US 6,207,710 B1 · Compounds for inhibiting β-amyloid peptide release and/or its synthesis

Abstract

Disclosed are compounds which inhibit β-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits β-amyloid peptide release and/or its synthesis.

A compound represented by formula:

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 alkynyl, 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, phthalimido, —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;
and
n is an integer equal to 1 or 2;
with the proviso 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;
with the further proviso that the compounds of formulas I-IV below are excluded:
wherein R1 is selected from the group consisting of:
(a) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and heteroaryl,
(b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and heteroaryl,
(c) cycloalkenyl,
(d) substituted alkyl provided that the substituent is not aryl and/or heteroaryl groups,
(e) substituted alkenyl provided that the substituent is not aralkenyl or heteroaralkenyl,
(f) substituted alkynyl provided that the substituent is not aralkynyl or heteroaralkynyl, and
(h) heterocyclic;
R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
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 —C(O)Y or —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, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 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 carboxyalkyl 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, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, phthalimido, —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, and
n is an integer equal to 1 or 2;
with the proviso excluding the following known compound:
when R1 is o-fluorophenyl, R2 is 3,4-dichlorophenyl or ethyl, R4 and R5 are hydrogen, X′ and X″ are hydrogen, then X is not —C(O)OCH3;
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
(a) substituted alkyl provided that such substituted alkyl groups do not include aryl or heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,
(b) substituted alkenyl provided that such substituted alkenyl groups do not include aryl or heteroaryl substituted alkenyl,
(c) substituted alkynyl provided that such substituted alkynyl groups do not include aryl or heteroaryl substituted alkynyl,
(d) heterocyclic,
(e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, and heteroaryl, and
(f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;
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 —C(O)Y or —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, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 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 carboxyalkyl 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, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, —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, and
n is an integer equal to 1 or 2;
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 alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl provided that at least one R4 is selected to be:
(a) substituted alkyl provided that such substituted alkyl groups do not include aryl or heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,
(b) substituted alkenyl provided that such substituted alkenyl groups do not include aryl or heteroaryl substituted alkenyl,
(c) substituted alkynyl provided that such substituted alkynyl groups do not include aryl or heteroaryl substituted alkynyl,
(d) heterocyclic,
(e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, and heteroaryl, and
(f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;
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 —C(O)Y or —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, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 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 carboxyalkyl 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, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, —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, and
n is an integer equal to 1 or 2;
and
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 alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
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
(a) —C(O)-alkyl,
(b) —C(O)-substituted alkoxy or substituted thioalkoxy provided that the substituted alkoxy groups do not include benzyl and phenethyl,
(c) —C(O)-aryl wherein the aryl group is substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl,
(d) —C(O)-heteroaryl wherein the heteroaryl group is substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy
(e) —C(O)—NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, substituted alkyl, 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 or alkoxy groups, and
X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′ is selected from the group consisting of amino, thiol, alkoxy, phthalimido, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
provided that R′ and R″ are not both independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl;
X′ is hydrogen, hydroxy or fluoro;
X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
n is an integer equal to 1 or 2;
with the proviso that:
when R1 is iso-propyl, R2 is phenyl, R4 is methyl, R5 is hydrogen, X′ and X″ are hydrogen, n is 2, and the second R4 at the carboxy terminus is methyl, then X is not —C(O)NH-pNO2-φ.

143 more elements

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

Life of this patent

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

Life of this patent

Abstract

Claims8