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

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: 2022-06-28
NANJING GENTAI PHARMA TECH CO LTD
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  • 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

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1: 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 give crude 2 (771 mg, 99.5%) which was used in the next step without purification.

[0083] (2) 2-((S)-1-phenethyl)-2-aza-bicyclo[2,2,1]heptane-7(R)-carbamic acid tert-butyl ester 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 give 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); 2.85...

Embodiment 2

[0089] Example 2: Synthesis of Intermediate I-2

[0090]

[0091] 4-Chloro-7-(benzenesulfonyl)-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) portionwise at 0 °C, stirred for 20 min, and then PhSO was added 2 Cl (1.12 g, 6.53 mmol), stirred at room temperature for 2 hours. Poured into water (20 mL) and extracted with EA (2×20 mL). Separate the organic phase with anhydrous Na 2 SO 4 It was dried, filtered and concentrated, purified by column chromatography, eluted with EA / PE=1 / 4 solvent to give 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] Example 3: Synthesis of Compound A-3

[0095] 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]hept-7(R )-ylcarbamate tert-butyl ester A-1

[0098]

[0099] A mixture of compound 1-2 (304 mg, 1.04 mmol), compound 1-1 (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 (2×20 mL). Separate the organic phase with anhydrous Na 2 SO 4 It was dried, filtered and concentrated, purified by column chromatography, eluted 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 temperature for 2 h...

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Abstract

The invention belongs to the field of medicine, and discloses (1R,4R,7R)-7-amino-2-azabicyclo[2,2,1]heptane derivatives and preparation methods, including: (S1) compound I-1 and I-2 undergoes nucleophilic aromatic substitution reaction to obtain compound A-1; (S2) compound A-1 is deprotected with hydrochloric acid or trifluoroacetic acid to obtain compound A-2; (S3) compound A-2 and organic acid or acid chloride Coupling reaction, or reaction with amine and solid phosgene, or reaction with amine and carbonyldiimidazole to obtain (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 present invention can avoid inhibiting JAK2, and selectively inhibit JAK1 or JAK1 / Tyk2, which has The treatment of autoimmune diseases is of great significance.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a (1R,4R,7R)-7-amino-2-azabicyclo[2,2,1]heptane derivative and a preparation method and application thereof. Background technique [0002] The JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines and is 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, including 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 regions of the receptor's intr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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
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