Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor

A technology of deuterated thiazolidinone and solvate, applied in the field of deuterated thiazolidinone analogs, can solve problems such as not mentioned

Inactive Publication Date: 2014-10-22
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, the prior art does not mention substituting one or more hydrogen (H) atoms in the above-mentioned reference compounds with deuterium (D)

Method used

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  • Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor
  • Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor
  • Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161] Example 1: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1,1,2,2-d 4 -2-(4-Hydroxy-3-methoxyphenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide

[0162]

[0163] step 1:

[0164]

[0165] Reference is made to the methods described in WO02 / 09705 and WO02 / 09706.

[0166] To a solution of 4-(phenylethynyl)benzaldehyde (2.8g, 13.6mmol, 1eq) in acetonitrile (240ml) was added (S)-2-mercaptosuccinic acid (6.12g, 40.8mmol, 3eq) and 3 - Aminobenzamide (1.85 g, 13.6 mmol, 1 eq). The reaction was stirred at 83°C for 3 days. The reaction was cooled and filtered to give a solid. with saturated Na 2 CO 3 The solution adjusted the solid to pH = 8-9, and extracted with ethyl acetate (50ml X3). The aqueous phase was adjusted to pH = 3-4 with 4N HCl, and filtered to obtain a solid. The solid was washed with ethanol (10ml) and acetonitrile (10ml) to give the title compound as a pale yellow solid (3g, 51.7%).

[0167] Step 2:

[0168]

[0169] Reference is ma...

Embodiment 2

[0173] Example 2: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1,1,2,2-d 4 -2-(3,4-dimethoxyphenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide

[0174]

[0175] To 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1,1,2,2- d 4 -2-(4-hydroxy-3-methoxyphenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide ( Example 1) (25.00 mg; 0.04 mmol; 1.00 eq.) Potassium carbonate (0.04 g; 0.27 mmol; 6.50 eq.) and dimethyl sulfate (0.18 μl; 0.008 mmol; 0.04 eq.) were added. The reaction was stirred overnight at room temperature. The desired product was isolated by flash chromatography (10 g, KPNH, 0 to 20% methanol / DCM) to give the product as a white solid (8.9 mg, 35%).

[0176] 1 H NMR (500MHz, cd 3 od) δ7.83–7.78 (m, 1H), 7.69–7.64 (m, 1H), 7.50–7.30 (m, 11H), 6.81 (dd, J=5.0, 3.1, 2H), 6.74 (dd, J= 8.2, 2.0, 1H), 6.42(s, 1H), 4.53–4.47(m, 1H), 3.76(t, J=4.6, 6H), 3.10(dd, J=15.3, 4.1, 1H), 2.89(dd , J=15.3, 8.5, 1H).

[0177] m / z: 624; 625 [M+H] + .

Embodiment 3

[0178] Example 3: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1,1,2,2-d 4 -2-(3-methoxy-4-(methoxy-d 3 )phenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide

[0179]

[0180] According to the procedure similar to Example 2, from 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1,1,2,2-d 4 -2-(4-hydroxy-3-methoxyphenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide ( 35.00mg; 0.06mmol; 1.00eq.) and dimethyl sulfate-d 6 (2.92 μl; 0.03 mmol; 0.50 eq.) to prepare the product. The reaction was stirred overnight at room temperature. The desired product was isolated by flash chromatography (10 g, KPNH, 0 to 20% methanol / DCM) to give the product as a white solid (22.3 mg, 63%).

[0181] 1 H NMR (500MHz, cd 3 od) δ7.83–7.79 (m, 1H), 7.70–7.65 (m, 1H), 7.48–7.30 (m, 11H), 6.83–6.77 (m, 2H), 6.74 (dd, J=8.2, 2.0, 1H), 6.42(s, 1H), 4.53–4.47(m, 1H), 3.75(s, 3H), 3.10(dd, J=15.2, 4.1, 1H), 2.89(dd, J=15.3, 8.5, 1H ).

[0182] m / z: 626; 627 [M+H] + .

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Abstract

The present invention relates to deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor and their use for treating fertility disorders.

Description

technical field [0001] The present invention relates to deuterated thiazolidinone analogues useful as follicle stimulating hormone receptor agonists and their use in the treatment of fertility disorders. Background of the invention [0002] Gonadotropins play an important role in many bodily functions including metabolism, temperature regulation and reproductive processes. Gonadotropins act on specific types of gonad cells to initiate ovarian and testicular differentiation and steroid production. The gonadotropin FSH (follicle stimulating hormone) is released by the anterior pituitary gland under the influence of gonadotropin-releasing hormone and beta-hormone, and by the placenta during pregnancy. FSH is a heterodimeric glycoprotein hormone with a similar structure to luteinizing hormone (LH) and thyroid-stimulating hormone (TSH) and chorionic gonadotropin (CG), where LH and TSH are produced in the pituitary gland , while CG is produced in the placenta. In women, FSH pla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/14A61K31/426A61P15/08C07B59/00
CPCC07B59/002C07D277/14C07B2200/05A61K31/426A61P15/00A61P15/08A61P43/00A61B17/435
Inventor H·余M·唐纳利
Owner MERCK PATENT GMBH
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