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Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof

A technology of use and solvate, applied in the field of a new type of dipeptidyl peptidase inhibitor, synthesis and use, capable of solving problems such as unsatisfactory inhibitory properties of dipeptidyl peptidase

Inactive Publication Date: 2008-12-10
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the inhibitory properties of these compounds to dipeptidyl peptidases in the prior art are not satisfactory enough, so there is an urgent need in this field to develop highly active dipeptidyl peptidase inhibitors in order to treat various diseases related to dipeptidyl peptidases. (DPP-IV) related diseases

Method used

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  • Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof
  • Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof
  • Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof

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preparation example Construction

[0047] In the preparation method of the present invention, each reaction is usually carried out in an inert solvent at 0°C to solvent reflux temperature (preferably room temperature to 80°C). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.

[0048] In a preferred example, the compound of formula (I) of the present invention can be prepared according to the following route I:

[0049] Route I

[0050]

[0051] Among them, a: SOCl 2 , CCl 4 , b: 1-chloroacetyl-2-cyanopyrrole, K 2 CO 3 , THF

[0052] Step 1.3-Hydroxy-1-adamantanamine hydrochloride 1 [Synthetic Communications; 1988, 18 (16): 1975-1978], in an aprotic solvent, reacted with a chlorination reagent in the presence of a base to obtain 3 in high yield -Chloro-1-adamantanamine.

[0053] Suitable solvents for the above reaction are carbon tetrachloride, dichloromethane, benzene, toluene, dimethylformamide and chloroform, and suitable bases are triethylamine and pyridine. The chlorinati...

Embodiment 1

[0139] Example 1: (2S)-1-[(3-fluoro-1-adamantyl)aminoacetyl]-2-cyanopyrrolidine (YF-1)

[0140] At room temperature, add 3-fluoro-1-adamantanamine hydrochloride (245mg, 1.45mmol), potassium carbonate (500mg, 3.6mmol) and tetrahydrofuran (15ml) into the reaction flask together, start stirring, dropwise add (2S )-1-Chloroacetyl-2-cyanopyrrole (100mg, 0.58mmol) in tetrahydrofuran, after the dropwise addition, sodium iodide (0.1g) was added. The reaction mixture was stirred at room temperature for 15 h, and was analyzed by TLC (CH 2 Cl 2 / MeOH=10:1) to monitor the reaction. After the reaction was complete, it was cooled, and the potassium carbonate solid was filtered off, and the filtrate was evaporated to dryness under reduced pressure, and directly carried out column chromatography, (developing agent: CH 2 Cl 2 / MeOH=25:1) to obtain a yellow viscous substance. A saturated solution of hydrogen chloride in diethyl ether was added to the yellow viscous substance to generate hy...

Embodiment 2

[0142] Embodiment 2: (2S)-1-[(3-chloro-1-adamantyl)aminoacetyl]-2-cyanopyrrolidine (YF-2) 1.3-chloro-1-adamantanamine (compound 2 )

[0143] Dissolve 3-hydroxyadamantamine (500mg, 3mmol) in carbon tetrachloride (20ml), add thionyl chloride (0.5ml, 7.5mmol), stir and reflux for 22h, spin out the solvent to obtain a viscous substance (650mg , 100%). directly into the next reaction.

[0144] 1 H NMR (400MHz, CDCl 3 ) δ 1.46-1.56 (m, 8H), 1.97-2.07 (m, 6H), 2.25 (s, 2H).

[0145] 2. (2S)-1-[(3-Chloro-1-adamantyl)aminoacetyl]-2-cyanopyrrolidine (YF-2)

[0146] Compound 2 (555 mg, 3.0 mmol) and (2S)-1-chloroacetyl-2-cyanopyrrole (172 mg, 1 mmol) were reacted and treated according to the method of Example 1 to obtain a white solid (54 g, 5.6%).

[0147] Mp: 134-138°C. 1 H NMR (400MHz, CDCl 3 ) δ 1.49-2.29 (m, 19H), 3.35-3.59 (m, 4H), 4.71-4.73 (dd, 1H).

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Abstract

The invention provides an inhibitor of dipeptidyl peptidase IV shown in formula (I). In the formula, R1 is hydrogen, chlorine, fluorine, bromine, hydroxide radical or alkoxy radical of C1-C6; R2 is hydrogen, fluorine, bromine or hydroxide radical; but R1 can not be the hydroxide or the alkoxy radical of C1-C6 when R2 is hydrogen; and R3 is hydrogen or fluorine. The compound can be used for treating or preventing diseases related with the dipeptidyl peptidase IV, such as diabetes mellitus, obesity and hyperlipoidemia. The invention also provides a method for preparing a compound shown in the formula (I), a preparation method of a pharmaceutically acceptable salt and a pharmaceutical composition thereof, and an application of the compound, the pharmaceutically acceptable salt and the pharmaceutical composition thereof in medicines used for treating or preventing the diseases related with the dipeptidyl peptidase IV.

Description

technical field [0001] The present invention relates to a new type of dipeptidyl peptidase IV (Dipeptidyl peptidases, DPP-IV) inhibitor, its preparation method and its use in the preparation and treatment of DPP-IV related disease medicines, especially the preparation and treatment of diabetes, obesity, hyperlipidemia application in medicine. Background of the invention [0002] Diabetes mellitus is a group of clinical syndromes characterized by chronic hyperglycemia (fasting blood glucose concentration greater than 130 mg / dL) and glucosuria due to abnormal carbohydrate, fat and protein metabolism caused by insufficient insulin secretion or insulin resistance. Sustained hyperglycemia can lead to many complications, such as retinal, renal, nervous system lesions and vascular complications, especially cardiovascular complications are the main threat to death and disability in diabetic patients, so controlling the patient's blood sugar level is very important for delaying or pr...

Claims

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Application Information

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IPC IPC(8): C07D207/16A61K31/40A61P3/06A61P3/10A61P3/04
Inventor 陈慧茹陈义朗
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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