Claims for Patent: 4,336,400

Summary for Patent: 4,336,400

Title:	3-(Hydroxy or hydroxymethyl)-4-hydroxy-alpha(aminomethyl)benzyl alcohols and methods of use
Abstract:	Mono-, di- and tri-esters of 3-(hydroxy or hydroxymethyl)-4-hydroxy-alpha-(aminomethyl)benzyl alcohols, obtained by methods involving reduction of the corresponding mono- and di-ester ketones, are useful for producing sympathomimetic effects, such as bronchodilation, of long duration with low cardiovascular stimulating effect, in warm-blooded mammals.
Inventor(s):	Hiroaki Minatoya, Benjamin F. Tullar, Walter D. Conway
Assignee:	Aventis Pharmaceuticals Inc
Application Number:	US05/937,949
Patent Claims:	1. An ester of 3,4-dihydroxy-alpha-(amino- and N-substituted amino-methyl)benzyl alcohol having the formula ##STR13## wherein R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or ethyl; Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cycloalkyl--Cn H2n --CO-- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, or Z--Cn H2n --CO-- wherein n is zero, one or two and Z is phenyl substituted by 1-3 members of the group consisting of alkoxy having 1-4 carbon atoms, and Y1 and Y2 are the same or different and are hydrogen or one of the acyl members defined by Y, and wherein at least one of Y and Y1 contains no less than four carbon atoms when R is tert-butyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl;or a pharmaceutically acceptable acid-addition salt thereof. 2. An ester of 3,4-dihydroxy-alpha-(amino- and N-substituted amino-methyl)benzyl alcohol having the formula ##STR14## wherein R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or ethyl; Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cycloalkyl--Cn H2n --CO-- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, or Z--Cn H2n --CO-- wherein n is zero, one or two and Z is phenyl substituted by 1-3 members of the group consisting of alkoxy having 1-4 carbon atoms, and Y1 and Y2 are the same or different and are hydrogen or one of the acyl members defined by Y, at least one of Y and Y1 being Z--Cn H2n --CO--; or a pharmaceutically acceptable acid-addition salt thereof. 3. A compound according to claim 2 wherein Y and Y1 are the same or different and each is Z--Cn H2n --CO--. 4. A compound according to claim 3 wherein Y2 and R' are hydrogen. 5. A compound according to claim 3 wherein n is zero. 6. A compound having the formula ##STR15## wherein R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or ethyl; Y and Y1 are the same or different and each is Z--Cn H2n --CO-- wherein n is zero, and Z is phenyl substituted by 1-3 members of the group consisting of alkoxy having 1-4 carbon atoms, or a pharmaceutically acceptable acid-addition salt thereof. 7. A compound according to claim 6 wherein R' is hydrogen. 8. A compound according to claim 7 wherein R is isopropyl. 9. A compound according to claim 6 wherein R' is ethyl. 10. A compound according to claim 9 wherein R is tert-butyl. 11. A compound having the formula ##STR16## wherein Y and Y1 are the same or different and each is Z--Cn H2n --CO-- wherein n is zero, and Z is phenyl substituted by 1-3 members of the group consisting of alkoxy having 1-4 carbon atoms, or a pharmaceutically acceptable acid-addition salt thereof. 12. A compound according to claim 11 wherein each of Y and Y1 is anisoyl. 13. A compound according to claim 2 wherein one of Y and Y1 is Z--Cn H2n --CO-- and the other is alkanoyl. 14. A compound according to claim 13 wherein n is zero. 15. A compound having the formula ##STR17## wherein R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or ethyl; One of Y and Y1 is an acyl member which is alkanoyl having 1-22 carbon atoms, and the other is Z--Cn H2n --CO-- wherein n is zero, and Z is phenyl substituted by 1-3 members of the group consisting of alkoxy having 1-4 carbon atoms, or a pharmaceutically acceptable acid-addition salt thereof. 16. A compound according to claim 15 wherein R' is hydrogen. 17. A compound according to claim 15 wherein R' is ethyl. 18. A compound having the formula ##STR18## wherein one of Y and Y1 is an acyl member which is alkanoyl having 1-22 carbon atoms, and the other is Z--Cn H2n --CO-- wherein n is zero, and Z is phenyl substituted by 1-3 members of the group consisting of alkoxy having 1-4 carbon atoms, or a pharmaceutically acceptable acid-addition salt thereof. 19. A compound according to claim 18 wherein one of Y and Y1 is anisoyl. 20. A compound according to claim 2 wherein one of Y and Y1 is Z--Cn H2n --CO-- and the other is hydrogen. 21. A compound according to claim 20 wherein n is zero. 22. A compound according to claim 21 wherein Y2 is hydrogen. 23. A compound having the formula ##STR19## wherein R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or ethyl; Y is Z-Cn H2n --CO-- wherein n is zero, and Z is phenyl substituted by 1-3 members of the group consisting of alkoxy having 1-4 carbon atoms, or a pharmaceutically acceptable acid-addition salt thereof. 24. A compound according to claim 23 wherein R' is ethyl. 25. A compound according to claim 23 wherein R' is hydrogen. 26. A compound according to claim 25 wherein R is tert-butyl. 27. An ester of 3,4-dihydroxy-alpha-(amino- and N-substituted amino-methyl)benzyl alcohol having the formula ##STR20## wherein R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or ethyl; Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cycloalkyl--Cn H2n --CO-- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, and Y1 and Y2 are the same or different and are hydrogen or one of the acyl members defined by Y, and wherein at least one of Y and Y1 contains no less than four carbon atoms when R is tert-butyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl; or a pharmaceutically acceptable acid-addition salt thereof. 28. A compound according to claim 27 wherein Y and Y1 are the same or different and each is alkanoyl. 29. A compound having the formula ##STR21## wherein: R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or ethyl; Y and Y1 are the same or different and each is an acyl member which is alkanoyl having 1-22 carbon atoms, and wherein at least one of Y and Y1 contains no less than four carbon atoms when R is tert-butyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl; or a pharmaceutically acceptable acid-addition salt thereof. 30. A compound according to claim 29 wherein R' is hydrogen. 31. A compound according to claim 29 wherein R' is ethyl. 32. A compound having the formula ##STR22## wherein Y and Y1 are the same of different and each is an acyl member which is alkanoyl having 1-22 carbon atoms, andwherein at least one of Y and Y1 contains no less than four carbon atoms; or a pharmaceutically acceptable acid-addition salt thereof. 33. A compound according to claim 27 wherein one of Y and Y1 is alkanoyl and the other is hydrogen. 34. A compound according to claim 33 wherein Y2 is hydrogen. 35. A compound having the formula ##STR23## wherein: R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or ethyl; Y is an acyl member which is alkanoyl having 1-22 carbon atoms; and wherein Y contains no less than four carbon atoms when R is tert-butyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl; or a pharmaceutically acceptable acid-addition salt thereof. 36. A compound according to claim 35 wherein R' is ethyl. 37. A compound according to claim 35 wherein R' is hydrogen. 38. A compound according to claim 37 wherein R is tert-butyl. 39. A compound selected from the group consisting of:3,4-bis(isovaleryloxy)-alpha-[(1-tert-butylamino)ethyl]benzoyl alcohol hydrochloride, 3. 4-bis(pivalyloxy)-alpha-[(1-tert-butylamino)-ethyl]benzyl alcohol hydrochloride and3,4-bis(p-toluyloxy)-alpha-(1-aminoethyl)benzyl alcohol methanesulfonate. 40. An ester of 3-hydroxymethyl-4-hydroxy-alpha-(amino- and N-substituted amino-methyl)benzyl alcohol having the formula ##STR24## wherein: R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or alkyl having 1-3 carbon atoms; Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cycloalkyl--Cn H2n --CO-- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, or Z--Cn H2n --CO-- wherein n is zero, one or two and Z is phenyl substituted by 1-3 members of the group consisting of alkoxy having 1-4 carbon atoms, and Y1 and Y2 are the same or different and are hydrogen or one of the acyl members defined by Y, and wherein at least one of Y and Y1 contains no less than four carbon atoms; or a pharmaceutically acceptable acid-addition salt thereof. 41. A compound according to claim 40 wherein Y2 is hydrogen. 42. A compound according to claim 41 wherein R' is alkyl. 43. A compound according to claim 41 wherein R' is hydrogen. 44. A compound according to claim 43 wherein R is alkyl. 45. A compound according to claim 44 wherein R is tert-butyl. 46. A compound according to claim 45 wherein Y and Y1 are the same or different and each is Z-Cn H2n -CO-. 47. A compound according to claim 46 wherein n is zero. 48. A compound according to claim 45 wherein one of Y and Y1 is alkanoyl and the other is Z-Cn H2n -CO-. 49. A compound according to claim 48 wherein n is zero. 50. A compound according to claim 45 wherein Y and Y1 are the same or different and each is alkanoyl. 51. A compound according to claim 45 wherein one of Y and Y1 is alkanoyl and the other is 1-adamantanecarbonyl. 52. A compound according to claim 45 wherein Y1 is hydrogen. 53. 3,4-Bis(p-anisoyloxy)-alpha-[(tert-butylamino)methyl]-benzyl alcohol hydrochloride according to claim 12. 54. 3-Acetoxy-4-p-anisoyloxy-alpha-[(tert-butylamino)-methyl]benzyl alcohol methanesulfonate according to claim 19. 55. 3-Hydroxy-4-p-anisoyloxy-alpha-[(tert-butylamino)-methyl]benzyl alcohol hydrochloride according to claim 26. 56. 3,4-Bis(pivalyloxy)-alpha-[(tert-butylamino)methyl]-benzyl alcohol hydrochloride according to claim 32. 57. 3,4-Bis(3,3-dimethylbutyryloxy)-alpha-[(tert-butylamino)methyl]benzyl alcohol hydrochloride according to claim 32. 58. 3-(Acetoxymethyl)-4-p-anisoyloxy-alpha-[(tert-butylamino)methyl]benzyl alcohol methanesulfonate according to claim 49. 59. 4-Pivalyloxy-3-(pivalyloxymethyl)-alpha-[(tert-butylamino)methyl]benzyl alcohol methanesulfonate according to claim 50. 60. 3-(Acetoxymethyl)-4-(1-adamantanecarbonyl)-alpha-[(tert-butylamino)methyl]benzyl alcohol methanesulfonate according to claim 51. 61. The method of producing bronchodilation in a warm-blooded mammal which comprises administering to said mammal an effective bronchodilator amount of a compound selected from the group consisting of:3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride, 3,4-bis(isobutyryloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride, 3,4-bis(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, 3,4-bis(2-methylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, 3. 4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride,3,4-bis(3-methylpentanoyloxy)-alpha-(tert-butyl-aminomethyl)benzyl alcohol hydrochloride, 3,4-bis(3,3-dimethylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, 3,4-bis(1-methylcyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, 3,4-bis(cyclohexanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, 3,4-bis(benzoyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride, 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol methanesulfonate, 3,4-bis(p-anisoyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride, 3-hydroxy-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-hydroxy-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(isovaleryloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, 3,4-bis(p-toluyloxy)-alpha-(isopropylaminomethyl)-benzyl alcohol methanesulfonate, 3,4-bis(m-toluyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol methanesulfonate, 3,4-bis(2,4-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3,4-bis(3,5-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3. 4-bis(p-methoxyphenylacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride,3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, 3-benzoyloxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3,4-bis(p-toluyloxy)-alpha-(methylaminomethyl)-benzyl alcohol methanesulfonate, 3,4-bis(p-toluyloxy)-alpha-(aminomethyl)benzyl alcohol methanesulfonate, 3,4-bis(p-toluyloxy)-alpha-[1-(isopropylamino)-propyl]benzyl alcohol hydrochloride, 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)-benzyl acetate methanesulfonate, 3,4-bis(isovaleryloxy)-alpha-[1-(cyclopentylamino)propyl]benzyl alcohol hydrochloride, 3-hydroxy-4-(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-hydroxy-4-(2,2-dimethylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3,4-bis(pivalyloxy)-alpha-[1-(tert-butylamino)-ethyl]benzyl alcohol hydrochloride, 3-benzoyloxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, 3,4-bis(p-toluyloxy)-alpha-[1-(tert-butylamino)-propyl]benzyl alcohol hydrochloride, 3-acetoxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(p-toluyloxy)-4-acetoxy-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(o-toluyloxy)-4-acetoxy-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(1-adamantanecarbonyloxy)-4-acetoxy-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(p-anisoyloxy)-4-acetoxy-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(pivalyloxymethyl)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(isovaleryloxymethyl)-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(acetoxymethyl)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(acetoxymethyl)-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3-(acetoxymethyl)-4-(1-adamantanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, 3,4-bis(benzoyloxy)-alpha-[1-(tert-butylamino)-propyl]benzyl alcohol methanesulfonate, and 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)-benzyl p-toluate methanesulfonate. 62. A compound of the group consisting of: 3-(Y1 -O-)-4-(Y-O-)phenyl (R-NH-)(R')methyl ketones having the formula ##STR25## and 3-(Y-O-CH2 -)-4-(Y1 -O-)phenyl (R-NH-)(R')methyl ketones having the formula ##STR26## wherein, in each formula: R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or alkyl having 1-3 carbon atoms; Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cycloalkyl-Cn H2n -CO- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one, or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl or naphthalenecarbonyl, and Y1 is hydrogen or an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cycloalkyl-Cn H2n -CO- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one, or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl or naphthalenecarbonyl, and wherein in Formula III at least one of Y and Y1 contains no less than four carbon atoms when R is tert-butyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl; and in Formula IV at least one of Y and Y1 contains no less than four carbon atoms; and acid-addition salts thereof. 63. A 3-(Y1 -O-)-4-(Y-O-)phenyl (R-NH-)(R')methyl ketone according to claim 62. 64. A compound according to claim 63 wherein R' is hydrogen. 65. A compound according to claim 64 wherein R is alkyl. 66. A compound according to claim 65 wherein R is tert-butyl. 67. A compound according to claim 66 wherein each of Y and Y1 is alkanoyl. 68. A compound according to claim 66 wherein Y1 is hydrogen. 69. A 3-(Y-O-CH2 -)-4-(Y1 -O-)phenyl (R-NH-)(R')methyl ketone according to claim 62. 70. A compound according to claim 69 wherein R' is hydrogen. 71. A compound according to claim 70 wherein R is alkyl. 72. A compound according to claim 71 wherein R is tert-butyl. 73. A compound according to claim 72 wherein at least one of Y and Y1 is alkanoyl. 74. A compound according to claim 72 wherein Y1 is hydrogen. 75. A compound according to claim 74 wherein Y is alkanoyl. 76. The method of producing sympathomimetic effects in a warm-blooded mammal which comprises administering to said mammal an effective amount of a compound having the formula ##STR27## wherein: R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or ethyl; Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cycloalkyl-Cn H2n -CO- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, or Z-Cn H2n -CO- wherein n is zero, one or two and Z is phenyl or phenyl substituted by 1-3 members of the group consisting of alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, halo or trifluoromethyl, and Y1 and Y2 are the same or different and are hydrogen or one of the acyl members defined by Y, and wherein at least one of Y and Y1 contains no less than four carbon atoms when R is tert-butyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl; or a pharmaceutically acceptable acid-addition salt thereof. 77. The method according to claim 76 wherein at least one of Y and Y1 is Z-Cn H2n -CO-. 78. The method according to claim 76 wherein:R is tert-butyl; R' and Y2 are each hydrogen, and Y and Y1 are the same or different and each is Z-Cn H2n -CO-. 79. The method according to claim 76 wherein:R is tert-butyl; R' and Y2 are each hydrogen, and one of Y and Y1 is an acyl member which is alkanoyl having 1-22 carbon atoms and the other is Z-Cn H2n -CO-. 80. The method of producing sympathomimetic effects in a warm-blooded mammal which comprises administering to said mammal an effective amount of a compound having the formula ##STR28## wherein: R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;R' is hydrogen or alkyl having 1-3 carbon atoms; Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cycloalkyl-Cn H2n -CO- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, or Z-Cn H2n -CO- wherein n is zero, one or two and Z is phenyl or phenyl substituted by 1-3 members of the group consisting of alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, halo or trifluoromethyl, and Y1 and Y2 are the same or different and are hydrogen or one of the acyl members defined by Y, and wherein at least one of Y and Y1 contains no less than four carbon atoms; or a pharmaceutically acceptable acid-addition salt thereof. 81. The method according to claim 80 wherein:R is tert-butyl, and R' and Y2 are each hydrogen.