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Fused cyclic gamma-amino acid derivative, preparation method of fused cyclic gamma-amino acid derivative, and application of fused cyclic gamma-amino acid derivative to pharmaceuticals

A compound and cycloalkyl technology, applied in the field of fused-ring γ-amino acid derivatives, can solve the problems of low safety, dependence, and patients with abuse

Active Publication Date: 2017-07-07
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, for gabapentin, the proportion of improving the pain of patients with diabetic peripheral neuropathy is about 60% (Acta Neurol. Scand. 101:359-371, 2000), for pregabalin, although its tolerance is better than gabapentin , but its safety is lower, and it has the possibility of abuse or making patients dependent (Am J Health SystPharm.2007; 64(14):1475-1482)

Method used

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  • Fused cyclic gamma-amino acid derivative, preparation method of fused cyclic gamma-amino acid derivative, and application of fused cyclic gamma-amino acid derivative to pharmaceuticals
  • Fused cyclic gamma-amino acid derivative, preparation method of fused cyclic gamma-amino acid derivative, and application of fused cyclic gamma-amino acid derivative to pharmaceuticals
  • Fused cyclic gamma-amino acid derivative, preparation method of fused cyclic gamma-amino acid derivative, and application of fused cyclic gamma-amino acid derivative to pharmaceuticals

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Example 1: (±)-2-((1R,5R,6S)-6-(aminomethyl)spiro[bicyclo[3.2.0]heptane-3,1'-cyclopropane]-6-yl) Acetic acid (compound 1)

[0118] (±)-2-((1R,5R,6S)-6-(aminomethyl)spiro[bicyclo[3.2.0]heptane-3,1'-cyclo propan]-6-yl)acetic acid

[0119]

[0120] The first step: (±)-2-((1S,5R)-bicyclo[3.2.0]hept-2-en-6-ylidene)ethyl acetate (1B)

[0121] (±)-ethyl 2-((1S,5R)-bicyclo[3.2.0]hept-2-en-6-ylidene)acetate

[0122] Sodium hydride (60%, 2.2g, 55.5mmol) and tetrahydrofuran (40mL) were added into the reaction flask, the temperature was lowered to 0°C, and a tetrahydrofuran solution (5mL ), dropwise, and keep warm for 1 hour, add dropwise a tetrahydrofuran solution (5mL) of bicyclo[3.2.0]hept-2-en-6-one (1A) (5g, 46.2mmol), dropwise, rise to room temperature for reaction 2 hours. Add water (50mL) and ethyl acetate (50mL) to the reaction solution, stir and separate the liquids, extract the aqueous phase with ethyl acetate (30mL×2), combine the organic phases, dry over anhydro...

Embodiment 2

[0208] Example 2: (±)-2-((1R,5R,6S)-6-(aminomethyl)spiro[bicyclo[3.2.0]heptane-3,1'-cyclobutane]-6-yl ) acetic acid (compound 2)

[0209] (±)-2-((1R,5R,6S)-6-(aminomethyl)spiro[bicyclo[3.2.0]heptane-3,1'-cyclobutan]-6-yl)acetic acid

[0210]

[0211] The first step: (±)-(1R,2S,3S,5R)-2-bromospiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolane]-3- Alcohol (2B)

[0212] (±)-(1R,2S,3S,5R)-2-bromospiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-3-ol

[0213] Add (±)-(1S,5R)-spiro[bicyclo[3.2.0]hept[2]ene-6,2'-[1,3]dioxolane](2A) (9.0g , 59.14mmol), add acetone (90mL) and water (45mL) to dissolve, add N-bromosuccinimide (12.63g, 70.96mmol) under stirring at room temperature, and continue stirring at room temperature for 5 hours. Concentrate to dryness under reduced pressure, add ethyl acetate (100 mL) and water (100 mL), stir and separate the layers, extract the aqueous phase with ethyl acetate (100 mL×2), combine the organic phases, wash with saturated brine (150 mL×1), The orga...

Embodiment 3

[0270] Example 3: (±)-2-((1R,5R,6S)-6-(aminomethyl)spiro[bicyclo[3.2.0]heptane-2,1'-cyclopropane]-6-yl) Acetic acid (compound 3)

[0271] (±)-2-((1R,5R,6S)-6-(aminomethyl)spiro[bicyclo[3.2.0]heptane-2,1'-cyclopropan]-6-yl)acetic acid

[0272]

[0273] The first step: (±)-(1'R,2'S,4'R,6'R)-3'-oxaspiro[[1,3]dioxolane-2,7'-tricyclo[4.2 .0.0 2,4 ]octane](3A)

[0274] (±)-(1'R,2'S,4'R,6'R)-3'-oxaspiro[[1,3]dioxolane-2,7'-tricyclo[4.2.0.02,4]octane]

[0275] Add (±)-(1S,5R)-spiro[bicyclo[3.2.0]hept[2]ene-6,2'-[1,3]dioxolane](2A)(2.7 g, 18.0mmol) and dichloromethane (50mL), m-chloroperoxybenzoic acid (6.2g, 36.0mmol) was added in portions at room temperature, and reacted at room temperature for 2 hours. Add dichloromethane (100mL) and 2M aqueous sodium thiosulfate (100mL) to the reaction solution, stir for 30 minutes, separate the layers, extract the aqueous phase with dichloromethane (50mL×2), combine the organic phases, and wash with 2M hydrogen Wash with sodium oxide solu...

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Abstract

The invention relates to a fused cyclic gamma-amino acid derivative, a preparation method of the fused cyclic gamma-amino acid derivative, and an application of the fused cyclic gamma-amino acid derivative to pharmaceuticals, and particularly relates to the fused cyclic gamma-amino acid derivative shown as in the formula (I), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt or co-crystal of the fused cyclic gamma-amino acid derivative, a pharmaceutical composition comprising the fused cyclic gamma-amino acid derivative, and the application of the compound or composition to the field of analgesia, wherein the definitions of various substituent groups in the formula (I) and the definitions in the description are the same.

Description

technical field [0001] The present invention relates to a fused ring γ-amino acid derivative represented by general formula (I), or its stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and its drug Composition and use in the field of analgesia. Background technique [0002] Voltage-gated calcium channels are composed of α1 subunits and accessory proteins α2δ, β, and γ subunits. α2δ protein can regulate the density and voltage-dependent dynamics of calcium channels (Felix et al(199 7) J.Neuroscience 17:6884-6891; Klugbauer et al(1999) J.Neuroscience 19:684-691; Hobom et al. al (2000) Eur. J. Neuroscience 12:1217-1226; and Qin et al (2002) Mol. Pharmacol. 62:485-496). Compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α2δ have been shown to be effective in the treatment of pain, such as pregabalin and gabapentin. In mammals, there are four subtypes of α2δ protein, each of which is encoded ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/28A61K31/195A61P25/04A61P25/06A61P29/00A61P25/08A61P25/22A61P25/14
CPCC07C229/28C07C229/50Y02P20/55
Inventor 李瑶石宗军李升陈雷肖至阳
Owner SICHUAN HAISCO PHARMA CO LTD