New compounds for the prevention and treatment of various autoimmune diseases

A compound, selected technology, applied in metabolic diseases, skin diseases, bone diseases, etc., can solve problems such as short half-life

Active Publication Date: 2018-04-03
ZHEJIANG DTRM BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, tofacitinib has a short half-life in some animals or humans and needs to be taken twice a day

Method used

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  • New compounds for the prevention and treatment of various autoimmune diseases
  • New compounds for the prevention and treatment of various autoimmune diseases
  • New compounds for the prevention and treatment of various autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0077]

[0078] ((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)(5-methyliso Oxazol-4-yl)methanone

[0079] Step A: 4-Chloro-7-(p-toluenesulfonyl)-pyrrolo[2,3-d]pyrimidine

[0080]

[0081] p-Toluenesulfonyl chloride (67.5g, 348mmol, 1.10eq.) and 4-chloro-7-Hpyrrolo[2,3-d]pyrimidine (50g, 320mmol, 1.0eq.) were dissolved in acetone (500ml), At 0°C, sodium hydroxide solution (2Minwater, 200ml, 1.20eq.) was slowly added thereto, the reaction was stirred at 20°C for 6 hours, the precipitated solid was filtered and washed with acetone and water to obtain the white target compound (90g, Yield = 90%).

[0082] LC / MS (method UFLC, total length 2 min): RT = 1.43 min; m / z = 307.9 [M+H] + . 1 H NMR (CDCl 3 400MHz): δ8.80(s, 1H), 8.04-8.15(d, 2H), 7.92(d, 1H), 7.30-7.40(d, 2H), 6.71(s, 1H), 2.39(s, 3H) .

[0083] Step B: N-[(3R,4R)-1-Benzyl-4-methyl-3-piperidine]-N-methyl-7-(p-toluenesulfonyl)pyrrolo[2,3-d] Pyrimidin-4-amine

[0084]

[0...

example 2

[0104]

[0105] 2-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carbonyl)-3-oxo Butyronitrile

[0106] Sodium methoxide (180mg, 3.39mmol, 1.5eq.) dissolved in methanol was slowly added to the compound ((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3- d] pyrimidin-4-yl)amino)piperidin-1-yl)(5-methylisoxazol-4-yl)methanone (0.8g, 2.26mmol, 1.0eq.) in tetrahydrofuran and at 25oC After stirring for two hours, the reaction solution was spin-dried and dissolved in water and adjusted to pH 3 with 2N HCl aqueous solution. The aqueous layer was extracted twice with dichloromethane, the combined organic layer was backwashed once with water, and the organic layer was dried over sodium sulfate. After spin-drying, the target compound (497.8mg, yield=62.5%) was obtained.

[0107] LC / MS (method UFLC, total length 7 minutes): RT=2.45min; m / z=355.2[M+H]+.

[0108] 1H NMR (CD3OD 400MHz): δ8.36(s, 1H), 7.40(d, 1H), 6.94(d, 1H), 5.03(br, 1H), 4.16(d, 2H), 3.97-3.8...

example 3

[0110]

[0111] (3-((7H-pyrrolo[2,3-d]-pyrimidin-4-yl)oxy)-piperidin-1-yl)(methylisoxazol-4-yl)methanone

[0112] Step A: 2-[[4-[(1-Benzyl-3-piperidinyl)oxy]-pyrrolo[2,3-d]-pyrimidin-7-yl]methoxy]ethyl-trimethyl - Silane

[0113]

[0114] Compound 1-benzyl-3-ol (4.82g, 25.2mmol, 1.3eq) was dissolved in 50ml of anhydrous tetrahydrofuran, and NaH (1.55g, 38.8mmol, 2.0eq.60% in mineral oil was added under ice-water bath ). Stirring at room temperature for one hour, 2-[(4-chloro-pyrrolo[2,3-d]-piperidin-7-yl)methoxy]ethyl-trimethyl-silane (5.5g, 19.4mmol, 1.0eq) was dissolved in anhydrous tetrahydrofuran (30mL), then added dropwise to the reaction solution, and stirred overnight at 60oC. Water (30 mL) was added to the reaction solution, followed by extraction three times with ethyl acetate (70 mL). Then it was backwashed once with water and brine, dried over sodium sulfate and spin-dried to obtain the target compound (10 g).

[0115] Step B: 2-[[4-[(1-Benzyl-3-piperidiny...

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Abstract

The present invention provides a series of novel compounds or salts for preventing and treating various immune diseases. The compounds have good inhibitory effects on JAK1, JAK2, and JAK3 kinase activities. A variety of immune diseases are initiated by abnormal cytokine signaling through these kinases. These conditions include autoimmune, inflammatory and allergic diseases (multiple sclerosis, lupus, rheumatoid arthritis, psoriasis, cancer, asthma, xerophthalmia, atopic dermatitis, autoimmune thyroid disease, chronic or acute organ transplant rejection, ulcerative colitis, Crohn's disease, leukemia, Alzheimer's disease, type 1 diabetes, etc.).

Description

technical field [0001] The invention relates to a series of new isoxazole and 3-oxobutyronitrile compounds and their preparation method, a pharmaceutical composition containing them as active ingredients and their application in immune diseases. Background of the invention [0002] Janus kinases (JAKS) are a class of intracellular non-receptor tyrosine kinases, which belong to the protein kinase family. The molecular weight of JAKs is about 120-140 kDa. In mammals, there are four members of the JAKs family: JAK1, JAK2, JAK3 and TYK2. These kinases exert their effects by interacting with cytokines and cytokine receptors (references: Rodig S. et al "Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biological responses". Cell1998, 93(3), 373-83). [0003] JAKS kinases reside in proline-rich regions of cytokine receptors. The binding of cytokines to cytokine receptors leads to conformational changes of the receptors a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61P37/02A61P29/00A61P37/08A61P35/00A61P19/02A61P17/06A61P11/06A61P27/02A61P17/00A61P37/06A61P1/04A61P35/02A61P25/28A61P3/10
CPCC07D487/04A61K45/06A61P1/04A61P3/10A61P11/06A61P17/00A61P17/06A61P19/02A61P25/28A61P27/02A61P29/00A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08
Inventor 何伟
Owner ZHEJIANG DTRM BIOPHARMA
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