US 6,888,022 B2 · Methods and 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 pharmaceutical compositions comprising a compound which inhibits β-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

A method for inhibiting β-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds effective in inhibiting the cellular release and/or synthesis of β-amyloid peptide wherein said compounds are represented by the formula I:

wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
each R3 is independently selected from the group consisting of hydrogen and methyl and R3 together with R4 can be used to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an optionally substituted aryl or optionally substituted heteroaryl group;
each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted 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) optionally substituted aryl,
(g) optionally substituted heteroaryl,
(h) optionally substituted heterocyclic,
(i)—NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkynyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 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, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic,
(k)—NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic,
(l)—ONR9(C(O)O)2R10 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, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted 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, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted 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 R′ 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 OC(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 —CHOHφor —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;
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;
P. when n is 2, R1 is —CH2C(O)CH3, R2 is —CH2)2 COOH, the first R4 is isopropyl and the second R4 is —(CH2)4NH2, X′,X″, and each R3 and each R5 are hydrogen and Z is a bond, then X is not —C(O)CH2)2(C(O)CF)CH2phenyl;
R. when n is 2, R1 is n—C17H35, Z is a bond, R2 is —CH2OH, the first R4 is —(CH2)2 COOH, the second R4 is isopropyl and X′, X″ and each R3 and each R5 are hydrogen then X is not —C(O)NHCH(—(CH2)4NH2)C(O)NH-CH(benzyl)CH2 Cl;
S. when n is 1, R1 is —(CH2)6 COOH, R2 is isopropyl, R4 is —(CH2)4NH2 and X′, X″, R3 and R5 are hydrogen and Z is a bond, the X is not —C(O)NHCH(benzyl) C(O) CH2 Cl;
T. when n is 2, R1 is —(CH2)3COOH, R2 is propyl, the first R4 is —(CH2)3 NH2, the second R4 is benzyl and X′, X″ and each R3 and each R5 are hydrogen and Z is a bond, then X is not acetyl;
U. when n is 2, R1 is —CH2C(O)OCH3, Z is a bond, R2 is —(CH2)3NH2 and X′, X″ each R3 and each R5 are hydrogen then X is not —C(O)NHCH(benzyl)C(O) CF3;
V. when n is 1, R1 is —CH(isopropyl) CH2COOH, Z is a bond, R2 is —(CH2)3NH2, R4 is benzyl, X′, X″, R3 and R5 are hydrogen, and Z is a bond, then X is not —C(O)CH2Cl;
W. when Z is a bond, or —O—, R1 is alkyl or substituted alkyl and X is —CR6R6 then Y is not hydroxy;
X. when Z is a bond or —O—, X′ and X″ are hydrogen and X is —C(O)Y, then Y is not haloalkyl, heterocyclic, heterocyclicmethylene-, alkoxymethylene-, phenoxymethylene-, benzyloxymethylene-, phenoxymethylene-, thioalkoxymethylene-, thiophenoxymethylene-, thiobenzyloxymethylene-, plienthioethoxylmethylene-, —NR′R″ wherein R′ and R″ are independently hydrogen, alkyl, phenyl, benzyl or phenethyl, or substituted alkyl having a terminal diazo, amino, substituted amino or —C(O) alkyl ORa substituent wherein Ra is hydrogen, alkyl, phenyl, benzyl or phenethyl;
and
Y. when Z is a bond or —O—, X′ and X″ are each hydrogen, X is —CR6R6Y′ wherein Y′ is hydroxy and one of R6 is hydrogen then the other R6 is not substituted alkyl having a terminal —C(O)ORa or —C(O)NRa Rb subsuituent wherein Ra and Rb are independently H, alkyl, phenyl, benzyl or phenethyl.

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

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

Life of this patent

Abstract

Claims71