WO1997036904A1 - Derive de la mitomycine c et inhibiteur des tyrosine kinases non receptrices - Google Patents
Derive de la mitomycine c et inhibiteur des tyrosine kinases non receptrices Download PDFInfo
- Publication number
- WO1997036904A1 WO1997036904A1 PCT/JP1997/001109 JP9701109W WO9736904A1 WO 1997036904 A1 WO1997036904 A1 WO 1997036904A1 JP 9701109 W JP9701109 W JP 9701109W WO 9736904 A1 WO9736904 A1 WO 9736904A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mitomycin
- receptor tyrosine
- derivative
- tyrosine kinase
- kinase inhibitor
- Prior art date
Links
Classifications
-
- 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
- C07D487/12—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 three hetero rings
- C07D487/14—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to mitomycin C having a docosahexaenoyl group and a drug containing the same as an active ingredient, particularly a non-receptor tyrosine kinase inhibitor.
- An inactive protein is phosphorylated to become an active form in the intracellular signal transduction system until the cell undergoes a certain stimulus to trigger a reaction such as substance production, differentiation, proliferation, etc., and exerts its function. It is known that there are many cases.
- Known protein kinases involved in the reaction include cyclic AMP-dependent protein kinase, protein kinase C, calmodulin-dependent protein kinase, and receptor tyrosine kinase found in growth factor receptors. . It has been known that tyrosine phosphorylation of intracellular proteins is also involved in intracellular signal transduction pathways of various site proteins such as interferons and interleukins.
- cytokinin receptor has no kinase activity and none of the above-mentioned protein kinases participate in this pathway, tyrosine kinases activated by cytokines have long been considered. It was unknown. By the end of 1993, non-receptor tyrosine kinases that were activated in association with cytokine receptors were discovered, and a series of non-receptor tyrosine kinases were subsequently identified. Among them, it became clear that the src gene product, one of the best-known oncogenes, and a gene group product with high homology to src were included.
- Antibiotics 32, 255, 1975
- the Rous sarcoma virus which has the virus-type src gene (V-src). It has been reported that cancerous cells are decancerized (Cancer Research, 49, 780-785, 1989), but they have not been clinically used due to their high toxicity. Harpimycin A also inhibits calmodulin-dependent kinase and has low selectivity.
- known protein kinase inhibitors such as H-7 and staurosporine, also inhibit multiple types of protein kinases, making their clinical application difficult. That is, the development of non-receptor protein kinase inhibitors having higher selectivity and lower toxicity has been desired. Disclosure of the invention
- the present inventors have made a new finding that mitomycin derivatives represented by the following general formula (I) have excellent inhibitory activity against non-receptor tyrosine kinases such as the src gene product.
- the present invention is based on Tti.
- the present invention provides a compound represented by the general formula (I):
- R represents a docosahexaenoyl group.
- a drug containing the mitomycin C derivative as an active ingredient particularly a non-receptor type
- An oral synkinase inhibitor is provided.
- the mitomycin C derivative represented by the above general formula (I) of the present invention is obtained, for example, by reacting mitomycin C and docosahexaenoic acid in a solvent in the presence of a dehydrating condensing agent such as diisopropylpyrucarbodiimide. It can be manufactured in some cases.
- the dose of the mitomycin C derivative of the present invention varies depending on age, sex, body weight, symptoms, or administration form, but is generally about 1 to 100 nig per day, and is taken once or several times. Can be done.
- the inhibitor of the present invention can be administered orally or parenterally.
- solid preparations such as powders, granules, capsules and tablets or liquid preparations such as syrups and elixirs can be used.
- injections can be prepared as parenteral administration preparations. These preparations are prepared in a conventional manner by adding a pharmaceutically acceptable production aid to the active ingredient.
- a sustained-release preparation can be prepared by a known technique.
- the active ingredient must be mixed with the active ingredient in a powder form, such as lactose, starch, crystalline cellulose, lactose calcium, magnesium metasilicate, magnesium anhydride, or the like to form a powder.
- a binder such as sucrose, hydroxypropyl cellulose and polyvinylpyrrolidone, and a disintegrating agent such as carboxymethylcellulose and carboxymethylcellulose calcium are added, and the mixture is granulated by wet or dry granulation to obtain granules.
- these powders and granules can be compressed as they are or by adding a lubricant such as magnesium stearate or talc.
- granules or tablets are coated with an enteric base such as hydroxypropyl methylcellulose phthalate, methacrylic acid, methyl methacrylate copolymer and the like, and coated with an enteric preparation, or coated with ethyl cellulose, carnauba wax, hydrogenated oil, etc. It can be a long-acting preparation.
- enteric base such as hydroxypropyl methylcellulose phthalate, methacrylic acid, methyl methacrylate copolymer and the like
- enteric preparation or coated with ethyl cellulose, carnauba wax, hydrogenated oil, etc. It can be a long-acting preparation.
- powders or granules can be filled in hard capsules, or the active ingredient can be dissolved in glycerin, polyethylene glycol, sesame oil, olive oil or the like, and then coated with a gelatin film to give soft capsules.
- a liquid preparation for oral administration the active ingredient and a sweetener such as sucrose, sorbitol, and glycerin are dissolved in water to give a clear syrup, and then an elixir by adding essential oils and ethanol.
- An emulsion or suspension may be prepared by adding arabia, tragacanth, polysorbate 80, carboxymethyl cellulose sodium and the like. If desired, flavoring agents, coloring agents, preservatives and the like may be added to these liquid preparations.
- the active ingredient In order to manufacture an injection, the active ingredient must be adjusted to a pH adjuster such as hydrochloric acid, sodium hydroxide, lactose, sodium lactate, sodium hydrogen phosphate, sodium hydrogen phosphate, etc., if necessary. Dissolve in distilled water for injection together with isotonic agents such as sodium and glucose, and sterile-filter to fill ampoules.Add mannitol, dextrin, cyclodextrin, gelatin, etc. and freeze-dry under vacuum. A time-dissolvable injection may be used.
- an active ingredient can be emulsified in water by adding lecithin, polysorbate 80, polyoxetylene hardened castor oil, and the like to obtain an emulsion for injection.
- the test was performed according to the method of Fukazawa et al. (Analytical Biochemistry, 13, 1957 1964, 1993). That is, NIH-3T3 cells having cAMP-dependent protein kinase, protein kinase II, calmodulin-dependent kinase, and EGF receptor tyrosine kinase were transformed with the v-src gene, and non-receptor protein tyrosine kinase was further introduced. The cells were reacted for 10 minutes on ice in lniM Hex buffer (pH 7.4) containing 5 mM MgCl 2 and 25 ⁇ g / ml each of antipain, leptin, and papstatin A.
- the cells were further disrupted by stirring at room temperature for 2 minutes using a vortex mixer, and the nuclei were sedimented by adding 20 mM phosphate buffer and centrifuging at 500 xg for 5 minutes. The supernatant was collected, so that the protein concentration 2. 5nig / na, to lOmM MgCl z / 0. ImM Na 3 V0 4 / 10mM y3 glycerin port phosphate / ⁇ NaF / 20mM Hepes (pH 7. 4) Diluted. To this, add a final concentration of 1 M phorbol 12-myristate-13-acetate, 10 M CaCl 2 , 20 M cAMP and a test substance in dimethyl sulfoxide to a final concentration of
- test example 1 The cells were subcultured into a 96-well plate and cultured for 24 hours. Then, a test substance was added and the cells were further cultured for 48 hours. The surviving cells were colorimetrically determined by sulfolo-damine B staining, and the cell number was determined. When the solvent dimethyl sulfoxide is added in place of the test substance, the cell number is 1003 ⁇ 4 The concentration of the test substance as 3 ⁇ 4 ⁇ was determined as IC so . Test example 1
- DHA-MMC docosahexaenoyl mitomicin C
- PTK non-receptor protein tyrosine kinase
- PKA cAMP-dependent protein kinase
- PKC protein kinase
- CAMK calmodulin-dependent kinase
- EGFR EGF receptor tyrosine kinase
- DHA-MMC docosahexaenoyl mitomycin C
- the compound of the present invention has excellent inhibitory activity against non-receptor tyrosine kinase, it can be expected to be used as a medicine, particularly as an anticancer agent or a therapeutic agent for immune diseases.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
L'invention concerne un dérivé de la mitomycine C, ayant une excellente activité d'inhibition des tyrosine kinases non réceptrices susceptibles de jouer un rôle dans les maladies du système immunitaire. Ce dérivé a une sélectivité réduite vis-à-vis des autres protéine kinases et il est représenté par la formule chimique (I). Dans cette formule, R représente un groupe docosahexanoyle. L'invention concerne également des médicaments contenant ce dérivé comme principe actif, en particulier un inhibiteur des tyrosine kinases non réceptrices.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8079969A JPH09268190A (ja) | 1996-04-02 | 1996-04-02 | マイトマイシンc誘導体及び非受容体型チロシンキナーゼ阻害剤 |
JP8/79969 | 1996-04-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997036904A1 true WO1997036904A1 (fr) | 1997-10-09 |
Family
ID=13705158
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1997/001109 WO1997036904A1 (fr) | 1996-04-02 | 1997-03-31 | Derive de la mitomycine c et inhibiteur des tyrosine kinases non receptrices |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPH09268190A (fr) |
WO (1) | WO1997036904A1 (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000064484A2 (fr) * | 1999-04-23 | 2000-11-02 | Alza Corporation | Conjugue a liaison pouvant etre clivee, destine a etre utilise dans un liposome |
US6495348B1 (en) | 1993-10-07 | 2002-12-17 | Regents Of The University Of Minnesota | Mitomycin biosynthetic gene cluster |
WO2004110497A2 (fr) | 2003-04-30 | 2004-12-23 | Alza Corporation | Methode de traitement de tumeurs resistantes aux antibiotiques |
US7238368B2 (en) | 1999-04-23 | 2007-07-03 | Alza Corporation | Releasable linkage and compositions containing same |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6524812B1 (en) | 1993-10-07 | 2003-02-25 | Regents Of The University Of Minnesota | Genes encoding resistance to DNA alkylating agents |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01113391A (ja) * | 1987-10-24 | 1989-05-02 | Kyowa Hakko Kogyo Co Ltd | マイトマイシン誘導体 |
JPH01160988A (ja) * | 1987-12-18 | 1989-06-23 | Nippon Oil & Fats Co Ltd | ドコサヘキサエノイルジアシルグリセロールの製造法 |
JPH01203322A (ja) * | 1988-02-05 | 1989-08-16 | Rikagaku Kenkyusho | 制癌剤 |
-
1996
- 1996-04-02 JP JP8079969A patent/JPH09268190A/ja active Pending
-
1997
- 1997-03-31 WO PCT/JP1997/001109 patent/WO1997036904A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01113391A (ja) * | 1987-10-24 | 1989-05-02 | Kyowa Hakko Kogyo Co Ltd | マイトマイシン誘導体 |
JPH01160988A (ja) * | 1987-12-18 | 1989-06-23 | Nippon Oil & Fats Co Ltd | ドコサヘキサエノイルジアシルグリセロールの製造法 |
JPH01203322A (ja) * | 1988-02-05 | 1989-08-16 | Rikagaku Kenkyusho | 制癌剤 |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6495348B1 (en) | 1993-10-07 | 2002-12-17 | Regents Of The University Of Minnesota | Mitomycin biosynthetic gene cluster |
US7303760B2 (en) | 1999-04-23 | 2007-12-04 | Alza Corporation | Method for treating multi-drug resistant tumors |
WO2000064484A3 (fr) * | 1999-04-23 | 2001-11-15 | Alza Corp | Conjugue a liaison pouvant etre clivee, destine a etre utilise dans un liposome |
US6984396B2 (en) | 1999-04-23 | 2006-01-10 | Alza Corporation | Conjugate having a cleavable linkage for use in a liposome |
US7238368B2 (en) | 1999-04-23 | 2007-07-03 | Alza Corporation | Releasable linkage and compositions containing same |
US7276248B2 (en) | 1999-04-23 | 2007-10-02 | Alza Corporation | Conjugate having a cleavable linkage for use in a liposome |
US7285622B2 (en) | 1999-04-23 | 2007-10-23 | Alza Corporation | Releasable linkage and compositions containing same |
WO2000064484A2 (fr) * | 1999-04-23 | 2000-11-02 | Alza Corporation | Conjugue a liaison pouvant etre clivee, destine a etre utilise dans un liposome |
CN100512879C (zh) * | 1999-04-23 | 2009-07-15 | 阿尔萨公司 | 用于脂质体中的有可裂解键的缀合物 |
US7592307B2 (en) | 1999-04-23 | 2009-09-22 | Alza Corporation | Releasable linkage and compositions containing same |
US7608687B2 (en) | 1999-04-23 | 2009-10-27 | Alza Corporation | Releasable linkage and compositions containing same |
WO2004110497A2 (fr) | 2003-04-30 | 2004-12-23 | Alza Corporation | Methode de traitement de tumeurs resistantes aux antibiotiques |
WO2004110497A3 (fr) * | 2003-04-30 | 2005-03-24 | Alza Corp | Methode de traitement de tumeurs resistantes aux antibiotiques |
Also Published As
Publication number | Publication date |
---|---|
JPH09268190A (ja) | 1997-10-14 |
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