Methods and compounds for inhibiting β-amyloid peptide release and/or its synthesis

A method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:

• wherein R′ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
• R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
• each R3 is independently selected from the group consisting of hydrogen and methyl and R3 together with R4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group;
• each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is selected from the group consisting of —C(O)Y and —C(S)Y where Y is selected from the group consisting of
• (a) alkyl or cycloalkyl,
• (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include α-haloalkyl, α-diazoalkyl, α-OC(O)alkyl, or α-OC(O)aryl groups,
• (c) alkoxy or thioalkoxy,
• (d) substituted alkoxy or substituted thioalkoxy,
• (e) hydroxy,
• (f) aryl,
• (g) heteroaryl,
• (h) heterocyclic,
• (i) —NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups,
• (j) —NHSO2—R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
• (k) —NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and
• (l) —ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
• X′ is hydrogen, hydroxy, or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group,
• Z is selected from the group consisting of a bond covalently linking R1 to —CX′X″—, oxygen and sulfur;
• n is an integer equal to 1 or 2;
• and
• pharmaceutically acceptable salts thereof
• with the provisos that:
• A. when R′ is phenyl or 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is —CH(OH)CH3, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)OH;
• B. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is —CH(OH)CH3 derived from D-threonine, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)OH or —C(O)OCH3;
• C. when R1 is phenyl, R2 is methyl, R4 is benzyl, R5 is hydrogen, X is methoxycarbonyl, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R3 is not methyl;
• D. when R1 is iso-propyl, R2 is —CH2C(O)NH2, R3 is hydrogen, R4 is iso-butyl, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)OCH3;
• E. when R1 is phenyl, R2 is methyl, R5 is hydrogen, X is —C(O)OCH3, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R3, the nitrogen atom attached to R3, and R4 do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl;
• F. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is —C(O)OCH3, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-n-butyl;
• G. when R1 is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is —CH(OH)CH3, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)NH2 or —CH2OH;
• H. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is —CH2OCH3, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R4 is not benzyl or ethyl;
• I. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —CHOHφ;
• J. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —CHOHφ or —CH2OH;
• K. when R1 is N-(2-pyrrolidinonyl), R2 is methyl, R3 is hydrogen, R4 is benzyl, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)OCH3;
• L. when R1 is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)NH-benzyl;
• M. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —CH2OH;
• N. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is 4-phenylphenyl, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)NHC(CH)3;
• and
• O. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)NHCH(CH3)φ.

A method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:

• wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
• R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
• each R3 is independently selected from the group consisting of hydrogen and methyl and R3 together with R4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group;
• each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is selected from the group consisting of —C(O)Y and —C(S)Y where Y is selected from the group consisting of
• (a) alkyl or cycloalkyl,
• (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include α-haloalkyl, α-diazoalkyl, α-OC(O)alkyl, or α-OC(O)aryl groups,
• (c) alkoxy or thioalkoxy,
• (d) substituted alkoxy or substituted thioalkoxy,
• (e) hydroxy,
• (f) aryl,
• (g) heteroaryl,
• (h) heterocyclic,
• (i) —NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups,
• (j) —NHSO2—R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
• (k) —NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and
• (l) —ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
• X′ is hydrogen, hydroxy, or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group,
• Z is selected from the group consisting of a bond covalently linking R1 to —CX′X″—, oxygen and sulfur;
• n is an integer equal to 1 or 2;
• and
• pharmaceutically acceptable salts thereof
• with the provisos that:
• A. when R1 is phenyl or 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is —CH(OH)CH3, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)OH;
• B. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is —CH(OH)CH3 derived from D-threonine, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)OH or —C(O)OCH3;
• C. when R1 is phenyl, R2 is methyl, R4 is benzyl, R5 is hydrogen, X is methoxycarbonyl, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R3 is not methyl;
• D. when R1 is iso-propyl, R2 is —CH2C(O)NH2, R3 is hydrogen, R4 is iso-butyl, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)OCH3;
• E. when R1 is phenyl, R2 is methyl, R5 is hydrogen, X is —C(O)OCH3, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R3, the nitrogen atom attached to R3, and R4 do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl;
• F. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is —C(O)OCH3, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-n-butyl;
• G. when R1 is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is —CH(OH)CH3, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)NH2 or —CH2OH;
• H. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is —CH2OCH3, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R4 is not benzyl or ethyl;
• I. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —CHOHφ;
• J. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —CHOHφ or —CH2OH;
• K. when R1 is N-(2-pyrrolidinonyl), R2 is methyl, R3 is hydrogen, R4 is benzyl, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)OCH3;
• L. when R1 is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)NH-benzyl;
• M. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —CH2OH;
• N. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is 4-phenylphenyl, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)NHC(CH3)3;
• and
• O. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)NHCH(CH3)φ.