US 8,008,315 B2Granted

Benzylether and benzylamino beta-secretase inhibitors for the treatment of alzheimer's disease

AssigneeMerck Sharp & Dohme Corp.

InventorsPhilippe G. Nantermet, Hemaka Anthony Rajapakse, Harold G. Selnick

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Abstract

The present invention is directed to compounds which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

Claims20

Dependent claims

A compound of formula (I):

wherein:
X is O or NH;
Y is N;
R1 is (1) aryl selected from the group consisting of phenyl and napthyl, or
(2) heterocyclyl selected from the group consisting of piperazinyl, piperidinyl, pyrrolidinyl, pyrazinyl, dihydropyrazinyl, pyrazolyl, dihydropyrazolyl, pyridazinyl, pyridyl, dihydropyridinyl, pyrimidinyl, dihydropyrimidinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, dihydrotetrazolyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, triazinyl, pyranyl, tetrahydropyranyl, thiazolyl, thienyl, dihydrothienyl, thiophenyl, triazolyl, dihydrotriazolyl, morpholinyl, thiomorpholinyl, dihydrothiadiazolyl, tetrahydrothienyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl,
wherein said aryl or heterocyclyl is unsubstituted or substituted with one or more
(a) halo,
(b) —C 1-6alkyl,
(c) —C2-6 alkenyl,
(d) —C2-6 alkynyl,
(e) —OH,
(f) —CN, or
(g) —O—C 1-6alkyl;
R2 is selected from the group consisting of:
(1) R4—S(O)2N(R7)—, wherein R4 is C1-6alkyl, wherein said alkyl is unsubstituted or substituted with one or more
(a) halo,
(b) —C2-6alkynyl,
(c) —OH,
(d) —CN, or
(e) —O—C1-6alkyl;
and
R7 is selected from the group consisting of
(a) hydrogen, and
(b) —C1-6alkyl,
wherein said alkyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —C1-6alkyl,
(iii) —OH,
(iv) —CN, or
(v) —O—C1-6alkyl;
R3 is selected from the group consisting of:
wherein R5 is C1-6alkyl, C2-6 alkenyl or C2-6 alkynyl;
R6a, R6b, and R6c are independently selected from the group consisting of:
(1) hydrogen,
(2) halo,
(3) —C1-6alkyl,
(4) —C2-6 alkenyl,
(5) —C2-6 alkynyl,
(6) —OH,
(7) —CN, and
(8) —O—C1-6alkyl;
R9 and R10 are independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-6alkyl,
(3) —C2-6 alkenyl, and
(4) —C2-6 alkynyl,
or R9 and R10 are joined together with the nitrogen atom to which they are attached to form a pyrrolidine ring, which is optionally substituted with
(a) C1-6alkyl,
(b) —C2-6 alkenyl,
(c) —C2-6 alkynyl,
(d) (CH2)n-phenyl, and
(e) (CH2)n-furanyl;
wherein said alkyl, phenyl and furanyl are unsubstituted or substituted with one or more
i) halo,
ii) —C1-6alkyl,
iii) —OH,
iv) —CN, or
v) —O—C1-6alkyl;
and
R11 is selected from the group consisting of
(1) —CH—,
(2) —O—, and
(3) —NH—,
provided that when R11 is —CH— the dotted line forms a bond and when R11 is —O— or —NH— the dotted line is absent;
R12 is hydrogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
m is 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
and pharmaceutically acceptable salts thereof.

66 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/772,711Filed 3 May 2010 · division
Priority: 23 Mar 2006
Published: US 2010/0210693 A119 Aug 2010
Granted: 30 Aug 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 213/81
Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals: amides; Imides
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07C 255/57
Having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton: containing cyano groups and carboxyl groups, other…

Family

Application10/573,232Parent of this division · filed 23 Mar 2006
US 2010/0210693 A1Pre-grant publication · published 19 Aug 2010
US 7,829,597 B2Parent of this division
US 2006/0293380 A1Published application
US 8,008,315 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I):

wherein:
X is O or NH;
Y is N;
R1 is (1) aryl selected from the group consisting of phenyl and napthyl, or
(2) heterocyclyl selected from the group consisting of piperazinyl, piperidinyl, pyrrolidinyl, pyrazinyl, dihydropyrazinyl, pyrazolyl, dihydropyrazolyl, pyridazinyl, pyridyl, dihydropyridinyl, pyrimidinyl, dihydropyrimidinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, dihydrotetrazolyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, triazinyl, pyranyl, tetrahydropyranyl, thiazolyl, thienyl, dihydrothienyl, thiophenyl, triazolyl, dihydrotriazolyl, morpholinyl, thiomorpholinyl, dihydrothiadiazolyl, tetrahydrothienyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl,
wherein said aryl or heterocyclyl is unsubstituted or substituted with one or more
(a) halo,
(b) —C 1-6alkyl,
(c) —C2-6 alkenyl,
(d) —C2-6 alkynyl,
(e) —OH,
(f) —CN, or
(g) —O—C 1-6alkyl;
R2 is selected from the group consisting of:
(1) R4—S(O)2N(R7)—, wherein R4 is C1-6alkyl, wherein said alkyl is unsubstituted or substituted with one or more
(a) halo,
(b) —C2-6alkynyl,
(c) —OH,
(d) —CN, or
(e) —O—C1-6alkyl;
and
R7 is selected from the group consisting of
(a) hydrogen, and
(b) —C1-6alkyl,
wherein said alkyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —C1-6alkyl,
(iii) —OH,
(iv) —CN, or
(v) —O—C1-6alkyl;
R3 is selected from the group consisting of:
wherein R5 is C1-6alkyl, C2-6 alkenyl or C2-6 alkynyl;
R6a, R6b, and R6c are independently selected from the group consisting of:
(1) hydrogen,
(2) halo,
(3) —C1-6alkyl,
(4) —C2-6 alkenyl,
(5) —C2-6 alkynyl,
(6) —OH,
(7) —CN, and
(8) —O—C1-6alkyl;
R9 and R10 are independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-6alkyl,
(3) —C2-6 alkenyl, and
(4) —C2-6 alkynyl,
or R9 and R10 are joined together with the nitrogen atom to which they are attached to form a pyrrolidine ring, which is optionally substituted with
(a) C1-6alkyl,
(b) —C2-6 alkenyl,
(c) —C2-6 alkynyl,
(d) (CH2)n-phenyl, and
(e) (CH2)n-furanyl;
wherein said alkyl, phenyl and furanyl are unsubstituted or substituted with one or more
i) halo,
ii) —C1-6alkyl,
iii) —OH,
iv) —CN, or
v) —O—C1-6alkyl;
and
R11 is selected from the group consisting of
(1) —CH—,
(2) —O—, and
(3) —NH—,
provided that when R11 is —CH— the dotted line forms a bond and when R11 is —O— or —NH— the dotted line is absent;
R12 is hydrogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
m is 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
and pharmaceutically acceptable salts thereof.

66 more elements

Facts

Application

12/772,711Filed 3 May 2010 · division

Priority

23 Mar 2006

Published

US 2010/0210693 A119 Aug 2010

Granted

30 Aug 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 213/81
Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals: amides; Imides
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07C 255/57
Having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton: containing cyano groups and carboxyl groups, other…