Substituted 1,2-ethylenediamines, methods for preparing them and uses thereof   

This application is a divisional of U.S. Ser. No. 11/278,059, filed Mar. 30, 2006. This application claims priority to European Patent Application No. 05 006 939.2, filed Mar. 30, 2005. The contents of each of the above are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to substituted 1,2-ethylenediamines of general formula (I)

wherein the groups R1 to R15, A, B, L, i and X1-X4 are defined below, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof. A further object of this invention relates to pharmaceutical compositions containing a compound of formula (I) according to the invention and the use of a compound according to the invention for preparing a pharmaceutical composition for the treatment and/or prevention of Alzheimer\'s disease (AD) and other diseases associated with abnormal processing of Amyloid Precursor Protein (APP) or aggregation of the Abeta peptide, as well as diseases which can be treated or prevented by the inhibition of β-secretase. Such diseases include MCI (“mild cognitive impairment”), trisomy 21 (Down\'s syndrome), cerebral amyloid angiopathy, degenerative dementias, hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D), Alzheimer\'s dementia with Lewy bodies, trauma, stroke, pancreatitis, Inclusion Body Myositis (IBM), and other peripheral amyloidoses, diabetes and arteriosclerosis.

The compounds according to the invention also inhibit the aspartylprotease cathepsin D and are therefore suitable for suppressing the metastasisation of tumour cells.

The invention further relates to processes for preparing a pharmaceutical composition and a compound according to the invention.

BACKGROUND OF THE INVENTION

EP 652 009 A1 describes inhibitors of aspartate protease which inhibit the production of beta-amyloid peptides in cell culture and in vivo.

WO 00/69262 discloses a beta-secretase and the use thereof in assays for finding potential active substances for the treatment of AD.

WO 01/00663 discloses memapsin 2 (human beta-secretase) as well as a recombinant catalytically active enzyme. Methods of identifying inhibitors of memapsin 2 are also described.

WO 01/00665 discloses inhibitors of memapsin 2 for the treatment of AD.

WO 03/057721 discloses substituted aminocarboxamides for the treatment of AD.

At present there are no effective treatment methods capable of preventing, stopping or reversing AD.

The objective of the present invention is therefore to provide new substituted 1,2-ethylenediamines which inhibit the cleaving of APP (Amyloid Precursor Protein) mediated by β-secretase.

A further objective of the present invention is to provide physiologically acceptable salts of the compounds according to the invention with inorganic or organic acids.

Another objective of the present invention is to provide pharmaceutical compositions containing at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.

The present invention further relates to pharmaceutical compositions containing one or more, preferably one active substance, which is selected from the compounds according to the invention and/or the corresponding salts, as well as one or more, preferably one additional active substance optionally together with one or more inert carriers and/or diluents.

This invention further relates to the use of at least one of the compounds according to the invention for inhibiting β-secretase.

The invention also sets out to provide new pharmaceutical compositions which are suitable for the treatment or prevention of diseases or conditions associated with the abnormal processing of Amyloid Precursor Protein (APP) or aggregation of Abeta peptide.

The invention also sets out to provide new pharmaceutical compositions which are suitable for the treatment or prevention of diseases or conditions which can be influenced by inhibiting the β-secretase activity.

The invention also sets out to provide new pharmaceutical compositions which are suitable for the treatment and/or prevention of Alzheimer\'s disease (AD) and other diseases which are associated with the abnormal processing of APP or aggregation of Abeta peptide, as well as diseases which can be treated or prevented by the inhibition of β-secretase, particularly AD.

The invention also relates to a method of inhibiting β-secretase activity.

Further objectives of the present invention will be apparent to the skilled man immediately from the foregoing remarks and those made hereinafter.

SUMMARY

In a first aspect the present invention relates to substituted 1,2-ethylenediamines of general formula (I)

wherein A denotes aryl or heteroaryl, wherein the group A in addition to the groups L may optionally be substituted by one or more fluorine atoms, L denotes in each case independently of one another hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, carboxy, formyl, cyano, nitro, F3C, HF2C, FH2C, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyl-S, C1-6-alkyl-S—C1-3-alkyl, C3-7-cycloalkyl, C3-7-cycloalkenyl, C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-C2-6-alkynyl, C3-7-cycloalkenyl-C1-6-alkyl, C3-7-cycloalkenyl-C2-6-alkenyl, C3-7-cycloalkenyl-C2-6-alkynyl, aryl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heterocyclyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl, heteroaryl-C2-6-alkynyl, R15—O, R15—O—C1-3-alkyl, (R14)2N, (R14)2N—CO, R14—CO—(R14)N, (R14)2N—CO—(R14)N, R14—SO2—(R14)N, (R14)2N—SO2 or R14—SO2, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F3C, HF2C, FH2C, hydroxy-C1-6-alkyl, C1-3-alkyl, C1-6-alkoxy, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO and HOSO2—, denotes 0, 1, 2 or 3, B denotes a C1-4-alkylene bridge, wherein in the case of a C3-4-alkylene bridge the CH2 group of the C3-4-alkylene bridge, which is bound to the group A, may be replaced by —O—, and the C1-4-alkylene bridge may optionally be substituted by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, cyano, nitro, F3C, HF2C, FH2C, C1-4-alkyl, C1-6-alkyl-S—C1-3-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl, heteroaryl-C1-3-alkyl, R15—O, (R14)2N—SO2, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO, R14—SO2, R14—CO—(R14)N, R14—SO2(R14)N, (R14)2N—SO2, R14—CO— and R14—SO—, and two C1-4-alkyl groups bound to the same carbon atom of the C1-4-alkylene bridge may be joined together forming a C3-7-cycloalkyl group, and the above-mentioned groups and the C3-7-cycloalkyl group formed from the C1-4-alkyl groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F3C, HF2C, FH2C, C1-3-alkyl, C1-3-alkoxy, R15—O—C1-3-alkyl, R14—CO(R14)N, R14—SO2(R14)N, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO, (R14)2N—SO2— and HOSO2—, R1 denotes hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-C2-6-alkynyl, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-6-alkyl, C3-7-cycloalkenyl-C2-6-alkenyl, C3-7-cycloalkenyl-C2-6-alkynyl, aryl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heterocyclyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F3C, HF2C, FH2C, C1-3-alkyl, C1-3-alkoxy, hydroxy-C1-6-alkyl, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO— (R14)2N—SO2, R14—CO—(R14)N, R14—SO2—(R14)N and HOSO2—, X1, denotes nitrogen or C(R10), X2, X3, X4 each independently of one another denote nitrogen or C(R11) with the proviso that 0, 1, 2 or 3 of the groups X1, X2, X3 and X4 may be nitrogen, R2 denotes C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, R15—O—C1-3-alkyl, C1-6-alkyl-S—C1-3-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C2-6-alkynyl, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-6-alkyl, C3-7-cycloalkenyl-C2-6-alkenyl, C3-7-cycloalkenyl-C2-6-alkynyl, heterocyclyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, C3-7-cycloalkyl-C2-3-alkenyl, heterocyclyl-C2-3-alkenyl, heterocyclyl-C2-3-alkynyl, aryl, heteroaryl, aryl-C1-3-alkyl, heteroaryl-C1-3-alkyl, aryl-C2-3-alkenyl, aryl-C2-3-alkynyl, heteroaryl-C2-3-alkenyl or heteroaryl-C2-3-alkynyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, F3C, HF2C, FH2C, hydroxy, oxo, carboxy, formyl, cyano, nitro, (R14)2N, HOSO2—, C1-3-alkyl, C1-6-alkyl-S—C1-3-alkyl, (R14)2N—SO2—, R14—CO—(R14)N, R14—SO2—(R14)N, (R14)2N—C1-3-alkyl, (R14)2N—CO, R15—O and R15—O—C1-3-alkyl, R3, R4 each independently of one another denote hydrogen, C1-6-alkyl, fluorine, F3C, HF2C or FH2C, R5, R7 each independently of one another denote hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, heterocyclyl, C3-7-cycloalkyl-C1-3-alkyl, C3-7-cycloalkyl-C2-6-alkynyl, heterocyclyl-C1-3-alkyl, C3-7-cycloalkyl-C2-4-alkenyl, heterocyclyl-C2-4-alkenyl, heterocyclyl-C2-4-alkynyl, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-6-alkyl, C3-7-cycloalkenyl-C2-6-alkenyl, C3-7-cycloalkenyl-C2-6-alkynyl, aryl, heteroaryl, aryl-C1-3-alkyl, heteroaryl-C1-3-alkyl, aryl-C2-3-alkenyl, heteroaryl-C2-3-alkenyl, aryl-C2-3-alkynyl or heteroaryl-C2-3-alkynyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C1-3-alkyl, R15—O, C1-3-alkyl-S, aryl, heteroaryl, heteroaryl-C1-3-alkyl, aryl-C1-6-alkyl, R14—CO—(R14)N, R14—SO2—(R14)N, (R14)2N—SO2—, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO and HOSO2—, R6, R9 each independently of one another denote hydrogen, C1-6-alkyl, C1-6-alkoxy-C1-3-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C2-6-alkenyl, heterocyclyl-C1-3-alkyl, heteroaryl, heteroaryl-C1-3-alkyl or C2-6-alkynyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, C1-3-alkyl, C1-6-alkoxy- and (R14)2N, R8 denotes hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C3-7-cycloalkyl-C2-4-alkenyl, C3-7-cycloalkyl-C2-4-alkynyl, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-6-alkyl, C3-7-cycloalkenyl-C2-6-alkenyl, C3-7-cycloalkenyl-C2-6-alkynyl, heterocyclyl, heterocyclyl-C1-3-alkyl, heterocyclyl-C2-4-alkenyl, heterocyclyl-C2-4-alkynyl, aryl, aryl-C1-3-alkyl, aryl-C2-4-alkenyl, aryl-C2-4-alkynyl, heteroaryl, heteroaryl-C1-3-alkyl, heteroaryl-C2-4-alkenyl or heteroaryl-C2-4-alkynyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, R15—O, R15—O—C1-3-alkyl, R15—S, R15—S—C1-3-alkyl, aryl, heteroaryl, heteroaryl-C1-3-alkyl, aryl-C1-6-alkyl, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO, (R14)2N—CO—N(R14)—, (R14)2N—SO2— and HOSO2—, R10 denotes hydrogen, fluorine, chlorine, bromine, iodine, cyano, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkynyl, heterocyclyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, C3-7-cycloalkyl-C2-6-alkenyl, heterocyclyl-C2-4-alkenyl, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-6-alkyl, C3-7-cycloalkenyl-C2-6-alkenyl, C3-7-cycloalkenyl-C2-6-alkynyl, aryl, aryl-C1-6-alkyl, heteroaryl, heteroaryl-C1-6-alkyl, aryl-C2-6-alkenyl, heteroaryl-C2-6-alkenyl, aryl-C2-6-alkynyl or heteroaryl-C2-6-alkynyl, R15—O, R15—O—C1-3-alkyl, R12—SO2—(R13)N or R12—CO—(R13)N, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyl-S, C1-6-alkyl-S—C1-3-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, aryl, aryl-C1-6-alkyl, heterocyclyl, heterocyclyl-C1-6-alkyl, heteroaryl, heteroaryl-C1-6-alkyl, R15—O, R15—O—CO, R15—CO, R15—O—CO—(R14)N, (R14)2N—CO—O, R14—O—C1-3-alkyl, (R14)2N, (R14)2N—CO, R14—CO—(R14)N, (R14)2N—CO—(R14)N, (R14)2N—SO2—, (R14)2N—SO2—(R14)N, R14—SO2—, F3C, HF2C, FH2C, F3C—O, HF2C—O, FH2C—O and R14—SO2—(R14)N, R11 each independently of one another denote hydrogen, fluorine, chlorine, bromine, iodine, R15—O, (R14)2N or C1-3-alkyl, wherein the C1-3-alkyl group may optionally be substituted by one or more fluorine atoms, R12 denotes C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl-C2-6-alkenyl, aryl-C2-3-alkenyl, heteroaryl-C2-4-alkenyl, heterocyclyl-C2-4-alkenyl, aryl-C2-3-alkynyl, C3-7-cycloalkyl-C2-4-alkynyl, heterocyclyl-C2-4-alkynyl-heteroaryl-C2-3-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, heterocyclyl, heterocyclyl-C1-4-alkyl, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-6-alkyl, C3-7-cycloalkenyl-C2-6-alkenyl, C3-7-cycloalkenyl-C2-6-alkynyl, aryl, aryl-C1-4-alkyl, heteroaryl, heteroaryl-C1-3-alkyl or (R14)2N, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, R15—O, R15—O—C1-3-alkyl, R14—CO(R14)N, R14—SO2(R14)N, (R14)2N—SO2—, R14—SO2—, R14—SO, R14—S, (R14)2N, (R14)2N—C1-3-alkyl and (R14)2N—CO, R13 denotes hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, heterocyclyl-C2-3-alkenyl, heterocyclyl-C2-3-alkynyl, heteroaryl, heteroaryl-C2-3-alkenyl, heteroaryl-C2-3-alkynyl or heteroaryl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, R15—O, R15—O—C1-3-alkyl, (R14)2N, (R14)2N—C1-3-alkyl and R14CO, or R12 and R13 together form a C2-6-alkylene bridge, so that with the inclusion of the nitrogen atom linked to R13 and the SO2— or CO group linked to R12 a heterocyclic ring is formed, wherein one or two CH2 groups of the C2-6-alkylene bridge may be replaced independently of one another by O, S, SO, SO2 or N(R14) in such a way that in each case two O or S atoms or an 0 and an S atom are not joined together directly, and the C atoms of the above-mentioned C2-6-alkylene bridge may optionally be substituted by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, carboxy, formyl, cyano, F3C, HF2C, FH2C, C1-6-alkyl, C1-6-alkoxy, oxo and nitro, R14 each independently of one another denote hydrogen, C1-6-alkyl, C1-6-alkoxy-C1-3-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, aryl or aryl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, heteroaryl or heteroaryl-C1-3-alkyl, wherein two C1-6-alkyl groups bound to the same nitrogen atom together may form a C2-6-alkylene bridge, so that with the inclusion of the nitrogen atom bound to the groups R14 a heterocyclic ring is formed, wherein a CH2 group of the C2-6-alkylene bridge may be replaced by O, S or N(R14), and the above-mentioned groups and the heterocyclic ring may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C1-3-alkyl, hydroxy-C1-3-alkyl, C1-3-alkoxy, (R15)2N—CO— and (R15)2N—, and R15 each independently of one another denote hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, heteroaryl or heteroaryl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C1-3-alkyl- and C1-3-alkoxy, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof.

The compounds according to the invention of general formula (I) and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on β-secretase activity, particularly the β-secretase mediated cleaving of APP. In addition, the compounds of the present invention are characterised by a surprisingly good cellular activity.

In view of the inhibitory properties of the compounds according to the invention on cathepsin D activity, the compounds are also suitable for suppressing the metastasisation of tumour cells. The present invention also relates to the physiologically acceptable salts of the compounds according to the invention with inorganic or organic acids.

The invention therefore also relates to the use of the compounds according to the invention, including the physiologically acceptable salts, as medicaments.

The invention further relates to pharmaceutical compositions containing at least one compound according to the invention or a physiologically acceptable salt according to the invention optionally together with one or more inert carriers and/or diluents.

This invention further relates to pharmaceutical compositions containing one or more, preferably one active substance, which is selected from the compounds according to the invention and/or the corresponding salts, as well as one or more, preferably one active substance, selected for example from among the beta-secretase inhibitors; gamma-secretase inhibitors; amyloid aggregation inhibitors such as e.g. alzhemed; directly or indirectly acting neuroprotective substances; anti-oxidants, such as e.g. vitamin E or ginkolide; anti-inflammatory substances, such as e.g. Cox inhibitors, NSAIDs additionally or exclusively having Aβ lowering properties; HMG-CoA reductase inhibitors (statins); acetylcholinesterase inhibitors, such as donepezil, rivastigmine, tacrine, galantamine; NMDA receptor antagonists such as e.g. memantine; AMPA agonists; substances modulating the concentration or release of neurotransmitters such as NS-2330; substances inducing the secretion of growth hormone such as ibutamoren mesylate and capromorelin; CB-1 receptor antagonists or inverse agonists; antibiotics such as minocyclin or rifampicin; PDE-IV and PDE-IX inhibitors, GABAA inverse agonists, nicotinic agonists, histamine H3 antagonists, 5 HAT-4 agonists or partial agonists, 5HT-6 antagonists, a2-adrenoreceptor antagonists, muscarinic M1 agonists, muscarinic M2 antagonists, metabotropic glutamate-receptor 5 positive modulators, and other substances that modulate receptors or enzymes in a manner such that the efficacy and/or safety of the compounds according to the invention is increased and/or unwanted side effects are reduced, optionally together with one or more inert carriers and/or diluents.

This invention further relates to pharmaceutical compositions containing one or more, preferably one active substance, which is selected from the compounds according to the invention and/or the corresponding salts, as well as one or more, preferably one active substance selected from among alzhemed, vitamin E, ginkolide, donepezil, rivastigmine, tacrine, galantamine, memantine, NS-2330, ibutamoren mesylate, capromorelin, minocyclin and/or rifampicin, optionally together with one or more inert carriers and/or diluents.

This invention further relates to the use of at least one of the compounds according to the invention for inhibiting β-secretase.

This invention also relates to the use of at least one compound according to the invention or a physiologically acceptable salt of such a compound for preparing a pharmaceutical composition, which is suitable for the treatment or prophylaxis of diseases or conditions associated with the abnormal processing of Amyloid Precursor Protein (APP) or aggregation of the Abeta peptide.

This invention also relates to the use of at least one compound according to the invention or a physiologically acceptable salt of such a compound for preparing a pharmaceutical composition which is suitable for the treatment or prophylaxis of diseases or conditions which can be influenced by inhibiting the β-secretase activity.

This invention also relates to the use of at least one compound according to the invention or a pharmaceutical composition according to the invention for preparing a medicament which is suitable for the treatment and/or prevention of Alzheimer\'s disease (AD) and other diseases which are associated with the abnormal processing of APP or aggregation of Abeta peptide, as well as diseases which can be treated or prevented by the inhibition of β-secretase, particularly AD. Such diseases include MCI (“mild cognitive impairment”), trisomy 21 (Down\'s syndrome), cerebral amyloid angiopathy, degenerative dementias, hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D), Alzheimer\'s dementia with Lewy bodies, trauma, stroke, pancreatitis, Inclusion Body Myositis (IBM), and other peripheral amyloidoses, diabetes and arteriosclerosis.

This invention further relates to a method of inhibiting β-secretase activity, characterised in that β-secretase is brought into contact with an inhibitory amount of one of the compounds according to the invention.

DETAILED DESCRIPTION

Unless otherwise stated the groups, residues and substituents R1 to R15, A, B, L, i and X1-X4 have the meanings given hereinbefore and below.

If residues, substituents or groups occur more than once in a compound, they may have the same or different meanings.

In a preferred embodiment of the compounds of the present invention the group

denotes a phenyl, biphenyl, naphthyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic mono- or bicyclic heteroaryl group which contains 1-4 heteroatoms selected from N, O and S.

In another preferred embodiment of the compounds of the present invention the group

denotes a phenyl ring or a 5- or 6-membered aromatic heteroaryl group which contains 1 or 2 heteroatoms selected from N, O and S, wherein a maximum of one O or S atom may be present.

In another preferred embodiment the group

has the following meanings:

In a particularly preferred embodiment the group

denotes a phenyl, thienyl, thiazolyl, particularly 2-thiazolyl, or a pyridyl group, wherein the phenyl, the thienyl, particularly the 3-thienyl, and the pyridyl group, particularly the 2-pyridyl group, are deemed to be particularly preferred.

Preferably the substituent L denotes independently of one another in each case hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, carboxy, cyano, nitro, F3C, HF2C, FH2C, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, heteroaryl, heteroaryl-C1-3-alkyl, R15—O, R15—O—C1-3-alkyl, (R14)2N, (R14)2N—CO, R14—CO—(R14)N, (R14)2N—CO—(R14)N, (R14)2N—SO2—, R14—SO2—(R14)N or C1-3-alkyl-SO2—, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, cyano, nitro, F3C, HF2C, FH2C, hydroxy-C1-3-alkyl, C1-3-alkyl, C1-3-alkoxy, (R14)2N, (R14)2N—C1-3-alkyl and (R14)2N—CO.

Particularly preferably the substituent L denotes independently of one another in each case hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxy, C1-6-alkyl, C1-6-alkoxy, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, phenyl, (R14)2N, (R14)2N—CO, R14—CO(R14)N, (R14)2N—CO—(R14)N, R14—SO2—(R14)N or (R14)2N—SO2—, wherein the above-mentioned groups may optionally be substituted by one or more fluorine atoms.

Most particularly preferred meanings for the substituent L, independently of one another in each case, are hydrogen, fluorine, chlorine, bromine, hydroxy, C1-4-alkyl or C1-4-alkoxy, wherein the above-mentioned groups may optionally be substituted by one or more fluorine atoms.

Particularly preferred meanings for the substituent L, independently of one another in each case, are hydrogen, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, methyl and methoxy.

Preferably the index i may assume the values 0, 1 or 2. In particularly preferred embodiments the value of the index i is 0 or 1.

In a preferred embodiment of the compounds according to the invention the group B represents a C1-4-alkylene bridge which may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, cyano, nitro, F3C, HF2C, FH2C, C1-4-alkyl, C1-6-alkyl-S—C1-3-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl, heteroaryl-C1-3-alkyl, R15—O, (R14)2N—SO2—, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO, R14—SO2—, R14—CO—(R14)N, R14—SO2(R14)N, (R14)2N—SO2—, R14—CO and R14—SO, and wherein two C1-4-alkyl groups bound to the same carbon atom of the C1-4-alkylene bridge may be joined together forming a C3-7-cycloalkyl group, and the above-mentioned groups and the C3-7-cycloalkyl group formed from the C1-4-alkyl groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F3C, HF2C, FH2C, C1-3-alkyl, C1-3-alkoxy, R15—O—C1-3-alkyl, R14—CO(R14)N, R14—SO2(R14)N, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO, (R14)2N—SO2— and HOSO2—.

In another preferred embodiment of the compounds according to the invention the group B represents a C1-4-alkylene bridge, which may optionally be substituted independently of one another by one or more groups selected from among fluorine, hydroxy, carboxy, cyano, nitro, F3C, HF2C, FH2C, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl, heteroaryl-C1-3-alkyl, R15—O, (R14)2N—SO2— and (R14)2N, and two C1-4-alkyl groups bound to the same carbon atom of the C1-4-alkylene bridge may be joined together forming a C3-7-cycloalkyl group, and the above-mentioned groups and the C3-7-cycloalkyl group formed from the C1-4-alkyl groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, carboxy, cyano, F3C, HF2C, FH2C, C1-3-alkyl, C1-3-alkoxy- and R15—O—C1-3-alkyl.

Particularly preferably the group B denotes a C1-4-alkylene bridge, wherein the C1-4-alkylene bridge may optionally be substituted independently of one another by one or more groups selected from among C1-4-alkyl, phenyl- and benzyl, and two C1-4-alkyl groups bound to the same carbon atom of the C1-4-alkylene bridge may be joined together forming a C3-6-cycloalkyl group, and the above-mentioned groups and the C3-7-cycloalkyl group formed from the C1-4-alkyl groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, hydroxy and C1-3-alkoxy.

Most particularly preferred are the compounds according to the invention wherein the group B is selected from among

wherein one or more hydrogen atoms may optionally be replaced by fluorine.

In another most particularly preferred embodiment B is a C1-2-alkylene bridge which may optionally be substituted by one or more C1-4-alkyl groups, and wherein two C1-4-alkyl groups bound to the same carbon atom of the C1-2-alkylene bridge may be joined together forming a cyclopropyl group, and one or more hydrogen atoms of the above-mentioned C1-2-alkylene bridge and/or the C1-4-alkyl groups and/or the cyclopropyl group formed therefrom may optionally be replaced by one or more fluorine atoms.

Particularly preferred are those compounds according to the invention wherein the group B is selected from among

wherein one or more hydrogen atoms may optionally be replaced by fluorine.

Another preferred embodiment comprises those compounds according to the invention wherein the partial formula (II)

is selected from among

Preferably the group R1 is selected from among hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, carboxy, cyano, nitro, F3C, HF2C, FH2C, C1-3-alkyl, C1-3-alkoxy and hydroxy-C1-3-alkyl.

Particularly preferred are those groups R1 selected from among hydrogen, C1-4-alkyl, C3-4-alkenyl, C3-6-cycloalkyl- and C3-6-cycloalkyl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, hydroxy and C1-3-alkoxy.

Most particularly preferred are the groups R1 selected from among hydrogen and C1-4-alkyl, wherein the C1-4-alkyl group may be substituted by one or more fluorine atoms.

Particularly preferred are those compounds according to the invention wherein R1 is hydrogen.

In a preferred embodiment X1 is C(R10) and X2, X3, X4 each independently of one another denote C(R11), wherein the groups R1 may each be selected independently of one another from the definitions given for R11 hereinbefore and below.

In a particularly preferred embodiment X1 is C(R10) and X2, X3, X4 in each case denote a ═CH— group.

Preferred groups R2 are groups selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy-C1-3-alkyl, C1-6-alkyl-S—C1-3-alkyl, C3-7-cycloalkyl, C3-7-cycloalkenyl-C1-3-alkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, F3C, HF2C, FH2C, hydroxy, carboxy, cyano, nitro, C1-3-alkyl, (R14)2N—SO2—, (R14)2N, R14—CO—(R14)N, R14—SO2(R14)N, (R14)2N—C1-3-alkyl, (R14)2N—CO, R15—O and R15—O—C1-3-alkyl.

Particularly preferred groups R2 are groups selected from among C1-6-alkyl, C2-6-alkynyl, C3-6-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl, wherein by the above-mentioned heteroaryl groups are meant 5- or 6-membered aromatic heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, and wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, hydroxy, C1-3-alkyl, F3C, HF2C, FH2C, C1-3-alkoxy and (R14)2N.

Other particularly preferred groups R2 are groups selected from among C1-6-alkyl, C2-6-alkynyl, C3-6-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl, wherein by the above-mentioned heteroaryl groups are meant 5- or 6-membered aromatic heteroaryl groups, which contain 1 or 2 heteroatoms selected from N, O and S, wherein a maximum of one O or S atom may be present, and wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, hydroxy, C1-3-alkyl, F3C, HF2C, FH2C, C1-3-alkoxy and (R14)2N.

Most particularly preferred are those groups R2 which are selected from among n-propyl, n-butyl, 2-propynyl, 2-butynyl, benzyl, 2-phenylethyl, pyridylmethyl, particularly 3-pyridylmethyl, furanylmethyl, thienylmethyl and thiazolylmethyl,

wherein the above-mentioned propyl, butyl, propynyl and butynyl groups may optionally be substituted by one or more fluorine atoms and the benzyl, 2-phenylethyl, furanylmethyl, thienylmethyl or thiazolylmethyl groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, methyl, F3C, HF2C, FH2C and H2N.

Also most particularly preferred are those groups R2 which are selected from among n-butyl, benzyl, 2-phenylethyl, pyridylmethyl, particularly 3-pyridylmethyl, thienylmethyl and thiazolylmethyl, wherein the above-mentioned phenyl groups of the benzyl and 2-phenylethyl groups may optionally be substituted by one or more fluorine atoms.

Particularly preferred are those groups R2 which are selected from among benzyl, 3,5-difluorobenzyl, thienylmethyl, particularly 3-thienylmethyl- and n-butyl, the benzyl group being the most preferred group.

Preferably the group R3 denotes hydrogen, C1-6-alkyl, fluorine, F3C, HF2C or FH2C— and particularly preferably R3 is hydrogen.

The group R4 is preferably hydrogen.

In a particularly preferred embodiment of the compounds according to the invention the group R3 is selected from among hydrogen, C1-6-alkyl, fluorine, F3C, HF2C or FH2C and the group R4 is hydrogen.

In a most particularly preferred embodiment of the compounds according to the invention the groups R3 and R4 are hydrogen.

Preferred groups R8 are groups selected from among hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, carboxy, cyano, nitro, C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl, heteroaryl-C1-3-alkyl, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO, (R14)2N—CO—N(R14)—, (R14)2N—SO2, R5—O, R15—O—C1-3-alkyl, R15—S and R15—S—C1-3-alkyl.

Particularly preferred groups R8 are groups selected from among hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl, wherein by the above-mentioned heteroaryl groups are meant 5- or 6-membered aromatic heteroaryl groups which contain 1, 2 or 3 heteroatoms selected from N, O and S, and wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, carboxy, hydroxy, cyano, C1-3-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-3-alkyl-S, C1-3-alkyl-S—C1-3-alkyl, hydroxy-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO—N(R14)— and (R14)2N—SO2—.

Other particularly preferred groups R8 are groups selected from among hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl, wherein by the above-mentioned heteroaryl groups are meant 5- or 6-membered aromatic heteroaryl groups which contain 1 or 2 heteroatoms selected from N, O and S, wherein a maximum of one O or S atom may be present, and wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, carboxy, hydroxy, cyano, C1-3-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-3-alkyl-S, C1-3-alkyl-S—C1-3-alkyl, hydroxy-C1-3-alkyl, heterocyclyl, heterocyclyl-C1-3-alkyl, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO—N(R14)— and (R14)2N—SO2—.

Most particularly preferred are those groups R8 which are selected from among hydrogen, C1-6-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, phenyl-C1-3-alkyl or tetrahydropyranyl-C1-3-alkyl, particularly 4-tetrahydropyranyl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, pyrrolidin-1-ylmethyl, hydroxy, cyano, C1-3-alkyl, C1-3-alkoxy, C1-3-alkyl-S, hydroxy-C1-3-alkyl, (R14)2N, (R14)2N—C1-3-alkyl, (R14)2N—CO—N(R14)— and (R14)2N—SO2—.

Particularly preferred as the group R8 is C1-6-alkyl, particularly C1-4-alkyl, C3-5-cycloalkyl-C1-2-alkyl, wherein R8 in its most preferred embodiment denotes a methyl or ethyl group.

Preferred groups R5 and R7 are each selected independently of one another from among hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, heterocyclyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-3-alkyl, aryl, heteroaryl, aryl-C1-3-alkyl- and heteroaryl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, carboxy, cyano, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-alkyl-S, aryl, heteroaryl, heteroaryl-C1-3-alkyl, aryl-C1-3-alkyl, (R14)2N—SO2—, (R14)2N, (R14)2N—C1-3-alkyl and (R14)2N—CO.

Particularly preferred groups R5 are selected from among C1-6-alkyl, cyclopropyl, C3-6-cycloalkyl-C1-3-alkyl and phenyl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, hydroxy, carboxy, C1-3-alkyl, C1-3-alkoxy and (R14)2N.

Particularly preferred groups R7 are selected from among C1-6-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, phenyl and phenyl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, hydroxy, carboxy, C1-3-alkyl, C1-3-alkoxy and (R14)2N.

In a most particularly preferred embodiment of the compounds according to the invention R5 is selected from among C1-6-alkyl, cyclopropyl, C3-6-cycloalkyl-C1-3-alkyl and phenyl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, hydroxy, carboxy, C1-3-alkyl, C1-3-alkoxy and (R14)2N, and R7 is selected from among C1-6-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, phenyl and phenyl-C1-3-alkyl, wherein the above-mentioned groups may optionally be substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, hydroxy, carboxy, C1-3-alkyl, C1-3-alkoxy and (R14)2N.

Particularly preferred compounds are those wherein R5 and R7 each independently of one another denote C1-4-alkyl or cyclopropyl groups, wherein one or more hydrogen atoms of the above-mentioned groups may optionally be replaced by fluorine atoms.

Particularly preferred compounds are those wherein R5 and R7 each independently of one another denote C1-4-alkyl groups, wherein one or more hydrogen atoms of the C1-4-alkyl groups may optionally be replaced by fluorine atoms, wherein R5 is most preferably a methyl group and R7 is most preferably an ethyl or isopropyl group.

Preferred groups R6 and R9 are in each case selected independently of one another from among hydrogen, C1-6-alkyl, C3-7-cycloalkyl-C1-3-alkyl, C2-6-alkenyl and C2-6-alkynyl, wherein one or more hydrogen atoms of the above-mentioned groups may be replaced by fluorine.

In a particularly preferred embodiment of the compounds according to the invention R6 is hydrogen and R9 is selected from among hydrogen and C1-4-alkyl, wherein one or more hydrogen atoms of the C1-4-alkyl group may be replaced by fluorine.