Compounds, compositions and methods for modulating beta-amyloid production

A method of treatment comprising modulating the production and/or release of β-amyloid in a non-human mammal in need of said treatment, said method comprising administering to said non-human mammal a compound of the formula (1)

• 80
• wherein, independently at each occurrence,
• W is selected from the group consisting of —OR4, —N(R5)2 and —NHN(R5)2;
• R2 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —NHOH, —OR7, —SR7, —C(O)OR7, —OC(O)R7, —C(O)N(R6)2, —C(S)R6, —C(O)R6, —N(R6)2, —N(R6)C(O)R6, —N(R6)C(O)OR7, —S(O)tR6 (where t is 0 to 2), —S(O)tN(R6)2 (where t is 0 to 2), —OC(S)NR6, —NR6C(S)OR7, —NR6S(O)tR6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
• R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —NHOH, —OR7, —SR7, —C(O)OR7, —OC(O)R7, —C(O)N(R6)2, —C(S)R6, —C(O)R6, —N(R6)2, —N(R6)C(O)R6, —N(R6)C(O)OR7, —OC(S)NR6, —NR6C(S)OR7, —OR7, —C(O)OR7, —OC(O)R7, —C(O)N(R6)2, heterocyclyl and heterocyclylalkyl;
• R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, heterocyclyl and heterocyclylalkyl;
• R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, heterocyclyl and heterocyclylalkyl;
• R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl;
• and
• R7 is selected from the group consisting of hydrogen, alkyl and aralkyl;
• Y is selected from the group consisting of an aryl radical of 6 to 10 carbon atoms,
• 81
• wherein
• R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —NHOH, —OR7, —SR7, —C(O)OR7, —OC(O)R7, —C(O)N(R6)2, —C(S)R6, —C(O)R6, —N(R6)2, —N(R6)C(O)R6, —N(R6)C(O)OR7, —S(O)tR6 (where t is 0 to 2), —S(O)tN(R6)2 (where t is 0 to 2), —OC(S)NR6, —NR6C(S)OR7, —NR6S(O)tR6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
• R18 is hydrogen or lower alkyl radical;
• R19 is hydrogen, H2N—,
• 82
• phenyl, (lower)alkoxyphenyl, or di(lower)alkoxy-phenyl, providing that when R18 is hydrogen and R19 is hydrogen, phenyl, (lower)alkoxyphenyl or di(lower)alkoxyphenyl, R16 is halo or lower alkoxy,
• m is 0, 1, 2, 3, 4 or 5;
• n is 0, 1 or 2;
• p is 0, 1, 2, 3, 4 or 5;
• q is 0, 1 or 2;
• E is selected from the group consisting of
• 83
• and
• 84
• wherein
• R23 is hydrogen or lower alkyl,
• R24 is hydrogen or alkyl, and
• r is 0, 1, 2 or 3;
• as a single stereoisomer, a mixture of stereoisomers, as a racemic mixture of stereoisomers;
• as a solvate, as a polymorph;
• or as a pharmaceutically acceptable salt thereof.

A method of treatment wherein the production and/or release of β-amyloid is modulated in a human in need of said treatment, said method comprising administering to said human a compound of formula (1)

• 89
• wherein, independently at each occurrence,
• W is selected from the group consisting of −OR4, —N(R5)2 and —NHN(R5)2;
• R2 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —NHOH, —OR7, —SR7, —C(O)OR7, —OC(O)R7, —C(O)N(R6)2, —C(S)R6, —C(O)R6, —N(R6)2, —N(R6) C(O)R6, —N(R6)C(O)OR7, —S(O)tR6 (where t is 0 to 2), —S(O)tN(R6)2 (where t is 0 to 2), —OC(S)NR6, —NR6C(S)OR7, —NR6S(O)tR6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
• R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —NHOH, —OR7, —SR7, —C(O)OR7, —OC(O)R7, —C(O)N(R6)2, —C(S)R6, —C(O)R6, —N(R6)2, —N(R6)C(O)R6, —N(R6)C(O)OR7, —OC(S)NR6, —NR6C(S)OR7, —OR7, —C(O)OR7, —OC(O)R7, —C(O)N(R6)2, heterocyclyl and heterocyclylalkyl;
• R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, heterocyclyl and heterocyclylalkyl;
• R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, heterocyclyl and heterocyclylalkyl;
• R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl;
• and
• R7 is selected from the group consisting of hydrogen, alkyl and aralkyl;
• Y is selected from the group consisting of an aryl radical of 6 to 10 carbon atoms,
• 90
• wherein
• R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —NHOH, —OR7, —SR7, —C(O)OR7, —OC(O)R7, —C(O)N(R6)2, —C(S)R6, —C(O)R6, —N(R6)2, —N(R6)C(O)R6, —N(R6)C(O)OR7, —S(O)tR6 (where t is 0 to 2), —S(O)tN(R6)2 (where t is 0 to 2), —OC(S)NR6, —NR6C(S)OR7, —NR6S(O)tR6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
• R18 is hydrogen or lower alkyl radical;
• R19 is hydrogen, H2N—,
• 91
• phenyl, (lower)alkoxyphenyl, or di(lower)alkoxy-phenyl, providing that when R18 is hydrogen and R19 is hydrogen, phenyl, (lower)alkoxyphenyl or di(lower)alkoxyphenyl, R16 is halo or lower alkoxy,
• m is 0, 1, 2, 3, 4 or 5;
• n is 0, 1 or 2;
• p is 0, 1, 2, 3, 4 or 5;
• q is 0, 1 or 2;
• E is selected from the group consisting of
• 92
• and
• 93
• wherein
• R23 is hydrogen or lower alkyl,
• R24 is hydrogen or alkyl, and
• r is 0, 1, 2 or 3;
• as a single stereoisomer, a mixture of stereoisomers, as a racemic mixture of stereoisomers;
• as a solvate, as a polymorph;
• or as a pharmaceutically acceptable salt thereof.

A method for modulating the production and/or release of β-amyloid in a cell, comprising treating said cell with a compound of the formula (2)

• 98
• wherein,
• R1b is selected from the group consisting of C1-C3 alkyl, hydrogen, metal cation and ammonium cation;
• R13b and R14b are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, haloalkyl, haloalkenyl, —OR12b, —C(O)OR12b, —N(R12b)2, —C(O)N(R12b)2, —N(R12b)C(O)OR12b, heterocyclyl and heterocyclylalkyl;
• R12b is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;
• and
• w is 1, 2 or 3.

A method of treatment comprising modulating the production and/or release of β-amyloid in a non-human mammal in need of said treatment, said method comprising administering to said non-human mammal a compound of the formula (2)

• 99
• wherein,
• R1b is selected from the group consisting of C1-C3 alkyl, hydrogen, metal cation and ammonium cation;
• R13b and R14b are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, haloalkyl, haloalkenyl, —OR12b, —C(O)OR12b, —N(R12b)2, —C(O)N(R12b)2, —N(R12b)C(O)OR2b, heterocyclyl and heterocyclylalkyl;
• R12b is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;
• and
• w is 1, 2 or 3.

A method of treatment comprising modulating the production and/or release of β-amyloid in a human in need of said treatment, said method comprising administering to said human a compound of the formula (2)

• 100
• wherein,
• R1b is selected from the group consisting of C1-C3 alkyl, hydrogen, metal cation and ammonium cation;
• R13b and R14b are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, haloalkyl, haloalkenyl, —OR12b, —C(O)OR12b, —N(R12b)2, —C(O)N(R12b)2, —N(R12b)C(O)OR2b, heterocyclyl and heterocyclylalkyl;
• R12b is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;
• and
• w is 1, 2 or 3.

A compound of the formula (1c)

• 101
• wherein, independently at each occurrence,
• R1a is an organic moiety having at least 4 carbons;
• Z is selected from —O—, —NH—NH—, and —N(R2a)—;
• R2a is selected from hydrogen and C1-C30 organic moieties with the proviso that R1a and R2a can join together with the nitrogen to which they are both attached and form a heterocyclic moiety;
• R3a and R4a are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy radicals;
• R5a, R6a, R7a, R8a and R9a are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, —R10a—N═N—O—R11a, —OR12a, —C(O)OR12a, —N(R12a)2, —C(O)N(R12a)2, —N(R12a)C(O)OR11a, heterocyclyl and heterocyclylalkyl;
• R10a is a bond or a straight or branched alkylene or alkenylene chain;
• R11a is hydrogen, alkyl or aralkyl;
• and
• R12a is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;
• with the proviso that Z is not NR2a when R3a is Cl, R4a is H, R5a is H, R6a is H, R7a is H, R8a is methyl and R9a is methyl.

A compound of the formula (1d)

• 102
• wherein,
• R1a is a hydrophobic moiety selected from non-aromatic organic moieties having at least 10 carbon atoms and aromatic moieties having at least 6 carbons, and R2a is hydrogen;
• or
• each of R1a and R2a is selected from hydrophobic organic moieties having at least one carbon atom, with the proviso that R1a and R2a in total have at least six carbon atoms, and with the further proviso that R1a and R2a can join together with the nitrogen to which they are both bonded and form a heterocyclic moiety.