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Derivatives of 6-(6-nh-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, preparation thereof, use thereof as drugs, and use thereof as met inhibitors

An alkyl and group technology, applied in the field of 6-benzothiazole and 6-benzimidazole derivatives

Inactive Publication Date: 2012-03-07
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These effects can be limited if the drugs used act selectively on cancer cells to the exclusion of healthy cells

Method used

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  • Derivatives of 6-(6-nh-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, preparation thereof, use thereof as drugs, and use thereof as met inhibitors
  • Derivatives of 6-(6-nh-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, preparation thereof, use thereof as drugs, and use thereof as met inhibitors
  • Derivatives of 6-(6-nh-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, preparation thereof, use thereof as drugs, and use thereof as met inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0305] 3-[(2-amino-1,3-benzothiazol-6-yl)thio]-N-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[ 4,3-b]pyridazin-6-amine

[0306] a) 3-[(2-amino-1,3-benzothiazol-6-yl)thio]-N-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazole And[4,3-b]pyridazin-6-amine can be prepared as follows:

[0307] The argon flow is 900mg thiocyanate 2-amino-1,3-benzothiazol-6-yl ester in 27cm 3 The mixture in ethanol was bubbled for 5 min. Add 21mg of potassium dihydrogen phosphate in succession at 2.7cm 3 Solution in water, 2.01 g DL-dithiothreitol and 1.21 g 3-chloro-N-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[4,3-b ] Pyridazin-6-amine. The reaction mixture was heated at 80 °C for 18 hours. The resulting suspension was cooled to 20°C and the precipitate was spin-filter-dried and washed with water. The resulting hydrochloride form of solid in 10cm 3 water and 5cm 3 Absorption in a mixture of 1N sodium hydroxide. The suspension was stirred at 20 °C for 10 minutes then the solid was dried by spin filtratio...

Embodiment 2

[0314] N-(6-{[6-(tetrahydro-2H-pyran-4-ylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]thio} -1,3-Benzothiazol-2-yl)acetamide

[0315] a) N-(6-{[6-(tetrahydro-2H-pyran-4-ylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfur Base}-1,3-benzothiazol-2-yl)acetamide can be prepared as follows:

[0316] At 20°C the 0.212cm 3 Acetyl chloride was added to 300 mg 3-[(2-amino-1,3-benzothiazol-6-yl)thio]-N-(tetrahydro-2H-pyran-4-yl)[1,2,4 ]triazolo[4,3-b]pyridazin-6-amine (1a) and 0.42cm 3 Triethylamine in 6cm 3 solution in dichloromethane. After 20 hours, the reaction mixture was concentrated to dryness and the solid residue was purified by chromatography (with dichloromethane) on a Biotage Quad 12 / 25 (KP-SIL, 60A; 32-63 μM) by solid deposit (solid deposit). / (38 dichloromethane / 17 methanol / 2 ammonia water) 95 / 5 to 70 / 30 gradient for elution). This gave 176 mg of N-(6-{[6-(tetrahydro-2H-pyran-4-ylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl ]thio}-1,3-benzothiazol-2-yl)acetamide in the...

Embodiment 3

[0320] N-(6-{[6-(tetrahydro-2H-pyran-4-ylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]thio} -1,3-Benzothiazol-2-yl)cyclopropanecarboxamide

[0321] a) N-(6-{[6-(tetrahydro-2H-pyran-4-ylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfur Base}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide can be carried out in a manner similar to Example 2a, but using 300 mg of 3-[(2-amino-1,3-benzothiazol-6-yl )thio]-N-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-6-amine (1a) at 3cm 3 The solution in pyridine and 0.138cm 3 Cyclopropanecarboxylic acid chloride, prepared after reaction at 20°C for 18 hours. This gave 292 mg of N-(6-{[6-(tetrahydro-2H-pyran-4-ylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl ]thio}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide in the form of a beige powder characterized as follows:

[0322] 1H NMR spectrum (400MHz, DMSO-d6) δ.ppm 0.89-1.00 (m, 4H) 1.18-1.33 (m, 2H) 1.58-1.70 (m, 2H) 1.93-2.03 (m, 1H) 3.19-3.28 (m , 2H) 3.46-3.61 (m, 1H) 3.69 (d, J = 11....

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Abstract

The invention relates to novel products of the formula (I) where: (II) is a single or double bond; Rb is a hydrogen or fluorine atom; Ra is a NH-Rc radical in which Rc is an optionally substituted heterocycloalkyl, aryl, heteroaryl or -alkylcycloalkyl radical; X is S, SO, or SO2; A is NH or S; W is H, alkyl, or COR with R being cycloalkyl; alkyl; alkoxy; O-phenyl; -O- (CH2)n-phenyl with n= 1 to 4; or NR1R2 with R1 being H or alk and R2 is H, cycloalkyl or alkyl; or R1, R2 form a cycle together with N optionally containing O, S, N and / or NH; all of said radicals being optionally substituted; wherein said products can be in any isomer or salt form, and can be used as drugs, in particular as MET inhibitors.

Description

technical field [0001] The present invention relates to novel 6-(6-substituted triazolopyridazinylthio)benzothiazoles and 6-(6-NH-substituted triazolopyridazinylthio)benzimidazole derivatives, their preparation Methods, new intermediates obtained, their use as medicines, pharmaceutical compositions containing them and the 6-(6-substituted triazolopyridazinylthio)benzothiazole and 6-(6-NH- Novel uses of substituted triazolopyridazinylthio)benzimidazole derivatives. [0002] The present invention more particularly relates to novel 6-(6-substituted triazolopyridazinylthio)benzothiazoles and 6-(6-NH-substituted Triazolopyridazinylthio) benzimidazole derivatives. Background technique [0003] To date, most of the commercially available compounds used in chemotherapy are cytotoxic agents with major problems of side effects and patient tolerability. These effects can be limited if the drugs used act selectively on cancer cells to the exclusion of healthy cells. One solution for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/82C07D487/04A61K31/5025A61P35/00
CPCC07D277/82C07D487/04A61P11/06A61P17/06A61P19/02A61P21/00A61P21/02A61P25/00A61P27/00A61P27/02A61P29/00A61P3/00A61P35/00A61P35/04A61P37/00A61P37/08A61P43/00A61P7/02A61P9/00A61P3/10C07D403/12A61K31/5025
Inventor E.巴克C.内梅切克A.乌戈里尼S.温茨勒
Owner SANOFI SA