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1,1a,6,6a-tetrahydrocycloprop[a]indene-1-amine derivatives and preparation method and applications thereof

A technology of amine derivatives and cyclopropanes, which is applied in the preparation of carboxylic acid amides, the preparation of amino compounds, the preparation of organic compounds, etc., can solve the problems of low inhibitory activity and poor selectivity.

Active Publication Date: 2019-03-29
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, phenylcyclopropylamine is the most studied class of inhibitors. The disadvantages are low inhibitory activity and poor selectivity to homologous enzymes such as monoamine oxidase and LSD2.

Method used

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  • 1,1a,6,6a-tetrahydrocycloprop[a]indene-1-amine derivatives and preparation method and applications thereof
  • 1,1a,6,6a-tetrahydrocycloprop[a]indene-1-amine derivatives and preparation method and applications thereof
  • 1,1a,6,6a-tetrahydrocycloprop[a]indene-1-amine derivatives and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0251] Example 1: Preparation of (trans)-1,1a,6,6a-tetrahydrocyclopropane[a]inden-1-amine (1)

[0252] (a) Ethyl (trans)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate (1a) and (cis)-1,1a,6,6a-tetrahydrocyclo Preparation of ethyl propane[a]indene-1-carboxylate (1a')

[0253] Indene (3.42g, 26.30mmol) and rhodium acetate dimer (115mg, 0.26mmol) were added to 50mL of dichloromethane, ethyl diazoacetate (2.0mL, 39.45mmol) was added under reflux, and the solution Stir at 45°C for 3 hours, then overnight at room temperature, remove the solvent in vacuo, and purify by silica gel column chromatography (petroleum ether / ethyl acetate=100:1) to give 1a and 1a' as colorless oils, 3.35g (59 %), directly used in the next step reaction.

[0254] (b) tert-butyl (trans)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carbamate (1b) and (cis)-1,1a,6,6a-tetrahydro Preparation of tert-butyl cycloprop[a]indene-1-carbamate (1b')

[0255] 1a and 1a' (3.35g, 15.49mmol) were added to 20mL MeOH, ...

Embodiment 2

[0258] Embodiment 2: the preparation of (cis)-1,1a,6,6a-tetrahydrocyclopropane[a]inden-1-amine (2)

[0259] The preparation method of 2 was the same as that of 1 in Example 1, except that 1b' (300mg, 1.16mmol) was used instead of 1b to obtain 2, a yellow solid, 213mg (94%). 1 H NMR (400MHz, Methanol-d 4 )δ7.38–7.35(m,1H),7.20–7.13(m,3H),3.26(d,J=6.9Hz,1H),3.09(d,J=17.7Hz,1H),2.85(dt,J =7.3,1.6Hz,1H),2.22(tdd,J=7.0,2.5,0.9Hz,1H),2.04(t,J=2.1Hz,1H). 13 C NMR (101MHz, Methanol-d 4 )δ143.1, 142.7, 128.1, 127.8, 126.3, 125.1, 37.0, 35.4, 30.6, 22.7.

Embodiment 3

[0260] Example 3: Preparation of (trans)-N-(2-methoxybenzyl)-1,1a,6,6a-tetrahydrocyclopropane[a]inden-1-amine (3)

[0261] 1 (50 mg, 0.26 mmol) was dissolved in 2.0 mL MeOH at room temperature and triethylamine (39 mg, 0.39 mmol) was added to give the free amine. Then 2-methoxybenzaldehyde (35mg, 0.26mmol) was added to the solution, magnetically stirred for 30min, 4A molecular sieves were added, stirred for 15min, sodium borohydride (30mg, 0.78mmol) was added, and reacted for 16 hours. The mixture was then filtered and the solvent removed in vacuo to give the crude product, dissolved in ethyl acetate, saturated NaHCO 3 Wash, collect the organic phase, anhydrous Na 2 SO 4 It was dried, filtered and concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / ethyl acetate=4:1) to give 3, yellow oil, 26 mg (40%). 1 H NMR (400MHz, Chloroform-d) δ7.25–7.17(m,3H),7.11–7.01(m,3H),6.91–6.83(m,2H),3.96–3.79(m,5H),3.15(dd ,J=17.0,7.0Hz,1H),2.91(d,J=17.1H...

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Abstract

The invention belongs to the technical field of medicine, and discloses a 1,1a,6,6a-tetrahydrocycloprop[a]indene-1-amine derivative which is represented as formula (I) and a preparation method and applications thereof. The 1,1a,6,6a-tetrahydrocycloprop[a]indene-1-amine derivatives provided by the invention has good inhibitory activity against LSD1, has good selectivity for homologous enzymes suchas monoamine oxidase and LSD2, and is expected to develop into therapeutic medicine for diseases such as acute myeloid leukemia.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a 1,1a,6,6a-tetrahydrocyclopropane[a]indene-1-amine derivative and a preparation method and application thereof. Background technique [0002] Acute myeloid leukemia (AML) is a heterogeneous malignant tumor in hematopoietic tissue, characterized by abnormal proliferation of primitive and immature myeloid cells in bone marrow and peripheral blood, clinical manifestations are anemia, hemorrhage, infection and fever, visceral Infiltration, abnormal metabolism, etc. Most cases are acute and severe, and the prognosis is dangerous. If not treated in time, it can often be life-threatening. The prevalence of AML is 3.8 cases per 100,000 people, increasing to 17.9 cases per 100,000 people over the age of 65. The standard treatment paradigm for AML has changed little in more than 40 years, relying on conventional cytotoxic drugs to induce remission with 1-2 cycles of "induction" chemothera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/58C07C213/02C07C211/42C07C209/00C07D213/61C07D213/64C07C237/06C07C231/12C07D205/04C07D211/26A61K31/137A61K31/165A61K31/135A61K31/44A61K31/4465A61K31/445A61K31/397A61P35/02
CPCC07C211/42C07C217/58C07C237/06C07D205/04C07D211/26C07D213/61C07D213/64
Inventor 于丽芳周宇波林森栋沈岽皓计悦阳苏明波汪玉洁杨帆李佳汤杰
Owner EAST CHINA NORMAL UNIV
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