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3-aminoalkaneacylamino-rutaecarpine and 3-aminoalkaneacylamino-7,8-dehydrorutaecarpine derivative

An aminoalkanoylamide group and evodiamine technology, which can be used in drug combinations, organic active ingredients, muscular system diseases, etc., can solve the problem of no significant improvement in butyrylcholinesterase activity, and achieve strong inhibitory activity, high selective effect

Inactive Publication Date: 2009-12-09
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

At the same time, the latest research found that the activity of butyrylcholinesterase in the synapses of patients with Alzheimer's disease did not increase significantly

Method used

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  • 3-aminoalkaneacylamino-rutaecarpine and 3-aminoalkaneacylamino-7,8-dehydrorutaecarpine derivative
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  • 3-aminoalkaneacylamino-rutaecarpine and 3-aminoalkaneacylamino-7,8-dehydrorutaecarpine derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 Synthesis of 3-(2-chloroacetamido)-evodiamine

[0027] Add 1.5g 3-amino-evodiamine and 0.83g K in 90mL dichloromethane 2 CO 3 , add 5 mL of methylene chloride containing 0.48 mL of chloroacetyl chloride dropwise at room temperature, heat to reflux for 4 hours after the dropwise addition, cool, filter, wash with methylene chloride and water successively, and obtain 1.5 g of a green solid after drying. 77%. mp 281.6-284.3°C; 1 H-NMR (400MHz, DMSO-d 6 ): δ11.86(s, 1H), 10.67(s, 1H), 8.49(d, J=2.1, 1H), 7.98(dd, J=8.8, 2.3, 1H), 7.67(dd, J=16.1, 8.4, 2H), 7.48 (d, J=8.3, 1H), 7.26 (t, J=7.7, 1H), 7.09 (t, J=7.5, 1H), 4.46 (t, J=6.8, 2H), 4.32 (s, 2H), 3.18 (t, J=6.8, 2H); ESI-MS: m / z 379 [M+1] + .

[0028] The structural formula of synthetic compound 1 is as follows:

[0029]

Embodiment 2

[0030] Example 2 Synthesis of 3-(2-chloropropionamido)-evodiamine

[0031] In 90mL of dichloromethane, add 1.5g 1.5g 3-amino-evodiamine and 0.83gK 2 CO 3 , add 5 mL of dichloromethane containing 0.53 mL of 3-chloropropionyl chloride dropwise at room temperature, heat to reflux for 4 hours after the dropwise addition, cool, filter, wash with dichloromethane and water successively, and dry to obtain 1.8 g of green solid, producing Rate 90%. mp 275.4-277.0°C; 1 H-NMR (400MHz, DMSO-d 6 ): δ11.84 (s, 1H), 10.44 (s, 1H), 8.51 (d, J=2.3, 1H), 8.00 (dd, J=8.8, 2.4, 1H), 7.66 (dd, J=14.1, 8.4, 2H), 7.49 (d, J=8.2, 1H), 7.26 (t, J=7.5, 1H), 7.09 (t, J=7.4, 1H), 4.46 (t, J=6.8, 2H), 3.93 (t, J = 6.2, 2H), 3.17 (t, J = 6.8, 2H), 2.89 (t, J = 6.2, 2H); ESI-MS: m / z 393 [M+1] + .

[0032] The structural formula of synthetic compound 2 is as follows:

[0033]

Embodiment 3

[0034] Example 3 Synthesis of 3-(2-acetylamino)-7,8-dehydroevodiamine

[0035] Add 0.76g 3-(2-chloroacetamido)-evodiamine to 50mL of dioxane, heat and stir; dissolve 0.54g DDQ in 5mL of dioxane, and slowly add it dropwise to the reaction solution; After the dropwise addition, heat and reflux for 4 hours, collect the precipitate by filtration, treat the precipitate with KOH solution (1.5g KOH dissolved in 25mL water) several times until all DDQ-2H is removed, and dry the obtained solid in vacuum to obtain 0.39g of light brown solid , yield 52%. mp299.6-302.4℃; 1 H-NMR (400MHz, DMSO-d 6 ): δ12.68(s, 1H), 10.69(s, 1H), 8.71(s, 1H), 8.61(d, J=7.4, 1H), 8.16(d, J=7.9, 1H), 8.07(d , J=8.8, 1H), 7.84 (dd, J=14.0, 8.3, 2H), 7.69 (d, J=8.2, 1H), 7.49 (t, J=7.5, 1H), 7.29 (t, J=7.4 , 1H), 4.34(s, 2H); ESI-MS: m / z 377[M+1] + .

[0036] The structural formula of synthetic compound 3 is as follows:

[0037]

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Abstract

The invention discloses a 3-aminoalkaneacylamino-rutaecarpine and 3- aminoalkaneacylamino-7,8-dehydrorutaecarpine derivative and a synthetic method and an appliance thereof. As shown in experiments, the 3-aminoalkaneacylamino-rutaecarpine and 3-aminoalkaneacylamino-7,8-dehydrorutaecarpine derivative of the invention has strong inhibition perforance on acetylcholine esterase and good inhibition selectivity and the inhibition ability to acetylcholine esterase is 500 times higher than that to butyrylcholine esterase. The compound is shown to have an application prospect of being the medicines for curing Alzheimer's disease, cerebral vascular dementia, etc.

Description

technical field [0001] The invention relates to a derivative of 3-aminoalkanoyl-evodiamine and 3-aminoalkanoyl-7,8-dehydroevodiamine and its synthesis method and application. Background technique [0002] Acetylcholinesterase (AChE) is a key enzyme in biological nerve transmission. In cholinergic synapses, this enzyme degrades acetylcholine, terminates the excitatory effect of neurotransmitter acetylcholine on the post-synaptic membrane, and ensures that nerve signals are transmitted in biological Normal delivery in the body. Cholinesterase is divided into acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) according to the specificity of its catalytic substrate. AChE, known as true or specific cholinesterase, is the most important hydrolase for maintaining cholinergic nerve impulses in the body. BuChE is called pseudo or non-specific cholinesterase, which belongs to the serine esterase family, and is mainly distributed in serum and liver, with a small amount in ...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/519A61P43/00A61P25/28A61P27/06A61P21/04
Inventor 黄志纾古练权王彬黄世亮
Owner SUN YAT SEN UNIV
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