CYCLOALKYL, LACTAM, LACTONE AND RELATED COMPOUNDS, PHARMACEUTICAL COMPOSITIONS COMPRISING SAME, AND METHOD FOR INHIBITING beta-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESISBY USE OF SUCH COMPOUNDS

摘要

6-C10aryl, heteroaryl and heterocyclyl, having 2-61. A method for inhibiting β-amyloid peptide release and/or its synthesis in a cell which methoendently is alkylen, substituted alkylen, alkenylen and substituted alkenylen, with proviso, that wh in inhibiting the cellular release and/or synthesis of β-amyloid peptide wherein said compound -S-, and q is integer from 1 to 3. 21. Pharmaceutical composition according to Claim 17, wherein cyclic group, determined as W together with -CHC(=X)-, forms the ring of formula or wherein T is oalkyl, C6-C10 arylamino, acyl, acylamino, aminoacyl, halo, carboxyC1-C10alkyl, C1-C10thioalkoxy, phenylC1-C10thioalkoxy, having from 1 to 3 phenyl groups, C6-C10aryl, optionally substituted with 1-3 d >NR<20>, wherein each R<20> is independently selected from the group, comprising C1-C10alkyl, substituted C1-C10alkyl, C6-C10aryl, heteroaryl and heeroaryl, having from 3 to 5 carbon atoms in the riatoms, independently selected from sulfur and nitrogen; each R<21> independently is alkylen, substit atoms in the ring. C2-C8alkenyl, optionally substituted with 1-3 substituents, independently selectaturation in alkenylen and substituted alkenylen does not include -O- or -S-, and q is integer from ly substituted phenyl, optionally having 1-3 substlected from the group, comprising: wherein each o, halo, C1-C10alkoxy, C1-C6alkyl, optionally substituted with 1-3 substituents, selected from hydroxy and halo, phenylC1-C10alkoxy, phenyl, optionally substituted with C1-C10alkyl aryloxy, selected from phenoxy, naphthyloxy and C1-C10alkylphenoxy; and heteroaryl, selected from furazanyl, benzofuranup, comprising alkylen, substituted alkylen, alkenl tetrazole, optionally substituted with C1-C10alkR21-, wherein Z is substituent, selected from the d pyrrolidinyl; W together with -CHC(=X) forms C3-ch R<20> independently is selected from the group, comprising C1-C10alkyl, substituted C1-C10alkyl, C6-C10aryl, heteroaryl and heterocyclyl, having 2-6 carbon atoms and 1-2 heteroatoms, independently ygen, sulfur and nitrogen, and wherein said heteropendently is alkylen, substituted alkylen, alkenylen and substituted alkenylen, with proviso, that when Z is -O- or -S-, any nonsaturation in alkenyleituents, independently selected from C1-C10alkoxy,r -S-, and q is integer from 1 to 3; wherein said alkylC(O)], C1-C10alkoxycarbonyl, C6-C10arylcarbon, comprising 23. The compound of formula I wheC10alkylamino, C6-C10aryl or C6-C10aryloxy, optionally substituted with one or two C1-C10alkyl groups, biphenyl, and mono or condensed bicyclic heteroaryl or heterocyclyl, having from 2 to 10 carbon atoms in the ring and from 1 to 3 heteroatoms, independently selected from oxygen, sulfur and nitrogephenyl groups, C6-C10aryl, optionally substituted with 1-3 substituents, independently selected from C1-C6alkyl, halo, C1-C10alkoxy, hydroxy and nitroted with one or two halos; alkoxyalkoxy, having 2-6 carbon atoms; heteroaryl or heterocyclyl, having 2-6 carbon atoms in the ring and 1 or 2 heteroato, hydroxamino and -SO2aryl, wherein aryl group hasand nitrogen; and wherein each of said cycloalkyl,onally is substituted with 1-3 substituents, independently selected from C6-C10aryls; C3-C12cycloalkyl; C3-C12cycloalkenyl; aryl, selected from naphthres, selected from the group, comprising C3-C12cycaving 1-3 substituents, independently selected fro ring and from 1 to 3 heteroatoms, independently soptionally substituted with 1-3 substituents, selected from hydroxy and halo, phenylC1-C10alkoxy, phenyl, optionally substituted with C1-C10alkyl aryloxy, selected from phenoxy, naphthyloxy and C1-C10 of such ring structure, in its turn is optionallynyl, benzofuranyl, thienyl, optionally substitutedthe group, comprising halo or nitro; X represents with C1-C10alkyl benzofuranyl, indanyl, indolyl, benzothienyl and pyrrolidinyl; W together with -CHndently selected from the group, comprising: C1-C1th 1-2 double bonds or heteroaryl or heterocyclyl,ts, independently selected from C1-C10cycloalkyl, halo, C1-C10thioalkoxy and hydroxy; C3-C12cycloalkyl; C6-C10aryl; and thiaryl, having 3-6 carbon atoms in the ring and 1 or 2 atoms of sulfur in the ring; Z represents the formula -T-CX'X"C(O)-, wherselected from: C1-C10alkyl, optionally substituted -CX'X"-, oxygen (-O-) or sulfur (-S-), and one ofm C1-C10alkoxy, halo, C3-C12cycloalkyl, C2-C7alkanoyl [i.e. C2-C7alkylC(O)], C1-C10alkoxycarbonyl, C6-C10arylcarbonyl, morpholinylcarbonyl; indolinyl, mono- or diC1-C10alkylamino, C6-C10aryl or C6-C10 oxygen or sulfur; m is 0 or 1; n is 0 or 1, with -C10alkyl groups, biphenyl and mono or condensed boviso, that: A) when R<1> is 3,5-difluorophenyl, Rto 10 carbon atoms in the ring and from 1 to 3 heteroatoms, independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1-3, Z is -CH2C(O)-, m is 1, n is 1, then W togetheralkyl, halo and trifluoromethyl; C6-C10aryl, optionally substituted with one or two halos; alkoxyalkoxy, having 2-6 carbon atoms; heteroaryl or heterocyclyl, having 2-6 carbon atoms in the ring and 1 r 5,5-dimethyl-gamma-butyrolactone group; D) when R<1> is phenyl, Z is -CH2C(O)-, m is 1, n is 0, then W together with >CH and >C=X does not form &eps optionally condensed with forming doubly or repeayl, R<2> is -CH3, Z is -CH2C(O)-, m is 1, n is 1, then W together with >CH and >C=X does not form N- C3-C12cycloalkyl, heterocyclyl with 2-8 carbon atenyl and T represents -O- or R<1> is 4-chlorobenzoyl-CH2-, R<2> is -CH3, Z is -CH2C(O)-, m is 1, n is 1, then W together with >CH and >C=X does not foin the ring and from 1 to 3 heteroatoms, independepine-2-one; G) when R<1> is 2-phenylphenyl, R<2> is -CH3, Z is -CH2C(O)-, m is 1, n is 1, then W togtionally is substituted with 1-2 substituents, sel-dihydro-6H-dibenz[b,d]azepine-6-one; H) when R<1>represents oxo (=O), hydroxyl (-H, -OH) or hydro (is 1, n is 1, then W together with >CH and >C=X does not form 2,3-dihydro-1-(tert-butyl-C(O)CH2)-5-(ising: C1-C10alkyl, optionally substituted with 1-3 substituents, independently selected from C1-C10phenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, CH3-C12cycloalkyl; C6-C10aryl; and thiaryl, having 3-r 2-trifluoromethyl-4-fluorophenyl, R<2> is -CH3, Z is -CH2C(O)-, m is 1, n is 1, then W together with >CH and >C=X does not form 2,3-dihydro-1-(N,N-diethylamino-CH2CH2-)-5-(2-pyridil)-1H-1,4-benzodia, and one of X' or X" represents hydrogen, fluoro or hydroxy, and the other represents hydrogen, or X' and X" together form oxo (=O), with proviso, th-dihydro-1-(N,N-diethylamino-CH2CH2)-5-(2-pyridil)xy, T is not oxygen or sulfur; m is 0 or 1; n is 0 is 1, then is not cycloalkyl with 3-8 carbon at and with proviso: A) when R<1> is 3,5-difluoropheps; L) W together with -CHC(=X) does not form satu then W together with >CH and >C=X does not form 2reventing the onset of Alzheimer's Disease in a human patient at risk for developing Alzheimer's Disease which method comprises administering to said patient a pharmaceutical composition comprising a is -CH2C(O)-, m is 1, n is 0, then W together with >CH and >C=X does not form gamma-butyrolactone group or 5,5-dimethyl-gamma-butyrolactone group; D)p, comprising: C1-C10alkyl, optionally substituted with 1-3 substituents, independently selected from C1-C10alkoxy, C3-C12cycloalkyl, C6-C10arylmino, acyl, acylamino, aminoacyl, halo, carboxyC1-C10alkyl, C1-C10thioalkoxy, phenylC1-C10thioalkoxy, having from 1 to 3 phenyl groups, C6-C10aryl, optionalitrophenyl and T represents -O- or R<1> is 4-chlory selected from C1-C6alkyl, halo, C1-C10alkoxy, hydroxy and nitro, C6-C10aryloxy, optionally substituted with 1-3 halos, heteroaryl, having from 3 to diazepine-2-one; G) when R<1> is 2-phenylphenyl, R<2> is -CH3, Z is -CH2C(O)-, m is 1, n is 1, then aryl group has 6-10 carbon atoms in the ring ; C2-C8alkenyl, optionally substituted with 1-3 substituents, independently selected from C6-C10aryls; C-, m is 1, n is 1, then W together with >CH and >Cd from naphthyl and optionally substituted phenyl, optionally having 1-3 substituents, independently selected from hydroxy, nitro, halo, C1-C10alkoxy,s 4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, CH3OC(O)CH2-, 4-HOCH2-phenyl, 2,4,6-trifluoC10alkoxy, phenyl, optionally substituted with C1-C10alkyl aryloxy, selected from phenoxy, naphthyloogether with >CH and >C=X does not form 2,3-dihydro-1-(N,N-diethylamino-CH2CH2-)-5-(2-pyridil)-1H-1,y substituted with C6-C10aryl tetrazole, optionally substituted with C1-C10alkyl benzofuranyl, indanyl, indolyl, benzothienyl and pyrrolidinyl; W toget form 2,3-dihydro-1-(N,N-diethylamino-CH2CH2)-5-(cloalkenyl with 1-2 double bonds or heteroaryl or heterocyclyl, having from 2 to 8 carbon atoms in the ring and from 1 to 3 heteroatoms in the ring independently selected from oxygen, sulfur and nitrorm saturated or unsaturated azetidinyl. 24. The cos optionally substituted with 1-3 substituents, inla I m is 0, R<1> is aryl or heteroaryl, mentioned substituted with 1-3 substituents, independently selected from C1-C10alkoxy, halo, C3-C12cycloalkyl, C2-C7alkanoyl [i.e. C2-C7alkylC(O)], C1-C10alkoxycarbonyl, C6-C10arylcarbonyl, morpholinylcarbonyll, C1-C10alkoxy, halo, hydrogen, nitro, trihalometyl or C6-C10aryloxy, optionally substituted with om the group, comprising hydrogen, nitro, halo, trihalomethyl and C1-C10alkoxy, with proviso, that when R is hydrogen, then R and R' are both m 1 to 3 heteroatoms, independently selected from m hydrogen; (c) 2-naphthyl; (d) heteroaryl, selected from furazanyl, benzofuranyl, thienyl, tetrazol from C1-C10alkyl, halo and trifluoromethyl; C6-C1; (e) tetrazole, substituted with C6-C10aryl, benzs; alkoxyalkoxy, having 2-6 carbon atoms; heteroarso, that said substituents are not in ortho-position heteroaryl wiring point to -NH group; wherein wntly selected from sulfur and nitrogen; and whereihe group, comprising mono-, di- and trisubstitutedyclic groups optionally condensed with forming dou