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Novel benzamide derivatives as modulators of the follicle stimulating hormone

A technology of solvates and compounds, applied in the field of new benzamide derivatives as follicle-stimulating hormone regulators, can solve the problems of inducing secondary effects, non-oral activity, etc.

Inactive Publication Date: 2010-03-24
ADDEX PHARM SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some current research attempts to develop steroid-based male contraceptives, but they are not orally active and may induce secondary effects (Peterson et al., Mol. Cell. Endocrin., 160, 203-217, 2000; Liu et al., Endocrine, 13, 361-367, 2000)

Method used

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  • Novel benzamide derivatives as modulators of the follicle stimulating hormone
  • Novel benzamide derivatives as modulators of the follicle stimulating hormone
  • Novel benzamide derivatives as modulators of the follicle stimulating hormone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0791] N-[4-(cyano-dimethyl-methyl)-phenyl]-3,4-dimethoxy-benzamide.

[0792] 1(A) 2-Methyl-2-(4-nitro-phenyl)-propionitrile.

[0793] to at 0°C and N 2 To a solution of (4-nitro-phenyl)-acetonitrile (5.00 g; 30.9 mmol) in dry DMF (30 mL) cooled under atmosphere was added gradually NaH (60% dispersion in mineral oil; 1.23 g; 30.9 mmol) and the mixture was stirred at 0 °C for 15 min. Iodomethane (1.92 mL; 30.9 mmol) was then added and the mixture was stirred at room temperature for 1.5 hours. The reaction was recooled at 0° C. and further NaH (60% dispersion in mineral oil; 1.23 g; 30.9 mmol) was added gradually. After stirring at 0 °C for 15 min, iodomethane (1.92 mL; 30.9 mmol) was added and the reaction was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was taken up with EtOAc, washed with brine, Na 2 SO 4 Dry with, filter and concentrate in vacuo. The crude product was purified by chromatography [SiO 2 , Petroleum ether / ...

Embodiment 2

[0804] N-[4-(1-cyano-cyclopropyl)-phenyl]-3,4-dimethoxy-benzamide.

[0805] 2(A) 1-(4-Nitro-phenyl)-cyclopropanenitrile.

[0806] KNO was cooled in an ice-acetone bath 3 (1.10g; 10.8mmol) in concentrated H 2 SO 4 (9 mL) was gradually added to 1-phenyl-cyclopropanenitrile (1.50 g; 10.8 mmol) in concentrated H 2 SO 4 (9 mL). The reaction was stirred at ambient temperature for 1.5 hours and then poured onto ice. The precipitate was filtered, dissolved in EtOAc and washed with water and then brine. use Na 2 SO 4 The organic phase was dried, filtered and evaporated in vacuo to give Title compound , as a yellow solid (1.30 g). This compound was used in the next step without any additional purification.

[0807] 2(B) 1-(4-Amino-phenyl)-cyclopropanenitrile.

[0808] According to Example 1(B) starting material was 1-(4-nitro-phenyl)-cyclopropanenitrile (1.30 g; 6.91 mmol) as prepared in Example 2(A), and using 10% Pd / C (20 mg) was prepared in MeOH (30 mL). The catal...

Embodiment 3

[0815] 2,3-Dihydro-benzo[1,4]dioxin-6-carboxylic acid [4-(1-cyano-cyclopentyl)-phenyl]-amide.

[0816] 3(A) 1-(4-Nitro-phenyl)-cyclopentanenitrile.

[0817] (4-Nitro-phenyl)-acetonitrile (6.00 g; 37.0 mmol) and 1,4-dibromo-butane (4.42 ml; 37.0 mmol) in DMSO / Et 2 A solution in O (20 mL / 20 mL) was added dropwise to a suspension of NaH (60% dispersion in mineral oil; 1.80 g; 81.4 mmol) in DMSO (20 mL), keeping the temperature below 30 °C. After stirring at room temperature for 1 day, the 2 O (5 mL) terminated the reaction. The mixture was concentrated in vacuo and the resulting aqueous solution was treated with 2N hydrochloric acid and washed with Et 2 O extracted three times. The organic layer was collected, washed with brine, washed with Na 2 SO 4Dry, filter and concentrate to dryness in vacuo. The crude compound was purified by chromatography [SiO 2 , Petroleum ether / EtOAc(9 / 1-8 / 2)] to get Title compound , as an orange solid (3.94 g; 50% yield).

[0818] LCMS (RT...

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Abstract

The present invention provides new compounds of formula I, wherein Q, R1, R2, R4, R5, R6, Xi, R7, R8, M and G1 n are defined as in formula I; inventi on compounds are modulators of follicle-stimulating hormone - ('FSH') which are useful for male and female contraception as well as other disorders modu lated by FSH receptor.

Description

Summary of the invention [0001] [0002] The present invention provides novel compounds of formula I, wherein Q, R 1 , R 2 , R 4 , R 5 , R 6 , X 1 , R 7 , R 8 , M and G 1 n As defined in Formula I; the compounds of the present invention are modulators of follicle stimulating hormone ("FSH") and are useful in male and female contraception and other FSH receptor modulated conditions. Background of the invention [0003] The present invention relates to compounds having negative allosteric modulator activity on the follicle stimulating hormone (FSH) receptor, in particular compounds of formula I, pharmaceutical compositions comprising them and the use of said compounds in medical therapy. [0004] Gonadotropins are involved in a variety of important bodily functions, including metabolism, temperature regulation, bone maintenance, and reproductive processes. The normal function of the ovaries and testes has long been considered dependent on the synthesis of gonadotr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/15C07C233/24
CPCC07C235/56C07C2101/08C07C235/60C07C311/08C07C2101/02C07C311/16C07C2601/02C07C2601/08A61P15/00A61P15/08A61P15/16A61P15/18A61P19/10A61P35/00C07C233/15C07C233/24A61K31/167
Inventor B·博内特B·卡姆珀L·拉维格里亚M·利卡波尼
Owner ADDEX PHARM SA
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