Spiroindoline derivatives for use as gonadotropin-releasing hormone receptor antagonists

A technology of indole and dioxide, applied in diseases, antineoplastic drugs, drug combinations, etc.

Inactive Publication Date: 2016-02-03
BAYER PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although non-peptide GnRH antagonists have been intensively researched for more than 15 years, none of them have successfully entered the market to date

Method used

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  • Spiroindoline derivatives for use as gonadotropin-releasing hormone receptor antagonists
  • Spiroindoline derivatives for use as gonadotropin-releasing hormone receptor antagonists
  • Spiroindoline derivatives for use as gonadotropin-releasing hormone receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0244] Preparation via Carbonyl Compounds: Step 1a Swern Oxidation

[0245] Preparation of 3,4,5,6-tetrahydro-2H-thiopyran-4-carbaldehyde

[0246]

[0247] 1.4 equivalents of oxalyl chloride (6.72 g, 52.9 mmol) were dissolved in 200 mL of dichloromethane, and the solution was cooled to -65°C. 2 equivalents of dimethylsulfoxide (5.91 g, 75.6 mmol) dissolved in 30 mL of dichloromethane were added dropwise over 10 minutes so that the temperature did not exceed -50°C. After 15 minutes, 1 equivalent of tetrahydrothiopyran-4-methanol (5.00 g, 37.8 mmol) dissolved in 30 mL of dichloromethane was added dropwise over 5 minutes at a temperature up to -45°C. The mixture was stirred for 1 h and warmed to -30 °C. 3 equivalents of triethylamine (11.5 g, 113 mmol) were added dropwise, then the mixture was allowed to warm to room temperature. After stirring for 1 h, the mixture was poured into water and extracted with dichloromethane. The combined organic phases were washed with water,...

Embodiment 1

[0424] 2-cyclopropyl-1-[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]methyl}-1,2, 2',3',5',6'-hexahydrospiro[indole-3,4'-thiopyran]-5-carboxamide 1',1'-dioxide

[0425]

[0426] With a slightly modified method to GP9.1: 100 mg (0.208 mmol) of intermediate F.1 and 83.5 mg (0.313 mmol, 1.5 equiv) of 1-[ 3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]methylamine dihydrochloride was reacted with 119 mg (0.313 mmol, 1.5 equiv) of HATU in 3.5 mL of DMF at room temperature overnight to yield 122 mg (89%) desired amide. The crude product was not subjected to further purification. 1 H-NMR (300MHz, DMSO-d6): chemical shift [ppm] = 0.21-0.33 (m, 1H), 0.34-0.66 (m, 3H), 0.78-0.90 (m, 1H), 0.94-1.08 (m, 1H), 1.46(dt, 1H), 3.63(dt, 1H), 4.36(d, 1H), 4.69(d, 2H), 7.40(m, 2H), 7.58(m, 1H), 7.80-7.96(m, 4H), 8.28 (m, 1H), 8.79 (s, 1H), 9.14 (t, 1H). UPLC-MS(ESI+): [M+H] + =656.

[0427] The enantiomer of the racemic substance of Example 1 was passed through chiral p...

Embodiment 11

[0428] Example 1.1, (2S)-2-cyclopropyl-1-[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl] Methyl}-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-thiopyran]-5-carboxamide 1',1'-dioxide: Rt=3.06min (enantiomer 1)

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Abstract

Spiroindoline derivatives, processes for their preparation and pharmaceutical compositions thereof, their use for the treatment of diseases, and their use for the manufacture of medicaments for the treatment of diseases, especially sex-hormone-related diseases in both men and women, in particularly those selected from the group of endometriosis, uterine leiomyoma (fibroids), polycystic ovarian disease, menorrhagia, dysmenorrhea, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrope pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception, infertility and assisted reproductive therapy such as in vitro fertilization. The present application relates in particular to spiroindoline derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists.

Description

technical field [0001] The present invention relates to spiroindoline derivatives of formula (I) as gonadotropin-releasing hormone (GnRH) receptor antagonists [0002] [0003] in [0004] x = 0, 1 or 2; [0005] R 1 selected from halogen, hydroxyl, C 1 -C 4 -Alkyl, halo-C 1 -C 4 -Alkyl, C 1 -C 4 -Alkoxy, halo-C 1 -C 4 -Alkoxy, CN, C(O)NH 2 ; [0006] R 2 selected from halogen, hydroxyl, C 1 -C 4 -Alkyl, halo-C 1 -C 4 -Alkyl, C 1 -C 4 -Alkoxy, halo-C 1 -C 4 - alkoxy, CN; [0007] R 3 selected from halogen, hydroxyl, C 1 -C 4 -Alkyl, halo-C 1 -C 4 -Alkyl, C 1 -C 4 -Alkoxy, halo-C 1 -C 4 - alkoxy, CN; [0008] But N-[(3-chloro-5-fluoropyridin-2-yl)methyl]-2-cyclopropyl-1-[(4-fluorophenyl)sulfonyl]-1,2,2',3 ',5',6'-hexahydrospiro[indole-3,4'-thiopyran]-5-carboxamides except 1',1'-dioxides, involving spiroindolines containing formula (I) Pharmaceutical compositions of indole derivatives and methods of treating diseases by administering spiroindo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/10A61K31/407A61P5/04
CPCC07D495/10A61P1/04A61P15/00A61P15/16A61P15/18A61P25/20A61P35/00A61P37/02A61P43/00A61P5/04A61P5/06A61P5/24
Inventor O·潘科宁S·灵S·布勒A·瓦根费尔德R·纳博迈耶K·诺瓦克-雷皮尔G·兰格
Owner BAYER PHARMA AG
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