WO1996021638A1 - Novel compounds - Google Patents
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- WO1996021638A1 WO1996021638A1 PCT/EP1996/000158 EP9600158W WO9621638A1 WO 1996021638 A1 WO1996021638 A1 WO 1996021638A1 EP 9600158 W EP9600158 W EP 9600158W WO 9621638 A1 WO9621638 A1 WO 9621638A1
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/44—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C45/41—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrogenolysis or reduction of carboxylic groups or functional derivatives thereof
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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- C07C47/235—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings
- C07C47/238—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings having unsaturation outside the aromatic rings
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- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
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- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
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- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
Definitions
- This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
- these compounds are also considered to possess anti- tumourtumor activity, antiviral activity (for example against Semliki Forest, Vesicular Stomatitis, Newcastle Disease, Influenza A and B, HIV viruses), antiulcer activity (for example the compounds may be useful for the treatment of chronic gastritis and peptic ulcer induced by Helicobacter pylori), immunosupressant activity, antilipidemic activity, antiatherosclerotic activity and to be useful for the treatment of ADDS and Alzheimer's disease.
- 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 is an alkyl group or a substituted or unsubstituted phenyl group
- R2 and R3 each independently represent hydrogen or alkyl
- RA represents T ⁇ wherein Tj is hydrogen or alkyl
- Rj3 represents a moiety of formula (a):
- T2 and T3 each independently represents hydrogen, hydroxy, amino, alkoxy, alkylcarbonyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, alkylamino, dialkylamino, chloro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl or T2 and T3 together represent a C3_5-alkylene chain each carbon atom of which is optionally substituted with up to three alkyl groups; or
- R together with Rg represents a moiety of formula (b):
- R4, R5, Rg and R9 each independently represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl or R4 and R5 together with the carbon atoms to which they are attached or Rg and R9 together with the carbon atoms to which they are attached form an optionally substituted phenylene ring;
- Rg and R7 each independently represent hydrogen, alkyl, aryl, alkoxy; or Rg and R7 together with the carbon atom to which they are attached form a saturated heterocyclic ring; or
- RA represents a moiety of formula (c) and Rg represents a moiety of formula (d):
- T4, T5, Tg and T7 each independently represents hydrogen, alkoxy, alkylcarbonyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, alkylamino, dialkylamino, chloro, alkyl, carboxy, carbalkoxy, carbamoyl or alkylcarbamoyl; and X ⁇ and Y each independently represent hydrogen or X together with Y represents a C3.5-alky.ene chain, a moiety of formula -CO-NH-,-CH2-NH- or -CH2-O-; and
- X represents hydroxy, alkoxy or a group of formula NR s R t wherein R s and R t each independently represent hydrogen, alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl or heteroarylalkyl; or R s and R t together with the nitrogen atom to which they are attached represent a saturated heterocyclic group;
- R ⁇ represents a Ci .4-alkyl group, for example methyl.
- R2 and R3 each independently represent hydrogen.
- R4 represents hydrogen.
- R5, Rg, or R9 represent a substituted alkyl group
- suitable substitutents include one or more hydroxy groups.
- suitable rings include tetrahydrofuran and dioxolane.
- Suitable substituents for alkyl groups represented by R s or R t include hydroxy groups and mono- or di-substituted amino groups.
- Suitable substituents for phenyl groups represented by R s or R t include hydroxyalkyl groups.
- Suitable saturated heterocyclic groups represented by NR s R t include morpolinyl, pirrolidinyl, piperidinyl or piperazynyl groups.
- a suitable phenylalkyl group represented by R s or R t is a benzyl group.
- T ⁇ represents hydrogen and methyl.
- T2 represents hydrogen, hydroxy, alkoxy or alkylcarbonyloxy.
- suitable chains are C3-or C4-alkylene chains, examples include:
- T4, T5, Tg and T7 each independently represent hydrogen.
- X represents alkoxy, especially methoxy.
- suitable chains are C2- alkylene chains.
- alkyl includes straight or branched chain alkyl groups having from 1 to 12 , suitably 1 to 6, preferably 1 to 4, carbon atoms and also includes such alkyl groups when forming part of other groups such as alkoxy or alkanoyl groups.
- Suitable optional substituents for any alkyl group include hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups, especially hydroxy.
- aryl includes phenyl and naphthyl, especially phenyl.
- Suitable optional substituents for any aryl group includes up to 5 substituents, suitably up to 3 substituents, selected from alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, acetyl, cyano, nitro, amino and alkylcarbonylamino.
- substituents for any aryl group includes up to 5 substituents, suitably up to 3 substituents, selected from alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, acetyl, cyano, nitro, amino and alkylcarbonylamino.
- heteroaryl includes single or fused heteroaryl groups, each ring having 5 to 7 ring atoms, especially 5 or 6, which ring atoms include 1, 2 or 3 heteroatoms selected from O, S, or N.
- Suitable hetereoaryl groups include pyridyl, especially 4-pyridyl, furanyl thiophenyl, pyrrolyl and heteroaryl groups comprising fused benzene rings such as quinolinyl, benzofuranyl and indolyl groups.
- Certain of the carbon atoms of the compounds of formula (I) - such as those compounds wherein R1-R9 contains chiral alkyl groups are chiral carbon atoms and may therefore provide stereoisomers of the compound of formula (I).
- the invention extends to all stereoisometric forms of the compounds of formula (I) including enantiomers and mixtures thereof, including racemates.
- the different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses.
- the compounds of formula (I) also possess two double bonds and hence can exist in one or more geometric isomers.
- the invention extends to all such isomeric forms of the compounds of formula (I) including mixtures thereof.
- the different isomeric forms may be separated one from the other by conventional methods or any given isomer may be obtained by conventional synthetic methods.
- Suitable salts of the compounds of the formula (I) are pharmaceutically acceptable salts, such as a hydrochloride, methansulfonate, maleate, succinate, acetate, propionate or a tartrate salt.
- Suitable solvates of the compounds of the formula (I) are pharmaceutically acceptable solvates, such as hydrates.
- salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form another aspect of the present invention.
- a compound of formula (I) or a salt thereof or a solvate thereof may be prepared:
- reaction between the compounds of formula (II) and the reagent capable of converting the group of formula -CO-R2 into the moiety of formula (e), may be carried out under the appropriate conventional conditions, depending upon the particular reagent chosen, for example:
- the reaction is carried out under conventional Horner-Emmons conditions, using a suitable aprotic solvent and in presence of a base.
- suitable solvents are conventional solvents for this type of reaction such as tetrahydrofuran (THF), dioxane, methylenedichloride or aromatic hydrocarbons such as toluene, preferably THF, at a temperature providing a suitable rate of formation of the required product, conveniently at ambient temperature or at an elevated temperature, such as a temperature in the range of from 30°C to 120°C.
- Suitable bases used in the above mentioned reaction include inorganic base such as caesium carbonate, potassium carbonate, sodium hydride, preferably sodium hydride or organic base such asl,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or diisopropylethylamine (DIPEA), preferably DBU.
- inorganic base such as caesium carbonate, potassium carbonate, sodium hydride, preferably sodium hydride or organic base such asl,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or diisopropylethylamine (DIPEA), preferably DBU.
- DIPEA diisopropylethylamine
- the reaction is carried out under conventional Wittig conditions.
- a base in any suitable aprotic solvent.
- Suitable solvents are conventional solvents for use in this type of reaction, such as THF, diethylether, methylenedichloride or aromatic hydrocarbons such as toluene, preferably methylenedichloride, at a temperature providing a suitable rate of formation of the required product, conveniently at ambient temperature or at an elevated temperature, such as a temperature in the range of from 30°C to 120°C.
- Suitable bases include conventional bases for this type of reaction such as sodium hydride, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or diisopropylethylamine (DIPEA), preferably DBU.
- reaction between the compounds of formulae (II) and the Horner-Emmons reagent of formula (III) may be carried out under conventional Horner-Emmons conditions such as those described above.
- a further suitable reagent capable of converting a moiety of the above defined formula -CO-R2 into a moiety of the above defined formula (e) is a compound of formula (IV): R 1 -O-CH 2 -CO.X 2 (IV)
- R ⁇ and X2 are as defined in relation to the compounds of formula (III).
- the reagent of formula (IV) is in an activated form, suitably an anionic form such as a salted form, for example an alkali metal salted form.
- an activated form suitably an anionic form such as a salted form, for example an alkali metal salted form.
- the reaction between the compounds of formulae (II) and (IV) may be carried out according to known procedures for example those disclosed in Liebigs Ann. Chem., 703, 1967, 37.
- Suitable conversions of one compound of formula (I) into another compound of formula (I) include converting a compound of formula (I) wherein X represents a hydroxy group or an alkoxy group into a compound of formula (I) wherein X represents a different alkoxy group or a moiety of the above defined formula NR s R t .
- the conversion of one compound of formula (I) into another compound of formula (I) may be carried out using the appropriate conventional procedure, for example the above mentioned conversion of a compound wherein X represents a hydroxy group or an alkoxy group into a compound wherein X represents a moiety of the above defined formula NR s t may be carried out as follows: (i) when X is alkoxy, by basic hydrolysis, using for example potassium hydroxide, to provide a compound of formula (I) wherein X is hydroxy, and thereafter treating with a compound of formula HNR s *R t > wherein R s > and R t ⁇ have the required value of R s and R t respectively; preferably the reaction with the compound of formula HNR s «R t * takes place in the presence of a condensing agent such as N.N'-dicyclohexylcarbodiimide (DCC) or after conversion of (I), wherein X is hydroxy, into the corresponding acid chloride and condensation in presence of a
- a compound of formula (II) wherein R ⁇ represents the above defined T and Rg represents a moiety of the above defined formula (a), may be prepared according to the reaction sequence shown in Scheme (I) below:
- the carboxylic ester (V) is then converted into the corresponding alcohol with a reducing agent suitably a complex metal reducing agent such as lithium aluminium hydride (LiAlH4), diisobutyl aluminium hydride (DIBAH) or lithium borohydride (UBH4) in any suitable aprotic, for example methylene dichloride, chloroform, dioxane, diethyl ether or THF at any temperature providingprovidng a suitable rate of formation of the required product, such as a temperature in the range of between -30°C and 60°C, for example at room temperature.
- a complex metal reducing agent such as lithium aluminium hydride (LiAlH4), diisobutyl aluminium hydride (DIBAH) or lithium borohydride (UBH4)
- a suitable aprotic for example methylene dichloride, chloroform, dioxane, diethyl ether or THF at any temperature providingprovidng a suitable rate
- the intermediate alcohol is oxidised to aldehydes (II) with an oxidising agent such as manganese dioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swem reaction), preferably manganese dioxide in methylene dichloride.
- an oxidising agent such as manganese dioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swem reaction), preferably manganese dioxide in methylene dichloride.
- a reducing agent suitably a complex metal reducing agent such as lithium aluminium hydride (LiAlH4), diisobutyl aluminium hydride (DIBAH) or lithium borohydride (LiBH4) in any suitable aprotic, for example methylene dichloride, chloroform, dioxane, diethyl ether or THF at any temperature providingprovidng a suitable rate of formation of the required product, such as a temperature in the range of between -30°C and 60°C, for example at room temperature.
- a complex metal reducing agent such as lithium aluminium hydride (LiAlH4), diisobutyl aluminium hydride (DIBAH) or lithium borohydride (LiBH4)
- aprotic for example methylene dichloride, chloroform, dioxane, diethyl ether or THF at any temperature providingprovidng a suitable rate of formation of the required product, such as a temperature in the range of between -30
- the intermediate alcohol is oxidised to aldehydes (II) with an oxidising agent such as manganese dioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swem reaction), preferably manganese dioxide in methylene dichloride.
- an oxidising agent such as manganese dioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swem reaction), preferably manganese dioxide in methylene dichloride.
- a compound of formula (II) wherein represents a moiety of above defined formula (c) and R ⁇ represents amoiety of above defined formula (d) may be prepared according to the reaction sequence shown in Scheme (HI) below:
- R2, R3, T4, T5, Tg, T7, Xj and Y are as defined in relation to formula (I).
- the carboxylic ester (XI) is then convened into the corresponding alcohol with a reducing agent suitably a complex metal reducing agent such as lithium aluminium hydride (LiAlH4), diisobutyl aluminium hydride (DIBAH) or lithium borohydride (IJBH4) in any suitable aprotic, for example methylene dichloride, chloroform, dioxane, diethyl ether or THF at any temperature providingprovidng a suitable rate of formation of the required product, such as a temperature in the range of between -30°C and 60°C, for example at room temperature.
- a complex metal reducing agent such as lithium aluminium hydride (LiAlH4), diisobutyl aluminium hydride (DIBAH) or lithium borohydride (IJBH4)
- a suitable aprotic for example methylene dichloride, chloroform, dioxane, diethyl ether or THF at any temperature providingprovid
- the alcohol is then oxidised to provide aldehyde (II) using an oxidising agent such as manganese dioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swem reaction), preferably manganese dioxide in methylene dichloride.
- an oxidising agent such as manganese dioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chloride and DMSO (Swem reaction), preferably manganese dioxide in methylene dichloride.
- R2 is other than -H , e.g. alkyl..
- compounds (II) are obtained directly from (XII) by Wittig or Horner-Emmons reaction with the appropriate phosphorous ylides or phosphonates using conditions described above.
- Salts and/or solvates of the compounds of formula (I) may be prepared using the appropriate conventional procedure.
- the compounds of formula (III) and (IV) are known compounds or they are prepared using methods analogous to those used to prepare known compounds, such as those described in Chem. Ber., 97, 1713 (1964); Tetrahedron, 50, 3177 (1994) and JAm.Chem.Soc, 70, 3569 (1948).
- the compounds of formula (VI), (VII), (VIII), (IX), (X), (XI) and (XII) are known compounds or they are prepared using methods analogous to those used to prepare known compounds, such as those described in J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
- a compound of formula (I) or a solvate thereof may be isolated from the above mentioned processes according to standard chemical procedures. Where required the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography. As mentioned above the compounds of the invention are indicated as having useful therapeutic properties:
- the present invention accordingly provides a compound of formula (I), or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of osteoporosis and related osteopenic diseases.
- the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of tumours, especially those related to renal cancer, melanoma, colon cancer, lung cancer and leukemia, viral conditions (for example those involving Semliki Forest virus, Vesicular Stomatitis virus, Newcastle Disease virus, Influenza A and B viruses, HIV virus), ulcers (for example chronic gastritis and peptic ulcer induced by Helicobacter pylori), for use as immunosupressant agents in autoimmune diseases and transplantation, antilipidemic agents for the treatment and/or prevention of hypercholesterolemic and atherosclerotic diseases and to be useful for the treatment of AIDS and Alzheimer's disease These compounds are also considered useful in treating angiogenic diseases, i.e.
- a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
- Active compounds or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is normally administered in unit dosage form.
- an amount effective to treat the disorder hereinbefore described depends upon such factors as the efficacy of the active compounds , the particular nature of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate chosen, the nature and severity of the disorders being treated and the weight of the mammal.
- a unit dose will normally contain 0.01 to 50 mg for example 1 to 25 mg, of the compound of the invention.
- Unit doses will normally be administered once or more than once a day, for example 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.01 to 250 mg, more usually 1 to 100 mg, for example 5 to 70 mg, that is in the range of approximately 0.0001 to 3.5 mg/kg/day, more usually 0.01 to 1.5 mg kg/day, for example 0.05 to 0.7 mg/kg/day.
- the present invention further provides a method for the treatment of osteoporosis and related osteopenic diseases in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I) or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
- the present invention also provides a method for the treatment of tumours, especially those related to renal cancer, melanoma, colon cancer, lung cancer and leukemia., viral conditions (for example those involving Semliki Forest, Vesicular Stomatitis, Newcastle Disease, Influenza A and B, HIV viruses), ulcers (for example chronic gastritis and peptic ulcer induced by Helicobacter pylori), autoimmune diseases and transplantation, for the treatment and/or prevention of hypercholesterolemic and atherosclerotic diseases, AIDS and Alzheimer's disease, angiogenic diseases, such as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumours, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I) or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
- viral conditions for example those involving Semliki Forest, Vesicular
- the active compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes.
- the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
- compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitu table powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices.
- Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
- Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
- the tablets may be coated according to well known methods in the art.
- Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
- Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
- Suitable lubricants include, for example, magnesium stearate.
- Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
- solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
- 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
- fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
- the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
- Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
- 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 uniform 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 compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
- Methyl (2Z,4E)-2-methoxy-5-phenyl-2,4-pentadienoate To a suspension of sodium methoxide (5.4 g, 0.1 mol) in dry toluene (50 ml) a solution of methyl methoxyacetate (29.7 ml , 31.18 g, 0.3 mol) and rr ⁇ /ty-cinnamaldehyde (12.6 ml , 0.1 mol) was added dropwise. The dark brown solution obtained was allowed to stir at room temperature for 24 hours. It was quenched with water (100 ml) and extracted with ethyl acetate (100 ml).
- (2Z,4E)-2-Methoxy-5-phenyI-2,4-pentadienoic acid To a solution of KOH 100% (4.5 g, 80 mmol) in absolute ethanol (45 ml), (2Z,4E)-methyl-2-methoxy-5-phenyl-2,4- pentadienoate (9 g, 41 mmol) was added. This solution was heated at 50°C for two hours.
- Benzyl (2Z,4E)-2-methoxy-5-phenyl-2,4-pentadienoate A mixture of (2Z,4E)-2- methoxy-5-phenyl-2,4-pentadienoic acid (0.5 g, 2.45 mmol), anhydrous K2CO3 (0.35 g, 2.45 mmol) and benzyl bromide (0.3 ml, 2.5 mmol) in anhydrous DMF (5 ml) was stirred at room temperature for two days. Distilled water (25 ml) was added and the suspension was extracted with E_2 ⁇ (3 x 50 ml). The organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography (EtOAc/hexane 1:9) yielding 0.35 g (48.5%) of the title compound as an oil.
- Example 12 Methyl (2Z,4E)-4-ethyI-2-methoxy-5-phenyl-2,4-pentadienoate.
- a solution of (E)-2-ethyl-3-phenyl-2-propenaldehyde (8 g, 50 mmol) (J.A.C.S., 1948, 3569) and methyl methoxyacetate (10 ml, 0.1 mol) was added dropwise. The suspension was stirred at 50°C for 24 hours.
- Methyl (2Z,4E)-2-methoxy-4-pentyl-5-phenyl-2,4-pentadienoate and Methyl (2E,4E)-2-methoxy-4-pentyl-5-phenyl-2,4-pentadienoate An oil dispersion of 60% NaH (0.3 g, 7.41 mmol) was washed with pentane (2x3 ml) and then suspended in anhydrous THF (15 ml) under nitrogen. Trimethyl 2-methoxyphosphonoacetate (1.6 g, 7.41 mmol), dissolved in dry THF (5 ml), was added dropwise and the reaction mixture was stirred at 40°C for 40 min.
- Methyl (2Z,4E)-2-methoxy-4-pentyl-5-phenyl-2,4-pentadienoate *H-NMR (CDCI3): 7.40-7.20 (m,5H); 6.90 (s, IH); 6.65 (s, IH); 3.85 (s, 3H); 3.75 (s, 3H); 2.55-2.48 (m, 2H); 1.59-1.50 (m, 2H); 1.39-1.28 (m,4H); 0.88 (t, 3H).
- These compounds were prepared following the Example 13 starting from ⁇ -ethyl-4- methoxycinnamaldehyde (0.5 g, 2.6 mmol), NaH 60% (0.12 g, 3 mmol) and trimethyl 2- methoxyphosphonoacetate (0.64 g, 3 mmol).
- These compounds were prepared following the Example 19 starting from 4-acetoxycinnamaldehyde (0.64 g, 3.34 mmol), CS2CO3 (1.65 g, 5.07 mmol) and trimethyl 2-methoxyphosphonoacetate (0.95 g, 4.5 mmol).
- These compounds were prepared following the Example 22 starting from (2E) 3(2-naphtyl)propenaldehyde (O.lg, 0.55 mmol), DBU (0.123 ml, 0.825 mmol) and methyl 2-methoxy-2- (triphenylphosphonium)acetate bromide (0.37 g, 0.825 mmol).
- Methyl (Z)-4-cyclohexylidene-2-methoxy-2-butenoate and Methyl (E)-4- cyclohexyIidene-2-methoxy-2-butenoate To a suspension of sodium hydride (0.42 g, 10.5 mmol; a 60% oil dispersion pre- washed with pentane was used) in anhydrous THF (10 ml) under nitrogen, a solution of trimethyl 2-methoxyphosphonoacetate (2.23 g, 10.5 mmol) in dry THF (5 ml) was added dropwise and the mixture was stirred at 40°C for 40 min.
- Methyl (Z)-4-(l ,4-dioxaspiro[4,5)decan-8-ylidene)-2-methoxy-2-butenoate ⁇ H-NMR (CDCI3): 6.99 (d, IH): 6.27 (d, IH), 3.99 (s, 4H);3.80 (s, 3H); 3.70 (s, 3H); 2.50 (dd, 2H); 2.40 (dd, 2H); 1.80-1.72 ( , 4H).
- Trimethyl 2-methoxyphosphonoacetate 0.5 g, 2.36 mmol
- NaH 0.19 g, 4.7 mmol; a 60% oil dispersion was used
- 2-[(5-hydroxypentyl)cyclohexylidene] acetaldehyde 0.17 g, 0.8 mmol
- Ethyl (10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetate To a suspension of sodium hydride (0.96 g, 24 mmol; a 60 % oil dispersion pre-washed with pentane was used) in anhydrous THF (20 ml) under nitrogen, a solution of triethyl phosphonoacetate (5.76 ml, 28.8 mmol) in dry THF (10 ml) was added dropwise and the reaction was stirred at room temperature for 30 min.
- Methyl (Z)-4-(10,ll-dihydro-5H-dtbenzo[a,d]cyclohepten-5-ylidene)-2-methoxy-2- butenoate To a suspension of sodium hydride (0.2 g, 5 mmol; a 60 % oil dispersion pre-washed with pentane was used) in anhydrous THF (10 ml) under nitrogen, a solution of trimethyl 2-methoxyphosphonoacetate (0.9 g, 4.24 mmol) in dry THF (5 ml) was added dropwise and the reaction mixture was stirred at 40°C for 40 min.
- Vesicles were prepared from medullar bone obtained from tibiae and femurs of egg- laying hens which were calcium- starved for at least 15 days. Briefly, bone fragments were scraped with a 24 scalpel blade, suspended in 40 ml of isolation medium (0.2 M sucrose, 50 mM KC1, 10 mM Hepes, 1 mM EGTA, 2 mM dithiotheitrol, pH 7.4) and filtered through a 100 ⁇ m pore size nylon mesh. The whole procedure was performed at 4°C.
- isolation medium 0.2 M sucrose, 50 mM KC1, 10 mM Hepes, 1 mM EGTA, 2 mM dithiotheitrol, pH 7.4
- 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 ⁇ l of membrane vesicles in 1 ml of buffer containing 0.2 M sucrose, 50 mM KC1, 10 mM Hepes pH 7.4, 1 mM ATP.Na2, 1 mM CDTA, 5 ⁇ M valinomycin and 4 ⁇ M acridine orange. The reaction was started by addition of 5 mM MgSO4- Results were expressed as the percent of the mean of two controls.
- bafilomycin-sensitive ATPase activity was assessed in purified membrane vesicles by measuring the release of inorganic phosphate (Pi) during 30 min of incubation at 37°C in a 96-well plate either in the presence or in the absence of bafilomycin Al.
- the reaction medium contained 1 mM ATP, 10 mM HEPES -Tris pH 8, 50 mM KC1, 5 uM valinomycin, 5 uM nigericin, 1 mM CDTA-Tris, 100 uM ammonium molybdate, 0.2 M sucrose and membranes (20 ug protein/ml).
- the reaction was initiated by MgSO4 (8-arm pipette) and stopped, after 30 min, by addition of 4 volumes of the malachite green reagent (96-arm pipette) prepared according to Chan [Anal. Biochem. 157, 375 (1986)]. Absorbance at 650 nm was measured after 2 min using a microplate reader. Results are expressed as ⁇ mol (Pi) x mg protein " l ⁇ hour ⁇ l and, for each experiment, represent the mean ⁇ sem of triplicates.
- Bone resorption can be assessed as described previously in the literature [T. J. Chambers et al., Endocrinology, 1985, 116, 234]. Briefly, osteoclasts were mechanically disaggregated from neonatal rat long bones into Hepes-buffered medium 199 (Flow, UK). The suspension was agitated with a pipette, and the larger fragments were allowed to setde for 30 sec. The cells were then added to two wells of a multiwell dish containing bone slices (each measuring 12 mm ⁇ ). After 15 min at 37°C the bone slices were removed, washed in medium 199 and placed in individual wells of a 96- well plate.
- 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 animals were sacrificed and the tibia and femur of the hind limb removed.
- the tibia wet and dry weight were determined, and the density (displacement of water) and ashes content (total weight, calcium and phosphorous content) also measured.
- the femur were fixed in 10% formalin, de-mineralised in 5% formic acid and the coronal midshaft and longitudinal section of the distal metaphysis cut and stained with haematoxilin and eosin. Histomorphometric evaluation was made using a semi-automated image analyser (Immagini & Computer, Milan, Italy).
- the % trabecular bone area in the secondary spongiosa (which is the trabecular bone 1 mm from the epiphyseal growth plate to about 4 mm towards the midshaft giving a total area of 5 mm 2 ) and the number of trabeculae (according to Parfitt et al., 7. Bone Min. Res. 2: 595, (1987)) were determined in all animals.
- Groups of 7-10 female Sprague-Dawley rats, about 90 days old and weighing 200-250 g are used. Rats are anesthetised by sodium pentobarbital (35 mg kg i.v.), laparotomy is performed and ovaries are bilaterally removed . Wounds are adequately disinfected and sutured. A group is sham operated. During a 4-week experimental period, the operated animals receive test compounds in the appropiate vehicle (0.1-100 mg/kg p.o. u.i.d.) or vehicle alone. Twenty-four-hr urine samples are collected for PYD, DPD, GHYL and GGHYL determinations before and 2, 4, 8, 11, 15, 18, 22 and 25 days after surgery. The aliquots of urine are frozen and stored at -20° C until HPLC analysis.
- results are expressed as % of prevention versus vehicle treated animals.
- Antitumor activity may be determined according to the methods disclosed in published International Application, Publication number 93/18652; in particular the screen employed, experimental details and bibliography of M.R. Boyd et al., Status of the NCI preclinical antitumor drug discovery screen; principles and practices of Oncology, 3, issue 10, Oct. 1989, Lippincott. 2.
- Antiviral activity may be assessed using the in vitro assays reported by H. Ochiai et al., Antiviral Research, 27, 425-430 (1995) or by C. Serra et al., Pharmacol. Res., 29, 359 (1994).
- Anti-HIV activity can be assessed as reported in the literature, for example by S. Velasquez et al., /. Med. Chem., 38, 1641-1649 (1995)
- Antiulcer activity may be assessed in vivo using the methods reported in the literature, for example, as described by CJ. Pfeiffer, Peptic Ulcer , C.J. Pfeiffer Ed., Munksgaard
- Alzheimer's disease may be determined using models in vitro such as inhibition of amiloyd- ⁇ production as descrided in the literature by J. Knops et al., J. Biol. Chem., 270, 2419-2422 (1995) or by models in vivo: such as the transgenic mouse model overexpressing human APP reported by D. Games et al., Nature, 373, 523- 527 (1995).
- Immunosuppressant activity can be assessed as reported in the literature, for example by M.-K. Hu et al. r J. Med. Chem. , 38, 4164-4170 (1995) ⁇ .Antilipidemic activity can be assessed as reported in the literature, for example by E.A.L. Biessen et al., J. Med. Chem. , 38, 1846-1852 (1995).
- Antiatherosclerotic activity may be assessed by using animal models of atherosclerosis, such as the atherosclerotic rabbit model, which are reported in the literature, for example by R.J. Lee et al., J. Pharm. Exp. Ther., 184, 105-112 (1973).
- Angiostatic activity may be assessed using the methods reported in the literature, for example as described by T. Ishii et al., J. Anibiot., 48, 12 (1995).
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ITMI950031A IT1272879B (it) | 1995-01-10 | 1995-01-10 | Composti dibenzoalchilenici |
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US6221075B1 (en) | 1998-03-06 | 2001-04-24 | Bionx Implants Oy | Bioabsorbable, deformable fixation plate |
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DE1287080B (de) * | 1965-01-14 | 1969-01-16 | Thomae Gmbh Dr K | Verfahren zur Herstellung von Alkoxyolefinen |
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1996
- 1996-01-08 WO PCT/EP1996/000158 patent/WO1996021638A1/en not_active Application Discontinuation
- 1996-01-08 EP EP96901276A patent/EP0802897A1/en not_active Withdrawn
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DE1287080B (de) * | 1965-01-14 | 1969-01-16 | Thomae Gmbh Dr K | Verfahren zur Herstellung von Alkoxyolefinen |
Non-Patent Citations (2)
Title |
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GUENTER NEEF ET AL.: "C-Nor-D-homoequilenen-3-methylaether", CHEMISCHE BERICHTE, vol. 109, WEINHEIM DE, pages 3025 - 3033 * |
RINDRA ANDRIAMIADANARIVO ET AL.: "PREPARATION OF FUNCTIONALIZED CYCLOBUTENONES AND PHENOLIC COMPOUNDS FROM ALPHA-DIAZO BETA-KETOPHOSPHONATES", TETRAHEDRON LETTERS, vol. 34, no. 49, 3 December 1993 (1993-12-03), OXFORD GB, pages 7923 - 7924 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US6221075B1 (en) | 1998-03-06 | 2001-04-24 | Bionx Implants Oy | Bioabsorbable, deformable fixation plate |
US6692497B1 (en) | 1998-03-06 | 2004-02-17 | Toermaelae Pertti | Bioabsorbable, deformable fixation plate |
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