Cyclic sulfones useful as BACE inhibitors

advertisement
Case 52216A
-1Claims
1. A compound of the formula
R4
R5
R6
R7
S
N
R3
R8
R2
R9
N
R1
OH
(I),
R10
H
in which
R1 is hydrogen; halogen; or (C1-8)alkyl;
R2 is hydrogen; halogen; (C1-8)alkyl; halogen-(C1-8)alkyl; (C1-8)alkoxy; or halogen(C1-8)alkoxy;
either
R3 is hydrogen; and
R4 is hydrogen; (C1-8)alkoxy-(C1-8)alkyl; (C1-8)alkylcarbonyloxy-(C1-8)alkyl; formyl;
(C1-8)alkylcarbonyl; or (C1-8)alkoxycarbonyl;
or
R3 is halogen-(C1-8)alkyl; hydroxy-(C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; formyl; (C1-8)alkylcarbonyl; (C3-8)cycloalkylcarbonyl; (C3-8)cycloalkyl-(C1-8)alkylcarbonyl; halogen-(C1-8)alkylcarbonyl; (C1-8)alkoxycarbonyl; halogen-(C1-8)alkoxycarbonyl; or an aryl-(C1-8)alkyl group,
which aryl-(C1-8)alkyl group is optionally ring-substituted by 1 to 4 substituents independently
selected from the group, consisting of halogen, (C1-8)alkyl, halogen-(C1-8)alkyl, (C1-8)alkoxy(C1-8)alkyl, halogen-(C1-8)alkoxy-(C1-8)alkyl, (C3-8)cycloalkyl, (C1-8)alkoxy and halogen-(C1-8)alkoxy; and
R4 is hydrogen; (C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; (C1-8)alkylcarbonyloxy-(C1-8)alkyl;
formyl; (C1-8)alkylcarbonyl; or (C1-8)alkoxycarbonyl;
R5 is hydrogen; halogen; (C1-8)alkyl; halogen-(C1-8)alkyl; halogen-(C1-8)alkyl
substituted by hydroxy; halogen-(C1-8)alkyl substituted by (C1-8)alkoxy; amino-(C1-8)alkyl; N(C1-8)alkylamino-(C1-8)alkyl; N,N-di-[(C1-8)alkyl]amino-(C1-8)alkyl with two identical or different
(C1-8)alkyl moieties in the N,N-di-[(C1-8)alkyl]amino moiety; (C2-8)alkenyl; (C3-8)cycloalkyl-(C28)alkenyl;
halogen-(C2-8)alkenyl; (C1-8)alkoxy; halogen-(C1-8)alkoxy; halogen-(C1-8)alkoxy
substituted by hydroxy; halogen-(C1-8)alkoxy substituted by (C1-8)alkoxy; halogen-(C1-8)alkoxy
substituted by amino; halogen-(C1-8)alkoxy substituted by N-(C1-8)alkylamino; halogen-(C18)alkoxy
substituted by N,N-di-[(C1-8)alkyl]amino with two identical or different (C1-8)alkyl
moieties, which two (C1-8)alkyl moieties, taken together, can complete, together with the
Case 52216A
-2nitrogen atom, to which they are attached, a ring with 3 to 7 ring members; (C1-8)alkoxy-(C18)alkyl;
halogen-(C1-8)alkoxy-(C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkoxy; halogen-(C1-8)alkoxy-(C1-
8)alkoxy;
(C1-8)alkoxy-(C1-8)alkoxy-(C1-8)alkyl; halogen-(C1-8)alkoxy-(C1-8)alkoxy-(C1-8)alkyl;
formyl; (C1-8)alkylcarbonyl; (C3-8)cycloalkylcarbonyl; (C3-8)cycloalkyl-(C1-8)alkylcarbonyl;
halogen-(C1-8)alkylcarbonyl; aminocarbonyl; N-(C1-8)alkylaminocarbonyl optionally substituted
by halogen; N,N-di-[(C1-8)alkyl]aminocarbonyl with two identical or different (C1-8)alkyl
moieties, which two identical or different (C1-8)alkyl moieties can be substituted, identically or
differently, by halogen; N-(C3-8)cycloalkylaminocarbonyl; N-[(C3-8)cycloalkyl-(C18)alkyl]aminocarbonyl;
8)cycloalkyl,
(C1-8)alkoxycarbonyl; halogen-(C1-8)alkoxycarbonyl; or a (C3-
(C3-8)cycloalkyl-(C1-8)alkyl, (C3-8)cycloalkyl-(C1-8)alkoxy, (C3-8)cycloalkoxy, aryl,
aryloxy, heteroaryl, heteroaryloxy, non-aromatic heterocyclyl or non-aromatic heterocyclyloxy
group, which (C3-8)cycloalkyl, (C3-8)cycloalkyl-(C1-8)alkyl, (C3-8)cycloalkyl-(C1-8)alkoxy, (C38)cycloalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, non-aromatic heterocyclyl or non-
aromatic heterocyclyloxy group is optionally ring-substituted by 1 to 4 substituents
independently selected from the group, consisting of halogen, (C1-8)alkyl, halogen-(C1-8)alkyl,
(C1-8)alkoxy-(C1-8)alkyl, halogen-(C1-8)alkoxy-(C1-8)alkyl, (C3-8)cycloalkyl, (C1-8)alkoxy and
halogen-(C1-8)alkoxy;
either
R6 is absent; and
R7 is absent;
or
R6 is oxo; and
R7 is absent;
or
R6 is oxo; and
R7 is oxo; imino; (C1-8)alkylimino; benzylimino; formylimino; or (C1-8)alkylcarbonylimino;
either
R8 is hydrogen; (C1-8)alkyl; halogen-(C1-8)alkyl; hydroxy-(C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; or a (C3-8)cycloalkyl group, which (C3-8)cycloalkyl group is optionally substituted by 1 to
4 substituents independently selected from the group, consisting of halogen and (C1-8)alkyl;
and
R9 is hydrogen; (C1-8)alkyl; halogen-(C1-8)alkyl; hydroxy-(C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; or a (C3-8)cycloalkyl group, which (C3-8)cycloalkyl group is optionally substituted by 1 to
4 substituents independently selected from the group, consisting of halogen and (C1-8)alkyl;
Case 52216A
-3or
R8 and R9, taken together, complete, together with the carbon atom, to which they
are attached, a (C3-8)cycloalkylidene moiety, in which (C3-8)cycloalkylidene moiety 1 of its
-CH2- ring members can be replaced with -O-; and
R10 is an aryl or heteroaryl group, which aryl or heteroaryl group is optionally mono-,
di-, tri- or tetra-substituted by substituents independently selected from the group, consisting
of (i) the univalent substituents halogen, hydroxy, (C1-8)alkyl, halogen-(C1-8)alkyl, hydroxy-(C18)alkyl,
hydroxy-(C1-8)alkyl substituted by halogen, (C1-8)alkoxy-(C1-8)alkyl, halogen-(C1-
8)alkoxy-(C1-8)alkyl,
cyano-(C1-8)alkyl, (C1-8)alkoxy, halogen-(C1-8)alkoxy, a heteroaryl group,
which heteroaryl group is optionally substituted by 1 to 4 substituents independently selected
from the group, consisting of halogen, (C1-8)alkyl and halogen-(C1-8)alkyl, and a (C38)cycloalkyl
group, in which (C3-8)cycloalkyl group 1 of its -CH2- ring members can be
replaced with -O-, and which (C3-8)cycloalkyl group, in which 1 of its -CH2- ring members is
optionally replaced with -O-, is optionally substituted by 1 to 4 substituents independently
selected from the group, consisting of halogen, (C1-8)alkyl and halogen-(C1-8)alkyl, and (ii) the
bivalent substituents (C3-16)alkylene, oxa-(C2-16)alkylene and (C1-8)alkylenoxa-(C1-8)alkylene,
any such optional bivalent substituent being attached to two adjacent ring carbon atoms of
the aryl or heteroaryl group,
in free form or in salt form.
2. A process for the preparation of a compound as defined in claim 1 of the formula I, in free
form or in salt form, comprising the steps of
a) for the preparation of a compound of the formula I, in free form or in salt form, in which R3
is hydrogen and R4 is hydrogen, treatment of a compound of the formula
R5
Ra
R6
R7
S
R8
R2
N
R1
OH
R9
(II),
R10
H
in which Ra is azido or nitro and all of the other variables are as defined for the formula I, in
free form or in salt form, with a reducing agent, in order to convert Ra into amino, or
b) for the preparation of a compound of the formula I, in free form or in salt form, in which R8
is hydrogen, treatment of a compound of the formula
Case 52216A
-4R4
R5
R6
R7
S
N
R3
(III),
R9
R2
N
R1
OH
R10
in which all of the variables are as defined for the formula I, in free form or in salt form, with a
reducing agent, in order to convert the moiety -N=C(R9)R10 into the moiety
-N(H)-C(H)(R9)R10,
in each case optionally followed by reduction, oxidation or other functionalisation of the resulting compound and/or by cleavage of any protecting group(s) optionally present,
and of recovering the so obtainable compound of the formula I in free form or in salt form.
3. A compound as defined in claim 1, in free form or in pharmaceutically acceptable salt
form, for use as a medicament.
4. A compound as defined in claim 1, in free form or in pharmaceutically acceptable salt
form, for use in the treatment of neurological or vascular disorders related to beta-amyloid
generation and/or aggregation.
5. A pharmaceutical composition comprising a compound as defined in claim 1, in free form
or in pharmaceutically acceptable salt form, as active ingredient and a pharmaceutical carrier
or diluent.
6. The use of a compound as defined in claim 1, in free form or in pharmaceutically acceptable salt form, as a medicament for the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation.
7. The use of a compound as defined in claim 1, in free form or in pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment of neurological or
vascular disorders related to beta-amyloid generation and/or aggregation.
8. A method for the treatment of neurological or vascular disorders related to beta-amyloid
generation and/or aggregation in a subject in need of such treatment, which comprises
Case 52216A
-5administering to such subject a therapeutically effective amount of a compound as defined in
claim 1, in free form or in pharmaceutically acceptable salt form.
9. A combination comprising a therapeutically effective amount of a compound as defined in
claim 1, in free form or in pharmaceutically acceptable salt form, and a second drug substance, for simultaneous or sequential administration.
Download
Related flashcards

Chemical weapons

46 cards

Metabolic disorders

39 cards

Nitrogen mustards

28 cards

Gene expression

44 cards

Phenylpropanoids

25 cards

Create Flashcards