
EP1800682A4 (fr) * 2004-10-04 2010-06-30 Masataka Ihara Préparation médicamenteuse pour le traitement prophylactique ou thérapeutique d une infection protozoaire parasitaire
EP3242555A4 (fr) * 2015-01-09 2018-06-27 The Regents of The University of California Composés oxathiazole thiazolium inhibiteurs de hsp 70

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006137258A1 (fr) * 2005-06-24 2006-12-28 Japan Science And Technology Agency Préparation pharmaceutique contenant un dérivé d’azarhodacyanine au titre de principe actif

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2020975A (en) * 1978-05-17 1979-11-28 Takeda Yahuhin Kogyo Kk Compositions containing cyanine compounds
JPS6267068A (ja) * 1985-09-18 1987-03-26 Mitsubishi Chem Ind Ltd シアニン化合物および光学記録体
EP0286252A2 (fr) * 1987-03-17 1988-10-12 Dana Farber Cancer Institute Composition et procédé contre le cancer, utilisant des colorants cyanins
EP0417941A2 (fr) * 1989-08-30 1991-03-20 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Utilisation d'un colorant cyanine dans un agent antitumoral
EP0527494A1 (fr) * 1991-08-13 1993-02-17 Fuji Photo Film Co., Ltd. Composition contenant des colorants du type rhodacyanine pour le traitement du cancer
JPH0680892A (ja) * 1992-09-01 1994-03-22 Fuji Photo Film Co Ltd 水溶性メチン化合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2020975A (en) * 1978-05-17 1979-11-28 Takeda Yahuhin Kogyo Kk Compositions containing cyanine compounds
JPS6267068A (ja) * 1985-09-18 1987-03-26 Mitsubishi Chem Ind Ltd シアニン化合物および光学記録体
EP0286252A2 (fr) * 1987-03-17 1988-10-12 Dana Farber Cancer Institute Composition et procédé contre le cancer, utilisant des colorants cyanins
EP0417941A2 (fr) * 1989-08-30 1991-03-20 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Utilisation d'un colorant cyanine dans un agent antitumoral
EP0527494A1 (fr) * 1991-08-13 1993-02-17 Fuji Photo Film Co., Ltd. Composition contenant des colorants du type rhodacyanine pour le traitement du cancer
JPH0680892A (ja) * 1992-09-01 1994-03-22 Fuji Photo Film Co Ltd 水溶性メチン化合物

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 107, no. 18, 2 November 1987, Columbus, Ohio, US; abstract no. 165598s, page 764; *
CHEMICAL ABSTRACTS, vol. 121, no. 14, 3 October 1994, Columbus, Ohio, US; abstract no. 159376r, page 94; *
CHEMICAL ABSTRACTS, vol. 93, no. 3, 21 July 1980, Columbus, Ohio, US; abstract no. 19532s, page 94; *
ISAO MINAMI ET AL: "Cyanine dyes,new potent antitumor agents", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 30, no. 9, TOKYO JP, pages 3106 - 3120 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1623981A4 (fr) * 2003-05-06 2008-07-23 Japan Science & Tech Agency Agent anti-leishmania
EP1800682A4 (fr) * 2004-10-04 2010-06-30 Masataka Ihara Préparation médicamenteuse pour le traitement prophylactique ou thérapeutique d une infection protozoaire parasitaire
US8193224B2 (en) 2004-10-04 2012-06-05 Fujifilm Corporation Medicinal composition for prevention or treatment of parasitic protozoan infection
EP3242555A4 (fr) * 2015-01-09 2018-06-27 The Regents of The University of California Composés oxathiazole thiazolium inhibiteurs de hsp 70
US10221171B2 (en) 2015-01-09 2019-03-05 The Regents Of The University Of California Oxathiazole thiazolium Hsp 70 inhibitors

Also Published As

Publication number Publication date
CA2187445A1 (fr) 1996-02-08
AU678116B2 (en) 1997-05-15
AU2936695A (en) 1996-02-22
EP0772607A1 (fr) 1997-05-14
JPH10506878A (ja) 1998-07-07

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