Combination of pure 5-HT6 receptor antagonists with NMDA receptor antagonist
The present invention relates to pure 5-HT6 receptor antagonist or the pharmaceutically acceptable salt(s) thereof in combination with or as adjunct to NMDA receptor antagonist and their use in the treatment of cognitive disorders. The invention further relates to the pharmaceutical composition containing the said combination.
1. A synergistic combination comprising pure 5-HT6 receptor antagonist and NMDA receptor antagonist as the only active agents, wherein the pure 5-HT6 receptor antagonist is selected from, 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof, wherein the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt thereof and wherein the 5-HT6 receptor antagonist or its pharmaceutically acceptable salt is in an amount of 1 mg to 300 mg.
2. The combination as claimed in claim 1 , wherein the pharmaceutically acceptable salt of the pure 5-HT6 receptor antagonist is 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate.
3. The combination as claimed in claim 1 , wherein the pharmaceutically acceptable salt of memantine is memantine hydrochloride.
4. The combination as claimed in claim 1 , wherein said pure 5-HT6 receptor antagonist is 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate and said NMDA receptor antagonist is memantine hydrochloride.
5. The combination as claimed in claim 1 , is for the treatment of a cognitive disorder in a patient, wherein the cognitive disorder is selected from Alzheimer's disease.
6. A method of treatment of a cognitive disorder comprising the step of administering to a patient in need thereof a therapeutically effective amount of the combination as claimed in claim 1 wherein the cognitive disorder is Alzheimer's disease.
7. A method of treating Alzheimer's disease in a patient comprising the step of administering to said patient a synergistic combination of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof, memantine or a pharmaceutically acceptable salt thereof as the only active agents and wherein the 5-HT6 receptor antagonist or its pharmaceutically acceptable salt is in an amount of 1 mg to 300 mg.
8. The method as claimed in claim 7 , wherein the pharmaceutically acceptable salt of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole is 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate.
9. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the patient is administered 1 mg to 200 mg of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof per day.
10. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the patient is administered 1 mg to 10 mg of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof per day.
11. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the patient is administered 25 mg to 125 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof per day.
12. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the patient is administered 150 mg to 200 mg of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof per day.
13. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the patient is administered 25 mg to 75 mg of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof per day.
14. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the patient is administered 75 mg to 150 mg of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof per day.
15. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the patient is administered 1 mg to 40 mg of memantine or a pharmaceutically acceptable salt thereof per day.
16. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the patient is administered 5 mg to 28 mg memantine or a pharmaceutically acceptable salt thereof per day.
17. A pharmaceutical composition comprising the combination of pure 5-HT6 receptor antagonist and the NMDA receptor antagonist as claimed in claim 1 , and pharmaceutically acceptable excipients.
18. The pharmaceutical composition as claimed in claim 17 , for treatment of cognitive disorder selected from Alzheimer's disease.
19. The pharmaceutical composition as claimed in claim 17 , wherein the 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof is present in an amount of 35 mg to 200 mg.
20. The pharmaceutical composition as claimed in claim 17 , wherein the 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof is present in an amount of 200 mg to 300 mg.
21. The pharmaceutical composition as claimed in claim 17 , wherein the 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof is present in an amount of 75 mg or 125 mg.
22. The pharmaceutical composition as claimed in claim 17 , wherein the memantine or a pharmaceutically acceptable salt thereof is present in an amount of 5 mg to 40 mg.
23. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof is administered to the patient by oral, nasal, local, dermal or parenteral routes.
24. The method of treating Alzheimer's disease as claimed in claim 7 , wherein the 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof is administered to the patient one to three times per day, one to three times per week or one to three times per month.