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Use of a mt kinase inhibitor for treating or preventing brain cancer

A brain cancer, use technology, applied in the field of use of MT kinase inhibitors for the treatment or prevention of brain cancer, can solve the problems of normal tissue toxicity, unaware side effects, mechanical damage or destruction, etc.

Inactive Publication Date: 2009-09-09
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, all current treatments involve serious limitations and dangers
Radiation therapy that often attempts to deliver high damaging doses of ionizing radiation through normal tissues of the body in an attempt to preferentially kill highly specific but often inaccurately defined areas of cancerous tissue, possibly due to damage to the normal nervous system or other tissues of the body, These include, causing memory loss and personality changes (below) with serious and significant side effects
Chemotherapy that attempts to preferentially kill cancer cells rather than normal cells by administering multiple chemicals or drugs to body tissues, is limited by the efficacy of currently available chemical agents and may result in toxicity to normal tissues and unintended side effects
Surgery that attempts to mechanically eliminate or interfere with the development of cancer may also result in serious side effects or consequences due to mechanical injury or destruction of normal tissue
Some of the problems associated with the above approaches are (i) adverse side effects, including changes in intelligence, learning ability, memory, motor function, consciousness, and emotion; Tumor reappears within 5 years; (iii) death due to failure of such treatment

Method used

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  • Use of a mt kinase inhibitor for treating or preventing brain cancer
  • Use of a mt kinase inhibitor for treating or preventing brain cancer
  • Use of a mt kinase inhibitor for treating or preventing brain cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] a) Preparation of 1-pentanol, 5-[[(4-bromo-2-nitrophenyl)methyl]amino]-(Intermediate 1)

[0040] Under RT, stir 4-bromo-2-nitro-benzaldehyde (0.013mol), 5-amino-1-pentanol (0.013mol) and tetrakis (2-propanolate) titanium (titanium, tetrakis (2- propanolato)) (0.014mol) in EtOH (15ml) for 1 hour, then heated the reaction mixture to 50°C and stirred for another 30min. Cool the mixture to RT and add NaBH in portions 4 (0.013 mol). The reaction mixture was stirred overnight, then poured into ice water (50ml). The resulting mixture was stirred for 20 min, the formed precipitate was filtered off (obtaining filtrate (I)), and washed with H 2 O washed, stirred in DCM (to dissolve product and remove it from Ti salt). The mixture was filtered, and the filtrate was dried (MgSO 4 ) and filtered, and finally the solvent was evaporated. Filtrate (I) was evaporated until EtOH was removed and the aqueous concentrate was extracted twice with DCM. The organic layer was separated a...

Embodiment 2

[0042] a) Preparation of 1-pentanol, 5-[[(4-bromo-2-nitrophenyl)methyl]methylamino]-(Intermediate 2)

[0043] A solution of intermediate 50 (0.0047 mol), formaldehyde (0.025 mol) and tetrakis(2-propyl titanate) (0.0051 mol) in EtOH (150 ml) was heated to 50 °C and stirred for 1 hour, then added in portions at RT NaBH 4 (0.026 mol). The reaction mixture was stirred overnight and quenched with water (100ml). The resulting mixture was stirred for 1 hour; the precipitate formed was filtered off and washed. The organic filtrate was concentrated and the aqueous concentrate was extracted with DCM and dried. The solvent was evaporated and the residue was filtered through silica gel (eluent: DCM / CH 3 OH from 98 / 2 to 95 / 5). The product fractions were collected and the solvent was evaporated, yielding 0.5 g of intermediate 2.

[0044] b) Preparation of 1-pentanol, 5-[[(4-bromo-2-nitrophenyl)methyl]methylamino]-, acetate (ester) (intermediate 3)

[0045] A solution of intermediate ...

Embodiment 3

[0053] a) 4,6-linked methylene (ethanediylidene) pyrimido [4,5-b] [6,1,12] benzoxadiazepine-pentadecene, 17-bromo-8,9 , 10, 11, 12, 13, 14, 19-Octahydro-20-methoxy-13-methyl-(Compound MTKI1) Preparation

[0054] At RT, a solution of Intermediate 6 (0.0011mol) in THF (50ml) was stirred, and tributylphosphine (0.0016mol) was added, followed by 1,1'-(azobiscarbonyl)bis-piperidine (0.0016mol) , and the reaction mixture was stirred for 2 hours. The solvent was evaporated to 1 / 3 of the original volume. The resulting precipitate was filtered off and washed. The filtrate was evaporated and the residue was purified by RP HPLC. The product fractions were collected and the organic solvent was evaporated. The aqueous concentrate was extracted twice with DCM and dried (MgSO4 ) organic layer, and then filtered. At 50°C, the solvent was evaporated and the residue was dried (vacuum), yielding 0.004 g (0.8%) of compound MTKI1.

[0055] To prepare the aforementioned pharmaceutical composi...

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Abstract

The present invention is concerned with the finding that some the macrocyclic quinazoline derivative 4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclo-pentadecine, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl-, described as compound 22 in PCT publication WO2004 / 105765, is useful in the manufacture of a medicament for the treatment or prevention of a primary brain cancer or brain metastasis. It accordingly provides methods for treating, preventing, delaying or mitigating brain cancer, or for preventing or slowing proliferation of cells of brain origin.

Description

field of invention [0001] The present invention relates to the discovery that the macrocyclic quinazoline derivative 17-bromo-8,9,10,11,12,13,14,19-octahydro- 20-Methoxy-13-methyl-4,6-bis-methylene (ethanediylidene) pyrimido[4,5-b][6,1,12]benzoxadiazepine-pentadecane Pentadecine is useful in the preparation of drugs for the treatment of primary brain cancer or for the treatment or prevention of brain metastasis. Therefore, the present invention provides methods for treating, preventing, alleviating or alleviating brain metastases and treating, alleviating or alleviating primary brain cancers. Background of the invention [0002] "Brain cancer" means (1) any abnormally increased proliferation of nerve cells of any type, hereinafter also referred to as primary brain cancer, or (2) any other cancer that has metastasized into the central nervous system (CNS), hereinafter Also called brain metastases. [0003] Most nerve cells (i.e., cells contained or found in the CNS, includ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61P35/00
CPCA61K31/519
Inventor T·P·S·佩雷拉M·J·帕奇M·M·F·贾尼科特E·J·E·弗雷恩
Owner JANSSEN PHARMA NV
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