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2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-amine derivative as well as preparation method and application thereof

A technology of amine derivatives and cyclopropane, applied in the field of medicine, can solve the problems of poor selectivity and low inhibitory activity

Inactive Publication Date: 2018-09-14
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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  • 2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-amine derivative as well as preparation method and application thereof
  • 2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-amine derivative as well as preparation method and application thereof
  • 2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-amine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0185] Example 1: Preparation of 2', 3'-dihydrospiro[cyclopropane-1,1'-indene]-2-amine (1)

[0186] (a) Preparation of 1-methylene-2,3-dihydro-1H-indene (1a)

[0187] 2,3-Dihydro-1H-inden-1-one (4.00g, 30.30mmol) and triphenylmethylphosphine bromide (16.24g, 45.45mmol) were added to 20mL THF, and the A solution of 1.0M potassium tert-butoxide in THF (45.45mL, 45.45mmol) was added to the liquid funnel, the reaction solution was stirred at room temperature for 16 hours, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=100:1 ) to afford 1a as a colorless oil, 3.42g (87%).

[0188] (b) Ethyl (trans)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-carboxylate (1b) and (cis)-2',3'-dihydro Preparation of ethyl spiro[cyclopropane-1,1'-indene]-2-carboxylate (1b')

[0189] 1a (3.42g, 26.30mmol) and rhodium acetate dimer (115mg, 0.26mmol) were added to 5.0mL of dichloromethane, ethyl diazoacetate (2.0mL, 39.45mmo...

Embodiment 2

[0194] Example 2: Preparation of (cis)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-amine (2)

[0195] The preparation method of 2 was the same as that of 1 in Example 1, except that 1c' (300 mg, 1.16 mmol) was used instead of 1c to obtain 2, a yellow solid, 213 mg (94%). 1 H NMR (400MHz, CD 3 OD)δ7.32(d,1H),7.27–7.18(m,2H),7.10–7.03(m,1H),3.21–3.06(m,1H),3.02–2.92(m,1H),2.88(dd ,1H),2.40–2.27(m,1H),1.99–1.94(m,1H),1.54–1.47(m,1H),1.43(t,1H). 13 C NMR (101MHz, CD 3 OD)δ147.5, 140.4, 128.7, 127.7, 126.3, 121.9, 36.6, 35.0, 33.1, 31.5, 15.7.

Embodiment 3

[0196] Example 3: Preparation of (trans)-N-(pyridine-3-methyl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-amine (3)

[0197] 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 nicotinaldehyde (28 mg, 0.26 mmol) was added to the solution, stirred magnetically for 30 min, 4A molecular sieves were added, stirred for 15 min, sodium borohydride (20 mg, 0.52 mmol) 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, CD 3 OD)δ8.47(d,1H),8.42–8.37(m,1H),7.82–7.76(m,1H),7.35(dd,1H),7.16–7.10(m,1H),7.07–7.02(m ,2H),6.62–6.57(m,1H)...

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Abstract

The invention belongs to the technical field of medicine and discloses a 2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-amine derivative of a formula (I) as well as a preparation method thereof. The preparation method comprises the following steps: performing Witting reaction on II to obtain III, catalyzing cyclopropanation reaction of ethyl diazoacetate and the III by rhodium acetate to obtain IVand V, performing hydrolysis, performing Curtius rearrangement to obtain VI and VII; (1) removing Boc from the VI or VII and performing reduction and ammoniation to obtain a compound VIII or IX; or (2) performing substitution on the VI or VII and 2-chlorine-1-morpholine ethane-1-ketone to obtain X or XI; or (3) performing reduction and ammoniation on the VI or VII and (4-oxycyclohexyl)tert-butylcarbamate, and removing Boc to obtain a compound XII or XIII; or (4) performing Suzuki coupling on the VI or VII and substituted arylboronic acid, removing Boc to obtain XIV or XV, and performing reduction and ammoniation to obtain VIII or IX. The derivative of the formula (I) has high inhibition activity, has high selectivity on homologous enzyme such as monoamine oxidase and LSD2, and is expected to be developed into a medicine for treating diseases such as acute myelogenous leukemia.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a 2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-amine derivative and its preparation method and application, which can be used as a selective LSD1 inhibitor For the preparation of drugs for the treatment of acute myeloid leukemia. 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 o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/42C07C209/62C07D213/38C07D213/64C07D213/61C07C213/02C07C217/54C07D295/185
CPCC07C211/42C07C217/54C07D213/38C07D213/61C07D213/64C07D295/185
Inventor 于丽芳周宇波吴嫣然计悅阳石英沈岽皓苏明波李佳杨帆汤杰
Owner EAST CHINA NORMAL UNIV
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