Tetrahydroisoquinoline derivative, and preparation method and medical application thereof

A technology of compounds and mixtures, applied in the field of medicine

Inactive Publication Date: 2020-08-07
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently listed SERMs include Tamoxifen, Raloxifene, Bazedoxifene, Toremifene, etc., but studies have found that the currently listed SERMs still have severe For example, long-term use of tamoxifen and toremifene can cause endometrial hyperplasia, polyps and endometrial cancer, while common side effects of raloxifene include hot flashes, leg pain, breast swelling and pain, and vein Embolism, etc.

Method used

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  • Tetrahydroisoquinoline derivative, and preparation method and medical application thereof
  • Tetrahydroisoquinoline derivative, and preparation method and medical application thereof
  • Tetrahydroisoquinoline derivative, and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0398] N-(3,5-difluoro-4-((1S,3R)-3-methyl-6-(1H-pyrazol-4-yl)-2-(2,2,2trifluoroethyl) -1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)-1-(3-fluoropropyl)azetidinyl-3-amine 1

[0399]

[0400]

[0401] first step

[0402] (R)-tert-butyl(1-(3-(benzyloxy)phenyl)propyl-2-yl)carbamate 1c

[0403] Dissolve benzyloxy-3-bromobenzene 1a (4.00g, 15.20mmol) in tetrahydrofuran (45mL), under argon protection, stir well, add n-butyllithium (15.20mmol, 9.5mL, 1.6M), -78°C Stir for 30 minutes. Then (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide 1b (3.60g, 15.17mmol, using the patent application "WO2016162325, implemented (prepared by the method disclosed in Example 1") was dissolved in 20 mL of tetrahydrofuran, the above solution was added to the reaction solution, and the reaction was stirred at -78°C for 0.5 hours. When the temperature was slowly raised to 0°C, the reaction was stopped after stirring in an ice bath for 30 minutes. The reaction was q...

Embodiment 2

[0451] N-(3,5-difluoro-4-((1S,3R)-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2-(2,2,2 -Trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)-1-(3-fluoropropyl)azetidinyl-3-amine 2

[0452]

[0453] Using the synthetic route of compound 1 in Example 1, the raw material compound 1r was replaced by the raw material compound 1-methyl-4-pyrazole boronic acid pinacol ester 2r (94mg, 451.78μmol), anhydrous sodium carbonate (56mg, 528.36umol ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17mg, 23.23umol) and compound 1q (140mg, 225.97umol) were reacted to obtain the title compound 2 (60mg), Yield: 39%.

[0454] MS m / z(ESI):552.2[M+1]

[0455] 1 H NMR (400MHz, CD 3 OD)7.91(s,1H),7.77(s,1H),7.26(s,1H),7.20(d,1H),6.71(d,1H),6.18-6.12(m,2H),5.18(s, 1H),4.74-4.64(m,1H),4.62(t,1H),4.50(t,1H),4.48-4.34(m,2H),4.22-4.12(m,1H),3.97-3.93(m, 1H),3.90(s,3H),3.58-3.50(m,1H),3.48-3.39(m,2H),3.37-3.33(m,1H),3.29-3.23(m,1H),2.97-2.86( m,1H),2.65(dd,1H),2.08-1.95(m,2H),1.07(d,...

Embodiment 3

[0457] N-(4-((1S,3R)-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)- 1,2,3,4-Tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidinyl-3-amine

[0458]

[0459] Using the synthetic route of compound 1 in Example 1, the raw material compound 1r was replaced by the raw material compound 1-ethyl-4-pyrazole borate pinacol ester 3r (100 mg, 450.27 μmol), anhydrous sodium carbonate (56 mg, 528.36 μmol ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17mg, 23.23umol) and compound 1q (140mg, 225.97umol) were reacted to obtain the title compound 3 (40mg), Yield: 31%.

[0460] MS m / z(ESI):566.3[M+1]

[0461] 1 H NMR (400MHz, CD 3 OD)7.93(s,1H),7.77(s,1H),7.28(s,1H),7.21(d,1H),6.72(d,1H),6.07(d,2H),5.15(s,1H) ,4.52(t,1H),4.41(t,1H),4.19(q,2H),4.10-4.04(m,1H),3.86-3.82(m,2H),3.55-3.51(m,1H),3.38 -3.34(m,1H),3.28-3.20(m,1H),3.07-3.03(m,2H),2.98-2.87(m,1H),2.70(t,2H),2.63(dd,1H),1.84 -1.71(m,2H),1.47(t,3H),1.07(d,3H).

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Abstract

The invention relates to a tetrahydroisoquinoline derivative, and a preparation method and medical application thereof. Particularly, the invention relates to the tetrahydroisoquinoline derivative asshown in a general formula (I), the preparation method of the tetrahydroisoquinoline derivative, a pharmaceutical composition containing the tetrahydroisoquinoline derivative, the application of the tetrahydroisoquinoline derivative as an estrogen receptor modulator, and the application of the tetrahydroisoquinoline derivative in preparation of drugs for treating estrogen receptor mediated or dependent diseases or symptoms. Each substituent in the general formula (I) is as defined in the specification.

Description

technical field [0001] The disclosure belongs to the field of medicine, and relates to a tetrahydroisoquinoline derivative, its preparation method and its application in medicine. In particular, the present disclosure relates to tetrahydroisoquinoline derivatives represented by general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as estrogen receptor modulators to treat estrogen receptor Use in a mediated or dependent disease or condition, particularly preferably breast cancer. Background technique [0002] After long-term basic research and clinical monitoring, it has been found that diseases such as breast cancer, ovarian cancer, osteoporosis, schizophrenia, and Alzheimer's are closely related to abnormal estrogen signaling pathways. Estrogen is a steroid hormone secreted by the endocrine system, which plays an important role in the reproductive system, bone tissue, cardiovascular, immune system and centr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/12A61K31/4725A61P35/00A61P35/02A61P25/00A61P9/00A61P7/00A61P29/00A61P37/00A61P31/00A61P3/00A61P15/00A61P25/06A61P25/32A61P9/12A61P9/10A61P7/02A61P19/02A61P1/16A61P31/20A61P19/10A61P3/04A61P13/02A61P25/28A61P25/16A61P25/18A61P25/24
CPCA61K31/4725A61P1/16A61P3/00A61P3/04A61P7/00A61P7/02A61P9/00A61P9/10A61P9/12A61P13/02A61P15/00A61P19/02A61P19/10A61P25/00A61P25/06A61P25/16A61P25/18A61P25/24A61P25/28A61P25/32A61P29/00A61P31/00A61P31/20A61P35/00A61P35/02A61P37/00C07D401/12C07D401/14
Inventor 杨方龙樊兴陈刚贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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