Patent EA-002031-B1 (EA)
Title: Benzamides for neurodegenerative disorder treatment
Inventor: FLITTER WILLIAM DAVID
IPC: A61K31/167
Filed: 1996-04-03
Abstract: 1. An acetamidobenzamide compound of the formula   where R' is a saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2, with the proviso that, when n is 1 and R' is either n-butyl or n-propyl, the acetamido group is not at the 2 position of the ring, when n is 1 the acetamido group is not at the 3 position of the ring and, when n is 2, the acetamido groups are not at the 3 and 5 positions of the ring. 2. The compound of claim 1 selected from the group consisting of N-isopropyl-4-acetamidobenzamide, N-tert-amyl-4-acetamidobenzamide and N-methylcyclopropyl-4-acetamidobenzamide. 3. The compound of claim 1 which is N-tert-butyl-3-acetamidobenzamide. 4. Nitro- or aminobenzamide of formula   wherein R' is a saturated alkyl of from 3 to 5 carbon atoms. each R is independently -NO2 or -NH2 or and n is 1 or 2 selected from the group consisting of N-tert-amyl-4-nitrobenzamide, N-1,2- dimethylpropyl-4-nitrobenzamide, N-n-butyl-3 -nitrobenzamide, N-pentyl-4-nitrobenzamide, N-2-methylbutyl-4- nitrobenzamide, N-n-butyl-3.5-dinitrobenzamide, N-methylcyclopropyl-4-nitrobenzamide, N-n-butyl-2-nitrobenzamide, N-n-pentyl-2-nitrobenzamide and N-methylcyclopropyl-4-aminobenzamide. 5. A method for preparing a benzamide of the formula   wherein R' is a saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2, comprising the steps of: a) condensing a saturated alkyl amine of from 3 to 5 carbon atoms with a nitrobenzoylhalide of the formula   wherein n is 1 or 2 and X is a halo such as I, Br, F or Cl, to yield a compound III   b) reducing the NO2. groups in a cmpound III to NH2- groups; and c) acetylating the NH2 groups to NHCOCH3 groups. 6. A method for preparing a benzamide of the formula   wherein R' is a saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2, with the following provisos: 1) when n is 1 and R is -NO2 at the 4 position of the ring, R' is not tert-butyl, iso-butyl, or propyl; 2) when n is 1 and R is -NO2 at the 2 position of the ring, R' is not iso-butyl or propyl; and 3) when n is 2 and R' is tert-butyl and both Rs are -NO2, the R groups are not at the 3 and 5 positions of the ring, comprising the step of condensing a saturated alkylamine from 3 to 5 carbon atoms with a nitrobenzoylhalide of the formula   wherein n is 1 or 2 and X is a halo such as I, Br, F or Cl, to yield a formula   7. A method for preparing a benzamide of the formula   wherein R' is a saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2, with the following provisos: a) condensing a saturated alkyl amine of from 3 to 5 carbon atoms with a nitrobenzoylhalide of the formula   wherein n is 1 or 2 and X is a halo such as I, Br, F or Cl, to yield a compound   b) reducing the NO2 groups to NH2 groups. 8. A pharmaceutical composition comprising a benzamide derivative of formula I   wherein R' is a saturated alkyl of from 3 to 5 carbon atoms, each R is independently -NO2 or -NH2 or -NH-CO-CH3 and n is 1 or 2, with the following provisos: 1) when n is 1 and R is -NO2 at the 4 position of the ring, R' is not tert-butyl, iso-butyl, or propyl; 2) when n is 1 and R is -NO2 at the 2 position of the ring, R' is not iso-butyl or propyl; and 3) when n is 2 and R' is tert-butyl and both Rs are -NO2, the R groups are not at the 3 and 5 positions of the ring, comprising the step of condensing a saturated alkylamine from 3 to 5 carbon atoms in a pharmaceutically acceptable carrier. 9. The pharmaceutical composition of claim 8 wherein the benzamide compound is an acetamidobenzamide of the formula   wherein R' is a saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2. 10. n is 1 and R' is tert-butyl or tert-amyl. 11. The pharmaceutical composition of claim 10 wherein the benzamide derivative is N-tert-butyl-4-aceramidobenzamide. 12. The pharmaceutical composition of claim 9 wherein the benzamide derivative is selected from the group consisting of N-isopropyl-4-acetamidobenzamide, N-tert-amyl-4-acetamidobenzamide, N-tert-butyl-3-acetamidobenzamide and N-methylcyclopropyl-4-acetamidobenzamide. 13. The pharmaceutical composition of claim 8 wherein R' is a saturated alkyl of from 3 to 5 carbon atoms, each R is independently -NO2 or -NH2 and n is 1 or 2, with the following provisos: 1) when n is 1 and R is -NO2 at the 4 position of the ring, R' is not tert-butyl, iso-butyl, or propyl; 2) when n is 1 and R is -NO2 at the 2 position of the ring, R' is not iso-butyl or propyl; and 3) when n is 2 and R' is tert-butyl and both Rs are -NO2, the R groups are not at the 3 and 5 positions of the ring, comprising the step of condensing a saturated alkylamine from 3 to 5 carbon atoms. 14. The pharmaceutical composition of claim 13 wherein the benzamide derivative is N-tert-butyl-4-aminobenzamide. 15. The pharmaceutical composition of claim 13 wherein the benzamide derivative is selected from the group consisting of N-isopropyl-4 nitrobenzamide, N tert-butyl-3-nitrobenzamide, N tert-butyl-2-nitrobenzamide, N-n-butyl-4-nitrobenzamide, N-n-propyl-4-nitrobenzamide, and N-tert-butyl-3.5-dinitrobenzamide, N-methylpropyl-4-nitrobenzamide and N-tert-butyl-3-aminobenzamide. 16. The pharmaceutical composition of Claim 8 wherein the carrier is an oral carrier or is an injectable carrier. 17. A method for treating a patient suffering from a neurodegenerative condition comprising administering to said patient an effective therapeutic amount of the pharmaceutical composition of Claims 8 through 16. 18. The method of Claim 17 wherein the neurodegenerative condition is one associated with a progressive loss of central nervous system function. 19. The method of Claim 18 wherein the neurodegenerative condition is a dopamine-associated neurodegenerative condition. 20. The method of Claim 19 wherein the dopamine-associated neurodegenerative condition is Parkinson's disease. 21. The method of Claim 17 wherein the neurodegenerative condition is Alzheimer's disease. 22. The method of Claim 17 wherein the neurodegenerative condition is one associated with a progressive loss of central nervous system function due to mitochondrial dysfunction. 23. The method of Claim 17 wherein said administration is oral. 24. The method of Claim 17 wherein said administration is parenteral. 25. The method of Claim 17 wherein said administration is by intravenous infusion. 26. The use of a benzamide compound of the formula I   wherein R' is a saturated alkyl of from 3 to 5 carbon atoms, each R is independently -NO2 or -NH2 or -NH-CO-CH3 and n is 1 or 2, with the following provisos: 1) when n is 1 and R is -NO2 at the 4 position of the ring, R' is not tert-butyl, iso-butyl, or propyl; 2) when n is 1 and R is -NO2 at the 2 position of the ring, R' is not iso-butyl or propyl; and 3) when n is 2 and R' is tert-butyl and both Rs are -NO2, the R groups are not at the 3 and 5 positions of the ring, for treating a neurodegenerative condition. 27. The use of claim 26 wherein the neurodegenerative condition is Parkinson's disease. 28. The use of claim 26 wherein the neurodegenerative condition is Alzheimer's disease. 29. The use of acetobenzamide of claim 1 for treating a neurodegenerative condition. 30. The use of claim 29 wherein the neurodegenerative condition is Parkinson's disease. 31. The use of claim 29 wherein the neurodegenerative condition is Alzheimer's disease. 32. The use of claim 26 wherein the benzamide derivative is N-tert-butyl-4-aminobenzamide. 33. The use of claim 32 wherein the neurodegenerative condition is Parkinson's disease. 34. The use of claim 32 wherein the neurodegenerative condition is Alzheimer's disease. 35. The use of claim 29 wherein the acetobenzamide is N-tert-butyl-4-aminobenzamide. 36. The use of claim 35 wherein the neurodegenerative condition is Parkinson's disease. 37. The use of claim 35 wherein the neurodegenerative condition is Alzheimer's disease. 38. A use of benzamide derivative of formula I       where R', R and n are as defined in claim 26 in the manufacture of a formulation for treating of neurodegenerative condition. 39. The use of claim 38 wherein the neurodegenerative condition is Parkinson's disease. 40. The use of claim 38 wherein the neurodegenerative condition is Alzheimer's disease. 41. A use of of an acetamidobenzamide of formula   42. The use of claim 41 wherein the neurodegenerative condition is Parkinson's disease. 43. The use of claim 41 wherein the neurodegenerative condition is Alzheimer's disease. 44. A use of claim 41 wherein acetamidobenzamide is a compound of claim 1.  45. The use of claim 44 wherein the neurodegenerative condition is Parkinson's disease. 46. The use of claim 44 wherein the neurodegenerative condition is Alzheimer's disease. 47. A use of N-tert-butyl-4-acetamidobenzamide in the manufacture of a formulation for treating of neurodegenerative condition. 48. The use of claim 47 wherein the neurodegenerative condition is Parkinson's disease. 49. The use of claim 47 wherein the neurodegenerative condition is Alzheimer's disease. 50. A use of claim 38 wherein the benzamide derivative is N-tert-butyl-4-aminoenzamide. 51. The use of claim 50 wherein the neurodegenerative condition is Parkinson's disease.