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Isotopically enriched 3-amino-1-propanesulfonic acid derivative and use thereof

An isotope enrichment and amino acid technology, applied in the direction of isotope introduction of heterocyclic compounds, isotope introduction of acyclic/carbocyclic compounds, medical preparations containing active ingredients, etc., can solve the problem of reduced reaction rate

Active Publication Date: 2018-10-09
RISEN SUZHOU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If C-1H bond cleavage is the rate-determining step in a metabolic reaction, then replacing hydrogen with deuterium will result in a decrease in the rate of the reaction

Method used

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  • Isotopically enriched 3-amino-1-propanesulfonic acid derivative and use thereof
  • Isotopically enriched 3-amino-1-propanesulfonic acid derivative and use thereof
  • Isotopically enriched 3-amino-1-propanesulfonic acid derivative and use thereof

Examples

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preparation example Construction

[0126] The preparation of the pharmaceutical composition can be carried out by methods known in the art (for example, referring to Remington: The Science and Practice of Pharmacy, 20 th Edition, 2000). For example, therapeutic compounds and / or compositions are combined with one or more pharmaceutical carrier substances and / or additives (or auxiliary substances) in solid or liquid form and, if desired, with other active compounds having a therapeutic or prophylactic effect, to form A suitable mode of administration or dosage form is then administered as a drug in humans or animals. Preparation of medicament can add many additives known in the art, such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, Flavoring agents, fragrances, thickeners, diluents, buffers, solvents, solubilizers, agents for depot effect, salts for changing osmotic pressure, coating agents or antioxidants, etc.

[...

Embodiment 1

[0169] Example 1: Synthesis of 3-amino-3,3-dideuterium-1-propanesulfonic acid (1) and 3-amino-3,3-dideuterium-1-propanesulfonic acid sodium salt (1s)

[0170] A solution of 3-hydroxypropionitrile (26.0g, 366mmol, 1.0eq.) in anhydrous THF (50mL) was slowly dropped into the solution containing LiAlD 4 (10.0 g, 238 mmol, 0.65 eq.) in anhydrous THF (200 mL), the reaction mixture was stirred under reflux overnight. After the reaction was cooled to room temperature, water (4.8 mL), 15% NaOH aqueous solution (4.8 mL) and water (14.4 mL) were added sequentially to quench, and stirred at room temperature for 2 hours, then filtered to remove solid impurities. The filtrate was concentrated under reduced pressure and dried to obtain a red oily liquid which was directly used in the next reaction without further purification.

[0171] The oily liquid (10.0g, 128mmol, 1.0eq.) was dissolved in 100mL of chloroform solution, stirred in an ice bath and slowly dropped into thionyl chloride (18.2...

Embodiment 2

[0174] Example 2: Synthesis of 3-((L-alanyl)amino)-3,3-dideuterium-1-propanesulfonic acid (2)

[0175]Compound 1s (0.30 g, 1.84 mmol, 1.0 eq.) and N-tert-butoxycarbonyl-L-alanine (0.37 g, 2.0 mmol, 1.1 eq.) were mixed in anhydrous DMF (10 mL). Add N,N'-dicyclohexylcarbodiimide (DCC, 0.56g, 2.7mmol, 1.5eq.) and 1-hydroxybenzotriazole (HOBt, 0.24g, 1.80mmol, 1.0eq. .) Stir overnight at room temperature. After adding water (2 mL), stirring was continued for one hour, the insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude white solid. The solid was dissolved in water (20 mL), extracted twice with ethyl acetate, the aqueous phase was concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain a white solid 3-((N-Boc-L-alanyl)amino 0.50 g of sodium )-3,3-dideuterium-1-propanesulfonate, and the yield was 81.3%. The white solid (0.50 g, 1.50 mmol, 1.0 eq.) was dissolved in 1...

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Abstract

The invention relates to isotopically enriched compounds of formula I, pharmaceutically acceptable salts or esters thereof, pharmaceutical compositions thereof and use thereof for prevention and treatment of amyloid beta-protein related diseases, such as use for Alzheimer's disease. R1R2X-CR2-CH2-CH2-SO3H (I).

Description

technical field [0001] The present invention relates to isotopically enriched 3-amino-1-propanesulfonic acid (3APS) and its derivatives, composition, and application thereof in preventing and treating Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD) is a progressive degenerative disease of the brain mainly associated with aging. In 2000, the prevalence of AD in the United States was close to 4.5 million. It is estimated that about one in ten individuals over the age of 65 and nearly half of those over the age of 85 have Alzheimer's disease. In the United States alone, approximately 360,000 patients are diagnosed with AD each year. [0003] The clinical manifestations of AD are characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and language abilities are also affected, until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C309/14C07C309/15C07D233/64C07C323/60A61K31/205A61K31/417A61P25/00A61P25/28
CPCC07C309/14C07C309/15C07C323/60C07D233/64C07B2200/05A61P25/28A61P25/00A61P25/16C07B59/001C07B59/002C07D233/61Y02P20/55C07C309/59
Inventor 吕佳声顾家敏吕新勇宋国伟吴冬冬胡代强顾俊陈刚吉祥张秀春艾进超孔宪起
Owner RISEN SUZHOU PHARMA TECH CO LTD
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