Claims for Patent: 4,816,456

Summary for Patent: 4,816,456

Title:	Administration of monoamine acridines in cholinergic neuronal deficit states
Abstract:	A method for treating central nervous system or peripheral nervous system cholinergic deficit states such as Alzheimer's disease in a mammal, said method comprising administering to said mammal an amount of a monoamine acridine derivative effective in the treatment of a cholinergic deficit state and for a time sufficient to achieve a suitable blood level to treat said cholinergic deficit state. The preferred monoamine acridine derivative is 1,2,3,4-tetrahydro-5-aminoacridine. A unit dosage pharmaceutical composition of matter comprising an effective amount of said monoamine acridine derivative sufficient to treat said cholinergic deficit state and a pharmaceutically acceptable inert carrier therefor is also disclosed.
Inventor(s):	Summers; William K. (Arcadia, CA)
Assignee:
Application Number:	07/098,871
Patent Claims:	1. A method of treating a central nervous system or peripheral nervous system cholinergic deficit state in a mammalian organism in need of such treatment, said method comprising administering to said mammal an amount of a monoamine acridine derivative effective in the treatment of a cholinergic deficit state and for a time sufficient to achieve a suitable blood level to treat said cholinergic deficit state, said monoamine acridine derivative having the formula: ##STR21## wherein R.sub.1 represents hydrogen, hydroxy, methyl, methoxy, ethyl or ethoxy; R.sub.1 and R.sub.2 together may form a double bond, R.sub.3 and R.sub.4 together may form a double bond, or R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; R.sub.5 represents hydrogen, hydroxy, methoxy or ethoxy; R.sub.6 represents hydrogen, hydroxy, methoxy or ethoxy; and R.sub.7 is without a substituent or R.sub.7 represents an oxygen atom; a C.sub.1 -C.sub.20 alkyl radical or a radical selected from the group consisting of ##STR22## wherein each R is independently selected from C.sub.1 -C.sub.20 alkyl; and pharmaceutically acceptable salts thereof. 2. The method as defined by claim 1, wherein said monoamine acridine derivative is administered orally, intramuscularly, subcutaneously, rectally or topically. 3. The method as defined by claim 2, wherein said monoamine acridine derivative is administered orally. 4. The method as defined by claim 1, wherein said monoamine acridine derivative is 1,2,3,4-tetrahydro-5-aminoacridine. 5. The method as defined by claim 1, wherein R.sub.7 is selected from the group consisting of ##STR23## 6. The method as defined by claim 1, wherein said central nervous system or peripheral nervous system cholinergic deficit state is Alzheimer's disease, Myasthenia gravis, Huntington's chorea, tardive dyskinesia, dementia associated with Down's syndrome or Parkinson's disease. 7. The method as defined by claim 6, wherein said central nervous system cholinergic deficit state is Alzheimer's disease. 8. The method as defined by claim 1, comprising administering from about 40 mg to about 1 gram of said monoamine acridine derivative per 24 hours. 9. The method as defined by claim 8, comprising administering from about 100 mg to about 300 mg of said monoamine acridine derivative per 24 hours. 10. The method as defined by claim 1, said monoamine acridine derivative further including a pharmaceutically acceptable inert carrier therefor. 11. A method of treating Alzheimer's disease in a mammal, said method comprising administering to said mammal about 100 mg to about 300 mg per 24 hours of 1,2,3,4-tetrahydro-5-aminoacridine and a pharmaceutically acceptable inert carrier therefor. 12. A method of maintaining a blood level of about 5 .mu.g to about 70 .mu.g of a monoamine acridine derivative having the formula: ##STR24## wherein R.sub.1 represents hydrogen, hydroxy, methyl, methoxy, ethyl or ethoxy; and R.sub.1 and R.sub.2 together may form a double bond, R.sub.3 and R.sub.4 together may form a double bond, or R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; R.sub.5 represents hydrogen, hydroxy, methoxy or ethoxy; R.sub.6 represents hydrogen, hydroxy, methoxy or ethoxy; and R.sub.7 is without a substituent or R.sub.7 represents an oxygen atom; a C.sub.1 -C.sub.20 alkyl radical or a radical selected from the group consisting of ##STR25## wherein each R is independently selected from C.sub.1 -C.sub.20 alkyl; and pharmaceutically acceptable salts thereof, in a mammalian organism having a central nervous system or peripheral nervous system cholinergic deficit state, comprising administering to said mammalian organism from about 40 mg to about 1 gram of said monoamine acridine derivative. 13. A method of treating central nervous system or peripheral nervous system cholinergic deficit states in a mammalian organism in need of such treatment, said method comprising orally administering to said mammal an amount of a monoamine acridine derivative effective in the treatment of cholinergic deficit states and for a time sufficient to achieve a suitable blood level to treat said cholinergic deficit state, said monoamine acridine derivative having the formula: ##STR26## wherein R.sub.1 represents hydrogen, hydroxy, methyl, methoxy, ethyl or ethoxy; R.sub.1 and R.sub.2 together may form a double bond, R.sub.3 and R.sub.4 together may form a double bond, or R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; R.sub.5 represents hydrogen, hydroxy, methoxy or ethoxy; R.sub.6 represents hydrogen, hydroxy, methoxy or ethoxy; and R.sub.7 is without a substituent or R.sub.7 represents an oxygen atom and pharmaceutically acceptable salts thereof. 14. The method as defined by claim 13, wherein said monoamine acridine derivative is 1,2,3,4-tetrahydro-5-aminoacridine. 15. The method as defined by claim 13, wherein said central nervous system or peripheral nervous system cholinergic deficit state is Alzheimer's disease, Myasthenia gravis, Huntington's chorea, tardive dyskinesia, dementia associated with Down's syndrome or Parkinson's disease. 16. The method as defined by claim 15, wherein said central nervous system cholinergic deficit state is Alzheimer's disease. 17. The method as defined by claim 13, comprising administering from about 40 mg to about 1 gram of said monoamine acridine derivative per 24 hours. 18. The method as defined by claim 17, comprising administering from about 100 mg to about 300 mg of said monoamine acridine derivative per 24 hours. 19. The method as defined by claim 18, comprising administering from about 100 mg to about 200 mg of said monoamine acridine derivative per 24 hours. 20. The method as defined by claim 13, said monoamine acridine derivative further including a pharmaceutically acceptable inert carrier therefor. 21. A pharmaceutical composition of matter for treating central nervous system or peripheral nervous system cholinergic deficit states in a mammalian organism in need of such treatment, said composition comprising a unit dosage amount of a monoamine acridine derivative having the formula: ##STR27## wherein R.sub.1 represents hydrogen, hydroxy, methyl, methoxy, ethyl or ethoxy; R.sub.1 and R.sub.2 together may form a double bond, R.sub.3 and R.sub.4 together may form a double bond, or R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are all hydrogen; R.sub.5 represents hydrogen, hydroxy, methoxy or ethoxy; R.sub.6 represents hydrogen, hydroxy, methoxy or ethoxy; and R.sub.7 is without a substituent or R.sub.7 represents an oxygen atom; a C.sub.1 -C.sub.20 alkyl radical or a radical selected from the group consisting of ##STR28## wherein each R is independently selected from C.sub.1 -C.sub.20 alkyl; and pharmaceutically acceptable salts thereof in an amount sufficient to treat said central nervous system or peripheral nervous system cholinergic deficit state and a pharmaceutically acceptable inert carrier therefor, with the provisos that (i) if R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each hydrogen, then R.sub.7 cannot be without a substituent, (ii) if R.sub.1 and R.sub.2 together form a double bond, R.sub.3 and R.sub.4 together form a double bond and R.sub.5 and R.sub.6 are each hydrogen, then R.sub.7 cannot be without a substituent, and (iii) if R.sub.3 and R.sub.4 together form a double bond and R.sub.7 is without a substituent then R.sub.1 cannot be a hydrogen atom. 22. The pharmaceutical composition of matter as defined by claim 21, said pharmaceutical composition of matter being suitable for oral, intramuscular, subcutaneous, rectal or topical administration. 23. The pharmaceutical composition of matter as defined by claim 22, said pharmaceutical composition of matter being suitable for oral administration. 24. The pharmaceutical composition of matter as defined by claim 21, wherein said central nervous system or peripheral nervous system cholinergic deficit state is Alzheimer's disease, Myasthenia gravis, Huntington's chorea, tardive dyskinesia, dementia associated with Down's syndrome or Parkinson's disease. 25. The pharmaceutical composition of matter as defined by claim 24, wherein said central nervous system cholinergic deficit state is Alzheimer's disease. 26. The pharmaceutical composition of matter as defined by claim 21, comprising from about 40 mg to about 1 gram of said monoamine acridine derivative. 27. The pharmaceutical composition of matter as defined by claim 26, comprising from about 100 mg to about 300 mg of said monoamine acridine derivative. 28. A compound having the formula ##STR29## wherein R.sub.1 represents hydrogen, hydroxy, methyl, methoxy, ethyl or ethoxy; R.sub.1 and R.sub.2 together may form a double bond, R.sub.3 and R.sub.4 together may form a double bond, or R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; R.sub.5 represents hydrogen, hydroxy, methoxy or ethoxy; R.sub.6 represents hydrogen, hydroxy, methoxy or ethoxy; and R.sub.7 represents a C.sub.1 -C.sub.20 alkyl radical or a radical selected from the group consisting of ##STR30## wherein each R is independently selected from C.sub.1 -C.sub.20 alkyl. 29. The compound as defined by claim 28, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are hydrogen and R.sub.7 is selected from the group consisting of ##STR31## 30. A pharmaceutical composition of matter for treating central nervous system or peripheral nervous system cholinergic deficit states in a mammalian organism in need of such treatment, said composition comprising a unit dosage amount of a monoamine acridine derivative having the formula: ##STR32## wherein R.sub.1 represents hydrogen, hydroxy, methyl, methoxy, ethyl or ethoxy; R.sub.1 and R.sub.2 together may form a double bond, R.sub.3 and R.sub.4 together form a double bond, or R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; R.sub.5 represents hydrogen, hydroxy, methoxy or ethoxy; R.sub.6 represents hydrogen, hydroxy, methoxy or ethoxy; and R.sub.7 is without a substituent or R.sub.7 represents an oxygen atom and pharmaceutically acceptable salts thereof in an amount sufficient to treat said central nervous system or peripheral nervous system cholinergic deficit state and a pharmaceutically acceptable inert carrier therefor, with the provisos that (i) if R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each hydrogen then R.sub.7 cannot be without a substituent, (ii) if R.sub.1 and R.sub.2 together form a double bond, R.sub.3 and R.sub.4 together form a double bond and R.sub.5 and R.sub.6 are each hydrogen, then R.sub.7 cannot be without a substituent, and (iii) if R.sub.3 and R.sub.4 together form a double bond and R.sub.7 is without a substituent then R.sub.1 cannot be a hydrogen atom. 31. The pharmaceutical composition of matter as defined by claim 30, wherein said central nervous system or peripheral nervous system cholinergic deficit state is Alzheimer's disease, Myasthenia gravis, Huntington's chorea, tardive dyskinesia, dementia associated with Down's syndrome or Parkinson's disease. 32. The pharmaceutical composition of matter as defined by claim 31, wherein said central nervous system cholinergic deficit state is Alzheimer's disease. 33. The pharmaceutical composition of matter as defined by claim 30, comprising from about 40 mg to about 1 gram of said monoamine acridine derivative. 34. The pharmaceutical composition of matter as defined by claim 33, comprising from about 100 mg to about 300 mg of said monoamine acridine derivative. 35. The pharmaceutical composition of matter as defined by claim 34, comprising from about 100 mg to about 200 mg of said monoamine acridine derivative. 36. A compound having the formula ##STR33## wherein R.sub.1 represents hydrogen, hydroxy, methyl, methoxy, ethyl or ethoxy; R.sub.1 and R.sub.2 together may form a double bond, R.sub.3 and R.sub.4 together may form a double bond, or R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; R.sub.5 represents hydrogen, hydroxy, methoxy or ethoxy; R.sub.6 represents hydrogen, hydroxy, methoxy or ethoxy; and R.sub.7 is without a substituent or R.sub.7 represents an oxygen atom, with the provisos that (i) if R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each hydrogen, then R.sub.7 cannot be without a substituent, (ii) if R.sub.1 and R.sub.2 together form a double bond, R.sub.3 and R.sub.4 together form a double bond and R.sub.5 and R.sub.6 are each hydrogen, then R.sub.7 cannot be without a substituent, and (iii) if R.sub.3 and R.sub.4 together form a double bond and R.sub.7 is without a substituent then R.sub.1 cannot be a hydrogen atom. 37. The pharmaceutical composition of matter as defined by claim 21, wherein R.sub.1 represents hydrogen, hydroxy, methyl, methoxy, ethyl or ethoxy; R.sub.1 and R.sub.2 together may form a double bond, R.sub.3 and R.sub.4 together may form a double bond, or R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; R.sub.5 represents hydrogen, hydroxy, methoxy or ethoxy; R.sub.6 represents hydrogen, hydroxy, methoxy or ethoxy; and R.sub.7 is without a substituent or R.sub.7 is an oxygen atom or a radical selected from the group consisting of ##STR34## wherein each R is independently selected from C.sub.1 -C.sub.20 alkyl; and pharmaceutically acceptable salts thereof in an amount sufficient to treat said central nervous system or peripheral nervous system cholinergic deficit state and a pharmaceutically acceptable inert carrier therefor with the provisos that (i) if R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each hydrogen then R.sub.7 cannot be without a substituent, (ii) if R.sub.1 and R.sub.2 together form a double bond, R.sub.3 and R.sub.4 together form a double bond and R.sub.5 and R.sub.6 are each hydrogen, then R.sub.7 cannot be without a substituent, and (iii) if R.sub.3 and R.sub.4 together form a double bond and R.sub.7 is without a substituent then R.sub.1 cannot be hydrogen. 38. The compound as defined by claim 28, wherein R.sub.1 represents hydrogen, hydroxy, methyl, methoxy, ethyl or ethoxy; R.sub.1 and R.sub.2 together may form a double bond, R.sub.3 and R.sub.4 together may form a double bond, or R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; R.sub.5 represents hydrogen, hydroxy, methoxy or ethoxy; R.sub.6 represents hydrogen, hydroxy, methoxy or ethoxy; and R.sub.7 represents a radical selected from the group consisting of ##STR35## wherein each R is independently selected from C.sub.1 -C.sub.20 alkyl.