5-INDOLYL-2,4-PENTADIENOIC ACID DERIVATIVES USEFUL AS INHIBITORS OF BONE RESORPTION

Abstract: A compound of formula (I) or a salt thereof, or a solvate thereof, wherein: R1 represents hydrogen, C1-6 alkyl, halo, azido, C1-6 alkylthio, phnylthio, benzylthio, alkoxyalkyloxy or a group NHR8 wherein R8 represents -CO-R9 or -(CH2)nR11, or R1 represents a group -NR12R13 wherein R12 and R13 each independently represent hydrogen, alkyl or aryl; R2, R3 and R4 each independently represent hydrogen, alkyl, aryl or substituted aryl; R5 and R6 each independently represent hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R5 and R6 together represent methylenedioxy, carbonyldioxy or carbonyldiamino; X represents a hydroxy or an alkoxy group wherein the alkyl group may be substituted or unsubstituted or X represents a group NRsRt wherein Rs and Rt each independently represent hydrogen, alkyl, substituted alkyl, optionally substitued alkenyl, optionally substituted aryl, optionally substituted arylalkyl, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group, or Rs and Rt together with the nitrogen to which they are attached form a heterocyclic group; R7 represents hydrogen, hydroxy, alkanoyl, alkylaminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl or aminosulphonyl; R9 represents R10 or OR10 wherein R10 is C1-6 alkyl, phenyl or benzyl; and R11 represents NR12R13, wherein R12 and R13 are as defined above, or R11 is hydroxy or C1-6 alkoxy; and n represents an integer 1, 2 or 3; a pharmaceutical composition containing such a compound, a process for preparing such a compound and the use of such a compound in medicine.

Description: 5-INDOLYL-2.4-PENTADIENOIC ACID DERIVATIVES USEFUL AS INHIBITORS OF BONE RE- SORPTION This invention relates to ccitain 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. Co-pending International Application, application number PCT/ EP96/ 00157 discloses certain indole derivatives which are indicated to reduce bone resorption by inhibiting osteoclast H+-ATPase Diseases associated with loss of bone mass are known to be caused by over activity of osteoclast cells It is also known that certain compounds, usually related to bafilomycin, are useful for treating such diseases For example International Patent Application, publication numbei WO 91/06296 discloses certain bafilomycin macrolides for the treatment of bone affecting diseases However, bafilomycin derivatives are not selective for osteoclasts in humans. The use of these compounds is therefoie associated with unacceptable toxicity due to generalised blockade of othei essential v-ATPases Indeed, to date there is no known treatment which is selective for the human osteoclasts. The search for a successful treatment for diseases associated with loss of bone mass in humans is further complicated in that the nature of the therapeutic target for the selective inhibition of the osteoclasts is controversial. Thus Baron et al (International Patent Application publication number WO93/01280) indicate that a specific vacuolar ATPase (V-ATPase) has been identified in osteoclasts as a potential therapeutic target. However, the Baron work was can ιed out in chickens and Hall et al (Bone and Mineral 27, 1994, 159- 166), in a study relating to mammals, conclude that in contrast to avian osteoclast V-ATPase, mammalian osteoclast V-ATPase is pharmacologically similar to the v-ATPase in other cells and, therefore, it is unlikely to be a good therapeutic target We have now found a gioup of compounds which aie selective for mammalian osteoclasts, acting to selectively inhibit their bone resorbing activity. These compounds are therefore considered to be particularly useful for the treatment and/or prophylaxis of diseases associated with loss of bone mass, such as osteoporosis and related osteopemc diseases, Paget's disease, hyperpai thyroidism and related diseases. These compounds are also considered to possess nli-tumoui activity, antiviral activity (for example against Semliki Forest, V sicular Stomatitis, Newcastle Disease, Influenza A and B, HIV viruses), anti ulcer activity (for example the compounds may be useful for the treatment of chronic gastritis and peptic ulcer induced by I le.lic.obacte.r pylori), immunosupressant activity, antilipidemic activity, aniialherosclerotic activity and to be useful for the treatment of AIDS 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 invention provides a compound of formula (I): or a salt thereof, or a solvate thereof, wherein: Rj represents hydrogen, Ci .β alkyl, halo, azido, C[. alkythio, phenylthio, benzylthio, alkoxyalkyloxy or a group NHR wherein R represents -CO-R9 or -(CH2) n j 1, or R I represents a group -N 12 13 wherein R]2 and R13 each independently represent hydrogen, alkyl or aryl; R2, R3 and R4 each independently represent hydrogen, alkyl, aryl or substituted aryl; R5 and Rβ each independently represents hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R5 and R together represent methylenedioxy, carbonyldioxy or carbonyldiamino; X represents a hydroxy or an alkoxy group wherein the alkyl group may be substituted or unsubstituted or X represents a group NR s R t wherein R s and R t each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group, or R s and R t together with the nitrogen to which they are attached form a heterocyclic group; R7 represents hydrogen, hydroxy, alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl or aminosulphonyl; Ro represents R ] ø or OR ] Q wherein and R \ Q is C] _ft alkyl, phenyl or benzyl; and R 1 1 represents NR j 2R ] 3, wherein R \ 2 and R ] 3 are as defined above, or R \ j is hydroxy or C] .(. alkoxy; and n represents an integer 1 ,2 or 3. When R | is alkyl, an example is methyl. When R | is halo an example is chloro or fluoro. When R I is alkoxyalkyloxy, an example is -0(CH2)2OCH3. When R \ is -NI IR^ wherein R is CO.R and R9 is R]ø, an example is NHCOCH3. When R ] is -NI IRχ wherein R^ is CO.R9 and R9 is OR J Q, examples include -NHCOO/ Bu and -NI ICOOCl bPh. Suitably, R | represents methyl, -0(CH2)2θCH3, -NHCOOr Bu Suitably, I 2« R and R4 each independently represent hydrogen, alkyl or phenyl. Examples of R2 include hydrogen and methyl. Suitably, Ri represents hydrogen. Examples of R3 include hydrogen and ethyl. Suitably, R3 represents hydrogen. Examples of R4 include hydrogen, propyl and phenyl. Suitably, R4 represents hydrogen. Suitably, R5 and (* each independently represents alkoxy, halo, trifluoromethyl, ni ro, and alkyl. When Rsor R represents alkoxy, said alkoxy group is suitably a C\ .fr alkoxy for example methoxy. When R5 or Represents halo, said halo group is suitably a fluoro or chloro group. When R5 or R^ represents alkyl, said alkyl group is suitably a C]_^ alkyl for a example butyl group. Suitable positions for substitution for R5 or R5 are the 4, 5, 6 or 7 position, favourably the 5 or 6 position. When neither of R ^or R^ represent hydrogen then favoured positions for bis- substitution are 5 and 6 positions. Favoured values for R5 and R ( , are hydrogen, halo, trifluoromethyl and alkoxy. In a preferred aspect R5 is halo, especially 5-halo, and R is halo, especially 6- hiilo. Most pi okTiihlv K ' ehloi o, especially 5-chloιo, and R is chloio, especially 6- chloio. Examples ol R7 include hydrogen, methyl and t-butoxycarbonylmethyl Suitably, R7 repi esents hydrogen When X repiesents an alkoxy group, the alkyl group thereof is preferably an unsubsliluied alkyl group. Suitably, X represents the above defined group N R s R t In one aspect, R s and R* each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, an optionally substituted heteiocyclic group 01 an optionally substituted heterocyclylalkyl group R s and R t can also each independently lepiesent cycloalkyl, substituted cycloalkyl. In a further aspect, R s and R t together represent a heterocyclic group. When R s or R t represent alkyl 01 substituted alkyl, suitable alkyl groups are C\. alkyl groups, for example C j . C2. C3, C4 and C5 alkyl groups, favourably ethyl, propyl or butyl. When R s or R t represent substituted alkyl, favoured groups are 2- (dialkylamino)ethyl or 3-(dialkylamιno)propyl or 4-(dιalkylamιno)butyl or heterocyclylmethyl or heterocyclylethyl or heterocyclylpropyl groups When R s or R t represent cycloalkyl or substituted cycloalkyl, suitable cycloalkyl groups are ^. cycloalkyl gioups, foi example a cyclopentyl or cyclohexyl group When R s or R x represent alkenyl or substituted alkenyl, suitable alkenyl groups are C2-6 alkenyl groups, for example a C5 alkenyl group When R s 01 R x represent aryl 01 substituted aryl, suitable aryl groups are phenyl groups In one f avoured aspect R ( is hydiogen Suitable values foi R s include hydiogen, C] _5 alkyl, mono- di- and tπ- hydroxyalkyl, alkoxyalkyl, carboxyalkyl, carbalkoxyalkyl, bisphosphonylalkyl, (substιtuied)amιιio-carboxyalkyl, hiscarbethoxy-hydioxyalkenyl, dialkylamtnoalkylpyπdyl, mono- di- and iπ-alkoxypyπdyl, clialkylaminoalkoxypyπdyl, aryloxypyndyl, aminopyπdyl, substituted pipcia/inyL quiiiuclulyl, saiin ated heleiocyclylalkyl, substituted piperidinyl, (dι)a/abιcycloalkyl, subslituied phenyl, substituted benzyl, substituted phenylethyl, 1 - imidazolylalkyl, tliia/.olinyl, (2-tetrahydroisoquinoIinyl)alkyl, lH-pyrazolo[3,4-d]pyrimidin- 4-yl, 7H-purin-2-yl, pyridylalkyl, (2-pyrimidinyl)piperazin- l -ylalkyl, substituted pyridazinyl, substituted pyrazinyl, substituted pyrimidinyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, tetrahydroquinolyl. Other suitable valuse for Rs include , (4-substituted)piperazinoalkyl and aminopyrimidiniyi. Preferred values for R s include diethylaminopropyl, 3-amino-3-carboxypropyl, 4- amino-4-carboxybutyI, 3-pyridyl, diethylaminoethyl, 3-quinuclidyl (or 1 - azabicyclo| 2.2.2|octan-3-yl), morpholinopropyl, piperidinopropyl, l -methyl-2- pyrrolidinylethyl, 2,2,6,6-tetramethyl-4-piperidinyl, 2-methoxy-5-pyridyl, 2- methylpiperidinopropyl, 8-methyl-8-azabicyclo[ 3.2. 1 ]oct-3β-yl, l -methyl-4-piperidinyl, lH-pyrazolo[ 3,4-d |pyrimidiιι-4-yl, 2,2,5,5-tetramethyl-3-pyπOlidinylmethyl, 2-methoxy-4- pyridyl, l-ethyl-3-piperidinyl, 3-|4-(2-pyrimidinyl)piperazin- l -yllpropyl. Other preferred values for R s include 1 , 2,2,6, 6-pentamethyl-4-piperidinyl, 1,2,6- trirnethyl-4-piperidinyl and l ,2,2,6-tetramethyl-4-piperidinyl groups. Suitable values for R t include hydrogen, methyl, C2-5 alkyl, 2-hydroxyethyl, 2- methoxyethyl, carboxymethyl, carbomethoxymethyl, 4-hydroxybutyl and 2,3- dihydroxypropyl, especially hydrogen. In one preferred aspect R t represents hydrogen. A favoured moiety NR S R, is an optionally substituted piperidinyl group, especially wherein one of the substituents is an N-alkyl group. Particular substituents for piperidinyl groups are alkyl groups, especially when attached to one or, favourably, both of the carbon atoms alpha to the ring nitrogen atom. Piperidinyl groups of especial interest are those wherein one or, favourably, both of the carbon atoms alpha to the ring nitrogen atom are substitued with one or, favourably, two alkyl groups. Further particular substituents for piperidinyl groups are alkylene groups, especially when attached to one, favourably both, of the carbon atoms alpha to the ring nitrogen atom. A particular 6 membered, saturated heterocyclic group is a group of formula (H I ): wherein X j , X2, X3, X4, X5, X 0 , X7 and X x are each independently selected from hydrogen, hydroxy, (C|-C () ), alkyl cycloalkyl (spirocondensed), mono or poly hydroxyalkyl, alkoxyalkyl, hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl (optionally alkylated or acylated at nitrogen); or one of X4 with X and X2 with X^ represents a C2-4 alkylene chain and the remaining variables X ] , X3, X7 and X7 each independently represent hydrogen, hydroxy, lower alkyl (C Cr,), cycloalkyl (spirocondensed), mono or poly hydroxyalkyl, alkoxyalkyl, hydroxy- alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl (optionally alkylated or acylated at nitrogen); and X5 represents hydrogen or lower alkyl, mono or polyhydroxyalkyl, mono or diaminoalkyl, aminocarbonyl, alkyl, carboxyalkyl, carbalkoxyalkyl, aryl, heterocyclyl, acyl, carbamoyl, alkylamino(cyanimidoyi), aminoalkanoyl, hydroxyalkanoyl. Suitably, X] , X2, X^ and X9 each represent hydrogen. Suitably, X3, and X4 each independently represent hydrogen or alkyl, especially alkyl . Suitably, Xβ and X7 each independently represent hydrogen or alkyl. Suitably, X5 represents alkyl In one preferred aspect X3, X4, X-ή and X7 each independently represent alkyl, especially methyl and X I , X2. and X9 each represent hydrogen. Particular examples of the invention are the compounds of example numbers: 3, 10, 13, 16 and 19. 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, such as methyl, ethyl, n- and iso- propyl and n- iso-, tert-butyl and pentyl groups, 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; alkoxy; a group of foπnula NR U R V wherein R u and R v each independently represent hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, carboxy, carboxyalkyl, or alkoxycarbonyl, nitro, or R u and R v together together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring; carboxy; alkoxycarbonyl; alkoxycarbonylalkyl; alkylcarbonyloxy; alkylcarbonyl; mono-and di-alkylphosphonate; optionally substituted aryl; and optionally substituted heterocyclyl. A preferred alkyl substituent is NR L1 R Vj wherein R u and R v each independently represent hydrogen, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl or R u and R v together together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring. When R s or R t represents substituted alkyl, especially C ] _4 alkyl, particular substituent values are the moieties of formulae (a), (b), (c), (d) and (e): Ru -CH 2 — A-N (a) Rv ■ C0 2 R t -A.- N -C0 2 R g (e) wherein A represents alkyl, suitably C ] .3 alkyl, A ] is alkyl, suitably C] _4 alkyl, and R a , fo, R c , R t ) and R c each independently represent hydrogen, alkyl or aryl and R u and R v are as defiened above. As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups having from 2 to 12 , suitably 2 to 6 carbon and also includes such groups when forming part of other groups, an example is a biitenyl group, such as a 2-butenyl group. Suitable optional substituents for any alkenyl group includes the alkyl substituents mentioned above. As used herein, the teπn "aryl" includes phenyl and naphthyl, especially phenyl. Suitable optional substituents for any aryl group include up to 5 substituents, suitably up to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, acetyl, cyano, nitro, amino, mono-and di-alkylamino and alkylcarbonylamino. Preferred optional substituents for any aryl group are selected from isobutyl, hydroxy, methoxy, phenoxy, diethylaminoethoxy, pyrrolidinoethoxy, carboxymethoxy, pyridyloxy, fluoro, chloro, amino, dimethylamino, aminomethyl, morpholino, bis(carbefhoxy)hydroxymethyl. Suitable arylalkyl groups include aryl-C ] _3~alkyl groups such as phenylethyl and benzyl groups, especially benzyl. Preferably, substituted aralkyl groups are substituted in the aryl moiety. As used herein, the teπns "heterocyclyl" or "heterocyclic" include saturated or unsaturated single or fused, including spiro, ring heterocyclic groups, each ring having 4 to 1 1 ring atoms , especially 5 to 8, preferably 5, 6 or 7 which ring atoms include 1, 2 or 3 heteroatoms selected from O, S, or N. Suitable heterocyclic groups include single ring saturated heterocyclic groups, single ring unsaturated heterocyclic groups, fused ring heterocyclic groups. Fused ring heterocyclic groups include spiro heterocyclic groups. Suitable single ring unsaturated heterocyclic groups comprise 5-, 6- or 7- membered rings. Suitable 5-membered single ring unsaturated heterocyclic groups are furanyl, thienyl, pyrrolyl, pyrazolyl, inudazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, furazanyl, thiazolyl and isothiazolyl groups; or partially saturated derivatives thereof, such as 4,5- dihydro-l ,3-thiazol-2-yl, 11 l-imida/.olinyl, pyrrolinyl, pyrazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl groups. Suitable 6-mcmbered single ring unsaturated heterocyclic groups are pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, 1 ,2- or 1,3- or 1,4-oxazinyl, 1,2- or 1 ,3- or 1 ,4-thiazinyl and pyranyl groups, or partially saturated derivatives thereof such as 1 ,2- or 1 ,3- or 1 ,4- dihydrooxazinyl, 1 ,4-dihydropyridyl, dihydropyridazinyl, dihydropyrazinyl or dihydropyrimidinyl. A further suitable 6-membered single ring unsaturated heterocyclic group is a pyridin-2-one-5-yl group. Suitable 7-membered single ring unsaturated heterocyclic groups are azepinyl, oxepinyl, diazepinyl, thiazepinyl, oxazepinyl or partially saturated derivatives thereof. Suitable, single ring saturated heterocyclic groups comprise 5-, 6- or 7- membered rings. Suitable 5-membered single ring saturated heterocyclic groups are pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl and terahydrofuranyl groups. Suitable 6-membered single ring saturated heterocyclic groups are piperidinyl, piperazinyl, tetrahydropyranyl, 1 ,3-dioxacyclohexyl, tetrahydro- l ,4-thiazinyl, morpholinyl and morpholino groups. Suitable 7-membered single ring saturated heterocyclic groups are hexamethyleniminyl, oxepanyl and thiepanyl. Suitable fused ring heterocyclic groups include fused saturated rings, fused unsaturated rings and saturated rings fused to unsaturated rings. Suitable groups having fused saturated rings are quinuclidyl, 8- azabicyclol 3.2.1 loctyl, 9-azabicyclo| 3.3.1 |nonyl, l -azabicyclo| 3.3.3 ]undecyl, 1 ,9- diazabicyclo| 3.3.1 1 and l ,5-diazabicyclo|3.3.1 |nonyl groups. A further suitable group comprising fused saturated ring is a nonyl 1- azabicyclo] 3.3.1 |nonyl, 3,7-diazabicyclo| 3.3.1 Jnonyl group. Suitable groups having fused unsaturated rings are pyrazo| 3.4-d]pyrimidinyl, l ,2,5-thiadiazolo|3,4-b|pyridyl, isoxazolo|4,5-b|pyridyl, thiazolo|4,5-b|pyridyl, oxazolo|4,5-d]pyrimidinyl, 71 1-purin-2-yl, quinolyl, isoquinolyl, benzol b|thienyl, benzofuranyl, isoben/.ofuranyl, benzoxazolyl, benzothiazolyl, indolizinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl and β-carbolinyl groups. Suitable groups having saturated rings fused to unsaturated rings includes groups which are fused to benzene rings such as tetrahydroquinolyl, 4H-quinolizinyl, tetrahydroi.soquinolyl, dihydrobenzofuryl, chiomenyl, chromanyl, isochromanyl, indolinyl and isoindolinyl groups. Suitable spiro heterocyclic groups include oxaspiro[4.5]decyl, azaspiro[4.5Jdecyl, l ,2,4-triazaspiro|5.5]undecyl, l ,4-dioxa-9-azaspiro[4.7jdodecyl and 1 - azaspiro|5.5|ιmdecyl. Suitable optional substituents for any heterocyclyl or heterocyclic group include up to 5 substituents, suitably up to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, hydroxy, halo, amino, mono- or di-alkyl amino, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, aryl, aryloxy and heterocyclyl. Preferred optional substituents for any heterocyclyl or heterocyclic group are selected from isobutyl, hydroxy, methoxy, phenoxy, diethylaminoethoxy, pyrrolidinoethoxy, carboxymethoxy, pyridyloxy, fluoro, chloro, amino, dimethylamino, aminomethyl, morpholino, bis(carbethoxy)hydroxymethyl. Further optional substituents for any heterocyclyl or heterocyclic group include up to 5, suitably up to 3, substituents selected from the list consisting of: isopropyl, cyano, oxo, arylcarbonyl, heterocyclyloxy, alkoxyalkoxy, alkoxycarbonylalkyloxy, carboxyalkyloxy, aminoalkyloxy, aminoalkylamino, aminoalkenylamino (especially aminomethyleneamino), alkanoylamino ,alkoxyamino, acetamido, 2- (dimethylamino)ethylamino, 2-methoxyethoxy, 3-carboxyprop-2-oxy and 2-pyrazinyl. Additional optional substituents for any hetrocyclyl or heterocyclic group include up to 5, suitably up to 3, substituents selected from the list consisting of: carbonylaminoalkyl, amincarbonylalkyl and alkylcarbonylaminoalkyl. For the avoidance of doubt a reference herein to "heterocylic" includes a reference to "heterocyclyl". As used herein, the teπn "halo" includes fluoro, chloro, bromo and iodo, suitably fluoro and chloro, favourably chloro. Certain of the carbon atoms of the compounds of formula (I) - such as those compounds wherein R j -R7 contains chiral alkyl chains are chiral carbon atoms and may therefore provide stereoisomers of the compound of formula (I). The invention extends to all stereoisomeric foπns 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 iso er may be obtained by conventional stereospecific or asymmetric syntheses. Hie 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 phannaceutically acceptable salts. Certain of the compounds herein can exist in various tautomeric forms, for example when hydroxy is a substituent on an aryl or heteroaryl ring; it is to be understood that the invention encompasses all such tautomeric forms. Suitable phannaceutically acceptable salts include acid addition salts and salts of carboxy groups. Suitable phannaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid. Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium and lithium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C \ .( * alkylamines such as triethylamine, hydroxy- C] _6 alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)-amine or rri-(2-hydroxyethyl)-amine, cycloalkylamines such as dicyclohexylamine, or with procaine, 1 ,4-dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylaιnine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline. Suitable solvates of the compounds of the formula (I) are phannaceutically acceptable solvates, such as hydrates. The salts and/or solvates of the compounds of the formula (I) which are not phannaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compounds of foπnula (I) or the compounds of the fonnula (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 by reacting a compound of fonnula (II): wherein R2, R3, R4, R5, Rβ and R7 are as defined in relation to fonnula (1), with a reagent capable of converting a moiety of fonnula into a moiety of fonnula (a): wherein R j , R2, R3, R4 and X are as defined in relation to foπnula (1); and thereafter, as necessary, carrying 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 formula into a moiety of the above defined formula (a), includes conventional reagents used to convert C=0 bonds into carbon carbon double bonds, such as Wittig or Horner-Emmons reagents, for example those of formula (III): X, ,-CH CO-X, 0 R ) (HI) wherein R | is as defined in relation to the compounds of formula (I), X ] ( ) represents X as defined in relation to formula (I) 01 a group convertible thereto and X \ \ represents a moiety (R \ 4θ)2P(0)- wherein R 14 is C | , alkyl or X j ] represents a group Ph3P-. Preferably, X \ ] represents a moiety (R j 4θ)2P(0)-. The reaction between the compounds of formula (II) and the reagent capable of converting the group of formula into the moiety of fonnula (a), may be carried out under the appiopπate conventional conditions, depending upon the particular reagent chosen, toi example. When the reagent is a compound of fonnula (III) wherein X j ] is a moiety (R j4θ)2P(0), then the reaction is canied out under conventional Horner-Emmons conditions, using any suitable, aprotic solvent for example an aromatic hydrocarbon such as benzene, toluene or xylene, DMF, DMSO, chloroform, dioxane, dichloromethane, preferably, THF, acetonitrile, N-methylpyrrohdone, and the like or mixtures thereof, preferably an anhydrous solvent, 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; preferably the reaction is conducted in the presence of a base Suitable bases for use in the last above mentioned reaction include organic bases, such as butyl lithium, lithium dnsopropylamide (LDA), N,N-dιιsopropylethylamιne, 1 ,5- dιazabιcyclo|4 3.0|-5-nonene (DBN), l ,5-dιazabιcyclo| 5 4.0|-5-undecene (DBU), 1 ,5- dιazabιcyclo[ 2.2 2|octane (DABCO) , and inoi ganic bases, such as sodium hydnde ; preferably sodium hydride, and geneially the leaction is carried out in an inert atmosphere such as nitrogen When the reagent is a compound of fonnula (III) wherein X2 is a moiety Pr^P-, 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 bases are organic bases such as tπethylamine, tπmethylamine, N,N-dnsopropylethylamιne (DIPEA), pyridine, N,N-dιmelhylanιlιne, N-methylmorpholine, l ,5-dιazabιcyclo|4.3.0]-5-nonene (DBN), l ,5-dιazabιcyclo|5.4.0|-5-Lindecene (DBU), l ,5-dιazabιcyclo[2.2.2|octane (DABCO) anil inorganic bases such as sodium hydride, caesium carbonate, potassium carbonate, prefeiably sodium hydride. Suitable solvents aie conventional solvents for use in this type of reaction, such as aromatic hydrocarbons such as benzene, toluene or xylene or the like, DMF, DMSO, chloroform, dioxane, dichloromethane, THF, ethyl acetate, acetonitπle, N-methylpyrrolidone or mixtures thereof, pieferably dichloromethane. This reaction is carried out at any temperature providing a suitable late of formation of the lequired product, conveniently at ambient tempeiature or at an elevated temperature, such as a temperature in the range of from -20°C to 140°C, preferably in the lan e of from about room temperature to the reflux temperature of the solvent Suitably, X I Q (and hence X in the resulting compound of formula (I)) represents alkoxy: Further compounds of formula (I) are then prepared from the compounds of fonnula (I) wherein X is alkoxy, using the methods disclosed herein For compounds of fonnula (I) wheiem X is azido, a suitable reagent is a compound of formula (IV) N.-CH 2 -CO-X 10 (IV) wherein X ]() is as defined in relation to the compound of fonnula (III). The reaction between the compounds of foπnulae (II) and (IV) is conveniently carried out in an alkanolic solvent, such as ethanol, in the piesence of a base such as sodium ethoxide, usually at a low to ambient tempeiatuie, for example at 0°C A compound of foπnula (II) may be piepaied accoiding to the leaction sequences shown in Schemes (Ia-c) below Scheme (la) Scheme (lb) Scheme (Ic) (R 9 0),OP OEt R, O COOEt (VIII) (IX) 1 ) DIBAH 2) Mn0 2 (ll) wherein, subject to any qualification mentioned below, R j , R2, R3, R4, R5, R 0 and R7 are as defined in relation to the compounds of formula (I) Compounds of formula (II) may be prepared using either Wittig or Horner- Emmons reactions of keto derivatives of fonnula (V) with the appropriate phosphonium salt or phosphonate using the reaction conditions which are known in the art and described, for example in 'The Wittig Reaction", R. Adams Ed., Vol. 14, p. 270 ( 1965) or in Angew. Chem. Int. Ed. Enχl.. 4, 645 ( 1965). When R2 is other than -H , e.g. alkyl, a compound of fonnula (II) is obtained directly from a compound of fonnula (V) by Wittig or Horner-Emmons reaction with the appropriate phosphonium salts or phosphonates according to Scheme (la). When a compound of fonnula (V) is reacted with the above mentioned phosphonates using the Horner-Emmons reaction, the experimental conditions used are conventional conditions such as those reported, in Tetrahedron Lett. 1981 , 461 ; Can. J. Chem., 55, 562 ( 1977); ./. Am. Chem. Sac. 102, 1 390 ( 1980); ./. Org. Chem., 44, 719 ( 1979); Synthesis; 1982, 3 1 ; and Tetrahedron Lett. 1982, 2183. The reaction of compounds of formula (V) with the above mentioned phosphonium salts are carried out in the presence of a base in any suitable solvent. Suitable bases include organic bases, such as triethylamine, trimethylamine, N,N- diisopropylethylamine (DIPEA), pyridine, N,N-dimethylaniline, N-methylmorpholine, 1 ,5- diazabicyclo|4.3.0|-5-nonene (DBN), 1 ,5-diazabicyclo| 5.4.0]-5-undecene (DBU), 1,5- diazabicyclol 2.2.2 loctane (DABCO) and inorganic bases, such as sodium hydride, caesium carbonate, potassium carbonate. Suitable solvents include conventionally used solvents, for example aromatic hydrocarbons such as benzene, toluene or xylene or the like; DMF, DMSO, chloroform, dioxane, dichloromethane, THE, ethyl acetate, acetonitrile, N-methylpyrrolidone and the like or mixtures thereof. Preferably, the reaction is earned out at a reaction temperature of in the range of about-20°C to 140°C, preferably about room temperature to the reflux temperature of the solvent. The reaction of compounds of formula (V) with phosphonates are carried out under conventional Horner-Emmons conditions, using any suitable, aprotic solvent for example an aromatic hydrocarbon such as benzene, toluene or xylene, DMF, DMSO, chloroform, dioxane, dichloromethane, preferably. THF, acetonitrile, N- methylpyrrolidone, and the like or mixtures thereof, preferably an anhydrous solvent, at a temperature providing a suitable rate of fonnation 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: preferably the reaction is conducted in the presence of a base. Suitable bases for use in the last above mentioned reaction include organic bases, such as butyl lithium, lithium diisopropylainide (LDA), N,N-diisopropylethylamine, 1 ,5- diazabicycIo|4.3.0]-5-nonene (DBN), l ,5-diazabicyclo| 5.4.0|-5-undecene (DBU), 1,5- diazabicyclo[ 2.2.2]octane (DABCO) , and inorganic bases, such as sodium hydride ; preferably sodium hydride, and generally the reaction is carried out in an inert atmosphere such as nitrogen. When R2= FI, aldehyde (VI ) is reacted with aliphatic aldehydes of formula (VI) in presence of bases such as sodium or potassium hydroxide affording compound (II) as in Scheme (lb), using the appropriate conventional procedure In a further aspect, when 2= 1 1, a compound of foπnula (V) is reacted with a substituted carbethoxymei ylphosphonium salt or carbethoxvmethylphosphonate (Scheme (Ic)), the carboxylic ester obtained ( IX ) is then converted into the corresponding alcohol with a reducing agent, suitably a complex metal 1 educing agent such as lithium aluminium hydride (L1AIH4), diisobutyl aluminium hydnde (DIBAH) or lithium borohydπde (L1BFI4), in any suitable apiotic solvent for example methylene dichlonde, chloioform, dioxane, diethyl ethei 01 THF, at any temperature pioviding a suitable rate of fonnation of the required product, such as a tempeiatuie in the l ange of from -30°C to 60°C, for example at room tempeiature Then, the inteπnediate alcohol is oxidised to aldehyde (II) with an oxidising agent such as manganese dioxide, peπodinane (Dess-Martin reagent), pyπdinuim chlorochi ornate (PCC) or pyπdinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swei n l eaction), preferably manganese dioxide in methylene dichlonde The compounds of fonnula (I II) can be piepaied accoiding to the reaction sequence shown in Scheme (I I) below wheiein, subject to any qualification mentioned below, R and R ] 4 are as defined in relation to fonnula (I) and X \ is as defined in telation to fonnula (III) The starting mateπal is an α-alkoxycai boxylic estei of foi mula (X) which is commeicially available 01 which is piepared accoiding to the methods known in the art, for example those iepoited in Rodd s Chemistry of Organic Compounds', Vol In, p 96 (1965), S Cof fey Ed , Elseviei s The compound of fonnula (XI) is reacted with an N- haloimide, toi example N biomosucc innnide in the piesence of a l adical pioducing agent such as azobisisobutyi ronitπle 01 benzoyl pei oxide in a suitable solvent such as carbon teti achloπde, benzene, toi example cai bon teti chloi ide and at a reaction tempei ature in the range of hom -3()°C and 80°O, foi example at 1 0m tempei atuie. examples of such a teaction may be found in the liiei atiue foi example / i g Chem , 41 , 2846 ( 1976) The halocompound obtained, oi fonnula (X I), is then leac ted eithei with ti iphenylphosphme 01 with a tπalkyl phosphite P(OR 14 )^ to give the tequiied compound of formula (II I ) When the compound of formula (XI) is reacted with triphenylphosphine, the reaction is performed in any conventionally used solvent , for example dioxane, tetrahydrofuran, , benzene, xylene or, preferably, toluene at a suitable reaction temperature in the range of from -30°C to 80°C, for example at room temperature (examples of this conversion are reported in the literature, for example in Chem. Ber., 97, 1713 (1964)). When the compound of foπnula (XI) is reacted with trialkyl phosphite P(OR j4)3, the reaction is perfoπned in any conventionally used solvent, preferably the trialkyl phosphite, and at a suitable reaction temperature, preferably at the boiling point of the solvent (examples of this conversion are reported in the literature, for example in Liebigs Ann. Chem., 699, 53 ( 1966). Alternatively, a compound of foπnula (III) in which R2 is (R i4θ)2PO may be prepared using the procedure depicted in Scheme (III), by reacting a diazophosphonoacetates of formula (XI) with an alcohol or phenol of formula R jH, wherein R \ is as defined in relation to foπnula (I), in the presence of rhodium" acetate as described in the literature, for example in Tetrahedron, 50, 3177 (1994) or in Tetrahedron, 48, 3991 ( 1992). A compound of formula (V), wherein R4 is other than hydrogen is prepared by condensing a compound of formula (XII): wherein R5, f, and R7 are as defined in relation to fonnula (I), with a haloketone of formula (XIII): X ) 2 -CH 2 -CO-R 4a (XIII) wherein X )2 is halo, especially bromo, and R4 a is R4 as defined in foπnula (VI) or a group which can be converted into R4. The reaction between the compounds of foπnula (XII) and (XIII) is carried out using conventional condensation conditions, usually in an aprotic solvent such as DMF and preferably at an elevated temperature, for example in the range of from 80°C to 90°C: Such conditions are described in . / .Org. Chem., 37 ( 1972), 3622. I H- The compounds of fonnula (XI) and (XII) are known compounds or they are prepared using to methods analogous to those used to prepare known compounds , such as those disclosed in ./. Org. Chem., ibid. A compound of formula (VI), that is a compound of formula (V) wherein R4 is hydrogen, is prepared according to the reaction sequence set out in Scheme (III): Scheme (III) 1 Reduction step b 2 Cyclisation wherein, subject to any qualification mentioned below, R5, R^ and R are as defined in relation to foπnula (I) and X \ ι is as defind in reation to fonnula (XII). In Scheme (III): step a, is suitably carried out in a solvent such as ethanol or solvent mixtures thereof, for example diethylether/ethanol, in the presence of a base such as potassium ethoxide (conveniently provided by adding metallic potassium to ethanol solvent), and usually at room temperature; step b, reduction and cyclisation, is conveniently accomplished using iron powder in an ethanol/acetic acid solvent mixture, at an elevated temperature such as the reflux temperature of the solvent; step c, is carried out using conventional alkylation conditions, for example in an aprotic solvent such as Tl IF or DMF using a base such as sodium hydride or in acetone using solid potassium hydroxide, preferably, sodium hydride in DMF, and usually at ambient temperature; step d, the reduction step, may be carried out using any 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 solvent for example, hexane, dioxane, diethyl ether or THF, preferably under anhydrous conditions and preferably under an inert atmosphere such as argon at any temperature providing a suitable rate of fonnation of the required product, such as a temperature in the range of from -30°C to 6()°C, for example in the range of from -20°C to 0°C. step d, is carried out 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 (Swern reaction), preferably manganese dioxide in methylene dichloride, usually at ambient temperature. The compounds of foπnula (VII) and (X) are known compounds or they are prepared using methods analogous to those used to prepare known compounds, such as those described in .1. March, Advanced Organic Chemistry, 3rd Edition ( 1985), Wiley Interscience. Suitable conversions of one compound of fonnula (I) into another compound of foπnula (I) includes 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 . Such conversions are shown below in Scheme (IV): Scheme (IV) (!) (I) (X=NH S R,) (X=OR) wherein, subject to any qualification mentioned below, R\ , R2, R3, R4, R5, R 0 , R7 and X are as defined in relation to the compounds of foπnula (I), R s ' is R s or a protected form thereof, R t ' is R t or a protected form thereof and R' is X when X is an alkoxy group. 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 co pound wherein X represents a moiety of the above defined formula NR R t 01 another alkoxy group may be carried out as follows: (i) when X is alkoxy. by basic hydrolysis, using for example potassium hydroxide, to provide a compound of tomiul.i (1 ) wherein X is hydroxy, and thereafter(a) for preparing compounds wheiein X represents a moiety of the above defined foπnula NR s R t treating with a compound of foπnula HNR s 'R t ' wherein R s ' and R t - are as defined above or (b) for preparing compounds of fonnula ( 1) wherein X represents alkoxy, by treating with a compound of formula R'OH wherein R' is the required alkoxy group; and thereafter optionally deprotecting; or (ii) when X is hydroxy, by using analogous procedures to those mentioned above in (I). Preferably the reaction with the compounds of foπnula HNR s 'R t ' or with compounds of formula R'OH takes place after activation of the carboxylic group. A carboxyl group may be activated in conventional manner, for example, by conversion into an acid anhydride, acid halide, acid azide or an activated ester such as cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nityrothiophenyl ester, 2,4,6- trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N- hydroxyphthalimido ester, 8-hydroxypiperidine ester, N-hydroxysuccinimide ester, N- hydroxybenzotriazole ester, or the carboxyl group may be activated using a carbodiimide such as N,N'-dicyclohexylcarbodiimide (DCC) or l -ethyl-3-| 3-(dimethylamino)propyl]- carbodiimide hydrochloride (WSC), either in the presence or the absence of hydroxybenzotriazole (HOBt) or l -hydroxy-7-azabenzotriazole (HOAt); or it may be activated using N,N'- carbonyldiimidazole, Woodward-K reagent, Castro's reagent or an isoxazolium salt. Condensation of an activated carboxyl group with an amino group or with an alcoholic group may be carried out in the presence of a base, in any suitable solvent. Suitable bases include organic bases, such as triethylamine, trimethylamine, N,N- diisopropylethylamine (DIPEA), pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine (DMAP), N-methylmorpholine, l ,5-diazabicyclo| 4.3.0|-5-nonene (DBN), 1 ,5- diazabicyclo| 5.4.0|-5-undecene (DBU), 1 ,5-diazabicyclo| 2.2.2 |octane (DABCO), and inorganic bases, such as potassium carbonate. Suitable solvents includeconventionally used solvents, for example DMF, dimethyl sulfoxide (DMSO), pyridine, chloroform, dioxane, dichloromethane, THF, ethyl acetate, acetonitrile, N-methylpyrrolidone and hexamethylphosphoric triamide and mixtures thereof. The reaction temperature may be within the usual temperature range employed in this type of condensation reaction, and generally in the range of about -40°C to about 60°C, preferably from about -20°C to about 40°C. When the reaction is carried out in the presence of a suitable condensing agent, for example a carbodiimide, N,N'- carbonyldiimidazole, Woodward-K reagent, Castro's reagent or the like, the condensing agent is preferably employed in an amount from equimolar to about 5 times the molar quantity of the starting material and the reaction is performed in a suitable solvent for example a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetnichloride, letrachloroethane or the like; an ether .1-). such as dioxane, THE, di ethoxyethane or the like, a ketone such as acetone, methyl ethyl ketone or the like; acetonitrile, ethyl acetate, DMF, dimethylacetamide, DMSO or the like. Preferably the condensation is carried out in an anhydrous solvent, and at a reaction temperature in the range of from about - 10°C to 60°C, preferably about 0°C to room temperature. Alternatively, conversion of one compound of formula (I) in which X is O-alkyl into another compound of formula (I) in which X is NR s R t may be effected by treating the said compound of fonnula (I) directly with a compound of fonnula HNR s 'R t ' in the presence of a trialkylaluminium reagent such as trimethylaluminium or triethylaluminium, according to known procedures, such as those disclosed in Tetrahedron Lett., 48, 4171 (1977); and, if necessary, deprotecting or converting the compound of foπnula (I) in which X is NR s 'R t ' into a compound of formula (1) in which X is NR s Rι- The trialkylaluminium reagent is generally employed in the above mentioned reactions in an amount of from equimolar to about 5 times the molar quantity of the starting material, preferably 2-3 times the molar quantity of the starting material and the reaction is performed in a suitable solvent for example a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, tetrachloroethane or the like; an ether such as dioxane, THF, dimethoxyethane or the like. Preferably the condensation is carried out in an anhydrous solvent, and at a reaction temperature of about, generally -20°C to 120°C, preferably about 0°C to the reflux temperature of the solvent. Amines of general fonnula HNR s R j may be prepared using the methods known in the art for the preparation of amines, for example as taught in Houben-Weil, Meihoden der Organischen Chemie, Vol. X I/1 ( 1957 ) and Vol. E 16d/2 ( 1992), Georg Thieme Verlag, Stuttgart. In particular, amines of the general formula HNR s R t wherein one of R s and R t represents hydrogen and the other represents a moiety (a), (b), (c), (d) (e) as defined above or a particular example thereof, are prepared according to the methods summarised in Scheme (V) below: SCHEME (V) H j N O y A L (i) Condense, .^ ^ Reduce > ^V A _ N ; Ru O Rv Rv Ru H-N Rv PO(O e) 2 H N PO(O e) 2 (iv) NC-A-COY . C-A-f-OH HΘOUCe > V_ A _L OH PO(OMe) ? PO(OMe) 2 -CO,R H-N (V) -C0 2 R -C0 2 R Y— A-N -CO j R -A-Y, Azidotnmethylsilane -co ? R Triphenylphosphme -C0 2 R H 2 N- ■ A-N -CO, R -CO,R wherein R an alkyl or aryl group, R u and R v are as defined above, Xi to X are as defined for (H2), A is a bond or an alkyl chain, R J Q is hydrogen (in ii) or halogen (in (iii)) and R\ \ is an alkyl group, R ] 2 ' s 'kyl or aryl, L and L j are leaving groups, for example halogen or mesylate, Y is halogen, Y ] is a leaving group, for example a halogen and and Y] and Y2 are leaving groups such as halogens, for example Y \ is chloride and Y2 is bromine. With regard to Scheme (V): The reduction of the amide function in (i) is suitably carried out using known methods, for example by using mixed hydride reducing agents, such as lithium aluminium hydride and methods described in Org Synth Coll Vol 4 564. The reduction of the nitropyridine in (ii) is suitably carried out using the method described in ./. Org. Chem. 58, 4742 ( 1 93). The alkylation of the hydioxy-nitropyridine in (ii) may be effected by using the method described in . I. Org. Chem 55, 2964 ( 1990). The displacement reaction in (iii) is suitably carried out using the method described in Helvetica Chemica Acta 47 (2), 45 ( 1 64) The reduction of the nitrile in (v) is suitably carried by catalytic hydrogenation over platinium oxide. The reaction of acid halide NC-A-COY to provide the dialkylphosphonate in (iv) is effected by following the procedure described in ./ Org Chem 36, 3843 (1971). The reaction of the azide with triphenylphosphine in (v) is carried out in wet tetrahydrofuran as described in Bull Soc Chim Fr 1985, 81 . The azides in (v) are prepared as shown using azidotrimethylsilane, following the procedure described in Synthesis 1995, 376. The reaction of compound Y 1-A-Y2 and the amine derivative in (v) proceeds under conventional displacement reaction conditions. The reactions in (vi) can be performed using known, conventional methods, as described in J. March, Advanced Organic Chemistry, 3rd Edition, 1985, Wiley Interscience. For example, oxidation can be performed using oxidising agents such as chromic acid (Jones reagent); reductive amination of the ketone in can be performed with benzylamine to give an imine intermediate which is then reduced using known methods and reducing agents such as sodium borohydride or lithium aluminium hydride. Debenzylation can then be peifonned again using conventional methods, for example with hydrogen in the presence of a catalyst such as palladium on charcoal. Protection of ketone as the ethylene ketal can be performed with ethylene glycol under acidic catalysis; acylations or alkylations can be pei fonned by treating the suitable piperidine derivatives with acyl or alkyl halides in the presence of an inorganic or organic base; deprotection of the dioxolane to the ketone can be effected by acidic treatment in aqueous or alcoholic solvents. Protection on the primary amino group in 4 aminopipcridines can entail the use of classical carbamate protecting agents such as t-btitoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc), or of the phthalimido protecting group: the synthesis and the removal of such protective groups is described in, for example, in Protective Groups in Organic Synthesis, T. W Greene Ed., Wiley, New York, 1981. 4-Oxopiperidines can be converted into the corresponding oximes by treatment with hydroxyl- or alkoxyl-amine in a suitable solvent; reduction of the oxime to amine can be performed using conventional reducing agents such as lithium aluminium hydride or sodium cyanoborohydryde. The tailing materials in the above reactions (i), (ii), (iii), (iv), (v) and (vi) are known commercially available compounds. A compound of formula (I) or a solvate thereof may be isolated from the above mentioned processes according to standard chemical procedures. The preparation of salts and/or solvates of the compounds of formula (I) may be peifonned using the appropriate conventional procedure. If required mixtures of isomers of the compounds of the invention may be separated into individual stereoisomers and diastereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent. Suitable optically active acids which may be used as resolving agents are described in "Topics in Stereochemistry" , Vol. 6, Wiley Interscience, 1971 , Allinger, N.L. and Eliel, W.L. Eds. Alternatively, any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials of known configuration. The absolute configuration of compounds may be determined by conventional methods such as X-ray crystallographic techniques. The protection of any reactive group or atom, may be carried out at any appropriate stage in the aforementioned processes. Suitable protecting groups include those used conventionally in the art for the particular group or atom being protected. Protecting groups may be prepared and removed using the appropriate conventional procedure, for example OH groups, including diols, may be protected as the silylated derivatives by treatment with an appropriate silylating agent such as di-tert- butylsilylbis(trifluoromethanesulfonate): the silyl group may then be removed using conventional procedures such as treatment with hydrogen fluoride, preferably in the form of a pyridine complex and optionally in the presence of alumina, or by treatment with acetyl chloride in methanol. Alternatively benzyloxy groups may be used to protect phenolic groups, the benzyloxy group may be removed using catalytic hydrogenolysis using such catalysts as palladium (II) chloride or 10% palladium on carbon. Amino groups may be protected using any conventional protecting group, for example tert-butyl esters of carbamic acid may be fonned by treating the amino group with di-tert-butyldicarbonate, the amino group being regenerated by hydrolysing the ester under acidic conditions, using for example hydrogen chloride in ethyl acetate or trifluoroacetic acid in methylene dichloride. An amino group may be protected as a benzyl derivative, prepared from the appropriate amine and a benzyl halide under basic conditions, the benzyl group being removed by catalytic hydrogenolysis, using for example a palladium on carbon catalyst. Indole NH groups and the like may be protected using any conventional group, for example benzenesulphonyl, methylsulphonyl, tosyl, fonnyl, acetyl (all of them removable by treatment with alkaline reagents), benzyl (removable either with sodium in liquid ammonia or with AICI3 in toluene), ally] (removable by treatment with rhodium (III) chloride under acidic conditions), benzyloxycarbonyl (removable either by catalytic hydrogenation or by alkaline treatment), trifluoroacetyl (removable by either alkaline or acidic treatment), t-butyldimethylsilyl (removable by treatment with tetrabutylammonium fluoride), 2-(trimethylsilyl)ethoxymethyl (SEM) (removable by treatment with tetrabutylammonium fluoride in the presence of ethylendiamine), methoxymethyl (MOM) or methoxyethyl (MEM) groups (removed by mild acidic treatment). Carboxyl groups may be protected as alkyl esters, for example methyl esters, which esters may be prepared and removed using conventional procedures, one convenient method for converting carbomethoxy to carboxyl is to use aqueous lithium hydroxide. A leaving group or atom is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms, mesyloxy, p-nitrobenzensLilphonyloxy and tosyloxy groups. The salts, esters, amides and solvates of the compounds mentioned herein may as required be produced by methods conventional in the an: for example, acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid. Esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid with the appropriate alkanol, generally under acidic conditions. Amides may be prepared using conventional amidation procedures, for example amides of fonnula CONR s R t may be prepared by treating the relevant carboxylic acid with an amine of formula HN R S R, wherein R s and R t are as defined above. Alternatively, a C]_6 alkyl ester such as a methyl ester of the acid may be treated with an amine of the above defined formula HNR s R t to provide the required amide. As mentioned above the com|xnmds of the invention are indicated as having useful therapeutic properties: The present invention therefore provides a method for the treatment and/or prophylaxis of diseases associated with over activity of osteoclasts in mammals which method comprises the administration of an effective non-toxic amount of a selective inhibitor of mammalian osteoclasts. A suitable selective inhibitor of a mammalian osteoclast is a selective inhibitor of the vacuolar ATPase located on the ruffled border of mammalian osteoclasts. One particular selective inhibitor of mammalian vacuolar ATPase is a compound of foπnula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Thus, 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. In a further aspect, the present invention provides an inhibitor of a mammalian osteoclasts, for example a compound of foπnula (I) or a phannaceutically acceptable salt thereof, or a phannaceutically acceptable solvate thereof, for use as an active therapeutic substance. In particular the present invention provides a compound of foπnula (I) or a phannaceutically acceptable salt thereof and/or a phannaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of osteo]X)rosis and related osteopenic diseases. Of particular interest is the osteoporosis associated with the peri and post menopausal conditions. Also encompassed are the treatment and prophylaxis of Paget's disease, hypercalcemia associated with bone neoplasms and all the types of osteoporotic diseases as classified below according to their etiology: Primary osteoporosis Involutional Type I or post enopausal Type II or senile Juvenile Idiopathic in young adults Secondary osteoporosis Endocrine abnormality Hyperthyroidis Hypogonadism Ovarian agenesis or Turner's syndrome Hyperadrenocorticism or Cushing's syndrome Hyperparathyroidism Bone marrow abnoπnahties Multiple myeloma and related disorders Systemic mastocytosis Disseminated carcinoma Gaucher's disease Connective tissue abnormalities Osteogenesis lmperfecta Homocystinuπa Ehlers-Danlos syndrome Marfan's syndrome Menke's syndrome Miscellaneous causes Immobilisation oi weightlessness Sudeck's atiophy Chronic obstructive pulmonary disease Chronic alcoholism Chronic heparin administration Chronic ingestion of anticonvulsant drugs In addition the invention encompasses the treatment of tumouis, especially those related to renal cancel , melanoma, colon cancer, lung cancer and leukemia, viral conditions (for example those involving Sein ki Forest virus, \ ' esιcular Stomatitis virus, Newcastle Disease virus. Influenza A and B viruses, HIV virus), ulcers (for example chronic gastritis and peptic ulcei induced by Helu obacter pylori), for use as immunosupressant agents in autoimmune diseases and transplantation, antilipidemic agents for the treatment and/or prevention of hypeicholesteiolemic and athero.sclerotic 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 tumouis A compound of formula ( I), oi a phannaceutically acceptable salt thereof and/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 piovides a pharmaceutical composition comprising a selective inhibitor ot the pharmacological activity of human osteoclast cells, in particular the bone resorption activity oi human osteoclast cells associated with abnormal loss of bone mass, and a pharmaceutically acceptable carrier thereof. A particular inhibitor of human osteoclast cells is a selective inhibitor of human osteoclast vacuolar ATPase such as a compound of formula (I ), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier thereof. Active compounds or a pharmaceutically acceptable salt thereof and/or a phannaceutically acceptable solvate thereof is normally administered in unit dosage form. An amount effective to treat the disorders 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 nonnally 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 1 , 2, 3, 4, 5 or 6 times a day, more usually I to 3 or 2 to 4 times a day such that the total daily dose is nonnally 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 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 Helicohacter pylori), autoimmune diseases and transplantation, for the treatment and/or prevention of hypercholesterolemic and atherosclerotic diseases, AI DS 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 fonnula (I) or a phannaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof. In such treatments 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 nonnally 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 dejoend 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, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdennal 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 arc 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 convent ional flavouring or colouring agents. For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invent ion and a sterile vehicle. The compound, depending on the vehicle and the concentration, can lie either suspended or dissolved. Parenteral solutions are nonnally 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 unifoπn 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) The present invention also provides the use of a selective inhibitor of the biological activity of human osteoclast cells, in paiticulai the bone resorption activity of human osteoclast cells associated with abnormal loss of bone mass, compound of foπnula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament lor the treatment and/or piophylaxis of diseases associated with over activity of osteoclasts in mammals, such as the tieatment and/or prophylaxis ot osteoporosis and related osteopenic diseases The present invention also pi ovides the use of a selective inhibitor of the biological activity of human osteoclast cells, in pai ticulai the bone resoi tion activity of human osteoclast cells associated with abnonnal loss of bone mass, f oi the manuf actuie of a medicament for the treatment of tumoui s, esjiecially those related to lenal cancer, melanoma, colon cancel , lung cancer and leukemia., vual conditions (for example those involving S mliki Forest, Ves ular Sloinatili s. Newcastle Disease, Influenza A and B, HIV viruses), ulcers (lor example chronic gastritis and peptic ulcer induced by Hel obacier pylori), autoimmune diseases and transplantation, tor the treatment and/or prevention of hypeicholesterolemic and atheioscleiotic diseases, AIDS and Alzheimer's disease, angiogenic diseases, such as rheumatoid arthritis, diabetic retmopathy, psoriasis and solid tumoui s. No unacceptable toxicological ef fects are expected with compounds of the invention when administeied in accordance with the invention. As is common practice, the compositions will usually be accompanied by written 01 printed directions foi use in the medical treatment concerned The following, descriptions, examples and phaπnacological methods illustrate the invention but do not limit it in any way. Preparation I 5-Chloro-l H-in(lole-2-carl)oxal(lehyde. Ethyl 5-chloro- l H-indole-2-carboxylate (9 g, 40.2 mmol) (Heterocycles, 1984, 22, 121 1 ) dissolved in dry THF (70 ml) was added dropwise to an ice cold solution of LJAIH4 (2.56 g, 67.5 mmol) in anhydrous THF ( 150 ml) under nitrogen. The mixture was stirred for 45 min at 0°C and then quenched by the sequential addition of water (2.5 ml), 15% aqueous NaOH (2.5 ml) and water (7.5 ml). The mixture was filtered through a Celite pad and then washed with THF (2 x 75 ml). The filtrate dried over Na2S04 and evaporated at reduced pressure yielded 8.12 g of an orange powder (m.p.= l 14- 1 1 5°C). This was dissolved in CH 2 C1 2 (200 ml) and activated Mn0 2 (20 g, 0.23 mol) was added. The mixture was stirred at RT for 12 hours and then filtered through a Celite pad which was washed with waπn acetone (4 x 100 ml), and the combined filtrates were evaporated to dryness, yielding pure title compound (6 g, 33.4 mmol, yield 83.1 %), m.p.= 208-209°C. Preparation 2 (E)-[3-(5-ChIoro-l H-indol-2-yl)]-2-propenaldehyde. 5-Chloro- l H-indole 2- carboxaldehyde (2.5 g, 1 .92 mmol) was dissolved in dry toluene (70 ml) and treated with (foπnylmethylene)triphenylphosphorane (5 g, 16.43 mmol). The reaction mixture was heated at reflux for 5 hours, cooled to RT, concentrated at reduced pressure and chromatographed over silicagel using toluene (2 x 300 ml) and then n-hexane/EtOAc 3/1 (2 x 300 ml) as eluent mixture. Evaporation of the solvent and recrystallization of the residue from isopropyl ether yielded pure title compound ( 1 g, 4.85 mmol, yield 34.8%), m.p.= 206-209°C. Preparation 3 Ethyl tt-oxo-3-(2-ni(ro-4,5-dichlυrophenyl)propanυate. To a suspension of potassium (24.5 g, 0.626 g.a.) in anhydrous Et 2 0 (245 ml), a solution of absolute EtOH ( 158 ml) and anhydrous Et 2 0 ( 126 ml) was added dropwise under nitrogen during four hours. The resulting solution was diluted with Et ? 0 (600 ml) and then diethyl oxalate (85.5 ml, 630 mmol) was added dropwise in about 30 min. To the resulting yellow mixture, a solution of 3-nitro-4,5-dichIorotoltιene ( 1 30 g, 630 mmol) in anhydrous Et 2 0 (225 ml) was added dropwise in l h at RT. Stirring was continued for additional three hours and the dark- brown mixture was settled at RT for two clays. The potassium salt was collected by filtration, washed with anhydrous Et?0 (200 ml) and dried to give 210 g of a dark-brown powder. The solid was suspended in a mixture of water (200 ml) and AcOEt (400 ml) and then acidified with 10% HCl. The organic layer was washed with brine, dried over Na 2 SO, and evaporated under vacuum to obtain pure title compound ( 1 15.1 g, 375.8 mmol, yield 59.7%) as a light brown solid, m.p.= 92-94°C. Preparation 4 Ethyl 5,6-dichloro-l H-indole-2-carbυxylak' A mixture of ethyl α-oxo-3-(2-nitro-4,5-dichlorophenyljpropanoate ( 100 g, 327 mmol) and iron powder ( 160 g) in EtOH (625 ml) and acetic acid (625 ml) was refluxed for two hours. After cooling, the resulting mixture was evaporated under vacuum and the solid residue was dissolved in THF ( 1000 ml) and chromatographed on Florisil (500 g) eluting with THF (5000 ml). Evaporation of the collected fractions gave pure title compound (77.5 g, 301 mmol, yield 92.0%) as a light brown powder, m.p. 215°-218°C. Preparation 5 5,6-Dichloro- l H-indυle-2-carl)oxaldchyde was obtained from ethyl 5,6-dichloro-lH- indole-2-carboxylate (77.5 g, 301 mmol) according to the method of preparation I . Pure title comjxnind was obtained (42. 1 g, 197 mmol, yield 65.4 %), mp= 207-208°C. Preparation 6 Ethyl (E)-3-(5,6-diehloι-o- I H-indol-2-yl)-2-propeiH)ate. 5,6-Dichloro- 1 H-indole-2- earboxaldehyde (35 g, 164 mmol) and (cthoxycarbonyimethylene) triphenylphosphorane (60 g, 176 mmol) were dissolved in toluene and refluxed for three hours. The solvent was evaporated under reduced pressure and the reaction mixture was purified by chromatography on silicagel (n-hexanc/AcOEt 8/2) obtaining pure title compound (28 g, 98.5 mmol, yield 60.1 %). Preparation 7 (E) 3-(5,6-Diehloro- l I I-2-indoI-2-yl )-2-propen- l -ol. Ethyl (E)-3-(5,6-dichloro-2- indolyl)-2-propenoate ( 16.23 g, 57.1 mmol) was dissolved under nitrogen in dry THF (300 ml) cooled at -20° and I M DIBAL in hexanes ( 1 15 ml, 1 15 mmol) was added dropwise at -20°C. The reaction mixture was maintained at this teιu]i>erauιre for 1 hour and then quenched with H 2 0. The mixture was wanned to RT, diluted with Et 2 0 (200 ml) and filtered on a Celite pad, washing with 300 ml of Et 2 0. The dark-red solution was dried over MgS0 and evaporated under vacuum to give pure title compound (13.8 g, 57.0 mmol, yield 99.8%). Preparation (E)-3-(5,6-Dichloro- l H-indoI-2-yl)-2-pι openaklehyde. To a solution of (E) 3-(5,6- dichloro-2-indolyl)-2-propen- l -ol ( 1 .8 g, 57.0 mmol) in Et 2 0 (450 ml), activated Mn0 2 (35 g) and NaCl (35 g) were added. The reaction mixture was stirred for two days at RT, filtered on a Celite pad, washed with Eι 7 0 and dried over MgSO, to afford pure title compound ( 1 1.5 g, 47.9 mmol, yield 84.1 % ). Example I Ethyl (2E,4E)-5-(5,6-Dic loro-l I l-in(lol-2-vI)-2-methyl-2,4-pentadienoate. To a mixture of (E) 3-(5,6-dichloro-2-indoly!)-2-propenaldehyde (900 mg, 3.75 mmol) in THF (20 ml), ethyl 2-methyl-2-(triphenylphosphonitιm)acetate bromide (2.6 g, 5.86 mmol) and DBU (.873 ml, 5.86 mmol) were added sequentially. The reaction was heated at 60°C for two days. The solvent was removed under reduced pressure and the crude compound was purified by chromatography on silicagel (n-hexane/EtOAc 8/2). After trituration with isopropyl ether pure title compound was obtained (270 mg, , .833 mmol, yield 22.2%), m.p.=203-2 () 4°C. Η-NMR(acetone-d 6 ): 10.88 (bs, IH); 7.73 (s, IH); 7.53 (s, IH); 7.35 (dd, IH); 7.27 (dd, IH); 7.02 (d, IH); 6.71 (s, IH); 4.19 (q, 2H); 2.02 (d, 3H); 1.30 (t, 311). MS (El; 70 eV; 200 A): 323 (JVT); 250; 215. Example 2 (2E,4E)-5-(5,6-Dichloιo-lH-indol-2-yl)-2-methyl-2,4-pentadienoic acid. To a solution of KOH (40 mg, 0.956 mmol) in water (3 ml), ethyl (2Z,4E)-5-(5,6-dichloro-lH-indol-2- yl)-2-methyl-2,4-pentadienoate (155 mg, 0.478 mmol) dissolved in CILOH HF 1/1 (5 ml) was added. The reaction mixture was heated at 7()°C for 1 hour. The solvent was then removed at reduced pressure and, after acidification with I HCl, the mixture was extracted with EtOAc (2x15 ml), dried over Na 2 SOj and evaporated under vacuum to afford pure title compound (140 mg, .473 mmol, yield 98.9%) as a yellow powder, m.p.=249-250°C Η-NMR (DMSO-d h ): 11.72 (s, III); 7.70 (s, 1H);7.54 (s, 1H);7.22 (dd, IH); 6.95 (d, IH); 6.81 (d, IH); 6.62 (s, IH); 2.05 (s, 3H) Example 3 (2E,4E)-5-(5,6-Diclιloro-lII-indol-2-yl)-N-[3-(diethylamino)piOpyl]-2-methyl-2,4- pcntadienamide. To a mixture ot (2E.4E)-5-(5,6-dichloro- 1 H-ιndol-2-yl)-2-methyl-2,4- pentadienoic acid (0.14 g, .473 mmol) in CH.CN/THF 1/1 (4 ml), DCC (0.1 lg, 55.5 mmol), HOBT (75 mg, 55.5 mmol) and 3-dιethylaιuino- 1-propylamine (0.083 ml, 53 mmol) were added under nitrogen. The reaction mixture was refluxed for 1.5 hours. After filtration the solvent was removed under reduced pressure and the crude compound was purified by chromatography on silicagel (CH 2 Cl 2 /CH,OH/NH_OH 75/15/1) affording, after trituration with pentane, pure title compound (70 mg, .171 mmol, yield 36.4%) as a yellow powder, m.p.= 160-162°C. Η-NMR(DMSO-d Λ ): 11.70(s, lH);7.99(t, lH);7.75(s, lH);7.54(s, lH);7.24(dd, IH); 6.96 (d, IH); 6.81 (d, IH); 6.62 (s, IH); 3.19 (dt, 2H); 2.55 ( , 6H): 2.01 (s, 3H); 1.50 (m,2H); 1.00 (t,6H) MS (El; 70 eV; 200 mA): 407 (M 4 ); 86 Example 4 Ethyl (2Z,4E)-5-[2-(5-chloro-lH-indol-2-yl)]-2,4-pentadienoatean(l Ethyl (2E,4E)-5- [2-(5-chloro-lH-indol-2-y!)l-2,4-pentadienoate. A solution of (E)-[3-(5-chloro-lH- indol-2-yl)l-2-propenaldehyde (0.2 g, 0.97 mmol) in anhydrous THF (10 ml) under nitrogen was treated with (ethoxycarbonylmethyl) triphenylphosphonium bromide (0.42 g, 0.97 mmol) and DBU (0.145 ml, 0.97 mmol). The reaction mixture was stirred at 50°C for 5 hours, then at RT for 12 hours, diluted with Et 2 0 (10 ml) and filtered. The filtrate was washed with 10% aqueous HCl (5 ml), saturated aqueous solution of NaHCO-, (5 ml) and brine (5 ml), dried over Na 2 SO,ι and evaporated under vacuum. The residue was purified by chromatography on silicagel (n-hexane/EtOAc 7/3) to afford, after trituration with isopropyl ether, ethyl (2Z,4E)-5-|2-(5-chloroindolyl)|-2,4-|3entadienoate (30 mg, .109 mmol, yield 11.2%), m.p.= 80- 1°C, and ethyl (2E,4E)-5-[2-(5-chloroindolyl)|-2,4- pentadienoate (100 mg, .363 mmol, yield 37.4% , ), m.p.= 178-180°C. EthyK2Z,4E)-5-l2-(5-chloro-lH-indol-2-yl)j-2,4-pentadienoate: Η-NMRtøcetone-dr,): ll.()0 (bs, 111): 8.03 (dd, 1H);7.57 (d, lH);7.40(d, IH); 7.13 (dd, IH); 7.01 (d, IH); 6.86 (dd, lH);6.70(s, IH); 5.72 (d, lH):4.20(q, IH); 1.30 (t.3H). MS(EI;70eV;200 Λ): 275 (M'); 202: 167 Ethyl(2E.4E)-5-l2-(5-chloro-IH-ιιulol-2-yl)l-2,4-penιadienoaιe: Η-NMR(acetone-d 6 ): 10.70 (bs, lH);7.56(d, lH);7.45(dd, lH);7.37(d, IH); 7.12 (dd. IH); 7.11 (d, IH); 7.02 (dd, IH); 6.71 (s ,111); 5.99 (d, 1 H); 4.20 (q, 2H); 1.25 (t, 3H). MS (EI;70eV; 200 mA): 275 (M'); 230: 202: 167 Example. Ethyl (2Z,4E)-5-[2-(5-chloro-UI-in(lol-2-yl)]-2-chloiO-2,4-penta(lienoate nd Ethyl (2E,4E)-5-[2-(5-chloro-l H-indoI-2-yl)]-2-chloro-2,4-pentadicnoatt\ An oil dispersion of 60% NaH (0.058g, 1.45 mmol) was washed with pentane (2x1 ml) and then suspended in anhydrous THF (5 ml) under nitrogen. TriethyI-2-chloro-2-phosphonoacetate (0.310 ml, 1.45 mmol) was added dropwise and the reaction was stirred at RT for 30 min. A solution of (E)f3-(5-chloro-lH-indol-2-yl)|-2-propenaldehyde (0.2 g, 0.97 mmol) in anhydrous THF (5 ml) was added dropwise and the reaction mixture was stiired at RT for 12 hours. The reaction was quenched with water and extracted with EtOAc (3x7 ml). The organic layers were washed with 10% aqueous HCl (5 ml), saturated aqueous solution of NaHC0 3 (5 ml) and brine (5 ml), dried over Na 2 S0 4 and evaporated in vacuum. The residue was purified by chromatography on silicagel (n-hexane/EtOAc 8/2) and triturated with isopropyl ether to afford ethyl (2Z,4E)-5-|2-(5-chIoro-lH-indoI-2-yl)|-2-chloro-2,4- pentadienoate (30 mg, .097 mmol, yield 9.97%) as a yellow oil and (2E,4E)-5-|2-(5- chloro-lH-indol-2-yl)|-2-chloro-2,4-pentadienoate (60 mg, 194 mmol, yield 19.9%), m.p.= 210-211°C. Ethyl (2Z,4E)-5-f2-( -chloro-IH-indol-2-yl)l-2-chloro-2.4-pentadιenoate: Η-NMR (C Λ D Λ ): 7.60 (d,lH): 7.47 (d, IH); 7.15 (dd. III); 6.85 (bs, lH):6.67(dd, lH);6.64(d, IH); 6.20 (d, lH);6.14(bs, IH): 4.05 (q.2H): 1.00 it, 3H). MS (El; 70 eV; 200 mA): 309 (M * ); 273: 245; 228: 201 Eth\l(2E.4E)-?-l2-(5-chloro-]H-ιndol-2-vl)l-2-chl<>r<>-2.4-pentadιenoate. Η-NMR (G,D 6 ): 7.75 (dd, IH); 7.4 (d, IH); 7.29 (bs, IH); 7.11 (dd, IH): 6.74 (d, III); 6.55 (d, IH); 6.19 (s, IH); 6.10 (d, IH).3.99 (q, 111): 0.96 (t, 3H). MS (El; 70 eV; 200 A): 309 (M 1 .); 273; 228; 201 Example 6 Ethyl (2Z,4E)-5-[2-(5-chlorϋ-lII-indol-2-yl)]-2-πιιoιυ-2,4-pentadienoateand Ethyl (2E,4E)-5-[2-(5-chk)ro-lII-in(l()l-2-yl)]-2-πιιoro-2,4-penladienυate. An oil dispersion of 60% NaH (0.058 g, 1.46 mmol) was washed with pentane (2x1 ml) and then suspended in anhydrous THF (5 ml) under nitrogen. Trιethyl-2-flιιoro-2-phosphonoacetate (0.296 ml, 1.46 mmol) was added dropwise and the reaction was stirred at RT for 30 min. A solution of (E)[3-(5-chloro-lH-indol-2-yI)|-2-pro|3enaldehyde (0.2 g, 0.97 mmol) in anhydrous THF (5 ml) was added dropwise and the reaction mixture was stirred at RT for 12 hours. The reaction was quenched with water and extracted with EtOAc (3x7 ml). The organic layers were washed with 10% aqueous HCl (5 ml), saturated aqueous solution of NaHCθ 3 (5 ml) and brine (5 ml), dried over Na 2 S0 4 and evaporated in vacuum. The residue was purified by chromatography on silicagel (n-hexane/EtOAc 8/2) and triturated with isopropyl ether to afford ethyl (2Z,4E)-5-|2-(5-chloro-lH-indol-2-yl)|-2-fluoro-2,4- pentadienoate (15 mg, .051 mmol, yield 5.3%), m.p.= 187-188°C and (2E,4E)-5-|2-(5- chloro-lH-indol-2-yl)]-2-flιιoro-2,4-pentadienoate (43 mg, .146 mmol, yield 15.1%), m.p.= 116-118°C. Ethyl (2Z,4E)-5-l2-(5 -chloro- 1 H-indol-2-yl)j-2-fluoro-2,4-peniadιenoate: Η-NMR (CD f) ): 7.49 (d, IH); 7.16 (dd; IH); 6.79 (bs, IH); 6.71 (dd, IH); 6.71 (d, IH); 6.46 (dd, IH); 6.10 (s, IH); 6.08 (d, IH); 4.05 (q, 2H): 0.96 (t, 3H). MS (El; 70 eV; 200 A): 293 (M + ); 245; 220; 185 Ethyl (2E,4E)-5-f2-(5-chloro-!H-indol-2-yl)l-2-flιιoro-2,4-pentadienoatc: Η-NMR (C ή D 6 ): 7.61 (dd, IH); 7.48 (d, IH); 7.14 (bs, IH); 7.11 (dd, IH); 6.52 (d, IH); 6.25 (dd, IH); 6.18 (s, IH): 6.12 (d, IH): 3.99 (q.2H); 0.95 (t, 3H). MS (El; 70 eV; 200 mA): 293 (M + ): 245: 220: 185 Example 7 Ethyl (2Z,4E)-2-a/Jdo-5-f2-(5-chloro-lII-iικlol-2-yl)]-2,4-pentadienυate. Sodium metal (368 mg, 1 mmol) was added to absolute EtOH (15 ml) and stirring continued until complete dissolution. The solution was cooled to 0" with an ice bath and (E)|3-(5-chloro- lH-indol-2-yl)|-2-pro|3enaldehyde (820 mg, 4 mmol) and azidoacetate (2.06 g, 16 mmoles) were added in one jiortion. The solution was warmed to RT and stirred for additional 4 hours. Et 2 0 (50 ml) was added and the organic phase was washed with aqueous saturated NH 4 C1, dried (MgS0 4 ) and concentrated to give a solid residue. This was chromatographed on silicagel (n-hepiane/ethyl acetate 1/1 ), producing the pure title compound ( 100 mg, .317 mmol, yield 7.91 %) as orange crystals, m.p.=160°dec. Η-NMR (DMSO-d ( ,): 1 1 .76 (bs, I H); 7.57 (d, I H); 7.35 (d, I H); 7.02-7.22 (m, 2H); 7.10 (s, I H); 6.83 (d, I H); 6.64 (s, I H); 4.29 (q, 2H); 1.31 (t, 3H). Example 8 Phenylmethyl (2Z,4E)-t4-(5,6-diehloro-lH-indol-2-yl)-l-methoxycarbonyl-buta-l,3- dienyl] carbamate. A solution of N-(benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester ( 1.52 g, 4.4 mmol) and DBU (0.66 ml, 4.4 mmol) in CH 2 C1 2 (10 ml) was stirred at RT for 10 minutes. (E) 3-(5,6-dichloro- l H-indol-2-yl)-2-propenaldehyde (1.0 g, 4.1 mmol) was then added and stirring at RT continued overnight. The solution was diluted with EtOAc (80 ml), washed with 1 N HCl (20 ml) and brine (2x20 ml). After drying (MgS0 4 ) and concentration of the organic phase the residue was chromatographed on silicagel (n-heptane/EtOAc 1/1 ). The collected fractions were pooled and concentrated to give pure title conηxumd ( 1.73 g, 3.89 mmol, yield 93.4%) as white crystals. Η-NMR (DMSO-d ): 1 1.84 (s. l H); 9. 10 (s, l H); 7.79 (s, ! H); 7.53 (s, l H); 7.34 (bs, 5H); 7.08 (s, 3H): 6.65 (s, I H): 5.1 1 (s, 2H); 3.69 (s, 311). Example 9 (2Z,4E)-4-(5,6-Diclιloi -l H-inclol-2-yI)- l-((phenylmethoxycarbonvl)aminυ)-2,4- penfadieπoic acid. A solution of phenylmethyl (2Z,4E)-|4-(5,6-dichloro- l H-indol-2-yl)- l-methoxycarbonyl-bιιta- l ,3-dienyl | carbamate ( 1.70 g, 3.82 mmol) and KOH (430 mg, 7.64 mmol) in EtOH/water 3/1 (30 ml) was stirred at RT overnight. The solvent was concentrated and the residue repeatedly washed with diisopropyl ether. The solid was dissolved in water (20 ml) and the pH adjusted to 2 with 1 N HCl. The resulting solid was filtered, washed repeatedly with water and dried to give pure title compound (1.35 g, 3.13 mmol, yield 1.9%) as light brown crystals. Η-NMR (DMS -d„): 11.80 (s, IH); 8.75 (s, lH);7.76(s, 1H);7.52 (s, HI); 7.39 (bs, 5H); 6.86-7.13 (m, 3H); 6.58 (s, IH); 5.10(s, 2H). Example 10 Phenylmethyl (2Z,4E)-[4-(5,6-dichioro-lH-indol-2-yl)-l-[(2,2,6,6-tetramethyl piperidin-2yl)aminocarbonyl]bula-l,3-dienyl] carbamate. A solution of (2Z,4E)-4- (5,6-dichloro-lH-indol-2-yl)-l-|(phenylmethoxycarbonyl)amino|2,4-pentadienoic acid (925 mg, 2.11 mmol), 4-amino-2,2,6,6-tetramethylpiperidine (0.42 mL, 2.40 mmol), 1- hydroxy-7-azabenzotriazole hydrate (324 mg, 2.40 mmol) and l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (456 mg, 2.40 mmol) in DMF (10 ml) was stirred at RT overnight. The solution was poured into brine (20 ml) and repeatedly extracted with EtOAc. The organic phase was washed with 5% aq. CaCO,, dried (MgS0 4 ) and concentrated. The residue was chromatographed on silicagel (EtOAc/MeOH/aq.NH^ 90/10/2). The collected fractions were pooled and concentrated and the residue was recrystallized twice from acetonitrile to produce pure title compound (160 mg, 0.28 mmol, yield 13.3%) as bright yellow crystals, m.p.=250dec. Η-NMR (DMSO-d„): 11.77 (s, I H); 9.25 (bs. Ill): 8.21 (d, IH); 8.18 (bs, 1H);7.77 (s, lH);7.53(s. IH); 7.38 (bs, 5H): 7.07 (dd. Ill): 6.84 (d.1H):6.63 (d, IH); 6.60 (s, IH); 5.09 (s, 2H): 4.13 ( , IH): 1.76 (Iκl, 2H); 1.59(bt.2H); 1.42 (s, 12H). Preparation 9 N-acetyl-alpha-phosphoiio lycine trimethyl ester. A suspension of N-(benzyloxy carbonyl)-alpha-phosphonoglycine trimethyl ester (1.33 g, 4.0 mmol), acetic anhydride (1 ml, 10.6 mmol) and 5% Pd/C (100 mg) in MeOH (15 ml) was hydrogenatcd at 3 atm and RT for 6 hours. The catalyst was filtered off and the solution concentrated to give an oil. This was crystallized from penianc:EtOAc 10 give after drying pure title compound (560 mg, 2.34 mmol, yield 58.5%) as white needles. Example 11 Methyl (2Z,4E) 2-acetylamino-5-(5,6-dichloro-lH-indoI-2-yl)-2,4-pentadienoate. A solution of N-acetyl-alpha-phosphonoglycine tiunethyl ester (540 mg, 225 mmol) and DBU (033 mL, 22 mmol) in CI I 2 C1 2 (5 ml) was stirred at RT for 10 min (E) 3-(5,6- dιchloro-lH-ιndol-2-yl)-2-propenaldehyde (504 mg, 210 mmol) was then added and stirring at RT continued overnight A yellow precipitate was filtered and repeatedly washed with CHC1 2 Aftei diymg it tesulted to be pine title compound (310 mg, 0878 mmol, yield 418%) as yellow ciystals, p =285 dec Η-NMR (DMSO d ft ) 1179 (bs, IH).959 (bs.111) 779 (s, IH), 7 < 5 (s, IH), 703 (s, 3H), 668 (s, IH), 370 (s, 311), 204 (s, 3H) Example 12 (2Z,4E)-2-Acetylamino-5-(5,6-dichloro-lIl-ind<)l-2-^l)-2,4-penta(lienoie acid. A solution of methyl (2Z,4E)-2-acetylamιno-5-(5,6-dιchloιo-lH ιndol-2-yl)-2,4- pentadienoate (270 mg, 0765 mmol) and KOH (86 mg, 153 mmol) in EtOH/water 3/1 (10 ml) was stnied at RT overnight After the same woi up seen foi example 9 pure title compound was isolated (190 mg, 0560 mmol, yield 732%) as oiange crystals Η-NMR (DMSO-d,,) 1176 (s, III).941 (s, III), 779 (s, IH), 704 (s, IH), 703 (d, IH), 699(s, 2H), 666 (s. Ill) 203 is, 3H) Preparation 10 l,2,2,6,6-Penlamcthyl-4-pipcri(lone hydroiodide. A solution of 2,2,6,6 tetiamethyl 4 pipendone monohydiate (10 g, 23 I mmol) άnά methyl iodide (9831 g, 693 mmol) in isopropyl alcohol (25 mL) was stiπed at RT foi 48 houis The lesulting suspension was filteied, the solid lesidue wasdned and leciystallized fiom MeOH Aftei filtiation and lepeated washings with MeOI I the solid was dried giving pure title compound (316 g, 106 mmol, yield 46 (Y/< ) as pale biown ciystals Preparation 1 1 l ,2,2,6,6-pentamel h\ l-4-piperidont' oxime. A suspension of l ,2,2,6,6-pentamethyl-4- pipeπdone hydioiodide (3 g, 10 1 mmol) and hydroxylamine hy ochloπde (980 mg, 14 mmol) in water (6 ml) was stiπed at RT foi 15 minutes Solid NaOH was added until basic pH and thickening of the suspension Water (3 ml) was added and stirring at RT was continued overnight The suspension was filteied and the solid washed with water (few ml) and dried The solid was then dissolved in Et 2 0, the solution was dned (MgS0 4 ) and concentrated to give aftei drying pure title compound ( 1.55 g, 8.41 mmol, yield 83 3%) as white ci ystals Preparation 12 4-Amino- l,2,2,6,6-pentamethyl-4-pipc idine. LiAlH-, (925 mg, 24 4 mmol) was added under stirring at (Y undei Ai to anhydi ous THF ( 100 ml), followed by 1 ,2,2,6,6- pentamethyl-4-ριpeudone oxime ( 1 50 g, 8 14 mmol) The suspension was lefluxed for 2 hours, then cooled to RI and stmed overnight Aftei cooling to 0° water (0 9 ml), 15% aq NaOH (0 9 ml) and watei (2 8 ml) wei e caiefully added diopwise The suspension was stirred tor 15 mm at RT, then MgS0 was added and stirring continued for 30 minutes After filtration, the liquid was oncenti ated and the oily lesidue chtomatogi aphed on silicagel (CI I 2 Cl 2 /MeOH/aq NI ~ 95/5/1 ) The collected fractions weie pooled and concentrated to give pin e title compound (750 mg, 4 40 mmol, yield 54 1 %) as a yellow Example 1 (2Z,4E)-2-Acefylamino-5-(5,6-dichloro- m-indol-2-vl)-N-[(l,2,2,6,6-pentamethyl)- piperidin-4-yl]-2,4-penladienamide. A solution of (2Z,4E)-2-acetylamιno-5-(5,6- dιchloιo- l H-ιndol-2-yl) 2,4-pentadιenoιc acid ( 185 mg, 0 546 mmol), 4-amιno 1 ,2,2,6,6- pcntamethylpipei idine ( 170 mg, 1 0 mmol), l -hydιoxy-7-azabenzotπazole hydrate (136 mg, 1 0 mmol) and l -(3-dιmethylamιnopιopyl)-3-ethylcarbodnmιde hydrochloride (191 mg, 1.0 mmol) in DMF (5 ml) was stm ed at RT overnight After the same work up as seen in example 10, three recrystallizations from acetonitrile and a final one from EtOAc produced pure title compound (35 mg, .07 1 micromol, yield 1 .0%) as yellow crystals, m.p.=258-60°. Η-NMR (DMSO-dr,): 1 1 .70 (bs, I H); 9.34 (bs, I H); 7.77 (s, I H); 7.69 (bd, I H); 7.54 (s, IH); 6.87 (d, IH); 6.83 (s, I H); 6.75 (m, I H); 6.62 (s, I H); 4.03 (m, I H); 2.17 (s, 3H); 2.05 (s, 3H); 2.10 (bd, 2H); 1 .38 (bt, 2H); 1.04 (d, 12H). Preparation 1 2-Naphthalenesulfonyl a ide. A solution of sodium azide (3. 1 g, 44 mmol) in water (10 ml) was added dropwise at RT to a stirred solution of 2-naphthalenesulfonyl chloride (10 g, 44 mmol) in acetone (60 ml) and stirring was continued for 2 hours. Water (50 ml) was added and the resulting mixture was decanted. The surnatant was discarded, while the brown oily residue was recrystallized from light petroleum producing after drying pure title compound (7.67 g, 32.9 mmol, yield 74.7%) as white needles, m.p.=45°. Preparation 14 Ethyl dia/o(dicthoxypho.sphoryl).ιcctnle. A suspension of potassium t-butoxide (4.42 g, 39.4 mmol) in toluene (200 ml) was stirred at 0° under Ar for 1 minutes. A solution of ethyl diethoxyphosphoryl acetate (6.53 ml, 32.9 mmol ) in toluene (20 ml) was added in 20 minutes keeping the temperature below 5°. A solution of 2-naphthalenesulfonyl azide (7.67 g, 32.9 mmol) in toluene (20 ml ) was added dropwise below 5°, and the reaction mixture was wanned to RT and stirred overnight. The resulting suspension was filtered and the filtrate washed with toluene. The pooled organic phase was concentrated and the brown oily residue distilled producing pure title compound (6.12 g, 24.5 mmol, yield 74.37 ) as a ycllo* oil. b.p.=70-73 0.02mmHg. Preparation IS N-(l,l-Dimetlιyleth()xyearb(Hiyl)-alpha-phosphonoglyeine triethylester. A suspension of ethyl diazo(diethoxyphosphoryl)acetate (2.02 g, 8.0 mmol), p-toluenesulfonic acid monohydrate (2.60 g, 8.0 mmol) and 10% Pd/C (1 g) in MeOH (40 ml) was hydrogenated at 5 atm and RT for 3 h. The catalyst was filtered off and the solution concentrated to give an oil. This was immediately dissolved into IN HCl (60 ml), washed with EtOAc and treated with solid NaHCOi until neutralization. The aqueous suspension was extracted with CHCU, the organic phase was dried (MgS0) and concentrated to give the unstable free amino compound as an oily residue (1.04 g, theorically 4.22 mmol). This was immediately dissolved in CH 2 C1 (4 ml) and treated with t-butylpyrocarbonate (1.0 g, 4.6 mmol). The solution was stirred at RT overnight, then it was diluted with CHC1 2 to 40 ml and washed with IN K.HSO4 and saturated aq. NaHCO-,. The organic phase, after drying and concentration, produced a residue that was recrystallyzed from pentane/Et 2 0 to give pure title compound (820 mg, 2.42 mmol, yield 30.2%) as white needles. Example 14 1,1-Dimethylethyl (2Z,4E)-(4-(5,6-dichloro-lH-indol-2-yl)-l-ethoxycaιbonyl-buta- 1,3-dienyl] carbamate. A solution of N-(l,l-dimethylethoxycarbonyl)-alpha- phosphonoglycine triethyl ester (410 mg, 1.21 mmol) and DBU (0.182 ml, 1.21 mmol) in CH 2 Ct 2 (3 ml) was stirred at RT for 10 min. (E) 3-(5,6-Dichloro-lH-indol-2-yl)-2- propenaldehyde (288 mg, 1.20 mmol) was then added and stirring at RT continued overnight. After a work up as seen for example X the solid residue was chromatographed on silicagel (n-heptane/EtOAc 4/1 ). The collected fractions were pooled and concentrated to give pure title compound (230 mg, 0.541 mmol, yield 44.7%) as yellow crystals. Η-NMR(DMSO-d ( ,): 11.80 (bs, II I): 8.69 (bs, IH); 7.79 (s, IH); 7.54 (s, IH); 6.85-7.08 (m, 2H);7.03(s, lH);6.64(s, 111); 4.17 (q,2H); 1.42 (s,9H); 1.25 (t, 3H). Example 15 (2Z,4E)-4-(5,6-Dichl()ro-iπ-ind<)l-2-yl)-l-[(l,l-dimethylethoxycarbonyl)amino]-2,4- pcntadienoic acid. A solution of 1,1-dimethylethyl (2Z,4E)-|4-(5,6-dichloro-lH-indol-2- yl)-l-ethoxycaι onyl-buta-L3-dιenyl| carbamate (230 mg, 0.541 mmol) and KOH (61 mg, 1.08 mmol) in EtOH/watei 3/1 (10 ml) was stiπed at RT overnight The work up seen for example 9 produced pure title con xnind (170 g, 0.433 mmol, yield 800%) as brown crystals. 'H-NMR (DMSO-d„): 11.74 (bs. III); 7.75 (bs, IH); 7.51 ( , 211); 7.37 (s, IH); 7.05 (dd, 1 H); 6.49-6.63 (m, 211); 6.34 (s; 1 H); 1.44 (s, 9H). Example 1 1,1-Dimethylethyi (2Z,4E)-[4-(5,6-dichloro-lH-indol-2-yl)-l-((l,2,2,6,6-penta methvlpiperidin-2yl)aminocarbonyl)buta-l,3-dienyl] carbamate. A solution of (2Z,4E)-4-(5,6-dιchloro- 1 H-mdol-2-yl)- 1 -[ ( 1 , 1 -dimethylethoxycarbonyl )amιnol2,4- pentadienoic acid (165 mg, 0.415 mmol), 4-amιno-l,2,2,6,6-pentamethylpιpeπdιne (010 mL, 0426 mmol), l-hydιoxy-7-azabenzotπazole hydrate (65 mg, 050 mmol) and l-(3- dιmethylammopιopy!)-3-ethylcarbodmπιde hydrochloride (95 mg.050 mmol) in DMF (2 ml) was stirred at RT overnight The solution was ponied into brine (20 mL) and repeatedly extracted with EtOAc. The organic phase was washed with 5% aq CaCOj, dried (MgS0 4 ), concentrated and the residue was chromatographed on silicagel (EtOAc/MeOH/aq NH-, 90/10/2) The collected fractions produced pine title compound (35 mg, 064 mmol, yield 153%) as yellow crystals, m p = 196°deι ' H-NMR (DMSO-d„) 11.68 (s. Ill), 8.54 (bs.111).7.76 (bs, 2H).753 (s. IH).704 (dd, lH);679(d, III), 659 (s, IH).647 (d.111), 405 (m, IH), 224 (bs, 3H), 165 (bs, 2H); 1.42 (bs, 1 IH), 109 (bd, 12H) Preparation 1 Ethyl (2-metlioxyetho\y)dietho\yphosphorvi acetate. A solution of ethyl dιazo(dιethoxyphosphoryl)acetate ( 1.01 g, 40 mmol), 2-methoxyethanol (14 ml, 17.6 mmol) and rhodium (II) acetate dimei (34 mg, SO miciomol) in toluene (20 ml) was refluxed for 3 hom s. Aftei cooling to RT and filtering the mixture through a celite pad, the solvent was concentrated and the residue was pure title compound (1.1 g, 3.86 mmoles, yield 96.4%) as a green oil. Η-NMR (CDC1,): 4.49 (d, IH); 4.15-4.34 (m, 6H); 3.72-3.85 (m, 2H); 3.59 (t, 2H); 3.35 (s, 3H); 1.28-1.38 (m,9H). Example 17 Ethyl (2Z,4E)-5-(5,6-dichloro-lH-indol-2-yl)-2-(2-methoxyethoxy)-2,4-penta dienoate. A solution of ethyl (2-methoxyethoxy) diethoxyphosphoryl acetate (1.15 g, 3.86 mmol) and DBU (0.580 mL, 4.0 mmol) in THF (20 ml) was stirred for 10 minutes at RT. Then (E) 3-(5,6-dichloro-2-indolyl)-2-propenaldehyde (840 mg, 3.5 mmoles) was added and the mixture was refluxed overnight. After cooling at RT the solvent was concentrated and the residue dissolved in EtOAc, washed with IN HCl and brine, then dried (MgS0 4 ) and concentrated to give an oily residue. This was chromatographed on silicagel (n- heptane/EtOAc 3/1) producing pure title compound (290 mg, 0.755 mmol, yield 21.6%) as yellow crystals. Η-NMR (DMSO-d„): 11.77 (bs, IH): 7.78 (s, IH): 7.55 (s, lH);7.24(dd, IH); 7.03 (s, IH); 6.89 (d, IH): 6.13 (s.111): 4.21 (q, 2H); 4.06 (t, 2H); 3.61 (t, 211): 3.28 (s, 3H); 1.28 (t, 3H). Example I (2Z,4E)-5-(5,6-Dichloro- 1 H-in(l<>l-2-yl)-2-(2-mcthυxyethoxy)-2,4-pentadienoic acid. A solution of ethyl (2Z,4E)-5-(5,6-dichloro- 1 H-indol-2-yl)-2-(2-methoxyethoxy)-2,4- pentadienoate (290 mg, 0.755 mmol) and KOH (85 mg, 1.51 mmol) in EtOH/water 3/1 (10 ml) was stirred at RT overnight. The work up seen for example 9 produced pure title compound (235 g, 0.660 mmol, yield 87.4%) as brown crystals. Η-NMR (DMSO-d„): 11.73 (bs, !H):7.68(s, IH);7.58(bs, 1 H); 7.50 (s, IH); 7.16 (dd, IH); 6.50 (d, IH); 6.42 (s, 111); 6.29 (d. II I); 4.16 (t, 2H); 3.54 (t, 2H): 3.28 (s, 3H). Example 19 (2Z,4E)-5-(5,6-Dichloro-lH-indol-2-yl)-2-(2-melhoxyelhoxy)-N-(l,2,2,6,6- pentamethylpiperidin-2-yl)-2,4-pentadienamide. A solution of (2Z,4E)-5-(5,6- dichloro-lH-indoI-2-y])-2-(2-methoxyethoxy)-2,4-pentadienoic acid (115 mg, 0.323 mmol), 4-amino-l ,2,2,6,6-pentamethylpiperidine (85 mg, 0.50 mmol), l-hydroxy-7- azabenzotriazole hydrate (65 mg, 0.50 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (95 mg, 0.50 mmol) in DMF (2 ml) was stirred at RT overnight. The solution was poured into brine (20 ml), repeatedly extracted with 5% aq. CaCO , dried (MgS0 ), concentrated and the residue was chromatographed on silicagel (EtOΛc/MeOH/aq.NH-> 90/10/2). The collected fractions produced pure title compound (15 mg, .029 mmol, yield 9.[%.) as yellow crystals, m.p.=208-210°dec. 'H-NMR (DMSO-d 6 ): 11.75 (s.111); 7.77 (s.111); 7.72 (d, lH);7.54(s, lH);7.17(dd, IH); 6.89 (d, IH); 6.72 (d, IH); 6.61 (s, IH); 4.04 (m, 3H); 3.67 (m, 2H); 3.37 (s, 3H); 2.20 (s,3H); 1.71 (bd, 2H); 1.31 (bt, 2H); 1.08 (bd, 12H). Preparation 17 Ethyl (phenyloxy)diethoxyphosρhoryl acetate. A solution of ethyl diazo(diethoxyphosphoryl)acetate (1.01 g, 4.0 mmol), phenol (380 mg, 4.0 mmol) and rhodium (11) acetate dimer (34 mg, .080 mmol) in toluene (20 ml) was refluxed for 4 hours. After the work up seen in preparation 13 pure title compound was obtained (450 mg, 1.42 mmol, yield 35.6%) as a yellow oil. Example 20 Ethyl (2Z, 4E)-5-(5,6-dichloro-lH-iιιdol-2-yl)-2-phenoxy-2,4-pentadienoate. A solution of ethyl (phenyloxy) diethoxyphosphoryl acetate (440 mg, 1.39 mmol) and DBU (0.205 ml, 1.40 mmol) in THF (15 ml) was stirred for 10 minutes at RT. Then (E) 3-(5,6- dichloro-2-indolyl)-2-propenaldehyde (335 mg, 1.40 mmol) was added and the mixture was refluxed overnight. After cooling to RT the solvent was concentrated and the residue dissolved in EtOAc, washed with IN MCI and brine, then dried (MgSO 4 ) and concentrated to give an oily residue. This was chromatographed on silicagel (n-heptane/EtOAc 4/1) producing a brown solid that was recrystallized from AcOEt/n-heptane to give pure title compound (70 mg, 0.174 mmol, yield 12.5%) as yellow needles, m.p.=179-180°. 'H-NMR (DMSO-d ): 11.82 (bs, IH); 7.78 (s, IH); 7.48 (s, IH); 7.31-7.40 (m, 3H); 7.18 (dd, lH);7.10(d, 1H);7.03 (d, IH); 6.97 (d, 2H); 6.66 (s, lH);4.14(q, 2H); 1.14 (t, 3H). Preparation 18 Ethyl (phenylthio)diethoxypho.sphυιyl acetate. A solution of ethyl diazo (diethoxyphosphoryl)acetate (1.01 g, 4.0 mmol), thiophenol (0.410 ml, 4.0 mmol) and rhodium (II) acetate dimer (34 mg, 80 micromol) in toluene (20 ml) was refluxed for 4 hours. After the work up seen in preparation 13 pure title compound was obtained (1.26 g, 3.79 mmol, yield 94.8%) as a green oil. Example 21 Ethyl (2Z,4E)-5-(5,6-dichlϋro-IH-indol-2-yl)-2-phenylthio-2,4-pentadienoate. A solution of ethyl (phenγlthio)diethoxyphosphoryl acetate (1.25 g.3.77 mmol) and DBU (0.580 ml, 4.0 mmol) in THF (20 ml) was stirred for 10 min at RT. (E) 3-(5,6-dichloro-2- indolyl)-2-propenaldehyde (840 mg, 3.5 mmol) was added and the mixture was refluxed overnight. After the work up seen in example / 7 chromatography on silicagel (n- heptane/EtOAc 4/1) produced a brown residue that was recrystallized from AcOEt/n- heptane to give pure title compound ( 1 0 mg 0.382 mmol, yield 10.1%) as orange needles, m.p.= 194-1 5°. Η-NMR (DMSO-df,): 11.96 (bs, lH);7.99(d, lH);7.82(s, IH); 7.19-7.59 (m, 8H); 6.76 (s, lH);4.09(q,2H): 1.06 (t, 311). Preparation 19 Ethyl (phcnylamino)die(hoxyphosphoryl acetate. A solution ot ethyl dιazo(dιethoxy phosphoιyl)acetate (101 g, 40 mmol), aniline (0370 ml, 40 mmol) and rhodium (II) acetate dimei (34 mg, 80 miciomol) in toluene (20 ml) was refluxed foi 3 hours After the work up seen in preparation 13 pure title compound was obtained (122 g, 387 mmol, yield 967%) as a light gieen oil Example 22 Ethyl (2Z, 4E)-5-(5,6-diehloιo-lH-indol-2-yl)-2-phenylamino-2,4-pentadienoate. A solution of ethyl (phenylamιno)dιethoxyphosphoryl acetate (120 g, 380 mmol) and DBU (0580 ml, 40 mmol) in Tl If (20 ml) was stmed foi 10 mm at RT Then (E) 3-(5,6 dιchloro-2-ιndolyl)-2 piopenaldehyde (840 mg, 35 mmol) was added and the mixture was refluxed overnight Aftei the oik up seen in ewmple /7chιomatography on silicagel (n- hcptane/EtOAc 3/1) produced a fiaction of 630 mg ot slightly impure title compound that was recrystallyzed from AcOEt/n-heptane to give pine title compound (100 mg, 0249 mmol, yield 6567r) as yellow ciystals, m p =210-21 l υ Η-NMR (DMSO d,,) 1166 (bs. III).794 (bs, IH) 775 (s, IH), 747 (s, IH), 6.88-719 (m,5H), 658-676(m, 411) 41S(q, 211), 1 16 (t, 3H) LIST OE AIIRKF.VIA ' I IONS USED IN THE ABOVE PREPARATIONS AND EXAMPLES Celite Registeied tiade m.uk foi dicalite DMF Dimethyl l nnamide El Election Impact AcOEt Ethyl acetate FAB POS Fast Atom Bombaidment / Positive ions detection MS Mass Speed um THF Tetiahydioluian TSP Theimo piay 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 piotons into the resorption miciOenvironment 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)1 and than confirmed by Bekker [P.J. Bekkei et al , ./ Bone Mm Res 5, 569 ( 1990) | and Vaananen | K.K Vaananen et al., ./ Cell Biol . I I I , 1 05 ( 1990)|. Evidence was based upon preparations of ruffled membi ane fragments l iom 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 acπdine 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 pioton transport was inhibited by N-ethylmaleimide (NEM), a sulphydryl reagent, and by baiilomycin A j , a selective inhibitor of vacuolar H + -ATPases [J.E Bowman et a'., Proc Natl Ac ad Sci USA . 85, 7972 ( 1988)), whilst it was not inhibited by ouabain, an mhibitoi of Na + /K + -ΛTP,ιses; sodium orthovanadate, an inhibitor of p- ATPases, or by omepi azoic oi SCH 28080, both ot which are inhibitors of gastric H+/K+-ATPase 1.1 P Mattson et ,ιl , At ta Phvsiol St and , 146, 253 ( 1992)) It is known that specific mhibitoi s of vacuolar ATPases, such as bafilomycin A] , are able to inhibit bone resoi ption in osteoclast cultui es I K Sundquist et al., Biochem Biophv.s Res Commun 16S, 309- 31 3 1 1990) 1 INHIBITION OF PROTON TRANSPORT AND v-ATPase ACTIVITY IN MEM BRANE VESICLES Preparation of crude bone microsomes I rom ealcium-slarved egg-laying hens. Vesicles were prepaied from medullai bone obtained from tibiae and femurs of egg-laying hens which weie calcium-stai ved foi at least 15 days. Brief ly, 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 He|ies, 1 mM EGTA, 2 mM dithiotheitrol, pH 7.4) and filtered through a 100 urn pore size nylon mesh The whole procedure was peifonned at 4°C. After homogenisation in a pottet (20 sri okes) in 40 ml of isolation medium an initial centrifugation (6,500 x g m;ιx x 20 min ) was peifonned to remove mitochondria and lysosomes. The supernatant was centrifuged at 100,000 x g max 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 ul 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 g ax for 2 hours (S W 41 Ti rotor). After centrifugation the 30-45% sucrose interfaces were collected, diluted approx. 20-fold in isolation medium and pelletted at 100,000 g max for 1 hour (SW 28 rotor). The. pellet was then resuspended in 1 ml of isolation medium, aliquoted and frozen in liquid NT and stored at -80°C until used. Human kidney membranes were obtained from the cortex of a human kidney, frozen immediately after surgery, according to the method reported in the literature for bovine kidney (S. Gluck, ./. Biol. Chem., 265, 2 1 957 ( 1990)). 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 ul of membrane vesicles in 1 ml of buffer containing 0.2 M sucrose, 50 mM KC1, 10 mM He|ies pH 7.4, 1 mM ATP.Na2, 1 mM CDTA, 5 uM valinomycin and 4 μM acridine orange. The reaction was started by addition of 5 M MgSO Results were expressed as the percent of the mean of two controls. Inhibition of bafilomycin-scπsitive 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 I lEPLS-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 MgS0 4 (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)1. Absorbance at 650 nm was measured after 2 min using a microplate reader. Results are expressed as μmol (Pi) x mg protein 'xhour ' and, for each experiment, represent the mean±sem of triplicates. PHARMACOLOGICAL DATA: INHIBITION OF BAFILOMYCIN-SENSITIVE ATPASE IN CHICKEN OSTEOCLASTS INHIBITION OF BONE RESORPTION In Vitro assays 1 ) Bone resorption by disaggregated rat osteoclasts can be assessed as described previously in the literature |T. .1. 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 settle for 30 sec. The cells were then added to two wells of a niultiwell dish containing bone slices (each measuring 12 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 Ins in a total volume of 2 ml of culture medium, consisting of 107 foetal calf serum in Hanks-buffered MEM, in the presence or absence of drug. The number of osteoclasts and bone resorption were quantified by con focal 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, multiniicleated, red-stained cells, the bone slices were immersed in 10% sodium hypochlorite for 5 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 bone slice, mean pit number per osteoclast, mean area per osteoclast or mean volume per osteoclast. 2) Bone resorption by human osteoclasts can be assessed using a modification of the method above. Briefly, human osteoclasts are purified from human giant cell tumours by negative selection using Pan Human HLA II antibodies in conjunction with Dynal magnetic beads. Osteoclasts are seeded onto bovine bone slices in Hepes-buffered medium 199 (Flow, UK). After 30 minutes, the bone slices are transferred into a 24-well multi- plate (4 slices per well) containing 2 ml/well of medium, consisting of 10% foetal calf serum in D-MEM. One hour later, vehicle (DMSO) or test compounds at different concentrations in DMSO were added and incubation was continued for 47 hours. Bone slices were then treated and analysed as described above for the rat osteoclast assay. 3) Inhibition of PTH-stimulated " ^C 2* release from pre-labelled foetal rat long bone. The assay is based on that described by Raisz (./. Clin. Invest. 44: 103- 1 16, 1965). Time-mated Sprague-Dawley rats were injected subcutaneously with 200 mCi of 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 rciinoid-indiiced by erealcaemia. The method used was that described by Trechsel et al., (./. Clin. Invest. 80: 1679- 1686, 1987). Briefly, male Sprague-Dawley rats weighing 1 0-200 g ( 10 per group) were thyroparathyroidectomised and were treated subcutaneously with the retinoid Ro 1 3-6298 (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 - 1 0 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% foπnic 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 7 ) and the number of trabeculae (according to Parfitt et al.. ./. Bone Min. Re . 2: 595, ( 1987)) were deteπnined 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 foπnula CI = CA/TA. Prevention of bone loss in υvariectomised 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, occiiring 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 yridinolinc ( 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 detenninations before and 2, 4, 8, 1 1 , 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 of bone loss versus vehicle treated animals, using the following equation, where BMD indicates the bone mineral density at the end of the experimental period and is expressed as the percent of pre-ovariectomy baseline: BM D(treatment) - BMD(vehicle) Percent prevention = x 100 BMD(sham) - BMD(vehicle) 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 deteπnined according to the methods disclosed in published International Application, Publication number 93/1 652: in particular the screen employed, experimental details and bibliography of M.R. Boyd et al., Status of the NCI prec inical 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, 16 1 - 1 49 ( 1 95) 3. Antiulcer activity may be assessed // vivo using the methods reported in the literature, for example, as described by C.J. Pfeiffer, Peptic Ulcer , C.J. Pfeiffer Ed., Munksgaard Publ., Copenaghen, 1971 . //; vitro assays for inhibition of vacuolization induced by Helicohacier pylori are described, for example, by E. Papini et al., FEMS Microbiol. Lett., 1 13, 155- 160 ( 1993) 4. Usefulness in treating Alzheimer's disease may be deteimined using models in vitro such as inhibition of amiloyd-fi production as descrided in the literature by J. Knops et al., ./. Biol. Chem., 270, 241 -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. Immunosiφpressant activity can be as.sessed as reported in the literature, for example by M.-K. Hu et al.. ./. Med. Chem. , 38, 4164-4170 (1995) 6. Antilipidemic activity can be assessed as reported in the literature, for example by E.A.L. Biessen et al., ./. 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., ./. Pharm. Exp. Ther., 1S4, 105- 1 12 ( 1973). 7. Angiostatic activity may be as.sessed using the methods reported in the literature, for example as described by T. Ishii et al., ./. Antihiot.. 48, 12 ( 1995).

Claims: Claims: A compound of formula (I): or a salt thereof, or a solvate thereof, wherein: R j represents hydrogen, C | -0 alkyl, halo, azido, C\ _(, alkythio, phenylthio, benzylthio, alkoxyalkyloxy or a group NHR^ wherein R# represents -CO-R9 or -(CH2) n Ri ] , or RI represents a group -NR J2R 13 wherein R j and R 1 each independently represent hydrogen, alkyl or aryl; R2, R3 and R4 each independently represent hydrogen, alkyl, aryl or substituted aryl; R5 and R6 each independently represents hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R5 and R 0 together represent methylenedioxy, carbonyldioxy or carbonyldiamino; X represents a hydroxy or an alkoxy group wherein the alkyl group may be substituted or unsubstituted or X represents a group NR s R t wherein R s and R t each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group, or R s and R t together with the nitrogen to which they are attached form a heterocyclic group; R7 represents hydrogen, hydroxy, alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl or aminosulphonyl; R9 represents R j () or OR J Q wherein and R ] () is Cι _ alkyl, phenyl or benzyl; and R] j represents NR 12^1 ' wherein R j2 and R 1 are as defined above, or R ] j is hydroxy or C ] _, alkoxy: and n represents an integer 1 , 2 or 3. 2. A compound according to claim 1 , wherein R j represents methyl, -0(CH2)2°CH3 or -NHCOOwrrBu 3. A compound according to claim 1 or claim 2, wherein R^, K3, R4 and R7 each independently represent hydrogen. 4. A compound according to any one of claims 1 to 3, wherein R5 is 5-chloro and R is 6-chloro. 5. A compound according to any one of claims 1 to 4, wherein X represents N R s R t . wherein R t is hydrogen and R s is selected for the list consisting of: 1 , 2, 2, 6, 6- pentamethyl-4-piperidinyl, 1 ,2,6-trimethyl-4-piperidinyl orl ,2,2,6- tetramethyl-4-piperidinyl groups. 6. A compound according to any one of claims 1 to 4, wherein X represents NR s R t . wherein NR,R, is a group of formula (H 1 ): wherein X ] , X2, X3, X4, X5, X( v X7 and X s are each independently selected from hydrogen, hydroxy, (C|-C < ,), alky! cycloalkyl, mono or poly hydroxyalkyl, alkoxyalkyl, hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl; or one of X4 with X D and X2 with X represents a C2-4 alkylene chain and the remaining variables X \ , X3, X7 and X7 each independently represent hydrogen, hydroxy, lower alkyl (Ci-C f i), cycloalkyl, mono or poly hydroxyalkyl, alkoxyalkyl, hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl; and X5 represents hydrogen or lower alkyl, mono or polyhydroxyalkyl, mono or diaminoalkyl, aminocarbonyl, alkyl, carboxyalkyl, carbalkoxyalkyl, aryl, heterocyclyl, acyl, carbamoyl, alkylamino(cyanimidoyl), aminoalkanoyl or hydroxyalkanoyl. 7. A process for preparing a compound of formula (I) or a salt thereof or a solvate thereof, which process comprises, reacting a compound of fonnula (11): wherein R-y, R3, R4, R5, R and R7 are as defined in relation to fonnula (I), with a reagent capable of converting a moiety of fonnula into a moiety of fonnula (a): wherein R ] , R . R3, R4 and X are as defined in relation to foπnula (I); and thereafter, as necessary, carrying out one or more of the following reactions: (i) converting one compound of formula (I) into another compound of fonnula (I); (ii) removing any protecting group; (iii) preparing a salt or a solvate of the compound so foπned. 8. A pharmaceutical composition comprising a compound of formula (1) as defined in claim 1, or a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier therefor. 9. A compound of formula (1) according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance. 10. A method for the treatment and/or prophylaxis of diseases associated with over activity of osteoclasts in mammals which method comprises the administration of an effective non-toxic amount of a compound of formula (I ) according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

Inventors: CONSOLANDI EMANUELA, FARINA CARLO, GAGLIARDI STEFANIA, NADLER GUY MARGUERITE MARIE GE, SENECI PIERFAUSTO, CONSOLANDI, EMANUELA, FARINA, CARLO, GAGLIARDI, STEFANIA, NADLER, GUY, MARGUERITE, MARIE, GERARD, SENECI, PIERFAUSTO
Applicants: CONSOLANDI EMANUELA, FARINA CARLO, GAGLIARDI STEFANIA, NADLER GUY MARGUERITE MARIE GE, SENECI PIERFAUSTO, SMITHKLINE BEECHAM LAB, SMITHKLINE BEECHAM SPA, CONSOLANDI, EMANUELA, FARINA, CARLO, GAGLIARDI, STEFANIA, NADLER, GUY, MARGUERITE, MARIE, GERARD, SENECI, PIERFAUSTO, SMITHKLINE BEECHAM LABORATOIRES PHARMACEUTIQUES, SMITHKLINE BEECHAM S.P.A.
Application year: 1997
Main classification: C07D209
IPC codes: A61K31, A61P19, C07D209, C07D401