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Spirocyclic heterocyclic derivatives and methods of their use

A compound and alkyl technology, applied in the field of spirocyclic heterocyclic derivatives, can solve problems such as unsuitable source of peptides

Inactive Publication Date: 2009-04-22
APOLOR CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] A number of selective delta opioid ligands are of peptide origin in nature and thus unsuitable for systemic administration

Method used

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  • Spirocyclic heterocyclic derivatives and methods of their use
  • Spirocyclic heterocyclic derivatives and methods of their use
  • Spirocyclic heterocyclic derivatives and methods of their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0393] Preparation of 1.4a:

[0394] To a solution of 1.1 (2.25 g, 5 mmol, 1 equiv) in anhydrous THF (40 mL) was added tetrakis(triphenylphosphine)palladium(0) (290 mg, 0.25 mmol, 0.05 equiv), followed by dropwise addition of (3-ethoxy -3-Oxopropyl)zinc(II) bromide 1.2 (0.5 M in THF, 16 mL, 8 mmol, 1.6 equiv). The reaction mixture was stirred at room temperature for 10 hours, then quenched with aqueous ammonium chloride (50 mL). The product was extracted with diethyl ether (3 x 100 mL) and the combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate mixtures of increasing polarity). Yield: 62.5%

[0395] 1 H NMR (400MHz, CDCl 3 )δ 7.23-7.12 (m, 2H), 6.95-6.83 (m, 2H), 5.36 (s, 1H), 4.14 (q, 2H), 3.82 (m, b, 2H), 3.27 (m, b, 2H ), 2.74(m, 2H), 2.54(m, 2H), 1.93(m, 2H), 1.60-1.45(m, 11H), 1.26(t, 3H). Mass spectrometry m / z=402...

Embodiment 1B

[0406] Preparation of 1.4b:

[0407] To a solution of 1.1 (2.25 g, 5 mmol, 1 equiv) in anhydrous THF (40 mL) was added tetrakis(triphenylphosphine)palladium(0) (290 mg, 0.25 mmol, 0.05 equiv), followed by dropwise addition of (5-ethoxy -5-Oxopentyl)zinc(II) bromide 1.3 (0.5 M in THF, 16 mL, 8 mmol, 1.6 equiv). The reaction mixture was stirred at room temperature for 10 hours, then quenched with aqueous ammonium chloride (50 mL). The product was extracted with diethyl ether (3 x 100 mL) and the combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate mixtures of increasing polarity). Yield: 58%

[0408] 1 H NMR (400MHz, CDCl 3 )δ 7.20(dd, 1H), 7.14(m, 1H), 6.90(m, 1H), 6.86(dd, 1H), 5.35(s, 1H), 4.14(q, 2H), 3.82(m, 2H) , 3.28(m, 2H), 2.43(m, 2H), 2.36(t, 2H), 1.99-1.83(m, 4H), 1.63-1.51(m, 2H), 1.47(s, 9H), 1.26(t , 3H). Ma...

Embodiment 1C

[0420] Preparation of 1C:

[0421] 1C (hydrochloride) was obtained according to a method similar to that described for 1D (hydrochloride) except that:

[0422] Step 1.5: Replace 1B with 1A.

[0423] 1 H NMR (400MHz, DMSO-d 6 )δ 8.94(m, 2H), 7.31(m, 1H), 7.11(m, 1H), 6.90(m, 1H), 6.83(m, 1H), 3.32-3.20(m, 6H), 3.11(m, 1H), 2.90(m, 2H), 2.31(m, 3H), 2.03(m, 1H), 1.88(m, 3H), 1.68(m, 2H), 1.50(m, 1H), 1.08(t, 3H ), 1.00(t, 3H)

[0424] Mass spectrometry m / z=331.0 (M+H) +

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PUM

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Abstract

Spirocyclic heterocyclic derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the spirocyclic heterocyclic derivatives are ligands of the d-opioid receptor and may be useful, inter alia, for treating and / or preventing pain, anxiety, gastrointestinal disorders, and other delta-opioid receptor-mediated diseases, disorders, and / or conditions.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application 60 / 790,416, filed April 6, 2006, and US Invention Patent Application 11 / 699,585, filed April 4, 2007, the disclosures of which are incorporated herein by reference in their entirety. technical field [0003] The present invention relates to spiroheterocyclic derivatives (including spiro(2H-1-benzopyran-2,4'-piperidine and spiro[1,2,3,4-tetralin-2,4'-piperidine) pyridine derivatives), pharmaceutical compositions comprising these compounds and methods for their use in medicine. In certain embodiments, spirocyclic heterocyclic derivatives are ligands for delta opioid receptors, particularly useful in the treatment of And / or prevent pain, anxiety, gastrointestinal dysfunction and other conditions mediated by delta opioid receptors. Background technique [0004] At least 3 different opioid receptors (μ, δ, and κ) are present in the central and peripheral nervou...

Claims

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Application Information

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IPC IPC(8): A61K31/438C07D221/20
Inventor 罗兰·E·多勒贝特朗·勒布尔多内克褚国华
Owner APOLOR CORP
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