WO1998001423A1 - Derives d'acide 5-indolyle-2,4-pentadienoique pouvant etre utilises comme inhibiteurs de la resorption osseuse - Google Patents

Derives d'acide 5-indolyle-2,4-pentadienoique pouvant etre utilises comme inhibiteurs de la resorption osseuse Download PDF

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WO1998001423A1
WO1998001423A1 PCT/EP1997/003710 EP9703710W WO9801423A1 WO 1998001423 A1 WO1998001423 A1 WO 1998001423A1 EP 9703710 W EP9703710 W EP 9703710W WO 9801423 A1 WO9801423 A1 WO 9801423A1
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alkyl
compound
group
mmol
optionally substituted
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PCT/EP1997/003710
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English (en)
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Carlo Farina
Stefania Gagliardi
Emanuela Consolandi
Guy Marguerite Marie Gérard NADLER
Pierfausto Seneci
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Smithkline Beecham S.P.A.
Smithkline Beecham Laboratoires Pharmaceutiques
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Priority to EP97937473A priority Critical patent/EP0912511A1/fr
Priority to JP10504813A priority patent/JP2000514079A/ja
Publication of WO1998001423A1 publication Critical patent/WO1998001423A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • Rj represents hydrogen, Ci . ⁇ 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 R ⁇ 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 ] ⁇ 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
  • R is halo
  • an example is chloro or fluoro.
  • R I is alkoxyalkyloxy
  • an example is -0(CH2)2OCH3.
  • R ⁇ is -NI IR ⁇ wherein R is CO.R and R9 is R] ⁇
  • an example is NHCOCH3.
  • R ] is -NI IR ⁇ wherein R ⁇ is CO.R9 and R9 is OR J Q, examples include
  • R represents methyl, -0(CH2)2 ⁇ CH3, -NHCOOr Bu
  • R2 examples include hydrogen and methyl.
  • Ri represents hydrogen
  • R3 examples include hydrogen and ethyl.
  • R3 represents hydrogen
  • R4 examples include hydrogen, propyl and phenyl.
  • R4 represents hydrogen
  • R5 and (* each independently represents alkoxy, halo, trifluoromethyl, ni ro, and alkyl.
  • said alkoxy group is suitably a C ⁇ .fr alkoxy for example methoxy.
  • said halo group is suitably a fluoro or chloro group.
  • 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.
  • R5 and R ( ) are hydrogen, halo, trifluoromethyl and alkoxy.
  • R5 is halo, especially 5-halo
  • R is halo, especially 6- hiilo.
  • Examples ol R7 include hydrogen, methyl and t-butoxycarbonylmethyl
  • the alkyl group thereof is preferably an unsubsliluied alkyl group.
  • X represents the above defined group N R s R t
  • 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.
  • R s and R t together represent a heterocyclic group.
  • suitable alkyl groups are C ⁇ . alkyl groups, for example C j . C2. C3, C4 and C5 alkyl groups, favourably ethyl, propyl or butyl.
  • favoured groups are 2- (dialkylamino)ethyl or 3-(dialkylam ⁇ no)propyl or 4-(d ⁇ alkylam ⁇ no)butyl or heterocyclylmethyl or heterocyclylethyl or heterocyclylpropyl groups
  • R s or R t represent cycloalkyl or substituted cycloalkyl
  • suitable cycloalkyl groups are ⁇ .
  • cycloalkyl gioups foi example a cyclopentyl or cyclohexyl group
  • suitable alkenyl groups are C2-6 alkenyl groups, for example a C5 alkenyl group
  • R s 01 R x represent aryl 01 substituted aryl
  • suitable aryl groups are phenyl groups
  • Suitable values foi R s include hydiogen, C] _5 alkyl, mono- di- and t ⁇ - hydroxyalkyl, alkoxyalkyl, carboxyalkyl, carbalkoxyalkyl, bisphosphonylalkyl, (subst ⁇ tuied)am ⁇ io-carboxyalkyl, hiscarbethoxy-hydioxyalkenyl, dialkylamtnoalkylpy ⁇ dyl, mono- di- and i ⁇ -alkoxypy ⁇ dyl, clialkylaminoalkoxypy ⁇ dyl, aryloxypyndyl, aminopy ⁇ dyl, substituted pipcia/inyL quiiiuclulyl, saiin ated heleiocyclylalkyl, substituted piperidinyl, (d ⁇ )a/ab ⁇ cycloalkyl, subslituied phenyl, substituted benzyl, substituted
  • Suitable valuse for Rs include , (4-substituted)piperazinoalkyl and aminopyrimidiniyi.
  • R s include diethylaminopropyl, 3-amino-3-carboxypropyl, 4- amino-4-carboxybutyI, 3-pyridyl, diethylaminoethyl, 3-quinuclidyl (or 1 - azabicyclo
  • 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.
  • 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.
  • 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 ):
  • X j , X2, X3, X4, X5, X 0 , X7 and X x are each independently selected from hydrogen, hydroxy, (C
  • X] , X2, X ⁇ and X9 each represent hydrogen.
  • X3, and X4 each independently represent hydrogen or alkyl, especially alkyl .
  • X ⁇ and X7 each independently represent hydrogen or alkyl.
  • X5 represents alkyl
  • X3, X4, X- ⁇ and X7 each independently represent alkyl, especially methyl and X I , X2. and X9 each represent hydrogen.
  • 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 fo ⁇ nula 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.
  • 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):
  • A represents alkyl, suitably C ] .3 alkyl
  • a ] is alkyl, suitably C] _4 alkyl
  • 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.
  • 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.
  • 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.
  • substituted aralkyl groups are substituted in the aryl moiety.
  • 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
  • a further suitable group comprising fused saturated ring is a nonyl 1- azabicyclo] 3.3.1
  • Suitable groups having fused unsaturated rings are pyrazo
  • 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
  • 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.
  • 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.
  • heterocyclylic includes a reference to “heterocyclyl”.
  • 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 fo ⁇ ns 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.
  • 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.
  • inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid
  • 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 acetyls
  • 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- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietyla ⁇ nine, 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.
  • 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 fo ⁇ nula (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):
  • R2, R3, R4, R5, R ⁇ and R7 are as defined in relation to fonnula (1), with a
  • R j , R2, R3, R4 and X are as defined in relation to fo ⁇ nula (1); and thereafter, as necessary, carrying out one or more of the following reactions:
  • 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 ⁇ 4 ⁇ )2P(0)- wherein R 14 is C
  • X ⁇ ] represents a moiety (R j 4 ⁇ )2P(0)-.
  • converting the group of formula into the moiety of fonnula (a) may be carried out under the appiop ⁇ ate conventional conditions, depending upon the particular reagent chosen, toi example.
  • 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-d ⁇ sopropylethylam ⁇ ne, 1 ,5- d ⁇ azab ⁇ cyclo
  • 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 t ⁇ ethylamine, t ⁇ methylamine, N,N-dnsopropylethylam ⁇ ne (DIPEA), pyridine, N,N-d ⁇ melhylan ⁇ l ⁇ ne, N-methylmorpholine, l ,5-d ⁇ azab ⁇ cyclo
  • DIPEA N,N-dnsopropylethylam ⁇ ne
  • DIPEA N,N-d ⁇ melhylan ⁇ l ⁇ ne
  • N-methylmorpholine N,N-d ⁇ azab ⁇ cyclo
  • 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, acetonit ⁇ le, 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
  • 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
  • a suitable reagent is a compound of formula (IV)
  • reaction between the compounds of fo ⁇ nulae (II) and (IV) is conveniently carried out in an alkanolic solvent, such as ethanol, in thearrance of a base such as sodium ethoxide, usually at a low to ambient tempeiatuie, for example at 0°C
  • a compound of fo ⁇ nula (II) may be piepaied accoiding to the leaction sequences shown in Schemes (Ia-c) 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. En ⁇ l.. 4, 645 ( 1965).
  • 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).
  • Suitable bases include organic bases, such as triethylamine, trimethylamine, N,N- diisopropylethylamine (DIPEA), pyridine, N,N-dimethylaniline, N-methylmorpholine, 1 ,5- diazabicyclo
  • 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.
  • 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.
  • 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.
  • aprotic solvent for example an aromatic hydrocarbon such as benzene, toluene or xylene, DMF, DMSO, chloroform, dioxane, dichloromethane, preferably.
  • 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
  • organic bases such as butyl lithium, lithium diisopropylainide (LDA), N,N-diisopropylethylamine, 1 ,5- diazabicycIo
  • 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
  • a compound of fo ⁇ nula (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 borohyd ⁇ de (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 tempei
  • R and R ] 4 are as defined in relation to fonnula (I) and X ⁇ is as defined in telation to fonnula (III)
  • the starting mate ⁇ al is an ⁇ -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 theernence of a l successionl pioducing agent such as azobisisobutyi ronit ⁇ le 01 benzoyl pei oxide in a suitable solvent such as carbon teti achlo ⁇ de, benzene, toi example cai bon teti chloi ide and at a reaction tempei ature in the range of hom
  • reaction is perfo ⁇ ned 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).
  • a compound of fo ⁇ nula (III) in which R2 is (R i4 ⁇ )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 fo ⁇ nula (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):
  • 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 fo ⁇ nula (VI) or a group which can be converted into R4.
  • reaction between the compounds of fo ⁇ nula (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.
  • 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):
  • R5 wherein, subject to any qualification mentioned below, R5, R ⁇ and R are as defined in relation to fo ⁇ nula (I) and X ⁇ ⁇ is as defind in reation to fonnula (XII).
  • 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 (LiAlH
  • 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.
  • 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 fo ⁇ nula (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 fo ⁇ nula (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)
  • R ⁇ , R2, R3, R4, R5, R 0 , R7 and X are as defined in relation to the compounds of fo ⁇ nula (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:
  • reaction with the compounds of fo ⁇ nula 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-
  • 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
  • organic bases such as triethylamine, trimethylamine, N,N- diisopropylethylamine (DIPEA), pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine (DMAP), N-methylmorpholine, l ,5-diazabicyclo
  • 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.
  • 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
  • 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.
  • 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 fo ⁇ nula (I) in which X is NR s 'R t ' into a compound of formula (1) in which X is NR s R ⁇ -
  • 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.
  • 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.
  • 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
  • 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.
  • 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:
  • 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.
  • 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 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.
  • azides in (v) are prepared as shown using azidotrimethylsilane, following the procedure described in Synthesis 1995, 376.
  • the reactions in (vi) can be performed using known, conventional methods, as described in J. March, Advanced Organic Chemistry, 3rd Edition, 1985, Wiley Interscience.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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 are halogen atoms, mesyloxy, p-nitrobenzensLilphonyloxy and tosyloxy groups.
  • 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.
  • 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.
  • 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 fo ⁇ nula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
  • the present invention further provides a method for the treatment of osteoporosis and related osteopenic diseases in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I) or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
  • the present invention provides an inhibitor of a mammalian osteoclasts, for example a compound of fo ⁇ nula (I) or a phannaceutically acceptable salt thereof, or a phannaceutically acceptable solvate thereof, for use as an active therapeutic substance.
  • a mammalian osteoclasts for example a compound of fo ⁇ nula (I) or a phannaceutically acceptable salt thereof, or a phannaceutically acceptable solvate thereof, for use as an active therapeutic substance.
  • the present invention provides a compound of fo ⁇ nula (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.
  • 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:
  • 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, ⁇ ' es ⁇ cular Stomatitis virus, Newcastle Disease virus.
  • 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.
  • the present invention also piovides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • a compound of fonnula (I) or a phannaceutically acceptable solvate thereof for the treatment and/or prevention of hypercholesterolemic and atherosclerotic diseases
  • AI DS and Alzheimer's disease
  • angiogenic diseases such as rheuma
  • the active compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes.
  • 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.
  • 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.
  • 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 mono
  • 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.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • 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.
  • a surfactant or wetting agent is included in the composition to facilitate unifo ⁇ n distribution of the active compound.
  • 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 fo ⁇ nula (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.
  • angiogenic diseases such as rheumatoid arthritis, diabetic retmopathy, psoriasis and solid tumoui s.
  • compositions will usually be accompanied by written 01 printed directions foi use in the medical treatment concerned
  • pha ⁇ nacological methods illustrate the invention but do not limit it in any way.
  • E Ethyl (E)-3-(5,6-diehlo ⁇ -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 %).
  • (2E,4E)-5-(5,6-Dichlo ⁇ o-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.
  • TriethyI-2-chloro-2-phosphonoacetate (0.310 ml, 1.45 mmol) was added dropwise and the reaction was stirred at RT for 30 min.
  • -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).
  • Tr ⁇ ethyl-2-fl ⁇ oro-2-phosphonoacetate (0.296 ml, 1.46 mmol) was added dropwise and the reaction was stirred at RT for 30 min.
  • 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).
  • 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.
  • (2Z,4E)-4-(5,6-Dicl ⁇ loi -l H-inclol-2-yI)- l-((phenylmethoxycarbonvl)amin ⁇ )-2,4- penfadie ⁇ oic acid A solution of phenylmethyl (2Z,4E)-
  • 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.
  • (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-acetylam ⁇ no-5-(5,6-d ⁇ chlo ⁇ o-lH ⁇ ndol-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
  • Ethyl (2-metlioxyetho ⁇ y)dietho ⁇ yphosphorvi acetate A solution of ethyl d ⁇ azo(d ⁇ ethoxyphosphoryl)acetate ( 1.01 g, 40 mmol), 2-methoxyethanol (14 ml, 17.6 mmol) and rhodium (II) acetate dimei (34 mg, SO macomol) 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.
  • 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.
  • Ethyl (2Z, 4E)-5-(5,6-dichloro-lH-i ⁇ dol-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.
  • Ethyl (phenylthio)diethoxypho.sph ⁇ yl 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.
  • NEM N-ethylmaleimide
  • baiilomycin A j a selective inhibitor of vacuolar H + -ATPases
  • 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
  • isolation medium 0. 2 M sucrose, 50 mM KC1, 10 mM He
  • 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
  • bafilomycin-sc ⁇ sitive 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 ⁇ mol (Pi) x mg protein 'xhour ' and, for each experiment, represent the mean ⁇ sem of triplicates.
  • Bone resorption by disaggregated rat osteoclasts can be assessed as described previously in the literature
  • 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.
  • DMSO vehicle
  • test compounds at different concentrations in DMSO were added and incubation was continued for 47 hours.
  • the bones were then transferred to fresh medium containing the test compounds (0.1 - 50 ⁇ M) 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
  • 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% fo ⁇ nic 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).
  • 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 dete ⁇ nined in all animals.
  • 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).
  • PYD cross-link residues yridinolinc
  • DPD deoxypyridinoline
  • lysine glycosides i.e. galactosyl-hydroxylysine (GHYL) and glucosy
  • 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.
  • 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:
  • Antitumor activity may be dete ⁇ nined 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.
  • 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)
  • 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)
  • 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).
  • Immunosi ⁇ pressant activity can be as.sessed as reported in the literature, for example by M.-K. Hu et al.. ./. Med. Chem. , 38, 4164-4170 (1995)
  • 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).
  • 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).

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Abstract

L'invention concerne un nouveau composé présentant la formule (I), ou un sel de ce dernier, ou un solvate de ce dernier. Dans la formule, R1 représente hydrogène, alkyle C1-6, halo, azido, alkythio C1-6, phénylthio, benzylthio, alkoxyalkyloxy ou un groupe NHR8 dans lequel R8 représente -CO-R9 ou -(CH2)nR11 ou R1 représente un groupe -NR12R13 où R12 et R13 représentent chacun indépendamment hydrogène, alkyle ou aryle; R2, R3 et R4 représentent chacun indépendamment hydrogène, alkyle, aryle ou de l'aryle substitué; R5 et R6 représentent chacun indépendamment de l'hydrogène, hydroxy, amino, alkoxy, de l'aryloxy éventuellement substitué, du benzyloxy éventuellement substitué, alkylamino, dialkylamino, halo, trifluorométhyle, trifluorométhoxy, nitro, alkyle, carboxy, carbalkoxy, carbamoyle, alkylcarbamoyl, ou R5 et R6 représentent ensemble méthylènedioxy, carbonyldioxy ou carbonyldiamino; X représente un groupe hydroxy ou alkoxy, dans lequel le groupe alkyle peut être substitué ou non substitué ou X représente un groupe NRSRt, où RS et Rt représentent chacun indépendamment hydrogène, alkyle, alkyle substitué, alkényle éventuellement substitué, aryle éventuellement substitué, arylalkyle éventuellement substitué, un groupe hétérocyclique éventuellement substitué ou un groupe hétérocyclylalkyle éventuellement substitué, ou RS et Rt avec l'azote auquel ils sont fixés forment un groupe hétérocyclique; R7 représente hydrogène, hydroxy, alkanoyle, alkyle, aminoalkyle, hydroxyalkyle, carboxyalkyle, carbalkoxyalkyle, carbamoyle ou aminosulphonyle; R9 représente R10 ou OR10 où R10 est alkyle C1-6, phényle ou benzyle; et R11 représente NR12R13, où R12 et R13 sont définis ci-dessus, ou R11 est hydroxy ou alkoxy C1-6; et n représente un chiffre entier 1, 2 ou 3. L'invention concerne aussi une composition pharmaceutique contenant ce composé, et un procédé pour préparer ce composé et utiliser ce composé en médecine.
PCT/EP1997/003710 1996-07-09 1997-07-07 Derives d'acide 5-indolyle-2,4-pentadienoique pouvant etre utilises comme inhibiteurs de la resorption osseuse WO1998001423A1 (fr)

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JP10504813A JP2000514079A (ja) 1996-07-09 1997-07-07 骨吸収阻害剤として有用な５―インドリル―２，４―ペンタジエン酸誘導体

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1408946A2 (fr) * 2001-03-27 2004-04-21 Circagen Pharmaceutical Inhibiteurs de l'histone deacetylase
WO2005105078A1 (fr) * 2004-04-30 2005-11-10 Nikem Research S.R.L. Derives d'indole utiles pour traiter une resistance a des agents anti-tumoraux

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0189936A2 (fr) * 1985-02-01 1986-08-06 Usv Pharmaceutical Corporation Composés à action hyposensible
EP0449196A2 (fr) * 1990-03-26 1991-10-02 Takeda Chemical Industries, Ltd. Dérivés d'indole, leur préparation et utilisation
WO1992014709A2 (fr) * 1991-02-11 1992-09-03 Cambridge Neuroscience, Inc. Antagonistes de canaux de calcium et methodologie d'identification de ces substances
WO1996021644A1 (fr) * 1995-01-10 1996-07-18 Smithkline Beecham S.P.A. Derives indole utiles dans le traitement de l'osteoporose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0189936A2 (fr) * 1985-02-01 1986-08-06 Usv Pharmaceutical Corporation Composés à action hyposensible
EP0449196A2 (fr) * 1990-03-26 1991-10-02 Takeda Chemical Industries, Ltd. Dérivés d'indole, leur préparation et utilisation
WO1992014709A2 (fr) * 1991-02-11 1992-09-03 Cambridge Neuroscience, Inc. Antagonistes de canaux de calcium et methodologie d'identification de ces substances
WO1996021644A1 (fr) * 1995-01-10 1996-07-18 Smithkline Beecham S.P.A. Derives indole utiles dans le traitement de l'osteoporose

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 108, no. 25, 20 June 1988, Columbus, Ohio, US; abstract no. 217684j, D.P. POPA ET AL.: "Synthesis of abscisic acid analogs with antitranspirant properties" page 201; column 2; XP002045406 *
IZV. AKAD. NAUK MOLD. SSR, SER. BIOL. KHIM. NAUK, no. 6, 1987, pages 54 - 56 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1408946A2 (fr) * 2001-03-27 2004-04-21 Circagen Pharmaceutical Inhibiteurs de l'histone deacetylase
EP1408946A4 (fr) * 2001-03-27 2004-06-09 Circagen Pharmaceutical Inhibiteurs de l'histone deacetylase
WO2005105078A1 (fr) * 2004-04-30 2005-11-10 Nikem Research S.R.L. Derives d'indole utiles pour traiter une resistance a des agents anti-tumoraux

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