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Prodrugs of riluzole and their method of use

a technology of riluzole and prodrugs, which is applied in the field of prodrugs of riluzole and their method of use, can solve the problems of limited clinical application of riluzole to other disease states, low solubility of riluzole in water, and liver metabolism problems, and achieve the effect of enhancing the activity of a serotonin reuptake inhibitor (sri)

Pending Publication Date: 2021-08-05
BIOHAVEN THERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a clinical trial to evaluate the effectiveness and safety of a drug called riluzole in treating Alzheimer's disease. The trial involves giving riluzole to patients with mild to moderate Alzheimer's disease for 48 weeks. The trial is designed to measure the change in cognitive function and behavior using a variety of tests. The trial is being conducted in parallel groups, with one group receiving riluzole and the other a placebo. The trial is blinded, meaning that both the researchers and the patients are unaware of which treatment they are receiving. The trial is designed to enroll 290 participants and has a duration of 42 days. The key inclusion criteria are age 50 to 85, diagnosis of probable Alzheimer's disease dementia, living in the community, and stable dosage regimen of FDA-approved AD medications. The key exclusion criteria include hepatic impairment, other neurodegenerative diseases, and certain cancers. The trial is designed to provide preliminary data on the effectiveness and safety of riluzole in treating Alzheimer's disease.

Problems solved by technology

Despite riluzole's approval over 20 years ago, these multiple clinical constraints of riluzole have persisted and limited the clinical application of riluzole to other disease states.
However, riluzole can have issues in liver metabolism.
Riluzole has a very low solubility in water, poor oral palatability, pH dependent chemical stability, and intense as well as persistent numbness or burning sensation throughout the oral cavity.

Method used

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  • Prodrugs of riluzole and their method of use
  • Prodrugs of riluzole and their method of use
  • Prodrugs of riluzole and their method of use

Examples

Experimental program
Comparison scheme
Effect test

example 1

of 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide

[0837]

[0838]To a solution of 2-amino-6-(trifluoromethoxy)benzimidazole (0.50 g, 2.1 mmol), N-(t-butyloxycarbonyl) glycine (0.56 g, 3.2 mmol) and N,N-diisopropylethylamine (0.41 g, 3.2 mmol, 0.57 ml) in dimethylformamide (7 ml) was added 1[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.2 g, 3.2 mmol) and the mixture stirred at 20° C. for 18 hours. Ethyl acetate (100 ml) was added and the mixture was washed with water (2×75 ml), 1N HCl (75 ml), water (75 ml), 1M sodium carbonate solution (75 ml) and brine. The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel eluted with a gradient of ethyl acetate in hexanes (50% to 75%) to leave the product as a white foamy solid (0.78 g, 95%). LC / MS method A: Rt=5.92 min., (M+H)+=392. The product was dissolved in 4N HCl / 1,4-dioxane and stirred for 2 h. The solvents were evaporat...

example 2

of 2-(Methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) acetamide hydrochloride

[0839]

[0840]2-(Methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) acetamide hydrochloride was prepared according to the procedure of example 1 from 2-amino-6-(trifluoromethoxy) benzimidazole (0.50 g, 2.1 mmol) and N-(t-butyloxycarbonyl)sarcosine (0.60 g, 3.2 mmol). Yield for intermediate=0.96 g (100%). LC / MS method A: Rt=5.92 min., (M+H)+=406. Yield for final product (0.82 g, 100%, 100% overall). LC / MS method A: Rt=3.60 min., (M+H)+=306.

example 3

of 2-(Ethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride

[0841]

[0842]2-(Ethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride was prepared according to the procedure of example 1 from 2-amino-6-(trifluoromethoxy)benzimidazole (117 mg, 0.5 mmol) and N-t-butyloxycarbonyl-2-(ethylamino)acetic acid (122 mg, 0.6 mmol). Yield for Boc protected intermediate 182 mg (87%). LC / MS method A: Rt=6.20 min., (M+H)+=420. Yield for final product (142 mg, 87% overall). LC / MS method A: Rt=3.67 min., (M+H)+=320.

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Abstract

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. application Ser. No. 16 / 865,498 filed May 4, 2020, which is a continuation of U.S. application Ser. No. 15 / 549,152 filed Aug. 5, 2017 issued as U.S. Pat. No. 10,639,298 on May 5, 2020, which is a national stage application under 35 U.S.C. § 371 of international application No. PCT / US2016 / 019773, filed Feb. 26, 2016, which claims priority to and the benefit of U.S. Provisional Application No. 62 / 127,684 filed Mar. 3, 2015, the contents of all of which applications and patents are herein incorporated by reference in their entireties.STATEMENT OF FEDERALLY FUNDED RESEARCH[0002]The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as provided for by the terms of grant number R43 CA156781-01 and R44 CA156781-02 awarded by the National Cancer Institute.FIELD OF INVENTION[0003]The prese...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/428A61P25/00A61P25/28A61K38/06C07K5/083C07K5/087C07D277/82A61K31/454A61K31/496A61K31/5377A61K38/05A61K45/06C07D417/12C07K5/062A61K9/00A61K9/16A61K9/20
CPCA61K31/428A61K2300/00A61P25/28A61K38/06C07K5/0806C07K5/0808C07K5/0812C07D277/82A61K31/454A61K31/496A61K31/5377A61K38/05A61K45/06C07D417/12C07K5/06026A61K9/006A61K9/1617A61K9/2004A61P25/00C07K5/06034C07K5/06078C07K5/06052C07K5/06139C07K5/06069C07K5/06043C07K5/06156C07K5/06104C07K5/06173A61K9/4866A61K9/0056A61K9/2018A61K9/2063A61K9/485A61K9/4858
Inventor WROBEL, JAY EDWARDREITZ, ALLEN B.PELLETIER, JEFFREY CLAUDESMITH, GARRY ROBERTBIAN, HAIYAN
Owner BIOHAVEN THERAPEUTICS LTD
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