Azatetracycle compounds

Abstract

An azatetracycle compound useful as 5HT3 antagonists of the general formula <IMAGE> wherein D is a tetracycle of the structure <IMAGE> or <IMAGE> wherein Ar is an aromatic moiety and B is either NH or O.

We claim: 
     
       1. A compound of the formula ##STR39## wherein D is ##STR40## wherein B is NH or O; wherein A is NH or a bond; wherein p is 1 or 0; and   when p is 1, Ar is ##STR41## and when p is 0, Ar is ##STR42## wherein X is O,S,N(R 4 ) or CH 2  ; wherein Y is N or CH;   wherein n is 1 or 2;   wherein Z is ##STR43## wherein R 1  is alkoxy of 1 to 6 carbon atoms; wherein R 2  and R 3  are the same or different and is hydrogen, halogen, CF 3 , hydroxyl, C 1-2  alkoxy, C 2-7  acyl, amino, amino substituted by one or two C 1-6  alkyl groups, C 2-7  acyl amino, amino carbonyl, or amino sulfone optionally substituted by one or two C 1-6  alkyl groups, C 1-6  alkyl sulfone or nitro groups;   wherein R 4  and R 4  ' can be the same or different and is hydrogen, alkyl or arylalkyl; wherein R 5  and R 6  is the same or different and is hydrogen, halogen, CF 3 , C 1-6  alkyl, C 1-7  acyl, C 1-7  acylamino, or amino, amino carbonyl or amino sulfonyl, optionally substituted by one or two C 1-6  alkyl or C 3-8  cycloalkyl groups, or by C 4-5  polymethylene or biphenyl, C 1-6  alkylsulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkoxy, C 1-6  alkylthio, hydroxy or nitro or when R 5  and R 6  are taken together are methylenedioxy or ethylenedioxy;   wherein R 9  and R 10  can be the same or different and is hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 1-4  alkynyl or together are C 2-4  polymethylene;   wherein R 7  and R 8  are the same or different and is hydrogen, halogen, CF 3 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 1-7  acyl, C 1-7  acylamino, C 1-6  alkylsulfonylamino, N-(C 1-6  alkylsulfonyl)-N-C 1-4  alkylamino, C 1-6  alkylsulfinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulfonyl, aminosulfonylamino or N-(aminosulfonyl)-C 1-4  alkylamino optionally N'-substituted by one or two groups selected from C 1-6  alkyl, C 3-8  cycloalkyl, phenyl, or phenyl C 1-4  alkyl groups or optionally N'-disubstituted by C 4-5  polymethylene; and wherein R 11  and R 12  can be the same or different and is hydrogen or C 1-4  alkyl or taken together are a covalent bond; and wherein R 13  is H, halogen or OR 4 .     
     
     
       2. A compound as recited in claim 1 wherein D is ##STR44## 
     
     
       3. A compound as recited in claim 2 wherein p is 1. 
     
     
       4. A compound as recited in claim 3 wherein B is NH. 
     
     
       5. A compound as recited in claim 4 wherein A is a covalent bond. 
     
     
       6. A compound as recited in claim 5 wherein Ar is ##STR45## 
     
     
       7. A compound as recited in claim 6 wherein R 1  is methoxy;   R 2  is amino; and   R 3  is chloro.   
     
     
       8. A compound as recited in claim 7 having the structure ##STR46## 
     
     
       9. A compound as recited in claim 5 wherein Ar is ##STR47## 
     
     
       10. A compound as recited in claim 9 wherein X is NH. 
     
     
       11. A compound as recited in claim 5 wherein Ar is ##STR48## 
     
     
       12. A compound as recited in claim 5 wherein Ar is ##STR49## 
     
     
       13. A compound as recited in claim 12 wherein R 4  is a methyl group. 
     
     
       14. A compound as recited in claim 5 wherein Ar is ##STR50## 
     
     
       15. A compound as recited in claim 4 wherein A is NH. 
     
     
       16. A compound as recited in claim 15 wherein Ar is ##STR51## 
     
     
       17. A compound as recited in claim 15 wherein Ar is ##STR52## 
     
     
       18. A compound as recited in claim 15 wherein Ar is ##STR53## 
     
     
       19. A compound as recited in claim 15 wherein Ar is ##STR54## 
     
     
       20. A compound as recited in claim 15 wherein Ar is ##STR55## 
     
     
       21. A compound as recited in claim 3 wherein B is 0. 
     
     
       22. A compound as recited in claim 2 wherein p is 0. 
     
     
       23. A compound as recited in claim 22 wherein Ar is ##STR56## 
     
     
       24. A compound as recited in claim 22 wherein Ar is ##STR57## 
     
     
       25. A compound as recited in claim 1 wherein D is ##STR58## 
     
     
       26. A compound as recited in claim 25 wherein p is 1. 
     
     
       27. A compound as recited in claim 26 wherein B is NH. 
     
     
       28. A compound as recited in claim 27 wherein A is a covalent bond. 
     
     
       29. A compound as recited in claim 28 wherein Ar is ##STR59## 
     
     
       30. A compound as recited in claim 29 wherein R 1  is methoxy;   R 2  is amino; and   R 3  is chloro.   
     
     
       31. A compound as recited in claim 28 wherein Ar is ##STR60## 
     
     
       32. A compound as recited in claim 28 wherein Ar is ##STR61## 
     
     
       33. A compound as recited in claim 28 wherein Ar is ##STR62## 
     
     
       34. A compound as recited in claim 28 wherein Ar is ##STR63## 
     
     
       35. A compound as recited in claim 27 wherein A is NH. 
     
     
       36. ##STR64## 
     
     
       37. A compound as recited in claim 35 wherein Ar is ##STR65## 
     
     
       38. A compound as recited in claim 35 wherein Ar is ##STR66## 
     
     
       39. A compound as recited in claim 35 wherein Ar is ##STR67## 
     
     
       40. A compound as recited in claim 35 wherein Ar is ##STR68## 
     
     
       41. A compound as recited in claim 26 wherein B is 0. 
     
     
       42. A compound as recited in claim 25 wherein p is 0. 
     
     
       43. A compound as recited in claim 42 wherein Ar is ##STR69## 
     
     
       44. A compound as recited in claim 42 wherein Ar is ##STR70## 
     
     
       45. A pharmaceutical composition comprising therapeutically or prophylactically effective amount of a compound of claim 1 of the formula ##STR71## and a pharmaceutical carrier. 
     
     
       46. A pharmaceutical composition as recited in claim 45 wherein D is ##STR72## 
     
     
       47. A pharmaceutical composition as recited in claim 45 wherein D is ##STR73## 
     
     
       48. A method of treating gastrointestinal motility disorders comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound according to claim 2 and a pharmaceutically acceptable carrier. 
     
     
       49. A method of treating gastrointestinal motility disorders comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound according to claim 25 and a pharmaceutically acceptable carrier. 
     
     
       50. A method of preventing emesis or ileus comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound according to claim 2 in a pharmaceutically acceptable carrier. 
     
     
       51. A method for preventing emesis or ileus comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound according to claim 25 in a pharmaceutically acceptable carrier. 
     
     
       52. A method of treating emesis, anxiety, pain, schizophrenia, depression, substance abuse, memory impairment, or related diseases having a serotonergic etiology benefiting from use of a serotonergic 5-HT 3  antagonist comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound according to claim 2 and a pharmaceutically acceptable carrier.