WO2006040149A1 - Heterocyclic ketone compounds for treating alzheimer’s disease - Google Patents

Abstract

The present invention relates to novel ketone compounds' of formula (I) wherein, inter alla, A-B represents -NR5p'SO2-; -W- represents -CH2-, -(CH2)2-, -(CH2)3- or -C(H)=C(H)-; X-Y-Z represents -C=CR8-NR9-, having Asp2 (ß-secretase, BACE1 or Memapsin-2) inhibitory activity, processes for their preparation, to -compositions containing them and to their use in the treatment of diseases characterised by elevated ß- amyloid levels or ß-amyloid deposits, particularly Alzheimer's disease.

Description

HETEROCYCLIC KETOE COMPOUNDS FOR TREATING ALZHEIMER ' S DISEASE

The present invention relates to novel ketone compounds having Asp2 (β-secretase, BACE1 or Memapsin-2) inhibitory activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases characterised by elevated β- amyloid levels or β-amyloid deposits, particularly Alzheimer's disease.

Alzheimer's disease is a degenerative brain disorder in which extracellular deposition of β-amyloid (Aβ) in the form of senile plaques represents a key pathological hallmark of the disease (Selkoe, D. J. (2001) Physiological Reviews 81 : 741-766). The presence of senile plaques is accompanied by a prominent inflammatory response and neuronal loss. Aβ exists in soluble and insoluble, fibrillar forms and a specific fibrillar form has been identified as the predominant neurotoxic species (Vassar, R. and Citron, M. (2000) Neuron 27: 419-422). In addition it has been reported that dementia correlates more closely with the levels of soluble amyloid rather than plaque burden (Naslund, J. et al. (2000) J. Am. Med. Assoc. 12: 1571-1577; Younkin, S. (2001) Nat. Med. 1: 8-19). Aβ is known to be produced through the cleavage of the beta amyloid precursor protein (also known as APP) by an aspartyl protease enzyme known as Asp2 (also known as β- secretase, BACE1 or Memapsin-2) (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472).

Therefore, it has been proposed that inhibition of the Asp2 enzyme would reduce the level of APP processing and consequently reduce the levels of Aβ peptides found within the brain. Therefore, it is also thought that inhibition of the Asp2 enzyme would be an effective therapeutic target in the treatment of Alzheimer's disease.

APP is cleaved by a variety of proteolytic enzymes (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472). The key enzymes in the amyloidogenic pathway are Asp2 (β-secretase) and γ-secretase both of which are aspartic proteinases and cleavage of APP by these enzymes generates Aβ. The non-amyloidogenic, α-secretase pathway, which precludes Aβ formation, has been shown to be catalysed by a number of proteinases, the best candidate being ADAM10, a disintegrin and metalloproteinase. Asp1 has been claimed to show both α- and β-secretase activity in vitro. The pattern of expression of Asp1 and Asp2 are quite different, Asp2 is most highly expressed in the pancreas and brain while Asp1 expression occurs in many other peripheral tissues. The Asp2 knockout mouse indicates that lack of Asp2 abolished Aβ production and also shows that in this animal model endogenous Asp1 cannot substitute for the Asp2 deficiency (Luo, Y. et al. (2001 ) Nat Neurosci. 4: 231-232; Cai, H. et a/. (2001 ) Nat Neurosci. 4: 233-234; Roberds, S. L. et al. (2001) Hum. MoI. Genet. 10: 1317-1324). For an agent to be therapeutically useful in the treatment of Alzheimer's disease it is preferable that said agent is a potent inhibitor of the Asp2 enzyme, but should ideally also be selective for Asp2 over other enzymes of the aspartyl proteinase family, e.g. Cathepsin D (Connor, G. E. (1998) Cathepsin D in Handbook of Proteolytic Enzymes, Barrett, A. J., Rawlings, N. D., & Woesner, J. F. (Eds) Academic Press London. pp828- 836).

WO 2004/014843 (Takeda) and WO 2004/043916 (Merck) describe a series of ketone compounds having β-secretase activity which are implicated to be useful in the treatment of Alzheimer's disease. WO2005/058915 (Glaxo Group Ltd.; published 30 June 2005) describes a series of hydroxyethylamine compounds having β-secretase activity, and their use in the treatment of Alzheimer's disease.

We have found a novel series of compounds which are potent inhibitors of the Asp2 enzyme, thereby indicating the potential for these compounds to be effective in the treatment of disease characterised by elevated β-amyloid levels or β-amyloid deposits, such as Alzheimer's disease.

Thus, according to a first aspect of the present invention we provide a compound of formula (I):

(I) wherein

R¹ represents halogen or C_1-3 alkyl; R² represents Ci_-3 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, halogen, Ci_-3 alkoxy, amino, cyano or hydroxy; m represents an integer from 0 to 4; n represents an integer from 0 to 2;

A-B represents -NR⁵-SO₂-; R⁵ represents hydrogen, C_1-6 alkyl, C_3-6 alkenyl, C₃.₆ alkynyl, C_3-10 cycloalkyl, -C_0-6 alkyl- aryl, -C_0-6 alkyl-heteroaryl, -C_0-6 alkyl-heterocyclyl, -C_3-10 cycloalkyl-aryl, -C_3-10 cycloalkyl- heteroaryl or -C_3-10 cycloalkyl-heterocyclyl;

-W- represents -CH₂-, -(CHz)₂-, -(CHz)₃- or -C(H)=C(H)-;

X-Y-Z represents -C=CR⁸-NR⁹-; R⁸ represents hydrogen, C_1-6 alkyl or C_3-10 cycloalkyl; R⁹ represents hydrogen, C_1-6 alkyl, C_1-6 alkoxy, C_3--I₀ cycloalkyl, -C_0-6 alkyl-aryl, -C_0-6 alkyl- heteroaryl, -C_0-6 alkyl-heterocyclyl, -C_3-10 cycloalkyl-aryl, -C_3-I0 cycloalkyl-heteroaryl or - C_3--_Io cycloalkyl-heterocyclyl;

R³ represents C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, -Ci_-6 alkyl-C_3-10 cycloalkyl, -C_0-6 alkyl- aryl, -C_0-6 alkyl-heteroaryl or -C_0-6 alkyl-heterocyclyl;

R⁴ represents hydrogen, C_1-I0 alkyl, C_3-10 alkenyl, C_3-10 alkynyl, -C_3-10 cycloalkyl, -C_3-10 cycloalkenyl, -C_0-6 alkyl-aryl, -C_0-6 alkyl-heteroaryl, -C_0-6 alkyl-heterocyclyl, -C_1-6 alkyl-C₃_ io cycloalkyl, -C_3-10 cycloalkyl-aryl, -C_3-10 cycloalkyl-heteroaryl, -C_3-10 cycloalkyl- heterocyclyl, -C(R^aR^b)-CONH-C_1-6 alkyl, -C(R^aR^b)-CO N H-C_3-10 cycloalkyl, -C_2-6 alkyl-S-C,. ₆ alkyl, -C_2-6 alkyl-NR^cR^d, -C_2-6 alkyl-O-C₀-₆ alkyl-aryl, -C_2-6 alkyl-O-C_0-6 alkyl-heteroaryl or -C_2-6 alkyl-0-C_o-6 alkyl-heterocyclyl;

R^a and R^b independently represent hydrogen, Ci_-6 alkyl or R^a and R^b together with the carbon atom to which they are attached may form a C_3-i₀ cycloalkyl or heterocyclyl group; R^c and R^d independently represent hydrogen, C_1-6 alkyl, C_3-10 cycloalkyl or R^c and R^d together with the nitrogen atom to which they are attached may form a nitrogen containing heterocyclyl group; wherein said alkyl and cycloalkyl groups may be optionally substituted by one or more (e.g. 1 to 6) halogen, C_1-6 alkyl, haloC_1-6 alkyl, Ci_-6 alkoxy, haloCi_-6 alkoxy, Ci_-6 alkylamino, amino, cyano, hydroxy or -COOR²² groups; and wherein said aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (e.g. 1 to 5) Ci_-6 alkyl, halogen, haloC_1-6 alkyl, haloCi_-6 alkoxy, oxo, hydroxy, C_1-6 alkoxy, C_2-6 alkynyl, C_2-6 alkenyl, amino, cyano, nitro, -NR²²COR²³, -CONR²²R²³ - SO₂R²², -SO₂NR²²R²³, -COOR²², -Ci_-6 alkyl-NR²²R²³, -Ci_-6 alkyl-O-Ci_-6 alkyl or -Ci_-6 alkanoyl groups (wherein R²² and R²³ independently represent hydrogen, Ci_-6 alkyl or C_{3- 8} cycloalkyl); or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, the invention provides compounds of formula (I) wherein: R¹ represents halogen or Ci_-3 alkyl;

R² represents Ci_-3 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, halogen, Ci_-3 alkoxy, amino, cyano or hydroxy; m represents an integer from 0 to 4; n represents an integer from 0 to 2; A-B represents -NR⁵-SO₂- or -NR⁵-CO-;

R⁵ represents hydrogen, Ci_-6 alkyl, C_3-6 alkenyl, C_3-6 alkynyl, C_3-I0 cycloalkyl, -C_0-6 alkyl- aryl, -C_0-6 alkyl-heteroaryl, -C₀.₆ alkyl-heterocyclyl, -C_3-I0 cycloalkyl-aryl, -C_3-I0 cycloalkyl- heteroaryl or -C_3-I0 cycloalkyl-heterocyclyl; -W- represents -CH₂-, -(CH₂)₂-, -(CH₂)₃-, -C(H)=C(H)- Or -CH₂-C(H)=C(H)-; X-Y-Z represents -C=CR⁸-NR⁹-;

R⁸ represents hydrogen, C_1-6 alkyl or C_3-I0 cycloalkyl; R⁹ represents hydrogen, C_1-6 alkyl, C_1-6 alkoxy, C_3-10 cycloalkyl, -C_0-6 alkyl-aryl, -C_0-6 alkyl- heteroaryl, -C_0-6 alkyl-heterocyclyl, -C_3-i₀ cycloalkyl-aryl, -C_3-I0 cycloalkyl-heteroaryl or - C_3-10 cycloalkyl-heterocyclyl;

R³ represents C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, -C_1-6 alkyl-C_3-10 cycloalkyl, -C_0-6 alkyl- aryl, -C_0-6 alkyl-heteroaryl or -C_0-6 alkyl-heterocyclyl;

R⁴ represents hydrogen, C_1-10 alkyl, C_2-10 alkenyl, C_2-i₀ alkynyl, -C_3-10 cycloalkenyl, -C_0-6 alkyl-aryl, -C_0-6 alkyl-heteroaryl, -C_0-6 alkyl-heterocyclyl, -C_0-6 alkyl-C_3-10 cycloalkyl, -C_3-10 cycloalkyl-aryl, -C_3-I0 cycloalkyl-heteroaryl, -C_3-10 cycloalkyl-heterocyclyl, -C(R^aR^b)- CONH-C_1-6 alkyl, -C(R^aR^b)-CONH-C_3-10 cycloalkyl, -C_2-6 alkyl-S-C_1-6 alkyl, -C_2-6 alkyl- NR^cR^d, -C(R^aR^b)-C_0-6 alkyl-aryl, -C(R^aR^b)-C_0-6 alkyl-heteroaryl, -C(R^aR^b)-C_0-6 alkyl- heterocyclyl, -C_2-6 alkyl-O-Co-6 alkyl-aryl, -C_2-6 alkyl-O-C_0-6 alkyl-heteroaryl or -C_2-6 alkyl- 0-C_0-6 alkyl-heterocyclyl;

R^a and R^b independently represent hydrogen, C_1-6 alkyl or R^a and R^b together with the carbon atom to which they are attached may form a C_3--_I0 cycloalkyl or heterocyclyl group;

R⁰ and R^d independently represent hydrogen, Ci_-6 alkyl, C_3-10 cycloalkyl or R^c and R^d together with the nitrogen atom to which they are attached may form a nitrogen containing heterocyclyl group; wherein said alkyl and cycloalkyl groups may be optionally substituted by one or more (e.g. 1 to 6) halogen, C_1-6 alkyl, haloC-ι_-6 alkyl, Ci_-6 alkoxy, haloC_1-6 alkoxy, Ci_-6 alkylamino, amino, cyano, hydroxy or -COOR²² groups; and wherein said aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (e.g. 1 to 5) Ci_-6 alkyl, halogen, haloCi_-6 alkyl, haloCi.₆ alkoxy, oxo, hydroxy, Ci_-6 alkoxy, C_2-6 alkynyl, C_2-6 alkenyl, amino, cyano, nitro, -NR²²COR²³, -CONR²²R²³ - SO₂R²², -SO₂NR²²R²³, -COOR²², -Ci_-6 alkyl-NR²²R²³, -Ci_-6 alkyl-O-Ci_-6 alkyl or -Ci_-6 alkanoyl groups (wherein R²² and R²³ independently represent hydrogen, Ci_-6 alkyl or C_3-

₈ cycloalkyl); or a pharmaceutically acceptable salt or solvate thereof.

In a more particular aspect, R⁴ represents hydrogen, Ci_-I0 alkyl, C_3-I0 alkenyl, C_3-10 alkynyl, -C_3-I0 cycloalkenyl, -C_0-6 alkyl-aryl, -C_0-6 alkyl-heteroaryl, -C_0-6 alkyl-heterocyclyl, -C_0-6 alkyl-C_3-10 cycloalkyl, -C_3-10 cycloalkyl-aryl, -C_3-10 cycloalkyl-heteroaryl, -C_3-i₀ cycloalkyl-heterocyclyl, -C(R^aR^b)-CONH-Ci_-6 alkyl, -C(R^aR^b)-CONH-C_3-i₀ cycloalkyl, -C_2-6 alkyl-S-Ci_-6 alkyl, -C_2-6 alkyl-NR^cR^d, -C(R^aR^b)-C_o-6 alkyl-aryl, -C(R^aR^b)-C_o-6 alkyl- heteroaryl, -C(R^aR^b)-C_o-6 alkyl-heterocyclyl, -C_2-6 alkyl-0-C_o-6 alkyl-aryl, -C_2-6 alkyl-O-C_0-6 alkyl-heteroaryl or -C_2-6 alkyl-O-C_0-6 alkyl-heterocyclyl.

In another aspect, -W- represents -CH₂-, -(CH₂)₂-, -(CH₂)₃- or -C(H)=C(H)-, particularly - (CH₂)₂- or -(CH=CH)-.

In a further aspect, A-B represents -NR⁵-SO₂-. The term 'C_x-y alkyl' as used herein as a group or a part of the group refers to a linear or branched saturated hydrocarbon group containing from x to y carbon atoms. Examples of C_1-6alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.

The term 'C_x-y alkenyl' as used herein refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds and having from x to y carbon atoms. Examples of C_2-6alkenyl groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.

The term 'C_x-y alkynyl' as used herein refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and having from x to y carbon atoms. Examples of C₂.₆alkynyl groups include ethynyl, propynyl, butynyl, pentynyl or hexynyl and the like.

The term 'C_x-y alkoxy' as used herein refers to an -O-C_x-y alkyl group wherein C_x-y alkyl is as defined herein. Examples of C_1-6alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.

The term 'C_x-y cycloalkyl' as used herein refers to a saturated monocyclic or bridged hydrocarbon ring of x to y carbon atoms. Examples of saturated monocyclic C_3--_I0 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like. Examples of bridged hydrocarbon rings include tricyclodecyl, bicycloheptyl and the like. In one aspect, the term 'C_x-y cycloalkyl' refers to a saturated monocyclic hydrocarbon ring.

The term 'C_x-y cycloalkenyl' as used herein refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of x to y carbon atoms containing one or more carbon- carbon double bonds. Examples of C_3--_I0 cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.

The term 'halogen' as used herein refers to a fluorine, chlorine, bromine or iodine atom.

The term 'haloC_x-y alkyl' as used herein refers to a C_x-y alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen. Examples of haloC_1-6alkyl groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like.

The term 'halo C_x-y alkoxy' as used herein refers to a C_x-y alkoxy group as herein defined wherein at least one hydrogen atom is replaced with halogen. Examples of haloC-i. ₆alkoxy groups include difluoromethoxy or trifluoromethoxy and the like. The term 'aryl' as used herein refers to a C_6-12 monocyclic or tricyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or tetrahydronaphthalenyl and the like.

The term 'heteroaryl' as used herein refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur. Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like. Examples of such fused aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.

The term 'heterocyclyl' refers to a 4-7 membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or partially unsaturated, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur. Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, azepanyl and the like. Examples of such bicyclic rings include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1H-3-benzazepine, tetrahydroisoquinolinyl and the like.

The term 'nitrogen containing heterocyclyl' is intended to represent any heterocyclyl group as defined above which contains a nitrogen atom.

In one embodiment, R⁵ represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl or i-propyl) optionally substituted by one or more (e.g. 1, 2 or 3) halogen atoms (e.g. trifluoroethyl)or -C_0-6 alkyl-aryl (e.g. phenyl or benzyl).

In a more particular embodiment, R⁵ represents C_1-6 alkyl (e.g. methyl or ethyl) optionally substituted by one or more (e.g. 1 , 2 or 3) halogen atoms (e.g. trifluoroethyl). Even more particularly, R⁵ represents unsubstituted C_1-6 alkyl (e.g. methyl or ethyl) particularly methyl.

In one embodiment, -W- represents -(CH₂)₂- or -(CH=CH)-. More particularly, -W- represents -(CH₂J₂-- In another embodiment, m represents 0 or 2. In a more particular embodiment, m represents 0-1 , particularly 0.

In certain embodiments in which R¹ is present, R¹ represents C_1-3 alkyl (e.g. methyl).

In one embodiment, n represents 0.

In yet another embodiment, R⁸ represents hydrogen.

In a further embodiment, R⁹ represents hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl). In a more particular embodiment, R⁹ represents C_1-6 alkyl (e.g. ethyl, propyl, isopropyl or butyl), particularly ethyl.

In one embodiment, R³ represents -C_0-6 alkyl-aryl (e.g. benzyl) optionally substituted by one or two halogen atoms (e.g. chlorine or fluorine). For example, R³ preferably represents unsubstituted benzyl, 3-chlorobenzyl, 3-fluorobenzyl or 3,5-difluorobenzyl. In a more particular embodiment, R³ represents unsubstituted benzyl.

In one embodiment, R⁴ represents C_1-10 alkyl, C_3-10 alkenyl, C_3-1oalkynyl, C_0-6alkylC_{3- 1o}cycloalkyl (i.e. C_3-1ocycloalkyl and/or C_1-6alkylC_3-i₀cycloalkyl), C^ocycloalkenyl, C_{0- 6}alkyl-aryl, C_0-6alkyl-heteroaryl, Co-ealkyl-heterocyclyl or C_2-6 alkyl-S-C_1-6 alkyl.

In a more particular embodiment, the aryl, heteroaryl and heterocyclyl groups of R⁴ may optionally be substituted by one or more (e.g. 1 , 2 or 3) substituents selected from the group consisting of halogen, C_1-6alkyl, C₁^aIkOXy, haloC_1-6alkyl and haloC_1-6alkoxy. More particularly, the substituents are selected from the group consisting of C_1-6alkyl, C_{1- 6}alkoxy or haloC_1-6alkyl.

In certain embodiments in which the aryl, heteroaryl or heterocyclyl groups of R⁴ are 6 membered rings that are substituted by one substituent, the substituent is in the 3- position relative to the attachment position.

In a more particular embodiment, the alkyl, and cycloalkyl groups of R⁴ may optionally be substituted by one or more (e.g. 1 to 6) substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy and C₂.₆alkynyl. More particularly, the substituents are selected from halogen, C_1-6alkoxy, haloC_1-6alkoxy and C_2-6alkynyl.

In an even more particular embodiment, R⁴ represents:

C_1-10 alkyl (e.g. ethyl, propyl, butyl, 1-methylpropyl, 2-ethylbutyl, 3-methylbutyl, 1- propylbutyl, 3,3-dimethylbutyl, 1 ,5-dimethylhexyl or 1 ,1 ,5-trimethylhexyl) optionally substituted by one or more halogen (e.g fluorine) atoms, C_1-6alkoxy groups (e.g. methoxy or propoxy) or haloC_1-6alkoxy groups (e.g. 2,2,2-trifluoroethoxy);

C_3-10 alkenyl (e.g. propenyl, 2-methyl-2-propenyl, 3-butenyl, 3-methyl-2-butenyl);

C_3-10 alkynyl (e.g. propynyl, 2-butynyl, 2-pentynyl, 1 ,1-dimethyl-2-propynyl); C_o-6alkylC_3-1o cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, cyclohexylethyl, tricyclodecyl or bicycloheptyl) optionally substituted by one or more halogen atoms (e.g. fluorine), C_1-6 alkyl groups (e.g. methyl, ethyl or propyl) or C₂-₆alkynyl (e.g. ethynyl);

(e.g. cyclopentenyl); C_o-6alkyl-aryl (e.g. phenyl or benzyl) optionally substituted by one or more halogen (e.g. chlorine) atoms, C_1-6alkyl (e.g. methyl), Ci_-6alkoxy (e.g. methoxy), haloC-i. ₆alkyl (e.g. trifluoromethyl), or haloCi_-6alkoxy (e.g. trifluoromethoxy) groups;

C_o-6alkyl-heteroaryl (e.g. CH₂-thienyl, CH₂-isoxazolyl, CH₂-pyrazolyl or CH₂- pyridinyl) optionally substituted by one or more C_1-6alkyl (e.g. methyl or ethyl) or haloC-i. ₆alkyl (e.g. 2,2,2-trifluoroethyl) groups;

Co-βalkyl-heterocyclyl (e.g. tetrahydropyranyl);

C_2-6 alkyl-S-C_1-6 alkyl (e.g. -ethyl-S-methyl, -ethyl-S-ethyl or -ethyl-S-tert butyl).

More particularly, R⁴ represents: C_1--_I0 alkyl (e.g. ethyl, propyl, butyl, 1-methylpropyl, 2-ethylbutyl, 3-methylbutyl, 1- propylbutyl, 3,3-dimethylbutyl, 1 ,5-dimethylhexyl or 1 ,1 ,5-trimethylhexyl) optionally substituted by one or more halogen (e.g. fluorine) atoms (to give, for example, 2- fluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl or 2,2,3,3,3-pentafluoropropyl), Ci_-6alkoxy groups (e.g. methoxy or propoxy) or haloC^ ₆alkoxy groups (e.g. 2,2,2-trifluoroethoxy); C_3-10 alkynyl (e.g. propynyl);

C_o-6alkylC_3-1o cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl or cyclohexylethyl) optionally substituted by one or more halogen atoms (e.g. fluorine) or C_1-6 alkyl groups (e.g. methyl, ethyl or propyl); C_o-6alkyl-aryl (e.g. phenyl or benzyl) optionally substituted by one or more halogen (e.g. chlorine) atoms, C-ι_-6alkyl (e.g. methyl), C_1-6alkoxy (e.g. methoxy), haloC-i. ₆alkyl (e.g. trifluoromethyl), or haloC_1-6alkoxy (e.g. trifluoromethoxy) groups;

C_o-6alkyl-heteroaryl (e.g. CH₂-thienyl, CH₂-isoxazol, CH₂-pyrazolyl or CH₂- pyridinyl) optionally substituted by one or more C-^alkyl (e.g. methyl or ethyl) or haloC-i. ₆alkyl (e.g. 2,2,2-trifluoroethyl) groups; or

C_o-6alkyl-heterocyclyl (e.g. tetrahydropyranyl).

Even more particularly, R⁴ represents heterocyclyl (e.g. tetrahydropyranyl) or C_3-i₀ alkynyl (e.g. propynyl). Most particularly, R⁴ represents heterocyclyl (e.g. tetrahydropyranyl), particularly tetrahydropyran-4-yl. In one aspect, the invention provides compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein: m and n represent 0;

A-B represents -NR⁵-SO₂-; R⁵ represents C_1-6 alkyl;

-W- represents -(CH₂)_Z- or -C(H)=C(H)-;

X-Y-Z represents -C=CR⁸-NR⁹-;

R⁸ represents hydrogen;

R⁹ represents C_1-6 alkyl; R³ represents -C_0-6 alkyl-aryl;

R⁴ represents C_1-10 alkyl, C_3-i₀ alkenyl, C_3-10alkynyl, C_o-6alkylC_3-i₀cycloalkyl, C_3-

₁₀cycloalkenyl, C_0-6alkyl-aryl, C₀-₆alkyl-heteroaryl, Co-ealkyl-heterocyclyl or C_2-6 alkyl-S-Ci. β alkyl; wherein the alkyl and cycloalkyl groups of R⁴ may be optionally substituted by one or more (e.g. 1 to 6) halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy or C_2-

₆alkynyl groups; and wherein the aryl, heteroaryl and heterocyclyl groups of R⁴ may optionally be substituted by one or more (e.g. 1 , 2 or 3) halogen, C_1-6alkyl, C_1-6alkoxy, haloC_1-6alkyl and haloC_1-6alkoxy groups.

In a more particular aspect, the invention provides compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein: m and n represent 0;

A-B represents -NR⁵-SO₂-; R⁵ represents C_1-6 alkyl;

-W- represents -(CH₂)₂-;

X-Y-Z represents -C=CR⁸-NR⁹-;

R⁸ represents hydrogen;

R⁹ represents C_1-6 alkyl; R³ represents benzyl;

R⁴ represents C_1--_I0 alkyl, C_3-1oalkynyl, C_o-6alkylC_3-1ocycloalkyl, C_o-6alkyl-aryl, C_o-6alkyl- heteroaryl or Co-ealkyl-heterocyclyl; wherein the alkyl and cycloalkyl groups of R⁴ may be optionally substituted by one or more (e.g. 1 to 6) halogen, C_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy or C_2-6alkynyl groups; and wherein the aryl, heteroaryl and heterocyclyl groups of R⁴ may optionally be substituted by one or more (e.g. 1 , 2 or 3) C_1-6alkyl, C_1-6alkoxy or haloCi_-6alkyl groups.

Compounds according to the invention include example E1 as shown below, or a pharmaceutically acceptable salt or solvate thereof.

The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. ScL, 1977, 66, 1-19, such as acid addition salts formed with inorganic or organic acids e.g. hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, nitrates, succinates, lactates, tartrates, fumarates, maleates, 1-hydroxy-2-naphthoates, palmoates, methanesulphonates, p-toluenesulphonates, naphthalenesulphonates, formates or trifluoroacetates. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.

The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, e.g. as the hydrate. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I) including hydrates and solvates as well as compounds containing variable amounts of solvent (e.g water).

Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof. Preferably, compounds of formula (I) are in the form of a single enantiomer of formula (Ia):

(Ia)

The compounds of formula (I) and salts and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention. A process according to the invention for preparing a compound of formula (I) which comprises:

(a) oxidation of a

(H) wherein R¹, R², R³, R⁴, m, n, A, B, W, X, Y and Z are as defined above and P¹ represents a suitable protecting group such as -COOC(CH₃)₃ followed by deprotection to remove the P¹ protecting group;

(b) deprotecting a compound of formula (I) which is protected; or

(c) interconversion from one compound of formula (I) to another.

Process (a) typically comprises the use of an oxidising reagent such as Dess-Martin periodinane in an appropriate solvent such as dichloromethane at an appropriate range of temperature such as O⁰C to room temperature.

In processes (a) and (b), examples of protecting groups and the means for their removal can be found in T. W. Greene and P. G. M. Wuts 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 3rd Ed. 1999). Suitable amine protecting groups include aryl sulphonyl (e.g. tosyl), acyl (e.g. acetyl), carbamoyl (e.g. benzyloxycarbonyl or t- butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate. Other suitable amine protecting groups include trifluoroacetyl (-COCF₃) which may be removed by base catalysed hydrolysis. Suitable hydroxy protecting groups would be silyl based groups such as t-butyldimethylsilyl, which may be removed using standard methods, for example use of an acid such as trifluoroacetic or hydrochloric acid or a fluoride source such as tetra n-butylammonium fluoride.

Process (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, aromatic substitution, ester hydrolysis, amide bond formation or removal and sulphonylation. For example, compounds of formula (I) wherein W represents -C(H)=C(H)- or -CH₂-C(H)=C(H)- may be converted to compounds of formula (I) wherein W represents -(CH₂)₂- or -(CH₂)₃- by catalytic hydrogenation. Compounds of formula (II) may be prepared in accordance with procedures described in WO2005/058915 (published 30 June 2005), which claims priority from GB Patent Application 0328900.6.

As a further aspect of the invention there is thus provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical, particularly in the treatment of patients with diseases characterised by elevated β- amyloid levels or β-amyloid deposits.

According to another aspect of the invention, there is provided the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with diseases characterised by elevated β- amyloid levels or β-amyloid deposits.

In a further or alternative aspect there is provided a method for the treatment of a human or animal subject with diseases characterised by elevated β-amyloid levels or β-amyloid deposits, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.

As a further aspect of the invention there is thus provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of diseases characterised by elevated β-amyloid levels or β-amyloid deposits.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of diseases characterised by elevated β-amyloid levels or β-amyloid deposits.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in the therapy of diseases characterised by elevated β-amyloid levels or β-amyloid deposits, comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together, if desirable, with one or more physiologically acceptable diluents or carriers.

It will be appreciated that diseases characterised by elevated β-amyloid levels or β- amyloid deposits include Alzheimer's disease, mild cognitive impairment, Down's syndrome, hereditary cerebral haemorrhage with β-amyloidosis of the Dutch type, cerebral β-amyloid angiopathy and various types of degenerative dementias, such as those associated with Parkinson's disease, progressive supranuclear palsy, cortical basal degeneration and diffuse Lewis body type of Alzheimer's disease. Most preferably, the disease characterised by elevated β-amyloid levels or β-amyloid deposits is Alzheimer's disease.

There is also provided a process for preparing such a pharmaceutical formulation which comprises mixing the ingredients.

Compounds of formula (I) may be used in combination with other therapeutic agents. Suitable examples of such other therapeutic agents may be acetylcholine esterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), gamma secretase inhibitors, histamine H3 antagonists, 5HT4 partial agonists, anti¬ inflammatory agents (such as cyclooxygenase Il inhibitors), antioxidants (such as Vitamin E and ginkolidesor), statins or p-glycoprotein (P-gp) inhibitors (such as cyclosporin A, verapamil, tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines, acridine derivatives such as GF120918, FK506, VX-710, LY335979 and PSC-833).

When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

The compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, enteral, parenteral, topical, sublingual, intrathecal or rectal administration, preferably for oral administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p- hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate. For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

The compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multi-dose containers with an added preservative. The compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. The dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.

When the compounds of the invention are administered topically they may be presented as a cream, ointment or patch.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.

The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 3000 mg; and such unit doses may be administered more than once a day, for example one, two, three or four times per day (preferably once or twice); and such therapy may extend for a number of weeks, months or years.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

Examples

Intermediates and compounds of the invention are characterised by their retention time (R.T.) in analytic LCMS. Analytical LCMS is conducted as described below:

• Column: Waters Atlantis 4.6mmx50mm ; 3 μm particle size • Flow Rate: 3ml/min

• Injection Volume: 5μl

• Temp: 30⁰C

• UV Detection Range: 220 to 330nm •

Solvents: A. Water + 0.05% Formic acid

B: Acetonitrile + 0.05% Formic Acid

Gradient: Time B%

0.00 3

0.10 3

4.00 97

4.80 97

4.90 3

5.00 3

Preparation of Intermediates

Description 1 1 ,1 -Dimethylethyl ((2/?,3S)-3-{[(6-ethyl-1 -methyI-2,2-dioxido-1 ,3,4,6- tetrahydro[1,2]thiazepino[5,4,3-cc/]indoI-8-yl)carbonyI]amino}-2-hydroxy-4- phenylbutyl)tetrahydro-2H-pyran-4-yl carbamate (D1)

6-Ethyl-Λ/-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4- ylamino)propyl]-1 -methyl-1 ,3,4,6-tetrahydro[1 ,2]thiazepino[5,4,3-cc(]indole-8- carboxamide 2,2-dioxide (may be prepared as described in Example 4 of

WO2005/058915) (0.083 g, 0.15 mmole) was dissolved in dry dichloromethane (2 ml) and treated with di-tertbutoxy dicarbonate (0.036 g, 0.165 mmol). The mixture was stirred at room temperature overnight and then evaporated. The residue was purified by column chromatography (eluting with hexane/ethyl acetate) to give the title compound (D1 ; 0.078 g) as a white foam. [M+H]+ = 655.3, RT = 3.26 min.

Description 2 1 ,1 -Dimethylethyl ((3S)-3-{[(6-ethyl-1 -methyl-2,2-dioxido-1 ,3,4,6- tetrahydro[1,2]thiazepino[5,4,3-cofjindol-8-yl)carbonyl]amino}-2-oxo-4- phenylbutyl)tetrahydro-2H-pyran-4-yIcarbamate (D2)

1 ,1 -Dimethylethyl ((2f?,3S)-3-{[(6-ethyl-1-methyl-2,2-dioxido-1 ,3,4,6- tetrahydro[1 ,2]thiazepino[5,4,3-cc(]indol-8-yl)carbonyl]amino}-2-hydroxy-4- phenylbutyl)tetrahydro-2H-pyran-4-yl carbamate (may be prepared as described in Description 1 ) (0.073 g, 0.112 mmole) was dissolved in dry dichloromethane (4 ml) and treated with Dess-Martin periodinane (0.071 g, 0.168 mmol). The mixture was stirred at room temperature for 1 hr and then treated with a saturated aqueous solution of sodium hydrogen carbonate containing 10% w/v sodium thiosulphate (5 ml) for 0.5 hr. The organic layer was then separated and evaporated in-vacuo. The residue was purified by column chromatography (eluting with hexane/ethyl acetate) to give the title compound (D2; 0.053 g) as a pale yellow foam. [M-H]- = 651.5, RT = 3.39 min.

Example 1

6-Ethyl-1 -methyl-yv-[(1 S)-2-oxo-1 -(phenyImethyl)-3-(tetrahydro-2H-pyran-4- ylamino)propyl]-1,3,4,6-tetrahydro[1,2]thiazepino[5,4,3-c(/]indoIe-8-carboxamide 2,2-dioxide 4-methylbenzenesulfonate (E1)

A solution of 0.047g of 1 ,1 -dimethylethyl ((3S)-3-{[(6-ethyl-1-methyl-2,2-dioxido-1 , 3,4,6- tetrahydro[1 ,2]thiazepino[5,4,3-co]indol-8-yl)carbonyl]amino}-2-oxo-4- phenylbutyl)tetrahydro-2/-/-pyran-4-ylcarbamate (may be prepared as described in Description 2) in dry dioxane (2.5 ml) at room temperature was treated with toluenesulfonic acid monohydrate (0.041 g, 0.216 mmol). After stirring overnight at room temperature the solid that had precipitated was collected by filtration. The solid was washed with more dioxane and then dried in vacuo to give 0.042 g of the title compound (E1) as a white solid. [M+H]+ = 553.5, RT = 2.25 min.

Compounds of the invention may be tested for in vitro biological activity in accordance with the following assays:

Asp-2 inhibitory assay

For each compound being assayed, in a 384 well plate, is added:- a) 0.5μl of a DMSO solution of the test compound (IC₅₀ curve uses eleven 1 in 3 serial dilutions from 100 μM). b) 10 μl of substrate (FAM-[SEVNLDAEFK]-TAMRA ) solution in buffer A. This is prepared by diluting 2ml of a 2mM DMSO solution of the substrate into 400ml of buffer A (10OmM Sodium acetate pH = 4.5, 1 I MiIIi-Q water, 0.06% Triton X-100 (0.5 ml/I) , pH adjusted to 4.5 using glacial acetic acid). Aminomethyl fluorescein (FAM) and tetramethyl rhodamine (TAMRA) are fluorescent molecules which co-operate to emit fluorescence at 535nm upon cleavage of the SEVNLDAEFK peptide. c) 10 μl enzyme solution. This is prepared by performing a 1 in 1750 dilution of a 3.5 μM enzyme stock in buffer B (100 mM Sodium acetate pH 4.5, 40 mM Sodium chloride, 10% (v/v) Glycerol, 0.2% (w/v) CHAPS). Blank wells (enzyme solution replaced by buffer) are included as controls on each plate. Wells are incubated for 4h at room temperature and fluorescence read using an LJL analyst spectrophotometer ( 485nm excitation, 535nm emission).

(II) Cathepsin D inhibitory assay For each compound being assayed, in a 384 well plate, is added:- a) 0.5μl of a DMSO solution of the test compound (IC₅₀ curve uses eleven 1 in 3 serial dilutions from 100 μM). b) 10 μl of substrate (FAM-[SEVNLDAEFK]-TAMRA ) solution in buffer. This is prepared by diluting 2ml of a 2mM DMSO solution of the substrate into 400ml of buffer A (10OmM Sodium acetate pH = 4.5, 1 I MiIIi-Q water, 0.06% Triton X-100 (0.5 ml/I) , pH adjusted to 4.5 using glacial acetic acid). c) 10 μl enzyme solution. This is prepared by performing a 1 in 2000 dilution of a 150 unit/ml (in 2OmM MES pH4.5, 15OmM NaCI, 0.5% (v/v) Triton X-100, 2mM EDTA) solution of Cathepsin D in buffer A (prepared as above). Blank wells (enzyme solution replaced by buffer) are included as controls on each plate. Wells are incubated for 1h at room temperature and fluorescence read using an LJL analyst spectrophotomer ( 485 nm excitation, 535nm emission).

Pharmacological Data

The compound of Example E1 was tested in the Asp-2 inhibitory assay and the Cathepsin D inhibitory assay and exhibited inhibition <10μM in the Asp-2 inhibitory assay and > 10 fold selectivity for Asp2 over CatD.

Abbreviations

DMF dimethylformamide

DMSO dimethylsulfoxide

DMAP 4-(dimethylamino)pyridine DABCO 1 ,4-diazabicyclo [2.2.2] octane

DME dimethyl ether

THF tetrahydrofuran HOBT N-hydroxybenzotriazole

FAM carboxyfluorescein

TAMRA carboxytetramethylrhodamine

[ ] single amino acid letter code relating to peptide sequence

Claims

Claims

1. A compound

(I) wherein

R¹ represents halogen or Ci_-3 alkyl;

R² represents C_1-3 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, halogen, Ci_-3 alkoxy, amino, cyano or hydroxy; m represents an integer from 0 to 4; n represents an integer from 0 to 2;

A-B represents -NR⁵-SO₂-;

R⁵ represents hydrogen, Ci_-6 alkyl, C_3-6 alkenyl, C_3-6 alkynyl, C₃.₁₀ cycloalkyl, -C_0-6 alkyl- aryl, -C_0-6 alkyl-heteroaryl, -C_0-6 alkyl-heterocyclyl, -C₃_io cycloalkyl-aryl, -C₃.₁₀ cycloalkyl- heteroaryl or -C_3-i₀ cycloalkyl-heterocyclyl;

-W- represents -CH₂-, -(CHz)₂-, -(CHz)₃- or -C(H)=C(H)-;

X-Y-Z represents -C=CR⁸-NR⁹-;

R⁸ represents hydrogen, Ci_-6 alkyl or C_3-10 cycloalkyl;

R⁹ represents hydrogen, Ci_-6 alkyl, Ci_-6 alkoxy, C_3-10 cycloalkyl, -C_0-6 alkyl-aryl, -C_0-6 alkyl- heteroaryl, -C_0-6 alkyl-heterocyclyl, -C_3-10 cycloalkyl-aryl, -C_3-I0 cycloalkyl-heteroaryl or -

C_3-I0 cycloalkyl-heterocyclyl;

R³ represents Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, -Ci_-6 alkyl-C_3-10 cycloalkyl, -C_0-6 alkyl- aryl, -C_0-6 alkyl-heteroaryl or -C_0-6 alkyl-heterocyclyl;

R⁴ represents hydrogen, C_1-I0 alkyl, C_3-10 alkenyl, C_3-10 alkynyl, -C_3-10 cycloalkyl, -C_3-10 cycloalkenyl, -C_0-6 alkyl-aryl, -C_0-6 alkyl-heteroaryl, -C_0-6 alkyl-heterocyclyl, -Ci_-6 alkyl-C_3-

_1o cycloalkyl, -C_3-10 cycloalkyl-aryl, -C_3-10 cycloalkyl-heteroaryl, -C_3--_I0 cycloalkyl- heterocyclyl, -C(R^aR^b)-CONH-C_1-6 alkyl, -C(R^aR^b)-CONH-C_3-10 cycloalkyl, -C_2-6 alkyl-S-d.

₆ alkyl, -C_2-6 alkyl-NR^cR^d, -C_2-6 alkyl-0-C_o-6 alkyl-aryl, -C_2-6 alkyl-0-C_o-6 alkyl-heteroaryl or

-C_2-6 alkyl-O-C_0-6 alkyl-heterocyclyl; R^a and R^b independently represent hydrogen, C_1-6 alkyl or R^a and R^b together with the carbon atom to which they are attached may form a C_3-10 cycloalkyl or heterocyclyl group;

R^c and R^d independently represent hydrogen, C_1-6 alkyl, C_3-10 cycloalkyl or R^c and R^d together with the nitrogen atom to which they are attached may form a nitrogen containing heterocyclyl group; wherein said alkyl and cycloalkyl groups may be optionally substituted by one or more (e.g. 1 to 6) halogen, C_1-6 alkyl, haloC_1-6 alkyl, Ci_-6 alkoxy, [IaIoC_1-6 alkoxy, Ci_-6 alkylamino, amino, cyano, hydroxy or -COOR²² groups; and wherein said aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (e.g. 1 to 5) Ci_-6 alkyl, halogen, haloC_1-6 alkyl, haloC_1-6 alkoxy, oxo, hydroxy, Ci_-6 alkoxy, C_2-6 alkynyl, C_2-6 alkenyl, amino, cyano, nitro, -NR²²COR²³, -CONR²²R²³ - SO₂R²², -SO₂NR²²R²³, -COOR²², -Ci_-6 alkyl-NR²²R²³, -Ci_-6 alkyl-O-Ci_-6 alkyl or -Ci_-6 alkanoyl groups (wherein R²² and R²³ independently represent hydrogen, Ci_-6 alkyl or C_{3- 8} cycloalkyl); or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1 which is a compound of formula E1 or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or claim 2 or a pharmaceutically acceptable salt or solvate thereof in admixture with one or more pharmaceutically acceptable diluents or carriers.

4. A compound of formula (I) as defined in claim 1 or claim 2 or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical.

5. Use of a compound of formula (I) as defined in claim 1 or claim 2 or a pharmaceutically acceptable salt or solvate thereof in the treatment of diseases characterised by elevated β-amyloid levels or β-amyloid deposits.

6. Use of a compound of formula (I) as defined in claim 1 or claim 2 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of diseases characterised by elevated β-amyloid levels or β-amyloid deposits.

7. A method of treatment or prophylaxis of diseases characterised by elevated β- amyloid levels or β-amyloid deposits which comprises administering to a patient an effective amount of a compound of formula (I) as defined in claim 1 or claim 2 or a pharmaceutically acceptable salt or solvate thereof.

8. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or claim 2 or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of diseases characterised by elevated β-amyloid levels or β-amyloid deposits.