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Pyrazolopyridine derivative having glp-1 receptor agonist effect

A technology of compound and alkyl, applied in the direction of medical preparations containing active ingredients, drug combination, organic chemistry, etc., can solve the problem of invasive subcutaneous administration, etc.

Active Publication Date: 2019-05-21
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although GLP-1 analogs have been commercialized as diabetes therapeutics and are regarded as one of the most effective diabetes therapeutics due to their potent effects of HbA1c lowering and weight loss, all GLP-1 analogs require invasive subcutaneous administration

Method used

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  • Pyrazolopyridine derivative having glp-1 receptor agonist effect
  • Pyrazolopyridine derivative having glp-1 receptor agonist effect
  • Pyrazolopyridine derivative having glp-1 receptor agonist effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0407] 3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl) )- 2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridine - 4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2, 4 - Synthesis of Oxadiazol-5-one (Compound 1)

[0408] [chemical formula 17]

[0409]

[0410]

[0411] [(5-cyano-1,2,3,6-tetrahydropyridin-4-yl)amide] potassium (compound 1b)

[0412] To a solution of 3-(2-cyanoethylamino)propionitrile (compound 1a, 22.0 g, 179 mmol) in tetrahydrofuran (THF) (179 mL) was added a 1M solution of potassium tert-butoxide in THF (179 mL), and the mixture was dissolved in Stir at room temperature for 1 hour. The reaction mixture was filtered, washed with THF (50 mL), and the filtrate was dried under reduced pressure to give the title compound 1b (23.8 g, 83% yield) as a light brown solid.

[0413] LC / MS mass spectrum: m / z 124 ([M+H] + ).

[0414] LC / MS retention time: 0.14 minutes (analysis conditions:...

Embodiment 2 to 50

[0467] Apply the combination of the 2-oxoimidazole compound shown in Table 2-2 and the halogen compound shown in the following Table 2-3, and an appropriate solvent, carry out the operation similar to Example 1 step 1-11, and pass The following reactions gave Example compounds 2 to 50 shown in Table 2-1.

[0468] [chemical formula 18]

[0469]

[0470] [table 2-1]

[0471] Table 2-1. Obtained embodiment compounds 2 to 50

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497] The compounds in Table 2-1 have rotamers, and as an example, the compound of Example 2 has 1 H-NMR is shown below.

[0498] Rotamer A

[0499] 1 H-NMR (600MHz, CDCl 3 )δ:11.29(1H,s),8.40(1H,d,J=5.2Hz),7.93(1H,s),7.74(1H,d,J=1.5Hz),7.70(1H,d,J=8.6 Hz...

Embodiment 51 to 53

[0951] By the following reaction, 3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1 -Methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole- 1-yl]-2-methylcyclopropyl]-4H-1,2,4- Oxadiazol-5-one (compound 51d), substituted morpholine and appropriate reagents, followed by the similar operation to Step 7-1 of Example 7, to obtain Example compounds 51 to 53 shown in Table 2-4.

[0952] [chemical formula 48]

[0953]

[0954] [Table 2-4]

[0955] Table 2-4. Obtained example compounds 51 to 53

[0956]

[0957]

[0958] Compound 51d was synthesized as follows.

[0959] [chemical formula 49]

[0960]

[0961]

[0962] 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4, 3-c] tert-butyl pyridine-5-carboxylate (compound 51a)

[0963] Add triethylamine (0.936mL, 6.72mmol), di-tert-butyl dicarbonate (0.425mL , 1.85 mmol), and the suspension was stirred at room temperature f...

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Abstract

The present invention provides a compound represented by formula (I) in which an indole ring or a pyrrolo[2,3-b]pyridine ring and a pyrazolopyridine skeleton are bonded using a substituent, or a saltof the compound; solvates thereof; and prophylactic or therapeutic agents for non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus), obesity, and the like in which said compound, salt, orsolvate is used as an active ingredient. (In the formula, X, Y, Q1, Q2, R1, R2, R3, R4, R5, R6, R7, R8, R9, n1, n2, Z1, and Z2 represent substances indicated in the present specification.)

Description

field of invention [0001] The present invention relates to a GLP-1 receptor agonist compound, a salt thereof, or a solvate of the compound or the salt of the compound, which has an action similar to that of GLP-1. The present invention further relates to a preventive or therapeutic agent for non-insulin-dependent diabetes (type 2 diabetes) or obesity comprising the compound, salt or solvate as an active ingredient. Background technique [0002] Glucagon-like peptide-1 (GLP-1) is an incretin secreted by L cells of the small intestine when nutrients pass through the digestive tract, and GLP-1 is known to exhibit various actions through the GLP-1 receptor, such as Promote glucose-dependent insulin secretion, inhibit glucagon secretion, delay gastric emptying, and inhibit food intake. Although GLP-1 analogs have been commercialized as diabetes therapeutics and are regarded as one of the most effective diabetes therapeutics due to their potent effects of HbA1c lowering and weigh...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61K31/444A61K31/4709A61K31/4725A61K31/496A61K31/506A61K31/5377A61K31/5386A61P1/16A61P3/04A61P3/06A61P3/10A61P9/10A61P25/16A61P25/28C07D519/00
CPCA61K31/437A61K31/5377A61K31/5386A61K31/4709C07D471/04A61K31/506A61K31/444A61K31/496A61K31/4725A61P1/16A61P3/10A61P3/04A61P3/06A61P25/16A61P9/10C07D519/00A61P25/28Y02A50/30C07D413/14
Inventor 吉野仁土屋智史松尾笃佐藤勉西本昌弘小栗京子小川纮子西村祥和古田佳之柏木浩孝堀伸行家门拓麻白石拓也吉田昌伸河合隆博谷田智嗣青木雅英
Owner CHUGAI PHARMA CO LTD
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