+

WO1997028166A1 - Thienoquinoleines - Google Patents

Thienoquinoleines

Info

Publication number
WO1997028166A1
WO1997028166A1 PCT/EP1997/000404 EP9700404W WO9728166A1 WO 1997028166 A1 WO1997028166 A1 WO 1997028166A1 EP 9700404 W EP9700404 W EP 9700404W WO 9728166 A1 WO9728166 A1 WO 9728166A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
substituted
phenyl
formula
Prior art date
Application number
PCT/EP1997/000404
Other languages
German (de)
English (en)
Inventor
Wolf-Rüdiger Ulrich
Thomas Bär
Peter Zimmermann
Rainer Boer
Volker Gekeler
Wolfgang Ise
Hildegard Boss
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik Gmbh filed Critical Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority to AU15971/97A priority Critical patent/AU1597197A/en
Publication of WO1997028166A1 publication Critical patent/WO1997028166A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention relates to new thienoquinolines, processes for their preparation and their use in the pharmaceutical industry for the production of medicaments.
  • the invention thus relates to compounds of the formula (I) (see attached formula sheet), in which the partial structure designated below (A) has the meanings (B), (C) or (D),
  • R1 is hydrogen or 1-4C-alkyl
  • R2 is hydrogen, halogen, 1-4C-alkyl, nitro or 1-4C-alkoxy
  • D is oxygen, sulfur, the group -N (Z) - or a bond, where Z is hydrogen or 1-4C-alkyl,
  • E means 1-4C-alkylene
  • R3 denotes hydrogen or 1-4C-alkyl
  • R4 means aryl-1-4C-alkyl, where aryl means phenyl substituted by R41, R42 and R43 and R41, R42 and R43 independently of one another mean hydrogen, 1-4C-alkyl or 1-4C-alkoxy, or
  • R3 and R4 together and including the nitrogen atom to which both are attached represent an unsubstituted or substituted 1,2,3,4-tetrahydroisoquinoline residue
  • a substituted 1,2,3,4-tetrahydroisoquinoline residue at positions 1, 3 and / or 4 can be substituted with one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, carboxy, phenyl, phenyl substituted by R31 and R32, phenyl-1-4C-alkyl and by R31 and R32 in the phenyl radical is substituted phenyl-1-4C-alkyl and can be substituted on the benzo part with one or two identical or different substituents selected from the group consisting of hydroxy, 1-4C-alkoxy and di-1-4C-alkylamino, in which
  • R31 and R32 independently of one another are hydrogen, hydroxy, 1-4C-alkyl, 1-4C-alkoxy, halogen or 1-4C-alkylamino
  • R5 and R6 independently of one another are hydrogen, halogen, 1-4C-alkoxy, nitro, di-1-4C-alkylaminocarbonyl, 1-4C-alkylaminocarbonyi.
  • Carbamoyl, carboxy, amino, 1-4C-alkyl, 1-4C-alkoxycarbonyl, cyano, phenyl, phenyl substituted by R7 or 1-4C-alkylthio, or, if they are adjacent, R5 and R6 together and including the carbon atom ⁇ me to which they are bound can also represent a cyclohexene ring,
  • R7 means halogen, and their salts.
  • One embodiment of the invention is compounds of the formula (I) in which the partial structure denoted by (A) has the meaning (C) and the other substituents and symbols have the meanings mentioned above.
  • 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • 1-4C-Aikoxy stands for a radical which, in addition to the oxygen atom, contains one of the 1-4C-alkyl radicals mentioned above.
  • the methoxy and ethoxy radicals may be mentioned, for example.
  • 1-4C-alkylene stands for straight-chain or branched 1-4C-alkylene radicals, for example for the methylene (-CH r ). Ethylene- (-CH 2 -CH r ), trimethylene- (-CH r CH r CHr), tetramethylene- (-CH 2 -CH 2 -CH 2 -CH 2 -).
  • Aryl-1-4C-alkyl represents one of the above-mentioned 1-4C-alkyl radicals which is substituted by R41, R42 and R43 substituted phenyl.
  • Examples include benzyl, phenethyl, 3,4-dimethoxybenzyl, 2- (3,4-dimethoxyphenyl) ethyl, 4-methoxybenzyl, 4-methylphenyl and 2-methoxybenzyl -, the 2- (4-methoxyphenyl) ethyl, the 2- (4-methylphenyl) ethyl, the 3-methoxybenzyl and the 3,4,5-trimethoxybenzyl radical.
  • Exemplary phenyl radicals substituted by R31 and R32 are the 3,4-dihydroxy, 3-hydroxy-4-methoxy, 3,4-dimethoxy, 2-methoxy, 2-ethoxy, 3-methoxy, 4-methoxy, 2-hydroxy, 3-hydroxy, 4-hydroxy, 4-fluoro, 4-chloro, 2-chloro, 3-chloro, 3,4-dichloro, 2- Methyl-, 3-methyl, 4-methyl, 2,3-dimethyl, 2,4-dimethyl, 3,4-dimethyl, 2,5-dimethyl, and 5-chloro-2-methylaminophenyl.
  • Phenyl-1-4C-alkyl stands for one of the abovementioned phenyl-substituted 1-4C-alkyl radicals. Examples include the phenethyl and benzyl radicals.
  • Phenyl-1-4C-alkyl substituted by R31 and R32 in the phenyl radical represents one of the abovementioned 1-4C-alkyl radicals which is substituted by R31 and R32 substituted phenyl. Examples include the 3,4-dihydroxybenzyl, 3-hydroxy-4-methoxybenzyl and the 3,4-dimethoxybenzyl radical.
  • Di-1-4C-alkylamino represents an amino radical which is substituted by two identical or different of the above-mentioned 1-4C-alkyl radicals. Examples include the dimethylamino, the diethylamino and the di-isopropylamino radical.
  • substituted 1,2,3,4-tetrahydroisoquinoline residues are 1-methyl-6,7-dihydroxy-1, 2,3,4-tetrahydro-2-isoquinolinyl-1 - (3,4-dihydroxybenzyl) -6 , 7-dihydroxy-1, 2,3,4-tetrahydro-2-isoquinolinyl-, 3-carboxy-1, 2,3,4-tetrahydro-2-isoquinolinyl-, 6,7-dimethoxy-1,2 , 3,4-tetra-hydro-2-isoquinolinyl-, 1-benzyl-1, 2,3,4-tetrahydro-2-isoquinolinyl-, 1- (3-hydroxy-4-methoxy-benzyl) -6-dimethylamino -1,2,3,4-tetrahydro-2-isoquinolinyl-, 3-tert-butyl-6-methoxy-4-phenyl-1,2,3 t 3,4-tetrahydr
  • 1-4C-alkoxycarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached.
  • the methoxycarbonyl (CH 3 0-CO-) and the ethoxycarbonyl (CH 3 CH 2 0-CO-) may be mentioned.
  • 1-4C-alkylthio stands for a radical which, in addition to the sulfur atom, contains one of the 1-4C-alkyl radicals mentioned above.
  • the methylthio and the ethylthio radical may be mentioned.
  • Di-1-4C-alkylamino-carbonyl stands for a radical which, in addition to the carbonyl group, contains one of the above-mentioned di-1-4C-alkylamino groups.
  • the dimethylcarbamoyl and diethylcarbamoyl radicals may be mentioned.
  • 1-4C-alkylaminocarbonyl stands for a radical which, in addition to the carbonyl group, contains one of the 1-4C-alkylamino radicals mentioned below.
  • the methyl carbamoyl and ethyl carbamoyl radicals may be mentioned, for example.
  • 1-4C-alkylamino represents an amino radical which is substituted by one of the above-mentioned 1-4C-alkyl radicals.
  • Exemplary phenyl radicals substituted by R7 are the 4-chlorophenyf, the 3-chlorophenyl, the 2-chlorophenyl, the 4-fluorophenyl, the 3-fluorophenyl and the 2-fluorophenyl radical.
  • Suitable as such are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid , Sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is is a mono- or polybasic acid and, depending on which salt is desired, can be used in an equimolar or a quantity ratio deviating therefrom.
  • acids such as, for example, hydrochloric acid,
  • salts with bases can also be used.
  • examples of salts with bases include alkali (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, with the here too Salt production, the bases are used in an equimolar or a quantity ratio deviating therefrom.
  • Pharmacologically incompatible salts which may initially be obtained as process products in the production of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
  • E means 1-4C-alkylene
  • R3 denotes hydrogen or 1-4C-alkyl
  • R4 means aryl-1-4C-alkyl, where aryl means phenyl substituted by R41, R42 and R43 and R41, R42 and R43 independently of one another mean hydrogen, 1-4C-alkyl or 1-4C-alkoxy, or
  • R3 and R4 together and including the nitrogen atom to which both are attached represent an unsubstituted or substituted 1, 2,3,4-tetrahydroisoquinoline residue, with a substituted 1,2,3,4-tetrahydroisoquinotine residue at positions 1, 3 and / or 4 can be substituted with one or two identical or different substituents selected from the group consisting of 1 -4 C-alkyl, phenyl, phenyl substituted by R31 and R32, phenyl-1-4C-alkyl and by R31 and R32 in the phenyl radical is substituted phenyl-1-4C-alkyl, and can be substituted on the benzo part with one or two identical or different substituents selected from the group consisting of hydroxy and 1-4C-alkoxy, where
  • R31 and R32 independently of one another are hydrogen, hydroxy, 1-4C-alkyl, 1-4C-alkoxy, halogen or 1-4C-alkylamino,
  • R5 and R6 independently of one another are hydrogen, halogen, 1-4C-alkoxy, carbamoyl, 1-4C-alkyl, cyano, phenyl, phenyl substituted by R7 or 1-4C-alkylthio, or, if they are adjacent, R5 and R6 together and including the carbon atoms to which they are attached can also represent a cyclohexene ring,
  • R7 means halogen, and their salts.
  • R1 is hydrogen or 1 -4C-alkyl
  • R2 means hydrogen
  • E means 1-4C-alkylene
  • R3 denotes 1 -4 C alkyl
  • R4 means aryl-1-4C-alkyl, where aryl means phenyl substituted by R41, R42 and R43 and R41, R42 and R43 independently of one another mean hydrogen, 1-4C-alkyl or 1-4C-alkoxy, or R3 and R4 together and including the nitrogen atom, to which both are bound, represent an unsubstituted or substituted 1,2,3,4-tetrahydroisoquinoline residue, where a substituted 1, 2,3,4-tetrahydroisoquinoline residue can be substituted on the benzo part with one or two identical or different 1-4C alkoxy substituents,
  • R5 and R6 independently of one another are hydrogen, halogen, 1-4C-alkyl, cyano, phenyl, phenyl substituted by R7 or 1-4C-alkylthio, or, if they are adjacent, R5 and R6 together and including the carbon atoms which are bound can also represent a cyclohexene ring,
  • R7 means halogen, and their salts.
  • Preferred compounds of the formula (I) are those in which the partial structure (A) has the abovementioned meanings (B), (C) or (D),
  • R1 and R2 are hydrogen
  • E means 1-4C-alkylene
  • R3 denotes 1-4C-alkyl
  • R4 means aryl-1-4C-alkyl, where aryl means phenyl substituted by R41, R42 and R43 and R41, R42 and R43 independently of one another mean hydrogen, 1-4C-alkyl or 1-4C-alkoxy, or
  • R3 and R4 together and including the nitrogen atom to which both are attached represent a substituted 1,2,3,4-tetrahydroisoquinoline residue, where a substituted 1, 2,3,4-tetrahydroisoquinoline residue on the benzo part can be substituted with one or two same or different 1-4C alkoxy substituents,
  • R5 and R6 independently of one another are hydrogen, halogen, 1-4C-alkyl, phenyl, phenyl substituted by R7 or 1-4C-alkylthio, or, if they are adjacent, R5 and R6 together and including the carbon atoms which are bound can also represent a cyclohexene ring,
  • R7 means halogen, and their salts.
  • One embodiment of the preferred compounds of the formula (I) are those compounds of the formula (I) in which the partial structure (A) has the meanings given above (B), (C) or (D),
  • R1 and R2 are hydrogen, D is a bond, E means 1-4C-alkylene,
  • R3 means 1-4C-alkyl
  • R4 is benzyl, 3,4-dimethoxybenzyl, 2- (3,4-dimethoxyphenyl) ethyl, 4-methylbenzyl or 4-methoxybenzyl, or
  • R3 and R4 together and including the nitrogen atom to which both are attached represent the 6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl radical
  • R5 and R6 independently of one another are hydrogen, halogen, 1-4C-alkyl, phenyl, phenyl substituted by R7 or 1-4C-alkylthio, or, if they are adjacent, R5 and R6 together and including the carbon atoms which are bound can also represent a cyclohexene ring,
  • R7 means halogen, and their salts.
  • Particularly preferred compounds of the formula (I) are those in which the partial structure (A) has the abovementioned meanings (C) or (D),
  • R1 and R2 are hydrogen
  • E means 1-2C-alkylene
  • R3 and R4 together and including the nitrogen atom to which both are attached represent the 6,7-dimethoxy-1, 2,3,4-tetrahydro-2-isoquinolinyl radical
  • R5 and R6 independently of one another are hydrogen or 1-4C-alkyl mean and their salts.
  • Substructure (A) has the meaning given above (C),
  • R1 and R2 are hydrogen
  • E means 1-2C-alkylene
  • R3 and R4 together and including the nitrogen atom to which both are bonded represent the 6,7-dimethoxy-1, 2,3,4-tetrahydro-2-isoquinolinyl radical, R5 and R6 independently of one another are hydrogen or 1-4C-alkyl mean and their salts.
  • the invention further relates to a process for the preparation of the compounds of the formula (I) (see attached formula sheet), in which R1, R2, D, E, R3 and R4 correspond to the abovementioned have meanings and the partial structure (A) has the meanings (B), (C) or (D) and their salts.
  • the compounds of the formulas (II) and (III) are reacted in a manner known per se to the person skilled in the art, preferably using a coupling reagent.
  • Suitable coupling reagents are, for example, N.N'-carbonyldiimidazole, phosphoric acid diphenyl ester azide or 1-benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), but N.N-dicyciohexylcarbodiimide (DCC) is preferred.
  • the reaction can be promoted by adding 1-hydroxy-1-H-benzotriazole.
  • the reaction is preferably carried out in polar, aprotic or protic solvents (for example in dimethylformamide) with the addition or in the absence of water and at reaction temperatures between 0 ° C. and the boiling point of the solvent used, but preferably at room temperature.
  • polar, aprotic or protic solvents for example in dimethylformamide
  • the substances according to the invention are isolated and purified in a manner known per se, e.g. in such a way that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.
  • Salts are obtained by dissolving the free compound in a suitable solvent, e.g. in a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol), which contains the desired acid or base, or which contains the desired acid or Base is then added.
  • a suitable solvent e.g. in a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol), which contains the desired acid or base, or which contains the desired acid or Base is then added.
  • the salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent.
  • Salts obtained can be converted into the free compounds by alkalization or by acidification, which in turn can be converted into salts. In this way, pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.
  • reaction can be carried out in a manner known to those skilled in the art (for example analogously as described by RO Sche ⁇ rer and HR Beatty in J. Org. Chem. 1980, 45, 2127-2131 or by GW Rewcastle and WA Denny in Synthesis 1985, 220-222 ) are carried out.
  • RT room temperature
  • h hour (s)
  • min minute
  • dec. decomposition
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • the reaction solution is concentrated, treated with 2 l of boiling THF and suction filtered.
  • the filtrate is concentrated, 1 l of dichloromethane and 500 ml of water are added, and the phases are separated.
  • the water phase is saturated with sodium chloride, the precipitated substance is suctioned off and the residue is washed three times with 50 ml of water.
  • After recrystallization in 30 ml of isopropanol 1.1 g of the titanium compound with a melting point of> 300 ° C. are obtained.
  • reaction solution is concentrated and chromatographed on silica gel [ethyl acetate / triethylamine (100: 1)]. Soak up in 200 ml of ethyl acetate and 100 ml of 0.1 N sodium hydroxide solution and suction. Separate the phases and dry the organic phase over magnesium sulfate. After concentration, the product is recrystallized from 15 ml of ethanol. The title compound is obtained with mp. 215-218'C.
  • reaction solution is concentrated and chromatographed on silica gel (ethyl acetate / triethylamine (100: 1)]. Take up in 30 ml of dichloromethane and suction. After concentration of the mother liquor, it is recrystallized from 50 ml of ethanol. The title compound is obtained with mp. 219-222'C .
  • the compounds of the formula (I) and their salts have valuable properties which make them commercially viable. They improve the effect of antibiotics and / or cytostatics in a synergistic manner, and they are also able to overcome resistance to antibiotics and / or cytostatics that already exist or that arise during the course of therapy. They can not only be used in combination with other cytostatics or antibiotics to overcome the so-called "drug resistance” or "multidrug resistance”. Rather, because of their antineoplastic properties, they are suitable per se for the treatment of tumor diseases, for example for reducing or preventing the formation of metastases and tumor growth in mammals, and because of their antiproliferative properties, for example for the treatment of dermatoses.
  • the compounds according to the invention are furthermore not only suitable for overcoming resistance to antibiotics. Rather, due to their antiparasitic properties, they can be used to treat parasitic, in particular tropical, parasitic diseases such as malaria, sleeping sickness, filariasis or onchocerciasis.
  • the dose of the cytostatics administered can be reduced, which leads to a significant reduction in the toxic side effects, and that the number of cytostatics that can be used increases , so that the cytostatic agent optimally suitable for the particular tumor and the particular patient can be selected.
  • the compounds of the formula (I) and / or their pharmacologically acceptable salts are administered as resistance modulators in antibiotic and cytostatic therapy
  • the compounds of the formula (I) can be administered together with the antibiotics or cytostatics in a fixed dose in the form of Combination preparations are administered, or the compounds of the formula (I) can be used separately in any dosage and in a suitable dosage form as accompanying and supporting active substances in antibiotic or cytostatic therapy.
  • the ratio of compounds of formula (I) to antibiotic or cytostatic agent depends on the disease to be treated, the patient's condition and the antibiotic or cytostatic agent used. It has generally proven to be advantageous here to use the compounds of the formula (I) in a daily dose of about 0.5 to 30 mg / kg of body weight when given orally, and in a daily dose of about 0.1 to 10 mg / kg in the case of intravenous administration. kg body weight, if necessary in the form of several single doses or as a continuous infusion to achieve the desired result.
  • the antibiotics or cytostatics are administered in the usual, but preferably in lower, doses.
  • the invention also relates to the compounds of the formula (I) and their pharmacologically compatible salts for use in the treatment of tumor diseases.
  • the invention also encompasses the use of compounds of the formula (I) and their pharmacologically acceptable salts in the production of medicaments which are used to combat tumor diseases.
  • Another object of the invention is the use of compounds of formula (I) in combination with antibiotics or cytostatics in antibiotic and / or cytostatic therapy.
  • the invention also relates to the use of compounds of the formula (I) for the production of medicaments which are to be used in combination with antibiotics or cytostatics in antibiotic and / or cytostatic therapy.
  • the invention further relates to medicaments which receive one or more compounds of the general formula (I) and / or their pharmacologically tolerable salts.
  • the pharmaceuticals are manufactured according to methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents for example anti-oxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
  • the active substances can be administered rectally, by inhalation, parenterally (perlingually, intravenously, percutaneously) or orally.
  • the activity of cells can be reduced via the mitochondrial succinate dehydrogenase by reducing the tetrazolium salt to blue Determine Fo ⁇ maza ⁇ (Mosmann, Br. J. Cancer, 52: 205-214, 1983). The respective cell number can then be concluded from the metabolic activity.
  • Rows were plated in 80 ⁇ l medium (RPM1 1640, 50% human serum) using an automatic pipette (Elektrapette, Tec ⁇ omara).
  • the modulators to be examined were dissolved in 100% DMSO and then further diluted with medium. The final DMSO concentration was 0.1% in all batches. 10 ⁇ l cytostatics solution and 10 ⁇ l modulator solution were added to the cell therapy. In the control, 20 ⁇ l of medium were pipetted accordingly.
  • the formazan formed was quantified using an automatic microtiter plate reader (EL 311, Bio-Tea Instruments) at 540 nm.
  • the reference wavelength was 690 nm.
  • the absorption data were given as mean values of a triple determination + -SEM. Dose-effect curves were obtained by plotting the formation of formazan as a percentage of the control against the respective cytostatic concentration.
  • Table 1 below shows the test results obtained.
  • CCRF-VCR 1000 was used as the cell line and vincristine as the cytostatic agent.
  • the concentration of the corresponding compounds was 3 ⁇ M and 10 ⁇ M, respectively.
  • the numbers of the compounds examined correspond to the numbers in the examples.
  • the RMF value resistance modulation factor
  • the RMF value is the quotient of the ICs value (ng / ml) cytostatic agent alone and the IC50 value cytostatic agent + compound tested.
  • RMF value IC50 (ng / ml) cytostatic / 1C50 (ng / ml) cytostatic + respective compound.
  • Multidrug resistant and sensitive cells of the t-lymphoblastoid leukemia cell lines CCRF-VCR1000 and CCRF-CEM are removed from the cell culture and harvested by centrifugation.
  • Rhodamine 123 is then added (final concentration 0.8 mg / l) and incubated for a further hour at 37 ° C.
  • the cellular Rhodamine 123 fluorescence is measured using a fluorescence activated cell sorter.
  • the excitation wavelength is 488 nm.
  • Rhodamine 123 fluorescence is measured at 520 nm. Dose-effect curves are generated from the old data, and their ECso value is used as a measure of the potency of a modulator Elimination of the P-glycoprotein-mediated rhodamine 123 reduced accumulation is used.
  • Table 2 shows the ECs ⁇ values determined for some of the compounds examined.
  • the numbers of the compounds examined correspond to the numbers in the examples.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des compositions de la formule (I), dans laquelle les substituents et les symboles ont les significations données dans la description, constituent d'intéressants modulateurs de la résistance.
PCT/EP1997/000404 1996-02-01 1997-01-30 Thienoquinoleines WO1997028166A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15971/97A AU1597197A (en) 1996-02-01 1997-01-30 Thienoquinolines

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19603508 1996-02-01
DE19603508.2 1996-02-01
EP96101790 1996-02-08
EP96101790.2 1996-02-08

Publications (1)

Publication Number Publication Date
WO1997028166A1 true WO1997028166A1 (fr) 1997-08-07

Family

ID=26022536

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/000404 WO1997028166A1 (fr) 1996-02-01 1997-01-30 Thienoquinoleines

Country Status (2)

Country Link
AU (1) AU1597197A (fr)
WO (1) WO1997028166A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274593B1 (en) 1997-05-01 2001-08-14 Smithkline Beecham P.L.C. Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors
US6414154B1 (en) 1998-05-20 2002-07-02 Smithkline Beecham P.L.C. Tetraisoquinoline derivatives as modulators of dopamine D3 receptors
US6605607B1 (en) 1998-10-08 2003-08-12 Smithkline Beecham P.L.C. Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)
US6693099B2 (en) 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
US7476680B2 (en) 2000-10-17 2009-01-13 H. Lee Moffitt Cancer Center & Research Institute, Inc. Substituted heterocyclic compounds for treating multidrug resistance

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012132A1 (fr) * 1991-01-11 1992-07-23 Laboratoires Glaxo S.A. Derives d'acridine
WO1994001408A1 (fr) * 1992-07-10 1994-01-20 Laboratoires Glaxo S.A. Derives d'anilide
WO1995026337A1 (fr) * 1994-03-25 1995-10-05 Vertex Pharmaceuticals Incorporated Nouveaux carbamates et urees utilises pour modifier la resistance multi-medicamenteuse

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012132A1 (fr) * 1991-01-11 1992-07-23 Laboratoires Glaxo S.A. Derives d'acridine
WO1994001408A1 (fr) * 1992-07-10 1994-01-20 Laboratoires Glaxo S.A. Derives d'anilide
WO1995026337A1 (fr) * 1994-03-25 1995-10-05 Vertex Pharmaceuticals Incorporated Nouveaux carbamates et urees utilises pour modifier la resistance multi-medicamenteuse

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274593B1 (en) 1997-05-01 2001-08-14 Smithkline Beecham P.L.C. Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors
US6414154B1 (en) 1998-05-20 2002-07-02 Smithkline Beecham P.L.C. Tetraisoquinoline derivatives as modulators of dopamine D3 receptors
US6605607B1 (en) 1998-10-08 2003-08-12 Smithkline Beecham P.L.C. Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)
US6693099B2 (en) 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
US7304053B2 (en) 2000-10-17 2007-12-04 H. Lee Moffitt Cancer Center & Research Institute, Inc. Substituted heterocyclic compounds for treating multidrug resistance
US7476680B2 (en) 2000-10-17 2009-01-13 H. Lee Moffitt Cancer Center & Research Institute, Inc. Substituted heterocyclic compounds for treating multidrug resistance

Also Published As

Publication number Publication date
AU1597197A (en) 1997-08-22

Similar Documents

Publication Publication Date Title
EP1071420B1 (fr) Derives d'acide indolyl-3-glyoxylique a action antitumorale
EP0348341B1 (fr) Aminoalkylindoles, procédé pour leur préparation et compositions pharmaceutiques les contenant
DE2354389C2 (de) 2-(4-Acyl-homopiperazino)-4-amino-6,7-dimethoxy-chinazolin-Verbindungen und Verfahren zu ihrer Herstellung
EP0281902B1 (fr) Bis-naphtalimides, leur préparation et leur utilisation
DE69726593T2 (de) Benzoheterocyclische distamycinderivate, verfahren zu ihrer herstellung und ihre verwendung als antitumor- und antivirale mittel
DE69925472T2 (de) Benzoheterocyclische distamycinderivate, verfahren zu ihrer herstellung und ihre verwendung als antitumormittel
CH655110A5 (de) Carbostyrilderivate, verfahren zu deren herstellung und arzneimittel, welche diese enthalten.
DE69706690T2 (de) Acryloyl-substituierte distamycin-derivate, verfahren zu ihrer herstellung und ihre verwendung als antitumor- und antivirale mittel
DE69705622T2 (de) Distamycin derivate, verfahren zu ihrer herstellung sowie ihre verwendung als antitumor und antiviral wirkstoffe
DE3034237A1 (de) Carbostyrilderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende, antihistaminisch wirkende mittel
EP0410208B1 (fr) Dérivés de chromane
EP0161599A2 (fr) Dérivés de benzazépine, médicaments contenant les composés et procédé pour leur préparation
DE69908371T2 (de) Thioethergruppen enthaltende distamycin-derivate, verfahren zu ihrer herstellung und ihre verwendung als antitumormittel
DE69922378T2 (de) Oxidierte sulfurierte distamycinderivate, verfahren zu ihrer herstellung und ihre verwendung als antitumormittel
DD147110A5 (de) Verfahren zur herstellung von 9-eckige klammer auf 3-(3.5-cis-dimethylpiperazino)-propyl eckige klammer zu-carbazol und dessen salzen
WO1997028166A1 (fr) Thienoquinoleines
WO2003059892A1 (fr) Alkyles uraciles substitues et leur utilisation
EP0618201A1 (fr) Thiadiazinones et leur utilisation pour le traitement d'affections cardiovasculaires ou asthmatiques
DE3917233A1 (de) 8-substituierte 4-(heterocyclylmethylamino)-chinoline, ihre verwendung und daraus hergestellte arzneimittel
DE69128788T2 (de) 1,2-dihydro-3h-dibenzoisochinolin-1,3-dione als antitumormittel
EP0505400B1 (fr) Naphtalimides n-substitues, leur fabrication et utilisation
DE102006024834B4 (de) Neue Indol-Pyrrol-Derivate und deren Verwendungen
DE2406065A1 (de) Neue isoindolinderivate, ihre herstellung und die zusammensetzungen, die sie enthalten
DE2854727A1 (de) Polyfluorhydroxyisopropyl-substituierte bicyclische und tricyclische carbostyrile, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
DE3874465T2 (de) 1,2,3,4-tetrahydroisochonoline als antiarrhythmische mittel.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BA BG BR CA CN CZ EE GE HU IL JP KR LT LV MK MX NO NZ PL RO SG SI SK TR UA US VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97527298

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载