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Prodrugs and codrusgs containing bio-cleavable disulfide linkers

A pharmaceutical, drug-based technology for use in the field of prodrugs and co-drugs containing biocleavable disulfide linkers

Inactive Publication Date: 2007-09-19
NICHOLAS PIRAMAL INDIA LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, especially during acute myocardial infarction, the early development of resistance to nitrate therapy has been a significant clinical drawback of GTN and some other available organic nitrates

Method used

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  • Prodrugs and codrusgs containing bio-cleavable disulfide linkers
  • Prodrugs and codrusgs containing bio-cleavable disulfide linkers
  • Prodrugs and codrusgs containing bio-cleavable disulfide linkers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0256] Another embodiment of the present invention is the following novel intermediates:

[0257]

[0258] 2-((2-Hydroxyethyl)disulfanyl)ethyl acetate 2-((2-(tetrahydro-2H-pyran-2-yloxy)

[0259] (LI-1a)ethyl)disulfanyl)ethanol (LI-1b)

[0260]

[0261] 2-((2-(trityloxy)ethyl)disulfanyl)ethanol 2-((2-hydroxyethyl)disulfanyl)ethyl2

[0262] (LI-1c) -Chloroacetate (LI-1d)

[0263]

[0264] (LI-1xy) 2-((2-bromoethyl)disulfanyl)ethanol (LI-2a)

[0265]

[0266] 2-((2-Hydroxyethyl)disulfanyl)ethyl nitrate 2-((2-Hydroxyethyl)dithio)ethyl

[0267] (LI-2b) tert-butyl carbamate (LI-2c)

[0268]

[0269] 2-((2-Hydroxyethyl)disulfanyl)ethyl nitrate 2-((2-(tert-butoxycarbonylamino)ethyl)

[0270] (LI-2c, TFA)disulfanyl)ethyl methanesulfonate (LI-2d)

[0271]

[0272] 2-((2-bromoethyl)disulfanyl)ethyl 2-((2-(nitrooxy)ethyl)disulfanyl)

[0273] tert-butyl carbamate (LI-2e) tert-butyl ethyl carbamate (LI-2f)

[0274]

[0275] 1,2-bis(2-bromoethyl)disu...

Embodiment 1

[0779] Synthesis of ethyl 2-[(2-hydroxyethyl)dithio]acetate (LI-1a):

[0780] Acetic anhydride (5.67ml, 56.87mmol) and pyridine (40.4ml, 499mmol) were added to a solution of 2-(hydroxyethyl)disulfide (SL-1, 15.39g, 99.78mmol) in DCM (350ml) at room temperature , the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue obtained after usual aqueous work-up and chromatographic purification 8.16 g of LI-1a (42%) as a pale yellow oil. 1 H-NMR (300MHz, CDCl 3 ): δ2.00(bs, 1H), 2.08(s, 3H), 2.80-2.95(m, 4H), 3.89(t, 2H, J=6Hz), 4.35(t, 2H, J=6Hz), MS : (m / z)219[M] + .

Embodiment 2

[0782] Synthesis of 2-{[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]dithio}ethanol (LI-1b):

[0783] This compound was synthesized by the method described by K.F.Bernady et al., J.Org.Chem., 1979, 44, 1438 . Dihydropyran (8.41 g, 100 mmol) was added to a solution of SL-1 (15.4 g, 100 mmol) in DCM (200 mL) at 0-5 °C, followed by PTSA (-5%) and stirred at room temperature for 5 hours. After the usual aqueous work-up and chromatographic purification of the mixture, 14.5 g of LI-1b (50%) were obtained. 1 H-NMR (300MHz, CDCl 3 ): δ1.5-1.9(m, 6H), 2.88(t, 2H, J=6Hz), 2.94(t, 2H, J=6Hz), 3.45-3.57(m, 1H), 3.67-3.78(m, 1H), 3.85-4.05 (m, 2H), 3.90 (t, 2H, J=6Hz), 4.65 (s, 1H).

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Abstract

The invention provides the compounds of formula (I) or pharmaceutically acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula (I) or intermediates thereof and one more of pharmaceutically acceptable carriers, vehicles or diluents. The invention further provides methods of preparation and methods of use of prodrugs including NO-releasing prodrugs, double prodrugs and mutual prodrugs comprising the compounds of formula (I).

Description

[0001] This application claims priority to US Provisional Application USSN: 60 / 604,632, filed August 26, 2004 and Indian Provisional Application 779 / MUM / 2005, filed July 01, 2005, the contents of which are incorporated herein in their entirety. technical field [0002] The present invention relates to a composition containing a biodegradable linker and a connected prodrug, a method for its preparation, a pharmaceutical composition containing the composition of the prodrug, and the use thereof, and the composition of the prodrug includes a NO releasing prodrug , codrugs, double prodrugs and synergistic prodrugs. Background technique [0003] Prodrugs are the chemical conversion of active drugs into their own inactive derivatives, which are converted to the parent drug in vivo either before or after reaching the site of action using chemical or enzymatic attack. The process of converting an active drug into an inactive form is called drug latentization. Prodrugs can be carrie...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K47/55A61K47/60A61K47/61
Inventor 阿帕拉奥·萨特亚姆
Owner NICHOLAS PIRAMAL INDIA LTD
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