WO2005113525A1

WO2005113525A1 - N, n’-substituted-1,3-diamino-2-oxopropane derivatives, their pharmaceutical compositions and use

Info

Publication number: WO2005113525A1
Application number: PCT/EP2005/005586
Authority: WO
Inventors: Emmanuel Hubert Demont; Sally Redshaw; Daryl Simon Walter
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2004-05-21
Filing date: 2005-05-19
Publication date: 2005-12-01
Anticipated expiration: 2006-11-21
Also published as: GB0411404D0

Abstract

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.

Description

N, N'-SUBSTITUTED-1 ,3-DIAMINO-2-OXOPROPANE DERIVATIVES, THEIR PHARMACEUTICAL COMPOSITIONS AND USE

Alzheimer's disease is a degenerative brain disorder in which extracellular deposition of 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, β-amyloid (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. al. (2001 ) Nat Neurosci. 4: 233-234; Roberds, S. L. er a/. (2001) Hum. Mol. 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 04/014843 (Takeda) describes a series of ketones having β-secretase activity which are implicated to be useful in the treatment of Alzheimer's disease. WO 01/70672, WO 02/02512, WO 02/02505, WO 02/02506 and WO 03/040096 (Elan Pharmaceuticals Inc.) describe a series of hydroxyethylamine compounds having β-secretase activity which are implicated to be useful 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 Alzheimer's disease.

Thus, according to a first aspect of the present invention we provide a compound of formula

(I) wherein

R¹ represents Cι.₆ alkyl, C₂.₆ alkenyl, halogen, C_1-6 alkoxy, amino, cyano, hydroxy, aryl, heteroaryl or heterocyclyl;

R^2a represents hydrogen, C_1-3 alkyl, C_1-3 alkoxy or halogen; m and n independently represent 0, 1 or 2; X represents CO, SO or SO₂; p represents an integer from 1 to 3;

R^2b represents hydrogen, C_1-6 alkyl, C_2-6 alkenyl, halogen, C_1-6 alkoxy, amino, cyano, hydroxy, aryl, heteroaryl or heterocyclyl;

R³ represents halogen, C_1-6 alkyl, C₂.₆ alkenyl, aryl, heteroaryl, heterocyclyl, -Cι_-6 alkyl-aryl, - Cι-₆ alkyl-heteroaryl, -C_1-6 alkyl-heterocyclyl, -C₂.₆ alkenyl-aryl, -C_2-6 alkenyl-heteroaryl, -C_2-6 alkenyl-heterocyclyl, C_3-8 cycloalkyl, -C_1-6 alkyl-C₃.₈ cycloalkyl, cyano, azido, nitro, -NR⁷R⁸, - NR⁹COR¹⁰, -NR¹¹SO₂R¹², -OR¹³, -SO₂R¹⁴, -SR¹⁵, -C≡CR¹⁶, -C_1-6 alkyl-(CF₂)_qCF₃, -CONR¹⁷R¹⁸, COOR¹⁹, -C_1-6 alkyl-NR²⁰R²¹ or -Cι.₆ alkyl-N₃, or R³ and R² together with the phenyl group to which they are attached form a naphthyl or benzofused heterocyclic or heteroaryl ring optionally substituted by one or two d-6 alkyl groups;

R⁴ represents -C₂.₆ alkynyl, -C^ alkyl-aryl, -Cι_-6 alkyl-heteroaryl or -C_1-6 alkyl-heterocyclyl; R⁵ represents hydrogen, -C_1-10 alkyl, -C₃.ι₀ cycloalkyl, -C_3-10cycloalkenyl, aryl, heteroaryl, heterocyclyl, -Cι_-6 alkyl-C₃-₁₀ cycloalkyl, -C3.10 cycloalkyl-CL.10 alkyl, -C₃.₁₀ cycloalkyl-Cι_-6 alkylaryl, -C₃.ιo cycloalkyl-aryl, -C_1-6 alkyl-aryl-heteroaryl, -C(R^aR^b)-CONH-C^ alkyl, -C(R^cR^d)- CONH-C3.10 cycloalkyl, -Cι_-6 alkyl-S-C_1-6 alkyl, -C^ alkyl-NR^eR^f, -C_1-6 alkyl-aryl, -C^ alkyl- heteroaryl, -C_1-6 alkyl-heterocyclyl -C_1-6 alkyl-C_1-6 alkoxy-aryl, -C_1-6 alkyl-d-e alkoxy-heteroaryl or -C_1-6 alkyl-C_1-6 alkoxy-heterocyclyl;

R⁷, R⁸, R⁹, R¹⁰, R¹³, R¹⁴, R ⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R² independently represent hydrogen,

C_1-6 alkyl, C₂.₆ alkenyl, C_3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C_1-6 alkyl-C_3-8 cycloalkyl, -

Cι_-6 alkyl-aryl, -C_1-6 alkyl-heteroaryl, -C_1-6 alkyl-heterocyclyl or -CO-C_1-6 alkyl;

R ¹, R¹², R^a, R^c, R^e and R^f independently represent hydrogen, C_1-6 alkyl or C_3-8 cycloalkyl;

R^b and R^d independently represent hydrogen, C_1-6 alkyl, C₃_s cycloalkyl or -Ci_-6 alkyl-SO₂-C_1-6 alkyl; q represents 1 to 3; wherein said alkyl groups may be optionally substituted by one or more (eg. 1, 2 or 3) halogen, Cι_-6 alkyl, C_1-6 alkoxy, C₂.₆ alkenoxy, C_3-8 cycloalkyl, amino, cyano or hydroxy groups; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (eg. 1 , 2 or 3) C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, haloC_1-6 alkyl, -OCF₃, oxo, C_1-6 alkoxy, -C^ alkoxy-CN, amino, cyano, nitro, -NR²²COR²³, -CONR²²R²³,

-COOR²², -SO₂R²², -C_1-6 alkyl-NR²² R²³ (wherein R²² and R²³ independently represent hydrogen or C_1-6 alkyl), -C_1-6 alkyl-C_1-6 alkoxy, -C_1-6 alkanol or hydroxy groups; or a pharmaceutically acceptable salt or solvate thereof.

References to alkyl include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl. It will be appreciated that references to alkenyl and alkenoxy shall be interpreted similarly. It will also be appreciated that when an alkenyl or alkenoxy group is attached to an O, N or S atom the double bond is not at the alpha position relative to said O, N or S atom.

References to haloC_1-6 alkyl include references to both straight chained and branched chain aliphatic isomers of C_1-6 alkyl in which one or more hydrogen atoms are substituted by halogen atoms (eg. fluorine, chlorine or bromine). Examples of haloC_1-6 alkyl groups include - CH₂CF₃ and -CF₃.

References to cycloalkyl include references to all alicyclic (including branched) isomers of the corresponding alkyl. When a cycloalkyl group is substituted by two or more C_1-6 alkyl groups, said cycloalkyl groups together with any two alkyl groups may form a bridged cycloalkyl group which includes bicycloheptyl, adamantyl, bicyclo-octyl and the like.

References to 'aryl' include references to monocyclic carbocyclic aromatic rings (eg. phenyl) and bicyclic carbocyclic aromatic rings (e.g. naphthyl) or carbocyclic benzofused rings (eg. C_3- ₈ cycloalkyl fused to a phenyl ring, such as dihydroindenyl or tetrahydronaphthalenyl).

References to 'heteroaryl' include references to mono- and bicyclic heterocyclic aromatic rings which monocyclic or bicyclic rings contain 1-4 hetero atoms selected from nitrogen, oxygen and sulphur. Examples of monocyclic heterocyclic aromatic rings include e.g. thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, tetrazolyl and the like. Examples of bicyclic heterocyclic aromatic rings include eg. quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.

References to 'heterocyclyl' include references to a 5-7 membered non-aromatic monocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen. Examples of heterocyclic non-aromatic rings include e.g. morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxathianyl, dithianyl, dioxanyl, pyrrolidinyl, dioxolanyl, oxathiolanyl, imidazolidinyl, pyrazolidinyl and the like.

References to 'benzofused heterocyclyl or heteroaryl ring' include quinolinyl, isoquinolinyl, indolyl, indazolyl, dihydroindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, dihydrochromene, benzotriazolyl, tetrahydroquinoxalinyl and the like.

In one aspect, m is 0 or 1. In a more particular aspect, m is 0. In one embodiment in which m represents 1 , R¹ is aryl (eg. phenyl).

In one embodiment, n is 0 or 1. In a more particular embodiment, n is 1.

When n represents 1 , R^2a is C_1-3 alkoxy (eg. methoxy) or halogen (eg. fluorine). In a more particular embodiment, R^2a is halogen (eg. fluorine).

In one embodiment in which n represents 1 , R^2a is in the position ortho to the sultam or lactam substituent of the phenyl ring.

In one embodiment in which X represents SO₂, p is 1 , 2 or 3. In a more particular embodiment in which X represents SO₂, p is 2.

In another embodiment in which X represents CO, p is 1 or 2. In a more particular embodiment in which X represents CO, p is 1.

In one aspect, R^2b is : hydrogen; halogen (eg. chlorine or fluorine); C_1-6 alkyl (eg. methyl); C_1-6 alkoxy (eg. methoxy); or heterocyclyl (eg. pyrrolidinyl) optionally substituted by an oxo group (eg. 2- oxopyrrolidin-1-yl).

In a more particular aspect, R^2b is hydrogen or halogen (eg. fluorine), particularly hydrogen. In another aspect, R³ represents: C_1-6 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl) optionally substituted by one or more (eg. 1 , 2 or 3) hydroxy, halogen (eg. fluorine) or C_1-6 alkoxy groups (eg. methoxy or ethoxy); C-₂.₆ alkenyl (eg. propenyl); C_3-8 cycloalkyl (eg. cyclopentyl or cyclohexyl); cyano; heterocyclyl (eg. piperidinyl, pyrrolidinyl or isothiazolidinyl) optionally substituted by one or two oxo groups; -NR⁷R⁸; -OR¹³; -SR¹⁵; or -CONR¹⁷R¹⁸.

In a more particular aspect, R³ represents: C_1-6 alkyl (eg. n-propyl); -NR⁷R⁸; C_3-8 cycloalkyl (eg. cyclopentyl or cyclohexyl); -OR¹³; or -CONR¹⁷R¹⁸.

Even more particularly, R³ represents d_-6 alkyl (eg. n-propyl), -NR⁷R⁸ or -OR¹³.

Alternatively, R³ and R^2b together with the phenyl group which they are attached represent indolyl, indazolyl, dihydroindolyl, benzofuranyl, dihydrochromenyl, benzotriazolyl, benzimidazolyl or tetrahydroquinoxalinyl, optionally substituted by one or two C_1-6 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl or pentyl) groups. More particularly, R³ and R^2b together with the phenyl group which they are attached represent benzimidazolyl or indolyl substituted by a Cι_-6 alkyl group (eg. ethyl).

In a further aspect, R⁷ and R⁸ independently represent: hydrogen; C_1-6 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, i-propyl, i-butyl, -CH₂C(CH₃)₃, -CH(CH₂CH₃)CH₂CH₃ or -(CH₂)₂CH(CH₃)₂); C₃.₈ cycloalkyl (eg. cyclopentyl or cyclohexyl); aryl (eg. phenyl); -C_1-6 alkyl-C_3-8 cycloalkyl (eg. -CH₂-cyclopropyl); -C_1-6 alkyl-aryl (eg. -CH₂-phenyl or -(CH₂)₂-phenyl); or -CO-C_1-6 alkyl (eg. -COCH₃).

In a more particular aspect, R⁷ represents hydrogen and R⁸ represents C^ alkyl (particularly ethyl or isopropyl). In another embodiment, R¹³ represents Cι.₆ alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl or pentyl) optionally substituted by a hydroxy or C₁-6 alkoxy (eg. methoxy) group, more particularly R¹³ represents ethyl or i-propyl. In a most particular embodiment R¹³ represents ethyl.

In a further embodiment, R¹⁵ represents Cι.₆ alkyl (eg. methyl or ethyl).

In one aspect, R¹⁷ and R¹⁸ both represent Cι.₆ alkyl (eg. both represent propyl or one represents propyl and the other represents methyl).

In a further aspect, R⁴ represents -Cι_-6 alkyl-aryl (eg. benzyl) or -C_1-6 alkyl-heteroaryl (eg. - CH₂-pyridinyl, -CH₂-thiazolyl, -CH₂-furanyl, -CH₂-thienyl or -CH₂-pyrazolyl) optionally substituted by one or two halogen atoms (eg. chlorine or fluorine). In a more particular aspect, R⁴ represents -Cι.₆ alkyl-aryl (eg. benzyl) optionally substituted by one or two halogen atoms (eg. chlorine or fluorine). In a most particular aspect, R⁴ represents unsubstituted benzyl.

In one embodiment, R⁵ represents -C_1-10 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl or n-hexyl) optionally substituted by one or more d-6 alkyl (eg. methyl), Cι.₆ alkoxy (eg. methoxy or - OCH₂CH(CH₃)₂) or C₂.₆ alkenoxy (eg.-OCH₂C(CH₃)=CH₂) groups; -C₃.ιo cycloalkyl (eg. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptyl, adamantyl or bicyclo-octyl) optionally substituted by one or more C₁-₆ alkyl (eg. methyl, ethyl or propyl) or halogen (eg. fluorine) groups; -Cι_-6 alkyl-C₃.ιo cycloalkyl (eg. -CH₂-cyclohexyl or -CH₂-cyclopropyl); -aryl (eg. phenyl, dihydroindenyl or tetrahydronaphthalenyl) optionally substituted by one or more hydroxy or Cι_-6 alkoxy (eg. methoxy) groups; -Cι_-6 alkyl-aryl (eg. benzyl, -ethyl-phenyl, -ethyl-naphthyl, -propyl-phenyl, -C(H)(Me)- phenyl, -C(H)(Et)-phenyl -C(Me)(Me)-benzyl or -C(Me)(Me)-phenyl) optionally substituted by one or more halogen (eg. chlorine, bromine or fluorine), hydroxy, -OCF₃, haloCι_-6 alkyl (eg. - CH₂CF₃ or -CF₃), C₁-₆ alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t- butyl), C_2-6 alkenyl (eg. ethenyl), C_2-6 alkynyl, C₁.₆ alkoxy (eg. methoxy, ethoxy, propoxy, isopropoxy or methylethoxy), cyano, nitro, -COOR²² (eg. COOH or COOMe), -SO₂R²² (eg. - SO₂Me), -NR²²COR²³ (eg. NHCOCH₃), -C_1-6 alkyl-NR²²R²³ (eg. -CH₂N(CH₃)₂), -C₁-₆ alkyl-C_1-6 alkoxy (eg. -CH₂OC(CH₃)₃), -C_1-6 alkanol (eg. -CH₂OH) or -d_-6 alkoxy-CN (eg. OCH₂CN) groups; -C_1-6 alkyl-heteroaryl (eg. -CH₂-furanyl, -CH₂-quinolinyl, -CH₂-thiophenyl, -CH₂- indolyl, -CH₂-benzoimidazolyl, -CH₂-imidazolyl, -CH₂-benzofuranyl, -CH₂-thiazolyl, -CH₂- pyridinyl, -CH₂-benzothiazolyl, -CH₂-pyrazolyl, -CH₂-isoxazolyl, -CH₂-oxazolyl, -CH₂-pyrrolyl, -CH₂-dihydrobenzofuranyl, -CH₂-dihydrobenzodioxinyl or -CH₂-dihydrochromenyl) optionally substituted by one or more C1-6 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl or t-butyl), C_2-6 alkenyl (eg. ethenyl or propenyl), C_2-6 alkynyl, halogen (eg. bromine or chlorine), haloCι_-6 alkyl (eg. fluoroethyl or trifluoroethyl), cyano, Cι_-6 alkoxy (eg. methoxy), - CONR²²R²³ (eg. -CONHMe) or -COOR²² (eg. -COOMe) groups; -heterocyclyl (eg. tetrahydropyranyl or tetrahydrothiopyranyl); -Cι_₅ alkyl-heterocyclyl (eg. -CH₂-tetrahydropyranyl); -C₃.₁₀ cycloalkyl-d.₁₀ alkyl (eg. -cyclobutyl-isopropyl, -cyclobutyl-ethyl, -cyclobutyl- propyl, -cyclopropyl-ethyl, -cyclopropyl-propyl, -cyclopropyl-isopropyl, -cyclopropyl-t-butyl, - cyclopropyl-CH₂CH(CH₃)2, -cyclopropyl-(CH₂)₂CH(CH₃)₂, -cyclopropyl-(CH₂)₂CH(CH₃)₂ or - cyclopropyl-(CH₂)₃CH(CH₃)₂); -C₃.ι₀ cycloalkyl-d-6 alkyl-aryl (eg. -cyclopropyl-CH₂-phenyl) optionally substituted by one or more halogen (eg. chlorine) atoms; -C₃.i₀ cycloalkyl-aryl (eg. -cyclopropyl-phenyl) optionally substituted by one or more halogen (eg. chlorine, bromine or fluorine), hydroxy, -OCF₃, haloCι.₆ alkyl (eg. -CH₂CF₃ or - CF₃), Cι_-6 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl), C₂^ alkenyl (eg. ethenyl), C₂-e alkynyl, C₁.₆ alkoxy (eg. methoxy, ethoxy, propoxy, isopropoxy or methylethoxy), cyano, nitro, -COOR²² (eg. COOH or COOMe), -SO₂R²² (eg. -SO₂Me), - NR²²COR²³ (eg. NHCOCH3), -C1-6 alkyl-NR²²R²³ (eg. -CH₂N(CH₃)₂), -Cι.₆ alkyl-C_1-6 alkoxy (eg. -CH₂OC(CH₃)₃), -Ci_-6 alkanol (eg. -CH₂OH) or -d-e alkoxy-CN (eg. OCH₂CN) groups; -C(R^aR^b)-CONH-Cι.₆ alkyl (eg. -C(R^aR )-CONH-i-butyl); -C(R^cR^d)-CONH-C₃.ιo cycloalkyl (eg. C(R^cR^d)-CONH-cyclohexyl); -d-₆ alkyl-S-Cι.₆ alkyl (eg. -propyl-S-methyl or -dimethylethyl-S-isobutyl); or -Cι.₆ alkyl-NR^eR^f (eg. -dimethylpropyl-NR^eR^f).

In a more particular embodiment, R⁵ represents: -C₁-₁0 alkyl (eg. i-propyl); -Q3.₁₀ cycloalkyl (eg. cyclohexyl); -C₁-₆ alkyl-aryl (eg. benzyl) optionally substituted by one or more halogen (eg. chlorine, bromine or fluorine), C₁-₆ alkoxy (eg. methoxy), -OCF₃ or haloC^ alkyl (eg. -CF₃) groups; -Cι.₆ alkyl-heteroaryl (eg. -CH₂-thienyl, -CH₂-pyrazolyl or -CH₂-isoxazolyl) optionally substituted by one or more Cι.₆ alkyl (eg. methyl, ethyl, isopropyl, propyl or butyl) or haloC^ alkyl (eg. CH₂CF₃) groups; -heterocyclyl (eg. tetrahydropyranyl such as tetrahydropyran-4-yl); or -C(R^cR^d)-CONH-C_3-10 cycloalkyl (eg. C(R^cR^d)-CONH-cyclohexyl).

In a most particular embodiment, R⁵ represents: -C₁.10 alkyl (eg. i-propyl), particularly unsubstituted -C_1-10 alkyl; -C₃.ιo cycloalkyl (eg. cyclohexyl), particularly unsubstituted -C₃.₁₀ cycloalkyl; - -6 alkyl-aryl (eg. benzyl) optionally substituted by one or more Cι_-6 alkoxy (eg. methoxy), -OCF₃ or haloC_1-6 alkyl (eg. -CF₃) groups; -heterocyclyl (eg. tetrahydropyran-4-yl), particularly unsubstituted heterocyclyl; or -C(R^cR^d)-CONH-C₃.i₀ cycloalkyl (eg. C(R^cR^d)-CONH-cyclohexyl).

In embodiments in which R⁵ represents substituted d-e alkyl-aryl, the aryl group may be substituted at the 3 position by C_1-6 alkoxy (eg. methoxy), -OCF₃ or haloCι.₆ alkyl (eg. -CF₃) groups. In one aspect, q represents 1 or 2.

In a further aspect, R^a represents hydrogen or Cι_-6 alkyl (methyl).

In yet another aspect, R^b and R^d independently represent C₁-₆ alkyl (eg. methyl, ethyl, propyl or butyl) or -C₁.6 alkyl-SO₂-d.₆ alkyl (eg. -CH₂CH₂SO₂CH₃) optionally substituted by one or more hydroxy groups. In a more particular aspect, R^b and R independently represent d^ alkyl (eg. methyl).

In one embodiment, R^c represents hydrogen or d_-6 alkyl (methyl), particularly hydrogen.

In another embodiment, R^e and R^f both represent Cι.₆ alkyl (eg. methyl).

In one aspect, the invention provides a compound of formula (I) wherein: m represents 0; n represents 0 or 1 ;

R^2a represents Cι.₃alkoxy or halogen;

X represents CO or SO₂ p represents 1 or 2;

R² is hydrogen or halogen;

R³ represents Cι.₆ alkyl, -NR⁷R⁸ or -OR¹³;

R⁴ represents unsubstituted benzyl.

R⁵ represents -d-₁0 alkyl, -C₃.ι₀ cycloalkyl,-Cι-6 alkyl-aryl, -heterocyclyl or -C(R^cR^d)-CONH-C₃.

₁₀ cycloalkyl; wherein said alkyl groups may be optionally substituted by one or more (eg. 1 , 2 or 3) groups selected from halogen, amino, cyano, hydroxy, C_1-6alkyl and Cι_-6alkoxy; and wherein said cycloalkyl, aryl or heterocyclyl groups may be optionally substituted by one or more (eg. 1 , 2 or 3) groups selected from halogen, amino, cyano, hydroxy, d-βalkyl, d.

₆alkoxy, haloCι_-6alkyl and -OCF₃

Compounds according to the invention include the compounds of examples E1-E12 or pharmaceutically acceptable salts thereof..

Particular compounds of the invention include the following compounds, or pharmaceutically acceptable salts thereof:

3-(1 ,1-Dioxidotetrahydro-2r-/-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]-Λ/-[(1 S)-3-({[3-

(methyloxy)phenyl]methyl}amino)-2-oxo-1-(phenylmethyl)propyl]benzamide

Λ/-[(1 S)-3-{[(1 S)-2-(Cyclohexylamino)-1-methyl-2-oxoethyl]amino}-2-oxo-1-

(phenylmethyl)propyl]-3-(1 , 1 -dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1 - methylethyl)amino]benzamide

3-(1 ,1-Dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]-Λ/-[(1 S)-2-oxo-

1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]benzamide 3-(1 ,1-Dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]-/V-{(1 S)-2-oxo- 1-(phenylmethyl)-3-[({3-[(trifluoromethyl)oxy]phenyl}methyl)amino]propyl}benzamide

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. Sci., 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.

The present invention also includes within its scope prodrugs of compounds of formula (I). As used herein, the term "prodrug" means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which are incorporated herein by reference. Esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.

The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, eg. as the hydrate. This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. 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 (la):

(la)

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 compound of formula (II)

(II) or a derivative thereof wherein R¹, m, X, p, R^2a, n, R² , R³, R⁴ and R⁵ are as defined above and P¹ represents a suitable protecting group such as -COOC(CH₃)₃, followed by a deprotection reaction; or

(b) deprotecting a compound of formula (I) which is protected; and optionally thereafter

(c) interconversion of compounds of formula (I) to other compounds of formula (I).

Process (a) typically comprises treatment of compounds of formula (II) with a suitable oxidising agent such as Dess-Martin periodinane in the presence of a suitable solvent, such as dichloromethane, and at a suitable temperature e.g. between 0°C and room temperature, followed by removal of the P¹ group with hydrogen chloride, formic acid or p-toluenesulfonic acid in the presence of a suitable solvent such as dioxane and at a suitable temperature, e.g. between 0°C and room temperature.

In process (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 t fluoroacetyl (-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. An example of such an interconversion reaction may include interconversion of a compound of formula (I) wherein R³ represents a C₂. ₆ alkenyl containing group to a corresponding compound of formula (I) wherein R³ represents a Cι.₆ alkyl containing group, using standard hydrogenation or reductive conditions. A further example of such an interconversion reaction may include interconversion of a compound of formula (I) wherein R³ represents - Cι.₆ alkyl-N₃ to a corresponding compound of formula (I) wherein R³ represents -Cι.₆ alkyl-NH₂, using standard hydrogenation or reductive conditions. A yet further example of such an interconversion reaction may include interconversion of a compound of formula (I) wherein R³ represents a nitro group to a corresponding compound of formula (I) wherein R³ represents NH₂, using standard hydrogenation or reductive conditions.

Compounds of formula (II) may be prepared in accordance with procedures analogous to those described in International Patent Application PCT/EP03/13806 (WO 2004/050619 A1 ).

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, anti-inflammatory agents (such as cyclooxygenase II 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 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

Preparation of Intermediates

Description 1

Methyl 3-amino-2-fluoro-5-nitrobenzoate (D1)

To a solution of methyl 2-fluoro-3,5-dinitrobenzoate (Description 137 from WO2004050619; 20 g, 82 mmol, 1 equiv) in acetic acid (800 ml) at room temperature (using a water bath) was added powdered iron portion-wise (22.6 g, 410 mmol, 5 equiv). The resulting solution was stirred for 3 hrs keeping the temperature of the mixture below 35^°C. Toluene (160 ml) was added to the mixture and the resulting mixture was filtered through hyflo and evaporated to dryness. The residue was dissolved in AcOEt and the organic phase washed with saturated aqueous NaHCO₃ solution, dried over MgSO₄ and concentrated in vacuo. The solid residue was triturated with diethyl ether to give methyl 3-amino-2-fluoro-5-nitrobenzoate (D1 ) (13.4 g, 77%) as a yellow solid. [M-H]- = 213.0, RT = 2.43 min.

Description 2

Methyl 3-{bis[(4-chlorobutyl)sulfonyl]amino}-2-fluoro-5-nitrobenzoate (D2)

To a solution of methyl 3-amino-2-fluoro-5-nitrobenzoate (D1 ) (13.4 g, 62.6 mmol, 1 equiv) and triethylamine (26 ml) in dichloromethane (250 ml) at 0^°C (ice bath) was added 4-chloro-1- butanesulfonyl chloride (Description D20 from WO2004050619; 30 g, 156.5 mmol, 2.5 equiv) dropwise. The resulting solution was allowed to warm to room temperature and stirred overnight. The mixture was diluted with dichloromethane and the organic phase was washed sequentially with 2M aqueous HCl solution, water and then dried over MgSO₄ and concentrated in vacuo to give crude methyl 3-{bis[(4-chlorobutyl)sulfonyl]amino}-2-fluoro-5- nitrobenzoate (38.9 g) (D2) as a black gum.

Description 3

Methyl 3-(1 ,1 -dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-nitrobenzoate (D3)

A solution of crude methyl 3-{bis[(4-chlorobutyl)sulfonyl]amino}-2-fluoro-5-nitrobenzoate (D2) (32.75 g, 62.6 mmol, 1 equiv) and triethylamine (20 ml, 137 mmol, 2.2 equiv) in methanol (250 ml) was heated at reflux for 2 hrs. The ethanol was evaporated off and the resulting residue was diluted with ethyl acetate. The organic phase was washed with 2M aqueous HCl solution and then dried over MgSO₄ and concentrated in vacuo to give the crude product. This material was partially purified by column chromatography (eluting with ethyl acetate//-hexane) to give methyl 3-(1 ,1-dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-nitrobenzoate (D3) (4.31 g) as a brown oil which was used without further purification.

Description 4

Methyl 5-amino-3-(1 ,1 -dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluorobenzoate (D4)

A solution of methyl 3-(1 ,1-dioxidotetrahydro-2/-/-1 ,2-thiazin-2-yl)-2-fluoro-5-nitrobenzoate (D3) (4.31 g, 12.98 mmol, 1 equiv) in acetic acid (250 ml) was treated with iron powder (7.1 g, 130 mmol, 10 equiv) and heated at 50^°C for 2 hrs. The mixture was cooled and filtered through hyflo and evaporated to dryness. The residue was dissolved in AcOEt and the organic phase washed with saturated aqueous NaHCO₃ solution, dried over MgSO₄ and concentrated in vacuo. The solid residue was triturated with diethyl ether to give methyl 5-amino-3-(1 ,1- dioxidotetrahydro-2/-/-1 ,2-thiazin-2-yl)-2-fluorobenzoate (D4) (3.65 g) as a pink/fawn solid. [M+NH4]+ = 344.4.

Description 5

Methyl 3-(1 ,1 -dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1 - methylethyl)amino]benzoate (D5)

A solution of methyl 5-amino-3-(1 ,1-dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluorobenzoate (D4) (3.65 g, 12.08 mmol, 1 equiv) in dichloromethane (36 ml) was treated with acetic acid (0.695 ml), acetone (1 ml) and sodium triacetoxyborohydride (2.52 g) at room temperature and then stirred for 1 hr. The mixture was evaporated and the residue was then dissolved in AcOEt and the organic phase washed with 2M aqueous NaOH solution, dried over MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography (eluting with ethyl acetate//-hexane) to give methyl 3-(1 ,1-dioxidotetrahydro-2H-1 ,2-thiazin-2- yl)-2-fluoro-5-[(1-methylethyl)amino]benzoate (D5) (2.32 g) as a white foam.

Description 6

3-(1 ,1 -Dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1 -methylethyl)amino]benzoic acid (D6)

A solution of methyl 3-(1 ,1-dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1- methylethyl)amino]benzoate (D5) (2.32 g, 6.74 mmol, 1 equiv) in methanol (20 ml) was treated with 2N aqueous NaOH (20 ml) and heated at reflux temperature for 1.5 hrs. The mixture was evaporated and the aqueous residue was adjusted to pH=6 by treatment with cone. HCl . The mixture was extracted with ethyl acetate and the combined organic layers were then dried over MgSO₄ and concentrated in vacuo to give 3-(1 ,1-dioxidotetrahydro-2/- - 1 ,2-thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]benzoic acid (D6) (2.56 g) as a pink foam. [M+H]+ = 331.4, RT = 1.89 min.

Description 7

(2 ?,3S)-3-Amino-1-({[3-(methyloxy)phenyl]methyl}amino)-4-phenyl-2-butanol bis(4- methylbenzenesulfonate) (D7)

1 ,1-Dimethylethyl[(1 S,2f?)-2-hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1- (phenylmethyl)propyl]carbamate (1.12 g, 2.8 mmol, 1 equiv; BOC-protected amine H2 from WO2004094430) was dissolved in acetonitrile (10 ml) and treated with p-toluenesulfonic acid (1.6 g, 8.4 mmol, 3 equiv). The resulting mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with diethyl ether and dried to give (2R,3S)- 3-amino-1-({[3-(methyloxy)phenyl]methyl}amino)-4-phenyl-2-butanol bis(4- methylbenzenesulfonate) (D7) (1.8 g) as a white solid.

Description 8

3-(1 ,1 -Dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-f luoro-Λ/-[(1 S,2R)-2-hydroxy-3-({[3-

(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-5-[(1- methylethyl)amino]benzamide (D8)

(2f?,3S)-3-Amino-1-({[3-(methyloxy)phenyl]methyl}amino)-4-phenyl-2-butanol bis(4- methylbenzenesulfonate) (D7) (0.106 g, 0.15 mmole) and 3-(1 ,1-dioxidotetrahydro-2H-1 ,2- thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]benzoic acid (D6) (0.050 g, 0.15 mmole) were suspended in dry dichloromethane (4 ml) and treated with Λ/-ethyl morpholine (0.076 ml, 0.6 mmol), N-hydroxybenzotriazole hydrate (0.025g, 0.165 mmole), and EDAC.HCI (0.035 g, 0.18 mmole). The resulting mixture was stirred at room temperature overnight and then treated with saturated aqueous sodium hydrogen carbonate (5 ml). The organic layer was separated and then dried over MgSO₄ and concentrated in vacuo. The crude material was chromatographed using an Isolute SPE Flash-NH2 column (eluting with methanol in dichloromethane) to give 3-(1 ,1-dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-Λ/-[(1S,2R)-2- hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-5-[(1-methylethyl) aminojbenzamide (D8) (0.098 g) as an off-white foam. [M+H]+ = 613.4, RT = 2.55 min.

Description 9

1,1-Dimethylethyl {(2 ?,3S)-3-[({3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2-fluoro-5- [(1-methylethyl)amino]phenyl}carbonyl)amino]-2-hydroxy-4-phenylbutyl}{[3- (methyloxy)phenyl]methyl}carbamate (D9)

3-(1 ,1-Dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-Λ/-[(1 S,2f?)-2-hydroxy-3-({[3- (methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-5-[(1-methylethyl)amino]benzamide (D8) (0.096 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 for 1.5 hrs and then evaporated. The residue was purified by column chromatography (eluting with hexane/ethyl acetate) to give 1 ,1-dimethylethyl {(2 ?,3S)-3-[({3-(1 ,1-dioxidotetrahydro-2H- 1 ,2-thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]phenyl}carbonyl)amino]-2-hydroxy-4- phenylbutyl}{[3-(methyloxy)phenyl]methyl}carbamate (D9) (0.091 g) as a clear gum. [M+H]+ = 713.5, RT = 3.69 min.

Description 10

1 ,1 -Dimethylethyl {(3S)-3-[({3-(1 ,1 -dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-f luoro-5-[(1 - methylethyl)amino]phenyl}carbonyl)amino]-2-oxo-4-phenylbutyl}{[3-

(methyloxy)phenyl]methyl}carbamate (D10)

1 ,1 -Dimethylethyl {(2R,3S)-3-[({3-(1 ,1-dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1- methylethyl)amino]phenyl}carbonyl)amino]-2-hydroxy-4-phenylbutyl}{[3- (methyloxy)phenyl]methyl}carbamate (D9) (0.083 g, 0.117 mmole) was dissolved in dry dichloromethane (4 ml) and treated with Dess-Martin periodinane (0.066 g, 0.156 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 1 ,1 -dimethylethyl {(3S)- 3-[({3-(1 ,1-dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino] phenyl}carbonyl)amino]-2-oxo-4-phenylbutyl}{[3-(methyloxy)phenyl]methyl}carbamate (D10) (0.056 g) as a yellow glass. [M-H]- = 709.4, RT = 3.85 min.

Descriptions 11-13 (D11-13) The following compounds have been obtained by hydrolysis of the corresponding methyl ester described in patent application WO 2004050619 using the general procedure outlined in Description 6.

Descriptions 14-19 (D14-19) The following compounds have been obtained according to the general procedures described in patent application WO 2004050619 and WO 2004094430:

Descriptions 20-30 (D20-30) The following compounds have been obtained from the appropriate carboxylic acid and amine precursors according to the general procedure described for the synthesis of D8 from D6 and D7:

Descriptions 31-41 (D31-41) The following compounds have been obtained from the appropriate intermediates according to the general procedure described for the synthesis of D9:

phenylbutyl}carbamate (D38) 1 , 1 -Dimethylethyl {(2R,3S)-3-[({3-(1 , 1 - dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)- 2-fluoro-5-[(1- methylethyl)amino]phenyl}carbonyl) D28 amino]-2-hydroxy-4-phenylbutyl}{[3-

(trifluoromethyl)phenyl]methyl} carbamate (D39) 1 , 1 -Dimethylethyl {(2f?,3S)-3-[({3-(1 , 1 - dioxidotetrahydro-2/-/-1 ,2-thiazin-2-yl)- 2-fluoro-5-[(1- methylethyl)amino]phenyl}carbonyl) D29 amino]-2-hydroxy-4-

phenylbutyl}tetrahydro-2H-pyran-4- ylcarbamate (D40) 1 , 1 -Dimethylethyl {(2 3S)-3-[({3-(1 , 1 - dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)- 2-fluoro-5-[(1- methylethyl)amino]phenyl}carbonyl) D30 amino]-2-hydroxy-4-phenylbutyl}({3-

[(trifluoromethyl)oxy]phenyl}methyl) carbamate (D41 )

Descriptions 42-52 (D42-52) The following compounds have been obtained from the appropriate intermediates according to the procedure described for the synthesis of D10:

Examples

Example 1 (E1) 3-(1 ,1 -Dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-f luoro-5-[(1 -methylethyl)amino]-Λ -[(1 S)-3- ({[3-(methyloxy)phenyl]methyl}amino)-2-oxo-1-(phenylmethyl)propyl]benzamide hydrochloride (E1)

A solution of 0.051g of 1 ,1 -dimethylethyl {(3S)-3-[({3-(1 ,1-dioxidotetrahydro-2H-1 ,2-thiazin-2- yl)-2-fluoro-5-[(1-methylethyl)amino]phenyl}carbonyl)amino]-2-oxo-4-phenylbutyl}{[3- (methyloxy)phenyl]methyl}carbamate (D10) in dry dioxane (2 ml) at room temperature was treated with 0.5 ml of a 4M solution of hydrogen chloride in dioxane. After stirring for 1 hr at room temperature the mixture was diluted with 8 ml of diethyl ether and the solid that precipitated was collected by filtration. The solid was washed with more diethyl ether and then dried in vacuo to give 0.044 g of 3-(1 ,1-dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5- [(1-methylethyl)amino]-Λ/-[(1 S)-3-({[3-(methyloxy)phenyl]methyl}amino)-2-oxo-1- (phenylmethyl)propyl]benzamide hydrochloride (E1 ) as a white solid. [M+H]+ = 611.5, RT = 2.56 min. Examples 2-12 (E2-12) The following compounds have been obtained from the appropriate intermediates according to the general procedure described for the synthesis of Example 1 (E1). In examples 2-5, the deprotection was carried out using tosic acid (ca 30 equivalents) in acetonitrile. The compound of Example 2 was purified using mass-directed auto purification (MDAP) using aqueous acetonitrile and formic acid for the elution.

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

(I) Asp-2 inhibitory assay For each compound being assayed, in a 384 well plate, is added:- a) 1μl of a DMSO solution of the test compound (IC₅₀ curve uses ten 1 in 2 serial dilutions from 500 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 (100mM Sodium acetate pH = 4.5, 1 I Milli-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 diluting 16ml of a 500nM enzyme solution into 384 ml of buffer (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 a Tecan Ultra Fluorimeter/Spectrophotometer ( 485nm excitation, 535nm emission).

(II) Cathepsin D inhibitory assay For each compound being assayed, in a 384 well plate, is added:- a) 1 μl of a DMSO solution of the test compound (IC₅₀ curve uses ten 1 in 2 serial dilutions from 500 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 (100mM Sodium acetate pH = 4.5, 1 I Milli-Q water, 0.06% Triton X-100 (0.5 ml/l) , pH adjusted to 4.5 using glacial acetic acid). c) 10 μl enzyme solution. This is prepared by diluting 1.6ml of a 200 unit/ml (in 10 mM HCl) enzyme solution into 398.4 ml of buffer (prepared as above). Blank wells (enzyme solution replaced by buffer) are included as controls on each plate. Wells are incubated for 1 h at room temperature and fluorescence read using a Tecan Ultra Fluorimeter/Spectrophotometer ( 485nm excitation, 535nm emission).

Pharmacological Data

The compound of examples E1-E12 were tested in the Asp2 inhibitory assay (assay (I)) and exhibited inhibition in the range 1-10000 nM.

The compounds of examples E1-E12 were also tested in the Cathepsin D inhibitory assay and exhibited inhibition in the range 500-32000 nM.

Abbreviations

DMSO dimethylsulfoxide

EDAC N-ethyl-N-(3-dimethylamino propyl)carbodiimide

AcOEt Ethyl acetate

FAM carboxyfluorescein

TAMRA carboxytetramethylrhodamine

[ ] single amino acid letter code relating to peptide sequence

Claims

1. A compound of formula (I):

(I) wherein

R represents C_1-6 alkyl, C₂.₆ alkenyl, halogen, d_-6 alkoxy, amino, cyano, hydroxy, aryl, heteroaryl or heterocyclyl;

R^2a represents hydrogen, Cι.₃ alkyl, C_1-3 alkoxy or halogen; m and n independently represent 0, 1 or 2; X represents CO, SO or SO₂; p represents an integer from 1 to 3;

R^2b represents hydrogen, d_-6 alkyl, C₂.₆ alkenyl, halogen, d.₆ alkoxy, amino, cyano, hydroxy, aryl, heteroaryl or heterocyclyl;

R³ represents halogen, d.₆ alkyl, C₂.₆ alkenyl, aryl, heteroaryl, heterocyclyl, -d_-6 alkyl-aryl, - Cι_-6 alkyl-heteroaryl, -d.₆ alkyl-heterocyclyl, -C₂.₆ alkenyl-aryl, -C₂.₆ alkenyl-heteroaryl, -C₂.₆ alkenyl-heterocyclyl, C₃.₈ cycloalkyl, -d_-6 alkyl-C_3-8 cycloalkyl, cyano, azido, nitro, -NR⁷R⁸, - NR⁹COR¹⁰, -NR¹¹SO₂R¹², -OR¹³, -SO₂R¹⁴, -SR¹⁵, -C≡CR¹⁶, -Cι.₆ alkyl-(CF₂)_qCF₃, -CONR¹⁷R¹⁸, COOR¹⁹, -Ci-e alkyl-NR²⁰R²¹ or -Ci-e alkyl-N₃, or R³ and R² together with the phenyl group to which they are attached form a naphthyl or benzofused heterocyclic or heteroaryl ring optionally substituted by one or two Ci.₆ alkyl groups;

R⁴ represents -C_2-6 alkynyl, -d.6 alkyl-aryl, -Cι_₆ alkyl-heteroaryl or -C₁-6 alkyl-heterocyclyl; R⁵ represents hydrogen, -C₁-₁0 alkyl, -C₃.₁₀ cycloalkyl, -C₃.ι₀ cycloalkenyl, aryl, heteroaryl, heterocyclyl, -Ci-e alkyl-C₃_₁₀ cycloalkyl, -C₃.ι₀ cycloalkyl-Cι.ι₀ alkyl, -C₃.ι₀ cycloalkyl-Cι.₆ alkylaryl, -C₃.ι₀ cycloalkyl-aryl, -d_-6 alkyl-aryl-heteroaryl, -C(R^aR^b)-CONH-d_-6 alkyl, -C(R^cR^d)- CONH-C3-10 cycloalkyl, -Ci-e alkyl-S-Cι.₆ alkyl, -C1.6 alkyl-NR^eR^f, -C1.6 alkyl-aryl, -d-e alkyl- heteroaryl, -C1.6 alkyl-heterocyclyl -Ci-e alkyl-d_-6 alkoxy-aryl, -C1.6 alkyl-Cι_-6 alkoxy-heteroaryl or -Cι_₆ alkyl-d.₆ alkoxy-heterocyclyl;

R⁷, R⁸, R⁹, R¹⁰, R¹³, R¹⁴, R¹⁵, R ⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ independently represent hydrogen, C₁.6 alkyl, C₂^ alkenyl, C₃.₈ cycloalkyl, aryl, heteroaryl, heterocyclyl, -C₁.₆ alkyl-C₃.₈ cycloalkyl, - C₁.6 alkyl-aryl, -C₁.₆ alkyl-heteroaryl, -C₁.6 alkyl-heterocyclyl or -CO-C₁.₆ alkyl; R¹¹, R¹², R^a, R^c, R^e and R^f independently represent hydrogen, Cι.₆ alkyl or C₃^ cycloalkyl; R^b and R^d independently represent hydrogen, C₁.₆ alkyl, C₃.₈ cycloalkyl or -d-e alkyl-SO₂-Cι_-6 alkyl; q represents 1 to 3; wherein said alkyl groups may be optionally substituted by one or more (eg. 1 , 2 or 3) halogen, C1.6 alkyl, Cι.₆ alkoxy, C₂.₆ alkenoxy, C₃.₈ cycloalkyl, amino, cyano or hydroxy groups; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (eg. 1 , 2 or 3) Ci-e alkyl, C₂-6 alkenyl, C₂.₆ alkynyl, halogen, halod.₆ alkyl, -OCF_3l oxo, d-β alkoxy, -Ci-e alkoxy-CN, amino, cyano, nitro, -NR²²COR²³, -CONR²²R²³, -COOR²², -SO₂R²², -d-β alkyl-NR²² R²³ (wherein R²² and R²³ independently represent hydrogen or d.₆ alkyl), -Cι_-6 alkyl-Cι_-6 alkoxy, -Ci.₆ alkanol or hydroxy groups; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1 , wherein X represents SO₂ and p represents 1 or 2.

3. A compound according to claim 1 , wherein X represents CO and p represents 1.

4. A compound according to any preceding claim, wherein m represents 0.

5. A compound according to any preceding claim, wherein n represents 1 and R^2a is Ci. ₃alkoxy or halogen.

6. A compound according to any preceding claim, wherein R^2b represents hydrogen, halogen, Ci-e alkyl, Ci-e alkoxy or heterocyclyl.

7. A compound according to claim 6, wherein R^2b represents hydrogen.

8. A compound according to any preceding claim, wherein R³ represents Ci-e alkyl, C_2-6 alkenyl, C₃^ cycloalkyl, cyano, heterocyclyl, -NR⁷R⁸, -OR¹³' -SR¹⁵ or -CONR¹⁷R¹⁸.

9. A compound according to claim 8, wherein R³ represents d_-6 alkyl, -NR⁷R⁸ or -OR¹³.

10. A compound according to any preceding claim, wherein R⁴ represents -Cι.₆ alkyl-aryl or -Cι.₆ alkyl-heteroaryl.

11. A compound according to claim 10, wherein R⁴ represents unsubstituted benzyl.

12. A compound according to any preceding claim wherein R⁵ represents -C₁-₁₀ alkyl, -C_3- ιo cycloalkyl, -d.₆ alkyl-C_3-10 cycloalkyl, -aryl, -Cι.₆ alkyl-aryl, -Ci-e alkyl-heteroaryl, - heterocyclyl, -Cι_₆ alkyl-heterocyclyl, -C3.10 cycloalkyl-d.₁0 alkyl, -C₃.₁₀ cycloalkyl-C_1-6 alkyl-aryl, -Cjuo cycloalkyl-aryl, -C(R^aR )-CONH-Cι.6 alkyl, -C(R^cR )-CONH-C₃.₁₀ cycloalkyl, -d-β alkyl-S- Cι_-6 alkyl or -C₁.6 alkyl-NR^eR^f.

13. A compound according to claim 12, wherein R⁵ represents -C_LIO alkyl, -C_3-10 cycloalkyl,-Cι.₆ alkyl-aryl, -heterocyclyl or -C(R^cR^d)-CONH-C₃.ι₀ cycloalkyl.

14. A compound according to claim 1 which is selected from the group consisting of: 3-(1 ,1-Dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]-Λ/-[(1 S)-3-({[3- (methyloxy)phenyl]methyl}amino)-2-oxo-1-(phenylmethyl)propyl]benzamide; Λ/-[(1 S)-3-(Cyclohexylamino)-2-oxo-1 -(phenylmethyl)propyl]-3-(ethyloxy)-5-(2-oxo-1 - pyrrolidinyl)benzamide;

Λ/-[(1 S)-3-(Cyclohexylamino)-2-oxo-1-(phenylmethyl)propyl]-3-(1 ,1-dioxido-2-isothiazolidinyl)-

5-(ethyloxy)benzamide;

3-(1 ,1-Dioxido-2-isothiazolidinyl)-5-(ethyloxy)-Λ/-[(1 S)-2-oxo-1-(phenylmethyl)-3-({[3-

(trifluoromethyl)phenyl]methyl}amino)propyl]benzamide;

Λ/-[(1 S)-3-(Cyclohexylamino)-2-oxo-1 -(phenylmethyl)propyl]-3-(2-oxo-1 -pyrrolidinyl)-5- propyl benzamide;

3-(Ethyloxy)-Λ/-[(1 S)-2-oxo-1-(phenylmethyl)-3-({[3-

(trifluoromethyl)phenyl]methyl}amino)propyl]-5-(2-oxo-1-pyrrolidinyl)benzamide;

3-(1 ,1-Dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]-Λ/-[(1 S)-3-[(1- methylethyl)amino]-2-oxo-1-(phenylmethyl)propyl] benzamide;

Λ/-[(1 S)-3-(Cyclohexylamino)-2-oxo-1-(phenylmethyl)propyl]-3-(1 ,1-dioxidotetrahydro-2/-/-1 ,2- thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]benzamide;

Λ/-[(1S)-3-{[(1 S)-2-(Cyclohexylamino)-1-methyl-2-oxoethyl]amino}-2-oxo-1-

(phenylmethyl)propyl]-3-(1 ,1-dioxidotetrahydro-2/-/-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1- methylethyl)amino]benzamide;

1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]benzamide;

1-(phenylmethyl)-3-(tetrahydro-2/-/-pyran-4-ylamino)propyl]benzamide; or

3-(1 ,1-Dioxidotetrahydro-2H-1 ,2-thiazin-2-yl)-2-fluoro-5-[(1-methylethyl)amino]-Λ/-{(1 S)-2-oxo-

1-(phenylmethyl)-3-[({3-[(trifluoromethyl)oxy]phenyl}methyl)amino]propyl}benzamide; or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof in admixture with one or more pharmaceutically acceptable diluents or carriers.

16. A compound of formula (I) as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical.

17. Use of a compound of formula (I) as defined in any one of claims 1 to 14 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.

18. 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 any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof.

19. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 14 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.