Therefore, we claim:
1. A method of preventing, treating, or ameliorating symptoms of Alzheimer’s Disease comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (I):
85
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein:
Ar1 and Ar2 are independently selected from the group consisting of aryl and R4-substituted aryl;
Ar3 is aryl or R5-substituted aryl;
X, Y and Z are independently selected from the group consisting of CH2, CH(lower alkyl)- and C(dilower alkyl)-;
R and R2 are independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9 and O(CO)NR6R7;
R1 and R3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
q is 0 or 1;
r is 0 or 1;
m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;
R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, -(lower alkylene)COOR6, CHCHCOOR6, CF3, CN, NO2 and halogen;
R5 is 1-5 substituents independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and CHCHCOOR6;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R9 is lower alkyl, aryl or aryl-substituted lower alkyl to prevent, treat, or ameliorate symptoms of Alzheimer’s Disease in the subject.
2. The method according to claim 1, wherein the subject exhibits no symptoms of Alzheimer’s Disease.
3. The method according to claim 1, wherein the subject has Alzheimer’s Disease.
4. The method according to claim 1, wherein the subject has a family history of Alzheimer’s Disease or dementia illness.
5. The method according to claim 1, wherein the subject is a human and has trisomy 21 (Down’s Syndrome).
6. The method according to claim 1, wherein the subject is a human.
7. The method according to claim 6, wherein the human carries one or more mutations in the genes that encode -amyloid precursor protein, presenilin-1 or presenilin-2.
8. The method according to claim 6, wherein the human carries the Apolipoprotein E4 gene.
9. The method according to claim 1, wherein the subject has an elevated level of amyloid peptide in the bloodstream andor the brain.
10. The method according to claim 9, wherein the subject has an elevated level of amyloid 42 peptide in the bloodstream andor the brain.
11. The method according to claim 9, wherein the level of amyloid (A) peptides in the bloodstream is reduced from about 10 to about 100 percent from a level of amyloid (A) peptides prior to administration of the composition.
12. The method according to claim 9, wherein the subject has an level of amyloid A-42 peptide greater than about 30 pM in the bloodstream.
13. The method according to claim 12, wherein the subject has an level of amyloid A-42 peptide greater than about 40 pM in the bloodstream.
14. The method according to claim 12, wherein the subject has an level of amyloid A-42 peptide ranging from about 30 pM to about 80 pM in the bloodstream.
15. The method according to claim 9, wherein the subject has an level of amyloid A-40 peptide greater than about 200 pM in the bloodstream.
16. The method according to claim 15, wherein the subject has an level of amyloid A-40 peptide greater than about 400 pM in the bloodstream.
17. The method according to claim 15, wherein the subject has an level of amyloid A-40 peptide ranging from about 200 pM to about 800 pM in the bloodstream.
18. The method according to claim 9, wherein the subject has an level of amyloid A-42 peptide of greater than about 50 pmolgram of wet brain tissue.
19. The method according to claim 9, wherein the subject has an level of amyloid A-40 peptide of greater than about 10 pmolgram of wet brain tissue.
20. The method according to claim 1, wherein the subject has an elevated blood cholesterol level.
21. The method according to claim 1, wherein the total serum cholesterol level of the subject is at least about 200 mgdl.
22. The method according to claim 1, wherein the total LDL cholesterol level of the subject is greater than about 100 mgdl.
23. The method according to claim 6, wherein the human is greater than about 40 years of age.
24. The method according to claim 7, wherein the human is greater than about 60 years of age.
25. The method according to claim 1, wherein the compound is represented by Formula (II) below:
86
26. The method according to claim 1, wherein the compound is represented by Formula (VIa) below:
87
27. The method according to claim 1, wherein the compound is administered to the subject in an amount ranging from about 0.1 to about 1000 milligrams of compound per day.
28. The method according to claim 1, wherein the composition further comprises at least one cholesterol biosynthesis inhibitor.
29. The method according to claim 28, wherein the at least one cholesterol biosynthesis inhibitor comprises at least one HMG CoA reductase inhibitor.
30. The method according to claim 29, wherein the at least one HMG CoA reductase inhibitor is selected from lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, cerivastatin, rosuvastatin or mixtures thereof.
31. The method according to claim 30, wherein the at least one HMG CoA reductase inhibitor is simvastatin.
32. The method according to claim 1, wherein the composition further comprises at least one fibric acid derivative.
33. The method according to claim 1, wherein the composition further comprises at least one bile acid sequestrant.
34. The method according to claim 1, wherein the composition further comprises nicotinic acid or a derivative thereof.
35. The method according to claim 1, wherein the composition further comprises at least one AcylCoA:Cholesterol O-acyltransferase Inhibitor.
36. The method according to claim 1, wherein the composition further comprises probucol or a derivative thereof.
37. The method according to claim 1, wherein the composition further comprises at least one low-density lipoprotein receptor activator.
38. The method according to claim 1, wherein the composition further comprises at least one Omega 3 fatty acid.
39. The method according to claim 1, wherein the composition further comprises at least one natural water soluble fiber.
40. The method according to claim 1, wherein the composition further comprises at least one of plant sterols, plant stanols or fatty acid esters of plant stanols.
41. The method according to claim 1, wherein the composition further comprises at least one antioxidant or vitamin.
42. The method according to claim 1, wherein the composition further comprises at least one Alzheimer’s treatment different from compound I above.
43. The method according to claim 1, wherein the composition further comprises at least one Alzheimer’s treatment different from compound I above selected from the group consisting of cholinesterase inhibitors, muscarinic receptor antagonists, M2 muscarinic receptor antagonists, acetylcholine release stimulators, choline uptake stimulators, nicotinic cholinergic receptor antagonists, anti-A vaccines, -secretase inhibitors, -inhibitors, amyloid aggregation inhibitors, amyloid precursor protein antisense oligonucleotides, monoamine reuptake inhibitors, human stem cells, gene therapy, nootropic agents, AMPA receptor ligands, growth factors or growth factor receptor agonists, anti-inflammatory agents, free radical scavengersantioxidants, superoxide dismutase stimulators, calcium channel blockers, apoptosis inhibitors, caspase inhibitors, monoamine oxidase inhibitors, estrogens, NMDA receptor antagonists, Jun N-terminal kinase (JNK) inhibitors, copperzinc chelators, 5-HT1 a receptor agonists, NGF stimulators, neuroprotective agents, H3 histamine receptor antagonists, calpain inhibitors, poly ADP ribose polymerase inhibitors, prolylendopeptidase inhibitors, calcium modulators, corticortropin releasing factor antagonists, corticortropin releasing factor binding protein inhibitor, GABA modulators, GABA-A receptor antagonists, GABA-B receptor antagonists, neuroimmunophilin ligands, sigma receptor ligands, galanin receptor ligands, imidazolinealpha adrenergic receptor antagonists, vasoactive intestinal peptide receptor agonists, benzodiazepine inverse agonists, cannabinoid receptor agonists, thyrotropin releasing hormone receptor agonists, protein kinase C inhibitors, 5-HT3 antagonists, prostaglandin receptor antagonists, topoisomerase II inhibitors, steroid receptor agonists, corticosteroid receptor antagonists, nitric oxide modulators, RAGE inhibitors, dopamine receptor agonists, and combinations thereof.
44. A method of preventing, treating, or ameliorating symptoms of Alzheimer’s Disease comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising a compound represented by Formula (II) below:
88
to prevent, treat, or ameliorate symptoms of Alzheimer’s Disease in the subject.
45. A method of regulating the production of at least one amyloid peptide in a subject or regulating a level of at least one amyloid peptide in bloodstream andor brain of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (I):
89
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein:
Ar1 and Ar2 are independently selected from the group consisting of aryl and R4-substituted aryl;
Ar3 is aryl or R5-substituted aryl;
X, Y and Z are independently selected from the group consisting of CH2, CH(lower alkyl)- and C(dilower alkyl)-;
R and R2 are independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9 and O(CO)NR6R7;
R1 and R3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
q is 0 or 1;
r is 0 or 1;
m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;
R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, -(lower alkylene)COOR6, CHCHCOOR6, CF3, CN, NO2 and halogen;
R5 is 1-5 substituents independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and CHCHCOOR6;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R9 is lower alkyl, aryl or aryl-substituted lower alkyl, to regulate the production or level of at least one amyloid peptide in the subject.
46. A method of regulating the amount of ApoE isoform 4 in the bloodstream andor brain of the subject comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (I):
90
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein:
Ar1 and Ar2 are independently selected from the group consisting of aryl and R4-substituted aryl;
Ar3 is aryl or R5-substituted aryl;
X, Y and Z are independently selected from the group consisting of CH2, CH(lower alkyl)- and C(dilower alkyl)-;
R and R2 are independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9 and O(CO)NR6R7;
R1 and R3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
q is 0 or 1;
r is 0 or 1;
m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;
R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, -(lower alkylene)COOR6, CHCHCOOR6, CF3, CN, NO2 and halogen;
R5 is 1-5 substituents independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and CHCHCOOR6;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R9 is lower alkyl, aryl or aryl-substituted lower alkyl, to regulate the amount of ApoE isoform 4 in the bloodstream andor brain of the subject.
47. A method of preventing, treating, or ameliorating symptoms of Alzheimer’s Disease comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (III):
91
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (III) above:
Ar1 is R3-substituted aryl;
Ar2 is R4-substituted aryl;
Ar3 is R5-substituted aryl;
Y and Z are independently selected from the group consisting of CH2, CH(lower alkyl)- and C(dilower alkyl)-;
A is selected from O, S, S(O) or S(O)2;
R1 is selected from the group consisting of OR6, O(CO)R6, O(CO)OR9 and O(CO)NR6R7; R2 is selected from the group consisting of hydrogen, lower alkyl and aryl; or R1 and R2 together are O;
q is 1, 2 or 3;
p is 0, 1, 2, 3 or 4;
R5 is 1-3 substituents independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR9, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2-lower alkyl, NR6SO2-aryl, CONR6R7, COR6, SO2NR6R7, S(O)0-2-alkyl, S(O)0-2-aryl, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR6, and CHCHCOOR6;
R3 and R4 are independently 1-3 substituents independently selected from the group consisting of R5, hydrogen, p-lower alkyl, aryl, NO2, CF3 and p-halogeno;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R9 is lower alkyl, aryl or aryl-substituted lower alkyl to prevent, treat, or ameliorate symptoms of Alzheimer’s Disease in the subject.
48. A method of regulating the production of at least one amyloid peptide in a subject or regulating a level of at least one amyloid peptide in bloodstream andor brain of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (III):
92
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (III) above:
Ar1 is R3-substituted aryl;
Ar2 is R4-substituted aryl;
Ar3 is R5-substituted aryl;
Y and Z are independently selected from the group consisting of CH2, CH(lower alkyl)- and C(dilower alkyl)-;
A is selected from O, S, S(O) or S(O)2;
R1 is selected from the group consisting of OR6, O(CO)R6, O(CO)OR9 and O(CO)NR6R7; R2 is selected from the group consisting of hydrogen, lower alkyl and aryl; or R1 and R2 together are O;
q is 1, 2 or 3;
p is 0, 1, 2, 3 or 4;
R5 is 1-3 substituents independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR9, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2-lower alkyl, NR6SO2-aryl, CONR6R7, COR6, SO2NR6R7, S(O)0-2-alkyl, S(O)0-2-aryl, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR6, and CHCHCOOR6;
R3 and R4 are independently 1-3 substituents independently selected from the group consisting of R5, hydrogen, p-lower alkyl, aryl, NO2, CF3 and p-halogeno;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R9 is lower alkyl, aryl or aryl-substituted lower alkyl, to regulate the production or level of at least one amyloid peptide in the subject.
49. A method of regulating the amount of ApoE isoform 4 in the bloodstream andor brain of the subject comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (III):
93
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (III) above:
Ar1 is R3-substituted aryl;
Ar2 is R4-substituted aryl;
Ar3 is R5-substituted aryl;
Y and Z are independently selected from the group consisting of CH2, CH(lower alkyl)- and C(dilower alkyl)-;
A is selected from O, S, S(O) or S(O)2;
R1 is selected from the group consisting of OR6, O(CO)R6, O(CO)OR9 and O(CO)NR6R7; R2 is selected from the group consisting of hydrogen, lower alkyl and aryl; or R1 and R2 together are O;
q is 1, 2 or 3;
p is 0, 1, 2, 3 or 4;
R5 is 1-3 substituents independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR9, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2-lower alkyl, NR6SO2-aryl, CONR6R7, COR6, SO2NR6R7, S(O)0-2-alkyl, S(O)0-2-aryl, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR6, and CHCHCOOR6;
R3 and R4 are independently 1-3 substituents independently selected from the group consisting of R5, hydrogen, p-lower alkyl, aryl, NO2, CF3 and p-halogeno;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R9 is lower alkyl, aryl or aryl-substituted lower alkyl, to regulate the amount of ApoE isoform 4 in the bloodstream andor brain of the subject.
50. A method of preventing, treating, or ameliorating symptoms of Alzheimer’s Disease comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (IV):
94
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (IV) above:
A is selected from the group consisting of R2-substituted heterocycloalkyl, R2-substituted heteroaryl, R2-substituted benzofused heterocycloalkyl, and R2-substituted benzofused heteroaryl;
Ar1 is aryl or R3-substituted aryl;
Ar2 is aryl or R4-substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
95
and
R1 is selected from the group consisting of:
(CH2)q, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
(CH2)e-G-(CH2)r, wherein G is O, C(O), phenylene, NR8 or S(O)0-2, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
(C2-C6 alkenylene)-; and
(CH2)fV(CH2)g, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
R5 is selected from:
96
R6 and R7 are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)-, C(di-(C1-C6) alkyl), CHCH and C(C1-C6 alkyl)CH; or R5 together with an adjacent R6, or R5 together with an adjacent R7, form a CHCH or a CHC(C1-C6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R6 is CHCH or C(C1-C6 alkyl)CH, a is 1; provided that when R7 is CHCH or C(C1-C6 alkyl)CH, b is 1; provided that when a is 2 or 3, the R6’s can be the same or different; and provided that when b is 2 or 3, the R7’s can be the same or different;
and when Q is a bond, R1 also can be selected from:
97
where M is O, S, S(O) or S(O)2;
X, Y and Z are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)- and C(di-(C1-C6) alkyl);
R10 and R12 are independently selected from the group consisting of OR14, O(CO)R14, O(CO)OR16 and O(CO)NR14R15;
R11 and R13 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl and aryl; or R10 and R11 together are O, or R12 and R13 together are O;
d is 1, 2 or 3;
h is 0, 1, 2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4; provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
v is 0 or 1;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
R2 is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, R17-substituted aryl, R17-substituted benzyl, R17-substituted benzyloxy, R17-substituted aryloxy, halogeno, NR14R15, NR14R15(C1-C6 alkylene)-, NR14R15C(O)(C1-C6 alkylene)-, NHC(O)R16, OH, C1-C6 alkoxy, OC(O)R16, COR14, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, NO2, S(O)0-2R16, SO2NR14R15 and (C1-C6 alkylene)COOR14; when R2 is a substituent on a heterocycloalkyl ring, R2 is as defined, or is O or
98
and, where R2 is a substituent on a substitutable ring nitrogen, it is hydrogen, (C1-C6)alkyl, aryl, (C1-C6)alkoxy, aryloxy, (C1-C6)alkylcarbonyl, arylcarbonyl, hydroxy, (CH2)1-6CONR18R18,
99
wherein J is O, NH, NR18 or CH2;
R3 and R4 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, OR14, O(CO)R14, O(CO)OR16, O(CH2)1-5OR14, O(CO)NR14R15, NR14R15, NR14(CO)R15, NR14(CO)OR16, NR14(CO)NR15R19, NR14SO2R16, COOR14, CONR14R15, COR14, SO2NR14R15, S(O)0-2R16, O(CH2)1-10COOR14, O(CH2)1-10CONR14R15, (C1-C6 alkylene)-COOR14, CHCHCOOR14, CF3, CN, NO2 and halogen;
R8 is hydrogen, (C1-C6)alkyl, aryl (C1-C6)alkyl, C(O)R14 or COOR14;
R9 and R17 are independently 1-3 groups independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, COOH, NO2, NR14R15, OH and halogeno;
R14 and R15 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R16 is (C1-C6)alkyl, aryl or R17-substituted aryl;
R18 is hydrogen or (C1-C6)alkyl; and
R19 is hydrogen, hydroxy or (C1-C6)alkoxy, to prevent, treat, or ameliorate symptoms of Alzheimer’s Disease in the subject.
51. A method of regulating the production of at least one amyloid peptide in a subject or regulating a level of at least one amyloid peptide in bloodstream andor brain of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (IV):
100
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (IV) above:
A is selected from the group consisting of R2-substituted heterocycloalkyl, R2-substituted heteroaryl, R2-substituted benzofused heterocycloalkyl, and R2-substituted benzofused heteroaryl;
Ar1 is aryl or R3-substituted aryl;
Ar2 is aryl or R4-substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
101
and
R1 is selected from the group consisting of:
(CH2)q, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
(CH2)e-G-(CH2)r, wherein G is O, C(O), phenylene, NR8 or S(O)0-2, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
(C2-C6 alkenylene)-; and
(CH2)fV(CH2)g, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
R5 is selected from:
102
R6 and R7 are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)-, C(di-(C1-C6) alkyl), CHCH and C(C1-C6 alkyl)CH; or R5 together with an adjacent R6, or R5 together with an adjacent R7, form a CHCH or a CHC(C1-C6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R6 is CHCH or C(C1-C6 alkyl)CH, a is 1; provided that when R7 is CHCH or C(C1-C6 alkyl)CH, b is 1; provided that when a is 2 or 3, the R6’s can be the same or different; and provided that when b is 2 or 3, the R7’s can be the same or different;
and when Q is a bond, R1 also can be selected from:
103
where M is O, S, S(O) or S(O)2;
X, Y and Z are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)- and C(di-(C1-C6) alkyl);
R10 and R12 are independently selected from the group consisting of OR14, O(CO)R14, O(CO)OR16 and O(CO)NR14R15;
R11 and R13 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl and aryl; or R10 and R11 together are O, or R12 and R13 together are O;
d is 1, 2 or 3;
h is 0, 1, 2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4; provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
v is 0 or 1;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
R2 is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, R17-substituted aryl, R17-substituted benzyl, R17-substituted benzyloxy, R17-substituted aryloxy, halogeno, NR14R15, NR14R15(C1-C6 alkylene)-, NR14R15C(O)(C1-C6 alkylene)-, NHC(O)R16, OH, C1-C6 alkoxy, OC(O)R16, COR14, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, NO2, S(O)0-2R16, SO2NR14R15 and (C1-C6 alkylene)COOR14; when R2 is a substituent on a heterocycloalkyl ring, R2 is as defined, or is O or
104
and, where R2 is a substituent on a substitutable ring nitrogen, it is hydrogen, (C1-C6)alkyl, aryl, (C1-C6)alkoxy, aryloxy, (C1-C6)alkylcarbonyl, arylcarbonyl, hydroxy, (CH2)1-6CONR18R18,
105
wherein J is O, NH, NR18 or CH2;
R3 and R4 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, OR14, O(CO)R14, O(CO)OR16, O(CH2)1-5OR14, O(CO)NR14R15, NR14R15, NR14(CO)R15, NR14(CO)OR16, NR14(CO)NR15R19, NR14SO2R16, COOR14, CONR14R15, COR14, SO2NR14R15, S(O)0-2R16, O(CH2)1-10COOR14, O(CH2)1-10CONR14R15, (C1-C6 alkylene)-COOR14, CHCHCOOR14, CF3, CN, NO2 and halogen;
R8 is hydrogen, (C1-C6)alkyl, aryl (C1-C6)alkyl, C(O)R14 or COOR14;
R9 and R17 are independently 1-3 groups independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, COOH, NO2, NR14R15, OH and halogeno;
R14 and R15 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R16 is (C1-C6)alkyl, aryl or R17-substituted aryl;
R18 is hydrogen or (C1-C6)alkyl; and
R19 is hydrogen, hydroxy or (C1-C6)alkoxy, to regulate the production or level of at least one amyloid peptide in the subject.
52. A method of regulating the amount of ApoE isoform 4 in the bloodstream andor brain of the subject comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (IV):
106
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (IV) above:
A is selected from the group consisting of R2-substituted heterocycloalkyl, R2-substituted heteroaryl, R2-substituted benzofused heterocycloalkyl, and R2-substituted benzofused heteroaryl;
Ar1 is aryl or R3-substituted aryl;
Ar2 is aryl or R4-substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
107
and
R1 is selected from the group consisting of:
(CH2)q, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
(CH2)e-G-(CH2)r, wherein G is O, C(O), phenylene, NR8 or S(O)0-2, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
(C2-C6 alkenylene)-; and
(CH2)fV(CH2)g, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
R5 is selected from:
108
R6 and R7 are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)-, C(di-(C1-C6) alkyl), CHCH and C(C1-C6 alkyl)CH; or R5 together with an adjacent R6, or R5 together with an adjacent R7, form a CHCH or a CHC(C1-C6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R6 is CHCH or C(C1-C6 alkyl)CH, a is 1; provided that when R7 is CHCH or C(C1-C6 alkyl)CH, b is 1; provided that when a is 2 or 3, the R6’s can be the same or different; and provided that when b is 2 or 3, the R7’s can be the same or different;
and when Q is a bond, R1 also can be selected from:
109
where M is O, S, S(O) or S(O)2;
X, Y and Z are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)- and C(di-(C1-C6) alkyl);
R10 and R12 are independently selected from the group consisting of OR14, O(CO)OR16 and O(CO)NR14R15;
R11 and R13 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl and aryl; or R10 and R11 together are O, or R12 and R13 together are O;
d is 1, 2 or 3;
h is 0, 1, 2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4; provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
v is 0 or 1;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
R2 is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, R17-substituted aryl, R17-substituted benzyl, R17-substituted benzyloxy, R17-substituted aryloxy, halogeno, NR14R15, NR14R15(C1-C6 alkylene)-, NR14R15C(O)(C1-C6 alkylene)-,NHC(O)R16, OH, C1-C6 alkoxy, OC(O)R16, COR14, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, NO2, S(O)0-2R16, SO2NR14R15 and (C1-C6 alkylene)COOR14; when R2 is a substituent on a heterocycloalkyl ring, R2 is as defined, or is O or
110
and, where R2 is a substituent on a substitutable ring nitrogen, it is hydrogen, (C1-C6)alkyl, aryl, (C1-C6)alkoxy, aryloxy, (C1-C6)alkylcarbonyl, arylcarbonyl, hydroxy, (CH2)1-6CONR18R18,
111
wherein J is O, NH, NR18 or CH2;
R3 and R4 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, OR14, O(CO)R14, O(CO)OR16, O(CH2)1-5OR14, O(CO)NR14R15, NR14R15, NR14(CO)R15, NR14(CO)OR16, NR14(CO)NR15R19, NR14SO2R16, COOR14, CONR14R15, COR14, SO2NR14R15, S(O)0-2R16, O(CH2)1-10COOR14, O(CH2)1-10CONR14R15, (C1-C6 alkylene)-COOR14, CHCHCOOR14, CF3, CN, NO2 and halogen;
R8 is hydrogen, (C1-C6)alkyl, aryl (C1-C6)alkyl, C(O)R14 or COOR14;
R9 and R17 are independently 1-3 groups independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, COOH, NO2, NR14R15, OH and halogeno;
R14 and R15 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R16 is (C1-C6)alkyl, aryl or R17-substituted aryl;
R18 is hydrogen or (C1-C6)alkyl; and
R19 is hydrogen, hydroxy or (C1-C6)alkoxy, to regulate the amount of ApoE isoform 4 in the bloodstream andor brain of the subject.
53. A method of preventing, treating, or ameliorating symptoms of Alzheimer’s Disease comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (V):
112
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (V) above:
Ar1 is aryl, R10-substituted aryl or heteroaryl;
Ar2 is aryl or R4-substituted aryl;
Ar3 is aryl or R5-substituted aryl;
X and Y are independently selected from the group consisting of CH2, CH(lower alkyl)- and C(dilower alkyl)-;
R is OR6, O(CO)R6, O(CO)OR9 or O(CO)NR6R7; R1 is hydrogen, lower alkyl or aryl; or R and R1 together are O;
q is 0 or 1;
r is 0, 1 or 2;
m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n and q is 1, 2, 3, 4 or 5;
R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and CHCHCOOR6;
R5 is 1-5 substituents independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, CF3, CN, NO2, halogen, -(lower alkylene)COOR6 and CHCHCOOR6;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R9 is lower alkyl, aryl or aryl-substituted lower alkyl; and
R10 is 1-5 substituents independently selected from the group consisting of lower alkyl, OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, CF3, CN, NO2 and halogen to prevent, treat, or ameliorate symptoms of Alzheimer’s Disease in the subject.
54. A method of regulating the production of at least one amyloid peptide in a subject or regulating a level of at least one amyloid peptide in bloodstream andor brain of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (V):
113
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (V) above:
Ar1 is aryl, R10-substituted aryl or heteroaryl;
Ar2 is aryl or R4-substituted aryl;
Ar3 is aryl or R5-substituted aryl;
X and Y are independently selected from the group consisting of CH2, CH(lower alkyl)- and C(dilower alkyl)-;
R is OR6, O(CO)R6, O(CO)OR9 or O(CO)NR6R7; R1 is hydrogen, lower alkyl or aryl; or R and R1 together are O;
q is 0 or 1;
r is 0, 1 or 2;
m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n and q is 1, 2, 3, 4 or 5;
R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and CHCHCOOR6;
R5 is 1-5 substituents independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, CF3, CN, NO2, halogen, -(lower alkylene)COOR6 and CHCHCOOR6;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R9 is lower alkyl, aryl or aryl-substituted lower alkyl; and
R10 is 1-5 substituents independently selected from the group consisting of lower alkyl, OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, CF3, CN, NO2 and halogen to regulate the production or level of at least one amyloid peptide in the subject.
55. A method of regulating the amount of ApoE isoform 4 in the bloodstream andor brain of the subject comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (V):
114
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (V) above:
Ar1 is aryl, R10-substituted aryl or heteroaryl;
Ar2 is aryl or R4-substituted aryl;
Ar3 is aryl or R5-substituted aryl;
X and Y are independently selected from the group consisting of CH2, CH(lower alkyl)- and C(dilower alkyl)-;
R is OR6, O(CO)R6, O(CO)OR9 or O(CO)NR6R7; R1 is hydrogen, lower alkyl or aryl; or R and R1 together are O;
q is 0 or 1;
r is 0, 1 or 2;
m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n and q is 1, 2, 3, 4 or 5;
R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and CHCHCOOR6;
R5 is 1-5 substituents independently selected from the group consisting of OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6, O(CH2)1-10CONR6R7, CF3, CN, NO2, halogen, -(lower alkylene)COOR6 and CHCHCOOR6;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R9 is lower alkyl, aryl or aryl-substituted lower alkyl; and
R10 is 1-5 substituents independently selected from the group consisting of lower alkyl, OR6, O(CO)R6, O(CO)OR9, O(CH2)1-5OR6, O(CO)NR6R7, NR6R7, NR6(CO)R7, NR6(CO)OR9, NR6(CO)NR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)0-2R9, O(CH2)1-10COOR6,
O(CH2)1-10CONR6R7, CF3, CN, NO2 and halogen to regulate the amount of ApoE isoform 4 in the bloodstream andor brain of the subject.
56. A method of preventing, treating, or ameliorating symptoms of Alzheimer’s Disease comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound Ho represented by Formula (VI):
115
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein:
R1 is
116
R2 and R3 are independently selected from the group consisting of: CH2, CH(lower alkyl)-, C(di-lower alkyl)-, CHCH and C(lower alkyl)CH; or R1 together with an adjacent R2, or R1 together with an adjacent R3, form a CHCH or a CHC(lower alkyl)- group;
u and v are independently 0, 1, 2 or 3, provided both are not zero; provided that when R2 is CHCH or C(lower alkyl)CH, v is 1; provided that when R3 is CHCH or C(lower alkyl)CH, u is 1; provided that when v is 2 or 3, the R2’s can be the same or different; and provided that when u is 2 or 3, the R3’s can be the same or different;
R4 is selected from B(CH2)mC(O), wherein m is 0, 1, 2, 3, 4 or 5;
B(CH2)q, wherein q is 0, 1, 2, 3, 4, 5 or 6;
B(CH2)e-Z-(CH2)r, wherein Z is O, C(O), phenylene, N(R8) or S(O)0-2, e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6;
B(C2-C6 alkenylene)-;
B(C4-C6 alkadienylene)-;
B(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B(CH2)fV(CH2)g, wherein V is C3-C6 cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;
B(CH2)tV(C2-C6 alkenylene)- or
B(C2-C6 alkenylene)V(CH2)t, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B(CH2)a-Z-(CH2)bV(CH2)d, wherein Z and V are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or
T-(CH2)s, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or
R1 and R4 together form the group
117
B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or
118
W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, CF3, OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2, N(R8)(R9), N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, OH, halogeno, CN, N3, NHC(O)OR10, NHC(O)R10, R11O2SNH, (R11O2S)2N, S(O)2NH2, S(O)0-2R8, tert-butyldimethyl-silyloxymethyl, C(O)R12, COOR19, CON(R8)(R9), CHCHC(O)R12, -lower alkylene-C(O)R12, R10C(O)(lower alkylenyloxy)-, N(R8)(R9)C(O)(lower alkylenyloxy)- and
119
for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, C(O)OR10, C(O)R10, OH, N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, S(O)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;
R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, COOH, NO2, N(R8)(R9), OH, and halogeno;
R8 and R9 are independently selected from H or lower alkyl;
R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl;
R11 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl;
R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,
120
N(R8)(R9), lower alkyl, phenyl or R7-phenyl;
R13 is selected from O, CH2, NH, N(lower alkyl)- or NC(O)R19;
R15, R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;
R19 is H, lower alkyl, phenyl or phenyl lower alkyl; and
R20 and R21 are independently selected from the group consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above, to prevent, treat, or ameliorate symptoms of Alzheimer’s Disease in the subject.
57. A method of regulating the production of at least one amyloid peptide in a subject or regulating a level of at least one amyloid peptide in bloodstream andor brain of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (VI):
121
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein:
R1 is
122
R2 and R3 are independently selected from the group consisting of: CH2, CH(lower alkyl)-, C(di-lower alkyl)-, CHCH and C(lower alkyl)CH; or R1 together with an adjacent R2, or R1 together with an adjacent R3, form a CHCH or a CHC(lower alkyl)- group;
u and v are independently 0, 1, 2 or 3, provided both are not zero; provided that when R2 is CHCH or C(lower alkyl)CH, v is 1; provided that when R3 is CHCH or C(lower alkyl)CH, u is 1; provided that when v is 2 or 3, the R2’s can be the same or different; and provided that when u is 2 or 3, the R3’s can be the same or different;
R4 is selected from B(CH2)mC(O), wherein m is 0, 1, 2, 3, 4 or 5;
B(CH2)q, wherein q is 0, 1, 2, 3, 4, 5 or 6;
B(CH2)e-Z-(CH2)r, wherein Z is O, C(O), phenylene, N(R8) or S(O)0-2, e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6;
B(C2-C6 alkenylene)-;
B(C4-C6 alkadienylene)-;
B(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B(CH2)fV(CH2)g, wherein V is C3-C6 cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;
B(CH2)tV(C2-C6 alkenylene)- or
B(C2-C6 alkenylene)V(CH2)t, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B(CH2)a-Z-(CH2)bV(CH2)d, wherein Z and V are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or
T-(CH2)s, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or
R1 and R4 together form the group
123
B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or
124
W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, CF3, OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2, N(R8)(R9), N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, OH, halogeno, CN, N3, NHC(O)OR10, NHC(O)R10, R11O2SNH, (R11O2S)2N, S(O)2NH2, S(O)0-2R8, tert-butyldimethyl-silyloxymethyl, C(O)R12, COOR19, CON(R8)(R9), CHCHC(O)R12, -lower alkylene-C(O)R12, R10C(O)(lower alkylenyloxy)-, N(R8)(R9)C(O)(lower alkylenyloxy)- and
125
for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, C(O)OR10, C(O)R10, OH, N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, S(O)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;
R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, COOH, NO2, N(R8)(R9), OH, and halogeno;
R8 and R9 are independently selected from H or lower alkyl;
R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl;
R11 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl;
R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,
126
N(R8)(R9), lower alkyl, phenyl or R7-phenyl;
R13 is selected from O, CH2, NH, N(lower alkyl)- or NC(O)R19;
R15, R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;
R19 is H, lower alkyl, phenyl or phenyl lower alkyl; and
R20 and R21 are independently selected from the group consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above, to regulate the production or level of at least one amyloid peptide in the subject.
58. A method of regulating the amount of ApoE isoform 4 in the bloodstream andor brain of the subject comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (VI):
127
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein:
R1 is
128
R2 and R3 are independently selected from the group consisting of: CH2, CH(lower alkyl)-, C(d i-lower alkyl)-, CHCH and C(lower alkyl)CH; or R1 together with an adjacent R2, or R1 together with an adjacent R3, form a CHCH or a CHC(lower alkyl)- group;
u and v are independently 0, 1, 2 or 3, provided both are not zero; provided that when R2 is CHCH or C(lower alkyl)CH, v is 1; provided that when R3 is CHCH or C(lower alkyl)CH, u is 1; provided that when v is 2 or 3, the R2’s can be the same or different; and provided that when u is 2 or 3, the R3’s can be the same or different;
R4 is selected from B(CH2)mC(O), wherein m is 0, 1, 2, 3, 4 or 5;
B(CH2)q, wherein q is 0, 1, 2, 3, 4, 5 or 6;
B(CH2)e-Z-(CH2)r, wherein Z is O, C(O), phenylene, N(R8) or S(O)0-2, e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6;
B(C2-C6 alkenylene)-;
B(C4-C6 alkadienylene)-;
B(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B(CH2)fV(CH2)g, wherein V is C3-C6 cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;
B(CH2)tV(C2-C6 alkenylene)- or
B(C2-C6 alkenylene)V(CH2)t, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B(CH2)a-Z-(CH2)bV(CH2)d, wherein Z and V are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or
T-(CH2)s, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or
R1 and R4 together form the group
129
B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or
130
W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, CF3, OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2, N(R8)(R9), N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, OH, halogeno, CN, N3, NHC(O)OR10, NHC(O)R10, R11O2SNH, (R11O2S)2N, S(O)2NH2, S(O)0-2R8, tert-butyldimethyl-silyloxymethyl, C(O)R12, COOR19, CON(R8)(R9), CHCHC(O)R12, -lower alkyleneC(O)R12, R10C(O)(lower alkylenyloxy)-, N(R8)(R9)C(O)(lower alkylenyloxy)- and
131
for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, C(O)OR10, C(O)R10, OH, N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, S(O)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;
R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, COOH, NO2, N(R8)(R9), OH, and halogeno;
R8 and R9 are independently selected from H or lower alkyl;
R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl;
R11 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl;
R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,
132
N(R8)(R9), lower alkyl, phenyl or R7-phenyl;
R13 is selected from O, CH2, NH, N(lower alkyl)- or NC(O)R19;
R15, R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;
R19 is H, lower alkyl, phenyl or phenyl lower alkyl; and
R20 and R21 are independently selected from the group consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above, to regulate the amount of ApoE isoform 4 in the bloodstream andor brain of the subject.
59. A method of preventing, treating, or ameliorating symptoms of Alzheimer’s Disease comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (VII):
133
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (VII) above,
R26 is H or OG1;
G and G1 are independently selected from the group consisting of
134
provided that when R26 is H or OH, G is not H;
R, Ra and Rb are independently selected from the group consisting of H, OH, halogeno, NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy or WR30;
W is independently selected from the group consisting of NHC(O), OC(O), OC(O)N(R31), NHC(O)N(R31) and OC(S)N(R31);
R2 and R6 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, C(O)(C1-C6)alkyl and C(O)aryl;
R30 is selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is selected from the group consisting of H and (C1-C4)alkyl;
T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (C1-C4)alkyl, OH, phenoxy, CF3, NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, N(CH3)2, C(O)NH(C1-C4)alkyl, C(O)N((C1-C4)alkyl)2, C(O)(C1-C4)alkyl, C(O)-(C1-C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
Ar1 is aryl or R10-substituted aryl;
Ar2 is aryl or R11-substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
135
and
R1 is selected from the group consisting of
(CH2)q, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
(CH2)e-E-(CH2)r, wherein E is O, C(O), phenylene, NR22 or S(O)0-2, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
(C2-C6)alkenylene-; and
(CH2)fV(CH2)g, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
R12 is
136
R13 and R14 are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)-, C(di-(C1-C6) alkyl), CHCH and C(C1-C6 alkyl)CH; or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a CHCH or a CHC(C1-C6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero;
provided that when R13 is CHCH or C(C1-C6 alkyl)CH, a is 1;
provided that when R14 is CHCH or C(C1-C6 alkyl)CH, b is 1;
provided that when a is 2 or 3, the R13’s can be the same or different; and
provided that when b is 2 or 3, the R14’s can be the same or different;
and when Q is a bond, R1 also can be:
137
M is O, S, S(O) or S(O)2;
X, Y and Z are independently selected from the group consisting of CH2, CH(C1-C6)alkyl- and C(di-(C1-C6)alkyl);
R10 and R11 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, OR19, O(CO)R19, O(CO)OR21, O(CH2)1-5OR19, O(CO)NR19R20, NR19R20, NR19(CO)R20, NR19(CO)OR21, NR19(CO)NR20R25, NR19SO2R21, COOR19, CONR19R20, COR19, SO2NR19R20, S(O)0-2R21, O(CH2)1-10COOR19, O(CH2)1-10CONR19R20, (C1-C6 alkylene)-COOR19, CHCHCOOR19, CF3, CN, NO2 and halogen;
R15 and R17 are independently selected from the group consisting of OR19, O(CO)R19, O(CO)OR21 and O(CO)NR19R20;
R16 and R18 are independently selected from the group consisting of H, (C1-C6)alkyl and aryl; or R15 and R16 together are O, or R17 and R18 together are O;
d is 1, 2 or 3;
h is 0, 1, 2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;
provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
v is 0 or 1;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
and when Q is a bond and R1 is
138
Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R19 and R20 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, C(O)R19 or COOR19;
R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, COOH, NO2, NR19R20, OH and halogeno; and
R25 is H, OH or (C1-C6)alkoxy, to prevent, treat, or ameliorate symptoms of Alzheimer’s Disease in the subject.
60. A method of regulating the production of at least one amyloid peptide in a subject or regulating a level of at least one amyloid peptide in bloodstream andor brain of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (VII):
139
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (VII) above,
R26 is H or OG1;
G and G1 are independently selected from the group consisting of
140
provided that when R26 is H or OH, G is not H;
R, Ra and Rb are independently selected from the group consisting of H, OH, halogeno, NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy or WR30;
W is independently selected from the group consisting of NHC(O), OC(O), OC(O)N(R31), NHC(O)N(R31) and OC(S)N(R31);
R2 and R6 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, C(O)(C1-C6)alkyl and C(O)aryl;
R30 is selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is selected from the group consisting of H and (C1-C4)alkyl;
T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (C1-C4)alkyl, OH, phenoxy, CF3, NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, N(CH3)2, C(O)NH(C1-C4)alkyl, C(O)N((C1-C4)alkyl)2, C(O)(C1-C4)alkyl, C(O)(C1-C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
Ar1 is aryl or R10-substituted aryl;
Ar2 is aryl or R11-substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
141
and
R1 is selected from the group consisting of
(CH2)q, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
(CH2)e-E-(CH2)r, wherein E is O, C(O), phenylene, NR22 or S(O)0-2, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
(C2-C6)alkenylene-; and
(CH2)fV(CH2)g, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
R12 is
142
R13 and R14 are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)-, C(di-(C1-C6) alkyl), CHCH and C(C1-C6 alkyl)CH; or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a CHCH or a CHC(C1-C6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero;
provided that when R13 is CHCH or C(C1-C6 alkyl)CH, a is 1;
provided that when R14 is CHCH or C(C1-C6 alkyl)CH, b is 1;
provided that when a is 2 or 3, the R13’s can be the same or different; and
provided that when b is 2 or 3, the R14’s can be the same or different;
and when Q is a bond, R1 also can be:
143
M is O, S, S(O) or S(O)2;
X, Y and Z are independently selected from the group consisting of CH2, CH(C1-C6)alkyl- and C(di-(C1-C6)alkyl);
R10 and R11 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, OR19, O(CO)R19, O(CO)OR21, O(CH2)1-5OR19, O(CO)NR19R20, NR19R20, NR19(CO)R20, NR19(CO)OR21, NR19(CO)NR20R25, NR19SO2R21, COOR19, CONR19R20, COR19, SO2NR19R20, S(O)0-2R21, O(CH2)1-10COOR19, O(CH2)1-10CONR19R20, (C1-C6 alkylene)-COOR19, CHCHCOOR19, CF3, CN, NO2 and halogen;
R15 and R17 are independently selected from the group consisting of OR19, O(CO)R19, O(CO)OR21 and O(CO)NR19R20;
R16 and R18 are independently selected from the group consisting of H, (C1-C6)alkyl and aryl; or R15 and R16 together are O, or R17 and R18 together are O;
d is 1, 2 or 3;
h is 0, 1, 2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;
provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
v is 0 or 1;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
and when Q is a bond and R1 is
144
Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R19 and R20 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, C(O)R19 or COOR19;
R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, COOH, NO2, NR19R20, OH and halogeno; and
R25 is H, OH or (C1-C6)alkoxy, to regulate the production or level of at least one amyloid peptide in the subject.
61. A method of regulating the amount of ApoE isoform 4 in the bloodstream andor brain of the subject comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (VII):
145
or a pharmaceutically acceptable salt thereof or solvate thereof, wherein, in Formula (VII) above,
R26 is H or OG1;
G and G1 are independently selected from the group consisting of
146
provided that when R26 is H or OH, G is not H;
R, Ra and Rb are independently selected from the group consisting of H, OH, halogeno, NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy or WR30;
W is independently selected from the group consisting of NHC(O), OC(O), OC(O)N(R31), NHC(O)N(R31) and OC(S)N(R31);
R2 and R6 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, C(O)(C1-C6)alkyl and C(O)aryl;
R30 is selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is selected from the group consisting of H and (C1-C4)alkyl;
T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (C1-C4)alkyl, OH, phenoxy, CF3, NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, N(CH3)2, C(O)NH(C1-C4)alkyl, C(O)N((C1-C4)alkyl)2, C(O)(C1-C4)alkyl, C(O)(C1-C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
Ar1 is aryl or R10-substituted aryl;
Ar2 is aryl or R11-substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
147
and
R1 is selected from the group consisting of
(CH2)q, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
(CH2)e-E-(CH2)r, wherein E is O, C(O), phenylene, NR22 or S(O)0-2, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
(C2-C6)alkenylene-; and
(CH2)fV(CH2)g, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
R12 is
148
R13 and R14 are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)-, C(di-(C1-C6) alkyl), CHCH and C(C1-C6 alkyl)CH; or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a CHCH or a CHC(C1-C6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero;
provided that when R13 is CHCH or C(C1-C6 alkyl)CH, a is 1;
provided that when R14 is CHCH or C(C1-C6 alkyl)CH, b is 1;
provided that when a is 2 or 3, the R13’s can be the same or different; and
provided that when b is 2 or 3, the R14’s can be the same or different;
and when Q is a bond, R1 also can be:
149
M is O, S, S(O) or S(O)2;
X, Y and Z are independently selected from the group consisting of CH2, CH(C1-C6)alkyl- and C(di-(C1-C6)alkyl);
R10 and R11 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, OR19, O(CO)R19, O(CO)OR21, O(CH2)1-5OR19, O(CO)NR19R20, NR19R20, NR19(CO)R20, NR19(CO)OR21, NR19(CO)NR20R25, NR19SO2R21, COOR19, CONR19R20, COR19, SO2NR19R20, S(O)0-2R21, O(CH2)1-10COOR19, O(CH2)1-10CONR19R20, (C1-C6 alkylene)-COOR19, CHCHCOOR19, CF3, CN, NO2 and halogen;
R15 and R17 are independently selected from the group consisting of OR19, O(CO)R19, O(CO)OR21 and O(CO)NR19R20;
R16 and R18 are independently selected from the group consisting of H, (C1-C6)alkyl and aryl; or R15 and R16 together are O, or R17 and R18 together are O;
d is 1, 2 or 3;
h is 0, 1, 2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;
provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
v is 0 or 1;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
and when Q is a bond and R1 is
150
Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R19 and R20 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, C(O)R19 or COOR19;
R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, COOH, NO2, NR19R20, OH and halogeno; and
R25 is H, OH or (C1-C6)alkoxy, to regulate the amount of ApoE isoform 4 in the bloodstream andor brain of the subject.
62. A method of preventing, treating, or ameliorating symptoms of Alzheimer’s Disease comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (VIII):
151
or a pharmaceutically acceptable salt or solvate thereof, wherein
R26 is selected from the group consisting of:
a) OH;
b) OCH3;
c) fluorine and
d) chlorine.
R1 is selected from the group consisting of
152
SO3H; natural and unnatural amino acids.
R, Ra and Rb are independently selected from the group consisting of H, OH, halogeno, NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy and WR30;
W is independently selected from the group consisting of NHC(O), OC(O), OC(O)N(R31), NHC(O)N(R31) and OC(S)N(R31);
R2 and R6 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, C(O)(C1-C6)alkyl and C(O)aryl;
R30 is independently selected form the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents independently selected from the group consisting of H, halogeno, (C1-C4)alkyl, OH, phenoxy, CF3, NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, N(CH3)2, C(O)NH(C1-C4)alkyl, C(O)N((C1-C4)alkyl)2, C(O)(C1-C4)alkyl, C(O)(C1-C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
Ar1 is aryl or R10-substituted aryl;
Ar2 is aryl or R11-substituted aryl;
Q is (CH2)q, wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group
153
R12 is
154
R13 and R14 are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)-, C(di-(C1-C6) alkyl), CHCH and C(C1-C6 alkyl)CH; or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a CHCH or a CHC(C1-C6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R13 is CHCH or C(C1-C6 alkyl)CH, a is 1; provided that when R14 is CHCH or C(C1-C6 alkyl)CH, b is 1; provided that when a is 2 or 3, the R13’s can be the same or different; and provided that when b is 2 or 3, the R14’s can be the same or different;
R10 and R11 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, OR19, O(CO)R19, O(CO)OR21, O(CH2)1-5OR19, O(CO)NR19R20, NR19R20, NR19(CO)R20, NR19(CO)OR21, NR19(CO)NR20R25, NR19SO2R21, COOR19, CONR19R20, COR19, SO2NR19R20, S(O)0-2R21, O(CH2)1-10COOR19, O(CH2)1-10CONR19R20, (C1-C6 alkylene)-COOR19, CHCHCOOR19, CF3, CN, NO2 and halogen;
R19 and R20 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, C(O)R19 or COOR19;
R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, COOH, NO2, NR19R20, OH and halogeno; and
R25 is H, OH or (C1-C6)alkoxy, to prevent, treat, or ameliorate symptoms of Alzheimer’s Disease in the subject.
63. A method of regulating the production of at least one amyloid peptide in a subject or regulating a level of at least one amyloid peptide in bloodstream andor brain of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (VIII):
155
or a pharmaceutically acceptable salt or solvate thereof, wherein
R26 is selected from the group consisting of:
a) OH;
b) OCH3;
c) fluorine and
d) chlorine.
R1 is selected from the group consisting of
156
SO3H; natural and unnatural amino acids.
R, Ra and Rb are independently selected from the group consisting of H, OH, halogeno, NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy and WR30;
W is independently selected from the group consisting of NHC(O), OC(O), OC(O)N(R31), NHC(O)N(R31) and OC(S)N(R31);
R2 and R6 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, C(O)(C1-C6)alkyl and C(O)aryl;
R30 is independently selected form the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents independently selected from the group consisting of H, halogeno, (C1-C4)alkyl, OH, phenoxy, CF3, NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, N(CH3)2, C(O)NH(C1-C4)alkyl, C(O)N((C1-C4)alkyl)2, C(O)(C1-C4)alkyl, C(O)(C1-C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
Ar1 is aryl or R10-substituted aryl;
Ar2 is aryl or R11-substituted aryl;
Q is (CH2)q, wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group
157
R12 is
158
R13 and R14 are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)-, C(di-(C1-C6) alkyl), CHCH and C(C1-C6 alkyl)CH; or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a CHCH or a CHC(C1-C6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R13 is CHCH or C(C1-C6 alkyl)CH, a is 1; provided that when R14 is CHCH or C(C1-C6 alkyl)CH, b is 1; provided that when a is 2 or 3, the R13’s can be the same or different; and provided that when b is 2 or 3, the R14’s can be the same or different;
R10 and R11 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, OR19, O(CO)R19, O(CO)OR21, O(CH2)1-5OR19, O(CO)NR19R20, NR19R20, NR19(CO)R20, NR19(CO)OR21, NR19(CO)NR20R25, NR19SO2R21, COOR19, CONR19R20, COR19, SO2NR19R20, S(O)0-2R21, O(CH2)1-10COOR19, O(CH2)1-10CONR19R20, (C1-C6 alkylene)-COOR19, CHCHCOOR19, CF3, CN, NO2 and halogen;
R19and R20 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, C(O)R19 orCOOR19;
R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, COOH, NO2, NR19R20, OH and halogeno; and
R25 is H, OH or (C1-C6)alkoxy, to regulate the production or level of at least one amyloid peptide in the subject.
64. A method of regulating the amount of ApoE isoform 4 in the bloodstream andor brain of the subject comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one compound represented by Formula (VIII):
159
or a pharmaceutically acceptable salt or solvate thereof, wherein
R26 is selected from the group consisting of:
a) OH;
b) OCH3;
c) fluorine and
d) chlorine.
R1 is selected from the group consisting of
160
SO3H; natural and unnatural amino acids.
R, Ra and Rb are independently selected from the group consisting of H, OH, halogeno, NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy and WR30;
W is independently selected from the group consisting of NHC(O), OC(O), OC(O)N(R31), NHC(O)N(R31) and OC(S)N(R31);
R2 and R6 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, C(O)(C1-C6)alkyl and C(O)aryl;
R30 is independently selected form the group consisting of R32-substituted , R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl (C1-C6)alkyl;
R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents independently selected from the group consisting of H, halogeno, (C1-C4)alkyl, OH, phenoxy, CF3, NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, N(CH3)2, C(O)NH(C1-C4)alkyl, C(O)N((C1-C4)alkyl)2, C(O)(C1-C4)alkyl, C(O)(C1-C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
Ar1 is aryl or R10-substituted aryl;
Ar2 is aryl or R11-substituted aryl;
Q is (CH2)q, wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group
161
R12 is
162
R13 and R14 are independently selected from the group consisting of CH2, CH(C1-C6 alkyl)-, C(di-(C1-C6) alkyl), CHCH and C(C1-C6 alkyl)CH; or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a CHCH or a CHC(C1-C6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R13 is CHCH or C(C1-C6 alkyl)CH, a is 1; provided that when R14 is CHCH or C(C1-C6 alkyl)CH, b is 1; provided that when a is 2 or 3, the R13’s can be the same or different; and provided that when b is 2 or 3, the R14’s can be the same or different;
R10 and R11 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, OR19, O(CO)R19, O(CO)OR21, O(CH2)1-5OR19, O(CO)NR19R20, NR19R20, NR19(CO)R20, NR19(CO)OR21, NR19(CO)NR20R25, NR19SO2R21, COOR19, CONR19R20, COR19, SO2NR19R20, S(O)0-2R21, O(CH2)1-10COOR19, O(CH2)1-10CONR19R20, (C1-C6 alkylene)-COOR19, CHCHCOOR19, CF3, CN, NO2 and halogen;
R19 and R20 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, C(O)R19 or COOR19;
R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, COOH, NO2, NR19R20, OH and halogeno; and
R25 is H, OH or (C1-C6)alkoxy, to regulate the amount of ApoE isoform 4 in the bloodstream andor brain of the subject.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A communication control device comprising:
an acquisition unit configured to acquire first interference information indicating a first interference from communication involving a communication node that is not control target and second interference information indicating a second interference from communication involving another communication node of control target, with respect to each of a plurality of communication nodes of control target; and
a classifying unit configured to classify the plurality of communication nodes into a plurality of groups related to a decision of a radio resource that a communication node is able to utilize, on the basis of the first interference information and the second interference information with respect to the plurality of communication nodes.
2. The communication control device according to claim 1, wherein
the plurality of groups are a plurality of groups corresponding to an order in which the radio resource is decided.
3. The communication control device according to claim 2, wherein
the plurality of groups include at least a first group and a second group, and
a communication node classified into the first group is a communication node in which a level of the first interference relative to the second interference is larger, as compared with a communication node classified into the second group.
4. The communication control device according to claim 3, wherein
the second group is a group for which the radio resource is decided after the first group.
5. The communication control device according to claim 4, further comprising:
a deciding unit configured to decide the radio resource with respect to each of the plurality of communication nodes,
wherein the deciding unit decides the radio resource with respect to each of one or more communication nodes classified into the first group, and decides the radio resource with respect to each of one or more communication nodes classified into the second group, on the basis of a decision result of the radio resource in the first group.
6. The communication control device according to claim 5, wherein
the deciding unit decides one or more radio resource candidates having a smaller level of the first interference among two or more radio resource candidates, as the radio resource for the communication node classified into the first group.
7. The communication control device according to claim 3, wherein
the second group is a group for which the radio resource is decided before the first group.
8. The communication control device according to claim 7, further comprising:
a deciding unit configured to decide the radio resource with respect to each of the plurality of communication nodes,
wherein the deciding unit decides the radio resource with respect to each of one or more communication nodes classified into the second group, and decides the radio resource with respect to each of one or more communication nodes classified into the first group, on the basis of a decision result of the radio resource in the second group.
9. The communication control device according to claim 8, wherein
the deciding unit decides one or more radio resource candidates having a smaller level of a third interference with the one or more communication nodes classified into the second group among two or more radio resource candidates, as the radio resource for the communication node classified into the first group.
10. The communication control device according to claim 3, further comprising:
a deciding unit configured to decide the radio resource with respect to each of the plurality of communication nodes,
wherein, when deciding the radio resource with respect to each of the one or more communication nodes classified into the second group, the deciding unit decides the radio resource with respect to the communication node having a smaller level of the second interference, and decides, on the basis of a decision result of the radio resource with respect to the communication node, the radio resource with respect to the communication node having a larger level of the second interference.
11. The communication control device according to claim 3, further comprising:
a deciding unit configured to decide the radio resource with respect to each of the plurality of communication nodes,
wherein the deciding unit decides one or more radio resource candidates having a smaller level of interference including the first interference and the second interference among two or more radio resource candidates, as the radio resource for the communication node classified into the second group.
12. The communication control device according to claim 3, wherein
the first interference information indicates the first interference in each of two or more radio resource candidates,
the second interference information indicates the second interference in each of the two or more radio resource candidates, and
the level of the first interference relative to the second interference corresponds to the number of the radio resource candidates for which a level of the first interference is larger than a level of the second interference by a predetermined threshold value or more.
13. The communication control device according to claim 1, further comprising:
a deciding unit configured to decide the radio resource with respect to each of the plurality of communication nodes,
wherein the plurality of communication nodes are communication nodes of a higher priority than one or more low priority communication nodes of control target, and
the deciding unit further decides the radio resource with respect to each of the one or more low priority communication nodes, on the basis of a decision result of the radio resource with respect to the plurality of communication nodes.
14. The communication control device according to claim 13, further comprising:
a determination unit configured to determine whether a predetermined condition for a fourth interference with communication involving the plurality of communication nodes is satisfied, with respect to each of the one or more low priority communication nodes,
wherein the deciding unit decides the radio resource with respect to each of the one or more low priority communication nodes, on the basis of a determination result with respect to the predetermined condition.
15. The communication control device according to claim 1, wherein
the first interference is an interference by a downlink signal transmitted by the communication node that is not control target or an uplink signal transmitted to the communication node that is not control target, and
the second interference is an interference by a downlink signal transmitted by the other communication node or an uplink signal transmitted to the other communication node.
16. The communication control device according to claim 15, wherein
the interference by the uplink signal transmitted to the other communication node is an interference estimated under an assumption that a transmission node that transmits the uplink signal to the other communication node exists in a predetermined range or at a predetermined position which are closer to the communication node of control target within a communication range of the other communication node.
17. The communication control device according to claim 1, wherein
the communication node that is not control target includes a communication node of a primary system, and
each of the plurality of communication nodes is a communication node of a secondary system that secondarily utilizes a radio resource for the primary system.
18. The communication control device according to claim 1, wherein
the communication node that is not control target includes a base station of a macro cell, and
each of the plurality of communication nodes is a base station of a small cell that overlaps the macro cell partially or entirely.
19. A communication control method comprising:
acquiring first interference information indicating a first interference from communication involving a communication node that is not control target and second interference information indicating a second interference from communication involving another communication node of control target, with respect to each of a plurality of communication nodes of control target; and
classifying the plurality of communication nodes into a plurality of groups related to a decision of a radio resource that a communication node is able to utilize, on the basis of the first interference information and the second interference information with respect to the plurality of communication nodes.
20. An information processing apparatus comprising:
a memory that stores a predetermined program; and
a processor configured to execute the predetermined program,
wherein the predetermined program is a program for executing
acquiring first interference information indicating a first interference from communication involving a communication node that is not control target and second interference information indicating a second interference from communication involving another communication node of control target, with respect to each of a plurality of communication nodes of control target, and
classifying the plurality of communication nodes into a plurality of groups related to a decision of a radio resource that a communication node is able to utilize, on the basis of the first interference information and the second interference information with respect to the plurality of communication nodes.