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Showing posts with label Ladostigil. Show all posts
Showing posts with label Ladostigil. Show all posts

Wednesday 1 June 2016

Ladostigil

Ladostigil.png
Ladostigil.png

Ladostigil, TV-3,326
(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate
(3R)-3-(Prop-2-ynylamino)indan-5-yl ethyl(methyl)carbamate; R-CPAI
Carbamic acid, ethylmethyl-, (3R)-2,3-dihydro-3-(2-propynylamino)-1H-inden-5-yl ester
Condition(s): Mild Cognitive Impairment
U.S. FDA Status: Mild Cognitive Impairment (Phase 2)
Company: Avraham Pharmaceuticals Ltd
Target Type: Cholinergic System
CAS No:209349-27-4
Synonyms:Ladostigil, TV-3326, UNII-SW3H1USR4Q
Molecular Weight:272.346 g/mol


Chemical Formula:C16-H20-N2-O2


IUPAC Name:(3R)-3-(Prop-2-ynylamino)indan-5-yl ethyl(methyl)carbamate N-Propargyl-(3R)-aminoindan-5-yl) ethyl methyl carbamate


Ladostigil tartrate Structure
CAS 209394-46-7, Ladostigil tartrate
N-Ethyl-N-methylcarbamic acid 3(R)-(2-propynylamino)-2,3-dihydro-1H-inden-5-yl ester L-tartrate
In 2010, ladostigil tartrate was licensed by Technion Research & Development Foundation and Yissum to Avraham for the treatment of Alzheimer's disease and other neurogenerative diseases.





Ladostigil (TV-3,326) is a novel neuroprotective agent being investigated for the treatment of neurodegenerative disorders likeAlzheimer's diseaseLewy body disease, and Parkinson's disease.[1] It acts as a reversible acetylcholinesterase andbutyrylcholinesterase inhibitor, and an irreversible monoamine oxidase B inhibitor, and combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule.[2][3] In addition to its neuroprotective properties, ladostigil enhances the expression of neurotrophic factors like GDNF and BDNF, and may be capable of reversing some of the damage seen in neurodegenerative diseases via the induction of neurogenesis.[4] Ladostigil also has antidepressant effects, and may be useful for treating comorbid depression and anxiety often seen in such diseases as well.[5][6]
Ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] is a dual acetylcholine-butyrylcholineesterase and brain selective monoamine oxidase (MAO)-A and -B inhibitor in vivo (with little or no MAO inhibitory effect in the liver and small intestine), intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression (presently in a Phase IIb clinical study). This suggests that the drug should not cause a significant potentiation of the cardiovascular response to tyramine, thereby making it a potentially safer antidepressant than other irreversible MAO-A inhibitors. Ladostigil was shown to antagonize scopolamine-induced impairment in spatial memory, indicating that it can cause significant increases in rat brain cholinergic activity. Furthermore, ladostigil prevented gliosis and oxidative-nitrative stress and reduced the deficits in episodic and spatial memory induced by intracerebroventricular injection of streptozotocin in rats. Ladostigil was demonstrated to possess potent anti-apoptotic and neuroprotective activities in vitro and in various neurodegenerative rat models, (e.g. hippocampal damage induced by global ischemia in gerbils and cerebral oedema induced in mice by closed head injury). These neuroprotective activities involve regulation of amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase signaling pathways; inhibition of neuronal death markers; prevention of the fall in mitochondrial membrane potential and upregulation of neurotrophic factors and antioxidative activity. Recent findings demonstrated that the major metabolite of ladostigil, hydroxy-1-(R)-aminoindan has also a neuroprotective activity and thus, may contribute to the overt activity of its parent compound. This review will discuss the scientific evidence for the therapeutic potential use of ladostigil in Alzheimer's and Lewy Body diseases and the molecular signaling pathways that are considered to be involved in the biological activities of the drug
    Example 3Ethylmethyl-carbamic acid 3-oxo-indan-5-yl ester
    Figure US20060199974A1-20060907-C00011
    Ethylmethyl carbamyl chloride (15.5 g, 127.57 mmol) was added to a stirred suspension of 6-hydroxy-1-indanone (17.2 g, 116.1 mmol) and potassium carbonate (31.8 g, 188 mmol) in acetonitrile (800 mL) at room temperature over a period of 15 minutes. The reaction mixture was heated to reflux and refluxed for 18 hours. The reaction mixture was cooled to ambient temperature, the solvent evaporated and the residue was diluted with water (250 mL) and extracted three times with toluene (250 mL). The combined organic phase was dried on MgSOand toluene was evaporated in a rotary evaporator. The crude crystalline product was purified by crystallization from 2-propanol (200 mL), collected by filtration, and dried under vacuum at 50° C. to afford the title compound (22 g, 81.5%). 1H NMR (300 MHz, CDCl3) δ ppm 7.47-7.44 (2H, m, Ar), 7.36 (1H, dd, J 8.4 and 2.1, Ar), 3.52-3.37 (2H, m, NCH2CH3), 3.14-3.108 [2H, m, OCCH2CHand incl. NCH(two rotamers), at 3.08 and 2.99 (3H, s, Me)], 2.74-2.71 (2H, m, OCCH2CH2) and 1.25 and 1.19 (two rotamers) (3H,two triplets, J 6.9). Mass Spectrum (FAB+) [MH+=234

      Example 6(S)-Dimethyl-carbamic acid 3-prop-2-ynylamino-indan-5-yl ester
      Figure US20060199974A1-20060907-C00014
      Methanesulfonyl anhydride (296 mg, 1.7 mmol) as a solution in dichloromethane (1.5 mL+0.5 mL) was added to a stirred solution of (R)-dimethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester (188 mg, 0.8 mmol, product of example 1a) and triethylamine (0.47 mL, 3.4 mmol) in dichloromethane (2 mL) at −78° C. (external) over 10 minutes. The reaction was maintained at this temperature for 1 hour before propargylamine (1.20 mL, 17.0 mmol) was added. The reaction was allowed to warm slowly to room temperature overnight before being partitioned between ethyl acetate (20 mL) and ice-water (20 mL). The organic material was concentrated under reduced pressure to afford a brown oil which was partitioned between methyl tert-butyl ether (10 mL) and aqueous hydrochloric acid (1M, 10 mL). The aqueous layer was basified by addition of aqueous sodium hydroxide solution (2M, 16 mL) before being extracted with ethyl acetate (10 mL). This final organic extract was dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (175 mg, 80%). 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (1H, d, J 8, Ar), 7.09 (1H, d, J 2, Ar), 6.94 (1H, dd, J 8 and 2, Ar), 4.39 (1H, dd, J 6 and 6, CHNH), 3.54 (1H, Dd, J 17 and 3, NCHH), 3.49 (1H, Dd, J 16 and 3, HNCHH), 3.09 (3H, s, Me), 3.03-2.96 [4H, m, NCHCHH and Me incl. at 3.00 (3H, s, Me)], 2.83-2.75 (1H, m, NCHCHH), 2.48-2.39 (1H, m, NCHCH2CHH), 2.25 (1H, t, J 2, ≡CH) and 1.92-1.83 (1H, m, NCHCH2CHH). Analysis of this material by chiral LC indicated it to be 70% e.e.
    Example 7b(R)-Ethyl-methyl-carbamic acid 3-prop-2-ynylamino-indan-5-yl ester (ladostigil)
    Figure US20060199974A1-20060907-C00016
    The procedure of example 7a is repeated with (S)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester instead of (R)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester. The R-enantiomer is produced.

PAPER

Tetrahedron: Asymmetry (2012), 23(5), 333-338
Image for unlabelled figure
Graphical absImg(R)-3-(Prop-2-ynylamino)-2,3-dihydro-1H-inden-5-yl ethyl(methyl)carbamate
C16H20N2O2
ee: 89%
View the MathML source (c 1.46, CHCl3)
Source of chirality: the precursor
Absolute configuration: (R)

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Yavneh, 81227
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Ladostigil
Ladostigil.png
Systematic (IUPAC) name
[(3R)-3-(prop-2-ynylamino)indan-5-yl]-N-propylcarbamate
Clinical data
Routes of
administration
Oral
Legal status
Legal status
  • Uncontrolled
Identifiers
CAS Number209349-27-4
ATC codenone
PubChemCID 208907
ChemSpider181005
UNIISW3H1USR4Q Yes
Synonyms[N-propargyl-(3R)-aminoindan-5yl]-N-propylcarbamate
Chemical data
FormulaC16H20N2O2
Molar mass272.34 g/mol
///////////Ladostigil, TV-3,326
c1c(cc2c(c1)CC[C@H]2NCC#C)OC(=O)N(CC)C