WO2004048391A1

WO2004048391A1 - Silicon compounds to be used as ligands for retinoid receptors

Info

Publication number: WO2004048391A1
Application number: PCT/GB2003/005026
Authority: WO
Inventors: John Gary Montana; Graham Andrew Showell; Reinhold Tacke
Original assignee: Amedis Pharmaceuticals Ltd.
Priority date: 2002-11-25
Filing date: 2003-11-19
Publication date: 2004-06-10
Also published as: AU2003286245A1

Abstract

A compound of formula (I) or formula (II) wherein A is alkylene, alkenylene, alkynylene, hydroxyalkylene, arylene, -C(O)N(R4)-, -N(R4)C(O)-, -C(O)- or -C(=NOR4)-; B is alkylene, alkenylene, alkynylene, arylene or heteroarylene; X is oxygen, -C(O)-, -S(O),-, -N(R4)-, -C(R6)2- or -Si(R5)2-; Y is -CH2-; or X is C(R6), Y is CH and X and Y taken together form -C(R6)=CH-; each R1 is the same or different and is alkyl; each R2 is the same or different and is halogen, hydroxy, alkyl or alkoxy; each R3 is the same or different and is hydrogen, alkyl or aryl; each R4 is the same or different and is hydrogen or alkyl; each R5 is the same or different and is alkyl; each R6 is the same or different and is hydrogen, alkyl or aryl; bis 0 or 1; I is O, 1 or 2; M is O, 1, or 3; and N is O, 1 or 2; or a pharmaceutically acceptable salt thereof.

Description

SILICON COMPOUNDS TO BE USED AS LIGANDS FOR RETINOID RECEPTORS

Field of the. Invention

This invention relates to silicon compounds and their use in therapy. Background to the Invention Retinoids are structural analogues of vitamin A and include both natural and synthetic compounds. Retinoids are pleiotrophic regulatory compounds that influence a number of immune and structural cells, e.g. by regulating, cell differentiation by modulating gene expression. The compounds are able to reverse the preneoplastic transformation of cells, and thus have potential as therapeutic agents for the treatment and prophylaxis of cancer. Retinoids, in particular retinoic acid analogues, have been used in the treatment of basal cell carcinoma, mycosis fungsides, psoriasis and leukaemia. However, systemic side effects, for example dermatitis, alopecia, systemic toxicity and bone remodelling, are common and a severely limiting factor to utility. Viruses such as HIV-1 have recently been shown to be activated by retinoid compounds.

The physiological activities of retinoids are mediated by two types of receptor; Retinoic Acid Receptors (RARs) and Retinoid X Receptors (RXRs). In dimer form, these receptors interact with specific DNA sequences termed "retinoic acid response elements" (RAREs). Retinoic acid has been shown to suppress collagenase gene expression through interactions with the transcription factor AP-1 (a protein heterodimer comprising c-jun and c-fos) in vitro. Compounds possessing anti-AP-1 activity have potential for the treatment of arthritis by suppressing collagenase and other AP-1 regulated matrix metalloproteinases (BeehleretaI, J. Rheumatology 2003, 30, 355-363).

Many retinoids have been synthesised (see for example, Dawson et al, J. Med. Chem., 32, 1504-1517, 1989), in attempts to provide compounds having beneficial activity but with no serious side-effects. However, attempts on the whole have been unsuccessful, either due to the persistence of undesirable activities or a severe reduction in the desired activity.

Sila-substitution (C/Si-exchange) of drugs is a relatively recent approach for searching for organo-silicon 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 compounds have changed. A review of this approach is provided in Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986). Summary of the Invention

A first aspect of the invention is a compound of formula (I) or formula (II)

wherein

A is alkylene, alkenylene, alkynylene, hydroxyalkylene, arylene, -C(O)N(R⁴)-, -N(R )C(O)-, -C(O)- or -C(=NOR⁴)-;

B is alkylene, alkenylene, alkynylene, arylene or heteroarylene;

X is oxygen, -C(O)-, -S(O)_r, -N(R⁴)-, -C(R⁶)₂- or -Si(R⁵)₂-;

Y is -CH₂-; or X is C(R⁶), Y is CH and X and Y taken together form -C(R⁶)=CH-; each R¹ is the same or different and is alkyl; each R² is the same or different and is halogen, hydroxy, alkyl or alkoxy; each R³ is the same or different and is hydrogen, alkyl or aryl; each R⁴ is the same or different and is hydrogen or alkyl; each R⁵ is the same or different and is alkyl; each R⁶ is the same or different and is hydrogen, alkyl or aryl; b is O or l ;

I is O, 1 or 2; m is 0, 1 , 2 or 3; and n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

Compounds of the invention may act as ligands for retinoid receptors, in particular retinoic acid receptors (RARs). Consequently, they may have utility in the treatment for prevention of diseases or conditions in which such receptors are implicated.

Another aspect of the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.

Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of disease or condition mediated by a retinoid receptor.

Another aspect of the invention is a product comprising a compound of the invention and an anti-cancer agent, as a combined preparation for separate, simultaneous or sequential use in cancer therapy. Description of the Preferred Embodiments

Certain compounds and combinations of substituents are preferred; in particular, see the subclaims.

With regard to formulae (I) and (II), A is preferably -CH=CH-, -C≡C-, -C(CH₃)=CH-, -C(O)-, -C(O)NH-, phenylene or naphthalene. When present, B is preferably phenylene, pyridinylene or naphthalene, any of which is optionally substituted, preferably with one or more halogen atoms. Each R¹ is preferably methyl. Each R² is preferably the same or different and is chlorine, bromine, hydroxy or hexoxy. Each R³ is preferably hydrogen or ethyl. X is preferably -S-, -S(O)₂- or ~Si(R⁵)₂-, wherein each R⁵ preferably methyl. Alternatively, when X is C(R⁶) and Y is CH, R⁶ is preferably phenyl. Preferably, n is 1.

The term "alkyl" as used herein refers to a straight or branched chain alkyl moiety having from one to ten carbon atoms. This term includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. "C,_₁₀ alkyl" has the same meaning. "Alkylene" refers to a similar, divalent group.

The term "alkenyl" as used herein refers to a straight or branched chain alkyl moiety having two to ten 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„ιo alkenyl" has the same meaning. "Alkenylene" refers to a similar, divalent group.

The term "alkynyl" as used herein refers to a straight or branched chain alkyl moiety having two to ten carbon atoms and having in addition at least one triple bond. "C_2-10 alkynyl" has the same meaning. "Alkynylene" refers to a similar, divalent group.

The term "alkoxy" as used herein refers to a straight chain or branched chain alkoxy group containing between one and ten carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, octoxy and the like. "C,. alkoxy" has the same meaning.

The term "aryl" as used herein refers to optionally substituted aromatic ring systems comprising six to ten 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 or derived from halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulphhydryl, alkylthio, imino, amido, phosphoryl, phosphonyl, phosphino, carbonyl, carboxyl, carboxamido, anhydrido, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, cyano, guanidino, amidino, acetal, ketal, amine oxide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, azido, aziridine, carbamate, epoxide, hydroxamic acid, imido, oxime, sulphonamido, thioamido, thiocarbamate, urea or thiourea. "Arylene" refers to a similar, divalent group. The term "heteroaryl" as used herein refers to optionally substituted aromatic ring systems of five to ten ring atoms of which at least one is selected from O, N and S and includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like. "Heteroarylene" refers to a similar, divalent group.

The term "halogen" as used herein refers to a group selected from F, Cl, Br or I.

Preferred compounds of the invention include: 4-[2-(5,5-dimethyl-8-phenyl-5-sila-5,6-dihydro-2-naphthyl)-vinyl]-benzoic acid;

6-(4,4-dimethyl-4-sila-thiochroman-6-ylethynyl)-nicotinicacid ethyl ester;

6-(4,4-dimethyl-4-sila-thiochroman-6-ylethynyl)-nicotinicacid;

4-(5,5,8,8-tetramethyl-5,8-disila-5,6,7,8-tetrahydro-anthracen-2-yl)- benzoic acid; δ'.S'.δ'^'-tetramethyl-S'.δ'-disila-S'.e'J'.δ'-tetrahydro-β.Zlbinaphthalenyl- 6-carboxylic acid;

2,6-difluoro-4-((5,8-disila-5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)carbamoyl)benzoic acid; 4-[2-(5,5,8,8-tetramethyl-5,8-disila-5,6,7,8-tetrahydro-2-naphthyl)- propenyl]-benzoic acid;

6-(5,5,8,8-tetramethyl-5,8-disila-5,6,7,8-tetrahydro-naphthalene-2- carbonyl)-naphthalene-2-carboxylicacid;

4-[2-(7-hexyloxy-4,4-dimethyl-1 , 1 -dioxo-4-sila-thiochroman-6-yl)- propenyl]-benzoic acid;

4-(5-chloro-6-hydroxy-1 , 1 ,4,4-tetramethyl-1 ,4-disila-1 ,2,3,4- tetrahydronaphthalene-7-carboxamido)benzoic acid; and

4-(5-bromo-6-hydroxy-1, 1,4, 4-tetramethyl-1 ,4-disila-1, 2,3,4- tetrahydronaphthalene-7-carboxamido)benzoicacid; the corresponding structures of which are shown below, respectively:

20

25

Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.

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 μsed 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. A hydroxy group can be protected by an alkyl or like group.

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, gluconic acid, glutamic acid, N-glycolylarsanilic acid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 1 -hydroxy-2-naphthoic acid, 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 etha no lam ine, ethanol am i ne , ethylened i am i ne, N , N ' - bis(dehydroabietyl)ethylenediamine, N-methylglucamine, procaine, tris(hydroxymethyl)aminomethane ("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 and/or by the following process (in which the group P, of - C(O)OP, is a suitable protecting group):

It will be understood that the process detailed above is solely for the purpose of illustrating the invention and should not be construed as limiting. A process utilising similar or analogous reagents and/or conditions known to one skilled in the art may also be used to obtain a compound of the invention.

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 useful in the treatment or prevention of various diseases and conditions including, but not limited thereto, cancer, chronic obstructive pulmonary disease, chronic bronchitis, asthma, emphysema, inflammatory diseases (including pulmonary fibrosis, ileitis, colitis, and Crohn's disease), neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease and stroke), improper pituitary function (including insufficient production of growth hormone), eye diseases (including proliferative vitreoretinopathy, retinal detachment, dry eye and other corneopathies), cardiovascular diseases (including diseases associated with lipid metabolism, e.g. dydislipidemias; postangioplasty restenosis; and enhancing circulating levels of tissue plasmonogen activator), skin diseases (including warts, inflammatory acne, non-inflammatory acne, ichthyoses, follicular disorders, benign epithelial tumours; perforated dermatoses, e.g. Kyrle's disease; disorders of keritinisation, e.g. psoriasis; hyperproliferative diseases, active keratoses, arsenic keratoses, actinic keratoses, psoriasis, eczema, atopic dermatitis, Darrier's disease, lichen planus, prevention or reversal of glucocorticoid damage, pigmentation diseases and microbial diseases), rheumatoid arthritis, non-insulin dependent diabetes and immune system diseases (including use as immunosuppressants and immunostimulants). The compounds may also be useful in the modulation of apoptosis (including induction of apoptosis and inhibition of T-cell activated apoptosis), wound healing (including modulation of chelosis), hair restoration and growth (including use in combination therapies), and modulation of organ transplant rejection.

In particular, the compounds of the invention may be useful in cancer therapy. The compounds may regulate the proliferative and differentiative capacities of mammalian cell types and thus can be used in a variety of chemopreventive and chemotherapeutic settings.

The term "cancer" as used herein refers to any disease or condition characterised by uncontrolled, abnormal growth of cells and includes all known types of cancer, for example cancer of the bladder, breast, colon, brain, bone, head, blood, eye, neck, skin, lungs, ovaries, testes, prostate and rectum; digestive, gastrointestinal, endometrial, hematological, AIDS-related, muscoskeletal, neurological and gynecological cancers; lympomas, melanomas and leukaemia. The term refers to both solid and liquid tumours.

A compound of the invention may be used in combination with one or more therapeutic agents. Accordingly, a composition of the invention may further comprise a second active ingredient, for example an anti-cancer agent.

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 or topical 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 compound 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 include 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 in 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 may contain the active compound in admixture with one or more suitable pharmaceutically acceptable excipients. 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 compound 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 may contain the active compound 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 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. Sweetening agents, such as those described 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 compound 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 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.

Claims

1. A compound of formula (I) or formula (II)

wherein

A is alkylene, alkenylene, alkynylene, hydroxyalkylene, arylene, -C(O)N(R⁴)-, -N(R⁴)C(O)-, -C(O)- or -C(=NOR⁴)-;

B is alkylene, alkenylene, alkynylene, arylene or heteroarylene;

X is oxygen, -C(O)-, -S(O)_r, -N(R⁴)-, -C(R⁶)₂- or -Si(R⁵)₂-;

Y is -CH₂-; or X is C(R⁶), Y is CH and X and Y taken together form -C(R⁶)=CH-; each R¹ is the same or different and is alkyl; each R² is the same or different and is halogen, hydroxy, alkyl or alkoxy; each R³ is the same or different and is hydrogen, alkyl or aryl; each R⁴ is the same or different and is hydrogen or alkyl; each R⁵ is the same or different and is alkyl; each R⁶ is the same or different and is hydrogen, alkyl or aryl; b is 0 or 1 ;

I is 0, 1 or 2; m is O, 1 , 2 or 3; and n is O, 1 or 2; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein A is -CH=CH- -C≡C- -C(CH₃)=CH-, -C(O)-, -C(O)NH-, phenylene or naphthalene.

3. A compound according to claim 1 or claim 2, wherein B is phenylene, pyridinylene or naphthylene, any of which is optionally substituted.

4. A compound according to claim 3, wherein B is phenylene optionally substituted with halogen.

5. A compound according to claim 1 or claim 2, wherein b is 0.

6. A compound according to any preceding claim, wherein each R¹ is methyl.

7. A compound according to any preceding claim, wherein each R² is the same or different and is chlorine, bromine, hydroxy or hexoxy.

A compound according to any preceding claim, wherein R³ is hydrogen or ethyl.

9. A compound according to any preceding claim, wherein X is -S-, -S(O)₂- or -Si(R⁵)₂-.

10. A compound according to claim 9, wherein each R⁵ is methyl.

11. A compound according to claim 1 to 8, wherein X is C(R⁶) and Y is CH.

12. A compound according to claim 11 , wherein R⁶ is phenyl.

13. A compound according to any preceding claim, wherein n is 1.

14. A compound according to claim 1 , selected from: 4-[2-(5,5-dimethyl-8-phenyl-5-sila-5,6-dihydro-2-naphthyl)-vinyl]-benzoic acid;

6-(4,4-dimethyl-4-sila-thiochroman-6-ylethynyl)-nicotinic acid ethyl ester; 6-(4,4-dimethyl-4-sila-thiochroman-6-ylethynyl)-nicotinic acid; 4-(5,5,8,8-tetramethyl-5,8-disila-5,6,7,8-tetrahydro-anthracen-2-yl)- benzoic acid;

S'.S'.δ'.δ'-tetramethyl-S'.δ'-disila-δ'.e'^'.δ'-tetrahydro-^^'Jbinaphthalenyl- 6-carboxylic acid;

4-[2-(5,5,δ,δ-tetramethyl-5,δ-disila-5,6,7,8-tetrahydro-2-naphthyl)- propenylj-benzoic acid; 6-(5,5,δ,δ-tetramethyl-5,8-disila-5,6,7,8-tetrahydro-naphthalene-2- carbonyl)-naphthalene-2-carboxylic acid; and

4-[2-(7-hexyloxy-4,4-dimethyl-1 ,1 -dioxo-4-sila-thiochroman-6-yl)- propenylj-benzoic acid.

15. A compound according to claim 1 , selected from: 2 , 6-difl uoro-4-( ( 5 , 8-d i s i l a-5 , 5 , δ , δ-tetra m ethyl -5 , 6 , 7 , δ- tetrahydronaphthalen-2~yl)carbamoyl)benzoic acid;

4-(5-chloro-6-hydroxy-1 , 1 ,4, 4-tetramethyl-1 ,4-di si la-!, 2,3,4- tetrahydronaphthalene-7-carboxamido)benzoic acid; and

4-(5-bromo-6-hydroxy-1 , 1 ,4,4-tetramethyl-1 ,4-disila-1 ,2,3,4- tetrahydronaphthalene-7-carboxamido)benzoic acid.

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

17. A pharmaceutical composition comprising, as an active ingredient, a compound of any of claims 1 to 15, and a pharmaceutically acceptable diluent or carrier.

1 δ. A composition according to claim 17, further comprising a second active ingredient which is an anti-cancer agent.

19. Use of a compound of any of claims 1 to 15, for the manufacture of a medicament for treatment or prevention of a disease or condition mediated by a retinoid receptor.

20. Use according to claim 19, wherein the receptor is a retinoic acid receptor.

21. Use according to claim 19 or claim 20, for the treatment of cancer or the modulation of apoptosis.

22 Use according to claim 21 , for the treatment of leukaemia.

23. Use according to claim 19 or claim 20, for the treatment or prevention of chronic obstructive pulmonary disease, chronic bronchitis, asthma or emphysema.

24. Use according to claim 19 or claim 20, for the treatment or prevention of inflammatory disease.

25. Use according to claim 24, for the treatment or prevention of pulmonary fibrosis, ileitis, colitis, Crohn's disease or rheumatoid arthritis.

26. Use according to claim 19 or claim 20, for the treatment or prevention of a neurodegenerative disease or an eye disease.

27. Use according to claim 26, for the treatment or prevention of Alzheimer's disease, Parkinson's disease, stroke, improper pituitary function, proliferative vitreoretinopathy, retinal detachment or dry eye.

26. Use according to claim 19 or claim 20, for the treatment or prevention of a cardiovascular disease.

29. Use according to claim 2δ, for the treatment or prevention of dyslipidermias or postangioplasty restenosis.

30. Use according to claim 19 or claim 20, for the treatment or prevention of a skin disorder.

31. Use according to claim 30, for the treatment or prevention of warts, acne, ichthyoses, a follicular disorder, a benign epithelial tumour, perforated dermatoses or a disorder of keratinisation.

32. Use according to claim 30, for the treatment or prevention of active keratoses.

33. Use according to claim 19 or claim 20, for the treatment or prevention of non-insulin dependent diabetes.

34. Use according to claim 19 or claim 20, for wound healing.

35. A product comprising a compound of any of claims 1 to 15 and an anti- cancer agent, as a combined preparation for separate, simultaneous or sequential use in cancer therapy.