Indole sulfonamide modulators of progesterone receptors

一种烷基、C1-C6的技术，应用在含有效成分的医用配制品、药物组合、性疾病等方向，能够解决没有描述有效治疗孕酮受体配体、子宫内膜异位症有效性有效性低、有效性低等问题

Inactive Publication Date: 2009-02-25
ELI LILLY & CO
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] None of the above documents describe effective treatments for abnormal tissue growth or compounds that can be used as progesterone receptor ligands
In addition, the compounds exhibit one or more undesirable characteristics, including low bioavailability, low binding affinity for progesterone, and often non-specific binding to hormone receptors, i.e., lack of progesterone receptors (PR ) specific binding, and generally no or low effectiveness in the treatment of tumors, more specifically in the treatment of fibroids, leiomyomas and endometriosis

Method used

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  • Indole sulfonamide modulators of progesterone receptors
  • Indole sulfonamide modulators of progesterone receptors
  • Indole sulfonamide modulators of progesterone receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 178

[0175] Example 178 N-[3-(6-cyano-5-fluoro-pyridin-3-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide

[0176] Method X will N 2 Bubble through N-[1-isopropyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H- Indol-6-yl]-methanesulfonamide (0.186g, 0.493mmol), 5-bromo-2-cyano-3-fluoropyridine (0.090g, 0.448mmol), K 3 PO 4 (1.3M) (0.60ml), and a mixture of dioxane (1.2ml) for 5 minutes. Add tricyclohexylphosphine (3.0 mg, 0.011 mmol) and Pd 2 (dba) 3 (4.1 mg, 0.0045 mmol). The tube was sealed and stirred at 100°C for 18 hours. After cooling to room temperature, extract with EtOAc and wash with NaHCO 3 washing. MgSO for organic phase 4 dry. The crude residue was purified using silica gel chromatography to afford 0.112 g (67% yield) of the title compound, MS: 373.0 (M+H)

[0177] N-[3-(3,5-Difluoro-4-hydroxymethyl-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide

[0178] Method S: Weigh N-(3-bromo-1-isopropyl-1H-indol-6-yl)-methanesulfonamide (100mg, 0.302mmol...

Embodiment 289

[0290] Example 289 N-[3-(5-cyano-4-fluoro-thiophen-2-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide

[0291]N-[3-(4-Chloro-5-cyano-thiophen-2-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (Example 118 ) (0.15g, 0.381mmol) and CsF (0.324g, 2.13mmol) in DMSO (5ml) was heated at 150°C for 6 hours. The mixture was cooled to 21 °C and diluted with EtOAc. The mixture was washed with water, brine, and MgSO 4 dry. The material was filtered and concentrated to dryness. The crude product was purified by reverse phase chromatography to afford 5 mg of the title compound. MS:378.0(MH+)

Embodiment 290

[0292] Example 290 2-fluoro-4-(1-isopropyl-6-methanesulfonylamino-1H-indol-3-yl)-thiobenzamide:

[0293] Add one drop of di-isopropylethylamine and one drop of water to the solution containing N-[3-(4-cyano-3-fluoro-phenyl)-1-isopropyl-1H-indol-6-yl] - Methanesulfonamide (100 mg, 0.27 mmol) in 10 mL of dimethoxyether. Heat to reflux, then add O,O'-diethyl dithiophosphate (151 mg, 0.81 mmol) and reflux overnight in a sealed tube. The solvent was evaporated. The residue was purified using silica gel chromatography eluting with a gradient of EtOAc and hexanes to afford 99 mg (91%) of the desired product.

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Abstract

Compounds of Formula (I), wherein n is 1 or 2, and R1, R2, R3, R4, R5, R6, R7, and R8 are as defined herein, their preparation, pharmaceutical compositions, and methods of use are disclosed.

Description

technical field [0001] The invention relates to the fields of medicinal organic chemistry, pharmacology and medicine. In addition, the present invention relates to novel compounds and methods for the treatment of tumors, gynecological diseases, and related symptoms and sequelae. Background technique [0002] Leiomyomas are the most common noncancerous tumors in women of reproductive age. Uterine leiomyomas (or uterine fibroids) are considered benign tumors of muscle and connective tissue that develop in or adhere to the uterine wall. It is estimated from ultrasonography that more than 70% of women will develop uterine fibroids by the time they reach menopause (Baird et al. Am J. Obstet. Gynecol .2005;188:100-107; and Cramer et al., Am. J. Clin Pathol .1990;90:435-438.). Although not all women exhibit symptoms that justify treatment, many experience moderate to severe symptoms, including abnormal uterine bleeding, pelvic pressure and pain, and reproductive dysfunction. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10C07D209/12C07D209/14C07D209/18C07D209/24C07D401/04C07D403/04C07D403/10C07D405/04C07D409/04C07D409/14C07D413/04C07D417/04A61K31/404A61P35/00
CPCC07D209/18C07D417/04C07D403/04C07D405/04C07D409/14C07D413/04C07D409/04C07D209/12C07D403/10C07D209/14C07D209/10C07D209/24C07D401/04A61P15/00A61P15/08A61P31/00A61P35/00A61P43/00A61P5/24A61P5/34A61K31/404
Inventor T·J·布莱施C·A·克拉克J·A·多奇S·A·琼斯J·E·罗佩斯C·W·卢加三世B·S·米尔T·I·理查森余迎广游国龙
Owner ELI LILLY & CO
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