Claims
- 1. A compound of the formula (XII):
- 2. A compound according to claim 1, wherein R1 is C1-C6 alkyl.
- 3. A compound according to claim 2, wherein R1 is —C4 alkyl.
- 4. A compound according to claim 3, wherein R1 is —CH2CH(CH3)2.
- 5. A compound according to claim 1, wherein R2 is -alkyl.
- 6. A compound according to claim 5, wherein R2 is C1 alkyl.
- 7. A compound according to claim 6, wherein R2 is —CH3.
- 8. A compound according to claim 1, wherein RN is:
(I) RN-1—XN— where XN is:
(A) —CO—, (B) —SO2—, (C) —(CR′R″)1-6 where R′ and R″ are the same or different and are —H or C1-C4 alkyl, (D) —CO—(CR′R″)1-6—XN-1 where XN-1 is —O—, —S— or —NR′R″— and where R′ and R″ are as defined above, or (E) a single bond;
where RN-1 is: (A) RN-aryl where RN-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with:
(1) C1-C6 alkyl, (2) —F, —Cl, —Br, or —I, (3) —OH, (4) —NO2, (5) —CO—OH, (6) —C≡N, (7) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) —H, (b) —C1-C6 alkyl unsubstituted or substituted with
(i) —OH, or (ii) —NH2, (c) —C1-C6 alkyl unsubstituted or substituted with —F, —Cl, —Br, or —I, (d) —C3-C7 cycloalkyl, (e) —(C1-C2 alkyl)—(C3-C7 cycloalkyl), (f) —(C1-C6 alkyl)—O—(C1-C3 alkyl), (g) —C1-C6 alkenyl with one or two double bonds, (h) —C1-C6 alkynyl with one or two triple bonds, (i) —C1-C6 alkyl chain with one double bond and one triple bond, (j) —R1-aryl where R1-aryl is as defined above, or (k) —R1-heteroaryl where R1-heteroaryl is as defined above, (8) —CO—(C3-C12 alkyl), (9) —CO—(C3-C6 cycloalkyl), (10) —CO—R1-heteroaryl where R1-heteroaryl is as defined above, (11) —CO—R1-heterocycle where R1-heterocycle is as defined above, (12) —CO—RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with C1-C3 alkyl, (13) —CO—O—RN-5 where RN-5 is:
(a) alkyl, or (b) —(CH2)0-2—(R1-aryl) where R1-aryl is as defined above, (14) —SO2—NRN-2RN-3 where RN-2 and RN-3 are as defined above, (15) —SO—(C1-C8 alkyl), (16) —SO2(C3-C12 alkyl), (17) —NH—CO—O—RN-5 where RN-5 is as defined above, (18) —NH—CO—N(C1-C3 alkyl)2, (19) —N—CS—N(C1-C3 alkyl)2, (20) —N(C1-C3 alkyl)—CO—RN-5 where RN-5 is as defined above, (21) —NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above, (22) —RN-4 where RN-4 is as defined above, (23) —O—CO—(C1-C6 alkyl), (24) —O—CO—N(C1-C3 alkyl)2, (25) —O—CS—N(C1-C3 alkyl)2, (26) —O—(C1-C6 alkyl), (27) —O—(C2-C5 alkyl)—COOH, (28) —S—(C1-C6 alkyl), (29) C1-C6 alkyl unsubstituted or substituted with halo, (30) —O—(C1-C6 alkyl unsubstituted or substituted with halo), or (31) —O-phenyl, (32) (C1-C6 alkyl) substituted with —CO—NH—C(═O)—, (B) RN-heteroaryl where RN-heteroaryl is:
(1) pyridinyl, (2) pyrimidinyl, (3) quinolinyl, (4) indenyl, (5) indanyl, (6) benzothiophenyl, (7) indolyl, (8) indolinyl, (9) pyridazinyl, (10) pyrazinyl, (11) isoindolyl, (12) isoquinolyl, (13) quinazolinyl, (14) quinoxalinyl, (15) phthalazinyl, (16) imnidazolyl, (17) isoxazolyl, (18) pyrazolyl, (19) oxazolyl, (20) thiazolyl, (21) indolizinyl, (22) indazolyl, (23) benzothiazolyl, (24) benzimidazolyl, (25) benzofuranyl, (26) furanyl, (27) thienyl, (28) pyrrolyl, (29) oxadiazolyl, (30) thiadiazolyl, (31) triazolyl, (32) tetrazolyl, (33) 1,4-benzodioxan (34) purinyl, (35) oxazolopyridinyl, (36) imidazopyridinyl, (37) isothiazolyl, (38) naphthyridinyl, (39) cinnolinyl, (40) carbazolyl, (41) β-carbolinyl, (42) isochromanyl, (43) chromanyl, (44) furazanyl, (45) tetrahydroisoquinoline, (46) isoindolinyl, (47) isobenzotetrahydrofuranyl, (48) isobenzotetrahydrothienyl, (49) isobenzothiophenyl, (50) benzoxazolyl, or (51) pyridopyridinyl, where the RN-heteroaryl group is bonded by any atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where RN-heteroaryl is unsubstituted or substituted with:
(1) C1-C6 alkyl, (2) —F, —Cl, —Br, or —I, (3) —OH, (4) —NO2, (5) —CO—OH, (6) —C≡N, (7) —CO—NRN-2RN-3 where RN-2 and RN-3 are as defined above, (8) —CO—(C3-C12 alkyl), (9) —CO—(C3-C6 cycloalkyl), (10) —CO—R1-heteroaryl where R1-heteroaryl is as defined above, (11) —CO—R1-heterocycle where R1-heterocycle is as defined above, (12) —CO—RN-4 where RN-4 is as defined above, (13) —CO—O—RN-5 where RN-5 is as defined above, (14) —SO2—NRN-2RN-3 where RN-2 and RN-3 are as defined above, (15) —SO—(C1-C8 alkyl), (16) —SO2(C3-C12 alkyl), (17) —NH—CO—O—RN-5 where RN-5 is as defined above, (18) —NH—CO—N(C1-C3 alkyl)2, (19) —N—CS—N(C1-C3 alkyl)2, (20) —N(C1-C3 alkyl)—CO—RN-5 where RN-5 is as defined above, (21) —NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above, (22) —RN-4 where RN-4 is as defined above, (23) —O—CO—(C1-C6 alkyl), (24) —O—CO—N(C1-C3 alkyl)2, (25) —O—CS—N(C1-C3 alkyl)2, (26) —O—(C1-C6 alkyl), (27) —O—(C2-C5 alkyl)—COOH, or (28) —S—(C1-C6 alkyl), (29) (C1-C6 alkyl) substituted with —CO—OH and —NH—C(═O)—, (C) —RN-aryl—RN-aryl where —RN-aryl is as defined above, (D) —RN-aryl—RN-heteroaryl where —RN-aryl and —RN-heteroaryl are as defined above, (E) —RN-heteroaryl—RN-aryl where —RN-aryl and —RN-heteroaryl are as defined above, (F) —RN-heteroaryl—RN-heteroaryl where RN-heteroaryl is as defined above, (G) —RN-aryl—O—RN-aryl where RN-aryl is as defined above, (H) —RN-aryl—S—RN-aryl where —RN-aryl is as defined above, (I) —RN-heteroaryl—RN-heteroaryl where RN-heteroaryl is as defined above, (J) —RN-heteroaryl—S—RN-heteroaryl where RN-heteroaryl is as defined above, (K) —RN-aryl—CO—RN-aryl where RN-aryl is as defined above, (L) —RN-aryl—CO—RN-heteroaryl where RN-aryl and RN-heteroaryl are as defined above, (M) —RN-aryl—SO2—RN-aryl where —RN-aryl is as defined above, (N) —RN-heteroaryl—CO—RN-heteroaryl where RN-heteroaryl is as defined above, (O) —RN-heteroaryl—SO2—RN-heteroaryl where RN-heteroaryl is as defined above, (P) —RN-aryl—O—(C1-C8 alkyl)-phenyl, where RN-aryl is as defined above, (Q) —RN-aryl—S—(C1-C8 alkyl)-phenyl, where RN-aryl is as defined above, (R) —RN-heteroaryl—O—(C1-C8 alkyl)-phenyl, where RN-heteroaryl is as defined above, or (S) —RN-heteroaryl—S—(C1-C8 alkyl)-phenyl, where RN-heteroaryl is as defined above.
- 9. A compound according to claim 8, wherein XN is —CO—.
- 10. A compound according to claim 9, wherein RN-1 is substituted or unsubstituted RN-aryl.
- 11. A compound according to claim 10, wherein RN-aryl is substituted or unsubstituted phenyl.
- 12. A compound according to claim 11, wherein phenyl is substituted with —CONPr2.
- 13. A compound according to claim 12, wherein RN is
- 14. A compound according to claim 10, wherein RN-aryl is substituted 1-naphthyl.
- 15. A compound according to claim 14, wherein 1-naphthyl is substituted with —CHOH.
- 16. A compound according to claim 15, wherein RN is:
- 17. A compound according to claim 10, wherein RN-aryl is substituted biphenyl.
- 18. A compound according to claim 17, wherein biphenyl is substituted with —CHOH.
- 19. A compound according to claim 18, wherein RN is:
- 20. A compound according to claim 11, wherein phenyl is substituted with —CHOH and —Br.
- 21. A compound according to claim 20, wherein RN is:
- 22. A compound according to claim 1, wherein RN is chosen from:
(II) —CO—(C1-C6 alkyl) where alkyl is unsubstituted or substituted with:
(A) —OH, (B) —C1-C6 alkoxy, (C) —C1-C6 thioalkoxy, (D) —CO—O—RN-8 where RN-8 is —H, C1-C6 alkyl or -phenyl, (E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above, (F) —CO—RN-4 where RN-4 is as defined above, (G) —SO2—(C1-C8 alkyl), (H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above, (I) —NH—CO—(C1-C6 alkyl), (J) —NH—CO—O—RN-8 where RN-8 is as defined above, (K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above, (L) —RN-4 where RN-4 is as defined above, (M) —O—CO—(C1-C6 alkyl), (N) —O—CO—NRN-8RN-8 where RN-8 are the same or different and are as defined above, or (O) —O—(C1-C5 alkyl)—COOH.
- 23. A compound according to claim 22, wherein RN is substituted —CO—(C1-C6 alkyl).
- 24. A compound according to claim 23, wherein RN is substituted with —OH, —C1-C6 thioalkoxy, —CO—O—RN-8, where RN-8 is —H, C1-C6 alkyl or -phenyl, or —CO—NRN-2RN-3, where RN-2 and RN-3 are the same or different and are as defined above.
- 25. A compound according to claim 24, wherien RN is substituted —CO—(C2 alkyl).
- 26. A compound according to claim 25, wherein —CO—(C2 alkyl) is substituted with —CO—NRN-2RN-3.
- 27. A compound according to claim 26, wherein —CO—NRN-2RN-3 is —CO—NH2.
- 28. A compound according to claim 27, wherein RN is:
- 29. A compound according to claim 28, wherein the free amine that is beta to the carbonyl is protected with Prot, wherein Prot is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, acetyl, trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl, difluoroacetyl, fluoroacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chorobenzyloxycarbonyT, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobomyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluorenylmethyl carbonate, —CH—CH═CH2, or phenyl-C(═N—)—H.
- 30. A compound according to claim 29, wherein Prot is t-butoxycarbonyl, or benzyloxycarbonyl.
- 31. A compound according to claim 22, wherein RN is doubly substituted —CO—(C1-C6 alkyl).
- 32. A compound according to claim 31, wherein one of the substituted with —OH, —C1-C6 thioalkoxy, —CO—O—RN-8, where RN-8 is —H, C1-C6 alkyl or -phenyl, or —CO—NRN-2RN-3, where RN-2 and RN-3 are the same or different and are as defined above; and the other substitution is with —NH—CO—(C1-C6 alkyl).
- 33. A compound according to claim 32, wherein —NH—CO—(C1-C6 alkyl) is substituted.
- 34. A compound according to claim 33, wherein C1-C6 alkyl is C2, one substituent is —CONH2 and one substituent is —NH—CO—C4 alkyl.
- 35. A compound according to claim 34, wherein C4 alkyl is substituted with —NH2.
- 36. A compound according to claim 35, wherein RN is
- 37. A compound according to claim 36, wherein the free amine that is beta to the carbonyl is protected with Prot, where Prot is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, acetyl, trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl, difluoroacetyl, fluoroacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop- 1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluorenylmethyl carbonate, —CH—CH═CH2, or phenyl-C(═N—)—H.
- 38. A compound according to claim 37, wherein Prot is t-butoxycarbonyl, or benzyloxycarbonyl.
- 39. A compound according to claim 1, wherein RC is chosen from:
(II) —C(RC-1)(RC-2)—CO—NH—RC-3 where RC-1 and RC-2 are the same or different and are:
(A) —H, (B) —C1-C6 alkyl, (C) —(C1-C4 alkyl)—RC′-aryl where RC′-aryl is as defined for RN-aryl, (D) —(C1-C4 alkyl)—RC-heteroaryl where RC-heteroaryl is as defined for RN-heteroaryl, and RN-heteroaryl is as defined above, (E) —(C1-C4 alkyl)—RC-heterocycle where RC-heterocycle is as defined for RN-heterocycle, and RN-heterocycle is as defined above, (F) —RC-heteroaryl where RC-heteroaryl is as defined above, (G) —RC-heterocycle where RC-heterocycle is as defined above, (H) —(CH2)1-4—OH, (I) —(CH2)1-4—RC-4—(CH2)1-4—RC′-aryl where RC-4 is —O—, —S—, —NH—, or —NRC-5— where RC-5 is C1-C6 alkyl, and where RC′-aryl is as defined above, (J) —(CH2)1-4—RC-4—(CH2)1-4-RC-heteroaryl where RC-4 and RC-heteroaryl are as defined above, or (K) —RC′-aryl where RC′-aryl is as defined above, and where RC-3 is:
(A) —H, (B) —C1-C6 alkyl, (C) —RC-aryl where RC′-aryl is as defined above, (D) —RC-heteroaryl where RC-heteroaryl is as defined above, (E) —RC-heterocycle where RC-heterocycle is as defined above, (F) —(C1-C4 alkyl)—RC′-aryl where RC′-aryl is as defined above, (G) —(C1-C4 alkyl)—RC-heteroaryl where RC-heteroaryl is as defined above, (H) —(C1-C4 alkyl)—RC-heterocycle where RC-heterocycle is as defined above, or (J) —C(RC-5)(RC-6)—CO—NH—C(RC-7)(RC-8)—COOH, where RC-5, RC-6, RC-7, and RC-8 are the same or different, and are as defined for RC-1 and RC-2 and where RC-1 and RC-2 are as defined above.
- 40. A compound according to claim 39, wherein RC-1 is —H, and RC-2 is —CH3.
- 41. A compound according to claim 40, wherein RC-3 is C2 alkyl.
- 42. A compound accoding to claim 41, wherein said C2 alkyl is substituted.
- 43. A compound according to claim 42, wherein said C2 alkyl is substituted with —COOH.
- 44. A compound according to claim 43, wherein RC is
- 45. A compound according to claim 39, wherein RC-3 is —C(RC-5)(RC-6)—CO—NH—C(RC-7)(RC-8)—COOH, where RC-5, RC-6, RC-7, and RC-8 are the same or different, and are as defined for RC-1 and RC-2 and where RC-1 and RC-2 are as defined above.
- 46. A compound according to claim 45, wherein RC-5 is —H, and RC-6 is —CH2CH2CO2H.
- 47. A compound according to claim 46, wherein RC-7 is —H, and RC-8 is —CH2— phenyl.
- 48. A compound of the formula (XIII)
- 49. A compound according to claim 48, wherein R1 is C1-C6 alkyl.
- 50. A compound according to 49, wherein R1 is —C4 alkyl.
- 51. A compound according to claim 50, wherein R1 is —CH2CH(CH3)2.
- 52. A compound according to claim 48, wherein R2 is -alkyl.
- 53. A compound according to claim 52, wherein R2 is C1alkyl.
- 54. A compound according to claim 53, wherein R2 is —CH3.
- 55. A compound according to claim 48, wherein R3 is —CH3.
- 56. A compound according to claim 48, wherein x is 1.
- 57. A compound according to claim 56, wherein R4 is —CH2CH2COOH.
- 58. A compound according to claim 56, wherein y is 1.
- 59. A compound according to claim 58, wherein R5 is —CH2-phenyl.
- 60. A compound of formula (XIV)
- 61. A compound according to claim 60, wherein R1 is C1-C6 alkyl.
- 62. A compound according to claim 61, wherein R1 is —C4 alkyl.
- 63. A compound according to claim 62, wherein R1 is —CH2CH(CH3)2.
- 64. A compound according to claim 60, wherein R2 is -alkyl.
- 65. A compound according to claim 64, wherein R2 is C1 alkyl.
- 66. A compound according to claim 65, wherein R2 is —CH3.
- 67. A compound according to claim 60, wherein R3 is —CH3.
- 68. A compound according to claim 60, wherein x is 1.
- 69. A compound according to claim 68, wherein R4 is —CH2CH2COOH.
- 70. A compound according to claim 68, wherein y is 1.
- 71. A compound according to claim 70, wherein R5 is —CH2-phenyl.
- 72. A compound according to claim 60, wherein XN is —CO—.
- 73. A compound according to claim 72, wherein RN-1 is substituted or unsubstituted RN-aryl.
- 74. A compound according to claim 73, wherein RN-aryl is substituted or unsubstituted phenyl.
- 75. A compound according to claim 74, wherein phenyl is substituted with —CONPr2.
- 76. A compound according to claim 75, wherein RN is
- 77. A compound according to claim 73, wherein RN-aryl is substituted 1-naphthyl.
- 78. A compound according to claim 77, wherein 1-naphthyl is substituted with —CHOH.
- 79. A compound according to claim 78, wherein RN is:
- 80. A compound according to claim 73, wherein RN-aryl is substituted biphenyl.
- 81. A compound according to claim 80, wherein biphenyl is substituted with —CHOH.
- 82. A compound according to claim 81, wherein RN is:
- 83. A compound according to claim 74, wherein phenyl is substituted with —CHOH, and —Br.
- 84. A compound according to claim 83, wherein RN is:
- 85. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a disubstituted amine of formula (XII)
- 86. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a disubstituted amine of formula (XIII)
- 87. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a disubstituted amine of formula (XIV)
- 88. A method of treatment according to claim 85, wherein the disease is Alzheimer's disease.
- 89. A method of treatment according to claim 85, wherein the method is helping prevent or delay the onset of Alzheimer's disease.
- 90. A method of treatment according to claim 85, wherein the disease is mild cognitive impairment.
- 91. A method of treatment according to claim 85, wherein the disease is Down's syndrome.
- 92. A method of treatment according to claim 85, wherein the disease is Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.
- 93. A method of treatment according to claim 85, wherein the disease is cerebral arnyloid angiopathy.
- 94. A method of treatment according to claim 85, wherein the disease is degenerative dementias.
- 95. A method of treatment according to claim 85, wherein the disease is diffuse Lewy body type of Alzheimer's disease.
- 96. A method of treatment according to claim 85, wherein the method is treating an existing disease.
- 97. A method of treatment according to claim 85, wherein the method is preventing a disease from developing.
- 98. A method of treatment according to claim 85, wherein the therapeutically effective amount for oral administration is from about 0.1 mg/day to about 1,000 mg/day; for parenteral, sublingual, intranasal, intrathecal administration is from about 0.5 to about 100 mg/day; for depo administration and implants is from about 0.5 mg/day to about 50 mg/day; for topical administration is from about 0.5 mg/day to about 200 mg/day; for rectal administration is from about 0.5 mg to about 500 mg.
- 99. A method of treatment according to claim 85, wherein the therapeutically effective amount for oral administration is from about 1 mg/day to about 100 mg/day and for parenteral administration is from about 5 to about 50 mg daily.
- 100. A method of treatment according to claim 85, where the therapeutically effective amount for oral administration is from about 5 mg/day to about 50 mg/day.
- 101. A method of treatment according to claim 85, 86, or 87, wherein the compound is:
- 102. A method of treatment according to claim 85, where the pharmaceutically acceptable salt is selected from the group consisting of salts of the following acids: acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic.
- 103. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a disubstituted amine of formula (XII)
- 104. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a disubstituted amine of formula (XIII)
- 105. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a disubstituted amine of formula (XIV)
- 106. A method of treatment according to claim 103, 104, or 105, wherein the disease is Alzheimer's disease.
- 107. A method of treatment according to claim 103, wherein the method is helping prevent or delay the onset of Alzheimer's disease.
- 108. A method of treatment according to claim 103, wherein the disease is mild cognitive impairment.
- 109. A method of treatment according to claim 103, wherein the disease is Down's syndrome.
- 110. A method of treatment according to claim 103, wherein the disease is Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.
- 111. A method of treatment according to claim 103, wherein the disease is cerebral amyloid angiopathy.
- 112. A method of treatment according to claim 103, wherein the disease is degenerative dementias.
- 113. A method of treatment according to claim 103, wherein the disease is diffuse Lewy body type of Alzheimer's disease.
- 114. A method of treatment according to claim 103, wherein the method is treating an existing disease.
- 115. A method of treatment according to claim 103, wherein the method is preventing a disease from developing.
- 116. A method of treatment according to claim 103, wherein the therapeutically effective amount for oral administration is from about 0.1 mg/day to about 1,000 mg/day; for parenteral, sublingual, intranasal, intrathecal administration is from about 0.5 to about 100 mg/day; for depo administration and implants is from about 0.5 mg/day to about 50 mg/day; for topical administration is from about 0.5 mg/day to about 200 mg/day; for rectal administration is from about 0.5 mg to about 500 mg.
- 117. A method of treatment according to claim 116, wherein the therapeutically effective amount for oral administration is from about 1 mg/day to about 100 mg/day and for parenteral administration is from about 5 to about 50 mg daily.
- 118. A method of treatment according to claim 117 where the therapeutically effective amount for oral administration is from about 5 mg/day to about 50 mg/day.
- 119. A method of treatment according to claim 103, 104, or 105, wherein the compound is:
- 120. A method of treatment according to claim 103, where the pharmaceutically acceptable salt is selected from the group consisting of salts of the following acids: acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic.
- 121. A method for inhibiting beta-secretase activity, comprising exposing said beta-secretase to an effective inhibitory amount of a compound according to claim 1, 48 or 60.
- 122. The method of claim 121, wherein said beta-secretase is exposed to said compound in vitro.
- 123. The method of claim 121, wherein said beta-secretase is exposed to said compound in a cell.
- 124. The method of claim 123, wherein said cell is in an animal.
- 125. The method of claim 124, wherein said animal is a human.
- 126. The method of claim 121, wherein the compound is selected from:
- 127. A method for inhibiting beta-secretase activity, comprising exposing said beta-secretase to an effective inhibitory amount of a compound according to claim 1.
- 128. The method of claim 127, wherein said beta-secretase is exposed to said compound in vitro.
- 129. The method of claim 127, wherein said beta-secretase is exposed to said compound in a cell.
- 130. The method of claim 129, wherein said cell is in an animal.
- 131. The method of claim 130, wherein said animal is a human.
- 132. The method of claim 127, wherein the compound is selected from:
- 133. A method for inhibiting cleavage of amyloid precursor protein (APP), in a reaction mixture, at a site between Met596 and Asp597, numbered for the APP-695 amino acid isotype; or at a corresponding site of an isotype or mutant thereof, comprising exposing said reaction mixture to an effective inhibitory amount of a compound according to claim 1.
- 134. The method of claim 133, wherein said cleavage site is between Met652 and Asp653, numbered for the APP-751 isotype; between Met 671 and Asp 672, numbered for the APP-770 isotype; between Leu596 and Asp597 of the APP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751 Swedish Mutation; or between Leu671 and Asp672 of the APP-770 Swedish Mutation.
- 135. The method of claim 133, wherein said reaction mixture is exposed in vitro.
- 136. The method of claim 133, wherein said reaction mixture is exposed in a cell.
- 137. The method of claim 136, wherein said cell is an animal cell.
- 138. The method of claim 137, wherein said cell is a human cell.
- 139. A method for inhibiting cleavage of amyloid precursor protein (APP), in a reaction mixture, at a site between Met596 and Asp597, numbered for the APP-695 amino acid isotype; or at a corresponding site of an isotype or mutant thereof, comprising exposing said reaction mixture to an effective inhibitory amount of a compound according to claim 1.
- 140. The method of claim 139, wherein said cleavage site is between Met652 and Asp653, numbered for the APP-751 isotype; between Met 671 and Asp 672, numbered for the APP-770 isotype; between Leu596 and Asp597 of the APP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751 Swedish Mutation; or between Leu671 and Asp672 of the APP-770 Swedish Mutation.
- 141. The method of claim 139, wherein said reaction mixture is exposed in vitro.
- 142. The method of claim 139, wherein said reaction mixture is exposed in a cell.
- 143. The method of claim 142, wherein said cell is an animal cell.
- 144. The method of claim 143, wherein said cell is a human cell.
- 145. A method for inhibiting production of amyloid beta peptide (A beta) in a cell, comprising administering to said cell an effective inhibitory amount of a compound according to claim 1.
- 146. The method of claim 145, wherein said administering is to an animal.
- 147. The method of claim 146, wherein said administering is to a human.
- 148. A method for inhibiting production of amyloid beta peptide (A beta) in a cell, comprising administering to said cell an effective inhibitory amount of a compound according to claim 1.
- 149. The method of claim 148 wherein said administering is to an animal.
- 150. The method of claim 149, wherein said administering is to a human.
- 151. A method for inhibiting the production of beta-amyloid plaque in an animal, comprising administering to said animal an effective inhibitory amount of a compound according to claim 1.
- 152. The method of claim 151, wherein said animal is a human.
- 153. A method for inhibiting the production of beta-amyloid plaque in an animal, comprising administering to said animal an effective inhibitory amount of a compound according to claim 1.
- 154. The method of claim 153, wherein said animal is a human.
- 155. A method for treating or preventing a disease characterized by beta-amyloid deposits in the brain comprising administering to a patient an effective therapeutic amount of a compound according to claim 1.
- 156. The method of claim 155, wherein said therapeutic amount is in the range of from about 0.1 to about 1000 mg/day.
- 157. The method of claim 155, wherein said therapeutic amount is in the range of from about 15 to about 1500 mg/day.
- 158. The method of claim 156, wherein said therapeutic amount is in the range of from about 1 to about 100 mg/day.
- 159. The method of claim 158, wherein said therapeutic amount is in the range of from about 5 to about 50 mg/day.
- 160. The method of claim 156, wherein said disease is Alzheimer's disease.
- 161. The method of claim 156, wherein said disease is Mild Cognitive Impairment, Down's Syndrome, or Hereditary Cerebral Hemmorrhage with Amyloidosis of the Dutch Type.
- 162. A method for treating or preventing a disease characterized by beta-amyloid deposits in the brain comprising administering to a patient an effective therapeutic amount of a compound according to claim 1.
- 163. The method of claim 162, wherein said therapeutic amount is in the range of from about 0.1 to about 1000 mg/day.
- 164. The method of claim 162, wherein said therapeutic amount is in the range of from about 15 to about 1500 mg/day.
- 165. The method of claim 163, wherein said therapeutic amount is in the range of from about 1 to about 100 mg/day.
- 166. The method of claim 165, wherein said therapeutic amount is in the range of from about 5 to about 50 mg/day.
- 167. The method of claim 161, wherein said disease is Alzheimer's disease.
- 168. The method of claim 161, wherein said disease is Mild Cognitive Impairment, Down's Syndrome, or Hereditary Cerebral Hemmorrhage with Amyloidosis of the Dutch Type.
- 169. A composition comprising beta-secretase complexed with a compound according to claim 1.
- 170. A method for producing a beta-secretase complex comprising: exposing beta-secretase to a compound according to claim 1, or a pharmaceutically acceptable salt thereof in a reaction mixture under conditions suitable for the production of said complex.
- 171. The method of claim 170, where said exposing is in vitro.
- 172. The method of claim 171, wherein said reaction mixture is a cell.
- 173. A kit comprising component parts capable of being assembled, wherein at least one component part comprises a compound according to claim 1, enclosed in a container.
- 174. The kit of claim 173, wherein said compound is lyophilized and at least one further component part comprises a diluent.
- 175. A kit comprising a plurality of containers, each container comprising one or more unit dose of a compound according to claim 1.
- 176. The kit of claim 175, wherein each container is adapted for oral delivery and comprises a tablet, gel, or capsule.
- 177. The kit of claim 175, wherein each container is adapted for parenternal delivery and comprises a depot product, syringe, ampoule, or vial.
- 178. The kit of claim 175, wherein each container is adapted for topical delivery and comprises a patch, medipad, ointment, or cream.
- 179. A kit comprising a plurality of containers, each container comprising one or more unit dose of a compound according to claim 1.
- 180. The kit of claim 179, wherein each container is adapted for oral delivery and comprises a tablet, gel, or capsule.
- 181. The kit of claim 179, wherein each container is adapted for parenternal delivery and comprises a depot product, syringe, ampoule, or vial.
- 182. The kit of claim 179, wherein each container is adapted for topical delivery and comprises a patch, medipad, ointment, or cream.
- 183. A kit comprising a compound according to claim 1 ;and one or more therapeutic agent selected from the group consisting of an antioxidant, an anti-inflamatory, a gamma secretase inhibitor, a neurotrophic agent, an acetylcholinesterase inhibitor, a statin, an A beta peptide, and an anti-A beta antibody.
- 184. A composition comprising a compound according to claim 1; and an inert diluent or edible carrier.
- 185. The composition of claim 184, wherein said carrier is an oil.
- 186. A composition comprising a compound according to claim 1; and a binder, excipient, disintegrating agent, lubricant, or gildant.
- 187. A composition comprising a compound according to claim 1 disposed in a cream, ointment, or patch.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent application Ser. Nos. 09/815,960 and 09/816,876, each of which claim priority of invention under 35 U.S.C. §119(e) from U.S. provisional application No. 60/191,528, filed Mar. 23, 2000, the disclosures of which are incorporated herein by reference.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60191528 |
Mar 2000 |
US |
Continuation in Parts (2)
|
Number |
Date |
Country |
| Parent |
09815960 |
Mar 2001 |
US |
| Child |
09960634 |
Sep 2001 |
US |
| Parent |
09816876 |
Mar 2001 |
US |
| Child |
09960634 |
Sep 2001 |
US |
Patent Application
20030013881
