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1,5 and 3,6- substituted indole compounds having NOS inhibitory activity

A technology of compounds and heterocyclic compounds, applied in the fields of organic active ingredients, active ingredients of heterocyclic compounds, organic chemistry, etc.

Inactive Publication Date: 2013-03-20
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, preservation of physiologically important nitric oxide synthase function suggests a need for the development of isozyme-selective inhibitors that preferentially inhibit nNOS over eNOS

Method used

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  • 1,5 and 3,6- substituted indole compounds having NOS inhibitory activity
  • 1,5 and 3,6- substituted indole compounds having NOS inhibitory activity
  • 1,5 and 3,6- substituted indole compounds having NOS inhibitory activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0264] Example 1. Preparation of N-(2-benzyl-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1H-indol-5-yl) Thiophene-2-carboximide (6)

[0265]

[0266] 1-Benzyl-5-nitro-1H-indole (2): Compound 1 (1.0 g, 6.167 mmol) was carried out according to the conditions described in Organic Syntheses, Coll. Vol. 6, p104. The crude product was slurried in boiling hexane, filtered and dried to obtain compound 2.

[0267] 1 H NMR(CDCl 3 )δ 8.61 (d, 1H, J = 2.1 Hz), 8.09 (dd, 1H, J = 2.2, 9.0 Hz), 7.37-7.27 (m, 5H), 7.14-7.09 (m, 2H), 6.74 (d, 1H, J = 3.2 Hz), 5.37 (s, 2H); ESI-MS (m / z, %): 253 (M+1, 100%).

[0268] 2-Benzyl-5-nitro-1H-indole (3): A solution of compound 2 (0.5 g, 1.982 mmol) was treated with polyphosphoric acid as described in Synthetic Communications 1997, 27(12), 2033-2039. The crude product was purified by silica gel column chromatography (EtOAc:hexane, 1:4) to obtain compound 3 (173 mg, 34.6%);

[0269] 1 H NMR(CDCl 3 )δ 8.50 (d, 1H, J = 2.1 Hz), 8.13 (brs, 1H), 8.05 (dd, 1H, J = 2.2,...

Embodiment 2

[0274] Example 2. Preparation of N-(1-(2-(diethylamino)ethyl)-2-(4-(trifluoromethoxy)benzyl)-1H-indole -5-yl)thiophene-2-carboximide (11)

[0275]

[0276] 5-nitro-1-(4-(trifluoromethoxy)benzyl)-1H-indole (7): Add freshly crushed potassium hydroxide (0.692g, 12.332mmol) to a magnetic stir bar And dimethyl sulfoxide (10 mL) in a small argon-purged flask, then the mixture was stirred vigorously for 5 minutes. Compound 1 (500 mg, 3.083 mmol) was added in one portion, and the resulting mixture was stirred at room temperature for 45 minutes, and then briefly cooled to 0°C. 1-(Bromomethyl)-4-(trifluoromethoxy)benzene (1.572g, 6.167mmol) was added dropwise, and then the mixture was stirred for 15 minutes, and then H 2 O dilution. The solution was diluted with ether, transferred to a separatory funnel, and then the organic layer was collected. The aqueous layer was further extracted with ether, and the combined organic layer was extracted with H 2 O (twice), washed with brine, dried ...

Embodiment 3

[0284] Example 3. Preparation of N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-2-(4-(trifluoromethoxy)benzyl (Yl)-1H-indol-5-yl)thiophene-2-carboximide (14)

[0285]

[0286] 1-(2-(1-Methylpyrrolidin-2-yl)ethyl)-5-nitro-2-(4-(trifluoromethoxy)benzyl)-1H-indole (12): Compound 8 (75mg, 0.223mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (45.2mg, 0.245mmol), potassium carbonate (92.4mg, 0.669mmol) and anhydrous two Methylformamide (5 mL) was added to a small, argon-purged flask equipped with a magnetic stir bar, and the resulting solution was heated in an oil bath at 65°C for 20 hours. After cooling to room temperature, use H 2 Dilute O and ethyl acetate, transfer to a separatory funnel, and then collect the organic layer. The aqueous layer was further extracted with ethyl acetate, and the combined organic layer was washed with brine (twice), dried over magnesium sulfate, filtered and concentrated to obtain a crude solid. The crude product was purified by dry silica gel co...

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Abstract

The present invention features inhibitors of nitric oxide synthase (NOS), particularly those inhibitors that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isozymes, the NOS inhibitors of the present invention, which Useful, alone or in combination with other pharmaceutically active agents, for the treatment or prevention of conditions such as: e.g. stroke, reperfusion injury, neurodegenerative disease, head trauma, CABG, migraine headache with aura and without aura, with allodynia of migraine, central post-stroke pain (CPSP), neuropathic pain, or chronic pain.

Description

technical background [0001] The present invention relates to new 1,5 and 3,6-substituted indole compounds with nitric oxide synthase (NOS) inhibitory activity, and pharmaceutical compositions and diagnostic compositions containing them, and their medical applications, especially As used to treat stroke, reperfusion injury, neurodegenerative diseases, head trauma, coronary artery bypass graft (CABG) related neurological injury, migraine with aura and without aura, allodynia (allodynia) Medical application of compounds for migraine, chronic tension-type headache (CTTH), neuropathic pain, central pain after stroke (CPSP) and chronic pain. Background technique [0002] Nitric oxide (NO) has different roles in normal and pathological processes, including blood pressure regulation, neurotransmission, and macrophage defense system (Snyder et al., Scientific American, May 1992: 68). NO is synthesized by three isoforms of nitric oxide synthase, which are constitutive in endothelial cells...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/14A61K31/4025A61K31/439A61K31/4436A61K31/454A61K31/5377A61K31/55C07D405/14C07D409/12C07D413/14C07D471/08
CPCC07D405/14C07D471/08C07D405/12C07D409/12C07D409/14C07D403/06A61P9/06A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/36A61P29/00A61P43/00
Inventor S·马达福特J·拉姆诺思S·拉基特J·帕特曼P·伦顿S·C·安尼迪
Owner 轴突公司
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