Cyclic Sulfones Useful As BACE Inhibitors
Case 52216A
- 1 -
Claims
1. A compound of the formula
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 andhalogen-(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)alkylmoieties in the N,N-di-[(C1-8)alkyl]amino moiety; (C2-8)alkenyl; (C3-8)cycloalkyl-(C2-8)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-(C1-8)alkoxy substituted by N,N-di-[(C1-8)alkyl]aminowith two identical or different (C1-8)alkylmoieties, which two (C1-8)alkylmoieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a ring with 3 to 7 ring members; (C1-8)alkoxy-(C1-8)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)alkylmoieties, which two identical or different (C1-8)alkylmoieties can be substituted, identically or differently, by halogen; N-(C3-8)cycloalkylaminocarbonyl; N-[(C3-8)cycloalkyl-(C1-8)alkyl]aminocarbonyl; (C1-8)alkoxycarbonyl; halogen-(C1-8)alkoxycarbonyl; or a (C3-8)cycloalkyl, (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, (C3-8)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 andhalogen-(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)cycloalkylgroup 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)cycloalkylgroup is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen and (C1-8)alkyl;
or
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 moiety1 of its -CH2- ring members can be replaced with -O-; and
R10 is an aryl or heteroaryl group, which aryl or heteroaryl groupis 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-(C1-8)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 groupis optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, (C1-8)alkyl andhalogen-(C1-8)alkyl, and a (C3-8)cycloalkyl group, in which(C3-8)cycloalkyl group1 of its -CH2- ring members can be replaced with -O-, and which (C3-8)cycloalkyl group, in which1 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 andhalogen-(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 1of 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 R3is hydrogen and R4is hydrogen, treatment of a compound of the formula
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 R8is hydrogen, treatment of a compound of the formula
in which all of the variables are as defined for the formula I, in free form or in saltform, with a reducing agent, in order to convert the moiety -N=C(R9)R10into 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 acceptablesalt
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 administering 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.