Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

(1R, 4R, 7R)-7-amino-2-azabicyclo [2, 2, 1] heptane derivative and preparation method thereof

A technology of azabicyclo and derivatives, which is applied in the field of 7-amino-2-azabicyclo[2,2,1]heptane derivatives and its preparation, and can solve the problem of red blood cells limiting the clinical dosage of drugs, etc.

Active Publication Date: 2021-11-26
NANJING GENTAI PHARMA TECH CO LTD
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the treatment of autoimmune diseases, although the clinical efficacy of JAK inhibitors becomes more significant as the dose increases, the side effects of reducing red blood cells due to JAK2 inhibition limit the clinical use of drugs (Genovese M.C., Smolen J.S., et al., Arthritis Rheumatol. 2016; 68:2857-2866; Milligan P.A., Brown M.J., et al., Clin. Pharmacol. Ther. 2013; 93:502-514; Keystone E.C., TaylorP .C. et al., Ann. Rheum. Dis. 2015; 74:333-340)

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • (1R, 4R, 7R)-7-amino-2-azabicyclo [2, 2, 1] heptane derivative and preparation method thereof
  • (1R, 4R, 7R)-7-amino-2-azabicyclo [2, 2, 1] heptane derivative and preparation method thereof
  • (1R, 4R, 7R)-7-amino-2-azabicyclo [2, 2, 1] heptane derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment 1: the synthesis of intermediate I-1

[0078] Synthetic route of intermediate I-1

[0079]

[0080] (1) 7(R)-amino-2-((S)-1-phenethyl)-2-aza-bicyclo[2,2,1]heptane 2

[0081]

[0082]A solution of compound 1 (1 g, 3.57 mmol) in a saturated solution of ammonia in methanol (10 mL) was stirred at 80°C for 2 hours. It was then concentrated to obtain crude 2 (771 mg, 99.5%), which was used in the next step without purification.

[0083] (2) tert-butyl 2-((S)-1-phenethyl)-2-aza-bicyclo[2,2,1]heptane-7(R)-carbamate 3

[0084]

[0085] To a solution of compound 2 (500 mg, 2.3 mmol) in DCM (20 mL) was added TEA (257 mg, 2.53 mmol) and Boc 2 O (555 mg, 2.53 mmol), then stirred at room temperature for 4 hours. It was concentrated and purified by column chromatography, eluting with a solvent of EA / PE=1:9 to obtain the desired compound 3 (444 mg, 61%). 1 HNMR (300MHz, DMSO): δ=7.15-7.30 (m, 5H); 6.71 (s, 1H); 4.00 (m, 1H); 3.50-3.60 (m, 2H); 3.05 (m, 1H); 2.8...

Embodiment 2

[0089] Embodiment 2: the synthesis of intermediate 1-2

[0090]

[0091] 4-Chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine I-2

[0092]

[0093] To a solution of compound 5 (1 g, 6.53 mmol) in THF (20 mL) was added NaH (391 mg, 9.79 mmol) in portions at 0 °C, stirred for 20 min, and then added PhSO 2 Cl (1.12 g, 6.53 mmol), stirred at room temperature for 2 hours. Poured into water (20 mL) and extracted with EA (2X20 mL). Separate the organic phase with anhydrous Na 2 SO 4 It was dried, filtered and concentrated, purified by column chromatography, and eluted with EA / PE=1 / 4 solvent to obtain compound I-2 (1.3 g, 68%). 1 H NMR (500MHz, CDCl 3 ): δ=8.82(s,1H); 8.26-8.27(d,2H,J=8.2Hz); 7.83-7.84(d,1H,J=3.95Hz); 7.68-7.71(m,1H); 7.57- 7.61 (m, 2H); 6.76-6.77 (d, 1H, J = 4.0 Hz).

Embodiment 3

[0094] Embodiment 3: the synthesis of compound A-3

[0095] The synthetic route of compound A-3

[0096]

[0097] (1) 2-(7-(Benzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-aza-bicyclo[2,2,1]heptane-7(R )-ylcarbamate tert-butyl ester A-1

[0098]

[0099] A mixture of compound I-2 (304 mg, 1.04 mmol), compound I-1 (220 mg, 1.04 mmol) and DIEA (268 mg, 2.08 mmol) in IPA (20 mL) was heated to 75° C. and stirred for 5 hours. Poured into water (20 mL) and extracted with EA (2X20 mL). Separate the organic phase with anhydrous Na 2 SO 4 It was dried, filtered and concentrated, and purified by column chromatography with EA / PE=1 / 4 solvent to give compound A-1 (381 mg, 81%). LC-MS m / z = 470.0 [M+1]+.

[0100] (2) 7(R)-amino-(7-(benzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-aza-bicyclo[2,2,1] Heptane A-2

[0101]

[0102] To a solution of compound A-1 (381 mg, 0.81 mmol) in MeOH (10 mL) was added 1 mL of 4M HCl in dioxane. The mixture was stirred at room tempe...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention belongs to the field of medicine, and discloses a (1R, 4R, 7R)-7-amino-2-azabicyclo [2, 2, 1] heptane derivative and a preparation method thereof. The preparation method comprises the following steps of: (S1) carrying out nucleophilic aromatic substitution reaction on compounds I-1 and I-2 to obtain a compound A-1; (S2) treating the compound A-1 with hydrochloric acid or trifluoroacetic acid for deprotection to obtain a compound A-2; and (S3) carrying out coupling reaction on the compound A-2 and organic acid or acyl chloride, or carrying out reaction on the compound A-2 and amine and triphosgene, or carrying out reaction on the compound A-2 and amine and carbonyl diimidazole to obtain the (1R, 4R, 7R)-7-amino-2-azabicyclo [2, 2, 1] heptane derivative. The (1R, 4R, 7R)-7-amino-2-azabicyclo [2, 2, 1] heptane derivative developed by the invention can avoid inhibition of JAK2 and selectively inhibit JAK1 or JAK1 / Tyk2, and has important significance in treatment of autoimmune diseases.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically relates to a (1R,4R,7R)-7-amino-2-azabicyclo[2,2,1]heptane derivative, a preparation method and application thereof. Background technique [0002] JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines, involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Many cytokines and growth factors signal through the JAK-STAT signaling pathway, this includes interleukin 2-7 (IL-2-7), GM-CSF (granulocyte / macrophage colony-stimulating factor), GH (growth hormone) , EGF (epidermal growth factor), PDGF (platelet-derived factor) and IFN (interferon) and so on. The JAK protein family includes four members: JAK1, JAK2, JAK3 and Tyk2. Binding of cytokines to receptors results in the formation of dimers or higher aggregates, allowing the recruitment of a pair of JAK kinases to the intracellular domain of ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D487/04C07D403/14C07D403/04C07D401/14A61K31/519A61K31/506A61P37/06A61P35/00A61P29/00A61P37/08A61P25/28A61P19/02A61P17/06A61P11/06A61P17/00A61P27/02A61P1/04A61P1/00A61P3/10A61P19/08A61P35/02
CPCC07D487/04C07D403/14C07D403/04C07D401/14A61P37/06A61P35/00A61P29/00A61P37/08A61P25/28A61P19/02A61P17/06A61P11/06A61P17/00A61P27/02A61P1/04A61P1/00A61P3/10A61P19/08A61P35/02
Inventor 沈宇校登明陈荣耀
Owner NANJING GENTAI PHARMA TECH CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com