Amino alcohol compounds, their preparation methods, pharmaceutical compositions containing such compounds and their uses

A compound and composition technology, applied in the fields of medicinal chemistry and pharmacotherapy, can solve the problems of large side effects, short half-life, anorexia, etc.

Inactive Publication Date: 2019-02-15
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, TSA and VPA have disadvantages such as relatively large side effects, short half-life, and low bioavailability.
SAHA, which has been approved for marketing, can also cause anorexia, weight loss, venous thrombosis, sudden cardiac death, gastrointestinal reactions, etc., and can only be used as an anti-tumor drug, but cannot be used for the treatment of benign diseases - polycystic kidney disease
[0006] In addition, studies have shown that Sphingosine-1-phosphate (S1P) is very similar in structure to SAHA and is an endogenous HDACs inhibitor, but the physical and chemical properties of S1P make it less druggable

Method used

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  • Amino alcohol compounds, their preparation methods, pharmaceutical compositions containing such compounds and their uses
  • Amino alcohol compounds, their preparation methods, pharmaceutical compositions containing such compounds and their uses
  • Amino alcohol compounds, their preparation methods, pharmaceutical compositions containing such compounds and their uses

Examples

Experimental program
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preparation example Construction

[0138] In a preferred example, the compound represented by the general formula I of the present invention is compound I 6 , the preparation method comprises the following steps:

[0139]

[0140] (a) Compound I 1 Reaction with bromoacetyl bromide gives compound I 2 ;

[0141] (b) Compound I obtained in step (a) 2 Reaction with diethyl acetamidomalonate to obtain compound I 3 ;

[0142] (c) Compound I obtained in step (b) 3 Compound I was obtained by reduction reaction 4 ;

[0143] (d) Compound I obtained in step (c) 4 Compound I is obtained through reduction reaction under the action of lithium aluminum hydride 5 ;

[0144] (e) Compound I obtained in step (d) 5 Compound I is obtained through reduction reaction under the action of lithium hydroxide 6 .

[0145] In another preferred example, the compound represented by the general formula I of the present invention is compound I 6 , the preparation method comprises the following steps:

[0146]

[0147] (a')...

Embodiment 1

[0243]

[0244] Step 1: Preparation of 1-n-octanoylnaphthalene

[0245] Add 6.38g (0.05mol) of naphthalene and 30mL of dichloromethane into a 100mL three-necked flask, cool down to -10°C, add 6.65g (0.05mol) of anhydrous aluminum trichloride in batches, and control the temperature below -10°C. A dichloromethane (5 mL) solution containing 8.1 g (0.05 mol) of n-octanoyl chloride was added dropwise, and reacted at this temperature for 10 h. The reaction solution was poured into ice water, extracted with ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine until neutral, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 9.2 g brown liquid. Petroleum ether was recrystallized to obtain 9.02 g of white crystals, with a yield of 71.2%.

[0246] 1 H NMR (400MHz, CDCl 3 )δ9.01(d,J=8.5Hz,1H),8.18-8.04(m,3H),7.68-7.50(m,3H),2.96(t,J=6.8Hz,2H),1.74-1.68(m ,2H),1.44-1.18(m,10H...

Embodiment 2

[0251]

[0252] Step 1: Preparation of 1-(2-bromoacetyl)-4-n-octylnaphthalene

[0253] Add 8.0g (33.3mmol) of 1-n-octylnaphthalene and 250mL of dichloromethane into a 500mL three-necked flask, and add 6.66g (49.9mmol) of anhydrous AlCl in batches at -20°C 3 A solution of 13.4 g (66.6 mmol) of bromoacetyl bromide in dichloromethane (150 mL) was added dropwise, and stirring was continued for 2 h. Pour the reaction solution into 500g of ice under vigorous stirring, bring it up to room temperature, separate the dichloromethane layer, extract the aqueous phase with dichloromethane (100mL×2), combine the organic phases, and wash with saturated brine until neutral (100mL×2 ), dried over anhydrous magnesium sulfate, filtered and concentrated, and recrystallized with 60mL of methanol to obtain 9.5g of light yellow crystals with a yield of 79.8%, which was directly used in the next step.

[0254] Step 2: Preparation of Diethyl 2-Acetamido-2-(2-(4-octylnaphthalen-1-yl)-2-carbonylethy...

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Abstract

The invention discloses an aminoalcohol compound, its preparation method, a pharmaceutical composition containing the compound and an application of the compound. The structure of the compound is as shown in the general formula (I), wherein A, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in the specification and the claims. The compound provided by the invention can be used in the preparation of drugs for preventing and / or treating autosomal dominant polycystic kidney disease.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to an aminoalcohol compound, its preparation method, pharmaceutical composition and medical application, especially its application in the treatment of autosomal dominant polycystic kidney disease. Background technique [0002] Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, with an incidence of about 1 / 400-1 / 1000. There are currently about 1.5-3 million patients in my country. ADPKD mainly manifests as numerous cysts of different sizes in the bilateral kidneys. The cysts are similar to benign tumors and progressively enlarge, eventually destroying the structure and function of the kidneys, leading to end-stage renal failure. 50% of patients over 60 years old progress to uremia, accounting for 5-10% of the causes of end-stage renal failure. In addition to involving the kidneys, ADPKD can also be accompan...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/28C07C217/72C07C255/59C07C253/30C07C213/02C07C233/18C07C231/12C07F9/09C07D215/20A61K31/137A61K31/277A61K31/165A61K31/47A61K31/661A61P13/12
Inventor 罗成李林柳红陈丽敏林岱宗李昕卢俊彦付莉莉赵飞李连春李国郁胜强梅长林蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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