Deuterated tetrahydrothieno [3, 4-d] pyrimidinedione compound and pharmaceutical composition containing same

A technology of tetrahydrothiophene and pyrimidinedione, applied in the field of medicine, can solve the problems of slow progress of GnRH inhibitor research and other problems

Pending Publication Date: 2021-11-19
SUZHOU ZELGEN BIOPHARML +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although gonadotropin-releasing hormone is one of the important targets in drug development for gynecological diseases, in addition to peptide gonadotropin-releasing hormone analogs such as Triptorelin and Alarelin, and Relugolix and Elagolix, etc. Except for a few newly marketed gonadotropin-releasing hormone inhibitor drugs, the research progress of GnRH inhibitors is still relatively slow

Method used

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  • Deuterated tetrahydrothieno [3, 4-d] pyrimidinedione compound and pharmaceutical composition containing same
  • Deuterated tetrahydrothieno [3, 4-d] pyrimidinedione compound and pharmaceutical composition containing same
  • Deuterated tetrahydrothieno [3, 4-d] pyrimidinedione compound and pharmaceutical composition containing same

Examples

Experimental program
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preparation example Construction

[0112] The preparation method of compound VI is shown in the following synthetic route 2:

[0113]

[0114] In an inert solvent (such as dichloromethane), the compound of formula XII and m-chloroperoxybenzoic acid undergo Bayer-Villiger oxidative rearrangement, and then further hydrolyze to obtain compound VI; wherein, R 8 , R 9 , R 10 , R 12 The definition is the same as before.

[0115] The preparation method of compound X is shown in the following synthetic route three:

[0116]

[0117] Active amide ester formula X is formed by acylation of the compound of formula XIII; wherein, R 11 The definition is the same as before.

[0118] Pharmaceutical compositions and methods of administration

[0119] Since the compound of the present invention has excellent inhibitory activity on gonadotropin-releasing hormone, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compou...

Embodiment 1

[0139] Example 1 prepares 3-(5-((2,3-difluoro-6-(methoxy-d 3 )phenyl)methoxy-d 2 )-2-fluoro-4-(methoxy-d 3 )phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 1)

[0140]

[0141] 1. Preparation of 2,3-difluoro-6-(methoxy-d 3 ) methyl benzoate (compound 3)

[0142] At room temperature, compound 2,3-difluoro-6-hydroxybenzoic acid (5.0g) and N,N-dimethylformamide (30ml) were added to the reaction flask, stirred and dissolved, and the reaction solution was clarified; potassium carbonate ( 12.2g), stirred for 30min, slowly added deuteroiodomethane (10.0g) dropwise, after the dropwise addition, the temperature was raised to 40°C, stirred for 15-20h, and detected by thin layer chromatography; after the reaction was completed, water (60ml), ethyl acetate Esters (60ml), stirred for 30min, extracted twice, combined organic phases, washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain an oily ...

Embodiment 2

[0167] Example 2 Preparation of 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy-d 2 )-2-fluoro-4-(methoxy-d 3 )phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 17)

[0168]

[0169] By the method described in Example 1, the difference is: in the steps from formula (II) to formula (III) according to the synthetic route, replace deuteromethyl iodide (CD) with methyl iodide 3 1), thereby obtaining target compound 17. 1 H NMR (400MHz, DMSO-d 6 )δ:14.55(s,1H),12.02(s,1H),7.51-7.44(m,1H),7.40(s,1H),7.26(d,J=7.2Hz,1H),7.13(d,J =11.6Hz, 1H), 6.93-6.90(m, 1H), 3.81(s, 3H). ESI-MS m / z 514[M+H] + .

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Abstract

The invention relates to a deuterated tetrahydrothieno [3, 4-d] pyrimidinedione compound and a pharmaceutical composition containing the compound. Specifically, the invention discloses the deuterated tetrahydrothieno [3, 4-d] pyrimidinedione compound shown as a formula (I) and a pharmaceutical composition containing the compound, or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. The compound provided by the invention can be used for treating and / or preventing gonadotropin releasing hormone (GnRH) dependent related diseases, such as hysteromyoma, endometriosis, hysterofibroma, amenorrhea, premenstrual syndrome and the like.

Description

technical field [0001] The invention belongs to the field of medicine. Specifically, the present invention relates to a novel deuterated tetrahydrothieno[3,4-d]pyrimidinedione compound and a pharmaceutical composition containing the compound. Background technique [0002] Gonadotropn-releasing hormone (GnRH) is a kind of hormone secreted by the hypothalamus, which stimulates or inhibits the secretion of pituitary gonadotropin and plays an important role in the regulation of vertebrate reproduction. [0003] Tetrahydrothieno[3,4-d]pyrimidinedione compounds and their derivatives are a class of gonadotropin-releasing hormone inhibitors. A series of tetrahydrothieno[3,4-d]pyrimidinedione derivatives are disclosed in the patent WO2007042392, wherein the compound Linzagolix is ​​a selective GnRH inhibitor with a chemical name of 3-(5-((2,3- Difluoro-6-methoxyphenyl)methoxy)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3 ,4-d] pyrimidine-5-carboxylic acid has the...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/519A61K45/06A61P35/00A61P9/00A61P29/00A61P31/00A61P37/00A61P31/12A61P3/00A61P13/08A61P15/08A61P25/20A61P17/10A61P17/14A61P1/00A61P17/00
CPCC07D495/04A61K31/519A61K45/06A61P35/00A61P9/00A61P29/00A61P31/00A61P37/00A61P31/12A61P3/00A61P13/08A61P15/08A61P25/20A61P17/10A61P17/14A61P1/00A61P17/00C07B2200/05A61K2300/00A61P15/00
Inventor 吕彬华李成伟杨金庚宋赠
Owner SUZHOU ZELGEN BIOPHARML
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