Agents for treating disorders involving modulation of ryanodine receptors

Abstract

The present invention relates to 1,4-benzothiazepine derivatives and their use to treat conditions, disorders and diseases associated with ryanodine receptors (RyRs) that regulate calcium channel functioning in cells. The invention also discloses pharmaceutical compositions comprising the compounds and uses thereof to treat diseases and conditions associated with RyRs, in particular cardiac, musculoskeletal and central nervous system (CNS) disorders.

1 . A method of treating or preventing a condition selected from the group consisting of cardiac disorders and diseases, muscle fatigue, musculoskeletal disorders and diseases; CNS disorders and diseases, cognitive dysfunction, neuromuscular disorders and diseases, bone disorders and diseases, cancer cachexia, malignant hyperthermia, diabetes, sudden cardiac death, and sudden infant death syndrome, or for improving cognitive function, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound which is represented by the structure of formula (I), or a pharmaceutical composition comprising such compound, to effectuate such treatment, 
       
         
           
           
               
               
           
         
         wherein 
         R is COOH; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the condition is associated with an abnormal function of a ryanodine receptor 1 (RyR1), a ryanodine receptor type (RyR2), a ryanodine receptor type 3 (RyR3), or a combination thereof. 
     
     
         3 . The method of  claim 1 , wherein the compound is administered to a subject to treat or prevent a cardiac disorder or disease selected from the group consisting of irregular heartbeat disorders and diseases, exercise-induced irregular heartbeat disorders and diseases, heart failure, congestive heart failure, chronic heart failure, acute heart failure, systolic heart failure, diastolic heart failure, acute decompensated heart failure, cardiac ischemia/reperfusion (I/R) injury, chronic obstructive pulmonary disease, I/R injury following coronary angioplasty or following thrombolysis for the treatment of myocardial infarction (MI); and high blood pressure. 
     
     
         4 . The method of  claim 3 , wherein the irregular heartbeat disorders and diseases are selected from the group consisting of atrial and ventricular arrhythmia, atrial and ventricular fibrillation, atrial and ventricular tachyarrhythmia, atrial and ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia (CPVT), and exercise-induced variants thereof. 
     
     
         5 . The method of  claim 1 , wherein the compound is administered to a subject to treat or prevent muscle fatigue that is due to a skeletal muscle disease, disorder or condition. 
     
     
         6 . The method of  claim 1 , wherein the compound is administered to a subject to treat or prevent a musculoskeletal disorder or disease selected from the group consisting of exercise-induced skeletal muscle fatigue, exercise-induced muscle fatigue which is due to prolonged exercise or high-intensity exercise, a congenital myopathy, muscular dystrophy, spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), age-related muscle fatigue, sarcopenia, central core disease, cancer cachexia, bladder disorders, and incontinence. 
     
     
         7 . The method of  claim 6 , wherein the muscular dystrophy is selected from the group consisting of Duchenne Muscular Dystrophy (DMD), Becker's Muscular Dystrophy (BMD), Limb-Girdle Muscular Dystrophy (LGMD), facioscapulohumeral dystrophy, myotonic muscular dystrophy, congenital muscular dystrophy (CMD), distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, and oculopharyngeal muscular dystrophy. 
     
     
         8 . The method of  claim 1 , wherein the compound is administered to a subject to treat or prevent a CNS disorder or disease selected from the group consisting of Alzheimer's Disease (AD), neuropathy, seizures, Parkinson's Disease (PD), and Huntington's Disease (HD); and the neuromuscular disorders and diseases are selected from the group consisting of spinocerebellar ataxia (SCA), and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). 
     
     
         9 . The method of  claim 1 , wherein the compound is administered to a subject to treat or prevent cognitive dysfunction which is stress-related or age-related, or to improve cognitive function selected from short term memory, long term memory, attention and learning, or wherein the compound is administered to a subject to treat or prevent cognitive dysfunction associated with a disease or disorder selected from the group consisting of Alzheimer's disease (AD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), Parkinson's Disease (PD), post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, and major depression. 
     
     
         10 . The method of  claim 1 , wherein the compound is administered to a subject to treat or prevent cancer cachexia. 
     
     
         11 . The method of  claim 10 , wherein cancer cachexia is due to a cancer having bone metastases. 
     
     
         12 . The method of  claim 1 , wherein the compound is administered at a dose sufficient to restore or enhance binding of calstabin2 to RyR2. 
     
     
         13 . The method of  claim 1 , wherein the compound is administered at a dose sufficient to restore or enhance binding of calstabin1 to RyR1. 
     
     
         14 . The method of  claim 1 , wherein the compound is administered at a dose sufficient to decrease Ca 2+  leak through a RyR channel. 
     
     
         15 . The method of  claim 1 , wherein the compound of formula (I) is in the form of a salt with a pharmaceutically acceptable acid or base. 
     
     
         16 . The method of  claim 15 , wherein the salt is selected from the group consisting of sodium, potassium, magnesium, hemifumarate, hydrochloride and hydrobromide. 
     
     
         17 . The method of  claim 1 , wherein the compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 1 , wherein the compound of formula (I) is represented by the structure of Formula (1): 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
         19 . The method of  claim 18 , wherein the compound of formula (I) is in the form of a salt with a pharmaceutically acceptable acid or base. 
     
     
         20 . The method of  claim 19 , wherein the salt is selected from the group consisting of sodium, potassium, magnesium, hemifumarate, hydrochloride and hydrobromide. 
     
     
         21 . The method of  claim 20 , wherein the salt is sodium. 
     
     
         22 . The method of  claim 20 , wherein the salt is hemifumarate.