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Bexarotene derivatives and their use in treating cancer

A compound, C1-C6 technology, applied in the field of bexarotene derivatives and their use in the treatment of cancer

Pending Publication Date: 2021-01-12
디제이테라퓨틱스엘엘씨
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, all currently available cancer treatments have limitations, and none are effective once the cancer has progressed or become refractory or treatment-resistant

Method used

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  • Bexarotene derivatives and their use in treating cancer
  • Bexarotene derivatives and their use in treating cancer
  • Bexarotene derivatives and their use in treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0166] Example 1: 4-(1-(6'-(difluoromethyl)-4',4'-dimethyl-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene Preparation of ]-7'-yl)vinyl)benzoic acid (DSP-109; or 109)

[0167]

[0168] To a -10°C solution of bromo(methyl)triphenyl-[5]-phosphorane (89.3 g, 250 mmol, 2.6 eq.) in THF (1 L) was added LDA (2M, in in THF, 145 mL, 3.0 eq.). To the resulting solution was added 6-chloro-4,4-dimethyl-1,2,3,4-tetralin-1-one (20 g, 95.8 mmol, 1.0 eq.) over 30 minutes. The resulting solution was stirred at 0 °C for 3 h, then cooled by adding 1000 g of ice / H 2 O quenching. The resulting mixture was washed with CH 2 Cl 2 (3 x 500 mL) extraction. The combined organic layers were dried (Na 2 SO 4 ) and concentrate. The residue was purified by chromatography on silica gel eluting with petroleum ether to afford 18 g (91%) of 7-chloro-1,1-dimethyl-4-methylene-1,2,3,4-tetrahydronaphthalene , as a colorless oil.

[0169]

[0170] To a solution of diethylzinc (106.6 g, 863 m...

Embodiment 2

[0185] Example 2: 4-(1-(4',4',6'-trimethyl-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-7'-yl) Preparation of vinyl)benzoic acid (DPS-107; 107)

[0186]

[0187] A mixture of 4-(4-methylphenyl)butanoic acid (50 g, 260 mmol, 1.0 eq.), MeOH (300 mL), and sulfuric acid (5 mL) was stirred at room temperature for 16 h, then concentrated under reduced pressure. The residue was added by adding saturated NaHCO 3 (200 mL), and the aqueous mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), and concentrated to give 59.1 g of methyl 4-(4-methylphenyl)butyrate as a yellow oil.

[0188]

[0189] To a solution of methyl 4-(4-methylphenyl)butyrate (59.1 g, 307 mmol, 1.0 eq.) in ether (500 mL) and toluene (1 L) was added methylmagnesium bromide in ether (3 m, 246 mL , 738mmol, 2.4eq.) in solution. The resulting solution was stirred at room temperature for 2 h, then 4 Quenched with aqueous Cl (100 mL). ...

Embodiment 3

[0204] Example 3: 4-(1-(1-fluoro-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid (DSP-106; 106) Preparation

[0205]

[0206]

[0207] Methyl 4-acetylbenzoate (17.8g, 100mmol, 1.0eq.), Na 2 CO 3 (17.0g, 160mmol, 1.6eq.), Tf 2 O (56.4g, 200mmol, 2.0eq.) in CH 2 Cl 2 (150 mL) was stirred at room temperature for 8 h, then the solids were removed by filtration. Filtrate with saturated NaHCO 3 Aqueous solution (150 mL), the layers were separated and the organic layer was washed with brine and dried (Na 2 SO 4 ), and concentrated to afford 16 g (52%) of methyl 4-[1-[(trifluoromethane)sulfonyloxy]vinyl]benzoate as a white solid.

[0208]

[0209] 2,5-dichloro-2,5-dimethylhexane (16.0g, 87.4mmol, 1.2eq.), AlCl 3 (1.98g, 17.5mmol, 0.20eq.) in CH 2 Cl 2 (90 mL) was added 2-bromo-1-fluoro-3-methylbenzene (14.0 g, 74.1 mmol, 1.0 eq.) in CH 2 Cl 2 (10 mL). The reaction mixture was stirred at -10 °C for 2 h, then by adding H 2 O (20 mL) a...

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Abstract

This disclosure relates to compositions and methods for treating cancer. Specifically, this disclosure relates to bexarotene derivatives, methods for treating cancer, autoimmune disorders, and / or skindermatitis, and / or methods for increasing peripheral blood counts and / or improving immune system function.

Description

[0001] Cross-references to related applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 637,387, filed March 1, 2018, which is incorporated by reference in its entirety. technical field [0003] The present disclosure relates to compositions and methods for treating cancer. In particular, the disclosure relates to bexarotene derivatives, methods of treating cancer, autoimmune diseases and / or dermatitis of the skin, and methods of increasing peripheral blood cell counts and / or improving immune system function. Background technique [0004] Cancer is the abnormal or uncontrolled growth of cells, often resulting in tumor formation, metastasis of cancer cells from one location to another, and death of the affected individual. Every year, more than ten million new cases are diagnosed worldwide. In addition, almost 10 million cancer-related deaths occur each year worldwide. Despite remarkable advances in understandi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/192C07C13/48C07C63/74
CPCC07C63/74C07C63/49A61K31/192C07C13/48A61P17/06C07C2602/10A61P35/02C07C63/66A61P35/00A61P17/00A61P5/14
Inventor D·蔡D·凯林
Owner 디제이테라퓨틱스엘엘씨
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