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Substituted amino triazoles, and methods using same

一种卤代烷基、卤代烷氧基的技术，应用在取代的氨基三唑及其使用领域

Inactive Publication Date: 2017-05-10
INST FOR DRUG DISCOVERY LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While there are therapies focused on reducing symptomatic bronchospasm and pneumonia, there is a growing understanding of the role of long-term airway remodeling in accelerated lung deterioration in asthmatics

Method used

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  • Substituted amino triazoles, and methods using same
  • Substituted amino triazoles, and methods using same
  • Substituted amino triazoles, and methods using same

Examples

Experimental program
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preparation example Construction

[0619] Scheme 1 illustrates the preparation of aminotriazolopiperazines. The reaction produces three possible tautomers, which are interchangeable. For convenience, only one triazole tautomer is depicted throughout the specification. In one method (Method A), substituted piperazines and dimethyl cyanocarbonimidodithioate were combined in anhydrous acetonitrile and refluxed overnight. After the intermediate was formed, hydrazine hydrate monohydrate was added to the reaction mixture, and reflux was continued until the reaction was complete. In another method (Method B), the above reaction was carried out by microwave irradiation at 160° C. for 1 hour for each step.

[0620] Scenario 2:

[0621]

[0622] Similar chemistry to BOC-protected piperazines can be used to prepare unsubstituted aminotriazolopiperazines as intermediates for further synthesis, eg, by reductive amination (Scheme 2). Other alkylation, acylation, or sulfonylation reactions may also be used to add subst...

Embodiment 1

[0636] Example 1: 5-(4-(2-(4-fluorophenoxy)ethyl)piperazin-1-yl)-1H-1,2,4-triazol-3-amine.

[0637]

[0638] Step 1: Methyl N-cyano-4-(2-(4-fluorophenoxy)ethyl)piperazine-1-carbimidothioate

[0639]

[0640] To a 100 mL single port RBF equipped with nitrogen inlet, reflux condenser, and bleach trap was added 1-[2-(4-fluorophenoxy)ethyl]piperazine (0.0553 g, 0.2466 mmol) , dimethyl cyanodithioimidate (0.0361 g, 0.2466 mmol), and anhydrous acetonitrile (20 mL). The reaction solution was refluxed overnight under nitrogen. TLC and MS confirmed the presence of the desired intermediate. The reaction solution was carried forward without purification. C 15 h 19 FN 4 Calculated ESI-LCMS m / z for OS: predicted 322.4; found 323.2 [M+H] + .

[0641] Step 2: 5-(4-(2-(4-fluorophenoxy)ethyl)piperazin-1-yl)-1H-1,2,4-triazol-3-amine

[0642] To the reaction solution from step 1 was added hydrazine hydrate monohydrate (0.1929 g, 2.466 mmol, 187 μL). The solution was refluxed for 16...

Embodiment 2

[0643] Example 2: 5-(4-(2-(4-Chlorophenoxy)ethyl)piperazin-1-yl)-1H-1,2,4-triazol-3-amine.

[0644]

[0645] Step 1: Methyl 4-(2-(4-chlorophenoxy)ethyl)-N-cyanopiperazine-1-thioimidate

[0646]

[0647] Prepared in a similar manner to Example 1 (Step 1) from 1-[2-(4-chlorophenoxy)-ethyl]piperazine. C 15 h 19 ClN 4 Calculated ESI-LCMS m / z for OS: predicted 338.9; found 339.2 [M+H] + .

[0648] Step 2: 5-(4-(2-(4-Chlorophenoxy)ethyl)piperazin-1-yl)-1H-1,2,4-triazol-3-amine

[0649] Prepared and purified in a similar manner to Example 1 (step 2) from methyl 4-(2-(4-chlorophenoxy)ethyl)-N-cyanopiperazine-1-thioimidate, The desired product was obtained as a white solid. (0.100 g, 62% yield). 1 H NMR (CD 3 OD, 300MHz) δ (ppm) 7.09-6.99 (m, 4H), 5.48 (s, 2H), 4.38 (t, J = 5.0Hz, 2H), 3.67 (t, J = 5.0Hz, 6H), 3.35 ( s, 2H); C 14 h 19 ClN 6 Calculated ESI-LCMS m / z for O: predicted 322.8; found 323.2 [M+H] + .

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Abstract

Disclosed are novel substituted amino triazoles of Formula (I), and pharmaceutically acceptable salts thereof. The compounds of Formula (I) are inhibitors of Acidic mammalian chitinase (AMCase) and are useful, in a non-limiting example, for treating asthma. Also provided are pharmaceutical compositions containing at least one compound of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent, and methods of using such compounds and / or compositions to treat asthma and / or to monitor asthma treatment.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application No. 61 / 919,117, filed December 20, 2013, which is hereby incorporated by reference in its entirety. [0003] Background of the invention [0004] Acid mammalian chitinase (AMCase) is a secreted enzyme with a molecular weight of approximately 52.2 kD and commonly found in the stomach, salivary glands and lungs. This enzyme catalyzes the hydrolysis of artificial chitin-like substrates and is unique among mammalian enzymes due to its acidic pH optimum. AMCase at T H 2 Induced during inflammation by an IL-13-dependent mechanism. Chitinases are thought to play a key role in innate immunity to parasites and other infectious agents. Chitinases have also been shown to play an important role in the pathogenesis of allergy and / or asthma when produced in a dysregulated manner. [0005] Asthma is a chronic inflammatory disease of the airways characterized by re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4196A61K31/497C07D249/08
CPCA61P11/06A61P43/00C07D249/14C07D401/04C07D401/14C07D403/12C07D405/12C07D405/14C07D413/14C07D471/04C07D487/04
Inventor M·L·科尔曼W·M·亨格福德A·古勒比奥斯基R·P·贝克特M·马祖尔S·奥雷尼扎克J·奥勒扎克
Owner INST FOR DRUG DISCOVERY LLC
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