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Trisubstituted thiophenes as progesterone receptor modulators

A compound and substituent technology, applied in the field of new tri-substituted thiophene derivatives, can solve problems such as side effects

Inactive Publication Date: 2007-12-12
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sometimes, however, side effects (such as breast tenderness, headache, depression, and weight gain) have been reported with these steroid-bound progestogens alone or in combination with estrogenic compounds

Method used

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  • Trisubstituted thiophenes as progesterone receptor modulators
  • Trisubstituted thiophenes as progesterone receptor modulators
  • Trisubstituted thiophenes as progesterone receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] A, 1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-pyridin-4-yl-ethylthione

[0114]

[0115] 1-Pyridin-4-yl-ethanone (12.1g, 0.1mol), sulfur (3.36g, 0.105mol) and 1,4-dioxa-8-aza-spiro[4.5]decane were mixed with p-toluene The sulfonic acid (0.50 g, 2.8 mmol) was mixed and heated to 120°C for 3 hours. The slurry was poured into methanol (50 mL). A pale yellow solid precipitated out. The solid precipitate was filtered and washed with another 20 mL of methanol. The solid was dried to give the product (24 g, 86.3%).

[0116] 1 H NMR (CD 3 OD) δ8.41(m, 2H), 7.42(m, 2H), 4.35(m, 4H), 3.91(m, 4H), 3.78(m, 2H), 1.80(m, 2H), 1.48(m, 2H). MS (m / z): 279 (MH + ).

[0117] B, 1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridine-4- yl-propenthione

[0118]

[0119] 1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-pyridin-4-yl-ethylthione (20g, 72mmol), triethyl orthoformate (21.3g, 144mol), morpholine (48g, 55mmol) were stirred at 125°C for 4 hours. The solvent...

Embodiment 2

[0127] [5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(4- Fluoro-phenyl)-methanone

[0128]

[0129] With 1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propenthione and 2 Starting from -bromo-1-(4-fluoro-phenyl)-ethanone, the title product was prepared in 33% yield as described in Example 1C.

[0130] 1 H NMR (CDCl 3 )δ8.61 (dd, J=1.5 and 4.6Hz, 2H), 7.86-7.83 (m, 2H), 7.53-7.50 (m, 3H), 7.20-7.15 (m, 2H), 3.98 (s, 4H) , 3.23(t, J=5.7Hz, 4H), 1.83(t, J=5.7Hz, 4H); MS(m / z): 425(MH + ).

Embodiment 3

[0132] (4-fluoro-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl- Thiophen-2-yl]-methanone

[0133]

[0134] With 1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propenthione (374.5 mg, 1 mmol) and 2-bromo-1-(4-chloro-phenyl)-ethanone (233 mg, 1 mmol), the title product was prepared in 29% yield as described in Example 1C.

[0135] 1 H NMR

[0136] (CDCl 3 )δ8.62-8.58 (m, 2H), 7.78-7.74 (m, 2H), 7.52-7.45 (m, 5H), 3.98 (s, 1H), 3.24 (t, J=5.7Hz, 4H), 1.83 (t, J=5.8Hz, 4H); MS (m / z): 441 (MH + );

[0137] HRMS: C 23 h 21 ClN 2 o 3 MH of S + The theoretical value is 441.1039; the measured value is 441.1025.

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Abstract

The present invention is directed to novel trisubstituted thiophene derivatives, pharmaceutical compositions containing them and their use in the treatment or prevention of disorders and diseases mediated by agonists and antagonists of the progesterone receptor. The clinical usage of these compounds are related to hormonal contraception, the treatment and / or prevention of secondary dysmenorrhea, amenorrhea, dysfunctional uterine bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon or prostate. Additional uses of the invention include stimulation of food intake.

Description

field of invention [0001] The present invention relates to novel trisubstituted thiophene derivatives, pharmaceutical compositions containing them and their use in the treatment or prevention of conditions and diseases mediated by progesterone receptor agonists and antagonists. The clinical uses of these compounds relate to hormonal contraception, treatment and / or prevention of secondary dysmenorrhea, amenorrhea, dysfunctional uterine bleeding, uterine leiomyoma, endometriosis; polycystic ovary syndrome; endometrium, ovarian , breast, colon, prostate cancer and adenocarcinoma. Additional uses of the invention include stimulating food intake. Background of the invention [0002] Intracellular receptors are a class of structurally related proteins involved in the regulation of gene proteins. Steroid receptors are those receptors including progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (M...

Claims

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Application Information

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IPC IPC(8): C07D409/14C07D409/04C07D333/36C07D491/10A61K31/4535
CPCC07D491/10C07D409/04C07D409/14A61P1/14A61P15/00A61P15/18A61P35/00A61P43/00
Inventor W·蒋J·J·菲奥尔德利索Z·隋
Owner JANSSEN PHARMA NV
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