Prodrugs containing novel bio-cleavable linkers

a technology of bio-cleavage and prodrugs, applied in the field of prodrugs compositions, can solve the problems of limited intestinal absorption, fast metabolism, cell damage or death,

Inactive Publication Date: 2006-09-14
PIRAMAL ENTERPRISES LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0097] Another aspect of the present invention is to provide new nitrate ester (NO-releasing) prodrugs of many types of existing drugs using novel biocleavable likers. Such prodrugs are expected to exhibit better efficacy and tolerability with reduced side effects compared to the corresponding original drugs.
[0140] In a further embodiment D2 is a peptide, protein or monoclonal antibody for achieving targeted delivery of prodrugs and drugs. Another embodiment of the invention is the compound of formula I, wherein D2 is a ligand or dipeptide or a dipeptide ligand. In a further embodiment D2 is a dipeptide ligand that is a substrate for intestinal transporters for selective intestinal absorption of the corresponding prodrugs thereby increasing the bioavailability of the prodrugs. In a further embodiment D2 is a targetable small peptide, i.e., dipeptide, tripeptide, tetrapeptide, etc.
[0392] It should also be understood that a pharmaceutical composition containing a combination of one of the above listed / qualified drug(s) and its own prodrug is also covered (i.e., a pharmaceutical composition consisting of NO-Paracetamol and Paracetamol in any proportion). In such pharmaceutical combinations, the free drug will be useful for faster onset of action and the prodrug will be useful for extension of the duration of action as it releases the drug in a controlled fashion over a longer period of time. Such combination drug therapy may also minimize the toxicity and other side effects due to excessive plasma concentration of free drug. It should also be understood that a pharmaceutical combination may contain a prodrug of one of the above listed / qualified drugs and an another type of prodrug of the same drug (i.e., NO prodrug of paracetamol and mutual prodrug of paracetamol with another drug) and these can be present in any therapeutic proportion depending on the medical need.EXPERIMENTAL

Problems solved by technology

Limited intestinal absorption, distribution, fast metabolism, and toxicity are some of the causes of failure of drug candidates during development.
In this setting, NO is often viewed as pathogenic.
In patients with cardiovascular problems, the production of superoxide is increased and level or location of NO synthesis is disrupted thereby causing cellular dysfunction as a result of vasoconstriction of blood vessels, which can lead to, if prolonged, cell damage or death.
However, early development of tolerance to nitrate therapy, particularly during acute myocardial infarction, has been the clinically significant drawback with GTN and some of the other available organic nitrates.
This is a significant clinical problem and there exists a need for novel nitrate-based anti-anginal agents, which do not cause the problem of nitrate tolerance.

Method used

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Examples

Experimental program
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Effect test

example 1

[0443] Synthesis of 2-[(2-hydroxyethyl)dithio]ethyl acetate (LI-1a):

[0444] Acetic anhydride (5.67 ml, 56.87 mmol) and pyridine (40.4 ml, 499 mmol) were added to a solution of 2-(hydroxyethyl)disulfide (SL-1, 15.39 g, 99.78 mmol) in DCM (350 mL) at RT and the mixture was stirred at RT for 16 h. The mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, afforded 8.16 g (42%) of LI-1a as a pale yellow oil. 1H-NMR (300 MHz, CDCl3): ( 2.00 (bs, 1H), 2.08(s, 3H), 2.80-2.95 (m, 4H), 3.89 (t, 2H, J = 6 Hz), 4.35 (t, 2H, J = 6 Hz), MS: (m / z) 219 [M]+.

Example 2

[0445] Synthesis of 2-{[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]dithio}ethanol (LI-1b):

[0446] This compound was synthesized by a 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 oC, followed by PTSA (~5%) and stirred at RT for 5 h. The mixture, after usual aqueou...

example 13

[0473] Synthesis of prodrug I-C1-PD6: Step 1: To a suspension of aspirin (3 g, 16.65 mmol) in benzene (25 mL) and DMF (2 drops) at 0-5 oC was added oxalyl chloride (1.7 mL, 19.98 mmol) in benzene (5 mL). The reaction mixture was refluxed at 85 oC for 2 h, cooled to RT and concentrated to give a yellow oil.

[0474] Step 2: The yellow oil was dissolved in benzene (30 mL), silver cyanate (2.99 g, 19.98 mmol) was added and the mixture was refluxed for 1h in the dark.

[0475] Step 3: The reaction mixture was cooled to RT, and a solution of SL-1 (2.56 g, 16.65 mmol) in benzene (5 mL). The reaction mixture was stirred for 1h, filtered through celite, concentrated and purified by column chromatography to afford 2.24 g (54%) of I-C1-PD6. 1H NMR (CDCl3, 300 MHz): ( 2.12 (s, 3H), 2.83-2.91 (m, 4H), 3.84 (t, J = 5.9 Hz, 2H), 4.27 (t, J = 5.16 Hz, 2H), 6.20 (br s, 1H), 7.06 (d, J = 8.21 Hz, 1H), 7.19 (t, J = 7.55 Hz, 1H), 7.59 (t, J = 7.24 Hz, 1H), 7.97 (d, J = 6.82 Hz, 1H). MS: m / z 360.06 [M+H]+,...

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Abstract

Abstract of the DisclosureThe 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 or 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

Detailed Description of the Invention[0001] This application takes priority from US Provisional Application USSN: 60 / 604,632 filed 26 August 2004 and Indian Provisional Application 779 / MUM / 2005 filed 01 July 2005, which are herein incorporated in their entirety.Field of the Invention[0002] The present invention relates to compositions of prodrugs, including NO-releasing prodrugs, codrugs, double prodrugs and mutual prodrugs, containing bio-labile linkers and linkages, processes for their preparation and pharmaceutical compositions containing them and their use.Background of the Invention[0003] A prodrug is an active drug chemically transformed into a per se inactive derivative which by virtue of chemical or enzymatic attack is converted to the parent drug within the body before or after reaching the site of action. The process of converting an active drug into inactive form is called drug latentiation. Prodrugs can be carrier-linked-prodrugs and bioprecursors. The carrier-linked p...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/04A61K31/7072A61K31/455A61K31/53A61K31/4172A61K31/4178A61K31/337A61K31/21
CPCC07C323/12C07C323/25C07C323/41C07C323/42C07D207/26C07D211/22C07D211/90C07D213/82C07D233/91C07D253/075C07D261/08C07D295/088C07D305/14C07D401/12C07D401/14C07D405/12C07D411/14C07D413/12C07D495/04C07C2601/14A61K47/60A61K47/55A61K47/551A61K47/555A61K47/61A61P13/00A61P13/10A61P17/00A61P19/00A61P21/00A61P23/00A61P25/28A61P27/02A61P27/16A61P3/00A61P31/00A61P35/00A61P37/00A61P37/08A61P9/00
Inventor SATYAM, APPARAO
Owner PIRAMAL ENTERPRISES LTD
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