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Novel benzo[d][1,3]-dioxol derivatives

a technology of benzo[d][1,3]-dioxol and derivatives, which is applied in the field of new isotopologues, can solve the problems of increased toxicity and blood levels of benzo[d][1,3]-dioxol derivatives, and achieve the effects of increasing, decreasing, or unchanged carcinogenicity, and significant effects on physiological and pharmacological activities

Inactive Publication Date: 2008-11-20
CONCERT PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0021]A compound of Formula I reduces the efficiency of benzodioxol ring cleavage by CY2D6 and beneficially decreases the rate of mechanism-based CYP2D6 inhibition relative to Compound 1. This beneficially decreases the rates of clearance as compared to Compound 1 and produces a corresponding increase in pharmacokinetic half-life.
[0022]The decreased CYP2D6 inhibition is important in reducing the pharmacokinetic interactions between Compound 1 and other drugs metabolized by that enzyme. This provides increased safety as compared to Compound 1.
[0023]In particular, this would produce benefits in the treatment of co-morbidities and the use of combinations of medications, which is common in patients suffering from depression, anxiety and other psychiatric disorders. Moreover, it would be useful in patients taking Compound 1, while being treated by different healthcare providers without disclosing all of their medications to each of them. It would also be beneficial in patients who are using drugs of abuse while taking Compound 1 without the knowledge of their physician.
[0024]The decreased substrate efficiency for CYP2D6 at the methylenedioxy portion of the benzodioxol ring demonstrated by the compounds of this invention will provide the further benefit of reducing inter-patient pharmacokinetic variability observed for Compound 1.
[0034]The compounds of this invention are less effective substrates for CYP2D6 than Compound 1 and therefore display a reduced rate of oxidative metabolism and decreased mechanism-based inactivation of CYP2D6. This reduces the extent of undesirable metabolic drug-drug interactions observed with Compound 1, reducing the need for dose adjustments of other drugs taken by patients treated with these agents.

Problems solved by technology

Co-dosing Compound 1 with those agents causes clinically significant increases in their blood levels, leading to the potential for increased toxicity.

Method used

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Examples

Experimental program
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Effect test

example 1

[0240]Deuterodibromomethane. A solution of 1.1 mole of sodium deuteroxide in 140 mL of deuterium oxide is treated under argon with 116 mmol of arsenious oxide to form a solution of sodium arsenite. Bromoform (190 mmol) is treated under argon with 6.5 mL of ethanol-d (CH3CH2OD) and 1 mL of the sodium arsenite solution and warmed briefly (heat gun) to initiate reaction. The remainder of the sodium arsenite solution is added via dropping funnel at a rate to maintain gentle reflux, then the mixture is heated in a 100° C. oil bath for an additional 4.5 h. The mixture is azeotropically distilled, then the distillate is separated and the aqueous layer extracted with 15 mL of pentane. The organic layers are combined, dried over CaCl2, and distilled to yield the title compound.

example 2

[0241]2-deuterobenzo[d][1,3]dioxole-5-carbaldehyde (Formula V wherein Y═H and R=formyl). A solution of 3,4-dihydroxybenzaldehyde (20 mmol) in 60 mL of dimethylformamide (DMF) is treated under argon with 60 mmol of the product of example 1 and 70 mmol of CsF. The mixture is heated in a 140° C. oil bath for 3 h with vigorous stirring. The mixture is then filtered, concentrated in vacuo, and the residue is purified by silica gel flash chromatography (ether / hexanes eluant), yielding the title product.

example 3

[0242]2-deuterobenzo[d][1,3]dioxol-5-yl formate. A 13.4 mL portion of acetic anhydride is warmed under an argon atmosphere in a 40° C. bath and treated, during 6 h in 3 equal portions, with 10 mmol of 50% hydrogen peroxide. The solution is treated with 10 mmol of the product of example 2, and reaction is allowed to proceed for 2 h at about 40° C. The solvents are removed in vacuo and the residue purified by Kugelrohr distillation at about 2 mm Hg to yield the title product.

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Abstract

The present invention relates to an isotopologue of Compound 1 substituted with deuterium at the methylene carbon of the benzodioxol ring. The isotopologues of this invention selective serotonin reuptake inhibitors (SSRIs) and possess unique biopharmaceutical and metabolic properties compared to Compound 1. They may also be used to accurately determine the concentration of Compound 1 in biological fluids and to determine metabolic patterns of Compound 1 and its isotopologues. The invention further provides compositions comprising these deuterated isotopologues and methods of treating diseases and conditions that are responsive to increased neuronal serotonin transmission, alone and in combination with additional agents.

Description

TECHNICAL FIELD OF THE INVENTION[0001]The present invention relates to novel isotopologues of Compound 1, its acceptable acid addition salts, solvates, hydrates and polymorphs thereof, substituted with deuterium on the methylene carbon atom situated between the oxygens of the benzodioxol ring, and optionally substituted with additional deuterium and 13C atoms in place of the normally abundant hydrogen and 12C, respectively. The compounds of this invention are selective serotonin reuptake inhibitors (SSRIs) and are poorer substrates for metabolism by cytochrome 2D6, and possess unique pharmacokinetic and biopharmaceutical properties compared to the corresponding non-isotopically substituted compounds. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by SSRIs, particularly those relating to major depressive disorder, obsessive compulsive disorder, panic ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4525C07D405/12C12Q1/00C07D317/46A61P25/00A61P15/00A61P9/00A61P3/00A61P35/04A61P17/00
CPCC07D405/12C07D317/64A61K31/4525A61P1/00A61P11/00A61P13/02A61P13/12A61P15/00A61P15/08A61P17/00A61P25/00A61P25/04A61P25/06A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P27/12A61P3/00A61P3/04A61P35/04A61P43/00A61P9/00A61P9/10A61P9/12A61P3/10C07D295/00
Inventor TUNG, ROGER
Owner CONCERT PHARMA INC
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