Inhibitors of d-amino acid oxidase and uses thereof

Abstract

Provided herein are potent compounds of Formula (I) and uses thereof for inhibiting the activity of D-amino acid oxidase (DAAO) or treating diseases or disorders associated with DAAO, such as a central nervous system (CNS) disorder, pain, obesity, diabetes, or hyperlipidemia. Also provided in the present disclosure are methods of synthesizing the Formula (I) compounds described herein. (I)

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is a 5 to 8 membered monocyclic ring system, which optionally comprises at least one heteroatom selected from the group consisting of N, O, P, and S; 
 each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , independently, is absent, or of the formula: 
 
       
         
           
           
               
               
           
         
         which is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C 1-3  alkyl, halogen, —CN, —NO 2 , —SH, —S(C 1-3  alkyl), —NH 2 , NH(C 1-3  alkyl), N(C 1-3  alkyl) 2 , and —O(C 1-3  alkyl); wherein 
         n is 0 or 1; 
         m is 1, 2, 3, 4, or 5; 
         and the total number of galloyl moieties is an integer of 4 to 35, inclusive, and 
       
       wherein when the compound of Formula (I) is 
       
         
           
           
               
               
           
         
       
       the total number of galloyl moieties is an integer of 15 to 35, inclusive. 
     
     
         2 . The compound of  claim 1 , wherein Ring A is: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , independently, is of the formula: 
       
         
           
           
               
               
           
         
       
       or absent. 
     
     
         4 . The compound of  claim 3 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       and optionally wherein R 1 , R 2 , R 3 , R 4 , and R 5  are each selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 3 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       and optionally wherein R 1 , R 2 , R 3 , R 4 , and R 5  are each selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       in which each of R 1 , R 2  and R 3 , is, independently, one of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein optionally at least one of R 1 , R 2  and R 3  is substituted. 
     
     
         7 . The compound of  claim 6 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       in which each of R 1 , R 2  and R 3  is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the compound is selected from the group consisting of Compounds 21, 24, 27, 30, 37, 40, 43, 46, 48, 51, 53, 56, and 58. 
     
     
         9 . A composition comprising the compound of  claim 1  and a carrier. 
     
     
         10 . The composition of  claim 9 , wherein the composition is a pharmaceutical composition, a nutraceutical composition, a health food, or a medical food. 
     
     
         11 . A method for inhibiting D-amino acid oxidase (DAAO) in a subject, comprising administering to a subject in need thereof an effective amount of the compound of  claim 1  or a composition comprising the compound. 
     
     
         12 . The method of  claim 11 , wherein the subject is a human having, suspected of having, or at risk for a central nervous system (CNS) disorder, a metabolic disorder, or pain. 
     
     
         13 . The method of  claim 12 , wherein the CNS disorder is selected from the group consisting of schizophrenia, psychotic disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, senile dementia, mild cognitive impairment, benign forgetfulness, closed head injury, autistic spectrum disorder, Asperger's disorder, fragile X syndrome, attention deficit hyperactivity disorders, attention deficit disorder, obsessive compulsive disorder, tic disorders, childhood learning disorders, premenstrual syndrome, depression, major depressive disorder, anhedonia, suicidal ideation and/or behaviors, bipolar disorder, anxiety disorders, panic disorder, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addiction disorders, personality disorders, Parkinson's disorder, Huntington's disorder, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette's syndrome, nocturnal enuresis, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy, or stroke. 
     
     
         14 . The method of  claim 12 , wherein the metabolic disorder is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetes. 
     
     
         15 . The method of  claim 12 , wherein the pain is selected from the group consisting of psychogenic pain, acute pain, chronic pain, chronic pain syndromes, neuropathic pain, nociceptive pain, and hyperalgesia. 
     
     
         16 . The method of  claim 15 , wherein the psychogenic pain is selected from the group consisting of headache, muscle pain, back pain and stomach pain, the neuropathic pain is selected from the group consisting of sciatica, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, and central pain syndrome, and the nociceptive pain is selected from the group consisting of radicular pain, somatic pain, and visceral pain. 
     
     
         17 . The method of  claim 11 , wherein the human subject is administered the compound or the composition comprising such at a frequency of four times a day to one time every three months. 
     
     
         18 . The method of  claim 11 , wherein the human subject is treated concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents for treating and/or reducing the risk for a CNS disorder. 
     
     
         19 . A method for preparing the compound of  claim 1 , comprising:
 (a) providing a compound of formula (Ia)   
       
         
           
           
               
               
           
         
       
       wherein RR 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 6′ , R 7′ , and R 8′ , independently, are each —OH, —NH 2  or absent; and wherein Ring A is a 5 to 8 membered monocyclic ring system, which optionally comprises at least one heteroatom selected from the group consisting of N, O, P, and S;
 (b) reacting the compound of formula (Ia) with 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride, to allow conjugation of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride to one or more of R 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 6′ , R 7′ , and R 8′  of the compound of formula (Ia), thereby producing a first intermediate; and 
 (c) de-protecting the allyl groups in 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride that is conjugated to the compound of Formula (Ia) to obtain the compound of  claim 1 . 
 
     
     
         20 . The method of  claim 19 , wherein step (c) is performed by:
 (c1) de-protecting the allyl groups;   (c2) de-protecting the cyclic acetal groups.   
     
     
         21 . The method of  claim 20 , further comprising, prior to step (c2), repeating the process consisting of steps (b) and (c1) for 3-7 times. 
     
     
         22 . The method of  claim 19 , wherein step (c) is performed by:
 (c3) de-protecting the cyclic acetal groups and the benzyl groups.   
     
     
         23 . The method of  claim 19 , wherein Ring A is: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of  claim 19 , wherein the compound of formula (Ia) is glucose. 
     
     
         25 . The method of  claim 23 , the glucose is in α form or in β form. 
     
     
         26 . The method of  claim 19 , further comprising purifying the compound of  claim 1  produced after step (c).