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(Spirocyclylamido) aminothiophene compounds as c-Kit proto-oncogene inhibitors

A compound, alkylamino technology, applied in the field of thiophene, can solve problems such as malignant phenotypes and proliferative diseases

Inactive Publication Date: 2007-10-24
OSI PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Through a different pathway, overexpression of normal proto-oncogene tyrosine kinases can also lead to proliferative disorders, sometimes leading to malignant phenotypes

Method used

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  • (Spirocyclylamido) aminothiophene compounds as c-Kit proto-oncogene inhibitors
  • (Spirocyclylamido) aminothiophene compounds as c-Kit proto-oncogene inhibitors
  • (Spirocyclylamido) aminothiophene compounds as c-Kit proto-oncogene inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] N-1,4-dioxaspiro[4.5]decac-8-yl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide

[0150]

[0151] Example 1 was prepared by the following procedure:

[0152]

[0153] Example 1

[0154] part 1:

[0155] Benzyl 4-hydroxycyclohexylcarbamate (1): trans-4-aminocyclohexyl alcohol hydrochloride (12.13g, 80mmol) and K 2 CO 3 (24.32 g, 176 mmol) in THF (160 mL) and water (320 mL) was cooled to 0°C. A solution of benzyl chloroformate (12.4 mL, 88 mmol) in THF (16 mL) was added dropwise. The mixture was then stirred at room temperature for 30 min. The mixture was then extracted with diethyl ether (200 mL), the organic phase was washed with brine (150 mL), MgSO 4 Dry, filter and concentrate in vacuo. The crude product was purified by recrystallization from ether to give benzyl 4-hydroxycyclohexylcarbamate as a white solid. 1 H NMR (CDCl 3, 400MHz): δ1.15-1.25(m, 2H), 1.35-1.45(m, 2H), 1.96-2.05(m, 4H), 3.46-3.53(m, 1H), 3.58-3.64(m...

Embodiment 2

[0170] cis-N-1-oxa-4-thiaspiro[4.5]deca-8-yl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide: MS(ES+ )440[M+1]

[0171]

Embodiment 3

[0173] trans-N-1-oxa-4-thiaspiro[4.5]deca-8-yl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide: MS(ES+ )440[M+1]

[0174]

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PUM

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Abstract

Compounds represented by Formula (I): or a pharmaceutically acceptable salt or N-oxide thereof, wherein A, R<1>, X and Y are defined herein, are useful in the treatment of tumors and cancers such as mastocytosis / mast cell leukemia, gastrointestinal stromal tumors (GIST), germ cell tumors, small cell lung carcinoma (SCLC), sinonasal natural killer / T-cell lymphoma, testicular cancer (seminoma), thyroid carcinoma, malignant melanoma, ovarian carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML), breast carcinoma, pediatric T-cell acute lymphoblastic leukemia, neuroblastoma, mast cell leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma, and prostate carcinoma.

Description

Background of the invention [0001] The present invention relates to disubstituted thiophenes. In particular, the present invention relates to (spirocyclylamido)(amino)thiophenes, which are inhibitors of the c-Kit proto-oncogene (also known as Kit, CD-117, stem cell factor receptor, mast cell growth factor receptor) agent. [0002] The c-Kit proto-oncogene is considered important in embryogenesis, melanogenesis, hematopoiesis, and the pathogenesis of mastocytosis, gastrointestinal and other solid tumors, and certain leukemias, including AML. Therefore, it is desirable to develop novel c-Kit receptor inhibitor compounds. [0003] Many current treatment regimens for hyperproliferative diseases (cancer) use compounds that inhibit DNA synthesis. The mechanism of action of this class of compounds is toxic to cells, especially to rapidly dividing tumor cells. Therefore, its widespread toxicity may be a problem for the patients tested. However, other approaches have been explored...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14C07D471/10C07D411/14A61K31/4709C07D495/10A61K31/475C07D491/10A61P35/02C07D487/10
CPCC07D471/10C07D491/107C07D495/10C07D491/113C07D491/10C07D409/14C07D487/10C07D411/14A61P13/08A61P35/00A61P35/02
Inventor 李安虎董汉清张涛
Owner OSI PHARMA INC