3-substituted acrylic acid compound as well as preparation method and application thereof

A compound and hydrate technology, applied in the field of medicine, can solve the problems of low efficacy and poor drug characteristics.

Active Publication Date: 2018-03-20
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Fulvestrant is currently the only SERDs drug approved for clinical use, but its drug-forming properties are poor, it must be injected intramuscularly, and its efficacy is low. The dose of 500mg / month can only reach less than 50% of patients Degradation of estrogen receptors (Wardell, et al., Biochem.Pharm., 2011, 82:122-130)

Method used

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  • 3-substituted acrylic acid compound as well as preparation method and application thereof
  • 3-substituted acrylic acid compound as well as preparation method and application thereof
  • 3-substituted acrylic acid compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] (E)-3-(3-fluoro-4-((1R,3R)-3-methyl-2-((1-methylcyclopropyl)methyl)-2,3,4,9-tetra Hydrogen-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (Compound 1)

[0136] Reaction route:

[0137]

[0138] The first step: (E)-3-(3-fluoro-4-formylphenyl)methyl acrylate (compound 1-2)

[0139] To a solution of 2-fluoro-4-bromobenzaldehyde (2.019 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol) in DMF (50 mL) was added palladium acetate (224 mg, 1 mmol), triphenylphosphine (1.048g, 4mmol) and methyl acrylate (1.6g, 20mmol), and stirred at 80°C for 12h. The post-processing crude product was subjected to silica gel column chromatography (EA:PE=5:1) to obtain compound 1-2 (2 g, yield 96%).

[0140] MS m / z(ESI): 209[M+H] + .

[0141] The second step: (1-methylcyclopropyl) formaldehyde (compound 1-4)

[0142] To a suspension of (1-methylcyclopropyl)methanol (500mg, 5.8mmol) and silica gel (500mg) in DCM (20mL) was added pyridinium chlorochromate (1.249g, 5.8mmol), then stirre...

Embodiment 2

[0154] (E)-3-(4-((1R,3R)-2-(cyclopropylmethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4 -b] indol-1-yl)-3-fluorophenyl)acrylic acid (compound 2)

[0155] Reaction route:

[0156]

[0157] Using a method similar to Example 1, replacing (1-methylcyclopropyl)methanol in Example 1 with cyclopropylmethanol, Compound 2 was obtained.

[0158] MS m / z(ESI):405[M+H] + .

[0159] 1 HNMR: (400MHz, CD 3 OD)δ: 7.58(d,J=16.0Hz,1H),7.51-7.47(m,2H),7.36–7.24(m,2H),7.14–7.01(m,3H),6.55(d,J=16.0 Hz,1H),5.75(s,1H),3.83(dd,J=12.1,6.8Hz,1H),3.15-3.08(m,1H),2.91(d,J=12.5Hz,1H),2.74(dd ,J=15.9,7.4Hz,1H),2.39(d,J=13.1Hz,1H),1.10-1.15(m,4H),0.54–0.44(m,2H),0.45–0.31(m,2H).

Embodiment 3

[0161] (E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((1-methylcyclopropyl)methyl)-2,3,4, 9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (Compound 3)

[0162]

[0163] Using a method substantially similar to Example 1, substituting 2,6-difluoro-4-bromobenzaldehyde for 2-fluoro-4-bromobenzaldehyde in Example 1, Compound 3 was obtained.

[0164] MS m / z(ESI):437[M+H] + .

[0165] 1 H NMR (400MHz, CD 3 OD) δ7.57(d, J=16.0Hz, 1H), 7.42(dd, J=6.9, 1.1Hz, 1H), 7.24–7.18(m, 3H), 7.04-6.95(m, 2H), 6.55( d,J=16.0Hz,1H),5.37(s,1H),3.87(dd,J=11.1,4.8Hz,1H),3.08(dd,J=15.1,3.6Hz,1H),2.68(dd,J =15.0,3.2Hz,1H),2.48(dd,J=27.8,12.9Hz,2H),1.31–1.29(m,1H),1.11(d,J=6.5Hz,2H),1.00(s,3H) ,0.42–0.33(m,2H),0.27-0.16(m,2H).

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Abstract

The invention provides a 3-substituted acrylic acid compound as well as a preparation method and application thereof and in particular relates to a 3-substituted acrylic acid compound, a stereoisomer,a pro-drug, a hydrate or pharmaceutically acceptable salt or ester thereof, and a pharmaceutical composition thereof as well as a preparation method and application thereof. The compound provided bythe invention can inhibit activity of an estrogen receptor, regulate expression level of the estrogen receptor down or induce degradation of the estrogen receptor and can be used for preventing or treating diseases related to overactivity of the estrogen receptor, especially estrogen receptor positive (ER+) drug-resistant diseases (such as breast cancer producing drug resistance to anti-estrogen therapy).

Description

technical field [0001] The present application relates to the field of medicine, specifically, the present application relates to 3-substituted acrylic compounds and their preparation methods and uses; more specifically, the present application relates to compounds as shown in formula I in inhibiting estrogen receptor activity, down-regulating estrogen receptor body expression level or inducing degradation of estrogen receptors; the application also relates to the use of compounds represented by formula I in the preparation of drugs for the prevention or treatment of diseases associated with estrogen receptor overactivity, especially estrogen receptor Body-positive (ER+) drug-resistant diseases (such as breast cancer resistant to anti-estrogen therapy, etc.). Background technique [0002] Estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) are steroid hormone receptors and members of a large family of nuclear receptors. Both receptors are involved in the regulati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4375A61P35/00A61P25/06A61P25/28A61P25/16A61P25/00A61P9/10A61P9/12A61P9/00A61P7/02A61P19/02A61P29/00A61P37/02A61P31/20A61P1/16A61P3/04A61P13/02A61P25/14A61P25/24A61P25/18A61P15/00A61P15/08
CPCC07D471/04
Inventor 刘钢于华董振文杜静王润江刘伟曾宏宋宏梅葛勇王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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