US2002052340A1PendingUtilityA1

Bupropion metabolites and methods of their synthesis and use

47
Priority: Mar 1, 1999Filed: Nov 16, 2001Published: May 2, 2002
Est. expiryMar 1, 2019(expired)· nominal 20-yr term from priority
Inventors:Thomas JerussiJohn Richard McculloughChrisantha H. SenanayakeQun Kevin Fang
A61P 43/00A61P 25/00A61P 25/08A61P 25/24A61P 25/20A61P 25/16A61P 25/34A61K 31/53A61K 31/00C07B 2200/07A61K 31/165C07D 265/32C07C 45/511A61K 31/415A61K 31/43A61K 31/535A61K 31/135A61K 31/50A61P 13/10A61K 31/46A61K 31/465A61K 31/5375A61K 31/435A61P 15/10C07C 45/63C07C 49/84A61K 45/06A61K 31/137
47
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Claims

Abstract

Methods and compositions are disclosed which utilize metabolites of bupropion for treating disorders ameliorated by inhibition of neuronal monoamine reuptake. Such disorders include, but are not limited to, erectile dysfunction, affective disorders, cerebral function disorders, cigarette smoking, and incontinence. The invention further discloses methods of making optically pure bupropion metabolites.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A method of treating or preventing a disorder that is ameliorated by the inhibition of neuronal monoamine reuptake which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         2 . The method of  claim 1  wherein the bupropion metabolite is optically pure.  
     
     
         3 . The method of  claim 2  wherein the optically pure bupropion metabolite is optically pure (S,S)-hydroxybupropion.  
     
     
         4 . The method of  claim 1  wherein the adverse effects associated with the inhibition of dopamine reuptake are reduced or avoided.  
     
     
         5 . The method of  claim 1  wherein the bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is adjunctively administered with a second pharmacologically active compound.  
     
     
         6 . A method of treating or preventing erectile dysfunction which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         7 . The method of  claim 6  wherein the bupropion metabolite is optically pure.  
     
     
         8 . The method of  claim 7  wherein the optically pure bupropion metabolite is optically pure (S,S)-hydroxybupropion.  
     
     
         9 . The method of  claim 6  wherein the bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered transdermally or mucosally.  
     
     
         10 . The method of  claim 6  wherein the bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is adjunctively administered with a 5-HT 3  antagonist.  
     
     
         11 . The method of  claim 10  wherein the 5-HT 3  antagonist is an antiemetic agent.  
     
     
         12 . The method of  claim 10  wherein the 5-HT 3  antagonist is selected from the group consisting of granisetron, metoclopramide, ondansetron, renzapride, zacopride, tropisetron, and optically pure stereoisomers, active metabolites, and pharmaceutically acceptable salts, solvates, and clathrates thereof.  
     
     
         13 . A method of treating or preventing an affective disorder which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         14 . The method of  claim 13  wherein the bupropion metabolite is optically pure.  
     
     
         15 . The method of  claim 14  wherein the optically pure bupropion metabolite is optically pure (S,S)-hydroxybupropion.  
     
     
         16 . The method of  claim 13  wherein the bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is adjunctively administered with a therapeutically or prophylactically effective amount of a second pharmacologically active compound.  
     
     
         17 . The method of  claim 13  wherein the affective disorder is depression.  
     
     
         18 . The method of  claim 13  wherein the affective disorder is narcolepsy.  
     
     
         19 . The method of  claim 13  wherein the affective disorder is nicotine addiction.  
     
     
         20 . A method of treating or preventing a cerebral function disorder which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         21 . The method of  claim 20  wherein the bupropion metabolite is optically pure.  
     
     
         22 . The method of  claim 21  wherein the optically pure bupropion metabolite is optically pure (S,S)-hydroxybupropion.  
     
     
         23 . The method of  claim 20  wherein the the bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is adjunctively administered with a therapeutically or prophylactically effective amount of a second pharmacologically active compound.  
     
     
         24 . The method of  claim 20  wherein the cerebral function disorder is Parkinson's disease.  
     
     
         25 . The method of  claim 20  wherein the cerebral function disorder is epilepsy.  
     
     
         26 . A method of eliciting smoking cessation which comprises administering to a patient who smokes tobacco a therapeutically effective amount of a bupropion metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         27 . The method of  claim 26  wherein the bupropion metabolite is optically pure.  
     
     
         28 . The method of  claim 27  wherein the optically pure bupropion metabolite is optically pure (S,S)-hydroxybupropion.  
     
     
         29 . The method of  claim 26  wherein the bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered orally, mucosally, or transdermally.  
     
     
         30 . The method of  claim 29  wherein the bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered transdermally.  
     
     
         31 . The method of  claim 26  wherein the bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is adjunctively administered with a therapeutically effective amount of nicotine.  
     
     
         32 . The method of  claim 31  wherein the nicotine and/or bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered orally, mucosally, or transdermally.  
     
     
         33 . The method of  claim 32  wherein the nicotine and/or bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered transdermally.  
     
     
         34 . A method of treating or preventing incontinence which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         35 . The method of  claim 34  wherein the bupropion metabolite is optically pure.  
     
     
         36 . The method of  claim 35  wherein the optically pure bupropion metabolite is optically pure (S,S)-hydroxybupropion.  
     
     
         37 . The method of  claim 34  wherein incontinence is stress urinary incontinence.  
     
     
         38 . The method of  claim 34  wherein the patient is a human of an age greater than 50 years or less than 13 years.  
     
     
         39 . A pharmaceutical composition which comprises a bupropion metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         40 . The pharmaceutical composition of  claim 39  wherein the bupropion metabolite is optically pure.  
     
     
         41 . The pharmaceutical composition of  claim 40  wherein the optically pure bupropion metabolite is optically pure (S,S)-hydroxybupropion.  
     
     
         42 . The pharmaceutical composition of  claim 40  wherein said pharmaceutical composition further comprises a second pharmacologically active compound selected from the group consisting of selective serotonin reuptake inhibitors, 5-IIT 3  inhibitors, and nicotine.  
     
     
         43 . A dosage form comprising a bupropion metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         44 . The dosage form of  claim 43  wherein said dosage form is solid.  
     
     
         45 . The dosage form of  claim 43  wherein said dosage form is a sterile solution.  
     
     
         46 . The dosage form of  claim 43  wherein said dosage form is a transdermal patch.  
     
     
         47 . The dosage form of  claim 43  wherein the bupropion metabolite is optically pure.  
     
     
         48 . The dosage form of  claim 47  wherein the optically pure bupropion metabolite is optically pure (S,S)-hydroxybupropion.  
     
     
         49 . The dosage form of  claim 43  wherein said dosage form further comprises a second pharmacologically active compound selected from the group consisting of selective serotonin reuptake inhibitors, 5-HT 3  inhibitors, and nicotine.  
     
     
         50 . The dosage form of  claim 43  wherein said dosage form is suitable for oral, mucosal, or transdermal administration to a patient.  
     
     
         51 . A dosage form suitable for transdermal administration to a patient which comprises nicotine and a bupropion metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         52 . A lactose-free solid dosage form comprising an optically pure bupropion metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof.  
     
     
         53 . The dosage form of  claim 52  wherein said dosage form is an oral dosage form.  
     
     
         54 . A process for preparing optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol or a pharmaceutically acceptable salt, solvate or clathrate thereof which comprises: 
 asymmetrically hydroxylating Z-1-(3-chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene to form an intermediate;    reacting the intermediate with 2-amino-2-methyl-1-propanol to form (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; and    isolating the (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol.    
     
     
         55 . A process for preparing optically pure (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol or a pharmaceutically acceptable salt, solvate or clathrate thereof which comprises: 
 asymmetrically hydroxylating Z-1-(3-chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene to form an intermediate;    reacting the intermediate with 2-amino-2-methyl-1-propanol to form (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; and    isolating the (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol.    
     
     
         56 . The process of  claim 54  or  55  wherein the intermediate formed by the asymmetric hydroxylation of Z-1-(3-chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene is an a-hydroxy ketone activated by trifluoromethane sulfonic anhydride.  
     
     
         57 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R is selected from the group consisting of hydrogen, triflate, tosylate, and nosylate; or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

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