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Spiroindoline derivatives as gonadotropin-releasing hormone receptor antagonists

A technology of compound and alkyl, which is applied in the field of disease treatment, can solve the problem that the activity of GnRH receptor antagonist is not described, etc.

Inactive Publication Date: 2014-11-26
BAYER IP GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Spiroindoline derivatives are known in the art as pharmaceutical active ingredients and in the field of crop science as insecticides, but their activity as GnRH receptor antagonists has not been described so far

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0602] N-[(3-chloropyridin-2-yl)methyl]-1-[(4-fluorophenyl)sulfonyl]-2-methyl-1,2,2',3',5',6 ′-Hexahydrospiro[indole-3,4′-pyran]-5-carboxamide

[0603]

[0604] According to GP 9.1, 250 mg (0.62 mmol) of intermediate F.3 and 105 mg (0.74 mmol, 1.2 eq) of 1-(3-chloro Pyridin-2-yl)methanamine (CAS No. [500305-98-6]) was reacted with 280 mg (0.74 mmol, 1.2 equiv) of HATU in 10 mL DMF to yield 300 mg (84%) of the desired amide. 1 H-NMR (300MHz, DMSO-d6): chemical shift [ppm]=-0.02(d, 1H), 0.97-1.08(m, 1H), 1.25(d, 3H), 1.67(d, 1H), 1.96- 2.08(m, 1H), 3.32-3.50(m, 3H), 3.79-3.87(m, 1H), 4.50(q, 1H), 4.63(d, 2H), 7.33(dd, 1H), 7.35-7.41( m, 2H), 7.54 (d, 1H), 7.76 (d, 1H), 7.81 (dd, 1H), 7.87-7.92 (m, 3H), 8.44 (dd, 1H), 8.80 (t, 1H). UPLC-MS(ESI+): [M+H] + =530 / 532 (chlorine isotope pattern).

[0605] The enantiomers of the racemic material of Example 1 were analyzed by chiral preparative HPLC (System: Dionex: Pump P 580, Gilson: Liquid Handler 215) , Nuoer Company (Knauer...

Embodiment 11

[0606] Example 1.1: R t =17.81min;

Embodiment 12

[0607] Example 1.2: R t =23.01min;

[0608] Table 1 Applying the indicated general procedures, the following examples (3 to 11) were prepared in analogy to example 1 starting from intermediate F.3 and commercially available amines. Example 2 was prepared from intermediate C.5 according to the given procedure.

[0609]

[0610]

[0611]

[0612] Example 12

[0613] N-(2-chlorobenzyl)-2-cyclopropyl-1-[(4-fluorophenyl)sulfonyl]-1,2,2',3',5',6'-hexahydrospiro[ Indole-3,4′-thiopyran]-5-carboxamide

[0614]

[0615] With GP 10: Dissolve 2.70 g (5.60 mmol) of intermediate C.1 in 40 mL 1,4-dioxane (containing 0.1 mL water) and add 2.38 g (3 equiv.) of 2-chlorobenzyl Amine (CAS No. [89-97-4]), 1.48 g (1 equivalent) of molybdenum hexacarbonyl, 1.78 g (3 equivalents) of sodium carbonate, 162 mg (0.1 equivalent) of tri-tert-butylphosphonium tetrafluoroborate and 126 mg (0.1 equivalent) palladium(II) acetate. The mixture was heated to reflux for 18h (bath temperature wa...

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PUM

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Abstract

Spiroindoline derivatives, process for their preparation and pharmaceutical compositions thereof, their use for the treatment and / or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, especially sex-hormone-related diseases in both men and women, in particularly those selded from the group of endometriosis, uterine fibroids, polycystic ovarian disease, 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 and infertility (e.g., assisted reprodudive 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 as gonadotropin-releasing hormone (GnRH) receptor antagonists, to pharmaceutical compositions comprising the spiroindoline derivatives of the present invention, and to methods for breastfeeding in need thereof. Methods of administering the spiroindoline derivatives of the invention to animals, especially humans, for the treatment of disorders. Background technique [0002] Gonadotropin-releasing hormone (GnRH) is a decapeptide released by the hypothalamus (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 ), also known as luteinizing hormone-releasing hormone (LHRH). GnRH acts on the pituitary gland to stimulate the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released by the pituitary gland is responsible for regulating gonadal steroid production in both sexes, late ovarian follicle development and ovulation in female mammals, and FSH regulates ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107C07D495/10A61K31/4439A61K31/407A61P5/04A61P15/18
CPCC07D495/10C07D491/107A61P1/00A61P11/00A61P13/08A61P15/00A61P15/08A61P15/16A61P15/18A61P17/00A61P35/00A61P37/02A61P43/00A61P5/00A61P5/04A61P5/06A61P5/08A61P5/24
Inventor O·潘科宁S·鲍尔勒S·灵W·施韦德W·博恩K·诺瓦克-雷皮尔E·本德R·纳博迈耶M·J·格诺斯
Owner BAYER IP GMBH
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