Amino acid derivatives useful for the treatment of alzheimer's disease

A method of treating a subject who has, or in preventing a subject from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating subjects with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, frontotemporal dementias with parkinsonism (FTDP), dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which includes administration of a therapeutically effective amount of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof:

• and when the compound of formula Ia comprises an amino group or pharmaceutically acceptable ammonium salts thereof,
• wherein W is selected from the group consisting of —(CH2)n—, and —CH2—XX—CH2—CH2—
• wherein n is 1, 2, 3, 4 or 5
• wherein XX is selected from the group consisting of 0, NR5, S, SO and SO2
• wherein Cx is selected from the group consisting of —COOM, —COOR5, —CH2 OH, —CONR5R6, —CONHOH, 9-fluorenylmethoxycarbonyl-lysyl-NH—CO—, benzyloxycarbonyl, and tetrazolyl,
• wherein M is an alkali metal or an alkaline earth metal,
• wherein R1 and R3, the same or different, are selected from the group consisting of H, tert-butoxycarbonyl, a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 7 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an arylalkyl group of formula (2)
• and a heterocycle-alkyl group of formula heterocycle-(CH2)m— wherein R2 and R4 the same or different are selected (i.e. independently) from the group consisting of H, CHO—, CF3—, CH3CO—, benzoyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 4-OH-7-CF3-quinoline-3-CO—, 3-indole-CH2CH2CO—, 3-indole-CH2CO—, 3-indole-CO—, 2-indole-CO—, C6H5OCH2CO—, (C6H5)2COHCO—, C6H5SCH2CO—, C6HCH2CH2CS—, cholesteryl-OCO—, 2-quinoline-CO—, xanthene-9-CO—, 4-C6H5CH2CH2CONHC6H4SO2—, 2-NO2C6H4CHCHCO—, 3-C5H4NCHCHCO—, 3-C5H4NCH2CH2CO—, fluorene-CH2CO—, camphor-10-CH2—SO2—, (C6H5)2CH—CO—, fluorene-CO—, 1-naphthyl-SO2—, 2-naphthyl-SO2—, fluorenyl-SO2—, phenanthryl-SO2—, anthracenyl-SO2—, quinoline-SO2—, 4-CH3COONHC6H4—SO2—, C6H5CHCH—SO2—, 4-NO2C6H4—SO2—, an aryalkyl group of formula (2) as defined above, a sulfonyl group of formula (3)
• a heterocycle-alkylsulfonyl group of formula heterocycle-(CH2)m—SO2— and a carbonyl group of formula (4)
• wherein T is selected from the group consisting of —(CH2)mm—, —CH═CH—, and —CH2—CH═CH—;
• wherein D is selected from the group consisting of O, NR7 and S,
• wherein m is 1, 2, 3 or 4;
• wherein mm is 0, 1, 2, 3 or 4;
• wherein X, Y and Z, the same or different, are selected (i.e. independently) from the group consisting of H, a straight or branched alkyl group of 1 to 6 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NH2 —NHR5, —NR5R6, —NHCOR5, —NHCOheterocycle, heterocycle being as defined above, —OR5, —SR5, —SOR5, —SO2R5, —COOR5, —CH2OH, —COR5, and —NHCOAryl, Aryl being an unsubstituted phenyl group or a phenyl group substituted by one or more members of the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NH2 —NHR5, —NR5R6, —NHCOR5—OR5, —SR5, —SOR5, —SO2R5, —COOR5, —CH2OH, —COR5, wherein R5 and R6, are independently selected from the group consisting of H, and a straight or branched alkyl group of 1 to 6 carbon atoms wherein R7 is selected from the group consisting of HO—, CH3O—, NC—, benzyloxy, and H2N— and wherein heterocycle is selected from the group consisting of heterocyclic groups comprising 5 to 7 ring atoms, said ring atoms comprising carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic groups being monocycylic, bicycylic or monocycylic fused with one or two benzene rings.

A method for inhibiting beta-secretase activity, comprising contacting an effective amount for inhibition of a compound of formula Ia:

• and when the compound of formula Ia comprises an amino group or pharmaceutically acceptable ammonium salts thereof,
• wherein W is selected from the group consisting of —(CH2)n—, and —CH2—XX—CH2—CH2—
• wherein n is 1, 2, 3, 4 or 5
• wherein XX is selected from the group consisting of 0, NR5, S, SO and SO2
• wherein Cx is selected from the group consisting of —COOM, —COOR5, —CH2OH, —CONR5R6, —CONHOH, 9-fluorenylmethoxycarbonyl-lysyl-NH—CO—, benzyloxycarbonyl, and tetrazolyl,
• wherein M is an alkali metal or an alkaline earth metal,
• wherein R1 and R3, the same or different, are selected from the group consisting of H, tert-butoxycarbonyl, a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 7 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an arylalkyl group of formula (2)
• and a heterocycle-alkyl group of formula heterocycle-(CH2)m— wherein R2 and R4 the same or different are selected (i.e. independently) from the group consisting of H, CHO—, CF3—, CH3CO—, benzoyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 4-OH-7-CF3-quinoline-3-CO—, 3-indole-CH2CH2CO—, 3-indole-CH2CO—, 3-indole-CO—, 2-indole-CO—, C6H5OCH2CO—, (C6H5)2COHCO—, C6H5SCH2CO—, C6HCH2CH2CS—, cholesteryl-OCO—, 2-quinoline-CO—, xanthene-9-CO—, 4-C6H5CH2CH2CONHC6H4SO2—, 2—NO2C6H4CHCHCO—, 3-C5H4NCHCHCO—, 3-C5H4NCH2CH2CO—, fluorene-CH2CO—, camphor-10-CH2—SO2—, (C6H5)2CH—CO—, fluorene-CO—, 1-naphthyl-SO2—, 2-naphthyl-SO2—, fluorenyl-SO2—, phenanthryl-SO2—, anthracenyl-SO2—, quinoline-SO2—, 4—CH3COONHC6H4—SO2—, C6H5CHCH—SO2—, 4—NO2C6H4—SO2—, an aryalkyl group of formula (2) as defined above, a sulfonyl group of formula (3)
• a heterocycle-alkylsulfonyl group of formula heterocycle-(CH2)m—SO2— and a carbonyl group of formula (4)
• wherein T is selected from the group consisting of —(CH2)mm—, —CH═CH—, and —CH2—CH═CH—;
• wherein D is selected from the group consisting of O, NR7 and S,
• wherein m is 1, 2, 3 or 4;
• wherein mm is 0, 1, 2, 3 or 4;
• wherein X, Y and Z, the same or different, are selected (i.e. independently) from the group consisting of H, a straight or branched alkyl group of 1 to 6 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NH2—NHR5, —NR5R6, —NHCOR5, —NHCOheterocycle, heterocycle being as defined above, —OR5, —SR5, —SOR5, —SO2R5, —COOR5, —CH2OH, —COR5, and —NHCOAryl, Aryl being an unsubstituted phenyl group or a phenyl group substituted by one or more members of the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NH2 —NHR5, —NR5R6, —NHCOR5—OR5, —SR5, —SOR5, —SO2R5, —COOR5, —CH2OH, —COR5, wherein R5 and R6, are independently selected from the group consisting of H, and a straight or branched alkyl group of 1 to 6 carbon atoms wherein R7 is selected from the group consisting of HO—, CH3O—, NC—, benzyloxy, and H2N— and wherein heterocycle is selected from the group consisting of heterocyclic groups comprising 5 to 7 ring atoms, said ring atoms comprising carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic groups being monocycylic, bicycylic or monocycylic fused with one or two benzene rings.

A method for inhibiting production of amyloid beta peptide (A beta) in a cell, comprising administering to said cell an effective inhibitory amount of a compound of formula Ia:

• and when the compound of formula Ia comprises an amino group or pharmaceutically acceptable ammonium salts thereof,
• wherein W is selected from the group consisting of —(CH2)n—, and —CH2—XX—CH2—CH2—
• wherein n is 1, 2, 3, 4 or 5
• wherein XX is selected from the group consisting of O, NR5, S, SO and SO2
• wherein Cx is selected from the group consisting of —COOM, —COOR5, —CH2OH, —CONR5R6, —CONHOH, 9-fluorenylmethoxycarbonyl-lysyl-NH—CO—, benzyloxycarbonyl, and tetrazolyl,
• wherein M is an alkali metal or an alkaline earth metal,
• wherein R1 and R3, the same or different, are selected from the group consisting of H, tert-butoxycarbonyl, a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 7 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an arylalkyl group of formula (2)
• and a heterocycle-alkyl group of formula heterocycle-(CH2)m— wherein R2 and R4 the same or different are selected (i.e. independently) from the group consisting of H, CHO—, CF3—, CH3CO—, benzoyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 4-OH-7-CF3-quinoline-3-CO—, 3-indole-CH2CH2CO—, 3-indole-CH2CO—, 3-indole-CO—, 2-indole-CO—, C6H5OCH2CO—, (C6H5)2COHCO—, C6H5SCH2CO—, C6HCH2CH2CS—, cholesteryl-OCO—, 2-quinoline-CO—, xanthene-9-CO—, 4-C6H5CH2CH2CONHC6H4SO2—, 2—NO2C6H4CHCHCO—, 3-C5H4NCHCHCO—, 3-C5H4NCH2CH2CO—, fluorene-CH2CO—, camphor-10-CH2—SO2—, (C6H5)2CH—CO—, fluorene-CO—, 1-naphthyl-SO2—, 2-naphthyl-SO2—, fluorenyl-SO2—, phenanthryl-SO2—, anthracenyl-SO2—, quinoline-SO2—, 4-CH3COONHC6H4—SO2—, C6H5CHCH—SO2—, 4-NO2C6H4—SO2—, an aryalkyl group of formula (2) as defined above, a sulfonyl group of formula (3)
• a heterocycle-alkylsulfonyl group of formula heterocycle-(CH2)m—SO2— and a carbonyl group of formula (4)
• wherein T is selected from the group consisting of —(CH2)mm—, —CH═CH—, and —CH2—CH═CH—;
• wherein D is selected from the group consisting of O, NR7 and S,
• wherein m is 1, 2, 3 or 4;
• wherein mm is 0, 1, 2, 3 or 4;
• wherein X, Y and Z, the same or different, are selected (i.e. independently) from the group consisting of H, a straight or branched alkyl group of 1 to 6 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NH2 —NHR5, —NR5R6, —NHCOR5, —NHCOheterocycle, heterocycle being as defined above, —OR5, —SR5, —SOR5, —SO2R5, —COOR5, —CH2OH, —COR5, and —NHCOAryl, Aryl being an unsubstituted phenyl group or a phenyl group substituted by one or more members of the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NH2—NHR5, —NR5R6, —NHCOR5—OR5, —SR5, —SOR5, —SO2R5, —COOR5, —CH2OH, —COR5, wherein R5 and R6, are independently selected from the group consisting of H, and a straight or branched alkyl group of 1 to 6 carbon atoms wherein R7 is selected from the group consisting of HO—, CH3O—, NC—, benzyloxy, and H2N— and wherein heterocycle is selected from the group consisting of heterocyclic groups comprising 5 to 7 ring atoms, said ring atoms comprising carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic groups being monocycylic, bicycylic or monocycylic fused with one or two benzene rings.