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Dipeptidyl peptidase-IV inhibitor-aminotetrahydropyrane derivative

An alkyl and aryl technology, applied in drug combinations, metabolic diseases, endocrine system diseases, etc.

Inactive Publication Date: 2017-01-04
北京睿创致远生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, long-term inhibition of DPP-IV may have a weight loss effect, but clinical trials are still needed to prove it

Method used

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  • Dipeptidyl peptidase-IV inhibitor-aminotetrahydropyrane derivative
  • Dipeptidyl peptidase-IV inhibitor-aminotetrahydropyrane derivative
  • Dipeptidyl peptidase-IV inhibitor-aminotetrahydropyrane derivative

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Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0091] Process 1:

[0092]

[0093] The compound of formula (I) can be prepared according to Scheme 1, and the compound of formula (II) can be prepared with suitable reagents such as sodium triacetoxyborohydride, sodium borohydride, decaborane, sodium cyanoborohydride, etc., in a suitable solvent For example, in N,N-dimethylacetamide, N,N-dimethylmethylamine, dimethyl sulfoxide, ethanol, methanol, toluene, pyridine, dichloromethane, etc., in the presence of the compound of formula (III), Reductive amination occurs to give compounds of formula (IV). Then remove the protecting group PG under suitable conditions and introduce R 1 and / or R 2 (when R 1 and R 2 are not hydrogen at the same time), the compound of formula (I) is obtained.

[0094] Process 2:

[0095]

[0096] The compound of formula (I) can also be prepared according to scheme 2. First, the compound of formula (II) removes the protecting group PG under appropriate conditions, and introduces R 1 and R 2 (...

Embodiment 1

[0100] Embodiment 1: preparation compound 1

[0101]

[0102] Step 1: Preparation of intermediate 1b

[0103]

[0104] 1a (9.0g, 43mmol) and hydrazine hydrochloride (4.5g, 43mmol) were dissolved in absolute ethanol (250ml), stirred at 60°C for 3h, the solvent was distilled off under reduced pressure, and saturated sodium bicarbonate solution (50ml) was added until solid It was completely dissolved, extracted with ethyl acetate, and the obtained organic phase was removed by evaporation under reduced pressure to obtain a white solid 1b (6.3 g, yield 66%) which was used in the next reaction without further purification.

[0105] Step 2: Preparation of intermediate 1c

[0106]

[0107] Dissolve 1b (500mg, 2.23mmol) in 10ml tetrahydrofuran, add 683 microliters of triethylamine, then add 200 microliters of methanesulfonyl chloride, react at room temperature for 2h, remove the solvent under reduced pressure, and perform column chromatography (P: E=1:1) afforded 1c (487 mg,...

Embodiment 2

[0120] Embodiment 2: preparation compound 2

[0121] Step 1: Preparation of intermediate 2a

[0122]

[0123] Dissolve 1c (200 mg, 0.66 mmol) in 5 ml of dichloromethane, then add 1 ml of trifluoroacetic acid, react at room temperature for 2 h, remove the solvent under reduced pressure, neutralize with an appropriate amount of ammonia, remove the water under reduced pressure, and perform column chromatography (2 Chloromethane:methanol=20:1) to obtain 125 mg of oily liquid 2a, yield 63.3%.

[0124] Step 2: Preparation of Intermediate 2b

[0125]

[0126] Dissolve 2a (125mg, 0.42mmol) and 1f (137mg, 0.42mmol) in DMA, place in an ice bath, then add sodium triacetoxyborohydride (131mg, 0.62mmol), react for 2h, then add water After extraction with ethyl acetate, the solvent was removed under reduced pressure, followed by column chromatography to obtain 143 mg of white solid with a yield of 56%.

[0127] Step 3: Preparation of Compound 2

[0128]

[0129] Dissolve 2b in ...

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PUM

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Abstract

The invention provides a DPPIV inhibitor which has the structure shown as the formula (I) (please see the formula (I) in the description). Experiments show that the inhibitor can effectively inhibit the activity of dipeptidyl peptidase IV (DPPIV) and be used for preventing DPPIV-mediated diseases or delaying progress of the DPPIV-mediated diseases or treating the DPPIV-mediated diseases, particularly 2 type and 1 type diabetes, obesity, arthritis, osteoporosis and part of tumors. The invention further provides a preparation method of the inhibitor.

Description

technical field [0001] The present invention relates to a compound that can be used for inhibiting dipeptidyl peptidase, its preparation method and the application of the compound alone or in combination with other drugs in treating diseases related to dipeptidyl peptidase activity. Background technique [0002] Diabetes is a major disease that seriously threatens human health. According to the statistics of the World Health Organization, there will be 366 million diabetics worldwide by 2030. More than 90% of them have type 2 diabetes. The number of diabetic patients in my country has exceeded 90 million, ranking second in the world, and the incidence rate is still rising year by year. Oral hypoglycemic agents commonly used in clinical practice mainly include insulin secretion enhancers (sulfonylureas and glitazones), insulin sensitizers (biguanides and thiazolidines) and carbohydrate regulators (α-glucosidase inhibitors). ). Although these drugs all showed good curative ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P5/50A61P3/10
CPCC07D487/04
Inventor 乔德华
Owner 北京睿创致远生物科技有限公司