ITMI950031A1 - DIBENZOALKYLENE COMPOUNDS - Google Patents
DIBENZOALKYLENE COMPOUNDS Download PDFInfo
- Publication number
- ITMI950031A1 ITMI950031A1 IT95MI000031A ITMI950031A ITMI950031A1 IT MI950031 A1 ITMI950031 A1 IT MI950031A1 IT 95MI000031 A IT95MI000031 A IT 95MI000031A IT MI950031 A ITMI950031 A IT MI950031A IT MI950031 A1 ITMI950031 A1 IT MI950031A1
- Authority
- IT
- Italy
- Prior art keywords
- formula
- alkyl
- independently represent
- represent hydrogen
- compounds according
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 90
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 239000012453 solvate Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 7
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 5
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract 2
- -1 carbalkoxy Chemical group 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 210000000988 bone and bone Anatomy 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 210000002997 osteoclast Anatomy 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 239000012528 membrane Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- 108091006112 ATPases Proteins 0.000 description 6
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000002955 isolation Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- 230000032258 transport Effects 0.000 description 5
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- 208000006386 Bone Resorption Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- XDHNQDDQEHDUTM-UHFFFAOYSA-N bafliomycin A1 Natural products COC1C=CC=C(C)CC(C)C(O)C(C)C=C(C)C=C(OC)C(=O)OC1C(C)C(O)C(C)C1(O)OC(C(C)C)C(C)C(O)C1 XDHNQDDQEHDUTM-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000024279 bone resorption Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DPKHZNPWBDQZCN-UHFFFAOYSA-N acridine orange free base Chemical compound C1=CC(N(C)C)=CC2=NC3=CC(N(C)C)=CC=C3C=C21 DPKHZNPWBDQZCN-UHFFFAOYSA-N 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- XDHNQDDQEHDUTM-JQWOJBOSSA-N bafilomycin A1 Chemical compound CO[C@H]1\C=C\C=C(C)\C[C@H](C)[C@H](O)[C@H](C)\C=C(/C)\C=C(OC)\C(=O)O[C@@H]1[C@@H](C)[C@@H](O)[C@H](C)[C@]1(O)O[C@H](C(C)C)[C@@H](C)[C@H](O)C1 XDHNQDDQEHDUTM-JQWOJBOSSA-N 0.000 description 3
- XDHNQDDQEHDUTM-ZGOPVUMHSA-N bafilomycin A1 Natural products CO[C@H]1C=CC=C(C)C[C@H](C)[C@H](O)[C@H](C)C=C(C)C=C(OC)C(=O)O[C@@H]1[C@@H](C)[C@@H](O)[C@H](C)[C@]1(O)O[C@H](C(C)C)[C@@H](C)[C@H](O)C1 XDHNQDDQEHDUTM-ZGOPVUMHSA-N 0.000 description 3
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- VOJKJRMDIMKQQS-JXAWBTAJSA-N methyl (2Z)-2-methoxy-5,5-diphenylpenta-2,4-dienoate Chemical compound c1ccccc1C(=C/C=C(\OC)C(=O)OC)c1ccccc1 VOJKJRMDIMKQQS-JXAWBTAJSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
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- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- AHBKPHMSWPIZDQ-UHFFFAOYSA-N 2-(5,6-dihydrodibenzo[2,1-b:2',1'-f][7]annulen-11-ylidene)acetaldehyde Chemical compound C1CC2=CC=CC=C2C(=CC=O)C2=CC=CC=C21 AHBKPHMSWPIZDQ-UHFFFAOYSA-N 0.000 description 2
- MWAFWBDWAWZJGK-UHFFFAOYSA-N 3,3-diphenylprop-2-enal Chemical compound C=1C=CC=CC=1C(=CC=O)C1=CC=CC=C1 MWAFWBDWAWZJGK-UHFFFAOYSA-N 0.000 description 2
- VOJKJRMDIMKQQS-NBVRZTHBSA-N C1(=CC=CC=C1)C(=C/C=C(C(=O)OC)/OC)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)C(=C/C=C(C(=O)OC)/OC)C1=CC=CC=C1 VOJKJRMDIMKQQS-NBVRZTHBSA-N 0.000 description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 2
- 108010083204 Proton Pumps Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- 108010067973 Valinomycin Proteins 0.000 description 2
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
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- FCFNRCROJUBPLU-UHFFFAOYSA-N compound M126 Natural products CC(C)C1NC(=O)C(C)OC(=O)C(C(C)C)NC(=O)C(C(C)C)OC(=O)C(C(C)C)NC(=O)C(C)OC(=O)C(C(C)C)NC(=O)C(C(C)C)OC(=O)C(C(C)C)NC(=O)C(C)OC(=O)C(C(C)C)NC(=O)C(C(C)C)OC1=O FCFNRCROJUBPLU-UHFFFAOYSA-N 0.000 description 2
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- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 2
- FCFNRCROJUBPLU-DNDCDFAISA-N valinomycin Chemical compound CC(C)[C@@H]1NC(=O)[C@H](C)OC(=O)[C@@H](C(C)C)NC(=O)[C@@H](C(C)C)OC(=O)[C@H](C(C)C)NC(=O)[C@H](C)OC(=O)[C@@H](C(C)C)NC(=O)[C@@H](C(C)C)OC(=O)[C@H](C(C)C)NC(=O)[C@H](C)OC(=O)[C@@H](C(C)C)NC(=O)[C@@H](C(C)C)OC1=O FCFNRCROJUBPLU-DNDCDFAISA-N 0.000 description 2
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
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Abstract
I composti di formula (I): (FORMULA I): o un suo sale, o un suo solvato, in cui: R1, rappresenta un gruppo alchile o un gruppo sostituito o non sostituito; R2 e R3 rappresentano ciascuno indipendentemente idrogeno o alchile; R4, R5,R6 e R7 rappresentano ciascuno indipendentemente idrogeno, alcossi, alchilcarbonilossi, fenossi eventualmente sostituito, benzilossi eventualmente sostituito, alchilammino, dialchilammino, cloro, alchile, carbosi, carbalcossi, carbammobile o alchilcarbammobile;X e Y rappresentano ciascuno indipendentemente idrogeno oppure X e Y rappresentano insieme una catena C3-5-alchilenica, un residuo di formula -CO-nh-, -CH2-NH-o -CH2-O; e X1 rappresenta idrossi, alcossi o un gruppo di formula NRsRt in cui Rs e Rt rappresentano ciascuno indipendentemente idrogeno, alchile, alchile sostituito, fenile, fenile sostituito, fenialchile o eteroarilalchile; oppure Rs e Rt, insieme all'atomo di azoto a cui sono legati, rappresentano un gruppo eterociclico saturo; sono utili per il trattamento dell'osteoporosi.The compounds of formula (I): (FORMULA I): either a salt thereof, or a solvate thereof, wherein: R1, represents an alkyl group or a substituted or unsubstituted group; R2 and R3 each independently represent hydrogen or alkyl; R4, R5, R6 and R7 each independently represent hydrogen, alkoxy, alkylcarbonyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, alkylamino, dialkylamino, chlorine, alkyl, carbose, carbalcoxy, carbammobile or alkylcarbammobile; X and Y each independently represent hydrogen or X and Y together represent a C3-5-alkylene chain, a residue of formula -CO-nh-, -CH2-NH-or -CH2-O; and X1 represents hydroxy, alkoxy or a group of formula NRsRt wherein Rs and Rt each independently represent hydrogen, alkyl, substituted alkyl, phenyl, substituted phenyl, phenyalkyl or heteroarylalkyl; or Rs and Rt, together with the nitrogen atom to which they are linked, represent a saturated heterocyclic group; they are useful for the treatment of osteoporosis.
Description
Descrizione dell'invenzione industriale avente per titolo: "COMPOSTI DIBENZOALCHILENICI" Description of the industrial invention entitled: "DIBENZOALKYLENE COMPOUNDS"
La presente invenzione ha per oggetto nuovi composti, un procedimento per preparare tali composti, composizioni farmaceutiche contenenti tali composti e l'uso di tali composti e composizioni in medicina. The present invention relates to new compounds, a process for preparing such compounds, pharmaceutical compositions containing such compounds and the use of such compounds and compositions in medicine.
Si è sorprendentemente scoperto che certi derivati dibenzoalchilenici sono indicati per ridurre il riassorbimento osseo mediante inibizione della degli osteoclasti e di conseguenza sono di potenziale uso per il trattamento e/o la profilassi della osteoporosi e delle malattie osteopeniche correlate. It has surprisingly been found that certain dibenzoalkylene derivatives are indicated to reduce bone resorption by inhibition of osteoclasts and consequently are of potential use for the treatment and / or prophylaxis of osteoporosis and related osteopenic diseases.
Di conseguenza, la presente invenzione fornisce un composto di formula (I) : Consequently, the present invention provides a compound of formula (I):
o un suo sale, o un suo solvato, in cui: or one of its salt, or one of its solvates, in which:
rappresenta un gruppo alchile o un gruppo fenile sostituito o non represents an alkyl group or a substituted or unsubstituted phenyl group
sostituito; replaced;
rappresentano ciascuno indipendentemente idrogeno o alchile; each independently represent hydrogen or alkyl;
rappresentano ciascuno indipendentemente idrogeno, alcossi, alchilcarbonilossi , fenossi eventualmente sostituito, benzilossi eventualmente sostituito, alchilammino, dialchilamnino, cloro, alchile, carbossi, carbalcossi, carbammoile o alchilcarbammoile; X e V rappresentano ciascuno indipendentemente idrogeno oppure X e Y rappresentano insieme una catena -alchilenica, un residuo di formula each independently represent hydrogen, alkoxy, alkylcarbonyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, alkylamino, dialkylamino, chloro, alkyl, carboxy, carbalkoxy, carbamoyl or alkylcarbamoyl; X and V each independently represent hydrogen or X and Y together represent an alkylene chain, a residue of formula
rappresenta idrossi, alcossi o un gruppo di formula in cui Rs e represents hydroxy, alkoxy or a group of formula wherein Rs e
rappresentano ciascuno indipendentemente idrogeno, alchile, alchile each independently represent hydrogen, alkyl, alkyl
sostituito, fenile, fenile sostituito, fenilalchile o eteroarilalchile; oppure insieme all'atomo di azoto a cui sono legati, rappresentano un gruppo eterociclico saturo. substituted, phenyl, substituted phenyl, phenylalkyl or heteroarylalkyl; or together with the nitrogen atom to which they are bound, they represent a saturated heterocyclic group.
Opportunamente, rappresenta un gruppo -alchile, per esempio metile . Suitably, it represents a -alkyl group, for example methyl.
Opportunamente , rappresentano ciascuno indipendentemente idrogeno. Conveniently, they each independently represent hydrogen.
Generalmente, rappresentano ciascuno indipendentemente idrogeno. Generally, they each independently represent hydrogen.
Quando X e Y rappresentano assieme una catena -alchilenica , catene adatte sono le catene -alchileniche . When X and Y together represent an alkylene chain, suitable chains are the alkylene chains.
Opportunamente, rappresenta un gruppo alcossi , per esempio metossi . Conveniently, it represents an alkoxy group, for example methoxy.
Gruppi eterociclici saturi adatti rappresentati da Suitable saturated heterocyclic groups represented by
comprendono i gruppi morfolinile. include morpholinyl groups.
Un gruppo fenilalchile adatto rappresentato da è un gruppo benzile. A suitable phenylalkyl group represented by is a benzyl group.
Come qui usato, il termine "alchile" comprende gruppi alchile a catena lineare o ramificata avente da 1 a 12 atomi di carbonio, opportunamente da 1 a 6, preferibilmente da 1 a 4, e comprende inoltre tali gruppi alchile quando fanno parte di altri gruppi quali gruppi alcossioalcanoile. As used herein, the term "alkyl" includes straight or branched chain alkyl groups having 1 to 12 carbon atoms, suitably 1 to 6, preferably 1 to 4, and further includes such alkyl groups when they are part of other groups which alkoxyalkanoyl groups.
Eventuali sostituenti adatti per un qualsiasi gruppo alchile conprendono gruppi idrossi, animino, nitro, carbossi, alcossicarbonile , alcossicarbonilalchile, alchilcarbonilossi o alchilcarbonile, in particolare idrossi. Any suitable substituents for any alkyl group include hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy or alkylcarbonyl groups, in particular hydroxy.
Come qui usato, il termine "arile" comprende gruppi fenile e naftile, inparticolare fenile. As used herein, the term "aryl" includes phenyl and naphthyl groups, particularly phenyl.
Eventuali sostituenti adatti per un qualsiasi gruppo arile comprendono fino a 5 sostituenti, preferibilmente fino a 3 sostituenti, scelti fra alchile, alcossi, idrossi, alogeno, trifluorometile, acetile, ciano, nitro, ammino ealchilcarbonilammino . Any suitable substituents for any aryl group comprise up to 5 substituents, preferably up to 3 substituents, selected from alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, acetyl, cyano, nitro, amino and alkylcarbonylamino.
Come qui usato, il termine"eteroarile" comprende gruppi eteroarile singoli o fusi, ciascun anello avendo da 5 a 7 atomi nell'anello, in particolare 5 o 6, i quali atomi d'anello comprendono 1, 2 o 3 eteroatomi scelti tra0, S, oN. As used herein, the term "heteroaryl" includes single or fused heteroaryl groups, each ring having 5 to 7 ring atoms, particularly 5 or 6, which ring atoms comprise 1, 2 or 3 heteroatoms selected from, S, oN.
Gruppi eteroarile adatti comprendono grippi piridile, in particolare 4-piridile, furanile, tiofenile, pirrolile e eteroarile comprendenti anelli benzenici fusi, quali i gruppi chinolinile, benzofuranile e indolile. Suitable heteroaryl groups include pyridyl groups, in particular 4-pyridyl, furanyl, thiophenyl, pyrrolyl and heteroaryl comprising fused benzene rings, such as quinolinyl, benzofuranyl and indolyl groups.
Alcuni degli atomi di carbonio dei composti di formula (I) - come quei composti in cui R1-R7 contengono gruppi alchile chirali - sono atomi di carbonio chirali e pertanto possono fornire stereoisomeri del composto di formula (I). L’invenzione comprende tutte le forme stereoisomere dei composti di formula (I), compresi gli enantiomeri e le loro miscele, racemati inclusi. Le differenti forme stereoisomere possono essere separate o risolte l'una dall'altra con metodi convenzionali, oppure un dato isomero può essere ottenuto per sintesi convenzionali stereospecifiche o asimmetriche. Some of the carbon atoms of the compounds of formula (I) - such as those compounds in which R1-R7 contain chiral alkyl groups - are chiral carbon atoms and therefore can yield stereoisomers of the compound of formula (I). The invention includes all stereoisomeric forms of the compounds of formula (I), including enantiomers and their mixtures, including racemates. The different stereoisomeric forms can be separated or resolved from each other by conventional methods, or a given isomer can be obtained by conventional stereospecific or asymmetric syntheses.
I composti di formula (I) possiedono anche due doppi legami e pertanto possono esistere in uno o più isomeri geometrici. L'invenzione si estende a tutte queste forme isomere dei conposti di formula (I), comprese le loro miscele. Le diverse forme isomere possono essere separate tra loro con mezzi convenzionali, oppure un dato isomero può essere ottenuto con metodi di sintesi convenzionali. The compounds of formula (I) also possess two double bonds and therefore can exist in one or more geometric isomers. The invention extends to all these isomeric forms of the compounds of formula (I), including their mixtures. The different isomer forms can be separated from each other by conventional means, or a given isomer can be obtained by conventional synthesis methods.
Sali adatti dei composti di formula (I) sono i sali farmaceuticamente accettabili, come un sale cloridrato, metansolfonato, maleato,succinato,acetato,propionato o tartrato. Suitable salts of the compounds of formula (I) are the pharmaceutically acceptable salts, such as a hydrochloride, methanesulfonate, maleate, succinate, acetate, propionate or tartrate salt.
Opportuni solvati dei composti di formula (I) sono i solvati farmaceuticamente accettabili,quali gli idrati. Suitable solvates of the compounds of formula (I) are pharmaceutically acceptable solvates, such as hydrates.
I sali e/o i solvati dei composti di formula (I) che non sono farmaceuticamente accettabili possono essere utili come intermedi nella preparazione di sali e/o solvati farmaceuticamente accettabili dei composti di formula (I) o degli stessi composti di formula (I), e costituiscono pertanto un ulteriore aspetto della presente invenzione. The salts and / or solvates of the compounds of formula (I) which are not pharmaceutically acceptable can be useful as intermediates in the preparation of pharmaceutically acceptable salts and / or solvates of the compounds of formula (I) or of the compounds of formula (I) themselves, and therefore constitute a further aspect of the present invention.
Uh composto di formula (I), o un suo sale o un suo solvato, può essere preparato: A compound of formula (I), or a salt or a solvate thereof, can be prepared:
(a) facendo reagire un conposto di formula (II): (a) by reacting a compound of formula (II):
in cui X e Y sono come definiti in relazione alla formula (I), con un reagente capace di convertire un residuo di formula in un residuo di formula (a): where X and Y are as defined in relation to formula (I), with a reactant capable of converting a residue of formula into a residue of formula (a):
in cui sono come definiti in relazione a formula (I); e successivamente, se necessario, realizzare una o più delle seguenti reazioni in which they are as defined in relation to formula (I); and then, if necessary, carry out one or more of the following reactions
(i) conversione di un conposto di formula (I) in un altro composto di formula (I); (i) converting a compound of formula (I) into another compound of formula (I);
(ii) rimozione di un eventuale gruppo protettore; (ii) removal of any protecting group;
(iii) preparazione di un sale o di un solvato del composto così formato. (iii) preparation of a salt or solvate of the compound thus formed.
Un reagente adatto capace di convertire un residuo della formula - A suitable reagent capable of converting a residue of the formula -
sopra definita in un residuo della formula (a) sopra definita, defined above in a residue of formula (a) defined above,
comprende reagenti convenzionali usati per convertire i legami C=0 in doppi legami carbonio carbonio, come un reagente di Wittig o un reagente di Horner-Emmons,per esempio quelli di formula (III): includes conventional reagents used to convert C = 0 bonds into carbon-carbon double bonds, such as a Wittig reagent or a Horner-Emmons reagent, for example those of formula (III):
in cui è come definito in relazione ai composti di formula (I) , X2 rappresenta X come definito in relazione a formula (I) o un gruppo convertibile in esso e X3 rappresenta un residuo -, in cui Rg è come sopra definito, o un gruppo where is as defined in relation to the compounds of formula (I), X2 represents X as defined in relation to formula (I) or a group convertible into it and X3 represents a residue -, in which Rg is as defined above, or a group
La reazione tra i composti di formula (II) e il reagente capace di convertire il gruppo di formula nel residuo di formula (a), può essere effettuata in condizioni convenzionali appropriate, a seconda del particolare reagente scelto, per esempio: The reaction between the compounds of formula (II) and the reagent capable of converting the group of formula into the residue of formula (a), can be carried out under appropriate conventional conditions, depending on the particular reagent selected, for example:
quando il reagente è un composto di formula (III) in cui X3 è un residuo allora la reazione viene effettuata in condizioni convenzionali di Homer-Emmons , usando un solvente come te traidrof urano (THF) , cloruro di metilene o toluene, di preferenza THF, a una temperatura che fornisce una adatta velocità di formazione del prodotto richiesto, convenientemente a temperatura ambiente o a temperatura elevata, come urna temperatura nell'intervallo da 30°C a 120°C; di preferenza la reazione è condotta in presenza di una base quale idruro di sodio, 1,8-diazabiciclo[5.4.0]undec-7-ene (DBU) o diisopropiletilammina (DIPEA) , preferibilmente idruro di sodio, e in generale la reazione è effettuata in atmosfera inerte, per esempio azoto. when the reagent is a compound of formula (III) in which X3 is a residue then the reaction is carried out under conventional Homer-Emmons conditions, using a solvent such as tetrahydrofuran (THF), methylene chloride or toluene, preferably THF , at a temperature which provides a suitable rate of formation of the required product, conveniently at room temperature or at an elevated temperature, such as a temperature in the range of 30 ° C to 120 ° C; preferably the reaction is carried out in the presence of a base such as sodium hydride, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or diisopropylethylamine (DIPEA), preferably sodium hydride, and in general the reaction it is carried out in an inert atmosphere, for example nitrogen.
Quando il reagente è un composto di formula (III) in cui X3 è un residuo allora la reazione viene effettuata in condizioni convenzionali di Hittig, utilizzando un solvente quale THF,dietiletere, cloruro di metilene o toluene, di preferenza cloruro di metilene, a una temperatura che fornisce una adatta velocità di formazione del prodotto richiesto, convenientemente a temperatura ambiente o a una temperatura elevata, come una temperatura nell'intervallo da 30°C a 120°c, preferibilmente la reazione è condotta in presenza di una base quale idruro di sodio, DBU o DIPEA, preferibilmente idruro di sodio. When the reagent is a compound of formula (III) in which X3 is a residue then the reaction is carried out under conventional Hittig conditions, using a solvent such as THF, diethyl ether, methylene chloride or toluene, preferably methylene chloride, at a temperature which provides a suitable rate of formation of the required product, conveniently at room temperature or at an elevated temperature, such as a temperature in the range of 30 ° C to 120 ° C, preferably the reaction is carried out in the presence of a base such as sodium hydride , DBU or DIPEA, preferably sodium hydride.
La reazione tra i composti di formula (II)e il reagente di Homer-Emmons di formula (III) può essere effettuata in condizioni convenzionali di Horner-Emmons come quelle sopra descritte. The reaction between the compounds of formula (II) and the Homer-Emmons reagent of formula (III) can be carried out under conventional Horner-Emmons conditions such as those described above.
Un altro reagente adatto capace di convertire un residuo della formula sopra definita in un residuo della formula (a) sopra definita è un composto di formula (IV): Another suitable reagent capable of converting a residue of the formula defined above into a residue of the formula (a) defined above is a compound of formula (IV):
(IV) (IV)
in cu sono come definiti in relazione ai composti di formula (III). in which they are as defined in relation to the compounds of formula (III).
In generale, il reagente di formula (IV) è in forma attivata, opportunamente in forma anionica, come una forma salificata, per esempio una forma salificata di un metallo alcalino. La reazione tra i composti di formula (II)e (IV)può essere effettuata secondo procedure note, per esempio quelle descritte in Liebigs Ann.Chem., 703,1967, 37. In general, the reagent of formula (IV) is in activated form, suitably in anionic form, such as a salified form, for example a salified form of an alkali metal. The reaction between the compounds of formula (II) and (IV) can be carried out according to known procedures, for example those described in Liebigs Ann.Chem., 703,1967, 37.
Conversioni adatte di un composto di formula (I) in un altro composto di formula (I) conprendono la conversione di un composto di formula (I) in cui X rappresenta un gruppo idrossi o un gruppo alcossi in un composto di formula (I) in cui X rappresenta un residuo della formula sopra definita. Suitable conversions of a compound of formula (I) to another compound of formula (I) include the conversion of a compound of formula (I) in which X represents a hydroxy group or an alkoxy group in a compound of formula (I) into where X represents a residue of the formula defined above.
La conversione di un composto di formula (I) in un altro composto di formula (I) può essere effettuata usando la procedura convenzionale adatta, per esempio la conversione sopra menzionata di un composto in cui rappresenta un gruppo idrossi o un gruppo al cossi in un composto in cui rappresenta un residuo della formila sopra definita, può essere effettuata come segue: The conversion of a compound of formula (I) to another compound of formula (I) can be carried out using the suitable conventional procedure, for example the above-mentioned conversion of a compound in which it represents a hydroxy group or an alkoxy group into a compound in which it represents a residue of the formula defined above, can be carried out as follows:
(i) quando è alcossi , mediante idrolisi basica, usando per esempio idrossido di potassio, per fornire un composto di formula (I) in cui è idrossi, e successivo trattamento con un composto di formula (i) when it is alkoxy, by basic hydrolysis, using for example potassium hydroxide, to provide a compound of formula (I) wherein it is hydroxy, and subsequent treatment with a compound of formula
in cui hanno il valore richiesto rispettivamente di e di where they have the required value of and of respectively
di preferenza la reazione col composto di formula avviene preferably the reaction with the compound of formula takes place
in presenza di un agente condensante, quale Ν,Ν'-dicicloesil carbodiimmide (DCC) o dopo conversione di (I), in cui è idrossi, nel corrispondente cloruro di acido e condensazione in presenza di una base quale trietilammina; alternativamente mediante trattamento di detto composto di formula (I ) direttamente con un composto di formula in the presence of a condensing agent, such as Ν, Ν'-dicyclohexyl carbodiimide (DCC) or after conversion of (I), in which it is hydroxy, to the corresponding acid chloride and condensation in the presence of a base such as triethylamine; alternatively by treating said compound of formula (I) directly with a compound of formula
in presenza di un trialchilalluminio , come trimetilalluminio , secondo procedure note, quali quelle descritte in Tetrahedron Lett. , 48, 1977, 4171. in the presence of a trialkylaluminium, such as trimethylaluminium, according to known procedures, such as those described in Tetrahedron Lett., 48, 1977, 4171.
(ii) quando è idrossi, mediante uso di procedure analoghe a quelle sopra menzionate in (i). (ii) when it is hydroxy, through the use of procedures similar to those mentioned above in (i).
Un composto di formula (II) può essere preparato secondo la sequenza di reazioni illustrata nello Schema (I) qui sotto: A compound of formula (II) can be prepared according to the sequence of reactions illustrated in Scheme (I) below:
Schema (I) Scheme (I)
in cui X e Y sono come definiti in relazione alla formula (I). where X and Y are as defined in relation to formula (I).
Le reazioni nello Schema (I) possono essere effettuate usando la procedura convenzionale appropriata, per esempio per i composti in cui R2 rappresenta idrogeno: The reactions in Scheme (I) can be carried out using the appropriate conventional procedure, for example for compounds where R2 represents hydrogen:
(i)I composti di formula (V) sono preparati mediante una reazione di Homer-Emmons a partire dai chetoni (VI) e trietilfosfonoacetato, utilizzando condizioni di reazione come quelle descritte sopra e in letteratura (Liebigs Ann.Chem.,1967,703,37). (i) The compounds of formula (V) are prepared by a Homer-Emmons reaction starting from ketones (VI) and triethylphosphonoacetate, using reaction conditions such as those described above and in the literature (Liebigs Ann.Chem., 1967,703 , 37).
(ii) L'estere carbossilico (V) viene poi convertito nell'alcol corrispondente con un agente riducente quale idruro di litio e alluminio, diisobutilalluminio idruro (DIBAH), o sodio boroidruro in un solvente quale cloruro di metilene dietilere o tetraidrofurano a una temperatura tra -10°C e 60°C,per esempio a temperatura ambiente. (ii) The carboxylic ester (V) is then converted to the corresponding alcohol with a reducing agent such as lithium aluminum hydride, diisobutylaluminium hydride (DIBAH), or sodium borohydride in a solvent such as methylene chloride diethyl or tetrahydrofuran at a temperature between -10 ° C and 60 ° C, for example at room temperature.
(iii) Poi l'alcol viene ossidato ad aldeide (II) usando un agente ossidante quelle PCC (piridinio clorocromato) o PDC (piridinio dicromato ) , preferibilmente con (iii) Then the alcohol is oxidized to aldehyde (II) using an oxidizing agent such as PCC (pyridinium chlorchromate) or PDC (pyridinium dichromate), preferably with
Per i composti in cui R2 è diverso da idrogeno, per esempio alchile, i composti (II) sono ottenuti direttamente dal (VI) con una reazione di Wittig o di Homer-Emmons, con le ilidi di fosforo o i fosfonati adatti, utilizzando le condizioni sopra descritte. For compounds in which R2 is different from hydrogen, e.g. alkyl, compounds (II) are obtained directly from (VI) with a Wittig or Homer-Emmons reaction, with suitable phosphorus ylides or phosphonates, using the conditions described above.
I sali e/o i solvati dei composti di formula (I) possono essere preparati usando la procedura tradizionale adatta. The salts and / or solvates of the compounds of formula (I) can be prepared using the suitable traditional procedure.
I composti di formula (III) sono composti noti o sono preparati utilizzando metodi analoghi a quelli usati per preparare composti noti, come quelli descritti in Chem. Ber., 97, 1964, 1713; Tetrahedron, 50, 1994,3177. The compounds of formula (III) are known compounds or are prepared using methods analogous to those used to prepare known compounds, such as those described in Chem. Ber., 97, 1964, 1713; Tetrahedron, 50, 1994,3177.
I composti di formula (IV) e (VI) sono composti noti o sono preparati impiegando metodi analoghi a quelli usati per preparare composti noti, quali quelli descritti in J. March, Advanced Organic Chemistry, 3rd Edition (1985),Wiley Interscience. The compounds of formula (IV) and (VI) are known compounds or 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.
Un composto di formula (I) o un suo sale o un suo solvato può essere isolato dai processi sopracitati secondo procedure chimiche standard. Quando richiesto è possibile determinare la stereochimica assoluta dei composti impiegando metodi convenzionali, quali cristallografia ai raggi X. A compound of formula (I) or its salt or solvate can be isolated from the aforementioned processes according to standard chemical procedures. When required, it is possible to determine the absolute stereochemistry of the compounds using conventional methods, such as X-ray crystallography.
Come sopra citato, i composti dell'invenzione sono dotati di utili proprietà terapeutiche. As mentioned above, the compounds of the invention are endowed with useful therapeutic properties.
La presente invenzione fornisce pertanto un composto di formula (I) o un suo solvato farmaceuticamente accettabile, per uso come sostanza terapeuticamente attiva. The present invention therefore provides a compound of formula (I) or a pharmaceutically acceptable solvate thereof, for use as a therapeutically active substance.
In particolare la presente invenzione fornisce un composto di formula (I) o un suo sale o solvato farmaceuticamente accettabile, per uso nel trattamento e/o profilassi dell'osteoporosi e delle malattie osteopeniche correlate. In particular, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prophylaxis of osteoporosis and related osteopenic diseases.
I composti attivi o i loro sali e/o solvati farmaceuticamente accettabili sono normalmente somministrati in forme di dosaggio unitario. Active compounds or their pharmaceutically acceptable salts and / or solvates are normally administered in unit dosage forms.
Una quantità efficace per trattare la patologia sopra descritta dipende da fattori quali l’efficacia dei composti attivi, la particolare natura del sale o solvato farmaceuticamente accettabile scelto, la natura e gravità delle malattie da trattare e il peso del paziente. An effective amount to treat the disease described above depends on factors such as the effectiveness of the active compounds, the particular nature of the pharmaceutically acceptable salt or solvate chosen, the nature and severity of the diseases to be treated and the weight of the patient.
Tuttavia, una dose unitaria conterrà normalmente da 0,01 a 50 mg, per esempio da 1 a 25 mg, del composto dell'invenzione. Dosi unitarie saranno normalmente somministrate una o più volte al giorno, per esempio 2, 3, 4, 5 o 6 volte al giorno, più frequentemente da 2 a 4 volte al giorno, in modo che la dose giornaliera totale sia normalmente nell'intervallo, per un adulto di 70 kg, da 0,01 a 250 mg, più frequentemente da 1 a 100 mg, per esempio da 5 a 70 mg, che equivale all'intervallo da circa 0,0001 a 3,5 mg/kg/giorno, più frequentemente da 0,01 a 1,5 mg/kg/giomo, per esenpio da 0,05 a 0,7 mg/kg/giomo. However, a unit dose will normally contain 0.01 to 50 mg, e.g. 1 to 25 mg, of the compound of the invention. Unit doses will normally be administered once or more times a day, for example 2, 3, 4, 5 or 6 times a day, more frequently 2 to 4 times a day, so that the total daily dose is normally within the range, for a 70 kg adult, 0.01 to 250 mg, more frequently 1 to 100 mg, for example 5 to 70 mg, which equates to the range of approximately 0.0001 to 3.5 mg / kg / day , more frequently from 0.01 to 1.5 mg / kg / day, for example from 0.05 to 0.7 mg / kg / day.
Nell'intervallo di dose sopra descritto, non sono stati riscontrati effetti tossici per i composti dell'invenzione. In the dose range described above, no toxic effects were found for the compounds of the invention.
La presente invenzione fornisce inoltre un metodo per il trattamento dell'osteoporosi e delle malattie osteopeniche correlate in un mammifero umano o non umano, che comprende la somministrazione di una quantità efficace,non tossica di un composto di formula (I)o di un suo sale o solvato farmaceuticamente accettabile al soggetto che necessita di tale trattamento. 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 the administration of an effective, non-toxic amount of a compound of formula (I) or a salt thereof. or pharmaceutically acceptable solvate to the person who needs such treatment.
In tale trattamento, il composto attivo può essere somministrato per una qualunque via adatta, per esempio per via orale, parenterale o topica. Per tale uso, il composto sarà normalmente impiegato sotto forma di una conposizione farmaceutica in associazione con un veicolo, diluente e/o eccipiente farmaceutico umano o veterinario, sebbene la precisa forma della composizione dipenda naturalmente dal modo di somministrazione. In such treatment, the active compound can be administered by any suitable route, for example by the oral, parenteral or topical route. For such use, the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical vehicle, diluent and / or excipient, although the precise form of the composition will of course depend on the mode of administration.
Le composizioni sono preparate per miscelazione e sono opportunamente adatte per somministrazione orale, parenterale o topica, e possono essere in forma di conpresse, capsule, preparazioni orali liquide, polveri, granuli, cialde, pastiglie, polveri ricostituibili, soluzioni o sospensioni iniettabili e per infusione, supposte e dispositivi transdermici. Sono preferite composizioni somministrabili per via orale, in particolari composizioni orali solide, poiché esse sono più convenienti per l'uso generale. The compositions are prepared by mixing and are suitably suitable for oral, parenteral or topical administration, and can be in the form of tablets, capsules, liquid oral preparations, powders, granules, pods, tablets, reconstitutable powders, injectable and infusion solutions or suspensions. , suppositories and transdermal devices. Orally administrable compositions are preferred, in particular solid oral compositions, since they are more convenient for general use.
Le compresse e le capsule per somministrazione orale sono normalmente presentate in dose unitaria e contengono eccipienti convenzionali quali agenti leganti, riempitivi, diluenti, agenti di pressatura, lubrificanti, disintegranti, coloranti, aromi e agenti bagnanti. Le compresse possono essere rivestite secondo metodi ben noti. The tablets and capsules for oral administration are normally presented in unit doses and contain conventional excipients such as binding agents, fillers, diluents, pressing agents, lubricants, disintegrants, dyes, flavors and wetting agents. The tablets can be coated according to well known methods.
Riempitivi adatti comprendono cellulosa, mannitolo, lattosio e altri agenti simili. Disintegranti adatti comprendono amido, polivinilpirrolidone e derivati di amido quale amido sodio glicolato. Lubrificanti adatti comprendono, per esempio, stearato di magnesio. Opportuni agenti bagnanti farmaceuticamente accettabili comprendono sodio laurilsolfato. Suitable fillers include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as starch sodium glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.
Queste composizioni orali solide possono essere preparate con metodi convenzionali di miscelazione, riempimento, compressione o simili. Ripetute operazioni di miscelazione possono essere usate per distribuire l'agente attivo in quelle composizioni che impiegano grandi quantità di riempitivi. Tale operazioni sono ovviamente di tipo convenzionale. These solid oral compositions can be prepared by conventional methods of mixing, filling, squeezing or the like. Repeated mixing operations can be used to distribute the active agent in those compositions which employ large amounts of fillers. These operations are obviously of a conventional type.
Preparazioni orali liquide possono essere, per esempio, nella forma di sospensioni acquose o oleose, soluzioni, emulsioni, sciroppi o elisir o possono essere presentate come prodotti secchi da ricostituire con acqua o altri opportuni veicoli prima dell'uso. Tali preparazioni liquide possono contenere additivi convenzionali quali agenti sospendenti, per esenpio sorbitolo, sciroppo, metilcellulosa, gelatina, idrossietilcellulosa, carbossimetilcellulosa, gel di alluminio stearato o grassi idrogenati commestibili, agenti emulsionanti, per esempio lecitina, sorbitan monoleato o gomma acacia; veicoli non acquosi (che possono comprendere olii commestibili), per esempio, olio di mandorla, olio frazionato di cocco, esteri oleosi quali esteri di glicerina, propilenglicol o alcol etilico; conservanti, per esempio metil o propil p-idrossibenzoato o acido sorbico e se desiderato agenti aromatizzanti o coloranti convenzionali. Liquid oral preparations can be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or they can be presented as dry products to be reconstituted with water or other suitable vehicles before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum gel stearate or edible hydrogenated fats, emulsifying agents, for example lecithin, sorbitan monoleate or acacia gum; non-aqueous carriers (which may include edible oils), for example, almond oil, coconut fractionated oil, oil esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid and if desired conventional flavoring or coloring agents.
Per la somministrazione parenterale, si preparano forme di dosaggio unitario fluide contenenti un composto della presente invenzione e un veicolo sterile. Il composto, a seconda del veicolo e della concentrazione, può essere in sospensione o in soluzione. Le soluzioni parenterali sono normalmente preparate sciogliendo il composto in un veicolo e sterilizzando per filtrazione prima della distribuzione in una opportuna fiala o flaconcino. Vantaggiosamente, nel veicolo vengono sciolti anche eccipienti e adiuvanti quali anestetici locali, agenti conservanti e tamponanti. Per aumentare la stabilità, la composizione può essere congelata dopo la distribuzione nella fiala e l'acqua eliminata sotto vuoto. For parenteral administration, flowable unit dosage forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and concentration, can be in suspension or in solution. The parenteral solutions are normally prepared by dissolving the compound in a vehicle and sterilizing by filtration before distribution in a suitable vial or vial. Advantageously, excipients and adjuvants such as local anesthetics, preservative and buffering agents are also dissolved in the vehicle. To increase stability, the composition can be frozen after dispensing into the vial and the water removed under vacuum.
Sospensioni parenterali sono preparate sostanzialmente allo stesso modo, salvo che il composto è sospeso anziché sciolto nel veicolo e sterilizzato per esposizione ad ossido di etilene prima della sospensione nel veicolo sterile. Vantaggiosamente, nella composizione viene incluso un agente tensioattivo o bagnante per facilitare la distribuzione uniforme del composto attivo. Parenteral suspensions are prepared in substantially the same way, except that the compound is suspended rather than dissolved in the vehicle and sterilized by exposure to ethylene oxide prior to suspension in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate the uniform distribution of the active compound.
Per la somministrazione topica, la composizione può essere sotto forma di pomata o cerotto transdermico per la somministrazione sistemica del composto attivo e può essere preparata in maniera convenzionale,per esempio come descritto nei testi standard quali "Dermatological Formulations" - B.W. Barry (Drugs and thè Pharmaceutical Sciences -Dekker)o Harrys Cosmeticology (Léonard Hill Books). For topical administration, the composition can be in the form of an ointment or transdermal patch for the systemic administration of the active compound and can be prepared in a conventional manner, for example as described in standard texts such as "Dermatological Formulations" - B.W. Barry (Drugs and the Pharmaceutical Sciences -Dekker) or Harrys Cosmeticology (Léonard Hill Books).
Come è pratica comune, le composizioni saranno accompagnate da istruzioni scritte o stampate per l'uso nell'indicazione medica prevista. As is common practice, the compositions will be accompanied by written or printed instructions for use in the intended medical indication.
Le seguenti descrizioni, esempi e metodi farmacologici illustrano l'invenzione senza limitarla in alcun modo. The following descriptions, examples and pharmacological methods illustrate the invention without limiting it in any way.
Le abbreviazioni utilizzate nel corso della descrizione e negli esempi successivi hanno i seguenti significati: The abbreviations used throughout the description and in the following examples have the following meanings:
Lista delle abbreviazioni List of abbreviations
Preparazione 1 Preparation 1
(10,ll-Diidro-5H-dibenzo[a,d]cicloepten-5-ilidene)acetato d'etile. Ad una sospensione di NaH (0,96 g, 24 mmol; 60 % dispersione in olio prelavata con pantano) in THF anidro (20 ml) sotto azoto, una soluzione di trietil fosfonoacetato (5,76 mi, 28,8 mmol) in THF anidro (10 ml) fu aggiunta goccia a goccia e la reazione fu agitata a temperatura ambiente per 30 min. Una soluzione di dibenzosuberone (5 g, 24 mmol) in THF anidro (5 mi) fu gocciolata e la reazione fu agitata sotto azoto a riflusso per sei giorni. Dopo raffreddamento, la reazione fu bloccata con acqua, estratta con (3 x 30 mi), anidrificata con ed evaporata sotto vuoto. Il residuo fu purificato mediante cromatografia flash per fornire 3,2 g (48%) del composto del titolo come olio. (10, 11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) ethyl acetate. To a suspension of NaH (0.96 g, 24 mmol; 60% dispersion in oil pre-washed with mud) in anhydrous THF (20 ml) under nitrogen, a solution of triethyl phosphonoacetate (5.76 ml, 28.8 mmol) in Anhydrous THF (10 ml) was added dropwise and the reaction was stirred at room temperature for 30 min. A solution of dibenzosuberone (5 g, 24 mmol) in anhydrous THF (5 ml) was dropped and the reaction stirred under nitrogen at reflux for six days. After cooling, the reaction was stopped with water, extracted with (3 x 30 ml), dried with and evaporated in vacuo. The residue was purified by flash chromatography to yield 3.2 g (48%) of the title compound as an oil.
Preparazione 2 Preparation 2
(10,ll-Diidro -5H-dibenzo [a,d]cicloepten -5-ilidene)acetaldeide. Ad una soluzione di (10,11-diidro-5H-dibenzo[a,d]cicloepten-5-ilidene)acetato d'etile (1 g, 3,6 mmol) in (15 ml) sotto azoto e raffreddata a -78°C, fu aggiunta goccia a goccia una soluzione di DIBAH 1M in esano (3,6 ml) e quindi la miscela di reazione fu fatta salire a temperatura ambiente.Dopo una ulteriore aggiunta di DIBAH 1M in esano (7 ml) la reazione fu agitata per 3h a temperatura ambiente, trattata con una soluzione satura di e estratta con (3 x 10 ml). Le fasi organiche riunite furono lavate con una soluzione satura di NaCl (10 ml), anidrificate con ed evaporate a secchezza, per fornire 0,84 g di (10,ll-diidro-5H-dibenzo[a,d]ciclohepten-5-ilidene) metanolo come olio incolore. Questo fu sciolto in cloruro di metilene (10 ml) e trattato con biossido di manganese attivato (0,62 g, 13,8 mmol) a temperatura ambiente. Dopo tre giorni altro biossido di manganese (1,2 g, 7,1 mmol) fu aggiunto e l'agitazione fu continuata a temperatura ambiente per altri due giorni. La miscela fu quindi filtrata sotto vuoto su un pannello di Celite, lavata con cloruro di metilene (3 x 20 ml), anidrificata con e concentrata sotto vuoto a dare 0,77 g (91,3%) del composto del titolo. (10, ll-Dihydro -5H-dibenzo [a, d] cyclohepten -5-ylidene) acetaldehyde. To a solution of (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) ethyl acetate (1 g, 3.6 mmol) in (15 ml) under nitrogen and cooled to -78 ° C, a solution of DIBAH 1M in hexane (3.6 ml) was added dropwise and then the reaction mixture was allowed to rise to room temperature. After a further addition of DIBAH 1M in hexane (7 ml) the reaction was stirred for 3h at room temperature, treated with a saturated solution of and extracted with (3 x 10 ml). The combined organic phases were washed with a saturated solution of NaCl (10 ml), dried with and evaporated to dryness, to yield 0.84 g of (10, ll-dihydro-5H-dibenzo [a, d] cyclohepten-5- ilidene) methanol as a colorless oil. This was dissolved in methylene chloride (10 ml) and treated with activated manganese dioxide (0.62 g, 13.8 mmol) at room temperature. After three days more manganese dioxide (1.2 g, 7.1 mmol) was added and stirring was continued at room temperature for another two days. The mixture was then vacuum filtered on a Celite panel, washed with methylene chloride (3 x 20 ml), dried with and concentrated in vacuo to give 0.77 g (91.3%) of the title compound.
Esempio 1 Example 1
( Z)-4-(10,11-Diidro-5H-dibenzo[a,d]cicloepten-5-ilidene)-2-metossi-2-butenoato di metile. Ad una sospensione di NaH (0,2 g, 5 mmol; 60 % dispersione in olio pre-lavata con pentano) in THF anidro (10 ml) sotto azoto, una soluzione di trimetil 2-metossifosfonoacetato (0,9 g, 4,24 mmol) in THF anidro (5 ml) fu aggiunta goccia a goccia e la miscela di reazione fu agitata a 40°C per 40 min. Dopo raffreddamento a temperatura ambiente, (10,11-diidro-5H-dibenzo[a,d]cicloepten-5-ilidene)acetaldeide (0,77 g, 3,28 mmol) fu aggiunta e l'agitazione fu continuata a temperatura ambiente per 12 h e poi a 50°C per due giorni. La miscela fu trattata con acqua, estratta con Et20 (3 x 10 ml), lavata con una soluzione satura di NaHS03, anidrificata con ed evaporata sotto vuoto. Il residuo fu cromatografato su gel di silice (Z) -4- (10,11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) -2-methoxy-2-methyl butenoate. To a suspension of NaH (0.2 g, 5 mmol; 60% dispersion in oil pre-washed with pentane) in anhydrous THF (10 ml) under nitrogen, a solution of trimethyl 2-methoxyphosphonoacetate (0.9 g, 4, 24 mmol) in anhydrous THF (5 ml) was added dropwise and the reaction mixture was stirred at 40 ° C for 40 min. After cooling to room temperature, (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) acetaldehyde (0.77 g, 3.28 mmol) was added and stirring was continued at room temperature for 12 h and then at 50 ° C for two days. The mixture was treated with water, extracted with Et20 (3 x 10 ml), washed with a saturated solution of NaHSO 3, dried with and evaporated under vacuum. The residue was chromatographed on silica gel
ottenendo 18 mg (1,7%) del composto del titolo,p.f. = 107-109°C. obtaining 18 mg (1.7%) of the title compound, m.p. = 107-109 ° C.
Esempio 2 Example 2
(2Z)-5,5-Difenil-2-metossi-2,4-pentadienoato di metile e (2E)-5,5-difenil-2-metossi-2,4-pentadienoato di metile. b-Fenilcinnamaldeide (1 g, 4,8 mmol) fu fatta reagire con trimetri 2-metossifosfonoacetato (1,3 g, 6,1 mmol) e NaH 60% dispersione in olio (0,3 g, 7,5 mmol), secondo la procedura descritta nell'Esempio 1, per fornire, dopo purificazione per cromatografia, 80 mg (6%) dell' isomero Z,p.f.= 93-94°C e 0,14 g (10%) dell' isomero E, come olio incolore. Methyl (2Z) -5,5-diphenyl-2-methoxy-2,4-pentadienoate and methyl (2E) -5,5-diphenyl-2-methoxy-2,4-pentadienoate. b-Phenylcinnamaldehyde (1 g, 4.8 mmol) was reacted with 2-methoxyphosphonoacetate (1.3 g, 6.1 mmol) and NaH 60% oil dispersion (0.3 g, 7.5 mmol), according to the procedure described in Example 1, to provide, after purification by chromatography, 80 mg (6%) of the isomer Z, m.p. = 93-94 ° C and 0.14 g (10%) of the isomer E, as colorless oil.
(2Z)-5,5-Difenil-2-metossi-2,4-pentadienoato di metile: Methyl (2Z) -5,5-Diphenyl-2-methoxy-2,4-pentadienoate:
(2E)-5, 5-Difenil-2-metossi-2, 4-pentadienoato di metile: Methyl (2E) -5, 5-Diphenyl-2-methoxy-2, 4-pentadienoate:
Esempio 3 Example 3
( 2Z ) -5 , 5-Difenil-2-metossi-2 , 4-pentadienoato di metile. Una soluzione di b-fenilcinnamaldeide (2 g, 9,6 mmol ), bromuro di 2-metossi-2 (trifenilfosfonio) acetato di metile ( Chem . Ber. , 97, 1964, 1713) ( 8,9 g, 18,6 mmol ) e DBU ( 2,9 ml, 19,2 mmol ) in THF anidro fu agitata a 50°C per 15 h sotto azoto. Dopo raffreddamento, e diluizione con etere etilico, il precipitato fu filtrato. Il filtrato fu lavato successivamente con HC1 10% (10 ml) , soluzione satura di e una soluzione satura di NaCl, anidrificato con ed evaporato sotto vuoto. Il residuo fu purificato mediante cromatografia flash Methyl (2Z) -5, 5-Diphenyl-2-methoxy-2, 4-pentadienoate. A solution of b-phenylcinnamaldehyde (2 g, 9.6 mmol), 2-methoxy-2 bromide (triphenylphosphonium) methyl acetate (Chem. Ber., 97, 1964, 1713) (8.9 g, 18.6 mmol) and DBU (2.9 ml, 19.2 mmol) in anhydrous THF was stirred at 50 ° C for 15 h under nitrogen. After cooling, and dilution with ethyl ether, the precipitate was filtered. The filtrate was subsequently washed with 10% HCl (10 ml), a saturated solution of and a saturated solution of NaCl, anhydrified with and evaporated under vacuum. The residue was purified by flash chromatography
e, dopo sgranamento con etere isopropilico, 1,8 g and, after shelling with isopropyl ether, 1.8 g
(63,8%) del composto del titolo furono ottenuti, p.f.= 93-94°C. (63.8%) of the title compound were obtained, mp = 93-94 ° C.
I composti seguenti sono stati preparati secondo i procedimenti dell' invenzione. The following compounds were prepared according to the processes of the invention.
Saggi biologici Biological assays
E' noto che, in seguito all'adesione alla superficie ossea, una adenosin trifostatasi (ATPasi) H<+ >elettrogenica è polarizzata alla interfaccia osteoclasto-osso. La pompa trasporta notevoli quantità di protoni nel microambiente di riassorbimento promuovendo la mobilizzazione del minerale osseo e creando il acido richiesto dalle collagenasi per degradare la matrice ossea. It is known that, following adhesion to the bone surface, an electrogenic H <+> adenosine triostatase (ATPase) is polarized at the osteoclast-bone interface. The pump transports large amounts of protons into the resorption microenvironment promoting bone mineral mobilization and creating the acid required by collagenases to degrade the bone matrix.
La natura vacuolare della pompa protonica dell'osteoclasto fu originalmente riconosciuta da Blair [H.C. Blair et al., Science, 245, 855 (1989)] e poi confermata da Bekker [P.J. Bekker et al., J. Bone. Min. Res., 5, 569 (1990)] e Vaananen [K.K. Vaananen et al., J. Cell. Biol., 111, 1305 (1990)]. L'evidenza era basata su preparazioni di frammenti di membrana da osteoclasti di uccello (ottenuti dall'osso midollare di galline ovaiole sottoposte a dieta priva di calcio). Le vescicole di membrana ottenute si acidificano in risposta all'ATP, il che è facilmente valutato misurando la diminuzione di fluorescenza dell'arancio di acridina, una base debole che si accumula nei compartimenti acidi. The vacuolar nature of the osteoclast proton pump was originally recognized by Blair [H.C. Blair et al., Science, 245, 855 (1989)] and later confirmed by Bekker [P.J. Bekker et al., J. Bone. Min. Res., 5, 569 (1990)] and Vaananen [K.K. Vaananen et al., J. Cell. Biol., 111, 1305 (1990)]. The evidence was based on preparations of membrane fragments from bird osteoclasts (obtained from the medullary bone of laying hens on a calcium-free diet). The obtained membrane vesicles acidify in response to ATP, which is easily assessed by measuring the decrease in fluorescence of acridine orange, a weak base that accumulates in the acid compartments.
Le caratteristiche biochimiche indicavano che la pompa pròtonica dell'osteoclasto apparteneva alle ATPasi di tipo vacuolare, poiché il trasporto protonico era inibito dalla N-etilmaleimmide (NEM), un reagente sulfidrilico, e dalla bafilomicina A1, un inibitore selettivo delle H<+>-ATPasi vacuolari [J.E. Bowman et al., Proc. Natl. Acad. Sci. USA, 85, 7972 (1988)], mentre non era inibito dalla ouabaina, un inibitore di Na<+>/K<+>-ATPasi; dall'ortovanadato di sodio, un inibitore delle p-ATPasi,o da parte di omeprazolo o SCH 28080, entrambi inibitori della H<+>/K<+>-ATPasi gastrica [J.P. Mattson et al., Acta Physiol. Scand., 146, 53 (1992)]. Biochemical characteristics indicated that the osteoclast proton pump belonged to vacuolar type ATPases, since proton transport was inhibited by N-ethylmaleimide (NEM), a sulfhydryl reagent, and by bafilomycin A1, a selective inhibitor of H <+> - Vacuolar ATPases [J.E. Bowman et al., Proc. Natl. Acad. Sci. USA, 85, 7972 (1988)], while it was not inhibited by ouabain, an inhibitor of Na <+> / K <+> - ATPase; by sodium orthvanadate, a p-ATPase inhibitor, or by omeprazole or SCH 28080, both inhibitors of gastric H <+> / K <+> - ATPase [J.P. Mattson et al., Acta Physiol. Scand., 146, 53 (1992)].
E' noto che gli inibitori specifici delle ATP-asi vacuolari, quali la bafilomicina A1, sono in grado di inibire il riassorbimento osseo in colture di osteoclasti [K. Sundquist et al., Biochem. Biophys. Res. Commun. 168,309-313 (1990)]. Specific vacuolar ATP-as inhibitors, such as bafilomycin A1, are known to inhibit bone resorption in osteoclast cultures [K. Sundquist et al., Biochem. Biophys. Res. Commun. 168,309-313 (1990)].
INIBIZIONE DEL TRASPORTO PROTONICO v-ATP-asi DIPENDENTE IN VESCICOLE DI MEMBRANE INHIBITION OF PROTONIC TRANSPORT v-ATP-asi DEPENDENT IN MEMBRANE VESICLES
Preparazione di microsomi grezzi da osso di galline ovaiole sottoposte a dieta priva di calcio. Preparation of raw microsomes from the bone of laying hens subjected to a calcium-free diet.
Furono preparate vescicole da osso midollare ottenuto da tibie e femori di galline ovaiole che erano sottoposte a dieta priva di calcio per almeno 15 giorni. In breve, frammenti ossei furono prelevati con uno scalpello (lama 24), sospesi in 40 ml di terreno di isolamento (0,2 M saccarosio, 50 mM KC1, 10 mM Hepes, 1 mM EGTA, 2 mM ditioteitrolo, pH 7,4) e filtrati attraverso una rete di nylon con pori da 100 μm. L'intera procedura era effettuata a 4°C. Dopo omogeneizzazione con un omogeneizzatore (20 colpi) in 40 ml di terreno di isolamento, fu effettuata una centrifugazione iniziale (6500 gma x 20 min) per rimuovere i mitocondri e lisosomi. Il surnatante fu centrifugato a 100.000 gmax per 1 h e il pellet fu raccolto in 1 ml di terreno di isolamento, suddiviso in aliquote da 200 μl, immediatamente congelato in azoto liquido e conservato a -80°C. Il contenuto proteico fu determinato impiegando un kit colorimetrico Biorad secondo Bradford [M. Bradford, Anal. Biochem., 72, 246 (1976)]. Per il saggio di trasporto protonico, si impiegarono 5-10 μl di membrane. Vesicles were prepared from medullary bone obtained from the tibias and femurs of laying hens which had been on a calcium-free diet for at least 15 days. Briefly, bone fragments were removed with a chisel (blade 24), suspended in 40 ml of isolation medium (0.2 M sucrose, 50 mM KC1, 10 mM Hepes, 1 mM EGTA, 2 mM dithioteitrol, pH 7.4 ) and filtered through a nylon mesh with 100 μm pores. The whole procedure was performed at 4 ° C. After homogenization with a homogenizer (20 strokes) in 40 ml of isolation medium, an initial centrifugation (6500 gma x 20 min) was performed to remove the mitochondria and lysosomes. The supernatant was centrifuged at 100,000 gmax for 1 h and the pellet was collected in 1 ml of isolation medium, divided into 200 μl aliquots, immediately frozen in liquid nitrogen and stored at -80 ° C. The protein content was determined using a Biorad colorimetric kit according to Bradford [M. Bradford, Anal. Biochem., 72, 246 (1976)]. For the proton transport assay, 5-10 μl of membranes were used.
Purificazione di membrane di osteoclasto. 1 ml di vescicole microsiomali grezze preparate come sopra fu applicato (circa 0,2 mi per provetta) sulla parte superiore di un gradiente discontinuo di saccarosio costituito da 3,5 ml di saccarosio al 15,30 e 45% (p/p)nel terreno di isolamento e centrifugato a 280.000 gmax per 2 ore (rotore SW 41 Ti). Dopo centrifugazione le interfacce al 30-45% di saccarosio furono raccolte, diluite di circa 20 volte nel terreno di isolamento e centrifugate a 100.000 gmax per 1 ora (rotore SW 28). Il pellet fu quindi risospeso in 1 ml di terreno di isolamento, suddiviso in aliquote e congelato in azoto liquido e conservato a -80°C fino al momento dell'impiego. Purification of osteoclast membranes. 1 ml of crude microsiomal vesicles prepared as above was applied (approximately 0.2 ml per tube) on top of a discontinuous sucrose gradient consisting of 3.5 ml of 15.30 and 45% (w / w) sucrose in the isolation medium and centrifuged at 280,000 gmax for 2 hours (SW 41 Ti rotor). After centrifugation the 30-45% sucrose interfaces were collected, diluted about 20 times in the isolation medium and centrifuged at 100,000 gmax for 1 hour (SW 28 rotor). The pellet was then resuspended in 1 ml of isolation medium, divided into aliquots and frozen in liquid nitrogen and stored at -80 ° C until use.
Il trasporto protonico nelle vescicole di membrana fu valutato semiquantitativamente misurando la pendenza iniziale della diminuzione di fluorescenza dell’arancio di acridina (eccitazione 490 nm; emissione 530) dopo aggiunta di 5-20 μl di vescicole di membrana in 1 ml di tampone contenente 0,2 M saccarosio, 50 mM KC1, 10 mM Hepes pH 7,4,1mM ATP Na2, 1 mM CDTA, 5 μΜ valinomicina e 4 μΜ arancio di acridina. La reazione fu avviata aggiungendo I risultati furono espressi come percentuale della media dei due controlli. Proton transport in membrane vesicles was evaluated semiquantitatively by measuring the initial slope of the decrease in fluorescence of acridine orange (excitation 490 nm; emission 530) after addition of 5-20 μl of membrane vesicles in 1 ml of buffer containing 0, 2 M sucrose, 50 mM KC1, 10 mM Hepes pH 7,4,1mM ATP Na2, 1 mM CDTA, 5 μΜ valinomycin and 4 μΜ acridine orange. The reaction was started by adding The results were expressed as a percentage of the mean of the two controls.
Inibizione della ATPasi sensibile alla bafilomicina: fu valutata in vescicole di membrana purificate misurando il rilascio di fosfato inorganico (Pi) durante 30 min.di incubazione a 37°C in una piastra da 96 pozzetti in presenza o in assenza di bafilomicina A1. IL terreno di reazione conteneva 1mM ATP, 10 mM HEPES-Tris pH 8, 50 μΜ valinomicina,5 μm nigericina, 1 mM CDTA-Tris, 100 yM ammonio molibdato, 0,2 M saccarosio e membrane (20 yg proteina/ml). La reazione fu iniziata con Bafilomycin-sensitive ATPase inhibition: It was evaluated 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 in the presence or absence of bafilomycin A1. The reaction medium contained 1mM ATP, 10mM HEPES-Tris pH 8, 50μ valinomycin, 5μm nigericin, 1mM CDTA-Tris, 100μm ammonium molybdate, 0.2M sucrose and membranes (20μg protein / mL). The reaction began with
(pipetta a 8 canali)e interrotta, dopo 30 min, per aggiunta di 4 (8-channel pipette) and interrupted, after 30 min, by adding 4
volumi del reagente verde malachite (pipetta a 96 canali), preparato secondo Chan [Anal. Biochem. 157, 375 (1986)] . L'assorbanza a 650 nm fu misurata dopo 2 min, usando un lettore per micropiastre. I risultati sono espressi come μmol (Pi) x mg di proteina<-1 >x ora<-1 >e per ciascun esperimento, rappresentano la media ± esm dei triplicati. volumes of malachite green reagent (96-channel pipette), prepared according to Chan [Anal. Biochem. 157, 375 (1986)]. The absorbance at 650 nm was measured after 2 min, using a microplate reader. The results are expressed as μmol (Pi) x mg of protein <-1> x hour <-1> and for each experiment, they represent the mean ± esm of triplicates.
INIBIZIONE DEL RIASSORBIMENTO OSSEO INHIBITION OF BONE RE-ABSORPTION
Il riassorbimento osseo può essere valutato come precedentemente descritto in letteratura [T.J. Chambers et al., Endocrinology, 1985, 116, 234]. Brevemente, si disaggregarono meccanicamente osteoclasti da ossa lunghe di ratti neonati in terreno 199 (Flow, UK) tamponato con Hepes. La sospensione fu agitata con una pipetta e i frammenti più grandi furono lasciati depositare per 30 secondi. Le cellule furono quindi aggiunte a due pozzetti di una piastra multipozzetto contenenti fettine ossee (ognuna della misura di 12 mm2) . Dopo 15 minuti a 37°C le fettine ossee furono rimosse, lavate in terreno 199 e poste in pozzetti individuali di una piastra a 96 pozzetti. Queste furono incubate per 24 ore in un volume totale di 2 mi di terreno di coltura, consistente di siero fetale di vitello al 10% in MEM tamponato con Hanks , in presenza o in assenza di farmaco. Il numero di osteoclasti e il riassorbimento osseo furono quantificati per microscopia a scansione laser confocale (CLSM):le fettine ossee furono fissate con glutaraldeide al 2% in 0,2 K tampone cacodilato e gli osteoclasti su ogni fettina ossea furono colorati per fosfatasi acida tartrato-resistente. Dopo la conta del numero di cellule colorate in rosso, grandi e multinucleate , le fettine ossee furono immerse in ipoclorito sodico al 10% per 60 minuti per rimuovere le cellule, lavate in acqua distillata e rivestite a spruzzo con oro. Bone resorption can be evaluated as previously described in the literature [T.J. Chambers et al., Endocrinology, 1985, 116, 234]. Briefly, osteoclasts were mechanically disaggregated from long bones of neonatal rats in Hepes-buffered medium 199 (Flow, UK). The suspension was stirred with a pipette and the larger fragments were allowed to settle for 30 seconds. The cells were then added to two wells of a multiwell plate containing bone slices (each measuring 12 mm2). After 15 minutes at 37 ° C the bone slices were removed, washed in medium 199 and placed in individual wells of a 96-well plate. These were incubated for 24 hours in a total volume of 2 ml of culture medium, consisting of 10% fetal calf serum in Hanks-buffered MEM, in the presence or absence of drug. The number of osteoclasts and bone resorption were quantified by confocal laser scanning microscopy (CLSM): the bone slices were fixed with 2% glutaraldehyde in 0.2 K cacodylated buffer and the osteoclasts on each bone slice were stained for acid phosphatase tartrate -resistant. After counting the number of large, multinucleated red-stained cells, the bone slices were immersed in 10% sodium hypochlorite for 60 minutes to remove the cells, washed in distilled water and spray coated with gold.
L'intera superficie di ogni fettina ossea fu quindi esaminata in CLSM. Il numero e la dimensione delle cavità osteoclastiche, l'area piana e il volume dell'osso riassorbito furono registrati. I risultati furono espressi come numero medio di cavità per osteoclasto, area media per osteoclasto o volume medio per osteoclasto. The entire surface of each bone slice was then examined in CLSM. The number and size of osteoclastic cavities, the flat area and the volume of resorbed bone were recorded. Results were expressed as mean number of cavities per osteoclast, mean area per osteoclast, or mean volume per osteoclast.
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---|---|
ITMI950031A0 ITMI950031A0 (en) | 1995-01-10 |
ITMI950031A1 true ITMI950031A1 (en) | 1996-07-10 |
IT1272879B IT1272879B (en) | 1997-07-01 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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ITMI950031A IT1272879B (en) | 1995-01-10 | 1995-01-10 | Dibenzoalkylene compounds |
Country Status (1)
Country | Link |
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IT (1) | IT1272879B (en) |
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1995
- 1995-01-10 IT ITMI950031A patent/IT1272879B/en active IP Right Grant
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Publication number | Publication date |
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ITMI950031A0 (en) | 1995-01-10 |
IT1272879B (en) | 1997-07-01 |
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