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Heteroaryl Amide Analogues

a technology of heteroaryl amide and analogues, which is applied in the field of heteroaryl amide analogues, can solve the problems of acute or chronic pain, more debilitating, and opiates, such as morphine, are potent analgesics, and achieve the effect of inhibiting the death of retinal ganglion cells

Inactive Publication Date: 2012-07-26
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inappropriate or excessive activation of nociceptors, however, can result in debilitating acute or chronic pain.
Neuropathic pain is typically burning, shooting and unrelenting in its intensity and can sometimes be more debilitating than the initial injury or disease process that induced it.
Opiates, such as morphine, are potent analgesics, but their usefulness is limited because of adverse side effects, such as physical addictiveness and withdrawal properties, as well as respiratory depression, mood changes, and decreased intestinal motility with concomitant constipation, nausea, vomiting, and alterations in the endocrine and autonomic nervous systems.
In addition, neuropathic pain is frequently non-responsive or only partially responsive to conventional opioid analgesic regimens, or to treatment with other drugs, such as gabapentin.
Treatments employing the N-methyl-D-aspartate antagonist ketamine or the alpha(2)-adrenergic agonist clonidine can reduce acute or chronic pain, and permit a reduction in opioid consumption, but these agents are often poorly tolerated due to side effects.
Another common condition for which existing therapies are insufficient or problematic is inflammation.
Uncontrolled inflammation, however, causes tissue damage and pain and is the underlying cause of many illnesses, including asthma, as well as other allergic, infectious, autoimmune, degenerative, and idiopathic diseases.
Existing treatments often exhibit low, delayed or only temporary efficacy, undesirable side-effects and / or a lack of selectivity.

Method used

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  • Heteroaryl Amide Analogues
  • Heteroaryl Amide Analogues
  • Heteroaryl Amide Analogues

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-(Adamantan-1-ylmethyl)-1-pyrimidin-2-yl-1H-indole-3-carboxamide

Step 1. Methyl 1-(pyrimidin-2-yl)-1H-indole-3-carboxylate

[0261]

[0262]Potassium t-butoxide (2.52 g, 0.022 mol) is added to a mixture of methyl 1H-indole-3-carboxylate (3.5 g, 0.02 mol) and 2-chloropyrimidine (2.28 g, 0.02 mol) in 50 mL of dioxane. The reaction mixture is heated to 110° C. and stirred for 20 h. The dioxane is removed in vacuo, and the residue is diluted with water (100 mL). The solid is filtered and purified by silica gel column chromatography (15% EtOAc / DCM) to afford the title compound as a white solid.

Step 2. 1-(Pyrimidin-2-yl)-1H-indole-3-carboxylic acid

[0263]

[0264]1.0 N aqueous NaOH (10 mL) is added to a mixture of methyl 1-(pyrimidin-2-yl)-1H-indole-3-carboxylate (1.4 g, 0.0055 moles) in 50 mL of EtOH and heated at 70° C. for 4 h. The reaction mixture is concentrated in vacuo, diluted with water (50 mL), acidified with concentrated HCl to pH 2.0. The white solid separated is filtered, washed with w...

example 2

N-[(1-Pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-4-(trifluoromethyl)-1H-indole-3-carboxamide

Step 1. 4-Bromo-1H-indole-3-carbaldehyde

[0267]

[0268]A round bottom flask charged with 50 mL of DMF is cooled to 0° C., and phosphorous oxychloride (8.1 mL, 88 mmol) is added dropwise. After stirring for approx. 5 min, a solution of 4-bromoindole (5.0 mL, 40 mmol) in 50 mL of DMF is added dropwise. The ice bath is removed, and the reaction mixture is stirred for 1 h at rt. The reaction becomes a very thick suspension. The mixture is cooled back to 0° C. and carefully quenched with 22g of KOH in 80 mL of water. The resulting mixture is partitioned between EtOAc (200 mL) and sat. NaHCO3 (100 mL). The EtOAc layer is washed with brine (100 mL) and water (100 mL), dried (Na2SO4), filtered, and evaporated in vacuo to give a brown solid, which is triturated with ether to afford the title compound as an off-white solid.

Step 2. 4-(Trifluoromethyl)-1H-indole-3-carbaldehyde

[0269]

[0270]Methyl 2-(fluo...

example 3

4-Chloro-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide

Step 1. 1-(4-Chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone

[0280]

[0281]Trifluoroacetic anhydride (27.5 mL, 200 mmol) is added to a solution of 4-chloroindole (25.0 g, 165 mmol) and DMF (170 mL) under N2 over 30 min. The reaction vessel is sealed. After 20 h, the solution is poured into water (700 mL) and extracted with EtOAc (300 mL). The organics are dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel column chromatography (4:1 hexane / EtOAc to 1:1 hexane / EtOAc) affords the title compound as a red-brown solid.

Step 2. 1-(4-Chloro-1-pyrimidin-2-yl-1H-indol-3-yl)-2,2,2-trifluoroethanone

[0282]

[0283]A mixture of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (10.1 g, 40.8 mmol), 2-chloropyrimidine (9.3 g, 81 mmol), cesium carbonate (26.6 g, 81.6 mmol), and 1,4-dioxane (80 mL) under N2 is warmed to 100° C. for 3 h. After cooling to rt, water (200 mL) is added. The precipita...

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Abstract

Compounds, pharmaceutical compositions, and methods of use are disclosed for heteroaryl amide analogues of formula Ia and / or Ib:In certain embodiments, the heteroaryl amide analogues are agonists and / or ligands of dopamine receptors and may be useful, inter alia, for the treatment of a condition responsive to P2X7 receptor modulation, for example, pain, inflammation, a neurological or neurodegenerative disorder, a cardiovascular disorder, an ocular disorder or an immune system disorder.

Description

FIELD OF THE INVENTION[0001]This invention relates generally to heteroaryl amide analogues that have useful pharmacological properties. The invention further relates to the use of such compounds for treating conditions related to P2X7 receptor activation, for identifying other agents that bind to P2X7 receptor, and as probes for the detection and localization of P2X7 receptors.BACKGROUND OF THE INVENTION[0002]Pain perception, or nociception, is mediated by the peripheral terminals of a group of specialized sensory neurons, termed “nociceptors.” A wide variety of physical and chemical stimuli induce activation of such neurons in mammals, leading to recognition of a potentially harmful stimulus. Inappropriate or excessive activation of nociceptors, however, can result in debilitating acute or chronic pain.[0003]Neuropathic pain, which typically results from damage to the nervous system, involves pain signal transmission in the absence of stimulus, pain from a normally innocuous stimul...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/506C07D401/14C07D413/14C07D209/42C07D403/06A61K31/4439A61K31/5377A61K31/404A61K31/497A61K31/444A61K31/4178A61P29/00A61P25/00A61P9/00A61P27/02A61P19/02A61P9/10A61P1/00A61P25/28A61P11/06A61P11/00A61P25/24A61P25/22A61P25/18A61P25/08C07D403/04
CPCB64D33/04B64D29/02A61P1/00A61P11/00A61P11/06A61P19/02A61P25/00A61P25/08A61P25/18A61P25/22A61P25/24A61P25/28A61P27/02A61P29/00A61P9/00A61P9/10
Inventor BAKTHAVATCHALAM, RAJAGOPALIHLE, DAVID C.CAPITOSTI, SCOTT M.WUSTROW, DAVID J.YUAN, JUN
Owner H LUNDBECK AS
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