WO2004020422A1

WO2004020422A1 - 1, 4- substituted piperidine derivatives and use thereof as base-inhibitors in treatment of alzheimer's disease

Info

Publication number: WO2004020422A1
Application number: PCT/GB2003/003719
Authority: WO
Inventors: Henriette Willems
Original assignee: De Novo Pharmaceuticals Ltd
Current assignee: De Novo Pharmaceuticals Ltd
Priority date: 2002-08-30
Filing date: 2003-08-28
Publication date: 2004-03-11
Anticipated expiration: 2005-02-28
Also published as: AU2003260744A1; GB0220214D0

Abstract

A compound of formula, (I) wherein R1 and R2 are the same or different and are each cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, polycyclyl or heteropolycyclyl; R3 and R4 are the same or different and are each hydrogen, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl or polycyclyl; X and Y are the same or different and are each a bond, alkylene, alkenylene, -O-alkyl- or -O-alkenyl-; and m and n are the same or different and are each 0 or 1;or a pharmaceutically-acceptable salt thereof.

Description

,4-SUBSTITUTED PIPERIDINE DERIVATIVES AND USE THEREOF AS BACE-INHIBITORS

IN TREATMENT OF ALZHEIMER'S DISEASE

Field of the Invention

This invention relates to compounds and their therapeutic use. Background to the Invention 5 Alzheimer's disease (AD) is the most common form of dementia among older people, and affects parts of the brain that control thought, memory and language. Susceptibility to Alzheimer's disease increases with age, but Alzheimer's disease is not a normal part of the ageing process.

Alzheimer's disease is associated with regions of accumulated proteins 0 in the brain. These dense regions, termed "amyloid plaques" and "neurofibrilliary tangles", contain β-amyloid precursor protein (β-APP). β-APP is degraded by β-amyloid converting enzyme (BACE, also known as β- secretase) to produce β-amyloid peptide Aβ 40/42, which accumulates in the plaques. Research has shown that the activity of BACE is an early step in the 5 pathogenesis pathway common to all familial and sporadic forms of Alzheimer's disease; thus inhibitors of BACE may have therapeutic utility in the treatment of this disease. Summary of the Invention

According to a first aspect of the invention, a compound has the formula 0 (I)

wherein

R¹ and R² are the same or different and are each cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, polycyclyl or heteropolycyclyl; 0 R³ and R⁴ are the same or different and are each hydrogen, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl or polycyclyl; X and Y are the same or different and are each a bond, alkylene, alkenylene, -O-alkyl- or -O-alkenyl-; and m and n are the same or different and are each 0 or 1 ; or a pharmaceutically-acceptable salt thereof. Compounds of the invention are inhibitors of BACE and as a consequence may have utility in the treatment or prevention of diseases or conditions in which BACE is implicated. In particular, they may have utility in the treatment or prevention of a disease or condition associated with the deposition and/or elevated levels of amyloid beta peptide (Aβ), for example Alzheimer's disease.

Accordingly, another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with the deposition and/or elevated levels of amyloid beta peptide (Aβ). Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. Description of the Invention

Certain compounds and combinations of substituents are preferred; in particular see the subclaims. With regard to formula (I), X and/or Y is preferably alkylene or -O-alkyl-. R¹ and/or R² are preferably polycyclyl, heteropolycyclyl or heteroaryl. When m and/or n is 1, R³ and/or R⁴ is preferably aryl, more preferably optionally substituted phenyl.

The term "alkyl" as used herein refers to an optionally substituted straight or branched chain alkyl moiety having from 1 to 8 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and ferτ-butyl, pentyl, hexyl, heptyl, hept-2-yl, octyl and the like. "C^ alkyl" has the same meaning. The substitutuent(s) may be the same or different and selected from hydroxy, thioxy, halogen and the like. "Alkylene" refers to a similar, divalent group. The term "alkenyl" as used herein refers to an optionally substituted straight or branched chain alkyl moiety having 2 to 8 carbon atoms and having in addition at least one double bond, of either E or Z stereochemistry where applicable. This term includes for example, vinyl, 1-propenyl, 1-and 2- butenyl, 2- methyl-2-propenyl etc. "C₂.₈ alkenyl" has the same meaning. The substituent(s) may be the same or different and selected from hydroxy, thioxy and the like. "Alkenylene" refers to a similar, divalent group. The term "aryl" as used herein refers to optionally substituted aromatic ring systems comprising 6 to 14 ring atoms, and optionally substituted polycyclic ring systems having two or more cyclic rings at least one of which is aromatic. This term includes for example, phenyl and naphthyl. The group may be optionally substituted with the substituents being the same or different in each occurrence and selected from hydroxy, halogen and the like.

The term "heteroaryl" as used herein refers to an optionally substituted aromatic ring systems comprising 5 to 15 ring atoms, and optionally substituted heteropolycyclic ring systems having two or more rings, at least one of which is aromatic. The group comprises at least one heteroatom selected from O, N, P and S, and includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like. The substituent(s) may be the same or different and selected from aryl, halogen, hydroxy and the like.

The term "cycloalkyl" as used herein refers to a saturated alicyclic moiety having from 3 to 8 carbon atoms and includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The substituent(s) may be the same or different and selected from halogen, hydroxy and the like.

The term "heterocycloalkyl" as used herein refers to a saturated heterocyclic moiety having from 3 to 8 carbon atoms and one or more heteroatoms selected from N, O, P and S, and includes for example azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like. The substituent(s) may be the same or different and selected from halogen, hydroxy and the like.

The term "cycloalkenyl" refers to an carbocyclic moiety having from 3 to 8 carbon atoms and having in addition at least one double bond, and includes for example cyclopentenyl or cyclohexenyl. The substituent(s) may be the same or different and selected from halogen, hydroxy and the like. The term "heterocycloalkenyl" as used herein refers to a unsaturated heterocyclic moiety having from 3 to 8 carbon atoms and one or more heteroatoms selected from N, 0, P and S. The substituent(s) may be the same or different and selected from halogen, hydroxy and the like. The term "polycyclyl" as used herein refers to an optionally substituted group comprising two or more rings in which two carbon atoms are common to two rings, and includes for example fused rings or bridged rings, such as fluorenyl and the like. The substituent(s) may be the same or different and selected from halogen, hydroxy and the like. The term "heteropolycyclyl" as used herein refers to an optionally substituted group comprising two or more rings, at least one of which comprises a heteroatom selected from N, O, P and S, wherein two atoms are common to two rings. The term includes, for example, fused rings or bridged rings.

The term "halogen" as used herein refers to F, Cl, Br or I. Preferred compounds of the invention include:

"1" 1 -(9H-fluoren-9-yl)-3-{4-[2-hydroxy-3-(1 ,3,6-tribromo-9H-fluoren-9-yl)- propyl]-piperazin-1-yl}-propan-2-ol; "2" 1-(3,6-dibromo-9H-fluoren-9-yl)-3-{4-[3-(3,6-dichloro-9H-fluoren-9-yl)-2- hydroxy-propyl]-piperazin-1-yl}-propan-2-ol; "3" 1 -carbazol-9-yl-3-[4-(3-carbazol-9-yl-2-hydroxy-propyl)-piperazin-1 -yl]- propan-2-ol; "4" 1-carbazol-9-yl-3-{4-[3-(3,6-dichloro-carbazol-9-yl)-2-hydroxy-propyl]- piperazin-1 -yl}-propan-2-ol; "5" 1-(3,6-dibromo-carbazol-9-yl)-3-{4-[3~(3,6-dibromo-carbazol-9-yl)-2- hydroxy-propyl]-piperazin-1 -yl}-propan-2-ol;

"6" 1-(3,6-dichloro-carbazol-9-yl)-3-{4-[3-(3,6-dichloro-carbazol-9-yl)-2- hydroxy-propyl]-piperazin-1-yl}-propan-2-ol; "7" 1-carbazol-9-yl-3-{4-[3-(3,6-dibromo-carbazol-9-yl)-2-hydroxy-propyl]- piperazin-1-yl}-ρrόpan-2-ol; "8" 1 -{4-[3-(3-chloro-carbazol-9-yl)2-hydroxy-propyl]-piperazin-1 -yl}-3-(3,6- dichloro-carbazol-9-yl)-propan-2-ol; "9" 1 ,4-bis-{2-[bis-(4-fluoro-phenyl)-methoxy]-ethyl}-piperazine;

"10" 1-(2,3-diphenyl-2,3-dihydro-indol-1-yl)-3-{4-[3-(2,3-diphenyl-2,3-dihydro- indol-1 -yl)-2-hydroxy-propyl]-piperazin-1 -yl}-propan-2-ol; and "11" 1 -carbazol-9-yl-3-(4-(9H-fluoren-9-yl)-piperazin-1 -yl]-propan-2-ol. Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer.

The compounds of the invention may be prepared in racemic form, or prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art. The compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base. Alternatively, the enantiomers of the novel compounds may be separated by HPLC using a chiral column. A compound of the invention may be in a protected amino, protected hydroxy or protected carboxy form. The terms "protected amino", "protected hydroxy" and "protected carboxy" as used herein refer to amino, hydroxy and carboxy groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert- butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group. A carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester.

Some compounds of the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention. Compounds of the invention may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids. Such inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid. Organic acid addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2- methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconicacid, glutamicacid, N-glycolylarsanilicacid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulphonic acid, 10-undecenoic acid and the like. Salts may also be formed with inorganic bases. Such inorganic base salts include, for example, salts of aluminium, bismuth, calcium, lithium, magnesium, potassium, sodium, zinc and the like. Organic base salts include, for example, salts of N, N'-dibenzylethylenediamine, choline (as a counterion), d i ethanolamine, ethanol am i ne , ethylened i am i ne , N , N' - bis(dehydroabietyl)ethylenediamine, N-methylglucamine, procaine, tris(hydroxymethyl)aminoethane ("TRIS") and the like.

It will be appreciated that such salts, provided that they are pharmaceutically acceptable, may be used in therapy. Such salts may be prepared by reacting the compound with a suitable acid or base in a conventional manner. A compound of the invention may be prepared by any suitable method known in the art.

Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.

The activity and selectivity of the compounds may be determined by any suitable assay known in the art.

The compounds of the invention may be used in the treatment of numerous ailments, conditions and diseases including, but not limited thereto, Alzheimer's disease. In therapeutic use, the active compound may be administered orally, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity. Oral administration is preferred. Thus, the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-500 mg. The excipients used in the preparation of these compositions are the excipients known in the art. Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease undergoing treatment.

Compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be add to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of injectables.

The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compositions for topical administration are also suitable for use in the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. The following Example illustrates the invention.

Example: activity assay

Compounds 1 to 11 are known, and were tested for their inhibitory activity towards BACE.

All enzyme assays were performed at 20°C on an AlphaFusion (Packard Instruments) using 384 well plates (Greiner Bio-One Ltd). The assay volume was 30 μl. Inhibitors were dissolved in dimethyl sulphoxide (DMSO) and added into a well with 50 mM sodium acetate buffer pH 4.5 and 10 μM EDANS- EVNLDAEFK-DABCYL peptide substrate. The DMSO concentration was set at 10% in the assay. The reaction was started with the addition of 1 μg/ml recombinant human soluble BACE-1. After 3 hours the fluorescence increase was measured in the plate reader at 365ex/485em. The EDANS-DABCYL peptide substrate becomes slightly fluorescent upon enzymatic cleavage due to disruption of the resonance energy transfer between the EDANS donor and DABCYL quenching acceptor in the intact substrate.

The activities (IC₅₀ values in μM) of the Example compounds are shown in Table 1.

Table 1

The results show that compounds of the invention have a desirable inhibitory activity to BACE.

Claims

1. A compound of formula (I)

wherein R¹ and R² are the same or different and are each cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, polycyclyl or heteropolycyclyl;

R³ and R⁴ are the same or different and are each hydrogen, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl or polycyclyl;

X and Y are the same or different and are each a bond, alkylene, alkenylene, -O-alkyl- or -O-alkenyl-; and m and n are the same or different and are each 0 or 1; or a pharmaceutically-acceptable salt thereof.

2. A compound according to claim 1 , wherein X and/or Y is alkylene.

3. A compound according to claim 2, wherein X and/or Y is substituted with hydroxy.

4. A compound according to claim 3, wherein X and/or Y is -CH₂CH(OH)CH₂-.

5. A compound according to claim 1 , wherein X and/or Y is -O-alkyl-.

6. A compound according to claim 5, wherein X and/or Y is -OCH₂CH₂-.

7. A compound according to any preceding claim, wherein R¹ and/or R² is polycyclyl or heteropolycyclyl.

8. A compound according to claim 7, wherein R¹ and/or R² is optionally substituted fluoren-9-yl or carbazol-9-yI.

9. A compound according to claim 7 or claim 8, wherein R¹ and/or R² is optionally substituted with halogen.

10. A compound according to claim 9, wherein R¹ and/or R² is substituted one or more times with Br, Cl or F, the substituents being the same or different in each occurance.

11. A compound according to any of claims 1 to 6, wherein R¹ and/or R² is heteroaryl.

12. A compound according to claim 11, wherein R¹ and/or R² is optionally substituted 2,3-dihydro-indol-1 -yl.

13. A compound according to claim 11 or claim 12, wherein R¹ and/or R² is optionally substituted once or twice with aryl.

14. A compound according to any preceding claim, wherein R¹ and/or R² is optionally substituted with halogen.

15. A compound according to claim 14, wherein R¹ and/or R² is substituted one or more times with Cl, Br or F, the substituents being the same or different in each occurrence.

16. A compound according to any preceding claim, wherein m and n are each

0.

17. A compound according to any of claims 1 to 15, wherein m and n are each 1.

18. A compound according to claim 17, wherein R³ and R⁴ are the same or different and are each aryl.

19. A compound according to claim 18, wherein R³ and R⁴ are each phenyl optionally substituted with halogen.

20. A compound according to claim 1 , selected from 1-(9H-fluoren-9-yl)-3-{4-[2-hydroxy-3-(1,3,6-tribromo-9H-fluoren-9-yl)- propyl]-piperazin-1 -yl}-propan-2-ol;

1-(3,6-dibromo-9H-fluoren-9-yl)-3-{4-[3-(3,6-dichloro-9H-fluoren-9-yl)-2- hydroxy-propyl]-piperazin-1-yl}-ρropan-2-ol;

1-carbazol-9-yl-3-[4-(3-carbazol-9-yl-2-hydroxy-propyl)-piperazin-1-yl]- propan-2-ol; 1-carbazol-9-yl-3-{4-[3-(3,6-dichloro-carbazol-9-yl)-2-hydroxy-propyl]- piperazin-1 -yl}-propan-2-ol; 1 -(3,6-dibromo-carbazol-9-yl)-3-{4-[3-(3,6-dibromo-carbazol-9-yl)-2- hydroxy-propyl]-piperazin-1-yl}-propan-2-ol;

1-(3,6-dichloro-carbazol-9-yl)-3-{4-[3-(3,6-dichloro-carbazol-9-yl)-2- hydroxy-propyl]-piperazin-1-yl}-propan-2-ol; 1-carbazol-9-yl-3-{4-[3-(3,6-dibromo-carbazol-9-yl)-2-hydroxy-propyl]- piperazin-1 -yl}-propan-2-ol;

1-{4-[3-(3-chloro-carbazol-9-yl)-2-hydroxy-propyl]-piperazin-1-yl}-3-(3,6- dichloro-carbazol-9-yl)-propan-2-ol;

1 ,4-bis-{2-[bis-(4-fluoro-phenyl)-methoxy]-ethyl}-piperazine; 1 -(2,3-diphenyl-2,3-dihydro-indol-1 -yl)-3-{4-[3-(2,3-diphenyl-2,3-dihydro- indol-1 -yl)-2-hydroxy-propyl]-piperazin-1 -yl}-propan-2-ol; and

1-carbazol-9-yl-3-(4-(9H-fIuoren-9-yl)-piperazin-1-yl]-propan-2-ol.

21. A compound according to any preceding claim, which is in the form of a single enantiomer or diastereomer.

22. A compound according to any preceding claim, for therapeutic use.

23. A pharmaceutical composition comprising a compound of any of claims 1 to 21 and a pharmaceutically acceptable carrier or diluent.

24. Use of a compound of any of claims 1 to 21, for the manufacture of a medicament for the treatment of prevention of a disease or condition associated with the deposition and/or elevated levels of amyloid beta peptide (Aβ)

25. Use of a compound of any of claims 1 to 21 , for the manufacture of a medicament for the treatment of Alzheimer's disease.