This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.

It has surprisingly been discovered that certain arylalkylene derivatives are indicated to reduce bone resorption by inhibiting osteoclast H ⁺ -ATPase and are therefore of potential use for the treatment and/or prophylaxis of osteoporosis and related osteopenic diseases. These compounds are also considered to possess anti- tumourtumor activity, antiviral activity (for example against Semliki Forest, Vesicular Stomatitis, Newcastle Disease, Influenza A and B, HIV viruses), antiulcer activity (for example the compounds may be useful for the treatment of chronic gastritis and peptic ulcer induced by Helicobacter pylori), immunosupressant activity, antilipidemic activity, antiatherosclerotic activity and to be useful for the treatment of ADDS and Alzheimer's disease. In a further aspect, these compounds are also considered useful in inhibiting angiogenesis, i.e. the formation of new blood vessels which is observed in various types of pathological conditions (angiogenic diseases) such as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumours.

Accordingly, the present invention provides a compound of formula (I):

or a salt thereof, or a solvate thereof, wherein: Rj is an alkyl group or a substituted or unsubstituted phenyl group; R2 and R3 each independently represent hydrogen or alkyl; and either: RA represents T\ wherein Tj is hydrogen or alkyl; and Rj3 represents a moiety of formula (a):

wherein T2 and T3 each independently represents hydrogen, hydroxy, amino, alkoxy, alkylcarbonyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, alkylamino, dialkylamino, chloro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl

or T2 and T3 together represent a C3_5-alkylene chain each carbon atom of which is optionally substituted with up to three alkyl groups; or

R together with Rg represents a moiety of formula (b):

wherein R4, R5, Rg and R9 each independently represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl or R4 and R5 together with the carbon atoms to which they are attached or Rg and R9 together with the carbon atoms to which they are attached form an optionally substituted phenylene ring; and

Rg and R7 each independently represent hydrogen, alkyl, aryl, alkoxy; or Rg and R7 together with the carbon atom to which they are attached form a saturated heterocyclic ring; or

RA represents a moiety of formula (c) and Rg represents a moiety of formula (d):

(c) (d)

wherein T4, T5, Tg and T7 each independently represents hydrogen, alkoxy, alkylcarbonyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, alkylamino, dialkylamino, chloro, alkyl, carboxy, carbalkoxy, carbamoyl or alkylcarbamoyl; and X\ and Y each independently represent hydrogen or X together with Y represents a C3.5-alky.ene chain, a moiety of formula -CO-NH-,-CH2-NH- or -CH2-O-; and

X represents hydroxy, alkoxy or a group of formula NR _s R _t wherein R _s and R _t each independently represent hydrogen, alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl or heteroarylalkyl; or R _s and R _t together with the nitrogen atom to which they are attached represent a saturated heterocyclic group;

Suitably, R\ represents a Ci .4-alkyl group, for example methyl.

Suitably, R2 and R3 each independently represent hydrogen.

Suitably, R4 represents hydrogen.

When R4, R5, Rg, or R9 represent a substituted alkyl group, suitable substitutents include one or more hydroxy groups.

Suitably, R4 and R5 together with the carbon atoms to which they are attached or Rg and R9 together with the carbon atoms to which they are attached form a phenylene ring

When Rg and R7 together with the carbon atom to which they are attached form a saturated heterocyclic ring, suitable rings include tetrahydrofuran and dioxolane.

Suitable substituents for alkyl groups represented by R _s or R _t include hydroxy groups and mono- or di-substituted amino groups. Suitable substituents for phenyl groups represented by R _s or R _t include hydroxyalkyl groups.

Suitable saturated heterocyclic groups represented by NR _s R _t include morpolinyl, pirrolidinyl, piperidinyl or piperazynyl groups.

A suitable phenylalkyl group represented by R _s or R _t is a benzyl group. Suitably, T\ represents hydrogen and methyl.

Suitably, T2 represents hydrogen, hydroxy, alkoxy or alkylcarbonyloxy.

When T2 and T3 together represent a C3_.5-alky.ene chain, suitable chains are C3-or C4-alkylene chains, examples include:

-(CH ₂ )4-and -C(CH3)2-(CH2)2-(CH ₃ )2C-. Generally, T4, T5, Tg and T7 each independently represent hydrogen.

Suitably, X represents alkoxy, especially methoxy.

When X\ and Y together represent a C3_.5-alky.ene chain, suitable chains are C2- alkylene chains.

As used herein, the term "alkyl" includes straight or branched chain alkyl groups having from 1 to 12 , suitably 1 to 6, preferably 1 to 4, carbon atoms and also includes such alkyl groups when forming part of other groups such as alkoxy or alkanoyl groups.

Suitable optional substituents for any alkyl group include hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups, especially hydroxy. As used herein, the term "aryl" includes phenyl and naphthyl, especially phenyl.

Suitable optional substituents for any aryl group includes up to 5 substituents, suitably up to 3 substituents, selected from alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, acetyl, cyano, nitro, amino and alkylcarbonylamino.

As used herein, the term "heteroaryl" includes single or fused heteroaryl groups, each ring having 5 to 7 ring atoms, especially 5 or 6, which ring atoms include 1, 2 or 3 heteroatoms selected from O, S, or N.

Suitable hetereoaryl groups include pyridyl, especially 4-pyridyl, furanyl thiophenyl, pyrrolyl and heteroaryl groups comprising fused benzene rings such as quinolinyl, benzofuranyl and indolyl groups.

Certain of the carbon atoms of the compounds of formula (I) - such as those compounds wherein R1-R9 contains chiral alkyl groups are chiral carbon atoms and may therefore provide stereoisomers of the compound of formula (I). The invention extends to all stereoisometric forms of the compounds of formula (I) including enantiomers and mixtures thereof, including racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses.

The compounds of formula (I) also possess two double bonds and hence can exist in one or more geometric isomers. The invention extends to all such isomeric forms of the compounds of formula (I) including mixtures thereof. The different isomeric forms may be separated one from the other by conventional methods or any given isomer may be obtained by conventional synthetic methods.

Suitable salts of the compounds of the formula (I) are pharmaceutically acceptable salts, such as a hydrochloride, methansulfonate, maleate, succinate, acetate, propionate or a tartrate salt.

Suitable solvates of the compounds of the formula (I) are pharmaceutically acceptable solvates, such as hydrates.

The salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form another aspect of the present invention.

A compound of formula (I) or a salt thereof or a solvate thereof, may be prepared:

(a) by reacting a compound of formula (II):

(ID

wherein R^. Rβ. R2 ^an d 3 are as defined in relation to formula (I), with a reagent capable of converting a moiety of formula -CO-R2 into a moiety of formula (e):

wherein Ri.R 2 and X are as defined in relation to formula (I); and thereafter, as necessary, earring out one or more of the following reactions:

(i) converting one compound of formula (I) into another compound of formula (I);

(ii) removing any protecting group;

(iii) preparing a salt or a solvate of the compound so formed.

A suitable reagent capable of converting a moiety of the above defined formula - CO-R2 into a moiety of the above defined formula (e), includes conventional reagents used to convert C=O bonds into carbon carbon double bonds, such as a Wittig reagent or a Horner-Emmons reagent, for example those of formula (III):

X _j -CH-CO-X _j

^0Rl (III) wherein Rj is as defined in relation to the compounds of formula (I), X2 represents X as defined in relation to formula (I) or a group convertible thereto and X3 represents a moiety (RιoO)2P(0)-, wherein R\Q is C1.4 alkyl group or a group Ph3P-.

The reaction between the compounds of formula (II) and the reagent capable of converting the group of formula -CO-R2 into the moiety of formula (e), may be carried out under the appropriate conventional conditions, depending upon the particular reagent chosen, for example:

When the reagent is a compound of formula (III) wherein X3 is a moiety (Ri QO)2P(O)-, then the reaction is carried out under conventional Horner-Emmons conditions, using a suitable aprotic solvent and in presence of a base. Suitable solvents are conventional solvents for this type of reaction such as tetrahydrofuran (THF), dioxane, methylenedichloride or aromatic hydrocarbons such as toluene, preferably THF, at a temperature providing a suitable rate of formation of the required product, conveniently at ambient temperature or at an elevated temperature, such as a temperature in the range of from 30°C to 120°C. Suitable bases used in the above mentioned reaction include inorganic base such as caesium carbonate, potassium carbonate, sodium hydride, preferably sodium hydride or organic base such asl,8-diazabicyclo[5.4.0]undec-7-ene

(DBU) or diisopropylethylamine (DIPEA), preferably DBU. Generally the reaction is carried out in an inert atmosphere such as nitrogen.

When the reagent is a compound of formula (III) wherein X3 is a moiety PI13P- then the reaction is carried out under conventional Wittig conditions. Usually the reaction is carried out in the presence of a base, in any suitable aprotic solvent. Suitable solvents are conventional solvents for use in this type of reaction, such as THF, diethylether, methylenedichloride or aromatic hydrocarbons such as toluene, preferably methylenedichloride, at a temperature providing a suitable rate of formation of the required product, conveniently at ambient temperature or at an elevated temperature, such as a temperature in the range of from 30°C to 120°C. Suitable bases include conventional bases for this type of reaction such as sodium hydride, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or diisopropylethylamine (DIPEA), preferably DBU.

The reaction between the compounds of formulae (II) and the Horner-Emmons reagent of formula (III) may be carried out under conventional Horner-Emmons conditions such as those described above.

A further suitable reagent capable of converting a moiety of the above defined formula -CO-R2 into a moiety of the above defined formula (e) is a compound of formula (IV): R ₁ -O-CH ₂ -CO.X ₂ (IV)

wherein R\ and X2 are as defined in relation to the compounds of formula (III).

Generally, the reagent of formula (IV) is in an activated form, suitably an anionic form such as a salted form, for example an alkali metal salted form. The reaction between the compounds of formulae (II) and (IV) may be carried out according to known procedures for example those disclosed in Liebigs Ann. Chem., 703, 1967, 37.

Suitable conversions of one compound of formula (I) into another compound of formula (I) include converting a compound of formula (I) wherein X represents a hydroxy group or an alkoxy group into a compound of formula (I) wherein X represents a different alkoxy group or a moiety of the above defined formula NR _s R _t .

The conversion of one compound of formula (I) into another compound of formula (I) may be carried out using the appropriate conventional procedure, for example the above mentioned conversion of a compound wherein X represents a hydroxy group or an alkoxy group into a compound wherein X represents a moiety of the above defined formula NR _s t may be carried out as follows:

(i) when X is alkoxy, by basic hydrolysis, using for example potassium hydroxide, to provide a compound of formula (I) wherein X is hydroxy, and thereafter treating with a compound of formula HNR _s *R _t > wherein R _s > and R _t < have the required value of R _s and R _t respectively; preferably the reaction with the compound of formula HNR _s «R _t * takes place in the presence of a condensing agent such as N.N'-dicyclohexylcarbodiimide (DCC) or after conversion of (I), wherein X is hydroxy, into the corresponding acid chloride and condensation in presence of a base such as triethylamine; alternatively by treating the said compound of formula (I) directly with a compound of formula HNR _s 'R _t * in the presence of a trialkylaluminium , such as trimethylaluminium, according to known procedures, such as those disclosed in Tetrahedron Lett., 48, 4171 (1977).

(ii) when X is hydroxy, by using analogous procedures to those mentioned above in (i).

A compound of formula (II) wherein R^ represents the above defined T and Rg represents a moiety of the above defined formula (a), may be prepared according to the reaction sequence shown in Scheme (I) below:

Scheme (I)

(VI)

The reactions in Scheme (I) may be carried out using the appropiate conventional procedure, for example: when R2 represents H, by means of the Claisen-Schmidt reaction, aldehyde (VII) can react with aliphatic aldehydes or ketones (VIII) in presence of bases such as sodium or potassium hydroxide affording compound (II) that can be alternatively prepared by the Wittig reaction of a keto derivatives (VI) with the appropriate phosphonium salt using the above mentioned conditions. When carbethoxy phosphorane is used, the carboxylic ester (V) is then converted into the corresponding alcohol with a reducing agent suitably a complex metal reducing agent such as lithium aluminium hydride (LiAlH4), diisobutyl aluminium hydride (DIBAH) or lithium borohydride (UBH4) in any suitable aprotic, for example methylene dichloride, chloroform, dioxane, diethyl ether or THF at any temperature providingprovidng a

suitable rate of formation of the required product, such as a temperature in the range of between -30°C and 60°C, for example at room temperature. Then, the intermediate alcohol is oxidised to aldehydes (II) with an oxidising agent such as manganese dioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swem reaction), preferably manganese dioxide in methylene dichloride.

A compound of formula (II) wherein R^ together with Rg represents a moiety of the above defined formula (b), may be prepared according to the reaction sequence shown in Scheme (II) below: Scheme (TI)

(II)

The reactions in Scheme (II) may be carried out using the appropriate conventional procedure, for example: when R2 represents hydrogen the compounds of formula (DC) are prepared by Horner-Emmons reaction starting from ketones (X) and triethyl phosphonoacetate as described in the literature (J. Am. Chem Soc, 83, 1961, 1733; Tetrahedron Lett., 35, 1994, 3383) and the carboxylic ester (IX) obtained is then converted into the corresponding alcohol with a reducing agent suitably a complex metal reducing agent such as lithium aluminium hydride (LiAlH4), diisobutyl aluminium hydride (DIBAH) or lithium borohydride (LiBH4) in any suitable aprotic, for example methylene dichloride, chloroform, dioxane, diethyl ether or THF at any temperature providingprovidng a suitable rate of formation of the required product, such as a temperature in the range of between -30°C and 60°C, for example at room temperature. Then, the intermediate alcohol is oxidised to aldehydes (II) with an oxidising agent such as manganese dioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate

(PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swem reaction), preferably manganese dioxide in methylene dichloride.

A compound of formula (II) wherein represents a moiety of above defined formula (c) and Rβ represents amoiety of above defined formula (d) may be prepared according to the reaction sequence shown in Scheme (HI) below:

Scheme (LIT)

wherein R2, R3, T4, T5, Tg, T7, Xj and Y are as defined in relation to formula (I).

The reactions in Scheme (III) may be carried out using the appropiate conventional procedure, for example for compounds wherein R2 represents hydrogen:

(i) Compounds of formula (XI) are prepared by Horner-Emmons reaction starting from ketones (XII) and triethyl phosphonoacetate using conditions as described above and in the literature (Liebigs Ann. Chem., 703, 37 (1967)).

(ii) The carboxylic ester (XI) is then convened into the corresponding alcohol with a reducing agent suitably a complex metal reducing agent such as lithium aluminium hydride (LiAlH4), diisobutyl aluminium hydride (DIBAH) or lithium borohydride (IJBH4) in any suitable aprotic, for example methylene dichloride, chloroform, dioxane, diethyl ether or THF at any temperature providingprovidng a suitable rate of formation of the required product, such as a temperature in the range of between -30°C and 60°C, for example at room temperature.

(iii) The alcohol is then oxidised to provide aldehyde (II) using an oxidising agent such as manganese dioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate

(PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swem reaction), preferably manganese dioxide in methylene dichloride.

When R2 is other than -H , e.g. alkyl.., compounds (II) are obtained directly from (XII) by Wittig or Horner-Emmons reaction with the appropriate phosphorous ylides or phosphonates using conditions described above.

Salts and/or solvates of the compounds of formula (I) may be prepared using the appropriate conventional procedure.

The compounds of formula (III) and (IV) are known compounds or they are prepared using methods analogous to those used to prepare known compounds, such as those described in Chem. Ber., 97, 1713 (1964); Tetrahedron, 50, 3177 (1994) and JAm.Chem.Soc, 70, 3569 (1948).

The compounds of formula (VI), (VII), (VIII), (IX), (X), (XI) and (XII) are known compounds or they are prepared using methods analogous to those used to prepare known compounds, such as those described in J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.

A compound of formula (I) or a solvate thereof may be isolated from the above mentioned processes according to standard chemical procedures. Where required the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography. As mentioned above the compounds of the invention are indicated as having useful therapeutic properties:

The present invention accordingly provides a compound of formula (I), or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

In particular the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of osteoporosis and related osteopenic diseases.

The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of tumours, especially those related to renal cancer, melanoma, colon cancer, lung cancer and leukemia, viral conditions (for example those involving Semliki Forest virus, Vesicular Stomatitis virus, Newcastle Disease virus, Influenza A and B viruses, HIV virus), ulcers (for example chronic gastritis and peptic ulcer induced by Helicobacter pylori), for use as immunosupressant agents in autoimmune diseases and transplantation, antilipidemic agents for the treatment and/or prevention of hypercholesterolemic and atherosclerotic diseases and to be useful for the

treatment of AIDS and Alzheimer's disease These compounds are also considered useful in treating angiogenic diseases, i.e. those pathological conditions which are dependent on angiogenesis, such as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumours. A compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

Active compounds or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is normally administered in unit dosage form.

An amount effective to treat the disorder hereinbefore described depends upon such factors as the efficacy of the active compounds , the particular nature of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate chosen, the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 0.01 to 50 mg for example 1 to 25 mg, of the compound of the invention. Unit doses will normally be administered once or more than once a day, for example 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.01 to 250 mg, more usually 1 to 100 mg, for example 5 to 70 mg, that is in the range of approximately 0.0001 to 3.5 mg/kg/day, more usually 0.01 to 1.5 mg kg/day, for example 0.05 to 0.7 mg/kg/day.

At the above described dosage range, no toxicological effects are indicated for the compounds of the invention.

The present invention further provides a method for the treatment of osteoporosis and related osteopenic diseases in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I) or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.

The present invention also provides a method for the treatment of tumours, especially those related to renal cancer, melanoma, colon cancer, lung cancer and leukemia., viral conditions (for example those involving Semliki Forest, Vesicular

Stomatitis, Newcastle Disease, Influenza A and B, HIV viruses), ulcers (for example chronic gastritis and peptic ulcer induced by Helicobacter pylori), autoimmune diseases and transplantation, for the treatment and/or prevention of hypercholesterolemic and atherosclerotic diseases, AIDS and Alzheimer's disease, angiogenic diseases, such as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumours, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I) or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.

In such treatment, the active compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes. For such use, the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.

Compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitu table powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use. Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional 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 reconstitution 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, gelatin, hydroxyethylcellulose, carboxymethyl cellulose,

aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound. For topical administration, the composition may be in the form of a transdermal ointment or patch for systemic delivery of the active compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as Dermatological Formulations' - B.W. Barry (Drugs and the Pharmaceutical Sciences - Dekker) or Harrys Cosmeticology (Leonard Hill Books). As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

The following, descriptions, examples and pharmacological methods illustrate the invention but do not limit it in any way.

COMPOUNDS WHEREIN R _A IS Ti AND R _B IS MOIETY (a)

Preparation 1.

(E)-3-(3-Hydroxyphenyl)-2-propenaldehyde. A mixture of 3-hydroxybenzaldehyde (3.66 g, 30 mmol), cesium carbonate (9.78 g, 30 mmol) and (formylmethylene) triphenylphosphorane (9.12 g, 30 mmol) in 1 ,4-dioxane (50 ml) and 2.4 ml of water, was heated at 70°C for 7 hours. The solvent was removed under vacuum, the residue was treated with CH2Q2' filtered and the filtrate was evaporated to dryness. The residue was purified by flash-chromatography (EtOAc/hexane 4:6) obtaining 1.5g of the crude title compound. After trituration with isopropyl ether, 0.5 g (11.2%) of pure title compound was obtained as an orange powder, m.p.= 108-109°C.

Preparation 2

A) Ethyl (2E)-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl)]- 2-butenoate.

To a solution of trietyl phosphonoacetate (27.1 g, 0.121 mol) in dry THF (100ml) cooled to 0°C, a 1.6M solution of n-butyllitium in hexane (77 ml, 0.123 mol) was added during one hour under nitrogen. Stirring was continued for additional 30 minutes, then 2-acetyl- 5,6,7, 8-tetrahydro-5,5,8,8,-tetramethylnaphtalene (5.65 g, 24.5 mmol; Drugs of the future, 1983, 8, 432-434) was added dropwise maintaining the temperature at 0°C. The solution was allowed to rise to room temperature and refluxed for 3 hours. After cooling, the solvent was removed under vacuum and the residue was extracted with E.2O. The organic layers were washed with a saturated solution of NH4CI, brine, dried over Na2SO4 and evaporated to dryness yielding 6.9 g of the crude E and Z mixture. The mixture was purified by column chromatography (hexane/EtOAc 9:1) giving 3 g (40.7%) of the title compound as an oil. B) (2E)-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl)]- 2-butenaIdehyde To a solution of ethyl (2E)-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthaleny l)]-2- butenoate (3 g, 10 mmol) in CH2CI2 (30 ml) a solution of DIBAH 1M in hexane (30 ml, 30 mmol) was added dropwise under nitrogen maintaining the temperature between -10° and 5°C. The solution was allowed to rise to room temperature and, after 30 min, a saturated solution of NH4CI (30 ml) was added. The mixture was filtered on a Celide pad and the organic phase was separated, dried over Na2SO4 and evaporated under vacuum giving 2.3 g (9 mmol) of the corresponding alcohol, as on oil. The crude alcohol was dissolved in CH2CI2 (30 ml) and treated with 85% activated Mnθ2 (3,3 g, 32.2 mmol). The mixture was stirred two days at room temperature, filtered on a Celite pad and the solvent removed under reduced pressure obtaining, after chromatography over silica gel (EtOAc/hexane 1:9), 1.1 g (43%) of the title compound as a yellow oil.

Preparation 3

3-[2-(5,6,7,8-Tetrahydronaphthyl)]-2-butenaIdehyde. A mixture of Montmorillonite K10 (20 g), trimethyl orthoformate (30 ml , 274 mmol) in methanol (15 ml) was stirred at room temperature for 15 minutes. After filtering, the wet powder was added to a solution of 2-acetyl-5,6,7,8-tetrahydronaphthalene (10 g, 57 mmol) in CCI4 (50 ml). The mixture was stirred for two hours at room temperature and filtered off. The solvent was removed under reduced pressure to afford an oil (10.5 g) to which Montmorillonite K10 (50 mg) and ethyl vinyl ether (3.43 g, 47.6 mmol) were added in nitrogen atmosphere. Stirring was continued for two hours and then formic acid (15 ml) and sodium formate (4 g, 59 mmol) were added. This mixture was refluxed for two hours. After cooling, cold water (100 ml) was added and the reaction was extracted with diethyl ether. The organic layers were washed with saturated solution of NaHCO3, brine, dried over Na2SO4 and evaporated to dryness. The residue was distilled to eliminate the unreacted starting material obtaining 1 g (8.7%) of the title compound as a yellow oil. Example I

Methyl (2Z,4E)-2-methoxy-5-phenyl-2,4-pentadienoate . To a suspension of sodium methoxide (5.4 g, 0.1 mol) in dry toluene (50 ml) a solution of methyl methoxyacetate (29.7 ml , 31.18 g, 0.3 mol) and rrα/ty-cinnamaldehyde (12.6 ml , 0.1 mol) was added dropwise. The dark brown solution obtained was allowed to stir at room temperature for 24 hours. It was quenched with water (100 ml) and extracted with ethyl acetate (100 ml). The combined organic layers were washed with 5% aqueous HC1 (50 ml) and water, dried over Na2SO4 _t filtered and evaporated under vacuum. The oily residue was treated with isopropyl ether to give after filtration 9.5 g (43%) of the title compound as a pale yellow solid, m.ρ.= 83-84°C. H-NMR (CDCI3): 7.84 (d, 2H); 7.36-7.25 (m, 3H); 7.18 (dd, IH); 6.89 (d, IH); 6.80 (d, IH); 3.81 (s, 3H); 3.79 (s, 3H).

MS (El, 70 eV, 200 mA): 218(M+ ); 186; 159.

Example 2

(2Z,4E)-2-Methoxy-5-phenyI-2,4-pentadienoic acid . To a solution of KOH 100% (4.5 g, 80 mmol) in absolute ethanol (45 ml), (2Z,4E)-methyl-2-methoxy-5-phenyl-2,4- pentadienoate (9 g, 41 mmol) was added. This solution was heated at 50°C for two hours. After cooling, the mixture was evaporated to dryness and the residue was acidified with 10% aqueous HC1 and the solid obtained was filtered, dried and triturated with isopropyl ether (100 ml) giving 4.5 g (53.7%) of the title compound as a white solid, m.p.= l 62- 164°C.

1H-NMR (CDCI3): 7.51 (dd, 2H); 7.40-7.28 (m, 3H); 7.21 (dd, IH); 7.05 (d, IH); 6.89 (d, IH); 3.86 (s, 3H).

MS (FAB POS): 205 (MH) ⁺ .

Example 3 (2Z,4E)-N-(4-Hydroxymethylphenyl)-2-methoxy-5-phenyI-2,4-pen tadienamide . (2Z,4E)-2-Methoxy-5-phenyl-2,4-pentadienoic acid (1 g, 4.9 mmol) was dissolved in CH2CI2 (20 πtf) ^an< -^ oxalyl chloride (0.85 ml, 9.7 mmol) was added. The solution was stirred at room temperature for two hours under nitrogen and then evaporated to dryness. The crude acid chloride was dissolved in anhydrous THF (15 ml) and added dropwise, at room temperature, to a mixture of 4-aminobenzyl alcohol (0.6 g., 4.9 mmol) and solid NaHCO3 in 1:1 H2O/THF (12 ml). Stirring was continued for one hour, the organic solvent was removed under vacuum and the solid precipitate was filtered to give after cristallization from isopropanol 1 g (66%) of the title compound as a off-white powder, m.p.= 156- 157°C. iH-NMR (DMSO): 10.22 (br s, IH); 8.08 (d, IH); 7.60 (d, 2H); 7.43-7.27 (m, 4H); 7.19 (dd, IH); 7.10 (ddd, IH); 6.99 (d, IH); 6.91 (d, IH); 5.75 (br s, IH); 4.62 (s, 2H); 3.85 (s, 3H).

MS (El, 70 eV, 200 mA): 309 (M ⁺ ); 291.

The following compounds were prepared using the procedure described in Example 3:

Example 4

(2Z,4E)-N-Hexyl-2-methoxy-5-phenyl-2,4-pentadienamide. m.p.= 99-100°C. H- NMR (CDCI3): 7.47 (d, 2H); 7.34 (dd, 2H); 7.26 (dd, IH); 7.07 (dd, IH); 6.91 (d, IH); 6.80 (d, IH); 6.52 (t br, IH); 3.78 (s, 3H); 3.35 (dt, 2H); 1.60-1.50 (m, 2H); 1.40-1.20 (m,6H); 0.89 (t, 3H).

MS (FAB POS): 288 (MH)+*

Example 5

(2Z,4E)-N-Benzyl-2-methoxy-5-phenyl-2,4-pentadienamide. m.p.= 123-124°C. ¹ H- NMR (CDCI3): 7.47 (d, 2H); 7.39-7.25 (m,8H); 7.80(dd, IH); 6.98 (d, IH); 6.82 (d, IH); 6.82 (t br, IH); 4.56 (d, 2H); 3.78 (s, 3H).

MS (FAB POS): 294 (MH) ⁺ .

Example 6

(2Z,4E)-N-(2 -Dihydroxypropyl)-2-methoxy-5-phenyl-2,4-pentadienamide. m.p.=

77-79°C. ^Ϊ H-NMR (CDCI3): 7.46 (dd, 2H); 1.31-1.24 (m, 3H); 7.06 (dd, IH); 7.05 (br s, IH); 6.93 (d, IH); 6.82 (d, IH); 3.87-3.79 (m, IH); 3.79 (s, 3H); 3.66-3.44 (m,4H); 3.30 (br s, 2H).

MS (FAB POS): 300 (MNa) ⁺ ; 278 (MH)+; 260.

Example 7

(2Z,4E)-2-Methoxy-5-phenyl-2,4-pentadienoyl-l-morpholine. m.p.=61-62°C. *H- NMR (CDCI3): 7.44 (d, 2H); 7.32-7.20 (m, 3H); 7.11 (dd, IH); 6.62 (d, IH); 6.01 (d, lH); 3.70 (m, 11H).

MS (TSP): 274 (MH) ⁺ .

Example 8

(2Z,4E)-N-(5-Hydroxypentyl)-2-methoxy-5-phenyl-2,4-pentad ienamide. m.p.=86-87

°C. !H-NMR (CDCI3): 7.47 (d, 2H); 7.38-7.25 (m, 3H); 6.60 (t br, IH); 3.79 (s, 3H); 3.67 (t, 2H); 3.39 (dt, 2H); 1.69-1.42 (m,6H).

MS (TSP): 290 (MH)+.

Example 9

(2Z,4E)-N-Benzyl-N-(5-hydroxypentyl)-2-methoxy-5-phenyI-2 ,4-pentadienamide.

Oil. iH-NMR (CDCI3): 7.44 (d, 2H); 7.39-7.21 (m,8H); 7.14 (dd, IH); 6.59 (d, IH); 5.98 (d, IH); 4.69 (s, 2H); 3.70 (s, 3H); 3.61 (t, 2H); 3.35 (t, 2H); 1.66-1.51 (m,6H).

MS (TSP): 380 (MH) ⁺ .

Example 10

Benzyl (2Z,4E)-2-methoxy-5-phenyl-2,4-pentadienoate. A mixture of (2Z,4E)-2- methoxy-5-phenyl-2,4-pentadienoic acid (0.5 g, 2.45 mmol), anhydrous K2CO3 (0.35 g, 2.45 mmol) and benzyl bromide (0.3 ml, 2.5 mmol) in anhydrous DMF (5 ml) was stirred at room temperature for two days. Distilled water (25 ml) was added and the suspension was extracted with E_2θ (3 x 50 ml). The organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography (EtOAc/hexane 1:9) yielding 0.35 g (48.5%) of the title compound as an oil.

!H-NMR (CDCI3): 7.50-7.28 (m, 10H); 7.19 (dd, IH); 6.92 (d, IH); 6.81 (d, IH); 5.28 (s, 2H); 3,80(s, 3H).

MS (El, 70 eV, 200 mA): 294 (M+); 203; 115; 91.

The following compound was prepared using the procedure described in Example 10

Example II Pentyl (2Z,4E)-2-methoxy-5-phenyl-2,4-pentadienoate. Oil. ΪH-NMR (CDCI3): 7.49 (d, 2H); 7.34-7.25 (m, 3H); 7.18 (dd, IH); 6.88 (d, IH); 6.82 (d, IH); 4.22 (t, 2H); 3.80 (s, 3H); 1.78-1.68 (m, 2H); 1.43-1.35 (m, 2H); 0.98-0.91 (m, 3H).

MS (El, 70 eV, 200 mA): 274 (M+); 186; 159; 115.

Example 12 Methyl (2Z,4E)-4-ethyI-2-methoxy-5-phenyl-2,4-pentadienoate. To a mixture of freshly prepared sodium methoxide (2.7 g, 50 mmol) in dry toluene (80 ml), a solution of (E)-2-ethyl-3-phenyl-2-propenaldehyde (8 g, 50 mmol) (J.A.C.S., 1948, 3569) and methyl methoxyacetate (10 ml, 0.1 mol) was added dropwise. The suspension was stirred at 50°C for 24 hours. After cooling, the mixture was evaporated to dryness and cold water (50 ml) and ethyl acetate (100 ml) were added. The organic layer was washed with 5% HC1, brine, dried over Na2SO4 and evaporated under vacuum. The oil residue was distilled (180°C, 0.01 mbar) to yield 5.6 g (45.5%) of the title compound as a light yellow oil. -NMR (CDCI3): 7.40-7.22 (m, 5H); 6.90 (s, IH); 6.67 (s, 1H);3,84 (s, 3H); 3.75(s, 3H); 2.58 (q, 2H); 1.17 (t, 3H).

MS (El, 70 eV, 200 mA): 246 (M+); 187.

Example 13

Methyl (2Z,4E)-2-methoxy-4-pentyl-5-phenyl-2,4-pentadienoate and Methyl (2E,4E)-2-methoxy-4-pentyl-5-phenyl-2,4-pentadienoate. An oil dispersion of 60% NaH (0.3 g, 7.41 mmol) was washed with pentane (2x3 ml) and then suspended in anhydrous THF (15 ml) under nitrogen. Trimethyl 2-methoxyphosphonoacetate (1.6 g, 7.41 mmol), dissolved in dry THF (5 ml), was added dropwise and the reaction mixture was stirred at 40°C for 40 min. A solution of α-amylcinnamaldehyde (1 g, 4.9 mmol) in dry THF (5 ml) was added dropwise and this suspension was stirred three days at room temperature. The reaction was quenched with water and extracted with E.2O (3x10 ml). The organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuum. The residue was purified by flash-chromatography (hexane/EtOAc 9: 1) affording 16 mg (1.1 %) of the (2Z,4E) isomer of the title compound as a pale yellow oil and 160 mg (11.3%) of the (2E,4E) isomer of the title compound as a pale yellow oil.

Methyl (2Z,4E)-2-methoxy-4-pentyl-5-phenyl-2,4-pentadienoate: *H-NMR (CDCI3): 7.40-7.20 (m,5H); 6.90 (s, IH); 6.65 (s, IH); 3.85 (s, 3H); 3.75 (s, 3H); 2.55-2.48 (m, 2H); 1.59-1.50 (m, 2H); 1.39-1.28 (m,4H); 0.88 (t, 3H).

MS (El, 70 eV, 200 mA): 288 (M+); 256; 229; 217. Methyl (2E,4E)-2-methoxy-4-pentyl-5-phenyl-2,4-pentadienoate: *H-NMR (CDCI3): 7.38-7.20 (m,5H); 6.33 (s, IH); 6, 16 (s, IH); 3.74 (s, 3H); 3.71 (s, 3H); 2.35 (dd, 2H); 1.60-1.48 (m, 2H); 1.35-1.27 (m,4H); 0.89 (t, 3H).

MS (El, 70 eV, 200 mA): 288 (M+); 256; 229; 217.

Example 14 Methyl (2Z,4E)-2-methoxy-4-methyl-5-phenyl-2,4-pentadienoate and Methyl

(2E,4E)-2-methoxy-4-methyI-5-phenyl-2,4-pentadienoate. These compounds were prepared following the procedure of Example 13 starting from α-methylcinnamaldehyde (2.92 g, 20 mmol), NaH 60% (0.8 g, 20 mmol) and trimethyl 2- methoxyphosphonoacetate (3.6 g, 17 mmol). After purification by flash-chromatography, 0.13 g (2.8%) of (2Z,4E) isomer of the title compound was obtained as a solid, m.p.= 60-61°C and 0.1 g (2%) of (2E,4E) isomer of the title compound as a colorless oil.

Methyl (2Z,4E)-2-methoxy-4-methyl-5-phenyl-2,4-pentadienoate: -NMR (CDCI3): 7.40-7.25 ( , 5H); 6.81 (s, IH); 6.77 (s, IH); 3.84 (s, 3H); 3.73 (s, 3H); 2.22 (d, 3H).

MS (TSP): 233 (MH) ⁺ . Methyl (2E,4E)-2-methoxy-4-methyl-5-phenyl-2,4-pentadienoate: -Η-NMR (CDCI3): 7.36-7.20 (m,5H); 6.41 (s, IH); 5.77 (s, IH); 3.79 (s, 3H); 3.70 (s, 3H); 1.99 (s, 3H).

MS (TSP): 233 (MH) ⁺ .

Example 15

Methyl (2Z,4E)-4-ethyI-2-methoxy-5-(4-methoxyphenyl)-2,4-pentadieno ate and Methyl (2E,4E)-4-ethyl-2-methoxy-5-(4-methoxyphenyl)-2,4-pentadieno ate. These compounds were prepared following the Example 13 starting from α-ethyl-4- methoxycinnamaldehyde (0.5 g, 2.6 mmol), NaH 60% (0.12 g, 3 mmol) and trimethyl 2- methoxyphosphonoacetate (0.64 g, 3 mmol). After purification by flash-chromatography, 64 mg (9%) of (2Z,4E) isomer of the title compound was obtained as a solid, m.p.= 68- 69°C and 64 mg (9%) of (2E,4E) isomer of the title compound as a solid, m.p.= 65-66° C.

Methyl (2Z,4E)-4-ethyl-2 -methoxy-5-(4-methoxyphenyl)-2 ,4-pentadienoate: * H-NMR (CDCI3): 7.28 (d, 2H); 6.90 (d, 2H); 6.81 (s, IH); 6.64 (s, IH); 3.84 (s, 6H); 3.74 (s, 3H); 2.59 (q, 2H);1.17 (t, 3H).

MS (El, 70 eV, 200 mA): 276 (M+); 244; 217.

Methyl (2E,4E)-4-ethyl-2 -methoxy-5-(4 -methoxyphenyl)-2 ,4-pentadienoate: * H-NMR (CDCI3): 7.16 (d, 2H); 6.85 (d, 2H); 6.25 (s, IH); 5.62 (s, IH); 3.81 (s, 3H); 3.71 (s, 3H); 3.70 (s, 3H);2.38 (q, 2H); 1.11 (t, 3H). MS (El, 70 eV, 200 mA): 276(M+); 244; 217.

Example 16

Methyl (2Z,4E)-5-(4-tert-butylphenyl)-2-methoxy-4-methyl-2,4-pentad ienoate and Methyl (2E,4E)-5-(4-tert-butylphenyI)-2-methoxy-4-methyl-2,4-pentad ienoate.

These compounds were prepared following the Example 13 starting from α-methyl-4- tert-butylcinnamaldehyde (1 g, 4.94 mmol), NaH 60% oil dispersion (0.3 g, 7.5 mmol) and trimethyl 2-methoxyphosphonoacetate (1.6 g, 7.4 mmol). After purification by flash- chromatography, 0.227 g (16%) of (2Z,4E) isomer of the title compound was obtained as a solid, m.p.= 40-41°C and 0.123 g (8.6%) of (2E,4E) isomer of the title compound as a pale yellow oil. Methyl (2Z,4E)-5-(4-tert-butylphenyl)-2-methoxy-4-methyl-2,4-pentad ienoate: ^H- NMR (CDCI3): 7.40 (d, 2H); 7.30 (d, 2H); 6.79 (br s, IH); 6.78 (s, IH); 3.83 (s, 3H); 3.74 (s, 3H); 2.25 (s, 3H); 1.33 (s,9H).

MS (El, 70 eV, 200 mA): 288(M+); 256; 57.

Methyl (2E,4E)-5-(4-tert-butylphenyl)-2-methoxy-4-methyl-2,4-pentad ienoate: *H- NMR (CDCI3): 7.37 (d, 2H); 7.22 (d, 2H); 6.40 (s, IH); 5.79 (s, IH); 3.79 (s, 3H); 3.71 (s, 3H); 2.00 (s, 3H); 1.35 (s,9H).

MS (El, 70 eV, 200 mA): 288(M ⁺ ); 256; 57.

Example 17

Methyl (2Z,4E)-2-methoxy-5-(2-nitrophenyl)-2,4-pentadienoate. These compounds were prepared following the Example 13 starting from 4-nitrocinnamaldehyde (0.5 g, 2.82 mmol), NaH 60% (0.13 g, 3.25 mmol) and trimethyl 2-methoxyphosphonoacetate (0.69 g, 3.25 mmol). After purification by flash-chromatography, 127 mg (17%) of the title compound was obtained as a yellow solid, m.p.= 66-70°C.

*H-NMR (CDCI3): 7.95 (dd, IH); 7.76 (dd, IH); 7.59 (ddd, IH); 7.42 (ddd, IH); 7.30 (d, IH); 7.17 (dd, IH); 6.89 (d, IH); 3.84 (3, 3H); 3.82 (s, 3H).

MS (El, 70 eV, 200 mA): 263(M ⁺ ); 204; 172.

Example 18

Methyl (2Z,4E)-2-methoxy-5-(2-methoxyphenyI)-2,4-pentadienoate. Amberlite IRA 68 (0.82 g, 1.82 meq) was suspended in dry CH2CI2 (5 ml) under nitrogen atmosphere and methyl 2-methoxy-2-(triphenylphosphonium)acetate bromide (Chem. Ber., 97, 1964, 1713) (0.6 mg, 1.35 mmol) was added and the mixture was stirred 20 min at room temperature. 2-Methoxycinnamaldehyde (0.146 mg, 0.9 mmol) was added dropwise and this suspension was stirred overnight at room temperature and then refluxed for 24 h. The resin was filtered off and the solvent evaporated at reduced pressure. Ethyl acetate was added and the organic layer was washed with a saturated solution of citric acid, aqueous NaHCO3, brine, dried over Na2SO4 and evaporated under vacuum. This crude residue was purified by flash-chromatography (hexane/EtOAc 4:1) yielding 44 mg (20%) of the title compound as a colourless oil.

^J H-NMR (CDCI3): 7.59 (dd, IH); 7.31-7.19 (m, 3H); 7.00-6.88 (m, 3H); 3.88 (s, 3H); 3.83 (s, 3H); 3.79 (s, 3H). MS (TSP): 249 (MH) ⁺ .

Example 19

Methyl (2Z,4E)-5-(3-hydroxyphenyI)-2-methoxy-2,4-pentadienoate and Methyl (2E,4E)-5-(3-hydroxyphenyI)-2-methoxy-2,4-pentadienoate. A mixture of (E)-3-(3- hydroxyphenyl)-2-propenaldehyde (0.5 g, 3.4 mmol), CS2CO3 (1.65 g, 5.07 mmol) and trimethyl 2-methoxyphosphonoacetate (0.95 g, 4.5 mmol) in 1,4-dioxane (15 ml) and 0.8 ml of water was stirred at 50°C for 12 hours. After cooling, the solvent was removed under vacuum and the residue was treated with ethyl acetate (50 ml), filtrated and the organic layer was washed with 5% HC1, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography (EtOAc/hexane 4:6) yielding 0.35 g (43.9%) of the (2Z,4E) isomer of the title compound as on orange powder, m.p.= 97-99° C and 0.05 g (6.3%) of the (2E,4E) isomer of the title compound as a brown oil.

Methyl (2Z,4E)-5-(3-hydroxyphenyl)-2-methoxy-2,4-pentadienoate: *H-NMR (CDCI3): 7.21 (t, IH); 7.15 (dd, IH); 7.05-6.99 (m, 2H); 6.89 (d, IH); 6.79 (dd, IH); 6.75 (d, IH); 5.65 (br s, IH); 3.85 (s, 3H); 3.79 (s, 3H). MS (El, 70 eV, 200 mA): 234 (M+); 202; 175.

Methyl (2E,4E)-5-(3-hydroxyphenyl)-2-methoxy-2,4-pentadienoate: -NMR (CDCI3): 7.81 (dd, IH); 7.19 (t, IH); 7.00 (d, IH); 6.95 (m, IH) 6.72 (dd, IH); 6.59 (d, IH); 6.08 (d, IH); 5.10 (br s, IH); 3.85 (s, 3H); 3.72 (s, 3H).

MS (El, 70 eV, 200 mA): 234 (M+); 202; 175.

Example 20

Methyl (2Z,4E)-5-(2-hydroxyphenyl)-2-methoxy-2,4-pentadienoate and Methyl (2E,4E)-5-(2-hydroxyphenyl)-2-methoxy-2,4-pentadienoate.

A mixture of (E)-3-(2-hydroxyphenyl)-2-propenaldehyde (0.7 g, 4.7 mmol), potassium carbonate (1.05 g, 7.6 mmol) and trimethyl 2-methoxyphosphonoacetate (1.35 g, 6.4 mmol) in 1,4-dioxane (15 ml) was stirred at 70°C for 24 hours. After cooling, the solvent was removed under vacuum and the residue was treated with ethyl acetate (50 ml), filtrated and the organic layer was washed with 5% HC1, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography (CH ₂ Cl2/MeOH 98:2) yielding 0.12 g ( 10.9%) of the (2Z,4E) isomer of the title compound as a brown powder, m.p.= 72-74°C and 0.15 g (13.6%) of (2E,4E) isomer of the the title compound as an orange powder, m.p.= 92-94°C.

Methyl (2Z,4E)-5-(2-hydroxyphenyl)-2-methoxy-2,4-pentadienoate: ΪH-NMR (CDCI3): 7.53 (dd, IH); 7.22 (dd, IH); 7.16 (ddd, IH); 7.13 (d, IH); 6.94 (d, IH); 6.93 (ddd, IH); 6.79 (dd, IH); 5.24 (br s, IH); 3.83 (s, 3H); 3.79 (s, 3H).

MS (El, 70 eV, 200 mA): 234(M ⁺ ); 202; 175.

Methyl (2E,4E)-5-(2-hydroxyphenyl)-2-methoxy-2,4-pentadienoate: ^l U-NMR (CDCI3): 7.86 (dd, IH); 7.51(dd, IH); 7.12 (ddd, IH); 6.92 (d, IH); 6.91 (ddd, IH); 6.79 (dd, IH); 6.13 (d, IH); 5.05 (br s, IH); 3.90 (s, 3H); 2.75 (s, 3H). MS (El, 70 eV, 200 mA): 234(M+); 202; 175.

Example 21

Methyl (2Z,4E)-5-(4-acetoxyphenyl)-2-methoxy-2,4-pentadienoate and Methyl (2E,4E)-5-(4-hydroxyphenyl)-2-methoxy-2,4-pentadienoate. These compounds were prepared following the Example 19 starting from 4-acetoxycinnamaldehyde (0.64 g, 3.34 mmol), CS2CO3 (1.65 g, 5.07 mmol) and trimethyl 2-methoxyphosphonoacetate (0.95 g, 4.5 mmol). After purification by flash-chromatography, 20 mg (2%) of (2Z,4E) isomer of the title compound was obtained as a white powder, m.p.=l 10-115°C and 20 mg (2.5%) of the (2E,4E) isomer of the title compound as a solid, m.p.=151-153°C.

Methyl (2Z,4E)-5-(4-acetoxyphenyl)-2-methoxy-2,4-pentadienoate: *H-NMR (CDCI3): 7.50 (d, 2H); 7.13 (dd, IH); 7.09 (d, 2H); 6.89 (d, IH); 6.80 (d, IH); 3.84 (s, 3H); 3.80 (s, 3H); 2.30 (s, 3H).

MS (CI): 277 (MH)+.

Methyl (2E,4E)-5-(4-hydroxyphenyl)-2-methoxy-2,4-pentadienoate: ΪH-NMR (CDCI3): 7.72 (dd, IH); 7.38 (d, 2H); 6.81 (d, 2H);6.61 (d, IH); 6.10 (d, IH); 5.00 (br s, IH); 3.89 (s, 3H);3.73 (s, 3H).

Example 22

Methyl (2Z,4E)-5-(4-chlorophenyI)-2-methoxy-2,4-pentadienoate. A solution of 4- chlorophenylcinnamaldehyde (1.9 g, 11.4 mmol) in methylenedichloride (40 ml) was treated with methyl 2-methoxy-2-(triphenylphosphonium) acetate bromide (Chem. Ber., 97, 1964, 1713) (4.95 g, 11.4 mmol) and DIPEA (2 ml, 11.4 mmol) was added dropwise at room temperature. The reaction mixture was stirred for 4h then washed with 10% aqueous HC1 (10 ml), saturated solution of NaHCO3 (10 ml) and brine (10 ml), dried over Na2SO4 and evaporated under vacuum. The residue was diluted with Et2θ, filtered and concentrated under vacuum. The solid obtained was cristallised with cyclohexane affording, after filtration, 0.2 g (7 %) of the title compound, m.ρ.= 92-93°C.

Example 23

Methyl (2Z,4E)-5-(3,4-dichlorophenyl)-2-methoxy-2,4-pentadienoate. These compounds were prepared following the Example 22 starting from 3,4- dichlorocinnamaldehyde (3.8 g, 18.9 mmol), DBU (2.8 ml, 18.9 mmol) and methyl 2- methoxy-2-(triphenylphosphonium)acetate bromide (8.41 g, 18.9 mmol). After purification the compound was cristallised with cyclohexane yielding 1.1 g (20.2 %) of the title compound, m.p.= 96-97°C

Example 24 Methyl (2Z,4E)-5-(4-dimethyIaminophenyI)-2-methoxy-2,4-pentadienoat e. These compounds were prepared following the Example 22 starting from 4- dimethylaminocinnamaldehyde (1.75 g, 10 mmol), DBU (1.5 ml, 10 mmol) and methyl 2- methoxy-2-(triphenylphosphonium)acetate bromide (4.45 g, 10 mmol). After purification the compound was triturated with isopropyl alcohol, filtered yielding 0.6 g (23%) of the title compound, m.p.= 84-86°C

Example 25

Methyl (2Z,4E)-2-methoxy-5-methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl naphthyl)]-2,4-pentadienoate and Methyl (2E,4E)-2-methoxy-5-methyl-5-[2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyInaphthyl)]-2,4-pentad ienoate. To a solution of trimethyl 2-methoxyphosphonoacetate (1.5 g, 7.07 mmol) in dry THF (45 ml), 60% oil dispersion NaH (0.3 g, 7.5 mmol) and (2E)-3-[2-(5,6,7,8-tetrahydro-5,5,8,8- tetramethylnaphthyl)]-2-butenaldehyde (1.2 g, 4.7 mmol) in dry THF (12 ml) were added portion wise under nitrogen following the procedure described in Example 13. After the usual work up and the purification by column chromatography 0.35 g (21.7%) of the (2Z,4E) isomer of the title compound was obtained as a white powder, m.p.=77-80°C and 0.3 g (18.6%) of the (2E,4E) isomer of the title compound as an oil.

Methyl (2Z,4E)-2-methoxy-5-methyl-5-[2-(5,6,7,8-tetrahydro-5m5,8,8- tetramethyl naphthyl)J-2,4-pentadienoate: H-NMR (CDCI3): 7.42 (t, IH); 7.30 (d, 2H); 7.16 (d, IH); 6.84 (dq, IH); 3.85 (s, 3H); 3.75 (s, 3H); 2.25 (d, 3H); 1.32 (s, 3H); 1.29 (s, 3H).

MS (El, 70 eV, 200 mA): 342(M ⁺ ); 327; 295. Methyl (2E,4E)-2 -methoxy-5-methyl-5-[2-(5,6,7,8-tetrahydro-5J,8,8-tetramethy l naphthyl)]-2,4-pentadienoate: H-NMR (CDCI3): 7.44 (dd, IH); 7.41 (d, IH); 7.28 (d, 2H); 6.30 (d, IH); 3.85 (s, 3H); 3.75 (s, 3H); 2.20 (s, 3H); 1.70 (s,4H); 1.31 (s,6H);1.28 (s,6H).

MS (El, 70 eV, 200 mA): 342 (M ⁺ ); 327; 295. Example 26

Methyl (2Z,4E)-2-methoxy-5-methyl-5-[2-(5,6,7,8-tetrahydronaphthyl) ]-2,4- pentadienoate and Methyl (2E,4E)-2-methoxy-5-methyl-5-[2-(5,6,7,8- tetrahydronaphthyl)]-2,4-pentadienoate. To a solution of trimethyl 2- methoxyphosphonoacetate (1 g, 4.7 mmol) in dry THF (10 ml), 60% oil dispersion NaH (0.2 g, 5 mmol) and 3-[2-(5,6,7,8-tetrahydronaphthyl)] 2-butenaldehyde (0.9 g, 4.5 mmol) in dry THF (10 ml) were added portion wise under nitrogen atmosphere following the procedure described in Example 13. After the usual work up and the purification by column chromatography 0.34 g (26.4%) of the (2Z,4E) isomer of the title compound as an oil and 0.23 g (17.8%) of the (2E,4E) isomer of the title compound as an oil. Methy (2Z,4E)-2-methoxy-5-methyl-5-[2-(5,6,7,8-tetrahydronaphthyl) ]-2,4- pentadienoate: *H-NMR (DMSO): 7.26 (dd, IH); 7.21 (br s, IH); 7.06 (d, IH); 7.04 (d, 1H);6.75 (dd, IH); 3.76 (s, 3H); 3.68 (s, 3H); 2.74 (m,4H); 2.18 (s, 3H);1.72 m,4H).

MS (El, 70 eV, 200 mA): 286(M+); 254; 227.

Methyl (2E,4E)-2-methoxy-5-methyl-5-[2-(5 ,6,7 ,8-tetrahydronaphthyl)]-2,4- pentadienoate: tø-NMR (CDCI3): 7.47 (dd, IH); 7.25 (dd, IH); 7.20 (m, IH); 7.04 (d, IH); 6.31 (d, IH); 3.88 (s, 3H); 3.77 (s, 3H); 2.78 (m, 4H); 2.19 (d, 3H); 1.80 (m, 4H).

MS (El, 70 eV, 200 mA): 286(M+); 254; 227.

Example 27

Methyl (2Z,4E)-2-methoxy-5-methyl-5-(2-naphthyI)-2,4-pentadienoate and Methyl (2E,4E)-2-methoxy-5-rnethyl-5-(2-naphthyl)-2,4-pentadienoate . These compounds were prepared following the Example 22 starting from (2E) 3(2-naphtyl)propenaldehyde (O.lg, 0.55 mmol), DBU (0.123 ml, 0.825 mmol) and methyl 2-methoxy-2- (triphenylphosphonium)acetate bromide (0.37 g, 0.825 mmol). After the usual work up and the purification by column chromatography 0.071 g (48.1%) of the (2Z,4E) isomer of the title compound was obtained as a yellow powder, m.p.= 75.76°C and 0.015 g

(10.1%) of the (2E,4E) isomer of the title compound as a yellow powder, m.p.= 99-101° C.

COMPOUNDS WHEREIN R _A TOGETHER WITH R _B IS MOIETY (b)

Preparation 4

2-CyclohexyIideneacetaldehyde. To an ice cold solution of LiAlH4 (0.25 g, 6.6 mmol) in anhydrous THF (10 ml) under nitrogen, ethyl cyclohexylideneacetate (lg, 6 mmol) (Organic Syntheses, coll. vol. 5, pag 547, John Wiley) dissolved in dry THF (5 ml) was added dropwise. The mixture was stiired for 2h at 0°C and then quenched by the sequential addition of water (0.25 ml), 15% aqueous NaOH (0.25 ml) and water. The organic layer was extracted with Et2θ, dried over Na2SO4 and evaporated in vacuum yielding 0.82 g of a colourless oil.

This was dissolved in dichloromethane (15 ml), and activated manganese dioxide (0.96 g, 11 mmol) was added. The mixture was stirred at room temperature for three days and then filtered through a Celite pad which was washed with dichloromethane (3 x 20 ml). The combined filtrates were evaporated to dryness yielding 0.68 g (91.2%) of the tide compound.

Example 28

Methyl (Z)-4-cyclohexylidene-2-methoxy-2-butenoate and Methyl (E)-4- cyclohexyIidene-2-methoxy-2-butenoate. To a suspension of sodium hydride (0.42 g, 10.5 mmol; a 60% oil dispersion pre- washed with pentane was used) in anhydrous THF (10 ml) under nitrogen, a solution of trimethyl 2-methoxyphosphonoacetate (2.23 g, 10.5 mmol) in dry THF (5 ml) was added dropwise and the mixture was stirred at 40°C for 40 min. After cooling to room temperature, 2-cyclohexyIideneacetaldehyde (0.87 g, 7 mmol) was added and stirring was continued for two days. The mixture was quenched with water, extracted with Et2θ (2 x 10 ml), washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was chromatographed over silica gel (hexane/iPr2θ 75:25) obtaining 0.22 g (15.1 %) of the Z isomer of the title compound and 0.06 g (4.06%) of the E isomer of the title compound. Methyl (Z)-4-cyclohexylidene-2-methoxy-2-butenoate: ^! H-NMR (CDCI3): 7.04 (d, IH);

6.21 (d, IH); 3.80 (s, 3H); 3.72 (s, 3H); 2.38 (m, 2H); 2.25 (m, 2H); 1.60(m, 6H).

MS (TSP): 211(MH) ⁺ .

Methyl (E)-4-cyclohexylidene-2-methoxy-2-butenoate: H-NMR (CDCI3): 6.79 (d, IH);

6.22 (d, IH); 3.85 (s, 3H); 3.69 (s, 3H); 2.30 (m, 2H); 2.25 (m, 2H); 1.60(m, 6H). MS (TSP): 211(MH)+.

Preparation 5

Ethyl 2-(l,4-dioxaspiro[4,5]decan-8-ylidene)acetate. To a suspension of sodium hydride (1.54 g, 38.5 mmol; a 60% oil dispersion pre- washed with pentane was used) in anhydrous THF (100 ml) under nitrogen, a solution of triethyl phosphonoacetate (7.64 ml, 38.5 mmol) in dry THF (20 ml) was added dropwise and the reaction was stirred at room temperature for lh. After the addition of 1 ,4-cyclohexanedione mønø-ethylene ketal (5 g, 32 mmol) dissolved in dry THF (15 ml), the reaction was stirred under nitrogen at reflux temperature for six days. After cooling, the reaction was quenched with water, extracted with Et2θ (3 x 30 ml), dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash-chromatography (hexane/EtOAc 7:3) to afford 3.45 g (47.6%) of the title compound as an oil.

Preparation 6

2-(l,4-dioxaspiro[4,5]decan-8-ylidene)acetaldehyde. Ethyl 2-(l ,4-dioxaspiro[4,5] decan-8-ylidene)acetate (1 g, 4.42 mmol) was dissolved in dichloromethane (20 ml) and IM solution of DIBAH in hexane (8.84 ml, 8.84 mmol) was added dropwise, under nitrogen at 0°C. Stirring was continued for 30 minutes, then the temperature was allowed to reach room temperature and a saturated solution of NH4CI (10 ml) was added. The resulting mixture was filtered on a Celite pad. The phases were separated and the organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to give the crude intermediate alcohol (0.8 g, 4.3 mmol) as an oil. This was dissolved in dichloromethane (10 ml) and activated Mnθ2 (1.5 g, 17.4 mmol) was added. After stirring at room temperature for three days, the mixture was filtered on a Celite pad. The filtrate was evaporated under reduced pressure to yield, after flash- chromatography (hexane/EtOAc 7:3), 0.71 g (88%) of the title compound as an oil. Example 29

Methyl (Z)-4-(l,4-dioxaspiro[4,5]decan-8-ylidene)-2-methoxy-2-buten oate and Methyl (E)-4-(l,4-dioxaspiro[4,S]decan-8-ylidene)-2-methoxy-2-buten oate.

Trimethyl 2-methoxyphosphonoacetate (0.7 g, 3.3 mmol) and NaH (0.14 g, 3.4 mmol; a 60% oil disperion was used) were treated with 2-(l,4-dioxaspiro[4,5]decan-8-ylidene) acetaldehyde (0.4 g, 2.2 mmol) according to the procedure of Example 28 to afford

0.175 g (30%) of the Z isomer of the title compound as an oil, and 0.23 g (39%) of the E isomer of the tiltle compound as an oil.

Methyl (Z)-4-(l ,4-dioxaspiro[4,5)decan-8-ylidene)-2-methoxy-2-butenoate: ^H-NMR (CDCI3): 6.99 (d, IH): 6.27 (d, IH), 3.99 (s, 4H);3.80 (s, 3H); 3.70 (s, 3H); 2.50 (dd, 2H); 2.40 (dd, 2H); 1.80-1.72 ( , 4H).

MS (El, 70 eV, 200 mA): 268(M+), 253, 237, 209.

Methyl (E)-4-(l,4-dioxaspiro[4j]decan-8-ylidene)-2-methoxy-2-buteno ate: H-NMR (CDCI3): 6.81 (d, IH); 6.15 (d, IH), 3.98 (s, 4H);3.82 (s, 3H); 3.69 (s, 3H); 2.45 (dd, 2H); 2.39 (dd, 2H); 1.77-1.69 (m, 4H).

MS (El, 70 eV, 200 mA): 268(M ⁺ ), 253, 237, 209. Preparation 7

Ethyl 2-[(5'-acetoxypentyI)cycIohexyIidene]acetate. Triethyl phosphonoacetate (5.4 g, 24.2 mmol) and NaH (0.96 g, 24.2 mmol; a 60% oil dispersion was used) were treated with 2-(5'-acetoxypentyl)cyclohexanone (J. Org. Chem., 1968, 2013.) (3.65 g, 16.13 mmol) according to the procedure of Preparation 5 to afford 2.54 g (53%) of the title compound as an oil.

Preparation 8

2-[(5-Hydroxypentyl)cyclohexylidene]acetaIdehyde. Ethyl 2-[(5-acetoxypentyl) cyclohexylidenejacetate (1.5 g, 5.06 mmol) was treated with IM solution of DIBAH in hexane (15 ml, 15 mmol), according to the procedure of Preparation 6, to afford 1 g (4.7 mmol) of 2-[(5 ^, -hydroxypentyl)cyclohexylidene]methanol which is successively oxidated with activated Mnθ2 (3 g, 34.5 mmol) to yield 0.9 g (85%) of the title compound.

Example 30

Methyl (2Z)-4-[2-(5-hydroxypentyl)cyclohexylidene]-2-methoxy-2-bute noate. A solution of 2-[(5-hydroxypentyl)cyclohexylidene]acetaldehyde (0.43 g, 2 mmol) in anhydrous THF (10 ml) under nitrogen was treated with methyl 2-methoxy-2-

(tryphenylphosphonium) acetate bromide (Chem. Ber., 97, 1964, 1713) (0.89 g, 2 mmol) and DBU (0.3 ml, 2 mmol), according to the procedure of the Wittig type reaction. The reaction mixture was stirred at 50°C for two days, allowed to cool, diluted with Et2θ (10 ml) and filtered. The filtrate was washed with 10% aqueous HC1 (5 ml), saturated solution of NaHCO3 (5 ml) and brine (5 ml), dried over Na2SO4 and evaporated in vacuum. The residue was purified by flash- chromatography (hexane/EtOAc 65:35) to afford 0.15 g (25.3%) of the title compound as an oil.

Methyl (2Z)-4 -[2 -(5 '-hydroxypentyl)cyclohexylidene] -2 -methoxy-2 -butenoate : * H-NMR (CDCI3): 7.04 (d, IH); 6.19 (d, IH); 3.79 (s, 3H);3.70 (s, 3H); 3.68-3.58 (m, 2H); 2.39- 2.10 (m, 3H); 1.80-1.15 (m, 14H).

MS (El, 70 eV, 200 mA): 296(M ⁺ ); 264; 237.

Example 31

Methyl (2E)-4-[2-(5-hydroxypentyl)cyclohexyIidene]-2-methoxy-2-bute noate.

Trimethyl 2-methoxyphosphonoacetate (0.5 g, 2.36 mmol) and NaH (0.19 g, 4.7 mmol; a 60% oil dispersion was used) were treated with 2-[(5-hydroxypentyl)cyclohexylidene]

acetaldehyde (0.17 g, 0.8 mmol) according to the procedure of Example 28 to afford 0.1 g (42.5%) of the title compound.

Methyl (2E)X[2-(5'-hydroxypentyl)cyclohexylidene]-2-methoxy-2-buten oate: -Η-NMR (CDC1 ₃ ): 6.79 (d, IH); 6.24 (d, IH); 3.83 (s, 3H);3.68 (s, 3H); 3.69-3.59 (m, 2H); 2.39- 2.00 (m, 3H); 1.85-1.20 (m, 14H).

MS (El, 70 eV, 200 mA): 296(M ⁺ ); 264; 237.

Preparation 9

Ethyl (l,2,3,4-tetrahydro-l-naphthylidene)acetate. Triethyl phosphonoacetate (17.7 ml, 89.2 mmol) and NaH (3.57 g, 89.2 mmol; a 60% oil dispersion was used) were treated with 1-tetralone (11.8 ml, 89 mmol), according to the procedure of Preparation 5, to afford 9.46 g (49%) of the title compound as an oil.

Preparation 10

1,2,3,4-tetrahydro-l-naphthyIideneacetaldehyde. Ethyl (1,2,3,4-tetrahydro-l- naphthylidene) acetate (3 g, 13.87 mmol) was treated with LiAlH4 (0.6 g, 15.8 mmol) in dry THF (20 ml) according to the procedure described in the Preparation 4. The following oxidation of the corresponding alcohol (2.3 g, 13.2 mmol) was carried out with PCC (4.3 g, 19.8 mmol) in dichloromethane (20 ml) for two days at room temperature.

After dilution with Et2θ (20 ml) the mixture was filtered on Florisil and the intermediate was purified by flash-chromatography (hexane/EtOAc 8:2), yielding 1.13 g (47.3%) of the title compound.

Example 32

Methyl (2Z,4E)-2-methoxy-4-(l^,3,4-tetrahydro-l-naphthylidene)-2-bu tenoate and Methyl (2E,4E)-2-methoxy-4-(l,2,3,4-tetrahydro-l-naphthylidene)-2-b utenoate. To a solution of trimethyl 2-methoxyphosphonoacetate ( 1.6 g, 7.5 mmol) in dry THF (20 ml), 60% oil dispersion NaH (0.3 g, 7.41 mmol) and 1,2,3,4-tetrahydro-l- naphthylideneacetaldehyde (1 g, 5.8 mmol) in dry THF (5 ml) were added portionwise under nitrogen following the procedure described in Example 28. After the usual work up and the purification by column chromatography (hexane/EtOAc 9:1) 0.42 g (28%) of the (2Z,4E) isomer of the title compound was obtained as a white powder, m.p. =73-75° C and 0.27 g (18%) of the (2E,4E) isomer of the title compound as an oil.

Methyl (2Z,4E)-2-methoxy-4-(l ,2 ,3 ,4-tetrahydro-l -naphthylidene)-2-butenoate: ^H- NMR (CDCI3): 7.79-7.73 (m, IH); 7.24-7.1 1 (m, 4H); 7.06 (dt, IH); 3.85 (s, 3H); 3.80 (s, 3H); 2.83 (t, 2H); 2.75 (dt, 2H); 1.94-1.86 (m, 2H). MS (El, 70 eV, 200 mA): 258(M+); 226; 199.

Methyl (2E,4E)-2-methoxy-4-(l ,2,3,4-tetrahydro-l -naphthylidene)-2-butenoate: iH- NMR (CDCI3): 7.78-7.72 (m, 2H); 7.22-7.09 (m, 3H); 6.32 (d, IH); 3.90 (s, 3H); 3.79 (s, 3H); 2.81 (t, 2H); 2.69 (dt, 2H); 1.94-1.86 (m, 2H).

MS (El, 70 eV, 200 mA): 258(M ⁺ ); 226; 199.

COMPOUNDS WHEREIN R _A IS A MOIETY (c) AND R _B IS MOIETY (d)

Preparation 11

Ethyl (10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetate. To a suspension of sodium hydride (0.96 g, 24 mmol; a 60 % oil dispersion pre-washed with pentane was used) in anhydrous THF (20 ml) under nitrogen, a solution of triethyl phosphonoacetate (5.76 ml, 28.8 mmol) in dry THF (10 ml) was added dropwise and the reaction was stirred at room temperature for 30 min. After the addition of dibenzosuberone (5 g, 24 mmol) dissolved in dry THF (5 ml), the reaction was stirred under nitrogen at reflux temperature for six days. After cooling, the reaction was quenched with water, extracted with Et2θ (3 x 30 ml), dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash-chromatography (hexaneAPr2θ 75:25) to afford 3.2 g (48%) of the title compound as an oil.

Preparation 12 (10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetalde hyde. To a solution of (10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetate (1 g, 3.6 mmol) in CH2CI2 (15 ^m l) ^un d ^er nitrogen and cooled at -78°C, a solution of IM DIBAH in hexane (3.6 ml) was added dropwise and then the reaction mixture was allowed to reach room temperature. After a further addition of IM DIBAH in hexane (7 ml) the reaction was stirred for 3h at room temperature, quenched with a saturated solution of NH4CI and extracted with CH2CI2 (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4 and evaporated to dryness, yielding 0.84 g of (10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)methanol as a colourless oil. This was dissolved in dichloromethane (10 ml) and treated with activated manganese dioxide (0.62 g, 13.8 mmol) at room temperature. After three days more manganese dioxide (1.2 g, 7.1 mmol) was added and the reaction was stirred again at room temperature for two days. The mixture was then filtered under vacuum through a Celite pad, washed with dichloromethane (3 x 20 ml), dried over Na2SO4 and evaporated to dryness yielding 0.77 g (91.3%) of the title compound. Example 33

Methyl (Z)-4-(10,ll-dihydro-5H-dtbenzo[a,d]cyclohepten-5-ylidene)-2 -methoxy-2- butenoate. To a suspension of sodium hydride (0.2 g, 5 mmol; a 60 % oil dispersion pre-washed with pentane was used) in anhydrous THF (10 ml) under nitrogen, a solution of trimethyl 2-methoxyphosphonoacetate (0.9 g, 4.24 mmol) in dry THF (5 ml) was added dropwise and the reaction mixture was stirred at 40°C for 40 min. After cooling to room temperature, (10,1 l-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetaldehyde

(0.77 g, 3.28 mmol) was added and stirring was continued at room temperature for 12 h and at 50°C for two days. The mixture was then quenched with water, extracted with Et2θ (3 x 10 ml), washed with a saturated solution of NaHSO3» dried over Na2SO4 and evaporated in vacuo. The residue was chromatographed over silica gel (hexane Pr2θ 75:25) obtaining 18 mg (1.7%) of the title compound, m.p. = 107-109°C. iH-NMR (CDCI3): 7.42-7.36 (m, IH); 7.29-7.05 (m, 7H); 6.92 (d, IH); 6.80 (d, IH); 3.80 (s, 3H); 3.75 (s, 3H); 3.50-2.70 (br m, 4H).

MS (El, 70 eV, 200 mA): 320(M+); 288; 261.

Example 34 Methyl (2Z)-5,5-diphenyI-2-methoxv-2,4-pentadienoate and Methyl (2E)-5-5- diphenyI-2-methoxy-2,4-pentadienoate. β-Phenylcynnamaldehyde (1 g, 4.8 mmol) was reacted with trimethyl 2-methoxyphosphonoacetate (1.3 g, 6.1 mmol) and 60% NaH oil dispersion (0.3 g, 7.5 mmol), according to the procedure described in Example 33, to afford, after chromatographic separation, 80 mg (6%) of the Z isomer, m.p.= 93-94°C and 0.14 g (10%) of the E isomer, as a colourless oil.

Methyl (2Z)-5,5-diphenyl-2-methoxy-2,4-pentadienoate: H-NMR (CDCI3): 7.45-7.21 (m, 10H); 7.11 (d, IH); 6.81 (d, IH); 3.80 (s, 3H); 3.73 (s, 3H).

MS (El, 70 eV, 200 mA): 294 (M+); 262.

Methyl (2E)-5,5-diphenyl-2-methoxy-2, 4 -pentadienoate: *H-NMR (CDCI3): 7.76 (d, IH); 7.44-7.21 (m, 10H); 6.03 (d, IH); 3.89 (s, 3H);3.50 (s, 3H).

MS (El, 70 eV, 200 mA): 294 (M ⁺ ); 262.

Example 35

Methyl (2Z)-5,5-diphenyI-2-methoxy-2,4-pentadienoate. A solution of β- phenylcinnamaldehyde (2 g, 9.6 mmol), methyl 2-methoxy-2-(triphenylphosphonium) acetate bromide (Chem. Ber., 97, 1964, 1713) ( 8.9 g, 18.6 mmol) and DBU ( 2.9 ml, 19.2 mmol) in anhydrous THF was stirred at 50°C for 15 h under nitrogen. After cooling, E.2O was added and the precipitated was filtered off. The filtrate was washed successively with 10% HC1 (10 ml), saturated solution of NaHCO3 and brine, dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash- chromatography (hexane/iP^O 75:25) and, after trituration with isopropyl ether, 1.8 g (63.8%) of the title compound were obtained, m.p.= 93-94°C.

Methyl (2Z)-5, 5 -diphenyl-2-methoxy-2, 4 -pentadienoate: H-NMR (CDCI3): 7.45-7.21 (m, 10H); 7.11 (d, IH); 6.81 (d, IH); 3.80 (s, 3H); 3.73 (s, 3H).

MS (El, 70 eV, 200 mA): 294 (M ⁺ ); 262.

Further Examples:

(a) The following compounds are prepared according to methods disclosed herein:

τ ₄ τ ₅ τ ₆ τ ₇ Xl Y

Methyl 2-methoxy-5-(2- 2-OMe H H H H H methoxyphenyl)-5-phenyl-2,4- pentadienoate

Methyl 2-methoxy-5-(4- 4-OMe H H H H H methoxyphenyl)-5-phenyl-2,4- pentadienoate

Methyl 2-methoxy-5,5-bis(4- 4-OMe H 4-OMe H H H methoxyphenyl)-2,4-pentadienoate

Methyl 4-(6,11- H H H H -CH2-O- dihydrodibenz[b,e]oxepin-11 - yiidene)-2- ethoxy-2-butenoate

Methyl 4-(6,11 -dihydro-5H- H H H H -CO-NH- dibenz[b,e]azepin-6-one-11 - ylidene)-2-methoxy-2-butenoate

BIOLOGICAL ASSAYS

Background. It is known that, upon attachment to bone, an electrogenic H ⁺ - adenosine triphosphatase (ATPase) is polarised to the osteoclast-bone interface. The pump transports massive quantities of protons into the resorption microenvironment to effect mobilisation of the bone mineral and to create the acidic pH required by collagenases to degrade the bone matrix.

The vacuolar nature of the osteoclast proton pump was originally recognised by Blair [H. C. Blair at al., Science, 245, 855 (1989)] and than confirmed by Bekker [P.J. Bekker et al., /. Bone Min. Res., 5, 569 (1990)] and Vaananen [K.K. Vaananen et al., J. Cell. Biol., Ill, 1305 (1990)]. Evidence was based upon preparations of ruffled membrane fragments from avian osteoclasts (obtained from the medullar bone of calcium-starved egg-laying hens). The resulting membrane vesicles acidify in response to ATP, which is easily assessed by measuring the fluorescence quench of acridine orange, a weak base which accumulates into acidic compartments.

The biochemical pattern indicated that the osteoclast proton pump belonged to the vacuolar-like ATPases since proton transport was inhibited by N-ethylmaleimide (NEM), a sulphydryl reagent, and by bafilomycin A \ , a selective inhibitor of vacuolar H ⁺ -ATPases [J.E. Bowman et al., Proc. Natl. Acad. Sci. USA, 85, 7972 (1988)], whilst it was not inhibited by ouabain, an inhibitor of Na ⁺ /K ⁺ -ATPases; sodium orthovanadate, an inhibitor of p- ATPases, or by omeprazole or SCH 28080, both of which are inhibitors of gastric H ⁺ /K ⁺ -ATPase [J.P. Mattson et al., Acta Physiol. Scand., 146, 253 (1992)].

It is known that specific inhibitors of vacuolar ATPases, such as bafilomycin A\, are able to inhibit bone resorption in osteoclast cultures [K. Sundquist et al., Biochem. Biophys. Res. Commun. 168, 309-313 (1990)]

INHIBITION OF v-ATPase PROTON TRANSPORT IN MEMBRANE VESICLES

Preparation of crude bone microso es from calcium-starved egg-laying hens. Vesicles were prepared from medullar bone obtained from tibiae and femurs of egg- laying hens which were calcium- starved for at least 15 days. Briefly, bone fragments were scraped with a 24 scalpel blade, suspended in 40 ml of isolation medium (0.2 M sucrose, 50 mM KC1, 10 mM Hepes, 1 mM EGTA, 2 mM dithiotheitrol, pH 7.4) and filtered through a 100 μm pore size nylon mesh. The whole procedure was performed at 4°C. After homogenisation in a potter (20 strokes) in 40 ml of isolation medium an initial centrifugation (6,500 x gmax ^x 20 min) was performed to remove mitochondria and

lysosomes. The supernatant was centrifuged at 100,000 x gmax for 1 hr and the pellet was collected in 1 ml of isolation medium, divided into 200 μl aliquots, immediately frozen in liquid nitrogen and stored at -80°C. The protein content was determined using a Biorad colourimetric kit according to Bradford [M. Bradford, Anal. Biochem., 72, 248 (1976)]. For the proton transport assay, 5- 10 μl of membranes were used.

Purification of osteoclast membranes. 1 ml of crude microsomal vesicles prepared above were applied (about 0.2 ml per tube ) on the top of a sucrose step-gradient consisting of 3.5 ml of 15%, 30% and 45 % (w/w) sucrose in isolation medium and centrifuged at 280,000 gm^ for 2 hours (SW 41 Ti rotor). After centrifugation the 30%-45% sucrose interfaces were collected, diluted approx. 20-fold in isolation medium and pelletted at 100,000 gm^ for 1 hour (SW 28 rotor). The pellet was then resuspended in 1 ml of isolation medium, aliquoted and frozen in liquid N2 and stored at -80 °C until used.

Proton transport in membrane vesicles was assessed, semi-quantitatively, by measuring the initial slope of fluorescence quench of acridine orange (excitation 490 nm; emission 530) after addition of 5-20 μl of membrane vesicles in 1 ml of buffer containing 0.2 M sucrose, 50 mM KC1, 10 mM Hepes pH 7.4, 1 mM ATP.Na2, 1 mM CDTA, 5 μM valinomycin and 4 μM acridine orange. The reaction was started by addition of 5 mM MgSO4- Results were expressed as the percent of the mean of two controls. Inhibition of bafilomycin-sensitive ATPase activity was assessed in purified membrane vesicles by measuring the release of inorganic phosphate (Pi) during 30 min of incubation at 37°C in a 96-well plate either in the presence or in the absence of bafilomycin Al. The reaction medium contained 1 mM ATP, 10 mM HEPES -Tris pH 8, 50 mM KC1, 5 uM valinomycin, 5 uM nigericin, 1 mM CDTA-Tris, 100 uM ammonium molybdate, 0.2 M sucrose and membranes (20 ug protein/ml). The reaction was initiated by MgSO4 (8-arm pipette) and stopped, after 30 min, by addition of 4 volumes of the malachite green reagent (96-arm pipette) prepared according to Chan [Anal. Biochem. 157, 375 (1986)]. Absorbance at 650 nm was measured after 2 min using a microplate reader. Results are expressed as μmol (Pi) x mg protein ^" lχhour ^~ l and, for each experiment, represent the mean±sem of triplicates.

INHIBITION OF BONE RESORPTION In Vitro assays

Bone resorption can be assessed as described previously in the literature [T. J. Chambers et al., Endocrinology, 1985, 116, 234]. Briefly, osteoclasts were mechanically disaggregated from neonatal rat long bones into Hepes-buffered medium 199 (Flow,

UK). The suspension was agitated with a pipette, and the larger fragments were allowed to setde for 30 sec. The cells were then added to two wells of a multiwell dish containing bone slices (each measuring 12 mm^). After 15 min at 37°C the bone slices were removed, washed in medium 199 and placed in individual wells of a 96- well plate. These were incubated for 24 hrs in a total volume of 2 ml of culture medium, consisting of 10% foetal calf serum in Hanks-buffered MEM, in the presence or absence of drug. The number of osteoclasts and bone resorption were quantified by confocal laser scanning microscopy (CLSM): the bone slices were fixed with 2% glutaraldehyde in 0.2 M cacodylate buffer and the osteoclasts on each bone slice were stained for tartrate- resistant acid phosphatase. After counting the number of large, multinucleated, red- stained cells, the bone slices were immersed in 10% sodium hypochlorite for 60 min to remove cells, washed in distilled water and sputter-coated with gold. The entire surface of each bone slice was then examined in CLSM. The number and the size of the osteoclastic excavations, the plain area and the volume of bone resorbed was recorded. Results were expressed as mean pit number per osteoclast, mean area per osteoclast or mean volume per osteoclast.

2) Inhibition of PTH-stimulated ⁴⁵ Ca ²⁺ release from p re-la belled foetal rat long bone. The assay is based on that described by Raisz (J. Clin. Invest. 44:103-116, 1965). Time-mated Sprague-Dawley rats were injected subcutaneously with 200 mCi of ⁴⁵ CaC12 on the 18th day of gestation. On the following day, the foetuses were removed aseptically and the radii and ulnae were dissected free of adjacent soft tissue and the cartilaginous ends, and then cultured for 24 hr at 37 °C in BGJ medium containing 1 mg/ml BSA. The bones were then transferred to fresh medium containing the test compounds (0.1 - 50 μM) with and without PTH (12 nM) and were incubated for an additional 48 hr. The media were collected and the bones extracted to determine the mean % calcium release by scintillation counting. Results were expressed as the % inhibition compared to the amount of calcium released from cultures incubated with PTH alone

In vivo assays

Prevention of retinoid-induced hypercalcaemia. The method used was that described by Trechsel et al., ( . Clin. Invest. 80:1679-1686, 1987). Briefly, male Sprague- Dawley rats weighing 160-200 g (10 per group) were thyroparathyroidectomised and were treated subcutaneously with the retinoid Ro 13-6298 (30 μg/day) for three days and this was found to significantly increase blood serum calcium by 4-5 mg/100 ml. For inhibition of this effect, rats were treated simultaneously with test compounds i.v. or p.o. at 0.1 - 100 mg/kg, or vehicle and blood calcium was measured as described above,

before treatment and one day after the last administration. Results were expressed as % inhibition with respect to vehicle-treated animals.

Prevention of bone loss in osteoporosis induced by ovariectomy and immobilisation. Seven groups of 10 Sprague-Dawley rats (200 g) underwent ovariectomy plus neurectomy of the sciatic nerve in the right hind limb, while one group was sham-operated according to the method described by Hayashi et al., (Bone 10:25- 28, 1989). It was demonstrated that a steady-state was attained in the amount of trabecular bone lost 6-12 weeks after the operations. During a 6- week period, the operated animals received the test compounds (0.1 - 100 mg/kg p.o. u.i.d.), or vehicle. At the end of this treatment period, the animals were sacrificed and the tibia and femur of the hind limb removed. The tibia wet and dry weight were determined, and the density (displacement of water) and ashes content (total weight, calcium and phosphorous content) also measured. The femur were fixed in 10% formalin, de-mineralised in 5% formic acid and the coronal midshaft and longitudinal section of the distal metaphysis cut and stained with haematoxilin and eosin. Histomorphometric evaluation was made using a semi-automated image analyser (Immagini & Computer, Milan, Italy). In the distal metaphysis, the % trabecular bone area in the secondary spongiosa (which is the trabecular bone 1 mm from the epiphyseal growth plate to about 4 mm towards the midshaft giving a total area of 5 mm ² ) and the number of trabeculae (according to Parfitt et al., 7. Bone Min. Res. 2: 595, (1987)) were determined in all animals. In the midshaft, the medullary, cortical (CA) and total (TA) cross-sectional area was measured and the cortical index (CI) determined from the formula CI = CA/TA.

Prevention of bone loss in ovariectomised mature rats. The methodology employed is based on that described by Wronsky et al. [J.Bone Min Res. ,6, 387 (1991)]. The bone loss, prevalently cancellous, occuring after the surgery is monitored by dual emission X- ray absorptiometry (DEXA) measurements of bone mineral density (BMD) of long bones and by HPLC measurements of urinary levels of products of bone collagen breakdown, such as the cross-link residues pyridinoline (PYD), deoxypyridinoline (DPD) and lysine glycosides, i.e. galactosyl-hydroxylysine (GHYL) and glucosyl-galactosyl-hydroxylysine (GGHYL).

Groups of 7-10 female Sprague-Dawley rats, about 90 days old and weighing 200-250 g are used. Rats are anesthetised by sodium pentobarbital (35 mg kg i.v.), laparotomy is performed and ovaries are bilaterally removed . Wounds are adequately disinfected and sutured. A group is sham operated. During a 4-week experimental period, the operated animals receive test compounds in the appropiate vehicle (0.1-100 mg/kg p.o. u.i.d.) or vehicle alone.

Twenty-four-hr urine samples are collected for PYD, DPD, GHYL and GGHYL determinations before and 2, 4, 8, 11, 15, 18, 22 and 25 days after surgery. The aliquots of urine are frozen and stored at -20° C until HPLC analysis.

Before and at the end of the experimental period, the bone metaphyseal mineral densities of left distal femur and proximal tibia were evaluated in vivo using lightly anaesthetised animals. Results are expressed as % of prevention versus vehicle treated animals.

OTHER THERAPEUTIC UTILITIES:

The activity of the compounds of the invention for the other utilities mentioned herein may be determined by according to the following methods which are incorprated herein: 1. Antitumor activity may be determined according to the methods disclosed in published International Application, Publication number 93/18652; in particular the screen employed, experimental details and bibliography of M.R. Boyd et al., Status of the NCI preclinical antitumor drug discovery screen; principles and practices of Oncology, 3, issue 10, Oct. 1989, Lippincott. 2. Antiviral activity may be assessed using the in vitro assays reported by H. Ochiai et al., Antiviral Research, 27, 425-430 (1995) or by C. Serra et al., Pharmacol. Res., 29, 359 (1994). Anti-HIV activity can be assessed as reported in the literature, for example by S. Velasquez et al., /. Med. Chem., 38, 1641-1649 (1995)

3. Antiulcer activity may be assessed in vivo using the methods reported in the literature, for example, as described by CJ. Pfeiffer, Peptic Ulcer , C.J. Pfeiffer Ed., Munksgaard

Publ., Copenaghen, 1971. In vitro assays for inhibition of vacuolization induced by Helicobacter pylori are described, for example, by E. Papini et al., FEMS Microbiol. Lett., 113, 155-160 (1993)

4. Usefulness in treating Alzheimer's disease may be determined using models in vitro such as inhibition of amiloyd-β production as descrided in the literature by J. Knops et al., J. Biol. Chem., 270, 2419-2422 (1995) or by models in vivo: such as the transgenic mouse model overexpressing human APP reported by D. Games et al., Nature, 373, 523- 527 (1995).

5. Immunosuppressant activity can be assessed as reported in the literature, for example by M.-K. Hu et al. _r J. Med. Chem. , 38, 4164-4170 (1995) ό.Antilipidemic activity can be assessed as reported in the literature, for example by E.A.L. Biessen et al., J. Med. Chem. , 38, 1846-1852 (1995). Antiatherosclerotic activity may be assessed by using animal models of atherosclerosis, such as the atherosclerotic rabbit model, which are reported in the literature, for example by R.J. Lee et al., J. Pharm. Exp. Ther., 184, 105-112 (1973).

7. Angiostatic activity may be assessed using the methods reported in the literature, for example as described by T. Ishii et al., J. Anibiot., 48, 12 (1995).

LIST OF ABBREVIATIONS USED HEREIN

Celite Registered trade mark for dicalite

DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

DCC N,N'-Dicyclohexylcarbodiimide

DIBAH Diisobutylaluminium hydride

DIPEA Diisopropylethylamine

DMF Dimethylformamide

El Electron Impact

EtOAc Ethyl acetate

MS Mass Spectrum

THF Tetrahydrofuran

CI Chemical Ionisation

FAB POS Fast Atom Bombardment / Positive ions detection

TSP ThermoSpray