ITMI960664A1 - USE OF BETA-CARBOLINIC DERIVATIVES AS ANTIMETASTATIC AGENTS - Google Patents
USE OF BETA-CARBOLINIC DERIVATIVES AS ANTIMETASTATIC AGENTS Download PDFInfo
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- ITMI960664A1 ITMI960664A1 IT96MI000664A ITMI960664A ITMI960664A1 IT MI960664 A1 ITMI960664 A1 IT MI960664A1 IT 96MI000664 A IT96MI000664 A IT 96MI000664A IT MI960664 A ITMI960664 A IT MI960664A IT MI960664 A1 ITMI960664 A1 IT MI960664A1
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- tetrahydronorharman
- carboxylic acid
- hydrogen
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- 239000002257 antimetastatic agent Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 230000005764 inhibitory process Effects 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- -1 diethylmethyl Chemical group 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
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- 208000004575 Infectious Arthritis Diseases 0.000 claims description 4
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- 239000002253 acid Substances 0.000 claims description 4
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052794 bromium Inorganic materials 0.000 claims description 3
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Descrizione dell’invenzione industriale avente per titolo: Description of the industrial invention entitled:
“USO DI DERIVATI BETA-CARBOLINICI COME AGENTI ANTIMETASTATICI” "USE OF BETA-CARBOLINE DERIVATIVES AS ANTIMETASTATIC AGENTS"
La presente invenzione riguarda l’uso di derivati beta-carbolinici portanti almeno un gruppo carbossilico libero o esterificato sull’anello piperidinico per la preparazione di composizioni farmaceutiche avaiti proprietà antimetastatiche. The present invention relates to the use of beta-carboline derivatives carrying at least one free or esterified carboxylic group on the piperidine ring for the preparation of pharmaceutical compositions with different antimetastatic properties.
Le cellule di tumori metastatizzanti sono in grado di migrare dal tumore originario verso altri organi bersaglio per mezzo di un procedimento che prevede la penetrazione attraverso le pareti dei capillari sanguigni, l’ingresso delle cellule tumorali nel flusso sanguigno, seguito da un successivo riattraversamento delle pareti dei vasi fino a raggiungere l’organo bersaglio. The cells of metastasizing tumors are able to migrate from the original tumor to other target organs by means of a procedure that involves the penetration through the walls of the blood capillaries, the entry of tumor cells into the bloodstream, followed by a subsequent re-crossing of the walls of the vessels until they reach the target organ.
La penetrazione attravèrso il tessuto connettivo dei vasi avviene grazie alla degradazione della matrice extracellulare ad opera di metalloproteinasi rilasciate da cellule del tessuto connettivo reridente ed attivate dalle cellule tumorali Tale meccanisno, comune anche ai tessuti non tumorali, è però normalmente in equilibrio dinamico con la rigenerazione del tessuto connettivo, mentre ri manifesta in maniera non controllata nelle cellule invadenti quali appunto le cellule tumorali o infiammatorie ed è coinvolto in numerose altre patologie quali artrite reumatoide, osteoartrite, artrite settica, ulcerazioni della cornea, epidermiche o gastriche, trombosi coronarica, proteinuria (WO 95/13289). Penetration through the connective tissue of the vessels occurs thanks to the degradation of the extracellular matrix by metalloproteinases released by cells of the resident connective tissue and activated by tumor cells This mechanism, also common to non-tumor tissues, is however normally in dynamic equilibrium with regeneration of connective tissue, while it manifests itself in an uncontrolled manner in invading cells such as tumor or inflammatory cells and is involved in numerous other diseases such as rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulcerations, coronary thrombosis, proteinuria ( WO 95/13289).
In detti processi sono coinvolti tre tipi di metallo proteinasi: collagenasi, gelatinasi e stromelisine. In condizioni normali il loro rilascio e la loro attività sono strettamente regolati da inibitori delle proteinasi endogeni, come ad esempio a2-macroglobulina. Three types of metallo proteinases are involved in these processes: collagenase, gelatinase and stromelysins. Under normal conditions their release and activity are strictly regulated by endogenous proteinase inhibitors, such as a2-macroglobulin.
Inibitori di metalloproteinasi possono quindi essere utili nella cura delle condizioni patologiche sopra descritte nonché delle conseguenze patologiche di traumi o anche come agenti contraccettivi, in quanto le metallo proteinasi sono implicate nei fenomeni di ovulazione e del successivo impianto dell’ovulo sulla parete uterina. In particolare, l’inibizione della metastasi tumorale ad opera di inibitori delle metalloproteinasi è descritta in Matrisian et aL, PNAS USA, 83, 9413-7 (1986); Wilhelm et aL, PNAS USA, 84, 6725-29 ( 1987); Werb et aL, J. Cell BioL, 109. 872-89 (1989); Liotta et aL, Lab. Invest., 49, 636-49 (1983). Metalloproteinase inhibitors can therefore be useful in the treatment of the pathological conditions described above as well as the pathological consequences of trauma or even as contraceptive agents, since metalloproteinases are involved in the phenomena of ovulation and subsequent implantation of the ovum on the uterine wall. In particular, the inhibition of tumor metastasis by metalloproteinase inhibitors is described in Matrisian et al, PNAS USA, 83, 9413-7 (1986); Wilhelm et aL, PNAS USA, 84, 6725-29 (1987); Werb et al, J. Cell BioL, 109, 872-89 (1989); Liotta et aL, Lab. Invest., 49, 636-49 (1983).
Inibitori di metallo proteinasi sono descritti in US 4,511,504, US 4,568,666, US 4,771,037, WO 95/13289. Metal proteinase inhibitors are disclosed in US 4,511,504, US 4,568,666, US 4,771,037, WO 95/13289.
Derivati beta-carbolinici sono descritti avere varie attività farmacologiche, quali ad esempio attività antitumorale [Anticancer Res., 13(6A). 2301-8 (1993); J. Antibiot., 46(11). 1672-7 (1993); EP 357. 122J, antiulcera [WO 92/04348 (19.03.92)], antimalarica [J. Nat. Prod., 54(5). 1360-7 (1991)] o sono descritti come agenti favorenti Γ assorbimento di farmaci antitumorali (JP 04275221). Beta-carboline derivatives are described to have various pharmacological activities, such as for example antitumor activity [Anticancer Res., 13 (6A). 2301-8 (1993); J. Antibiot., 46 (11). 1672-7 (1993); EP 357. 122J, antiulcer [WO 92/04348 (19.03.92)], anti-malarial [J. Nat. Prod., 54 (5). 1360-7 (1991)] or are described as promoting agents for the absorption of anticancer drugs (JP 04275221).
Per nessuna di queste molecole è però descritta un’attività antiinetastatica. For none of these molecules, however, an anti-inetastatic activity is described.
Abbiamo sorprendentemente trovato che le beta-carbolie di formula (I) sono dotate di una notevole attività di inibizione del processo metastatico: We have surprisingly found that the beta-carbolias of formula (I) are endowed with a remarkable activity of inhibition of the metastatic process:
in cui: in which:
R è scelto nel gruppo comprendente idrogeno, alchile lineare o ramificato, fenile( eventualmente sostituito da un gruppo alcossi), dove n è un intero da 1 a 3; R is selected from the group comprising hydrogen, linear or branched alkyl, phenyl (optionally substituted by an alkoxy group), where n is an integer from 1 to 3;
R1 è idrogeno o un gruppo - dove R4 è idrogeno o alchile; R1 is hydrogen or a group - where R4 is hydrogen or alkyl;
R2 è idrogeno 0 un gruppo come sopra definito; R2 is hydrogen or a group as defined above;
R3 è scelto nel gruppo comprendente idrogeno, alogeno (cloro, bromo, fluoro o iodio), (C1-C4)alcossi, benzàlossi, con la condizione che, quando R è diverso da - allora almeno un gruppo R1 o R2 è un gruppo -COOR4 come sopra definito. R3 is selected from the group comprising hydrogen, halogen (chlorine, bromine, fluorine or iodine), (C1-C4) alkoxy, benzaloxy, with the proviso that, when R is different from - then at least one R1 or R2 group is a - COOR4 as defined above.
Oggetto della presente invenzione è l’uso dei composti di formula (I), come agenti antimetastatici ed inibitori del processo di invasione tumorale. The object of the present invention is the use of the compounds of formula (I), as antimetastatic agents and inhibitors of the tumor invasion process.
Sono compresi nella presente invenzione anche gli enantiomeri, i racemati ed i diastereoisomeri dei composti di formula (I), nonché i loro sali con acidi o basi farmaceuticamente accettabili. Also included in the present invention are the enantiomers, racemates and diastereomers of the compounds of formula (I), as well as their salts with pharmaceutically acceptable acids or bases.
Esempi preferiti di composti di formula (I) sono, Preferred examples of compounds of formula (I) are,
acido 6-metossi-1,2,3,4-tetraidronorharman-1-carbossilico; 6-methoxy-1,2,3,4-tetrahydronorharman-1-carboxylic acid;
acido 1-(4-metossifenil)- 1,2,3,4-tetraidronorharman-3-carbossilico; 1- (4-methoxyphenyl) - 1,2,3,4-tetrahydronorharman-3-carboxylic acid;
acido 1-metil- 1 ,2,3,4-tetraidronorharman-3-carbossilico; 1-methyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;
acido 1-metil- 1,2,3, 4-tetraidronorharman-1,3-dicarbossihco; 1-methyl-1,2,3, 4-tetrahydronorharman-1,3-dicarboxylic acid;
acido 1-(dietilmetil)-1,2,3,4-tetraidronorharman-3-carbossilico; 1- (diethylmethyl) -1,2,3,4-tetrahydronorharman-3-carboxylic acid;
acido (6-bromo- 1,2,3, 4-tetraidronorharman- 1-il)-3-propionico. (6-bromo- 1,2,3, 4-tetrahydronorharman- 1-yl) -3-propionic acid.
acido 1-isobutil-1,2,3,4-tetraidronorharman-3-carbossilico; 1-isobutyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;
acido 1-fenil-1,2,3,4-tetraidronorharman-3-carbossilico; 1-phenyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;
acido 1-propil- 1,2,3, 4-tetraidronorharman-3-carbossilico; 1-propyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;
1-metil- 1-metossicarbonil-6-benzilossi- 1,2, 3, 4-tetraidronorharmano; 1-methyl- 1-methoxycarbonyl-6-benzyloxy- 1,2, 3, 4-tetrahydronorharmane;
1-metil- 1-metossicarbomil-6-metossi- 1,2,3, 4-tetraidronorharmano; 1-methyl- 1-methoxycarbomyl-6-methoxy-1,2,3,4-tetrahydronorharmane;
m 1-metil-1-metossicarbonil-6-idrossi-1,2,3,4-tetraidronorharmano; m 1-methyl-1-methoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydronorharmane;
1-metil- 1-metossicarbonil-6-cloro- 1 ,2,3,4-tetraidronorharmano; 1-methyl- 1-methoxycarbonyl-6-chloro- 1, 2,3,4-tetrahydronorharmane;
1-metil- 1-metossicarbonil-6-bromo- 1 , 2,3 ,4-tetraidronorharmano ; 1-methyl- 1-methoxycarbonyl-6-bromo- 1, 2,3, 4-tetrahydronorharmane;
1-metil- 1-metossicarbonil 1,2, 3, 4-tetraidronorharmano. 1-methyl- 1-methoxycarbonyl 1,2, 3, 4-tetrahydronorharmane.
I composti compresi nella presente invenzione sono composti noti e sono disponibili in commercio o possono essere ottenuti per estrazione da matrici vegetali o sintetizzati secondo metodi riportati in letteratura (vedi ad esempio WO 92/04348). The compounds included in the present invention are known compounds and are commercially available or can be obtained by extraction from vegetable matrices or synthesized according to methods reported in the literature (see for example WO 92/04348).
I composti della presente invenzione sono stati saggiati in un test farmacologico “in vitro” di inibizione della gelatinasi B. H test prevede la determinazione per fluorescenza dell’inibizione dell’attività di degradazione di un substrato fluorescente (DNP-Pro-Leu-GSy-Leu-Trp-Ala-D-Arg-NH2, MI 855 Bachem) ad opera del dominio catalitico (92 kDa) della gelatinasi B. The compounds of the present invention were tested in an "in vitro" pharmacological test for inhibition of gelatinase B. H test involves the determination by fluorescence of the inhibition of the degradation activity of a fluorescent substrate (DNP-Pro-Leu-GSy- Leu-Trp-Ala-D-Arg-NH2, MI 855 Bachem) by the catalytic domain (92 kDa) of gelatinase B.
Reagenti.· Reagents.
1) DNP-substrato = DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 (MI 855 BachemX P.M. 1) DNP-substrate = DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 (MI 855 BachemX P.M.
977.1 g/mol, concentrazione 25 μΜ in DMSO; 2) tampone di misurazione = 50 mM TRIS / 100 mM NaCl / 10 mM CaC12.2H20, aggiustato a pH 7.6 con acido cloridrico. 3) Enzima = gelatinasi B, dominio catalitico 92 kDa, concentrazione 0.055 mg/ml in tampone TRIS. Substrato ed enzima sono mantenuti a 0°C con ghiaccio. 977.1 g / mol, concentration 25 μΜ in DMSO; 2) measurement buffer = 50 mM TRIS / 100 mM NaCl / 10 mM CaC12.2H20, adjusted to pH 7.6 with hydrochloric acid. 3) Enzyme = gelatinase B, catalytic domain 92 kDa, concentration 0.055 mg / ml in TRIS buffer. Substrate and enzyme are kept at 0 ° C with ice.
Prova di inibizione : Inhibition test:
Volume totale = 1 ml di soluzione mantenuto sotto agitazione in una cuvetta. Total volume = 1 ml of solution kept under stirring in a cuvette.
Controllo: 0.98 ml DMSO Control: 0.98 ml DMSO
0.01 ml di DNP-substrato 0.01 ml of DNP substrate
0.01 ml di enzima 0.01 ml of enzyme
Esperimento: 0.98 ml DMSO Experiment: 0.98 ml DMSO
0.01 ml DNP-sub strato 0.01ml DNP-sub layer
0.01 ml enzima 0.01ml enzyme
0.01 ml inibitore (10 μg/ml ) 0.01 ml inhibitor (10 μg / ml)
Viene misurata la fluorescenza a 346 nm sia della soluzione di controllo (senza inibitore) che della soluzione contenente l'inibitore. L’inibizione dell’attività catalitica della gelatinasi B provoca una diminuzione della lisi di DNP-substrato, con conseguente diminuzione della fluorescenza. The fluorescence at 346 nm of both the control solution (without inhibitor) and the solution containing the inhibitor is measured. The inhibition of the catalytic activity of gelatinase B causes a decrease in the lysis of DNP-substrate, with a consequent decrease in fluorescence.
La percentuale di inibizione viene espressa dalla seguente formula: The percentage of inhibition is expressed by the following formula:
Ripetendo l’esperimento a varie concentrazioni di inibitore è possibile calcolarne la rispettiva IC50-La tabella mostra i dati di inibizione enzimatica per un composto rappresentativo dell’invenzione. Repeating the experiment at various concentrations of inhibitor it is possible to calculate the respective IC50-The table shows the enzyme inhibition data for a representative compound of the invention.
Tabella Table
I composti della presente invenzione sono anche risultati attivi in un test “in vivo” di chemoinvasione. Nel test di chemoinvasione delle camere Costar Transwell per coltura cellulare (diametro: 6.5 mm; diametro pori: 8 pm) sono rivestite sul fondo con 100 μΐ di collagene tipo IV (soluzione diluita 50 μg/ml, quindi evaporazione per ima notte). Con lo stesso procedimento si ricoprono le camere di un secondo strato di collagene tipo IV (100 μΐ di soluzione a concentrazione 50 μg/ml ). Prima dell’uso, le camere sono lavate due volte con acqua sterile ed incubate per circa 1 ora a 37°C in un mezzo (DMEM) privato di siero. Le cellule HT1080 sono raccolte per trattamento con tripsina-EDTA, lavate con DMEM 10% FCS ed incubate per almeno 30 minuti a 37°C nello stesso mezzo. Le cellule sono qundi lavate con DMEM privato di siero e risospese in DMEM privato di siero addizionato di 0.1% BSA (frazione V), contate e diluite fino ad ottenere una densità finale di 3x10<5 >cellule/mL The compounds of the present invention were also found to be active in an "in vivo" chemoinvasion test. In the chemoinvasion test the Costar Transwell cell culture chambers (diameter: 6.5 mm; pore diameter: 8 pm) are coated on the bottom with 100 μΐ of type IV collagen (diluted solution 50 μg / ml, then evaporation overnight). With the same procedure, the chambers are covered with a second layer of type IV collagen (100 μ of solution at a concentration of 50 μg / ml). Before use, the chambers are washed twice with sterile water and incubated for about 1 hour at 37 ° C in a medium (DMEM) deprived of serum. HT1080 cells are harvested by trypsin-EDTA treatment, washed with DMEM 10% FCS and incubated for at least 30 minutes at 37 ° C in the same medium. The cells are then washed with serum-deprived DMEM and resuspended in serum-deprived DMEM added with 0.1% BSA (fraction V), counted and diluted until a final density of 3x10 <5> cells / mL is obtained.
Dalle camere preincubate viene rimosso per aspirazione il mezzo privo di siero. Il comparto inferiore delle camere è rìempoto con 600 μl di DMEM 20% FCS 1% BSA (frazione V) composto da testare. 200 μl di sospensione cellulare (6x10<4 >cellule) contenenti il composto da testare sono aggiunti nel comparto superiore e le camere sono incubate a 37°C in atmosfera umida con CO2. Dopo una prima incubazione di 24 ore i mezzi dei comparti inferiore e superiore sono rimpiazzati con sospensioni fresche e le camere sono incubate per altre 24 ore. The serum-free medium is aspirated from the pre-incubated chambers. The lower compartment of the chambers is filled with 600 μl of DMEM 20% FCS 1% BSA (fraction V) compound to be tested. 200 μl of cell suspension (6x10 <4> cells) containing the compound to be tested are added to the upper compartment and the chambers are incubated at 37 ° C in a humid atmosphere with CO2. After a first 24 hour incubation the media from the lower and upper compartments are replaced with fresh suspensions and the chambers are incubated for another 24 hours.
I filtri incubati sono quindi lavati con PBS, le cellule sono fissate per 15 minuti in paraformaldeide 4%, permebilizzate in metanolo ( 10 minuti, -20°C) e colorate con May-Grunwald-Giemsa. Le cellule che aderiscono alla fàccia superiore dei filtri sono rimosse con un tampone di cotone, i filtri vengono staccati dal fondo delle camere ed analizzate al microscopio per determinare il numero di cellule sulla faccia inferiore dei filtri. The incubated filters are then washed with PBS, the cells are fixed for 15 minutes in 4% paraformaldehyde, permebilized in methanol (10 minutes, -20 ° C) and stained with May-Grunwald-Giemsa. The cells adhering to the upper face of the filters are removed with a cotton swab, the filters are detached from the bottom of the chambers and analyzed under a microscope to determine the number of cells on the lower face of the filters.
In un esperimento di controllo, in assenza di inibitore di metallo proteinasi, le cellule HT1080, che iper-esprimono coflagenasi A e B, sono in grado di degradare il collagene tipo IV e di migrare sulla faccia inferiore dei filtri. Nell’esperimento con l’mibitore invece l’attività delle collagenasi è parzialmente o totalmente inibita, con un conseguente minor numero di cellule che migrano sulla fàccia inferiore dei filtri. La lettura dell'esperimento consiste quindi nella determinazione della differenza tra cellule contate sulla faccia inferiore del filtro nell’ esperimento di controllo e nell’esperimento con rinibitore. In a control experiment, in the absence of a metalloproteinase inhibitor, HT1080 cells, which hyper-express coflagenase A and B, are able to degrade type IV collagen and migrate to the underside of the filters. In the experiment with the inhibitor, however, the activity of collagenases is partially or totally inhibited, resulting in a lower number of cells that migrate to the lower face of the filters. The reading of the experiment therefore consists in determining the difference between cells counted on the lower face of the filter in the control experiment and in the experiment with a reninhibitor.
Da quanto detto sopra è evidente che i composti dell’invenzione possono anche essere usati nella cura di tutte le condizioni associate all’azione delle matrice- metallo proteinasi, quali artrite reumatoide, osteoartrite, artrite settica, ulcerazioni della cornea, epidermiche o gastriche, trombosi coronarica, proteinuria, conseguenze patologiche di traumi o anche come agenti contraccettivi From the above it is evident that the compounds of the invention can also be used in the treatment of all conditions associated with the action of the matrix-metalloproteinases, such as rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulcerations, thrombosis coronary artery disease, proteinuria, pathological consequences of trauma or even as contraceptive agents
I composti della presente invenzione possono essere somministrati in quantità variabili tra 0.01 mg e 0.4 g per chilogrammo di peso corporeo al giorno. Un regime di dosaggio preferito al fine di ottenere risultati ottimali è quello che prevede l’uso da circa 1 mg a circa 50 mg per chilogrammo di peso corporeo al giorno, impiegando dosi unitarie cosi da somministrare da circa 70 mg a circa 3.5 g del composto attivo ad un soggetto di circa 70 kg di peso corporeo in un periodo di 24 ore. Questo regime di dosaggio può essere regolato per fornire la risposta terapeutica ottimale. Per esempio, possono essere somministrate dosi suddivise a seconda delle esigenze della situazione terapeutica. Il composto attivo può essere somministrato per via orale, endovenosa, intramuscolare o sottocutanea. The compounds of the present invention can be administered in amounts ranging from 0.01 mg to 0.4 g per kilogram of body weight per day. A preferred dosage regimen in order to obtain optimal results is that which involves the use of about 1 mg to about 50 mg per kilogram of body weight per day, using unit doses so as to administer from about 70 mg to about 3.5 g of the compound. active to a subject of about 70 kg of body weight in a period of 24 hours. This dosage regimen can be adjusted to provide the optimal therapeutic response. For example, divided doses may be administered according to the needs of the therapeutic situation. The active compound can be administered orally, intravenously, intramuscularly or subcutaneously.
Le composizioni farmaceutiche cui la presente invenzione fa riferimento contengono almeno un composto defl’invenzione in quantità terapeuticamente efficaci in miscela con eccipienti farmaceuticamente compatibili The pharmaceutical compositions to which the present invention refers contain at least one compound of the invention in therapeutically effective quantities in admixture with pharmaceutically compatible excipients
Composizioni per via orale includeranno generalmente un diluente inerte o un carrier edibile. Esse possono essere incluse in capsule di gelatina o compresse in tavolette. Altre forme di somministrazioni orali sono capsule, pillole, elisir, sospensioni o sciroppi. Oral compositions will generally include an inert diluent or an edible carrier. They can be included in gelatin capsules or tablets in tablets. Other forms of oral administration are capsules, pills, elixirs, suspensions or syrups.
Le tavolette, pillole, capsule e conposizioni similari possono contenere i seguenti ingredienti (in aggiunta al principio attivo): un legante quale cellulosa microcristallina, gomma adragante o gelatina; un eccipiente quale amido o lattosio; un agente disgregante quale acido alginico, primogel, amido di mais e simili; un lubrificante quale magnesio stearato; un fluidificante quale biossido di silicio colloidale; un agente dolcificante quale sucrosio o saccarina o un agente aromatizzante quale aroma di menta, metil salicilato o aroma di arancio. Quando la composizione scelta è in forma di capsule, essa può contenere in aggiunta un carrier liquido quale un olio grasso. Altre composizioni possono contenere vari materiali che ne alterano la forma fisica, quali agenti ricoprenti (per tavolette e pillole) come zucchero e gommalacca. I materiali usati nella preparazione delle composiziom dovrebbero essere farmaceuticamente puri e non tossici ai dosaggi impiegati. The tablets, pills, capsules and similar compositions may contain the following ingredients (in addition to the active ingredient): a binder such as microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, primogel, corn starch and the like; a lubricant such as magnesium stearate; a fluidifier such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin or a flavoring agent such as mint flavor, methyl salicylate or orange flavor. When the selected composition is in capsule form, it may additionally contain a liquid carrier such as a fatty oil. Other compositions may contain various materials that alter their physical form, such as coating agents (for tablets and pills) such as sugar and shellac. The materials used in the preparation of the compositions should be pharmaceutically pure and non-toxic at the dosages employed.
Per la preparazione di composizioni farmaceutiche per via di somministrazione parenterale, il principio attivo può essere incorporato in soluzioni o sospensioni, che possono includere in aggiunta i seguenti componenti: un diluente sterile come acqua per iniezioni, soluzione salina, oli, glicoli polietilenici, glicerina, glicole propflenico o altri solventi sintetici; agenti antibatterici quale alcool benzilico; antiossidanti quali acido ascorbico o sodio bisolfito; agenti chetanti quale acido etilendiamminotetraacetico; tamponi quali acetati, citrati o fosfati e agenti per aggiustare la tonicità della soluzione quali sodio cloruro o destrosio. For the preparation of pharmaceutical compositions for parenteral administration, the active ingredient can be incorporated in solutions or suspensions, which may additionally include the following components: a sterile diluent such as water for injections, saline, oils, polyethylene glycols, glycerin, propflenic glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; ketant agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting the tonicity of the solution such as sodium chloride or dextrose.
La preparazione parenterale può essere inclusa in ampolle, siringhe mono-uso o fiale in vetro o plastica. The parenteral preparation can be included in ampoules, disposable syringes, or glass or plastic vials.
Da quanto detto sopra è evidente che i composti dell’invenzione possono anche essere usati nella cura di tutte le condizioni associate all’azione delle matrice-metallo proteinasi, quali artrite reumatoide, osteoartrite, artrite settica, ulcerazioni della cornea, epidermiche o gastriche, trombosi coronarica, proteinuria, conseguenze patologiche di traumi o anche come agenti contraccettivi From the above it is evident that the compounds of the invention can also be used in the treatment of all conditions associated with the action of matrix-metallo proteinases, such as rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulcerations, thrombosis coronary artery disease, proteinuria, pathological consequences of trauma or even as contraceptive agents
I composti della presente invenzione possono essere somministrati in quantità variabili tra 0.01 mg e 0.4 g per chilogrammo di peso corporeo al giorno. Un regime di dosaggio preferito al fine di ottenere risultati ottimali è quello che prevede l’uso da circa 1 mg a circa SO mg per chilogrammo di peso corporeo al giorno, impiegando dosi unitarie cosi da somministrare da circa 70 mg a circa 3.5 g del composto attivo ad un soggetto di circa 70 kg di peso corporeo in un periodo di 24 ore. Questo regime di dosaggio può essere regolato per fornire la risposta terapeutica ottimale. Per esempio, possono essere somministrate dosi suddivise a seconda delle esigenze della situazione terapeutica. Il composto attivo può essere somministrato per via orale, endovenosa, intramuscolare o sottocutanea. The compounds of the present invention can be administered in amounts ranging from 0.01 mg to 0.4 g per kilogram of body weight per day. A preferred dosage regimen in order to obtain optimal results is that which involves the use of about 1 mg to about SO mg per kilogram of body weight per day, using unit doses so as to administer from about 70 mg to about 3.5 g of the compound. active to a subject of about 70 kg of body weight in a period of 24 hours. This dosage regimen can be adjusted to provide the optimal therapeutic response. For example, divided doses may be administered according to the needs of the therapeutic situation. The active compound can be administered orally, intravenously, intramuscularly or subcutaneously.
Le composizioni farmaceutiche cui la presente invenzione fa riferimento contengono almeno un composto dell’invenzione in quantità terapeuticamente efficaci in miscela con eccipienti farmaceuticamente compatibili. The pharmaceutical compositions to which the present invention refers contain at least one compound of the invention in therapeutically effective quantities in admixture with pharmaceutically compatible excipients.
Composizioni per via orale includeranno generalmente un diluente berte o un carrier edibile. Esse possono essere incluse m capsule di gelatina o compresse in tavolette. Altre forme di somministrazioni orali sono capsule, pillole, elisir, sospensioni o sciroppi Oral compositions will generally include a shearwater diluent or an edible carrier. They may include gelatin capsules or tablets in tablets. Other forms of oral administration are capsules, pills, elixirs, suspensions or syrups
Le tavolette, pillole, capsule e composizioni similari possono contenere i seguenti ingredienti (in aggiunta al principio attivo): un legante quale cellulosa microcristallina, gomma adragante o gelatina; un eccipiente quale amido o lattosio; un agente disgregante quale acido alginico, primogel, amido di mais e simili; un lubrificante quale magnesio stearato; un fluidificante quale biossido di silicio colloidale; un agente dolcificante quale sucrosio o saccarina o un agente aromatizzante quale aroma di menta, metil salicilato o aroma di arancio. Quando la composizione scelta è in forma di capsule, essa può contenere in aggiunta un carrier liquido quale un olio grasso. Altre composizioni possono contenere vari materiali che ne alterano la forma fisica, quali agenti ricoprenti (per tavolette e pillole) come zucchero e gommalacca. I materiali usati nella preparazione delle composizioni dovrebbero essere farmaceuticamente puri e non tossici ai dosaggi impiegati. The tablets, pills, capsules and similar compositions may contain the following ingredients (in addition to the active ingredient): a binder such as microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, primogel, corn starch and the like; a lubricant such as magnesium stearate; a fluidifier such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin or a flavoring agent such as mint flavor, methyl salicylate or orange flavor. When the selected composition is in capsule form, it may additionally contain a liquid carrier such as a fatty oil. Other compositions may contain various materials that alter their physical form, such as coating agents (for tablets and pills) such as sugar and shellac. The materials used in the preparation of the compositions should be pharmaceutically pure and non-toxic at the dosages employed.
Per la preparazione di composizioni farmaceutiche per via di somministrazione parenterale, il principio attivo può essere incorporato in soluzioni o sospensioni, che possono includere in aggiunta i seguenti componenti: un diluente sterile come acqua per iniezioni, soluzione salina, oli, glicoli polietilenici, glicerina, glicole propilenico o altri solventi sintetici; agenti antibatterici quale alcool benzilico; antiossidanti quali acido ascorbico o sodio bisolfito; agenti chelanti quale acido etilendiamminotetraacetico; tamponi quali acetati, citrati o fosfati e agenti per aggiustare la tonicità della soluzione quali sodio cloruro o destrosio. For the preparation of pharmaceutical compositions for parenteral administration, the active ingredient can be incorporated in solutions or suspensions, which may additionally include the following components: a sterile diluent such as water for injections, saline, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting the tonicity of the solution such as sodium chloride or dextrose.
La preparazione parenterale può essere inclusa in ampolle, siringhe mono-uso o fiale in vetro o plastica. The parenteral preparation can be included in ampoules, disposable syringes, or glass or plastic vials.
Claims (8)
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT96MI000664 IT1283574B1 (en) | 1996-04-04 | 1996-04-04 | Use of tetra:hydro-beta-carboline derivatives - for preparation of medicaments having anti-metastatic activity or tumour invasion or matrix metallo-proteinase inhibitory activity |
US09/142,058 US6069150A (en) | 1996-04-04 | 1997-03-27 | Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents |
AU25069/97A AU710079B2 (en) | 1996-04-04 | 1997-03-27 | Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents |
DE69710182T DE69710182T2 (en) | 1996-04-04 | 1997-03-27 | USE OF TETRAHYDROBETACARBOLIN DERIVATIVES FOR PREVENTING METASTASIS |
EP97916410A EP0891187B1 (en) | 1996-04-04 | 1997-03-27 | Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents |
AT97916410T ATE212549T1 (en) | 1996-04-04 | 1997-03-27 | USE OF TETRAHYDROBETACARBOLINE DERIVATIVES TO PREVENT METASTASIS |
PT97916410T PT891187E (en) | 1996-04-04 | 1997-03-27 | USING TETRAHYDRO-BETA-CARBOLINOS DERIVATIVES AS ANTIMESTATIC AGENTS |
ES97916410T ES2169857T3 (en) | 1996-04-04 | 1997-03-27 | USE OF TETRAHIDRO-BETA-CARBOLINAS DERIVATIVES AS ANTIMETASTATIC AGENTS. |
DK97916410T DK0891187T3 (en) | 1996-04-04 | 1997-03-27 | Use of tetrahydro-beta-carboline derivatives as antimetastatic agents |
KR1019980707846A KR20000005175A (en) | 1996-04-04 | 1997-03-27 | Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents |
PCT/EP1997/001582 WO1997037658A1 (en) | 1996-04-04 | 1997-03-27 | Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents |
CA002250898A CA2250898A1 (en) | 1996-04-04 | 1997-03-27 | Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents |
CN97193568A CN1113648C (en) | 1996-04-04 | 1997-03-27 | Use of derivativ |
JP9535798A JP2000508302A (en) | 1996-04-04 | 1997-03-27 | Use of tetrahydro-.BETA.-carboline derivatives as antimetastatic agents |
TR1998/01970T TR199801970T2 (en) | 1996-04-04 | 1997-03-27 | Use of tetrahydro-beta-carbolines as antimetastatic agents. |
BR9708480A BR9708480A (en) | 1996-04-04 | 1997-03-27 | Use of tetrahydro-beta-cabolines derivatives as antimetastatic agents |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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IT96MI000664 IT1283574B1 (en) | 1996-04-04 | 1996-04-04 | Use of tetra:hydro-beta-carboline derivatives - for preparation of medicaments having anti-metastatic activity or tumour invasion or matrix metallo-proteinase inhibitory activity |
Publications (3)
Publication Number | Publication Date |
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ITMI960664A0 ITMI960664A0 (en) | 1996-04-04 |
ITMI960664A1 true ITMI960664A1 (en) | 1997-10-04 |
IT1283574B1 IT1283574B1 (en) | 1998-04-22 |
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IT96MI000664 IT1283574B1 (en) | 1996-04-04 | 1996-04-04 | Use of tetra:hydro-beta-carboline derivatives - for preparation of medicaments having anti-metastatic activity or tumour invasion or matrix metallo-proteinase inhibitory activity |
Country Status (1)
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IT (1) | IT1283574B1 (en) |
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IT1283574B1 (en) | 1998-04-22 |
ITMI960664A0 (en) | 1996-04-04 |
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