(+)-3-hydroxymorphinan-based polycycle derivatives as neuroprotectants

A hydroxyl, neurodegenerative technology, applied in nervous system diseases, drug combinations, medical preparations containing active ingredients, etc., can solve problems such as lack of efficacy or safety of drugs, and failure to achieve clinical efficacy.

Inactive Publication Date: 2013-01-30
GREEN CROSS CORP THE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite advances in understanding the mechanisms of ischemic injury and in identifying drugs that are effective in animal models of stroke, clinical efficacy has yet to be achieved
Several drugs that have entered phase III clinical trials have been discontinued due to lack of efficacy or safety concerns

Method used

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  • (+)-3-hydroxymorphinan-based polycycle derivatives as neuroprotectants
  • (+)-3-hydroxymorphinan-based polycycle derivatives as neuroprotectants
  • (+)-3-hydroxymorphinan-based polycycle derivatives as neuroprotectants

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] (6S, 6aS, 10aS)-2,3,4,5,6,6a,7,8,9,10-decahydro-6,10a-(cycloimine bridge ethylene)phenanthrene[2,1 -b][1,4]oxazin-12-ol TFA salt (11)

[0161] step 1:

[0162] (4bS, 8aS, 9S)-benzyl 3-hydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(cycloiminoethylene)phenanthrene-11-carboxylic acid Esters (2)

[0163]

[0164] To (4bS, 8aS, 9S)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(cycloimine bridge ethylene)phenanthrene-3-alcohol HBr(1)(50.0 g, 154 mmol) and sodium hydroxide (12.3 g, 308 mmol) in 1,4-dioxane (500 mL) and water (500 mL) was added Cbz-Cl (24.2 mL, 170 mmol) dropwise. The reaction mixture was vigorously stirred overnight at room temperature. After the reaction was complete, water (200 mL) was added. The mixture was extracted with ether (500 mL x 2). The combined organic phases were washed with MgSO 4 Dry, filter and evaporate under vacuum. The residue was subjected to flash column chromatography (Biotage SP1 TM ) to afford the title compound (54.6 g, 94%) as a white solid...

Embodiment 2

[0213] (7S, 7aS, 11aS)-3, 4, 5, 6, 7, 7a, 8, 9, 10, 11-decahydro-2H-7, 11a- (cycloimine bridge ethylene) phenanthrene [2 , 1-b][1,4]oxazepine -13-alcohol TFA salt (12)

[0214]

[0215] Using N-(3-bromopropyl)phthalimide (13) to replace N-(2-bromoethyl)phthalimide (7), repeat the steps of Example 1 to prepare Example 2 compounds.

[0216] 1 H NMR (400MHz, CD 3 OD) 4.14-4.13(m, 1H), 4.07-4.06(m, 1H), 3.74-3.72(m, 1H), 3.35-3.33(m, 2H), 3.06(dd, J=12.8, 2.8Hz, 1H), 2.97-2.90(m, 1H), 2.75(td, J=13.2, 3.6Hz, 1H), 2.68-2.63(m, 1H), 2.36-2.33(m, 1H), 2.10-1.99(m, 3H), 1.85(dt, J=12.4, 2.8Hz, 1H), 1.78-1.65(m, 2H), 1.58-1.45(m, 4H), 1.42-1.21(m, 4H), 1.16-1.06(m, 1H).

[0217] MH+315.

Embodiment 3

[0219] 1-((6S, 6aS, 10aS)-12-hydroxyl-2,3,6,6a,7,8,9,10-octahydro-6,10a-(cycloimine bridge ethylene)phenanthrene[ 2,1-b][1,4]oxazin-4(5H)-yl)ethanone TFA salt (15)

[0220] step 1:

[0221] (6S, 6aS, 10aS)-benzyl 4-acetyl-12-(benzyloxy)-2,3,4,5,6,6a,7,8,9,10-decahydro-6,10a- (Cycloiminoethylene)phenanthrene[2,1-b][1,4]oxazine-15-carboxylate (14)

[0222]

[0223] (6S, 6aS, 10aS)-benzyl 12-(benzyloxy)-2,3,4,5,6,6a,7,8,9,10-decahydro-6,10a- (Cycloiminoethylene)phenanthrene[2,1-b][1,4]oxazine-15-carboxylate (10) (120mg, 0.229mmol), DMAP (33.6mg, 0.275mmol) and To a solution of DIPEA (0.36 mL, 2.06 mmol) in DCM (20 mL) was added acetyl chloride (0.1 mL, 1.37 mmol). The reaction mixture was stirred overnight at 50 °C. The reaction mixture was evaporated under vacuum to remove solvent. The residue was subjected to flash column chromatography (Biotage SP1 TM ) to afford the title compound (96 mg, 74%) as a brown gum.

[0224] MH+567.

[0225] Step 2: 1-((6S,6aS,10S)-12-Hydr...

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Abstract

A (+)-3-hydroxymorphinan-based polycycle derivative of formula (I) is effective as a neuroprotective agent for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemic stroke.

Description

technical field [0001] The present invention relates to novel (+)-3-hydroxymorphinan ((+)-3-HM) based polycyclic derivatives effective as neuroprotective agents. Background technique [0002] The concept of neuroprotection applies to chronic diseases of the brain as well as acute neurological disorders, since some of the underlying mechanisms to central nervous system (CNS) injury are similar in these disorders. Neurodegenerative diseases include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Neuroprotection has been implicated as a mechanism of action for some drugs used to treat these conditions. [0003] Neurodegeneration in PD, AD, and other neurodegenerative diseases appears to be multifactorial, in which a series of complex toxicities (including inflammation, glutamatergic neurotoxicity, increases in iron and nitric oxide, Depletion, decreased expression of trophic factors, dysregulation of the u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/08C07D491/08A61K31/5386A61P25/00
CPCC07D471/08C07D491/08C07D498/08A61P25/00A61P25/16A61P25/28A61K31/5386
Inventor 李镇华金钟烨金政民安光羽
Owner GREEN CROSS CORP THE
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