ITMI962241A1 - USE OF TETRAIDRO-BETA-CARBOLINIC DERIVATIVES AS ANTIMETASTATIC AGENTS - Google Patents

USE OF TETRAIDRO-BETA-CARBOLINIC DERIVATIVES AS ANTIMETASTATIC AGENTS Download PDF

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ITMI962241A1
ITMI962241A1 IT96MI002241A ITMI962241A ITMI962241A1 IT MI962241 A1 ITMI962241 A1 IT MI962241A1 IT 96MI002241 A IT96MI002241 A IT 96MI002241A IT MI962241 A ITMI962241 A IT MI962241A IT MI962241 A1 ITMI962241 A1 IT MI962241A1
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tetrahydronorharman
carboxylic acid
methyl
methoxycarbonyl
tetrahydronorharmane
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IT96MI002241A
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Italian (it)
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Boehringer Mannheim Italia
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Priority to IT96MI002241 priority Critical patent/IT1286060B1/en
Application filed by Boehringer Mannheim Italia filed Critical Boehringer Mannheim Italia
Priority to DK97916410T priority patent/DK0891187T3/en
Priority to AT97916410T priority patent/ATE212549T1/en
Priority to EP97916410A priority patent/EP0891187B1/en
Priority to DE69710182T priority patent/DE69710182T2/en
Priority to AU25069/97A priority patent/AU710079B2/en
Priority to US09/142,058 priority patent/US6069150A/en
Priority to TR1998/01970T priority patent/TR199801970T2/en
Priority to KR1019980707846A priority patent/KR20000005175A/en
Priority to CA002250898A priority patent/CA2250898A1/en
Priority to JP9535798A priority patent/JP2000508302A/en
Priority to PCT/EP1997/001582 priority patent/WO1997037658A1/en
Priority to BR9708480A priority patent/BR9708480A/en
Priority to ES97916410T priority patent/ES2169857T3/en
Priority to PT97916410T priority patent/PT891187E/en
Priority to CN97193568A priority patent/CN1113648C/en
Publication of ITMI962241A1 publication Critical patent/ITMI962241A1/en
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Description

"USO DI DERIVATI TETRAIDRO-BETA-CARBOLI NI CI COME AGENTI ANTI-METASTATICI " "USE OF TETRAHYDRO-BETA-CARBOL NI CI DERIVATIVES AS ANTI-METASTATIC AGENTS"

La presente invenzione riguarda l’uso di derivati beta-carbolinici per la preparazione di omposizioni farmaceutiche aventi proprietà antimetastatiche. The present invention relates to the use of beta-carboline derivatives for the preparation of pharmaceutical compositions having antimetastatic properties.

Le cellule di tumori metastatizzanti sono in grado di migrare dal tumore originario verso altri organi bersaglio per mezzo di un meccanismo 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 mechanism 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 attraverso il tessuto connettivo dei vasi avviene grazie alla degradazione della matrice extracellulare ad opera di metalloproteinasi rilasciate da cellule del tessuto connettivo residente ed attivate dalle cellule tumorali Tale meccanismo, comune anche ai tessuti non tumorali è però normalmente in equilibrio dinamico con la rigenerazione del tessuto connettivo, mentre si 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, osteo artrite, artrite settica, ulcerazioni della cornea, epidermiche o gastriche, trombosi coronarica, 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. The 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 the tumor cells This mechanism, common also to non-tumor tissues, is however normally in dynamic equilibrium with the regeneration of the 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). _ _ 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, rinibizione 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. Celi 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, re-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 farma colo giche, quali ad esempio attività antitumorale [Anticancer Res., 13(6A1, 2301-8 (1993); J. Antibiot., 46(111, 1672-7 (1993); EP 357.122], antiulcera [WO 92/04348 (19.03.92)], antimalarica [J. Nat. Prod., 54(51, 1360-7 (1991)] o sono descritti come agenti favorenti l’assorbimento di farmaci antitumorali (JP 04275221). Beta-carboline derivatives are described to have various pharmaceutical activities, such as for example antitumor activities [Anticancer Res., 13 (6A1, 2301-8 (1993); J. Antibiot., 46 (111, 1672-7 (1993); EP 357.122], anti-ulcer [WO 92/04348 (19.03.92)], anti-malarial [J. Nat. Prod., 54 (51, 1360-7 (1991)] or are described as agents promoting the absorption of anticancer drugs ( JP 04275221).

Per nessuna di queste molecole è però descritta un’attività antimetastatica. However, for none of these molecules an antimetastatic activity is described.

Abbiamo sorprendentemente trovato che le tetraidro-beta-carboline di formula (I) sono dotate di ima notevole attività di inibizione del processo metastatico: We have surprisingly found that the tetrahydro-beta-carbolines of formula (I) are endowed with a remarkable activity of inhibition of the metastatic process:

U) U)

R è scelto nel gruppo comprendente idrogeno, (Ci-Cj)alchile lineare o ramificato, fenile (eventualmente sostituito da un gruppo (Ci-C5)alcossi), -(CH2)n-COOH, dove n è un intero da 1 a 3; R is selected from the group comprising hydrogen, (Ci-Cj) linear or branched alkyl, phenyl (optionally substituted by a (Ci-C5) alkoxy group), - (CH2) n-COOH, where n is an integer from 1 to 3 ;

Ri è idrogeno o un gruppo -COOR4, dove R4 è idrogeno o (Ci-Csjalchile; Ri is hydrogen or a -COOR4 group, where R4 is hydrogen or (C1-Csjalkyl;

R2 è idrogeno o un gruppo -COOR4 come sopra definito; R2 is hydrogen or a -COOR4 group as defined above;

R3 è scelto nel gruppo comprendente idrogeno, alogeno (cloro, bromo, fluoro o iodio), (Cj-C4)alcossi, benzilossL R3 is selected from the group comprising hydrogen, halogen (chlorine, bromine, fluorine or iodine), (Cj-C4) alkoxy, benzyloxL

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 diastereoisomeii 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 diastereoisomes 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:

6-metossi-l,2,3,4-tetraidronorharmano; 6-methoxy-1,2,3,4-tetrahydronorharmane;

acido 1,2,3 ,4-tetraidronorharman- 3- carb o ssilico ; 1,2,3, 4-tetrahydronorharman-3-carb or silicon acid;

acido 6-metossi- 1,2, 3, 4-tetraidronorharman- 1-carbossilico; 6-methoxy-1,2, 3, 4-tetrahydronorharman-1-carboxylic acid;

acido l-(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-dicarbossilico; 1-methyl-1,2,3, 4-tetrahydronorharman-1,3-dicarboxylic acid;

acido l-(dietilmetil)-l,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- l,2,3,4-tetraidronorharman-3-carbossilico; 1-isobutyl-1,1,3,4-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- l-metossicarbonil-6-benzilossi- 1,2,3, 4-tetraidronorharmano; 1-methyl-1-methoxycarbonyl-6-benzyloxy-1,2,3, 4-tetrahydronorharmane;

1-metil- l-metossicarbonil-6-metossi- 1,2, 3, 4-tetraidronorharmano; 1-methyl-1-methoxycarbonyl-6-methoxy-1,2, 3, 4-tetrahydronorharmane;

l-metil-l-metossicarbonil-6-idrossi-l,2,3,4-tetraidronorhannano; 1-methyl-1-methoxycarbonyl-6-hydroxy-1,1,3,4-tetrahydronorhannane;

1-metil- l-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-tetraidronorfiannano. 1-methyl- 1-methoxycarbonyl- 1,2,3,4-tetrahydronorphiannane.

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).

1 composti della presente invenzione sono stati saggiali in un test fàrmacologico “in vitro” di inibizione di MMP8 (collagenasi dei neutrofili umani). Il test prevede la determinazione per fluorescenza dell’inibizione dell’attività di degradazione di un substrato fluorescente (DNP-Pro-Leu-Gly-Leu-Tip-Ala-D-Arg-NH2, M1855 Bachem) ad opera del dominio catalitico di MMP8. The compounds of the present invention were assayed in an "in vitro" pharmacological test for inhibition of MMP8 (human neutrophil collagenase). The test involves the determination by fluorescence of the inhibition of the degradation activity of a fluorescent substrate (DNP-Pro-Leu-Gly-Leu-Tip-Ala-D-Arg-NH2, M1855 Bachem) by the catalytic domain of MMP8 .

Reagenti : Reagents:

1) DNP- sub strato = DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 (MI 855 Bachem), P.M. 1) DNP- sub layer = DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 (MI 855 Bachem), P.M.

977.1 g/mol, concentrazione 25 μΜ in DMSO; 2) tampone di misurazione - 50 mM TRIS / 100 mM NaCl / 10 mM CaCl2.2H20, aggiustato a pH 7.6 con acido cloridrico. 3) Enzima = dominio catalitico di MMP8 (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) measuring buffer - 50 mM TRIS / 100 mM NaCl / 10 mM CaCl2.2H20, adjusted to pH 7.6 with hydrochloric acid. 3) Enzyme = catalytic domain of MMP8 (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 mi di soluzione mantenuto sotto agitazione in una cuvetta. Total volume = 1 ml of solution kept under stirring in a cuvette.

Controllo: 0. 98 mi DMSO Control: 0. 98 mi DMSO

0.01 mi di DNP-substrato 0.01 ml of DNP-substrate

0.01 mi di enzima 0.01 ml of enzyme

Esperimento: 0.98 mi DMSO Experiment: 0.98 mi DMSO

0.01 mi DNP- sub strato 0.01 mi DNP- sub layer

0.01 mi enzima 0.01 ml enzyme

0.01 mi inibitore (10 pg/ml) 0.01 mi inhibitor (10 pg / 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 di MMP8 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 MMP8 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:

Inibizione % = 100 - (unità rekt./tempOcon bibit/unità relat./tempOcon<«>iio x 100) Ripetendo l’esperimento a varie concentrazioni di inibitore è possibile calcolarne la rispettiva ICso-La tabella I mostra i dati di inibizione enzimatica per alcuni composti rappresentativi dell’invenzione. Inhibition% = 100 - (unit rekt./tempOcon bibit / relative unit/tempOcon<>iio x 100) Repeating the experiment at various concentrations of inhibitor it is possible to calculate the respective ICso-Table I shows the enzyme inhibition data for some representative compounds of the invention.

Tabella I Table I.

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 μιη) sono rivestite sul fondo con 100 μΐ di collagene tipo IV (soluzione diluita 50 pg/ml, quindi evaporazione per una notte). Con Io stesso procedimento si ricoprono le camere di un secondo strato di collagene tipo IV (100 μΐ di soluzione a concentrazione 50 pg/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 di fibrosarcoma umano 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 3xl05 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 μιη) are coated on the bottom with 100 μΐ of type IV collagen (diluted solution 50 pg / 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 pg / 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 human fibrosarcoma 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 to obtain a final density of 3x105 cells / ml.

Dalle camere preincubate viene rimosso per aspirazione il mezzo privo di siero. H comparto inferiore delle camere è riempito con 600 μΐ di DMEM 20% FCS 1% BSA (frazione V) composto da testare. 200 μΐ di sospensione cellulare (6x104 cellule) contenenti il composto da testare sono aggiunti nel comparto superiore e le camere sono incubate a 37°C in atmosfera umida con C02. Dopo ima 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 μΐ of DMEM 20% FCS 1% BSA (fraction V) compound to be tested. 200 μΐ of cell suspension (6x104 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 C02. After a first 24 hour incubation, the media from the lower and upper compartments are replaced with fresh suspensions and the chambers incubated for another 24 hours.

I filtri incubati sono quindi lavati con PBS, le cellule sono fissate per 15 minuti in paraformaldeide 4%, penneabilizzate in metanolo (10 minuti, -20°C) e colorate con May-Grunwald-Giemsa. Le cellule che aderiscono alla faccia superiore dei filtri sono rimosse con un tampone di cotone, i filtri vengono staccati dal fondo delle camere ed analizzati 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, penneabilized 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-metallo-proteinasi, sono in grado di degradare il collagene tipo IV e di migrare sulla faccia inferiore dei filtri. Nell’esperimento con l’inibitore invece Γ attività delle metallo-proteinasi è parzialmente o totalmente inibita, con un conseguente minor numero di cellule che migrano sulla faccia 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 l’inibitore. In a control experiment, in the absence of a metalloproteinase inhibitor, HT1080 cells, which hyper-metallo-proteinase, are able to degrade type IV collagen and migrate to the underside of the filters. In the experiment with the inhibitor, on the other hand, the activity of the metallo-proteinases is partially or totally inhibited, with a consequent lower number of cells that migrate on the lower face of the filters. bottom of the filter in the control experiment and in the inhibitor experiment.

La tabella Π mostra i dati relativi a due composti rappresentativi dell’invenzione. Table Π shows the data relating to two compounds representative of the invention.

Tabella II Table II

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 metallo-proteinasi della matrice, 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, coronary thrombosis, 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 dipeso corporeo al giorno, impiegando dosi unitarie così 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 active compound. 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 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 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 incoiporato 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 embedded 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)

RIVENDICAZIONI: 1. Uso dei composti di fomula (I): ( i ) R R in cui: R è scelto nel gruppo comprendente idrogeno, (Ci-Cs)alchile lineare o ramificato, fenile (eventualmente sostituito da un gruppo (Ci-Cj)alcossi), -(CH2)B-COOH, dove n è un intero da 1 a 3; Ri è idrogeno o un gruppo -COOR4, dove R4 è idrogeno o (Ci-Cs)alchile; R2 è idrogeno o un gruppo -COOR4 come sopra definito; R3 è scelto nel gruppo comprendente idrogeno, alogeno (cloro, bromo, fluoro o iodio), (C r C4)alcossi, benzilossi, di loro enantiomeri, racemati, diastereoisomeri e di loro sali con acidi e basi farmaceuticamente accettabili, per la preparazione di una composizione farmaceutica avente attività antimetastatica o di inibizione dell’invasione tumorale. CLAIMS: 1. Use of compounds of fomula (I): (i) R R in which: R is selected from the group comprising hydrogen, (Ci-Cs) linear or branched alkyl, phenyl (optionally replaced by a (Ci-Cj) alkoxy group), - (CH2) B-COOH, where n is an integer from 1 to 3 ; R1 is hydrogen or a -COOR4 group, where R4 is hydrogen or (Ci-Cs) alkyl; R2 is hydrogen or a -COOR4 group as defined above; R3 is selected from the group comprising hydrogen, halogen (chlorine, bromine, fluorine or iodine), (C r C4) alkoxy, benzyloxy, their enantiomers, racemates, diastereoisomers and their salts with pharmaceutically acceptable acids and bases, for the preparation of a pharmaceutical composition having antimetastatic or tumor invasion inhibition activity. 2. Uso secondo la rivendicazione 1, in cui detti composti sono: 6-metossi- 1,2, 3, 4-tetraidronoiharmano; acido l,2,3,4-tetraidronorharmano-3-carbossilico; acido 6-metossi- 1,2,3, 4-tetraidronorharman- 1-carbossilico; acido l-(4-metossifenil)-l,2,3,4-tetraidronorharman-3-carbossiIico; acido 1-metil- l,2,3,4-tetraidronorharman-3-carbossilico; acido 1-metil- 1,2,3,4-tetraidronorharman- 1 ,3-dicarbossilico; acido l-(dietilmetil)- 1 ,2,3,4-tetraidronorharman-3-carbossilico; acido (6-bromo- 1,2,3,4-tetraidronorharman- l-il)-3-propionico; acido 1-isobutil- 1,2,3, 4-tetraidronorharman-3-carbossilico; acido 1-fenil- 1,2,3, 4-tetraidronorharman-3-carbossilico; acido 1-propil- 1,2,3, 4-tetraidronorharman-3-carbossilico; 1-metil- l-metossicarbonil-6-benzilossi- 1,2,3, 4-tetraidronorharmano; 1-metil- l-metossicarbonil-6-metossi- 1,2,3, 4-tetraidronorhannano; / 1-metil- l-metossicarbonil-6-idrossi- 1,2, 3, 4-tetraidronorharmano; 1-metil- l-metossicarbonil-6-cloro- 1,2, 3, 4-tetraidronorharmano; 1-metil- l-metossicarbonil-6-bromo- 1,2, 3, 4-tetraidronorharmano; 1-metil- 1-metossicarbonil- 1 ,2, 3, 4-tetraidronorharmano. Use according to claim 1, wherein said compounds are: 6-methoxy- 1,2, 3, 4-tetrahydronoiharmane; 1,3,4-tetrahydronorharmano-3-carboxylic acid; 6-methoxy-1,2,3, 4-tetrahydronorharman-1-carboxylic acid; 1- (4-methoxyphenyl) -1, 2,3,4-tetrahydronorharman-3-carboxylic acid; 1-methyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid; 1-methyl-1,2,3,4-tetrahydronorharman-1,3-dicarboxylic acid; 1- (diethylmethyl) - 1,2,3,4-tetrahydronorharman-3-carboxylic acid; (6-bromo-1,2,3,4-tetrahydronorharman-1-yl) -3-propionic acid; 1-isobutyl-1,2,3, 4-tetrahydronorharman-3-carboxylic acid; 1-phenyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid; 1-propyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid; 1-methyl-1-methoxycarbonyl-6-benzyloxy-1,2,3, 4-tetrahydronorharmane; 1-methyl-1-methoxycarbonyl-6-methoxy-1,2,3, 4-tetrahydronorhannane; / 1-methyl-1-methoxycarbonyl-6-hydroxy-1,2, 3, 4-tetrahydronorharmane; 1-methyl-1-methoxycarbonyl-6-chloro- 1,2, 3, 4-tetrahydronorharmane; 1-methyl-1-methoxycarbonyl-6-bromo-1,2, 3, 4-tetrahydronorharmane; 1-methyl- 1-methoxycarbonyl- 1, 2, 3, 4-tetrahydronorharmane. 3. Uso secondo la rivendicazione 2, in cui i principi attivi sono: 6-metossi- 1 ,2, 3 , 4-tetraidronorharmano ; acido l,2,3,4-tetraidronorharmano-3-carbossilico; acido 6-metossi- 1,2,3,4-tetraidronorharman- 1-carbossilico. Use according to claim 2, wherein the active ingredients are: 6-methoxy-1, 2, 3, 4-tetrahydronorharmane; 1,3,4-tetrahydronorharmano-3-carboxylic acid; 6-methoxy- 1,2,3,4-tetrahydronorharman- 1-carboxylic acid. 4. Uso dei composti di fonatila (I): (i) R è scelto nel gruppo comprendente idrogeno, (Ci-C5)alchile lineare o ramificato, fenile (eventualmente sostituito da un gruppo (CrC5)alcossi), -(CH2)n-COOH, dove n è un intero da 1 a 3 ; Ri è idrogeno o un gruppo -COOR4, dove R4 è idrogeno o (Ci-Cs)alchile; R2 è idrogeno o un gruppo -COOR4 come sopra definito; R3 è scelto nel gruppo comprendente idrogeno, alogeno (cloro, bromo, fluoro o iodio), (Ci-C4)alcossi, benzilossi, di loro enantiomeri, racemati, diastereoisomeri e di loro sali con acidi e basi farmaceuticamente accettabili, per la preparazione di una composizione farmaceutica per la prevenzione o la cura delle condizioni associate. all’azione delle matrice-metallo proteinasi. 4. Use of compounds of phonatyl (I): (i) R is selected from the group comprising hydrogen, (Ci-C5) linear or branched alkyl, phenyl (optionally substituted by a (CrC5) alkoxy group), - (CH2) n-COOH, where n is an integer from 1 to 3; R1 is hydrogen or a -COOR4 group, where R4 is hydrogen or (Ci-Cs) alkyl; R2 is hydrogen or a -COOR4 group as defined above; R3 is selected from the group comprising hydrogen, halogen (chlorine, bromine, fluorine or iodine), (Ci-C4) alkoxy, benzyloxy, their enantiomers, racemates, diastereoisomers and their salts with pharmaceutically acceptable acids and bases, for the preparation of a pharmaceutical composition for the prevention or treatment of associated conditions. to the action of matrix-metallo proteinases. 5. Uso secondo la rivendicazione 4, in cui detti composti sono: 6-meto ssi- 1 ,2 ,3 ,4-tetraidronorharmano ; acido l,2,3,4-tetraidronorhannano-3-carbossilico; acido 6-metossi- 1 ,2,3,4-tetraidronorharman- 1-carbossilico; acido l-(4-metossifenil)- 1,2,3, 4-tetraidronorharman-3-carbossilico; acido l-metil-l,2,3,4-tetraidronorbarman-3-carbossilico; acido 1-metil- 1 ,2,3,4-tetraidronorharman- 1,3-dicarbossilico; acido l-(dietilmetil)- 1,2,3, 4-tetraidronorharman- 3 -carb ossifico; acido (6-bromo- 1,2, 3, 4-tetraidronorharman- l-il)-3-propionico; acido 1-isobutil- 1,2,3, 4-tetraidronorharman-3-carbossilico; acido 1-fenil- 1 ,2,3,4-tetraidronorharman-3-carbossilico; acido 1-propil- 1 ,2,3,4-tetraidronorharman-3-carbossilico; 1-metil- l-metossicarbonil-6-benzilossi- 1,2,3, 4-tetraidronoiharmano; 1-metil- l-metossicarbonil-6-metossi- 1,2,3, 4-tetraidronoiharmano; l-metil- l-metossicarbonil-6-idrossi- 1,2,3, 4-tetraidronorharmano; l-metil- l-metossicarbonil-6-cloro- 1,2,3, 4-tetraidronorharmano; l-metil- l-metossicarbonil-6-bromo- 1,2, 3, 4-tetraidronorharmano; 1 -metil- 1 -meto ssicarb onil- 1 ,2,3 ,4-tetr aidronorhannano . 5. Use according to claim 4, wherein said compounds are: 6-methoxysi- 1, 2, 3, 4-tetrahydronorharmane; 1,3,4-tetrahydronorhannano-3-carboxylic acid; 6-methoxy-1,2,3,4-tetrahydronorharman-1-carboxylic acid; 1- (4-methoxyphenyl) - 1,2,3, 4-tetrahydronorharman-3-carboxylic acid; 1-methyl-1,3,4-tetrahydronorbarman-3-carboxylic acid; 1-methyl- 1, 2,3,4-tetrahydronorharman-1,3-dicarboxylic acid; 1- (diethylmethyl) - 1,2,3, 4-tetrahydronorharman- 3-carbonic acid; (6-bromo- 1,2, 3, 4-tetrahydronorharman-1-yl) -3-propionic acid; 1-isobutyl-1,2,3, 4-tetrahydronorharman-3-carboxylic acid; 1-phenyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid; 1-propyl-1, 2,3,4-tetrahydronorharman-3-carboxylic acid; 1-methyl-1-methoxycarbonyl-6-benzyloxy-1,2,3, 4-tetrahydronoiharmane; 1-methyl-1-methoxycarbonyl-6-methoxy-1,2,3,4-tetrahydronoiharmane; 1-methyl-1-methoxycarbonyl-6-hydroxy-1,2,3, 4-tetrahydronorharmane; 1-methyl-1-methoxycarbonyl-6-chloro-1,2,3, 4-tetrahydronorharmane; 1-methyl-1-methoxycarbonyl-6-bromo-1,2, 3, 4-tetrahydronorharmane; 1 -methyl- 1 -metus ssicarb onyl- 1, 2,3, 4-tetr aidronorhannano. 6. Uso secondo la rivendicazione 5, in cui i principi attivi sono: 6-metossi- 1 ,2,3,4-tetraidronorharmano; acido 1 , 2, 3,4-tetraidronorharmano- 3 - carb ossilico ; acido 6-metossi- 1,2,3, 4-tetraidronorharman- 1-carbossilico. 6. Use according to claim 5, wherein the active ingredients are: 6-methoxy- 1, 2,3,4-tetrahydronorharmane; 1,2,3,4-tetrahydronorharmano-3 - carboxylic acid; 6-methoxy- 1,2,3, 4-tetrahydronorharman- 1-carboxylic acid. 7. Uso secondo una qualsiasi delle rivendicazioni 4-6, in cui la condizione da trattare è selezionata nel gruppo consistente in: artrite reumatoide, osteoartrite, artrite settica, ulcerazioni della cornea, epidermiche o gastriche, trombosi coronarica, proteinuria, conseguenze patologiche di traumi. Use according to any one of claims 4-6, wherein the condition to be treated is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulcerations, coronary thrombosis, proteinuria, pathological consequences of trauma . 8. Uso secondo una qualsiasi delle rivendicazioni 4-6, per la prevenzione dell’ovulazione o dell’impianto dell’ovulo nell’utero. 8. Use according to any of claims 4-6, for the prevention of ovulation or implantation of the ovum in the uterus.
IT96MI002241 1996-04-04 1996-10-29 Use of tetra:hydro-beta-carboline derivatives - for preparation of medicaments having anti-metastatic activity or tumour invasion or matrix metallo-proteinase inhibitory activity IT1286060B1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
IT96MI002241 IT1286060B1 (en) 1996-10-29 1996-10-29 Use of tetra:hydro-beta-carboline derivatives - for preparation of medicaments having anti-metastatic activity or tumour invasion or matrix metallo-proteinase inhibitory activity
JP9535798A JP2000508302A (en) 1996-04-04 1997-03-27 Use of tetrahydro-.BETA.-carboline derivatives as antimetastatic agents
EP97916410A EP0891187B1 (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
AU25069/97A AU710079B2 (en) 1996-04-04 1997-03-27 Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents
US09/142,058 US6069150A (en) 1996-04-04 1997-03-27 Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents
TR1998/01970T TR199801970T2 (en) 1996-04-04 1997-03-27 Use of tetrahydro-beta-carbolines as antimetastatic agents.
KR1019980707846A KR20000005175A (en) 1996-04-04 1997-03-27 Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents
DK97916410T DK0891187T3 (en) 1996-04-04 1997-03-27 Use of tetrahydro-beta-carboline derivatives as antimetastatic agents
AT97916410T ATE212549T1 (en) 1996-04-04 1997-03-27 USE OF TETRAHYDROBETACARBOLINE DERIVATIVES TO PREVENT METASTASIS
PCT/EP1997/001582 WO1997037658A1 (en) 1996-04-04 1997-03-27 Use of derivatives 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
ES97916410T ES2169857T3 (en) 1996-04-04 1997-03-27 USE OF TETRAHIDRO-BETA-CARBOLINAS DERIVATIVES AS ANTIMETASTATIC AGENTS.
PT97916410T PT891187E (en) 1996-04-04 1997-03-27 USING TETRAHYDRO-BETA-CARBOLINOS DERIVATIVES AS ANTIMESTATIC AGENTS
CN97193568A CN1113648C (en) 1996-04-04 1997-03-27 Use of derivativ
CA002250898A CA2250898A1 (en) 1996-04-04 1997-03-27 Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents

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