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

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.

1 . An isolated compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a salt thereof; or a prodrug or a salt of a prodrug thereof; or a hydrate, solvate or polymorph thereof; wherein:
 D is deuterium; 
 each Y is independently selected from deuterium or hydrogen; 
 each hydrogen is independently optionally replaced with deuterium; and 
 each carbon is independently optionally replaced with  13 C. 
 
     
     
         2 . The compound or prodrug thereof according to  claim 1  wherein Y 1  is deuterium. 
     
     
         3 . The compound according to  claim 2 , wherein up to 4 hydrogen atoms are replaced by deuterium. 
     
     
         4 . The compound according to  claim 3 , wherein 1 carbon atom is  13 C. 
     
     
         5 . The compound according to  claim 1  or  2 , wherein at least one of Y 2  and Y 3  is independently deuterium. 
     
     
         6 . The compound according to  claim 1  or  2 , wherein both Y 2  and Y 3  are independently deuterium. 
     
     
         7 . A compound selected from any one of: 
       
         
           
           
               
               
           
         
       
       or a salt thereof; or a prodrug or a salt of a prodrug thereof; or a hydrate, solvate or polymorph thereof; wherein all hydrogen atoms and all carbon atoms are present at their natural isotopic abundance. 
     
     
         8 . The compound or prodrug according to any one of  claims 1  to  4 , or  7 , wherein the salt of the compound or the prodrug thereof is a pharmaceutically acceptable salt. 
     
     
         9 . The compound or prodrug according to  claim 5 , wherein the salt of the compound or the prodrug thereof is a pharmaceutically acceptable salt. 
     
     
         10 . The compound or prodrug according to  claim 6 , wherein the salt of the compound or the prodrug thereof is a pharmaceutically acceptable salt. 
     
     
         11 . A mixture consisting essentially of:
 a. a compound of formula I or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; and   b. lighter isotopologues of said compound of formula I or said prodrug, or said salt of said prodrug; or said hydrate, solvate, or polymorph thereof;   
       wherein at least 50% of said mixture is said compound of formula I. 
     
     
         12 . A mixture consisting essentially of:
 a. a compound of formula I or a salt thereof; or a or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; and   b. lighter isotopologues of said compound of formula I, said prodrug, said salt of said prodrug thereof; or said hydrate, solvate, or polymorph thereof;   
       wherein at least 50% of the compounds in said mixture comprise an isotope at each position occupied by an isotope in the compound of formula I. 
     
     
         13 . A composition comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof; or a prodrug, or a pharmaceutically acceptable salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; and an acceptable carrier. 
     
     
         14 . The composition according to  claim 13 , wherein said composition is formulated for pharmaceutical use, and wherein the carrier is a pharmaceutically acceptable carrier. 
     
     
         15 . The composition according to  claim 14  further comprising an effective amount of a second therapeutic agent, wherein said second therapeutic agent is useful alone or in combination with a compound of formula I for treating or preventing a condition selected from depression, hypertension, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction; eating disorders including bulimia, anorexia nervosa, and binge eating; obesity, chemical dependencies, cluster headache, migraine; pain, including neuropathic pain, diabetic nephropathy, post-operative pain, psychogenic pain disorders, and chronic pain syndrome; Alzheimers disease, obsessive-compulsive disorder, panic disorder with or without agoraphobia, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, Fibromyalgia Syndrome; urinary incontinence, including stress incontinence; Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and headache in a mammal, sleep-related breathing disorders, cognitive deficits due to aging, stroke, head trauma, neurodegenerative diseases, schizophrenia, anxiety, aggression and stress, disorders of thermoregulation, respiratory disease, bipolar disorder, psychosis, sleep disorder; mania, including acute mania; bladder disorder, genitourinary disorder, cough, emesis, nausea, psychotic disorders such as paranoia and manic-depressive illness, tic disorder, diabetic cardiomyopathy, diabetic retinopathy, cataracts, myocardial infarction, prolonged fatigue, chronic fatigue, chronic fatigue syndrome, premature ejaculation, dysphoria, post partum depression, premenstrual syndrome, social phobia, disruptive behavior disorders, impulse control disorders, borderline personality disorder, attention deficit disorders without hyperactivity, Shy-Drager Syndrome, cerebral ischemia, spinal cord trauma, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscular spasms, convulsions, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemic neuronal damage, ocular damage and retinopathy, brain edema, tardive dyskinesia, cerebral deficits subsequent to cardiac bypass surgery and grafting, affective disorders, mood disorders, agoraphobia without history of panic disorder, and acute stress disorders; or wherein said additional therapeutic agent is useful alone or in combination with a compound of formula I for reducing the side effects of Compound 1, enhancing or potentiating its activity, increasing its duration of pharmacological action, or any combination thereof. 
     
     
         16 . The composition according to  claim 15 , wherein said second therapeutic agent is selected from one or more of a 5-HT 1A  antagonist or ligand; an NK 1 -receptor antagonist; a serotonin receptor antagonist; 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (pramipexole), the (+)- or (−)-enantiomer thereof; a sulfamate anticonvulsant agent; a precursor or prodrug of serotonin, or an intermediate in the biosynthesis of serotonin; selective agonists and antagonists of one or both of the 5-HT 1A  and 5-HT 1D  receptors; a composition containing dimethylaminoethanol (DMAE), omega 3-fatty acids, betaine, oligomeric proanthocyanidins, folic acid, vitamins C, E, B 12 , B 6 , B 5  and beta-carotene and minerals (calcium, magnesium, zinc and selenium); naltrexone; cyclobenzaprine, or metabolites thereof; olanzapine; olanazapine-N-oxide; 2-hydroxymethylolanzapine; an atypical antipsychotic; tramadol; an aldose reductase inhibitor, or a prodrug thereof; 1-threo-methylphenidate; a Type III, Type IV, mixed Type III-Type IV, or Type V phosphodiesterase inhibitor, or an ester, amide, prodrug, active metabolite, or combination thereof; a substituted indole estrogenic agent; (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane; folic acid; methyltetrahydrofolate; WAY 100635; betaxolol; (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate; R-tofisopam; N-acetyl-serotonin; a DRD2-specific dopamine agonist; a 5HT 4  receptor antagonist; nalmefene; moxonidine; mirtazapine; chromium; a cyclooxygenase-2 selective inhibitor; a 5HT 2A  selective receptor antagonist; a CB 1  receptor antagonist; a MCH-1R receptor antagonist; a tetra-substituted pyrimidopyrimidine; a selective dopamine D 4  receptor ligand; trimebutine, fedotozine and mixtures thereof; an NMDA partial receptor agonist; an NMDA receptor antagonist; a cholinesterase inhibitor; a GSK-3 inhibitor; an alpha-2-delta ligand or a prodrug thereof; an extract of kava; a norephinephrine reuptake inhibitor; a corticosteroid; a non-steroidal immunophilin-dependent immunosuppressant; N-desmethylclozapine; an (R)-2,3-benzodiazepine as disclosed in US Patent Application 20040224943; a selective neuronal nitric oxide synthase inhibitor; modafinil; a selective oxytocin antagonist; a nicotine receptor antagonist; an adenosine A2a receptor antagonist; a 5-HT 2C  receptor antagonist; an AMPA receptor potentiator; a nicotine partial agonist; irindalone; a delta opioid receptor ligand; a growth hormone secretagogue; p-chloro-N-(2-morpholinoethyl)-benzamide and its metabolites; or a pharmaceutically acceptable salt of any of the said additional therapeutic agents; and combinations thereof. 
     
     
         17 . An article of manufacture comprising separate dosage forms of a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof; or a prodrug, or a pharmaceutically acceptable salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; and an acceptable carrier; and a second therapeutic agent, wherein both dosage forms are in a single container. 
     
     
         18 . A method of inhibiting the uptake of serotonin in a subject comprising the step of administering to said subject a composition comprising an effective amount of a compound of formula I; or a pharmaceutically acceptable salt thereof; or a prodrug, or a pharmaceutically acceptable salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; and a pharmaceutically acceptable carrier. 
     
     
         19 . A method of treating a human or non-human subject suffering from or susceptible to depression, obsessive-compulsive disorder, generalized anxiety, post-traumatic stress, major depression, panic disorder, social phobia, premenstrual syndrome, cardiac disorders, non-cardiac chest pain; smoking to cause cessation or prevent relapses; reducing platelet activation states, alcoholism and alcohol dependence; psychiatric syndromes including anger, rejection sensitivity, and lack of mental of physical energy; late luteal phase dysphoric disorder, premature ejaculation, senile dementia, obesity, Parkinson's disease, canine affective aggression, cancer cell growth, osteoporosis, dermatological diseases or disorders such as hyperproliferative or inflammatory skin diseases, or premature female orgasm; said method comprising the step of administering to said subject a composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; or a prodrug, or a pharmaceutically acceptable salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; and an acceptable carrier. 
     
     
         20 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent depression. 
     
     
         21 . The method according to  claim 19 , wherein the subject is treated to alleviate or obsessive-compulsive disorder. 
     
     
         22 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent generalized anxiety. 
     
     
         23 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent post-traumatic stress. 
     
     
         24 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent major depression. 
     
     
         25 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent panic disorder. 
     
     
         26 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent social phobia. 
     
     
         27 . The method according to  claim 19 , wherein the subject is treated to alleviate premenstrual syndrome. 
     
     
         28 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent cardiac disorders. 
     
     
         29 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent non-cardiac chest pain. 
     
     
         30 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent smoking, to cause cessation or prevent relapses. 
     
     
         31 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent reducing platelet activation states. 
     
     
         32 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent alcoholism and alcohol dependence. 
     
     
         33 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent psychiatric syndromes including anger, rejection sensitivity, and lack of mental of physical energy. 
     
     
         34 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent late luteal phase dysphoric disorder. 
     
     
         35 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent premature ejaculation. 
     
     
         36 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent senile dementia. 
     
     
         37 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent obesity. 
     
     
         38 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent Parkinson's disease. 
     
     
         39 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent canine affective aggression. 
     
     
         40 . The method according to  claim 19 , wherein the subject is treated to inhibit cancer cell growth. 
     
     
         41 . The method according to  claim 19 , wherein the subject is treated to stimulating bone formation by osteoblast stimulation. 
     
     
         42 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent dermatological diseases or disorders such as hyperproliferative or inflammatory skin diseases. 
     
     
         43 . The method according to  claim 19 , wherein the subject is treated to alleviate or prevent premature female orgasm. 
     
     
         44 . The method according to  claim 19 , comprising the additional step of administering to said patient a second therapeutic agent, wherein said second therapeutic agent is conventionally used, or is effective in combination with a compound of formula I for treating or preventing a condition selected from depression, hypertension, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction; eating disorders including bulimia, anorexia nervosa, and binge eating; obesity, chemical dependencies, cluster headache, migraine; pain, including neuropathic pain, diabetic nephropathy, post-operative pain, psychogenic pain disorders, and chronic pain syndrome; Alzheimers disease, obsessive-compulsive disorder, panic disorder with or without agoraphobia, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, Fibromyalgia Syndrome; urinary incontinence, including stress incontinence; Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and headache in a mammal, sleep-related breathing disorders, cognitive deficits due to aging, stroke, head trauma, neurodegenerative diseases, schizophrenia, anxiety, aggression and stress, disorders of thermoregulation, respiratory disease, bipolar disorder, psychosis, sleep disorder; mania, including acute mania; bladder disorder, genitourinary disorder, cough, emesis, nausea, psychotic disorders such as paranoia and manic-depressive illness, tic disorder, diabetic cardiomyopathy, diabetic retinopathy, cataracts, myocardial infarction, prolonged fatigue, chronic fatigue, chronic fatigue syndrome, premature ejaculation, dysphoria, post partum depression, premenstrual syndrome, social phobia, disruptive behavior disorders, impulse control disorders, borderline personality disorder, attention deficit disorders without hyperactivity, Shy-Drager Syndrome, cerebral ischemia, spinal cord trauma, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscular spasms, convulsions, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemic neuronal damage, ocular damage and retinopathy, brain edema, tardive dyskinesia, cerebral deficits subsequent to cardiac bypass surgery and grafting, affective disorders, mood disorders, agoraphobia without history of panic disorder, and acute stress disorders; or wherein said second therapeutic agent is useful for reducing the side effects of Compound 1, enhancing or potentiating the activity of Compound 1, increasing the duration of pharmacological action of Compound 1, or any combination thereof. 
     
     
         45 . The method according to  claim 44 , wherein said additional therapeutic agent is selected from one or more of a 5-HT 1A  antagonist or ligand; an NK 1 -receptor antagonist; a serotonin receptor antagonist; 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (pramipexole), the (+)- or (−)-enantiomer thereof; a sulfamate anticonvulsant agent; a precursor or prodrug of serotonin, or an intermediate in the biosynthesis of serotonin; selective agonists and antagonists of one or both of the 5-HT 1A  and 5-HT 1D  receptors; a composition containing dimethylaminoethanol (DMAE), omega 3-fatty acids, betaine, oligomeric proanthocyanidins, folic acid, vitamins C, E, B 12 , B 6 , B 5  and beta-carotene and minerals (calcium, magnesium, zinc and selenium); naltrexone; cyclobenzaprine, or metabolites thereof; olanzapine; olanazapine-N-oxide; 2-hydroxymethylolanzapine; an atypical antipsychotic; tramadol; an aldose reductase inhibitor, or a prodrug thereof; 1-threo-methylphenidate; a Type III, Type IV, mixed Type III-Type IV, or Type V phosphodiesterase inhibitor, or an ester, amide, prodrug, active metabolite, or combination thereof; a substituted indole estrogenic agent; (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane; folic acid; methyltetrahydrofolate; WAY 100635; betaxolol; (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate; R-tofisopam; N-acetyl-serotonin; a DRD2-specific dopamine agonist; a 5HT 4  receptor antagonist; nalmefene; moxonidine; mirtazapine; chromium; a cyclooxygenase-2 selective inhibitor; a 5HT 2A  selective receptor antagonist; a CB 1  receptor antagonist; a MCH-1R receptor antagonist; a tetra-substituted pyrimidopyrimidine; a selective dopamine D 4  receptor ligand; trimebutine, fedotozine and mixtures thereof; an NMDA partial receptor agonist; an NMDA receptor antagonist; a cholinesterase inhibitor; a GSK-3 inhibitor; an alpha-2-delta ligand or a prodrug thereof; an extract of kava; a norephinephrine reuptake inhibitor; a corticosteroid; a non-steroidal immunophilin-dependent immunosuppressant; N-desmethylclozapine; an (R)-2,3-benzodiazepine as disclosed in US Patent Application 20040224943; a selective neuronal nitric oxide synthase inhibitor; modafinil; a selective oxytocin antagonist; a nicotine receptor antagonist; an adenosine A2a receptor antagonist; a 5-HT 2C  receptor antagonist; an AMPA receptor potentiator; a nicotine partial agonist; irindalone; a delta opioid receptor ligand; a growth hormone secretagogue; p-chloro-N-(2-morpholinoethyl)-benzamide and its metabolites; or a pharmaceutically acceptable salt of any of the said second therapeutic agents; of combinations of two or more of said second therapeutic agents or salts thereof. 
     
     
         46 . A method of determining the concentration of Compound 1 in a biological sample comprising the steps of:
 a. adding a known concentration of a compound of formula I, or a salt thereof, to a biological sample;   b. subjecting said biological sample to a measuring device that distinguishes Compound 1 from said compound of formula I;   c. calibrating said measuring device to correlate the detected quantity of said compound of formula I with the known concentration of said compound of formula I added to said biological sample; and   d. determining the concentration of Compound 1 in said biological sample by comparing the detected quantity of Compound 1 with the detected quantity and known concentration of said compound of formula I.   
     
     
         47 . The method according to  claim 46 , wherein said compound of formula I contains at least 3 heavy atom isotopes including the explicitly drawn deuterium and wherein each of said additional heavy atom isotopes is chosen independently from deuterium and  13 C. 
     
     
         48 . The method according to  claim 46 , comprising the additional step of separating Compound 1 and said compound of formula I from said biological sample by organic or solid phase extraction prior to step b. 
     
     
         49 . A diagnostic kit comprising a compound of formula I or a salt thereof, in a sealed vessel; and instructions for using said compound to determine the concentration of Compound 1 in a biological sample. 
     
     
         50 . The kit according to  claim 49 , wherein the compound of formula I contains at least 3 heavy atom isotopes including the explicitly drawn deuterium and wherein each of said additional heavy atom isotopes is chosen independently from deuterium and  13 C. 
     
     
         51 . A method of evaluating the metabolic stability of a compound of formula I, comprising the steps of:
 a. contacting the compound of formula I or a salt thereof with a metabolizing enzyme source for a period of time; and   b. comparing the amount of said compound or salt thereof and metabolic products of said compound or salt thereof after said period of time.   
     
     
         52 . The method according to  claim 51 , wherein the method comprises an additional step of comparing the amount of said compound or salt thereof and said metabolic products of said compound or salt thereof at an interval during said period of time. 
     
     
         53 . The method according to  claim 51 , wherein the method comprises the additional steps of: c) contacting an isotopologue of said compound or salt thereof with said metabolizing enzyme source; d) comparing the amount of said isotopologue and metabolic products of said isotopologue after said period of time; and e) comparing the metabolic stability of said compound or salt thereof and said isotopologue, wherein steps c and d are performed before, simultaneously with in a different reaction vessel from, simultaneously with in the same reaction vessel as, or after, steps a and b. 
     
     
         54 . The method according to  claim 53 , wherein said isotopologue is Compound 1 or a salt of Compound 1. 
     
     
         55 . A diagnostic kit comprising, in separate vessels, Compound 1 and a metabolizing enzyme source. 
     
     
         56 . The diagnostic kit according to  claim 55 , further comprising instructions for using said kit to compare the metabolic stability of one or more compounds of formula I with the metabolic stability of Compound 1. 
     
     
         57 . A compound of formula II 
       
         
           
           
               
               
           
         
       
       wherein:
 D is deuterium; 
 Y 1  is independently selected from hydrogen or deuterium; 
 each carbon atom is independently optionally replaced by  13 C; and 
 each hydrogen atom is independently optionally replaced by deuterium. 
 
     
     
         58 . The compound according to  claim 57 , wherein Y 1  is deuterium. 
     
     
         59 . The compound according to  claim 57 , wherein Y 1  is deuterium and each hydrogen directly attached to the aromatic ring is deuterium. 
     
     
         60 . The compound according to  claim 57 , wherein all hydrogen atoms and all carbon atoms, are present at their natural isotopic abundance. 
     
     
         61 . A compound of formula III 
       
         
           
           
               
               
           
         
       
       wherein:
 D is deuterium; 
 each of Y 1-3  is independently selected from hydrogen or deuterium; 
 W is a removable N-protecting group; 
 each carbon atom is independently optionally replaced by  13 C; and 
 each hydrogen atom is independently optionally replaced by deuterium. 
 
     
     
         62 . The compound according to  claim 61 , wherein Y 1  is deuterium 
     
     
         63 . The compound according to  claim 61 , wherein at least one of at least one of Y 1  and Y 2  is independently deuterium. 
     
     
         64 . The compound according to  claim 61 , wherein both of Y 1  and Y 2  are independently deuterium. 
     
     
         65 . The compound according to  claim 61 , wherein each of Y 1 , Y 2 , and Y 3  independently is each deuterium. 
     
     
         66 . The compound according to  claim 61 , wherein up to 4 hydrogen atoms are replaced by deuterium. 
     
     
         67 . The compound according  claim 62 , wherein all hydrogen atom not explicitly designated as deuterium, and all carbons, are present at their natural isotopic abundance. 
     
     
         68 . The compound according to any one of  claims 61 - 67 , wherein W is chosen from methyl, benzyl, methyl carbamate, ethyl carbamate, vinyl carbamate, phenyl carbamate, benzyl carbamate, and tert-butyl carbamate.