Methods of making N-desmethylzopiclone

Abstract

The invention is directed to compositions comprising, and methods of using, racemic N-desmethylzopiclone, optically pure (+)-N-desmethylzopiclone, and optically pure (−)-N-desmethylzopiclone in the treatment and prevention of diseases and conditions in mammals. The invention is further directed to novel methods of preparing N-desmethylzopiclone, optically pure (+)-N-desmethylzopiclone, and optically pure (−)-N-desmethylzopiclone.

What is claimed is:  
     
         1 . A method of treating or preventing anxiety in a patient, which comprises administering to a patient suffering from anxiety a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         2 . The method of  claim 1 , wherein the anxiety is acute anxiety.  
     
     
         3 . The method of  claim 1  where in the anxiety is chronic anxiety  
     
     
         4 . The method of  claim 1  where in the anxiety is general anxiety disorder.  
     
     
         5 . A method of treating or preventing a convulsive state in a patient, which comprises administering to a patient suffering from, or prone to suffer from, convulsions a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         6 . The method of  claim 5  wherein the convulsive state is epilepsy.  
     
     
         7 . A method of treating or preventing spasticity or acute muscle spasms in a patient, which comprises administering to a patient suffering from spasticity or acute muscle spasms a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         8 . A method of treating or preventing an affective disorder in a patient, which comprises administering to a patient suffering from an affective disorder a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         9 . The method of  claim 8 , wherein the affective disorder is depression.  
     
     
         10 . The method of  claim 8 , wherein the affective disorder is attention deficit disorder or attention deficit disorder with hyperactivity.  
     
     
         11 . A method of treating or preventing a behavioral disorder in a patient, which comprises administering to a patient suffering from a behavioral disorder a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         12 . A method of treating or preventing schizophrenic disorder in a patient, which comprises administering to a patient suffering from schizophrenic disorder a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         13 . A method of treating or preventing aggressive behavior in a patient, which comprises administering to a patient suffering from aggressive behavior a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         14 . A method of treating or preventing alcohol or drug addiction in a patient, which comprises administering to a patient suffering from alcohol or drug addiction a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         15 . A method of treating or preventing abnormal plasma hormone levels in a patient, which comprises administering to a patient suffering from abnormal plasma hormone levels a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         16 . The method of  claim 15 , wherein the abnormal plasma hormone level is endocrine.  
     
     
         17 . A method of treating or preventing a sleep disorder in a patient, which comprises administering to a patient suffering from a sleep disorder a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         18 . The method of  claim 17 , wherein the sleep disorder is insomnia.  
     
     
         19 . A method of treating or preventing a disease or condition or symptom thereof in a patient affected by the modulation of one or more central or peripheral benzodiazepine receptors, which comprises administering to said patient a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         20 . The method of  claim 1 ,  5 ,  7 ,  8 ,  11 - 15 ,  17 , or  19  wherein the N-desmethylzopiclone is racemic.  
     
     
         21 . The method of  claim 1 ,  5 ,  7 ,  8 ,  11 - 15 ,  17 , or  19  wherein the N-desmethylzopiclone is (+)-N-desmethylzopiclone, substantially free of its (−) enantiomer.  
     
     
         22 . The method of  claim 1 ,  5 ,  7 ,  8 ,  11 - 15 ,  17  or  19  wherein the N-desmethylzopiclone is (−)-N-desmethylzopiclone, substantially free of its (+) enantiomer.  
     
     
         23 . The method of  claim 21  wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount N-desmethylzopiclone.  
     
     
         24 . The method of  claim 22  wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.  
     
     
         25 . The method of  claim 23  wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.  
     
     
         26 . The method of  claim 24  wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.  
     
     
         27 . The method of  claim 25  wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.  
     
     
         28 . The method of  claim 26  wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.  
     
     
         29 . The method of  claim 1 ,  5 ,  7 ,  8 ,  11 - 15 ,  17 , or  19  wherein the patient is human.  
     
     
         30 . The method of  claim 1 ,  5 ,  7 ,  8 ,  11 - 15 ,  17 , or  19  wherein the therapeutically or prophylactically effective amount of N-desmethylzopiclone or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof is from about 0.1 mg to about 500 mg.  
     
     
         31 . The method of  claim 30  wherein the therapeutically or prophylactically effective amount of N-desmethylzopiclone or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof is from about 0.5 mg to about 250 mg.  
     
     
         32 . The method of  claim 31  wherein the therapeutically or prophylactically effective amount of N-desmethylzopiclone or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof is from about 1 mg to about 200 mg.  
     
     
         33 . A pharmaceutical composition comprising N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         34 . The pharmaceutical composition of  claim 33  wherein said pharmaceutical composition further comprises a pharmaceutically acceptable carrier.  
     
     
         35 . The pharmaceutical composition of  claim 33  wherein the N-desmethylzopiclone is racemic.  
     
     
         36 . The pharmaceutical composition of  claim 33  wherein the N-desmethylzopiclone is (+)-N-desmethylzopiclone, substantially free of its (−) enantiomer.  
     
     
         37 . The pharmaceutical composition of  claim 33  wherein the N-desmethylzopiclone is optically pure (−)-N-desmethylzopiclone, substantially free of its (+) enantiomer.  
     
     
         38 . The pharmaceutical composition of  claim 36  wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.  
     
     
         39 . The pharmaceutical composition of  claim 37  wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.  
     
     
         40 . The pharmaceutical composition of  claim 38  wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.  
     
     
         41 . The pharmaceutical composition of  claim 39  wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.  
     
     
         42 . The pharmaceutical composition of  claim 40  wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.  
     
     
         43 . The pharmaceutical composition of  claim 41  wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.  
     
     
         44 . The pharmaceutical composition of  claim 33  wherein said pharmaceutical composition is suitable for parenteral, oral, topical, transdermal, or mucosal administration to a patient.  
     
     
         45 . The pharmaceutical composition of  claim 44  wherein said pharmaceutical composition is suitable for oral administration to a patient.  
     
     
         46 . An individual dosage form of N-desmethylzopiclone which comprises N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         47 . The dosage form of  claim 46  wherein said dosage form further comprises a pharmaceutically acceptable carrier.  
     
     
         48 . The dosage form of  claim 46  wherein the N-desmethylzopiclone is racemic.  
     
     
         49 . The dosage form of  claim 46  wherein the N-desmethylzopiclone is (+)-N-desmethylzopiclone, substantially free of its (−) enantiomer.  
     
     
         50 . The dosage form of  claim 46  wherein the N-desmethylzopiclone is optically pure (−)-N-desmethylzopiclone, substantially free of its (+) enantiomer.  
     
     
         51 . The dosage form of  claim 49  wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.  
     
     
         52 . The dosage form of  claim 50  wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.  
     
     
         53 . The method of  claim 51  wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.  
     
     
         54 . The method of  claim 52  wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.  
     
     
         55 . The method of  claim 53  wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.  
     
     
         56 . The method of  claim 54  wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.  
     
     
         57 . The dosage form of  claim 46  wherein said dosage form is suitable for parenteral, oral, topical, transdermal, or mucosal administration to a patient.  
     
     
         58 . The dosage form of  claim 57  wherein said dosage form is a tablet, caplet, or capsule.  
     
     
         59 . The dosage form of  claim 46  wherein said dosage form comprises from about 0.1 mg to about 500 mg of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         60 . The dosage form of  claim 59  wherein said dosage form comprises from about 0.5 mg to about 250 mg of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         61 . The dosage form of  claim 60  wherein said dosage form comprises from about 1 mg to about 200 mg of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         62 . A method of preparing N-desmethylzopiclone which comprises contacting zopiclone with an azodicarboxylate under conditions sufficient to form a product and hydrolyzing the product under mild conditions.  
     
     
         63 . The method of  claim 62  wherein the azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, and di-trichloromethyl azodicarboxylate.  
     
     
         64 . The method of  claim 63  wherein the azodicarboxylate is diethyl azodicarboxylate.  
     
     
         65 . A method of preparing racemic N-desmethylzopiclone which comprises contacting racemic zopiclone with α-chloroethyl chloroformate to form a mixture and refluxing said mixture in methanol.  
     
     
         66 . A method of preparing (+)-N-desmethyl zopiclone which comprises contacting (+)-zopiclone with α-chloroethyl chloroformate to form a mixture and refluxing said mixture in methanol.  
     
     
         67 . A method of preparing (−)-N-desmethylzopiclone which comprises contacting (−)-zopiclone with α-chloroethyl chloroformate to form a mixture and refluxing said mixture in methanol.  
     
     
         68 . A method of increasing the optical purity of zopiclone or desmethylzopiclone which comprises contacting zopiclone or desmethylzopiclone with L-N-benzyloxycarbonyl phenyl alanine in a water and ethanol solvent system, and isolating optically enriched zopiclone or desmethylzopiclone.