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Substituted estratrien derivatives as 17beta hsd inhibitors

A technology of substituents and compounds, applied in the field of substituted estratriene derivatives, can solve problems such as no display

Inactive Publication Date: 2009-10-28
SOLVAY PHARMA GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds have been developed as selective inhibitors of the 17β-HSD5 enzyme and did not show significant inhibitory potential against the 17β-HSD1, 17β-HSD2 or 17β-HSD3 enzymes

Method used

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  • Substituted estratrien derivatives as 17beta hsd inhibitors
  • Substituted estratrien derivatives as 17beta hsd inhibitors
  • Substituted estratrien derivatives as 17beta hsd inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0940] Example 1: 15α-(4-morpholin-4-yl-4-oxobutyl)-17-oxoestro-1(10), 2,4-triene-3-carboxamide

[0941]

[0942] Example 1 According to the method described in Scheme 6B and 6C(I) and from 3-hydroxy-15α-(4-morpholin-4-yl-4-oxo-butyl)-estr-1,3, 5(10)-triene-17-ones were prepared, the detailed synthesis of which is described in International Patent Application WO2005 / 047303 (Example 40 therein) and can generally follow Route 1, Route 14 or 15 and Scheme Ia or the reaction of Ib to achieve.

[0943] 15α-(4-morpholin-4-yl-4-oxo-butyl)-3-trifluoromethanesulfonate-estro -1,3,5(10)-trien-17-one

[0944] Dissolve 5.4g of 3-hydroxy-15α-(4-morpholin-4-yl-4-oxo-butyl)-estro-1,3,5(10)-triene-17-one in 120ml without water in DCM. 10,72 g of 2,6-lutidine were added slowly. 6.76 g of trifluoromethanesulfonic anhydride in 40 ml of anhydrous DCM was added slowly at 0°C. After stirring at 0 °C for 30 min, the reaction mixture was kept at room temperature overnight and washed with H...

Embodiment 2

[0955] Example 2: 15α-(4-morpholin-4-yl-4-oxobutyl)-17-oxoestro-1(10), 2,4-triene-3-carboxylic acid

[0956]

[0957] Example 2 According to the method described in scheme 6B and from 3-hydroxy-15α-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)- Trien-17-ones start to be prepared, the detailed synthesis of which is described in International Patent Application WO2005 / 047303 (Example 40 therein) and can generally follow the reactions of Route 1, Route 14 or 15 and Scheme Ia or Ib to accomplish. The detailed synthesis method of Example 2 has been described during the synthesis of Example 1.

[0958] 13 C NMR (126MHz, chloroform-d)

[0959] δppm 15.6 (q, 1C) 23.7 (t, 1C) 26.2 (t, 1C) 27.6 (t, 1C) 29.5 (t, 1C) 31.6 (t, 1C) 33.1 (t, 1C) 36.2 (d, 1C) 36.3 (t, 1C) 39.2 (d, 1C) 42.1 (t, 1C) 43.1 (t, 1C) 45.0 (d, 1C) 46.1 (t, 1C) 50.3 (s, 1C) 54.8 (d, 1C) 66.6 (t , 1C) 67.0 (t, 1C) 126.0 (d, 1C) 127.0 (s, 1C) 127.5 (d, 1C) 130.6 (d, 1C) 136.5 (s, 1C) 145.7 (s, 1C) 170.8 (s, 1C)...

Embodiment 3

[0962] Example 3: 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxoestro-1(10), 2 , 4-triene-3-carboxamide

[0963]

[0964] Example 3 was prepared according to the methods described in Schemes 6B and 6C(I) and for Example 1 herein, from 3-(3-hydroxy-17-oxo-estro-1,3,5 Starting with (10)-triene-15β-yl)-N-(5-methyl-thiazol-2-yl)-propionamide, its detailed synthesis is described in International Patent Application WO2005 / 047303 (Example 329A ) and can generally be achieved by following the reactions of Scheme 1, Scheme 13 and Scheme Ia or Ib herein.

[0965] 3-(17-Oxo-3-trifluoromethanesulfonate-estra-1,3,5(10)-triene-15β- base)-N-(5-methyl-thiazol-2-yl)-propionamide

[0966] This intermediate was obtained from 3-(3-hydroxy-17-oxo-estro-1,3,5(10)-trien-15β-yl)-N-(5 -Methyl-thiazol-2-yl)-propionamide Preparation.

[0967] 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxo Estro-1(10), 2,4-triene-3-carboxylic acid methyl ester

[0968] 2 g of...

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Abstract

This invention relates to novel substituted estratrien derivatives of general formula (I) useful in therapy, especially for use in the treatment and / or prevention of a steroid hormone dependent disorder requiring the inhibition of a 17beta-hydroxysteroid dehydrogenase (17beta- HSD) type 1, type 2 and / or type 3 enzyme, as well as to their salts, to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds.

Description

field of invention [0001] The present invention relates to novel, substituted estratriene derivatives representing 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), type 2 (17β-HSD2) or type 3 (17β-HSD3) enzymes and to salts of these compounds, to pharmaceutical formulations containing these compounds and to processes for the preparation of these compounds. Furthermore, the present invention relates to the therapeutic use of said novel substituted estratriene derivatives, in particular they require inhibition of 17β-HSD1, 17β-HSD2 or 17β-HSD3 enzymes and / or reduction of endogenous Use of 17β-estradiol and / or androgen concentrations in steroid hormone-dependent diseases or conditions. Background of the invention [0002] The publications and other materials used herein serve to illustrate the background of the invention and, in particular, the cases which provide supplementary details relevant to the practice are incorporated herein by reference. [0003] Mammalian 17β-hy...

Claims

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Application Information

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IPC IPC(8): C07J41/00C07J43/00C07J51/00A61K31/565A61K31/58A61K31/566A61P5/32
CPCC07J41/0005C07J41/0044C07J51/00C07J43/003A61P1/04A61P3/10A61P5/14A61P5/24A61P5/28A61P5/32A61P5/38A61P11/06A61P13/02A61P13/08A61P15/00A61P15/16A61P17/00A61P17/02A61P17/04A61P17/06A61P17/08A61P17/10A61P17/14A61P19/02A61P19/10A61P21/04A61P25/00A61P25/28A61P27/02A61P29/00A61P35/00A61P37/02A61P37/06A61P37/08A61P43/00
Inventor J·梅辛格B·胡森U·肖恩H-H·托勒P·科斯基米斯M·昂基拉
Owner SOLVAY PHARMA GMBH
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