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  Compounds to treat alzheimer's diseaseUSPTO Application #: 20060287306Title: Compounds to treat alzheimer's disease Abstract: useful in treating Alzheimer's disease and other similar diseases.
The present invention is directed toward substituted hydroxyethylene compounds of formulas (XII) (XIII), and (XIV) (end of abstract)
Agent: Mcdonnell Boehnen Hulbert & Berghoff LLP - Chicago, IL, US Inventors: Roy Hom, Shumeye S. Mamo, Jay Tung, Andrea Gailunas, Varghese John, Lawrence Fang USPTO Applicaton #: 20060287306 - Class: 514227800 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered And Includes At Least Nitrogen And Sulfur As Ring Members, 1,4-thiazines, Additional Hetero Ring Attached Directly Or Indirectly To The 1,4-thiazine By Nonionic Bonding The Patent Description & Claims data below is from USPTO Patent Application 20060287306. Brief Patent Description - Full Patent Description - Patent Application Claims
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. .sctn.119(e) from U.S. provisional application No. 60/191,528, filed Mar. 23, 2000, the disclosures of which are incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention is directed to compounds useful in treatment of Alzheimer's disease and more specifically to compounds that are capable of inhibiting beta-secretase, an enzyme that cleaves amyloid precursor protein to produce amyloid beta peptide (A beta), a major component of the amyloid plaques found in the brains of Alzheimer's sufferers. BACKGROUND OF THE INVENTION [0003] Alzheimer's Disease (AD) is a degenerative brain disorder presented clinically by progressive loss of memory, cognition, reasoning, judgement, and emotional stability that gradually leads to profound mental deterioration and ultimately death. Individuals with AD exhibit characteristic beta amyloid deposits in the brain (beta amyloid plaques) and in cerebral blood vessels (beta amyloid angiopathy) as well as neurofibrillary tangles. On autopsy of AD patients, large numbers of these lesions are generally found in areas of the human brain important for memory and congnitive function. Smaller numbers are found in the brains of most aged humans not showing clinical symptoms of AD. Beta amyloid plaques and beta amyloid angiopathy also characterize the brains of individuals with Down's Syndrome (Trisomy 21) and Hereditary Cerebral Hemorrhage with Beta amyloidosis of the Dutch-Type, and other such disorders. [0004] Beta amyloid plaques are a defining feature of AD, now believed to be a causative precursor or factor in the development of disease. Beta amyloid plaques are predominantly composed of beta amyloid beta peptide (A beta, also sometimes designated betaA4). [0005] Several isotypes of APP are known to date, including "normal" APP-695, APP-751, and APP770, having a sequence of 695, 751, and 770 amino acids, respectively. The identification of mutations in the beta amyloid precursor protein gene that cause familial, early onset AD implicate beta amyloid metabolism in the pathology of the disease. Such reported mutations include the double Swedish mutation (SW), changing Lys.sup.595 and Met.sup.596 to Asp.sup.595-Leu.sup.596, and mutations altering Val.sup.717 to Gly, Ile, or Phe. [0006] A beta peptide is derived by proteolysis of the beta amyloid precursor protein (APP) and is comprised of 39-42 amino acids. Several proteases called secretases are involved in the processing of APP. Deposition of A.beta. in areas of the brain responsible for cognitive activities is a major factor in the development of AD. Cleavage of APP at the N-terminus of the beta A4 peptide by beta-secretase and at the C-terminus by one or more gamma-secretases constitutes the beta amyloidogenic pathway, i.e. the pathway by which A beta is formed. Cleavage of APP by alpha-secretase and the same or a different gamma-secretase produces alpha-sAPP, a secreted form of APP that does not result in beta amyloid plaque formation. This alternate I-sAPP pathway precludes the formation of A beta peptide. It has been proposed that A beta accumulates as a result of processing of APP by beta-secretase, and that therefore inhibition of the activity of this enzyme is desireable for the treatment of AD. In vivo processing of APP at the beta-secretase site is thought to be the rate-limiting step in A beta production, and is thus a therapeutic target for the treatment of AD. See, for example, Sabbagh et. al., 1997, Alz. Dis. Rev. 3:1-19). A description of the proteolytic processing fragments of APP can be found, for example, in U.S. Pat. Nos. 5,441,870, 5,721,130, and 5,942,400. [0007] Several lines of evidence indicate that progressive cerebral deposition of particular beta amyloidogenic peptides, beta-amyloid peptides, (A beta), play a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe, 1991, Neuron 6:487. Recently, it has been shown that A beta is released from neuronal cells grown in culture and is present in cerebrospinal fluid (CSF) of both normal individuals and AD patients. See, for example, Seubert et al., 1992, Nature 359:325-327. [0008] An aspartyl protease has been identified as the enzyme responsible for processing of APP at the beta-secretase cleavage site. The beta-secretase enzyme has been disclosed using varied nomenclature, including BACE and Asp. See, for example, Sindha et. al., 1999, Nature 402:537-554 (p 501) and published PCT application WO00/17369 (hAsp2a and hAsp2b). [0009] At present there are no effective treatments for halting, preventing, or reversing the progression of Alzheimer's disease. Therefore, there is an urgent need for pharmaceutical agents capable of slowing the progression of Alzheimer's disease and/or preventing it in the first place. [0010] Compounds that are effective inhibitors of beta-secretase, that inhibit beta-secretase-mediated cleavage of APP, that are effective inhibitors of A beta production, and/or are effective to reduce beta amyloid beta deposits or plaques are needed for the treatment and prevention of disease characterized by beta amyloid beta deposits or plaques, such as AD. SUMMARY OF INVENTION [0011] The present invention is the compounds of the formula (XII), formula (XIII), and formula (XIV) below, compositions thereof, and methods useful in the treatment of Alzheimer's disease and more specifically compounds that are capable of inhibiting beta-secretase, an enzyme that cleaves amyloid precursor protein to produce A beta peptide, a major component of the amyloid plaques found in the brains of Alzheimer's sufferers. [0012] The present invention is compounds of formula (XII): [0013] where R.sub.1 is: [0014] (I) C.sub.1-C.sub.6 alkyl, [0015] (II) C.sub.1-C.sub.6 alkyl-5-alkyl [0016] (III) C.sub.1-C.sub.6 alkyl-(C.sub.2-C.sub.6 alkenyl), [0017] (IV) --(CH.sub.2).sub.0-6-alkyl --(R.sub.1-aryl) where R.sub.1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with: [0018] (A) C.sub.1-C.sub.6 alkyl, [0019] (B) --CF.sub.3, [0020] (C) --F, Cl, --Br or --I, [0021] (D) C.sub.1-C.sub.3 alkoxy, [0022] (E) --O--CF.sub.3, [0023] (F) --NH.sub.2, [0024] (G) --OH, or [0025] (H) --C.ident.N, [0026] (V) --(CH.sub.2).sub.0-6-alkyl --(R.sub.1-heteroaryl) where R.sub.1-heteroaryl is: [0027] (A) pyridinyl, [0028] (B) pyrimidinyl, [0029] (C) quinolinyl, [0030] (D) indenyl, [0031] (E) indanyl, [0032] (G) indolyl, [0033] (H) indolinyl, [0034] (I) pyridazinyl, [0035] (J) pyrazinyl, [0036] (K) isoindolyl, [0037] (L) isoquinolyl, [0038] (M) quinazolinyl, [0039] (N) quinoxalinyl, [0040] (O) phthalazinyl, [0041] (P) imidazolyl, [0042] (Q) isoxazolyl, [0043] (R) pyrazolyl, [0044] (S) oxazolyl, [0045] (T) thiazolyl, [0046] (U) indolizinyl, [0047] (V) indazolyl, [0048] (W) benzothiazolyl, [0049] (X) benzimidazolyl, [0050] (Y) benzofuranyl, [0051] (Z) furanyl, [0052] (AA) thienyl, [0053] (BB) pyrrolyl, [0054] (CC) oxadiazolyl, [0055] (DD) thiadiazolyl, [0056] (EE) triazolyl, [0057] (FF) tetrazolyl, [0058] (GG) 1,4-benzodioxan [0059] (HH) purinyl, [0060] (II) oxazolopyridinyl, [0061] (JJ) imidazopyridinyl, [0062] (KK) isothiazolyl, [0063] (LL) naphthyridinyl, [0064] (MM) cinnolinyl, [0065] (NN) carbazolyl, [0066] (OO) .beta.-carbolinyl, [0067] (PP) isochromanyl, [0068] (QQ) chromanyl, [0069] (RR) furazanyl, [0070] (SS) tetrahydroisoquinoline, [0071] (TT) isoindolinyl, [0072] (UU) isobenzotetrahydrofuranyl, [0073] (VV) isobenzotetrahydrothienyl, [0074] (WW) isobenzothiophenyl, [0075] (XX) benzoxazolyl, or [0076] (YY) pyridopyridinyl, [0077] where the R.sub.1-heteroaryl group is bonded to -alkyl- by any ring atom of the parent R.sub.1-heteroaryl group substituted by hydrogen such that the new bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and its bond, where R.sub.1-heteroaryl is unsubstituted or substituted with: [0078] (1) C.sub.1-C.sub.3 alkyl, [0079] (2) --CF.sub.3, [0080] (3) --F, Cl, --Br, or I, [0081] (4) C.sub.1-C.sub.3 alkoxy, [0082] (5) --O--CF.sub.3, [0083] (6) --NH.sub.2, [0084] (7) --OH, or [0085] (8) --C.ident.N, [0086] (VI) --(R.sub.1-heteroaryl) where R.sub.1-heteroaryl is as defined above, [0087] (VII) --C.sub.1-C.sub.5 alkyl-(R.sub.1-heterocycle) where R.sub.1-heterocycle is: [0088] (A) morpholinyl, [0089] (B) thiomorpholinyl, [0090] (C) thiomorpholinyl S-oxide, [0091] (D) thiomorpholinyl S,S-dioxide, [0092] (E) piperazinyl, [0093] (F) homopiperazinyl, [0094] (G) pyrrolidinyl, [0095] (H) pyrrolinyl, [0096] (I) tetrahydropyranyl, [0097] (J) piperidinyl, [0098] (K) tetrahydrofuranyl, or [0099] (L) tetrahydrothiophenyl, [0100] where the R.sub.1-heterocycle group is bonded by any atom of the parent R.sub.1-heterocycle group substituted by hydrogen such that the new bond to the R.sub.1-heterocycle group replaces the hydrogen atom and its bond, where R.sub.1-heterocycle is unsubstituted or substituted with: [0101] (1) .dbd.O, [0102] (2) C.sub.1-C.sub.3 alkyl, [0103] (3) --CF.sub.3, [0104] (4) --F, Cl, --Br or --I, [0105] (5) C.sub.1-C.sub.3 alkoxy, [0106] (6) --O--CF.sub.3, [0107] (7) --NH.sub.2, [0108] (8) --OH, or [0109] (9) --C.ident.N, or [0110] (VIII) --R.sub.1-heterocycle, where R.sub.1-heterocycle is as defined above; [0111] where R.sub.2 is: [0112] (I) --H, [0113] (II) alkyl, or [0114] (III) --C.sub.1-C.sub.5 alkyl-R.sub.2-1 where R.sub.2-1 is cycloalkyl, R.sub.1-aryl or R.sub.1-heteroaryl where R.sub.1-aryl and R.sub.1-heteroaryl are as defined above; [0115] where R.sub.N is: [0116] (I) R.sub.N-1--X.sub.N-- where X.sub.N is: [0117] (A) --CO--, [0118] (B) --SO.sub.2--, [0119] (C) --(CR'R'').sub.1-6 where R' and R'' are the same or different and are --H or C.sub.1-C.sub.4 alkyl, [0120] (D) --CO--(CR'R'').sub.1-6--X.sub.N-1 where X.sub.N-1 is --O--, --S-- or --NR'R''-- and where R' and R'' are as defined above, or [0121] (E) a single bond; [0122] where R.sub.N-1 is: [0123] (A) R.sub.N-aryl where R.sub.N-aryl is phenyl, biphenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with: [0124] (1) C.sub.1-C.sub.6 alkyl, [0125] (2) --F, --Cl, --Br, or --I, [0126] (3) --OH, [0127] (4) --NO.sub.2, [0128] (5) --CO--OH, [0129] (6) --C.ident.N, [0130] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the same or different and are: [0131] (a) --H, [0132] (b) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted with [0133] (i) --OH, or [0134] (ii) --NH.sub.2, [0135] (c) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted with --F, --Cl, --Br, or --I, [0136] (d) --C.sub.3-C.sub.7 cycloalkyl, [0137] (e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), [0138] (f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), [0139] (g) --C.sub.1-C.sub.6 alkenyl with one or two double bonds, [0140] (h) --C.sub.1-C.sub.6 alkynyl with one or two triple bonds, [0141] (i) --C.sub.1-C.sub.6 alkyl chain with one double bond and one triple bond, [0142] (j) --R.sub.1-aryl where R.sub.1-aryl is as defined above, or [0143] (k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined above, [0144] (8) --CO--(C.sub.3-C.sub.12 alkyl), [0145] (9) --CO--(C.sub.3-C.sub.6 cycloalkyl), [0146] (10) --CO--R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined above, [0147] (11) --CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined above, [0148] (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with C.sub.1-C.sub.3 alkyl, [0149] (13) --CO--O--R.sub.N-5 where R.sub.N-5 is: [0150] (a) alkyl, or [0151] (b) --(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as defined above, [0152] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined above, [0153] (15) --SO--(C.sub.1-C.sub.8 alkyl), [0154] (16) --SO.sub.2--(C.sub.3-C.sub.12 alkyl), [0155] (17) --NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [0156] (18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0157] (19) --N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0158] (20) --N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as defined above, [0159] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 can be the same or different and are as defined above, [0160] (22) --R.sub.N-4 where R.sub.N-4 is as defined above, [0161] (23) --O--CO--(C.sub.1-C.sub.6 alkyl), [0162] (24) --O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0163] (25) --O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0164] (26) --O--(C.sub.1-C.sub.6 alkyl), [0165] (27) --O--(C.sub.2-C.sub.5 alkyl)-COOH, [0166] (28) --S--(C.sub.1-C.sub.6 alkyl), [0167] (29) C.sub.1-C.sub.6 alkyl unsubstituted or substituted with halo, [0168] (30) --O--(C.sub.1-C.sub.6 alkyl unsubstituted or substituted with halo), or [0169] (31) --O-phenyl, [0170] (32) (C.sub.1-C.sub.6 alkyl) substituted with --CO--NH--C(.dbd.O)--, [0171] (B) --R.sub.N-heteroaryl where R.sub.N-heteroaryl is: [0172] (1) pyridinyl, [0173] (2) pyrimidinyl, [0174] (3) quinolinyl, [0175] (4) indenyl, [0176] (5) indanyl, [0177] (6) benzothiophenyl, [0178] (7) indolyl, [0179] (8) indolinyl, [0180] (9) pyridazinyl, [0181] (10) pyrazinyl, [0182] (11) isoindolyl, [0183] (12) isoquinolyl, [0184] (13) quinazolinyl, [0185] (14) quinoxalinyl, [0186] (15) phthalazinyl, [0187] (16) imidazolyl, [0188] (17) isoxazolyl, [0189] (18) pyrazolyl, [0190] (19) oxazolyl, [0191] (20) thiazolyl, [0192] (21) indolizinyl, [0193] (22) indazolyl, [0194] (23) benzothiazolyl, [0195] (24) benzimidazolyl, [0196] (25) benzofuranyl, [0197] (26) furanyl, [0198] (27) thienyl, [0199] (28) pyrrolyl, [0200] (29) oxadiazolyl, [0201] (30) thiadiazolyl, [0202] (31) triazolyl, [0203] (32) tetrazolyl, [0204] (33) 1,4-benzodioxan [0205] (34) purinyl, [0206] (35) oxazolopyridinyl, [0207] (36) imidazopyridinyl, [0208] (37) isothiazolyl, [0209] (38) naphthyridinyl, [0210] (39) cinnolinyl, [0211] (40) carbazolyl, [0212] (41) .beta.-carbolinyl, [0213] (42) isochromanyl, [0214] (43) chromanyl, [0215] (44) furazanyl, [0216] (45) tetrahydroisoquinoline, [0217] (46) isoindolinyl, [0218] (47) isobenzotetrahydrofuranyl, [0219] (48) isobenzotetrahydrothienyl, [0220] (49) isobenzothiophenyl, [0221] (50) benzoxazolyl, or [0222] (51) pyridopyridinyl, [0223] where the R.sub.N-heteroaryl group is bonded by any atom of the parent R.sub.N-heteroaryl group substituted by hydrogen such that the new bond to the R.sub.N-heteroaryl group replaces the hydrogen atom and its bond, where R.sub.N-heteroaryl is unsubstituted or substituted with: [0224] (1) C.sub.1-C.sub.6 alkyl, [0225] (2) --F, --Cl, --Br, or --I, [0226] (3) --OH, [0227] (4) --NO.sub.2, [0228] (5) --CO--OH, [0229] (6) --C.ident.N, [0230] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined above, [0231] (8) --CO--(C.sub.3-C.sub.12 alkyl), [0232] (9) --CO--(C.sub.3-C.sub.6 cycloalkyl), [0233] (10) --CO--R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined above, [0234] (11) --CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined above, [0235] (12) --CO--R.sub.N-4 where R.sub.N-4 is as defined above, [0236] (13) --CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [0237] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined above, [0238] (15) --SO--(C.sub.1-C.sub.8 alkyl), [0239] (16) --SO.sub.2--(C.sub.3-C.sub.12 alkyl), [0240] (17) --NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [0241] (18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0242] (19) --N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0243] (20) --N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as defined above, [0244] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 can be the same or different and are as defined above, [0245] (22) --R.sub.N-4 where R.sub.N-4 is as defined above, [0246] (23) --O--CO--(C.sub.1-C.sub.6 alkyl), [0247] (24) --O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0248] (25) --O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0249] (26) --O--(C.sub.1-C.sub.6 alkyl), [0250] (27) --O--(C.sub.2-C.sub.5 alkyl)-COOH, or [0251] (28) --S--(C.sub.1-C.sub.6 alkyl), [0252] (29) (C.sub.1-C.sub.6 alkyl) substituted with --CO--OH and --NH--C(.dbd.O)--, [0253] (C) --R.sub.N-aryl--R.sub.N-aryl where --R.sub.N-aryl is as defined above, [0254] (D) --R.sub.N-aryl--R.sub.N-heteroaryl where --R.sub.N-aryl and --R.sub.N-heteroaryl are as defined above, [0255] (E) --R.sub.N-heteroaryl--R.sub.N-aryl where --R.sub.N-aryl and --R.sub.N-heteroaryl are as defined above, [0256] (F) --R.sub.N-heteroaryl--R.sub.N-heteroaryl where R.sub.N-heteroaryl is as defined above, [0257] (G) --R.sub.N-aryl--O--R.sub.N-aryl where --R.sub.N-aryl is as defined above, [0258] (H) --R.sub.N-aryl--S--R.sub.N-aryl where --R.sub.N-aryl is as defined above, [0259] (I) --R.sub.N-heteroaryl--O--R.sub.N-heteroaryl where R.sub.N-heteroaryl is as defined above, [0260] (J) --R.sub.N-heteroaryl--S--R.sub.N-heteroaryl where R.sub.N-heteroaryl is as defined above, [0261] (K) --R.sub.N-aryl--CO--R.sub.N-aryl where --R.sub.N-aryl is as defined above, [0262] (L) --R.sub.N-aryl--CO--R.sub.N-heteroaryl where --R.sub.N-aryl and R.sub.N-heteroaryl are as defined above, [0263] (M) R.sub.N-aryl--SO.sub.2--R.sub.N-aryl where --R.sub.N-aryl is as defined above, [0264] (N) --R.sub.N-heteroaryl--CO--R.sub.N-heteroaryl where R.sub.N-heteroaryl is as defined above, [0265] (O) --R.sub.N-heteroaryl--SO.sub.2--R.sub.N-heteroaryl where R.sub.N-heteroaryl is as defined above, [0266] (P) --R.sub.N-aryl--O--(C.sub.1-C.sub.8 alkyl)-phenyl, where R.sub.N-aryl is as defined above, [0267] (Q) --R.sub.N-aryl--S--(C.sub.1-C.sub.8 alkyl)-phenyl, where R.sub.N-aryl is as defined above, [0268] (R) --R.sub.N-heteroaryl--O--(C.sub.1-C.sub.8 alkyl)-phenyl, where R.sub.N-heteroaryl is as defined above, or [0269] (S) --R.sub.N-heteroaryl--S--(C.sub.1-C.sub.8 alkyl)-phenyl, where R.sub.N-heteroaryl is as defined above, or [0270] (II) --CO--(C.sub.1-C.sub.6 alkyl) where alkyl is unsubstituted or substituted with: [0271] (A) --OH, [0272] (B) --C.sub.1-C.sub.6 alkoxy, [0273] (C) --C.sub.1-C.sub.6 thioalkoxy, [0274] (D) --CO--O--R.sub.N-8 where R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or -phenyl, [0275] (E) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the same or different and are as defined above, [0276] (F) --CO--R.sub.N-4 where R.sub.N-4 is as defined above, [0277] (G) --SO.sub.2--(C.sub.1-C.sub.8 alkyl), [0278] (H) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the same or different and are as defined above, [0279] (I) --NH--CO--(C.sub.1-C.sub.6 alkyl), [0280] (J) --NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [0281] (K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the same or different and are as defined above, [0282] (L) --R.sub.N-4 where R.sub.N-4 is as defined above, [0283] (M) --O--CO--(C.sub.1-C.sub.6 alkyl), [0284] (N) --O--CO--NR.sub.N-8R.sub.N-8 where R.sub.N-8 are the same or different and are as defined above, or [0285] (O) --O--(C.sub.1-C.sub.5 alkyl)-COOH; [0286] where B is --O--, --NH--, or --N(C.sub.1-C.sub.6 alkyl)-; and [0287] where R.sub.C is: [0288] (I) C.sub.1-C.sub.8 alkyl unsubstituted or substituted with --OH, --O-phenyl, halo, or (C.sub.1-C.sub.6 alkoxy unsubstituted or substituted with halo), or [0289] (II) --C(R.sub.C-1)(R.sub.C-2)--CO--NH--R.sub.C-3 where R.sub.C-1 and R.sub.C-2 are the same or different and are: [0290] (A) --H, [0291] (B) --C.sub.1-C.sub.6 alkyl, [0292] (C) --(C.sub.1-C.sub.4 alkyl)-R.sub.C'-aryl, where R.sub.C'-aryl is as defined for R.sub.N-aryl, [0293] (D) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heteroaryl, where R.sub.C-heteroaryl is as defined for R.sub.N-heteroaryl, and R.sub.N-heteroaryl is as defined above, [0294] (E) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle, where R.sub.C-heterocycle is as defined for R.sub.N-heterocycle, and R.sub.N-heterocycle is as defined above, [0295] (F) --R.sub.C-heteroaryl, where R.sub.C-heteroaryl is as defined above, [0296] (G) --R.sub.C-heterocycle, where R.sub.C-heterocycle is as defined above, [0297] (H) --(CH.sub.2).sub.1-4--OH, [0298] (I) --(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C'-aryl, where R.sub.C-4 is --O--, --S--, --NH--, or --NR.sub.C-5-- where R.sub.C-5 is C.sub.1-C.sub.6 alkyl, and where R.sub.C'-aryl is as defined above, [0299] (J) --(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-heteroaryl, where R.sub.C-4 and R.sub.C-heteroaryl are as defined above, or [0300] (K) --R.sub.C'aryl, where R.sub.C'-aryl is as defined above, [0301] and where R.sub.C-3 is: [0302] (A) --H, [0303] (B) --C.sub.1-C.sub.6 alkyl, substituted or unsubstituted with; [0304] (1) --H, [0305] (2) --C.sub.1-C.sub.6 alkyl, [0306] (3) --(C.sub.1-C.sub.4 alkyl)-R.sub.C'-aryl where R.sub.C'-aryl is as defined for R.sub.N-aryl, [0307] (4) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined for R.sub.N-heteroaryl, and R.sub.N-heteroaryl is as defined above, [0308] (5) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle where R.sub.C-heterocycle is as defined for R.sub.N-heterocycle, and R.sub.N-heterocycle is as defined above, [0309] (6) --R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined above, [0310] (7) --R.sub.C-heterocycle where R.sub.C-heterocycle is as defined above, [0311] (8) --(CH.sub.2).sub.1-4--OH, [0312] (9) --(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C'-aryl) where R.sub.C-4 is --O--, --S--, --NH--, or --NR.sub.C-5-- where R.sub.C-5 is C.sub.1-C.sub.6 alkyl, and where R.sub.C'-aryl is as defined above, [0313] (10) --(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-heteroaryl where R.sub.C-4 and R.sub.C-heteroaryl are as defined above, or [0314] (11) --R.sub.C'-aryl where R.sub.C'-aryl is as defined above, [0315] (12) --CO--OH and --NH--C(.dbd.O)--, [0316] (C) --R.sub.C'-aryl where R.sub.C'-aryl is as defined above, [0317] (D) --R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined above, [0318] (E) --R.sub.C-heterocycle where R.sub.C-heterocycle is as defined above, [0319] (F) --(C.sub.1-C.sub.4 alkyl)-R.sub.C'-aryl where R.sub.C'-aryl is as defined above, [0320] (G) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined above, [0321] (H) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle where R.sub.C-heterocycle is as defined above, or [0322] (J) --C(R.sub.C-5)(R.sub.C-6)--CO--NH--C(R.sub.C-7)(R.sub.C-8)--COOH, where R.sub.C-5, R.sub.C-6, R.sub.C-7, and R.sub.C-8 are the same or different, and are as defined for R.sub.C-1 and R.sub.C-2 and where R.sub.C-1 and R.sub.C-2 are as defined above; [0323] or pharmaceutically acceptable salts thereof. [0324] The present invention also includes compounds of the formula (XIII) [0325] wherein R.sub.1 is: [0326] (I) C.sub.1-C.sub.6 alkyl, [0327] (II) C.sub.1-C.sub.6 alkyl-5-alkyl [0328] (III) C.sub.1-C.sub.6 alkyl-(C.sub.2-C.sub.6 alkenyl), [0329] (IV) --(CH.sub.2).sub.0-6-alkyl --(R.sub.1-aryl) where R.sub.1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with: [0330] (A) C.sub.1-C.sub.6 alkyl, [0331] (B) --CF.sub.3, [0332] (C) --F, Cl, --Br or --I, [0333] (D) C.sub.1-C.sub.3 alkoxy, [0334] (E) --O--CF.sub.3, [0335] (F) --NH.sub.2, [0336] (G) --OH, or [0337] (H) --C.ident.N, [0338] (V) --(CH.sub.2).sub.0-6-alkyl --(R.sub.1-heteroaryl) where R.sub.1-heteroaryl is: [0339] (A) pyridinyl, [0340] (B) pyrimidinyl, [0341] (C) quinolinyl, [0342] (D) indenyl, [0343] (E) indanyl, [0344] (F) benzothiophenyl, [0345] (G) indolyl, [0346] (H) indolinyl, [0347] (I) pyridazinyl, [0348] (J) pyrazinyl, [0349] (K) isoindolyl, [0350] (L) isoquinolyl, [0351] (M) quinazolinyl, [0352] (N) quinoxalinyl, [0353] (O) phthalazinyl, [0354] (P) imidazolyl, [0355] (Q) isoxazolyl, [0356] (R) pyrazolyl, [0357] (S) oxazolyl, [0358] (T) thiazolyl, [0359] (U) indolizinyl, [0360] (V) indazolyl, [0361] (W) benzothiazolyl, [0362] (X) benzimidazolyl, [0363] (Y) benzofuranyl, [0364] (Z) furanyl, [0365] (AA) thienyl, [0366] (BB) pyrrolyl, [0367] (CC) oxadiazolyl, [0368] (DD) thiadiazolyl, [0369] (EE) triazolyl, [0370] (FF) tetrazolyl, [0371] (GG) 1,4-benzodioxan [0372] (HH) purinyl, [0373] (II) oxazolopyridinyl, [0374] (JJ) imidazopyridinyl, [0375] (KK) isothiazolyl, [0376] (LL) naphthyridinyl, [0377] (MM) cinnolinyl, [0378] (NN) carbazolyl, [0379] (OO) .beta.-carbolinyl, [0380] (PP) isochromanyl, [0381] (QQ) chromanyl, [0382] (RR) furazanyl, [0383] (SS) tetrahydroisoquinoline, [0384] (TT) isoindolinyl, [0385] (UU) isobenzotetrahydrofuranyl, [0386] (VV) isobenzotetrahydrothienyl, [0387] (WW) isobenzothiophenyl, [0388] (XX) benzoxazolyl, or [0389] (YY) pyridopyridinyl, [0390] where the R.sub.1-heteroaryl group is bonded to -alkyl- by any ring atom of the parent R.sub.1-heteroaryl group substituted by hydrogen such that the new bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and its bond, where R.sub.1-heteroaryl is unsubstituted or substituted with: [0391] (1) C.sub.1-C.sub.3 alkyl, [0392] (2) --CF.sub.3, [0393] (3) --F, Cl, --Br, or I, [0394] (4) C.sub.1-C.sub.3 alkoxy, [0395] (5) --O--CF.sub.3, [0396] (6) --NH.sub.2, [0397] (7) --OH, or [0398] (8) --C.ident.N, [0399] (VI) --(R.sub.1-heteroaryl) where R.sub.1-heteroaryl is as defined above, [0400] (VII) --C.sub.1-C.sub.5 alkyl-(R.sub.1-heterocycle) where R.sub.1-heterocycle is: [0401] (A) morpholinyl, [0402] (B) thiomorpholinyl, [0403] (C) thiomorpholinyl S-oxide, [0404] (D) thiomorpholinyl S,S-dioxide, [0405] (E) piperazinyl, [0406] (F) homopiperazinyl, [0407] (G) pyrrolidinyl, [0408] (H) pyrrolinyl, [0409] (I) tetrahydropyranyl, [0410] (J) piperidinyl, [0411] (K) tetrahydrofuranyl, or [0412] (L) tetrahydrothiophenyl, [0413] where the R.sub.1-heterocycle group is bonded by any atom of the parent R.sub.1-heterocycle group substituted by hydrogen such that the new bond to the R.sub.1-heterocycle group replaces the hydrogen atom and its bond, where R.sub.1-heterocycle is unsubstituted or substituted with: [0414] (1) .dbd.O, [0415] (2) C.sub.1-C.sub.3 alkyl, [0416] (3) --CF.sub.3, [0417] (4) --F, Cl, --Br or --I, [0418] (5) C.sub.1-C.sub.3 alkoxy, [0419] (6) --O--CF.sub.3, [0420] (7) --NH.sub.2, [0421] (8) --OH, or [0422] (9) --C.ident.N, or [0423] (VIII) --R.sub.1-heterocycle, where R.sub.1-heterocycle is as defined above; Continue reading... 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