Substituted 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane derivatives as orexin receptor antagonists

A technology of heterocycloalkyl and cycloalkyl is applied in the field of synthetic routes for the production of the compound, and can solve the problems of affecting appetite, sleep disturbance, anhedonia and the like

Pending Publication Date: 2020-06-19
CHRONOS THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This is a potentially highly differentiated factor for OX1R antagonists in BED, as other underlying mechanisms such as opioid antagonists may cause anhedonia, and stimulants may affect appetite and cause sleep disturbances

Method used

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  • Substituted 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane derivatives as orexin receptor antagonists
  • Substituted 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane derivatives as orexin receptor antagonists
  • Substituted 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane derivatives as orexin receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

example

[1348] The following examples were synthesized according to one of the general procedures reported in the table below, as indicated in the table.

[1349] General procedure A:

[1350] 2-Azabicyclo[3.1.1]heptane (p17-18, p21-22, p28-29, p35; 1 equivalent as reported), carboxylic acid (p58, 61, 62, 65-67, 71 or, if not specified in the table, commercially available; a mixture of 1.2 eq), DIPEA (3 eq) and T3P (3 eq) in anhydrous DMF (33 vol) was stirred at 90 °C for 40 min, Stirring was then continued for 1 hour at RT. The solvent was evaporated and the crude material was purified by FC on a C18 column (eluent: water+0.1% HCOOH / acetonitrile+0.1% HCOOH), then the compound was dissolved in 3-5 mL NaHCO 3 saturated aqueous solution and extracted with DCM. The organic layer was dried, and the solvent was removed under reduced pressure to give the title compound.

[1351] General procedure B:

[1352] 2-Azabicyclo[3.1.1]heptane (p17-18, p21-22, p28-29, p35; 1 equivalent as repor...

example 62 and 63

[1391] Examples 62 and 63: (3S,4R or 3R,4S)-4-fluoro-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-5- Phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptane (E62) and (3R,4S or 3S,4R)-4-fluoro-3-{[(5 -Fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptane Alkane (E63)

[1392]

[1393] Step a:

[1394] 2-Methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (1.18 g, 5.38 mmol) was dissolved in DMF (5 mL), then HATU (2.4 g, 6.36 mmol) was added, followed by DIPEA (1.87 mL, 10.76 mmol). The resulting solution was stirred for 10 minutes and cis / trans 3-(hydroxymethyl)-2-azabicyclo[3.1.1]heptan-4-ol (p9, 700 mg, 4.89 mmol), and stirring continued for 1 hour. The mixture was treated with NH 4 Cl ss and DCM were diluted, the two phases were separated and the product was extracted several times with DCM. The combined organic phases were dried and evaporated. The residue was purified by FC (from DCM to 10% MeOH) on silica ge...

example 261

[1505] The orexin type 1 and type 2 receptor binding activities of the example compounds were determined using the scintillation proximity assay and intracellular calcium measurement methods described above. The results are shown in Table 1.

[1506] Table 1: OX for representative examples 1 and OX 2 Binding and functional antagonist values.

[1507]

[1508]

[1509]

[1510] ND: not determined

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Abstract

There is provided a compound of formula (I), wherein L1 to L3, R1 to R4, X, A and B have meanings given in the description, and pharmaceutically acceptable salts, solvates and prodrugs thereof, whichcompounds are useful as antagonists of the orexin-1 and orexin-2 receptors or as selective antagonists of the orexin-1 receptor, and thus, in particular, in the treatment or prevention of inter alia substance dependence, addiction, anxiety disorders, panic disorders, binge eating, compulsive disorders, impulse control disorders, cognitive impairment and Alzheimer's disease.

Description

technical field [0001] The present invention relates to novel pharmaceutically useful compounds which are useful as antagonists of the orexin 1 and orexin 2 receptors or as selective antagonists of the orexin 1 receptor. The compounds have potential utility in the treatment of addictive disorders such as binge eating disorder and behavioral disorders such as obsessive compulsive disorder and impulse control disorders. The invention also relates to the use of such compounds as medicines, to pharmaceutical compositions containing said compounds, and to synthetic routes for the production of said compounds. Background technique [0002] There are many addictive behaviors that represent a clear unmet medical need for novel treatments. These addictive behaviors include binge eating, alcohol use disorder and nicotine addiction. [0003] Binge eating is an eating disorder in which a person feels compelled to overeat on a regular basis by regularly "binging" or ingesting huge amou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D413/14C07D401/10C07D417/06C07D417/10C07D417/14C07D487/04C07D498/04C07D513/04C07D471/04A61K31/439A61P25/30
CPCC07D401/14C07D413/14C07D401/10C07D417/06C07D417/10C07D417/14C07D471/04C07D487/04C07D498/04C07D513/04A61P25/30A61K31/439A61K31/472A61K31/506A61K31/444A61K31/4709A61K31/4725A61K31/498A61K31/519A61K45/06C07D471/08C07D519/00
Inventor F·米凯利B·贝尔塔尼K·R·吉布森R·迪法比奥L·拉维格利亚R·扎纳莱蒂S·克雷莫纳西A·波赞T·塞梅拉罗L·塔尔西T·J·卢克
Owner CHRONOS THERAPEUTICS
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