Aminoindan derivatives

Abstract

This invention is directed to compounds of the following formula: wherein when a is 0, b is 1 or 2; when a is 1, b is 1, m is from 0-3, X is O or S, Y is halogeno, R 1 is hydrogen C 1-4 alkyl, R 2 is hydrogen, C 1-4 alkyl, or optionally substituted propargyl and R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, C 6-12 aryl, C 6-12 aralkyl each optionally substituted. This invention is also directed to the use of these compounds for treating depression, Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD), Tourette's Syndrome, Alzheimer's Disease and other dementia's such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia. This invention is further directed to a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

1. A method of treating a subject suffering from depression comprising administering to the subject a therapeutically effective amount of a compound having the structure: 
                 
 wherein when a is 0, b is 1 or  2, and when a is 1, b is 1 ;  
 wherein when a is 1, b is 1,  m is 0-3,; X is O or S,; Y is halogeno,; R 1  is hydrogen or C 1-4  alkyl,; R 2  is hydrogen, C 1-4  alkyl, propargyl, or optionally  substituted propargyl; and R 3  and R 4  are each independently hydrogen,  C 1-8  alkyl, C 6-12  aryl, C 6-12  arylaralkyl or C 6-12  cycloalkyl, each of which may be optionally substituted, or is hydrogen, such compound being a racemic mixture, an enantiomer, or a salt thereof; 
 a racemic mixture, an enantiomer, or salt thereof,so as to thereby treat the subject's depression.  
 
     
     
       2. The method of  claim 1  wherein the enantiomer is the R enantiomer. 
     
     
       3. The method of  claim 1  wherein the enantiomer is the S enantiomer. 
     
     
       4. The method of  claim 1  wherein the compound has the structure: 
                 
 
     
     
       5. The method of  claim 4  wherein the enantiomer is the R enantiomer. 
     
     
       6. The method of  claim 4  wherein the enantiomer is the S enantiomer. 
     
     
       7. The method of  claim 1  wherein the compound has the structure: 
                 
 
     
     
       8. The method of  claim 7  wherein the enantiomer is the R enantiomer. 
     
     
       9. The method of  claim 7  wherein the enantiomer is the S enantiomer. 
     
     
       10. A method of selectively inhibiting monoamine oxidase-B (MAO-B) activity in the brain of a subject in need of such inhibition comprising administering to the subject a therapeutically effective amount of a compound having the structure: 
                 
 wherein when a is 0, b is 1 or  2, and when a is 1, b is 1 ;  
 wherein when a is 1, b is 1,  m is 0-3,; X is O or S,; Y is halogeno,; R 1  is hydrogen or C 1-4  alkyl,; R 2  is hydrogen, C 1-4  alkyl, propargyl, or optionally  substituted propargyl; and R 3  and R 4  are each independently hydrogen,  C 1-8  alkyl, C 6-12  aryl, C 6-12  arylaralkyl or C 6-12  cycloalkyl, each of which may be optionally substituted, or is hydrogen, such compound being a racemic mixture, an enantiomer, or a salt thereof; 
 a racemic mixture, an enantiomer, or salts thereof,so as to thereby selectively inhibit MAO-B activity in the brain of the subject.  
 
     
     
       11. The method of  claim 10  wherein the enantiomer is the R enantiomer. 
     
     
       12. The method of  claim 10  wherein the enantiomer is the S enantiomer. 
     
     
       13. The method of  claim 10  wherein the compound has the structure: 
                 
 
     
     
       14. The method of  claim 13  wherein the enantiomer is the R enantiomer. 
     
     
       15. The method of  claim 13  wherein the enantiomer is the S enantiomer. 
     
     
       16. The method of  claim 10  wherein the compound has the structure: 
                 
 
     
     
       17. The method of  claim 16  wherein the enantiomer is the R enantiomer. 
     
     
       18. The method of  claim 16  wherein the enantiomer is the S enantiomer. 
     
     
       19. A method of treating a subject suffering from depression comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure: 
                 
 wherein when a is 0, b is 1 or  2, and when a is 1, b is 1;   
 wherein when a is 1, b is 1,  m is 0-3,; X is O or S,; Y is halogeno,; R 1  is hydrogen or C 1-4  alkyl,; R 2  is hydrogen, C 1-4  alkyl, propargyl, or optionally  substituted propargyl; and R 3  and R 4  are each independently hydrogen,  C 1-8  alkyl, C 6-12  aryl, C 6-12  arylaralkyl or C 6-12  cycloalkyl, each of which may be optionally substituted, or is hydrogen, such compound being a racemic mixture, an enantiomer, or a salt thereof a racemic mixture, an enantiomer, or salt thereof , and  
 a pharmaceutically acceptable carrier, ; so as to thereby treat the subject's depression.  
 
     
     
       20. The method of  claim 19  wherein the pharmaceutically acceptable carrier is a solid and the therapeutically effective amount is an amount from about 0.5 mg to about 2000 mg. 
     
     
       21. The method of  claim 19  wherein the pharmaceutically acceptable carrier is a liquid and the therapeutically effective amount is an amount from about 0.5 mg to about 2000 mg. 
     
     
       22. The method of  claim 19  wherein the pharmaceutically acceptable carrier is a gel and the therapeutically effective amount is an amount from about 0.5 mg to about 2000 mg. 
     
     
       23. The method of  claim 19  wherein the therapeutically effective amount is an amount from about 1 mg to about 1000 mg. 
     
     
       24. A method of selectively inhibiting monoamine oxidase-B (MAO-B) activity in the brain of a subject in need of such inhibition comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure: 
                 
 wherein when a is 0, b is 1 or  2, and when a is 1, b is 1 ;  
 wherein when a is 1, b is 1,  m is 0-3,; X is O or S,; Y is halogeno,; R 1  is hydrogen or C 1-4  alkyl,; R 2  is hydrogen, C 1-4  alkyl, propargyl or optionally  substituted propargyl; and R 3  and R 4  are each independently hydrogen,  C 1-8  alkyl, C 6-12  aryl, C 6-12  arylaralkyl or C 6-12  cycloalkyl, each of which may be optionally substituted, or is hydrogen, such compound being a racemic mixture, an enantiomer, or a salt thereofa racemic mixture, an enantiomer, or salt thereof , and  
 a pharmaceutically acceptable carrier, ; so as to thereby selectively inhibit MAO-B activity in the brain of the subject.  
 
     
     
       25. The method of  claim 24  wherein the pharmaceutically acceptable carrier is a solid and the therapeutically effective amount is an amount from about 0.5 mg to about 2000 mg. 
     
     
       26. The method of  claim 24  wherein the pharmaceutically acceptable carrier is a liquid and the therapeutically effective amount is an amount from about 0.5 mg to about 2000 mg. 
     
     
       27. The method of  claim 24  wherein the pharmaceutically acceptable carrier is a gel and the therapeutically effective amount is an amount from about 0.5 mg to about 2000 mg. 
     
     
       28. The method of  claim 24  wherein the therapeutically effective amount is an amount from about 1 mg to about 1000 mg. 
     
     
       29. A compound having the structure: 
                     wherein when a is  0 , b is  1  or  2 , and when a is  1 , b is  1 ;        m is  0 - 3 ; X is O or S; Y is halogeno; R   1    is hydrogen or C   1-4    alkyl; R   2    is hydrogen, C   1-4    alkyl, propargyl or substituted propargyl; and R   3    and R   4    are each independently C   1-8    alkyl, C   6-12    aryl, C   6-12    aralkyl or C   6-12    cycloalkyl, each of which may be optionally substituted, or hydrogen,        such compound being a racemic mixture, an enantiomer, or a salt thereof.     
     
     
       30. The compound of  claim 29 , having the structure: 
                   
         wherein the group OC ( O ) NR   3   R   4    is on the  6  position of the indan ring counting from the amino substituted carbon atom; m is  0 ; R   1    is H; R   2    is H; R   3    is methyl; and R   4    is ethyl.   
     
     
       31. The compound of  claim 30 , wherein the compound is the R enantiomer. 
     
     
       32. The compound of  claim 29 , having the structure: 
                   
         wherein the group OC ( O ) NR   3   R   4    is on the  6  position of the indan ring counting from the amino substituted carbon atom; m is  0 ; R   1    is H; R   2    is H; R   3    is H; and R   4    is ethyl.   
     
     
       33. The compound of  claim 29 , having the structure: 
                   
         wherein the group OC ( O ) NR   3   R   4    is on the  6  position of the indan ring counting from the amino substituted carbon atom; m is  0 ; R   1    is H; R   3    is H; and R   4    is ethyl.   
     
     
       34. The compound of  claim 29 , wherein the compound is R-   6   -( N - methyl, N - ethyl - carbamyloxy )- N′ - propargyl -   1   - aminoindan hemi -( L )- tartrate.   
     
     
       35. A pharmaceutical composition comprising the compound of  claim 29  and a pharmaceutically acceptable carrier. 
     
     
       36. A pharmaceutical composition comprising the compound of  claim 30  and a pharmaceutically acceptable carrier. 
     
     
       37. A pharmaceutical composition comprising the compound of  claim 31  and a pharmaceutically acceptable carrier. 
     
     
       38. A pharmaceutical composition comprising the compound of  claim 32  and a pharmaceutically acceptable carrier. 
     
     
       39. A pharmaceutical composition comprising the compound of  claim 33  and a pharmaceutically acceptable carrier. 
     
     
       40. A pharmaceutical composition comprising the compound of  claim 34  and a pharmaceutically acceptable carrier. 
     
     
       41. A method of treating a subject suffering from Alzheimer's disease comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 35  so as to treat the subject. 
     
     
       42. A method of treating a subject suffering from Alzheimer's disease comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 36  so as to treat the subject. 
     
     
       43. A method of treating a subject suffering from Alzheimer's disease comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 37  so as to treat the subject. 
     
     
       44. A method of treating a subject suffering from Alzheimer's disease comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 38  so as to treat the subject. 
     
     
       45. A method of treating a subject suffering from Alzheimer's disease comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 39  so as to treat the subject. 
     
     
       46. A method of treating a subject suffering from Alzheimer's disease comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 40  so as to treat the subject. 
     
     
       47. A method of treating a subject suffering from depression comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 35  so as to treat the subject. 
     
     
       48. A method of treating a subject suffering from depression comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 36  so as to treat the subject. 
     
     
       49. A method of treating a subject suffering from depression comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 37  so as to treat the subject. 
     
     
       50. A method of treating a subject suffering from depression comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 38  so as to treat the subject. 
     
     
       51. A method of treating a subject suffering from depression comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 39  so as to treat the subject. 
     
     
       52. A method of treating a subject suffering from depression comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 40  so as to treat the subject. 
     
     
       53. A method of treating a subject suffering from Attention Deficit Disorder, Attention Deficit and Hyperactivity Disorder, Tourette's syndrome, dementia, neurotraumatic disorder or memory disorder which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 35  so as to treat the subject. 
     
     
       54. A method of treating a subject suffering from Attention Deficit Disorder, Attention Deficit and Hyperactivity Disorder, Tourette's syndrome, dementia, neurotraumatic disorder or memory disorder which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 36  so as to treat the subject. 
     
     
       55. A method of treating a subject suffering from Attention Deficit Disorder, Attention Deficit and Hyperactivity Disorder, Tourette's syndrome, dementia, neurotraumatic disorder or memory disorder which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 37  so as to treat the subject. 
     
     
       56. A method of treating a subject suffering from Attention Deficit Disorder, Attention Deficit and Hyperactivity Disorder, Tourette's syndrome, dementia, neurotraumatic disorder or memory disorder which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 38  so as to treat the subject. 
     
     
       57. A method of treating a subject suffering from Attention Deficit Disorder, Attention Deficit and Hyperactivity Disorder, Tourette's syndrome, dementia, neurotraumatic disorder or memory disorder which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 39  so as to treat the subject. 
     
     
       58. A method of treating a subject suffering from Attention Deficit Disorder, Attention Deficit and Hyperactivity Disorder, Tourette's syndrome, dementia, neurotraumatic disorder or memory disorder which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 40  so as to treat the subject.