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Mavacamten for use in the treatment of hypertrophic cardiomyopathy

A kind of hypertrophic cardiomyopathy, general technology, applied in the treatment of myocardial diastolic dysfunction, the field of treatment of hypertrophic cardiomyopathy

Pending Publication Date: 2020-05-19
MYOKARDIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In patients with hemodynamically significant outflow tract obstruction (gradient ≥50 mmHg), myectomy or interval alcohol ablation can be used to relieve hemodynamic obstruction but is associated with significant clinical morbidity and mortality

Method used

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  • Mavacamten for use in the treatment of hypertrophic cardiomyopathy
  • Mavacamten for use in the treatment of hypertrophic cardiomyopathy
  • Mavacamten for use in the treatment of hypertrophic cardiomyopathy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0263] Example 1. Preparation of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0264]

[0265] Compound 1.1. Isopropylurea. To isopropylamine (15.3 g, 0.258 mol, 1.0 equiv) in CH at 0 °C under argon 2 Cl 2 To a stirred solution in (200 mL) was added trimethylsilyl isocyanate (30 g, 0.26 mol, 1.0 equiv) dropwise. The resulting mixture was allowed to come to ambient temperature and stirred overnight. After cooling to 0°C, CH was added dropwise 3 OH (100 mL). The resulting solution was stirred at room temperature for 2 hours (h) and then concentrated under reduced pressure. The crude residue was converted from CH 3 OH:Et 2 Recrystallization from O (1:20) yielded 15.4 g (58%) of the title compound as a white solid. LC / MS: m / z(ES+)103(M+H) + .

[0266]

[0267] Compound 1.2.1-Isopropylbarbituric acid. To 1.1 (14.4g, 0.14mol, 1.00 equiv) in CH 3 To a stirred solution in OH (500 mL) was added dimethyl malonate (19.55 g, 0.148 mol, 1.05 eq)...

Embodiment 2I

[0272] Embodiment 2. Phase I clinical research

[0273] Three clinical studies have investigated the safety and tolerability of Compound 1 to date; the conduct of 2 studies has been completed and 1 study is ongoing. A double-blind, placebo-controlled, single ascending dose study (SAD) (Compound 1-002) was conducted in healthy men. Subjects receive a single dose ranging from 1 mg to 48 mg. An open-label sequential cohort SAD study (Compound 1-001) in clinically stable HCM was also completed; single doses up to 144 mg were administered. In addition, a double-blind, placebo-controlled, multiple ascending dose (MAD) study (Compound 1-003) is ongoing in which healthy adult subjects receive multiple doses of Compound 1 up to 25 mg once daily (QD), Lasts up to 28 days.

[0274]

[0275]

[0276] (1) 48 mg cohort (n=4 patients); 96 mg cohort (n=6); 144 mg cohort (n=5).

[0277] (2) Each cohort is randomized 6:2 to Compound 1 or matching placebo.

[0278] (3) Each cohort i...

Embodiment 3

[0302] Example 3. For evaluation in subjects with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction Phase 2 Development Label Preliminary Study of Efficacy, Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Compound 1 (Pioneer-HCM-A)

[0303] Research purposes:

[0304] the main purpose:

[0305] To characterize the effect of 12 weeks of Compound 1 treatment on reducing post-exercise peak left ventricular outflow tract (LVOT) gradient in subjects with symptomatic hypertrophic cardiomyopathy (HCM) and LVOT obstruction

[0306] Secondary purpose:

[0307] Proportion of subjects achieving LVOT gradient response with peak post-exercise gradient <30 mm Hg assessed in subjects with symptomatic HCM and LVOT obstruction

[0308] Evaluation of 12 weeks of Compound 1 treatment on dyspnea symptom score, peak oxygen consumption (pVO) in subjects with symptomatic HCM and LVOT obstruction 2 ) and expiratory volume (VE) / carbon dioxid...

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Abstract

Provided are methods for treating hypertrophic cardiomyopathy and diastolic dysfunction.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application Serial No. 62 / 541,591 filed August 4, 2017; U.S. Provisional Application Serial No. 62 / 584,537 filed November 10, 2017; U.S. Provisional Application Serial No. 62 / 584,537 filed March 7, 2018 62 / 639,922; and the benefit of priority to U.S. Provisional Application Serial No. 62 / 671,585, filed May 15, 2018, the entire contents of which are hereby incorporated by reference. Background technique [0003] Hereditary (inheritable) hypertrophic cardiomyopathy (HCM) comprises a group of highly penetrant, monogenic, autosomal dominant cardiomyopathy. HCM is caused by one or more of more than 1,000 known point mutations in any of the proteins that contribute to the functional unit of heart muscle, the sarcomere. In the general population, approximately 1 in 500 individuals are found to have left ventricular hypertrophy unexplained by other known causes (eg, hypertension or valvu...

Claims

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Application Information

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IPC IPC(8): A61K31/513A61P9/04A61P9/10
CPCA61K31/513A61P9/00A61P9/10
Inventor M·J·塞米格兰J·H·李J·兰宾E·格林M·埃文奇克
Owner MYOKARDIA
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