GB2394714A - Piperidinyl-diarylsilanol compounds and their use in therapy - Google Patents

Abstract

A compound of formula <B>I</B>: <EMI ID=1.1 HE=27 WI=135 LX=454 LY=694 TI=CF> <PC>wherein Ar and Ar<1> are each aryl groups; ```R and R<1> are, independently, selected from H, C1-6 alkyl, C1-6 alkyl substituted with one or more groups individually selected from OR<2>, substituted or unsubstituted with aryl or heteroaryl, including aryl substituted with Si(R<3>)3, C1-6 alkyl, C1-6 carboxy, where R<2> is H or C1-6 alkyl and each R<3> is aryl or C1-6 alkyl; ```Alk is C1-6 alkanediyl optionally substituted with one or more substituents selected from OH, halogen, C1-6 alkoxy and amino; and ```the benzene ring in formula <B>I</B> is optionally substituted with one or more substituents selected from OH, halogen, C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)amino, pyrrolidino, piperidino, morpholino and N-alkylpiperazino; or a pharmaceutically acceptable salt or prodrug thereof. These compounds may be useful in the treatment of diseases such as allergic rhinitis, eczema, asthma or insect bites and stings or other conditions mediated by the histamine receptor. A preferred compound is (1-(4-(4-(1-carboxy-1-methylethyl)phenyl)-4-hydroxybutyl)piperidin-4-yl) diphenysilanol.

Description

239471 4

PIPERIDINYL-DIARYLSILANOL COMPOUNDS

AND THEIR USE IN THERAPY

Field of the Invention

This invention relates to compounds and their therapeutic use.

5 Backoround of the Invention Sila-substitution (C/Si-exchange) of drugs is a relatively recent approach for searching for organosilicon compounds which have beneficial biological properties. The approach involves the replacement of specific carbon atoms in compounds by silicon, and monitoring how the biological properties of the 10 compounds have changed. A review of this approach is provided in Tacke and Zilch, Endeavour, New Senes, 1986, 10, 191-197.

Summary of the Invention

The present invention provides compounds containing one or more silicon atoms and which have desirable properties.

15 Compounds of the invention are silicon analogues of fexofenadine, and have the formula l: 20 HO-AN-Alk3C-COOH I wherein Ar and Ar' are each aryl groups; R and R' are, independently, selected from the group consisting of H. C, 6 alkyl, C, 6 alkyl substituted with one or more groups individually selected from 25 ore, substituted or unsubstituted with aryl or heteroaryl, including aryl substituted with Si(R3)3, C, 6 alkyl, C, 6 carboxy, where R2 is H or C, 6 alkyl and each R3 is aryl or C, .6 alkyl; and Alk is a C, 6 alkyl chain optionally substituted with one or more substituents selected from OH, C, 6 alkoxy and amino; and the benzene ring of 30 formula I is optionally substituted with one or more substituents selected from OH, halogen, C, 6 alkyl, C, 6 alkoxy, di(C, 6 alkyl)amino, pyrrolidino, piperidino, morpholino and N-alkylpiperazino;

or a pharmaceutically acceptable salt or a prodrug thereof.

Compounds of the invention, most or all of which are new, have therapeutic utility. The compounds are useful as active ingredients in medicines, for the treatment of diseases which are treated presently with drugs which 5 reduce or block the action of the histamine receptor (usually by blocking binding of histamine to that receptor). Such diseases or conditions include allergic rhinitis, vasomotor rhinitis, urticaria, eczema, insect bites and stings, and asthma, in particular allergy-induced or allergy-aggravated asthma. They may also be useful in shortening prolonged QT intervals in a patient with a trafficking 10 defective HERG mutation.

Compounds of the invention may have an improved pharmacological profile compared to the parent compound. For example, the compounds may be better tolerated by the patient, and may have longer half-life and so require reduced dosing frequency, and may be more potent and/or have reduced side 15 effects and hence have a widened therapeutic window, making them safer for general use.

Description of the Invention

Certain compounds of this invention are preferred. In particular, see the sub-claims. 20 The term "Con alkyl" as used herein refers to straight and branched chain alkyl groups having up to 6 carbon atoms. Examples are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and teff-butyl.

The term "aryl" as used herein refers to optionally substituted aromatic ring systems comprising five to ten ring atoms, and optionally substituted 25 polycyclic ring systems having two or more 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 ordifferent in each occurrence and selected from halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imino, amide, phosphoryl, 30 phosphonate, phosphino, carbonyl, carboxyl, carboxamido, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidino, amidino, acetal, ketal, amine oxide, aryl, o

heteroaryl, arylalkyl, heteroarylalkyl, azido, aziridine, carbamate, epoxide, hydroxamicacid, imide, oxime, oxosulfonamide, thioamide, thiocarbamate, urea and thiourea.

The term "heteroaryl" as used herein refers to aromatic ring systems of 5 five to ten atoms of which at least one atom is selected from O. N and S and includes for example furanyl, thienyl, pyridyl, indolyl, quinolyl and the like. The group may be optionally substituted by any substituent described herein.

In preferred embodiments, Ar and Ar' are each phenyl, R and R' are each methyl, Alk is a C4 straight alkyl chain substituted on the benzylic carbon by OH.

10 A preferred compound of the invention is (1-(4-(4-(1-carboxy-1 methylethyl)phenyl)-4-hydroxybutyl)piperidin-4-yl)diphenylsilanol or a pharmaceutically acceptable salt thereof.

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.

15 A compound of the invention may be in a protected amino form. The term "protected amino" as used herein refers to an amino group which is protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tertbutoxycarbonyl, cetyl or like groups, or in the form of a phthalimido or like group.

20 A compound of the invention may be in the form of a racemate, a single diastereomer or a single enantiomer. It will be appreciated that where a particular stereoisomer of formula I is required, the synthetic processes described herein may be used with the appropriate homochiral starting material and/or isomers may be resolved from mixtures using conventional separation 25 techniques (e.g. HPLC).

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 30 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, glutamic acid, N-glycolylarsanilicacid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoic acid, 1 -hydroxy-2-naphthoic acid, 3-hydroxy-

2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, ndodecyl 5 sulphate, maleic acid, malicacid, mandelic acid, methanesulphonicacid, methyl sulphate, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl) phosphonic acid), picric acid, salicyclic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-

toluenesulphonic acid, 1 0-undecenoic acid and the like.

10 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), diethanolamine, ethanolamine, ethylenediamine, N. N' 15 bis(dehydroabietyl)ethylenediamine, N-methylglucamine, procaine, tris(hydroxymethyl)aminomethane ("TRISn) 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 20 conventional manner.

As used hereinafter, the term "active compound" denotes a compound of formula I including pharmaceutically acceptable salts thereof.

A compound of the invention may be prepared by any suitable method known in the art.

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

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

The compounds of the invention are useful as antihistamines, antiallergy compounds and antiasthmatic compounds.

The active compound may be combined with a carrier material to produce a single dosage form that varies depending upon the host treated and the 5 particular mode of administration. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

Appropriate dosage levels may be determined by any suitable method 10 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 1 5 treatment.

In therapeutic use, the active compound may be administered orally, rectally, parenterally, by inhalation (pulmonary delivery), nasally, orto the buccal cavity. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of 20 administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a desired release, for example rapid 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. 25 The pharmaceutical composition containing the active compound may be in a form suitable for oral use, for example as 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 30 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, 5 calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch, gelatin or acacia 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 10 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 15 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 compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such 20 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 25 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 30 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 compound 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.

5 Sweetening agents such as those set forth above, and flavouring agents may be added 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 10 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 15 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 20 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 25 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 30 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 5 use in the preparation of injectables.

A compound of formula I 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 10 melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc containing the compounds of formula I may be employed.

The following Example illustrates the preparation of compounds of the 15 invention (see Schemes 1 and 2). Unless otherwise stated, the starting materials used in the Example are available commercially and may be obtained by methods known to those skilled in the art.

Example

General Procedures. All syntheses were carried out under dry nitrogen.

20 Tetrahydrofuran (THF), diethyl ether, n-pentane, methanol and dichloromethane were dried and purified according to standard procedures and stored under nitrogen. Preparation of Intermediates Difluorodiphenylsilane (1). This compound was synthesised according 25 to Lickiss, P. D.; Lucas, R. J. Organomet. Chem. 1996, 510, 167-172.

Preparation of Fluoro(1-methylpiperidin-4-yl)diphenylsilane (2). A mixture of magnesium turnings (2.84 9, 117 mmol) and iodine (500 mg, 3.94 mmol) was heated at 80 C for 30 minutes in a sealed flask and was then cooled to 20 C, followed by successive addition of THF (4 mL) and 4- chloro-1 30 methylpiperidine (1.00 g, 7.48 mmol). After the reaction had started (reflux), a solution of 4-chloro-1-methylpiperidine (12.3 g, 92.1 mmol) in THF (40 mL) was added dropwise in such a way that the solvent reflexed permanently. The mixture

was stirred for a further 2 hours under reflux and was then added dropwise at 20 C within 1 hour to a stirred solution of 1 (22.0 9,99.9 mmol) in THE (200 mL).

After the resulting mixture was stirred at 20 C for 16 hours, n-pentane (200 mL) was added and the precipitate was filtered off. The solvent of the filtrate was 5 removed under reduced pressure and the residue was distilled in a Kugelrohr apparatus (oven temperature 195 C, 0.01 mbar) to give 2 in 65% yield as a colourless oily liquid (19.3 9, 64.4 mmol). Anal. Calcd for C,BH22FNSi: C, 72.20; H. 7.40; N. 4.68. Found: C, 72.5; H. 7.4; N. 4.6.

Preparation of 4-(Fluorodiphenylsilyl)piperidinium Chloride (3).

10 1-Chloroethyl chloroformate (14.3 9, 100 mmol) was added dropwise at 0 C within 10 minutes to a stirred solution of 2 (15.0 g, 50.1 mmol) in dichloromethane (75 mL). The mixture was stirred for 10 minutes at 0 C and then for a further 1.5 hours at 20 C. The solvent was removed under reduced pressure and diethyl ether (50 mL) was added to the residue. The resulting oily 15 precipitate was separated by centrifugation and discarded, and the solvent of the supernatant was removed under reduced pressure, followed by addition of methanol (40 mL). The resulting solution was stirred for 1 hour at 50 C, and the solvent was then slowly removed under reduced pressure and the solid residue recrystallized from methanol at -20 C to give 3 in 58% yield as a colourless 20 crystalline solid (9.34 g, 29.0 mmol); mp 211 C (dec). Anal. Calcd for C,7H2,CIFNSi: C, 63.43; H. 6.58; N. 4.35. Found: C, 63.3; H. 6.6; N. 4.2.

Preparation of Methoxydiphenyl(piperidin-4-yl)silane (4). A solution of 3 (13.4 9, 41.6 mmol) in methanol (100 mL) was added dropwise at 20 C within 30 minutes to a stirred solution of sodium methanolate in methanol 25 (prepared from sodium (1.91 g, 83.1 mmol) and methanol (45 mL)). After the mixture was stirred for 1 hour at 20 C, the solvent was removed under reduced pressure and diethyl ether (100 mL) was added. The precipitate was filtered off and washed with diethyl ether (2 x 25 mL), and the filtrate and the wash solutions were combined. The solvent was removed under reduced pressure and a 30 colourless oil remained, which crystallised at 20 C over a period of cat 3 days to give 4 in 82% yield as a colourless crystalline solid (10.2 g, 34.3 mmol); mp

38 C. Anal. Calcd for C,BH23NOSi: C, 72.68; H. 7.79; N. 4.71. Found: C, 72.5; H. 7.8; N. 4.7.

Preparation of 2-(1 -(4-Bromophenyl)-1 -methylethyl) 4,4-dimethyl,5-

dihydro-1,3-oxazole (5). This compound was prepared according to Orjales 5 Venero, A.; Rubio Royo, V.; Borden Martin, M. (Inventors). Fabrica Espanola de Productos Qulmicos y Farmaceuticos, S.A. ES 2151442 A1, 16 Dec 2000; Chem. Abstr. 2001, 135, 257230x.

Preparation of 4-(4-(1-(4,4-Dimethyl,5-dihydro-1,3-oxazol-2-yl)-1-

methylethyl)phenyl)-oxobutanoic Acid (6). A Grignard reagent was prepared 10 from 5 (20.0 9, 67.5 mmol) and magnesium turnings (2.13 9,87.6 mmol) in THE (60 mL) and then added dropwise at-78 C within 90 minutes to a stirred solution of butanedioic anhydride (6.75 9, 67.5 mmol) in THE (270 mL). After the mixture was warmed to 20 C within 4 hours and stirred for a further 12 hours at this temperature, the solvent was removed under reduced pressure and water (100 15 mL) and dichlorormethane (150 mL) were added. The organic phase was separated and dried over anhydrous sodium sulphate, the solvent was removed under reduced pressure, and the residue was crystallized from diethyl ether at -20 C to give 6 in 59% yield as a colourless crystalline solid (12.7 9,40.0 mmol); mp 87 C. Anal. Calcd for C,BH23NO4: C, 68.12; H. 7.30; N. 4.41. Found: C, 67.8; 20 H. 7.2; N. 4.2.

Example 1: Sila-fexofenadine (rac-7) OH 25 (3x ACT O H rac-7 in OH 30 Preparation of rac-(1-(4-(4-(1-Carboxy-1-methylethyl)phenyl)-4 hydroxybutyl)piperidin-4-yl)diphenylsilanol (rac-Sila-fexofenadine, rac-7) .

Triethylamine (4.26 9, 42.1 mmol) was added dropwise at -20 C within 5 minutes to a stirred solution of 6 (4.16 9, 13.1 mmol) in THF (55 mL).

Subsequently, ethyl chloroformate (1.42 9, 13.1 mmol) was added dropwise at the same temperature within 1 minute, and the resulting mixture was then stirred 5 for 30 minutes at -20 C. A solution of 4 (3.90 9,13.1 mmol) in THF (15 mL) was added dropwise at -20 C within 1 minute, and the resulting mixture was then warmed to 20 C and stirred for 16 hours. The precipitate was separated by centrifugation and discarded, and the solvent of the supernatant was removed under reduced pressure. The solid residue (consisting of 8; crude product, not 10 further purified) was dissolved in THF (100 mL), and the resulting solution was added dropwise at 0 C within 1 hour to a stirred suspension of lithium aluminium hydride (2.23 9, 58.8 mmol) in THF (25 mL). After the mixture was stirred for 1 hour at 0 C, a solution of potassium sodium tartrate (6.97 9,33.2 mmol) in water (65 mL) was added dropwise at 0 C within 30 minutes, and the mixture was 15 stirred for 16 hours at 20 C, followed by the addition of ethyl acetate (100 mL).

The organic phase was separated and dried over anhydrous sodium sulphate, and the solvent was removed under reduced pressure. Water (30 mL) was added to the solid residue (consisting of rac-9; crude product, not further purified), followed by the addition of 4 M hydrochloric acid (30 mL; after the 20 addition of the first few drops, the solid dissolved), and the mixture was then kept undisturbed for 3 hours. The resulting oily precipitate was separated by Recantation, dried in vacua and dissolved in methanol (55 mL), followed by the addition of a solution of sodium hydroxide (21.2 9, 530 mmol) in water (55 mL).

The mixture was heated under reflux for 4 days, the solvents were removed 25 under reduced pressure, and the remaining solid was dissolved in water (60 mL), followed by the addition of 12 M hydrochloric acid (ca.45 mL) until a pH of 8 was achieved. The precipitate was isolated by centrifugation, washed with water and dried in vacua. The remaining product was redissolved in methanol (10 mL), and the solution was then kept at -20 C for 2 days to give rac-7 in 42% yield as a 30 colourless solid (2.86 9, 5.52 mmol). Anal. Calcd for C3,H39NO4Si: C, 71.92; H. 7.59; N. 2.71. Found: C, 71.2; H. 7.7; N. 2.8.

<3, once NMe \F OF

1 2

O Cl Clot 2. MeOH NaOMe,RCJ Come L@! \ F 4 3 Scheme 1 _.

1. Mg 2 OO̳ - 0 3. H2O;,';

5 6 1. NEt3 2. ClCO2Et 3.4 Posit 1 \OMe J 1. LiAIH4 8 2. H2O

: 1 \OH J rack 1. H2O / HCI

- OH 2. NaOH GNU O 3. HCI

si \OH rack Scheme 2

Claims (10)

1. A compound of formula l: HO AN Alk|-COOH wherein Ar and Ar' are each aryl groups; 10 R and R' are, independently, selected from H. C,6 alkyl, Cry alkyl substituted with one or more groups individually selected from oR2, substituted or unsubstituted with aryl or heteroaryl, including aryl substituted with Si(R3)3, C'.6 alkyl, Cry carboxy, where R2 is H or C, 6 alkyl and each R3 is aryl or C, 6 alkyl; 15 Alk is Con alkanedlyl optionally substituted with one or more substituents selected from OH, halogen, C, 6 alkoxy and amino; and the benzene ring in formula I is optionally substituted with one or more substituents selected from OH, halogen, C' 6 alkyl, C, 6 alkoxy, di(C, 6 alkyl)amino, pyrrolidino, piperidino, morpholino and N-alkylpiperazino; 20 or a pharmaceutically acceptable salt or prodrug thereof.

2. A compound according to claim 1, wherein Ar and Ar' are each phenyl.

3. A compound according to claim 1 or claim 2, wherein Alk is -(CH2)3CHoH-.

4. A compound which is (1-(4-(4-(1-carboxy-1-methylethyl)phenyl)-4 25 hydroxybutyl)piperidin-4-yl)diphenylsilanol or a pharmaceutically acceptable salt thereof.

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

6. A pharmaceutical composition comprising as an active ingredient a compound according to any preceding claim, together with a carrier or diluent.

30

7. Use of a compound according to any of claims 1 to 5, for the manufacture of a medicament for anti-histamine therapy.

8. Use of a compound according to any of claims 1 to 5, for the manufacture of a medicament for the treatment or prevention of urticaria, asthma, allergic rhinitis or eczema.

9. A method of shortening prolonged QT intervals in a patient with a 5 trafficking defective HERG mutation, which comprises treating the patient with an effective amount of a compound of any of claims 1 to 5.

10. A method according to claim 9, wherein the patient has a N470D or G601 S mutation.

:q -