WO1997028166A1 - Thienoquinolines - Google Patents

Thienoquinolines Download PDF

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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
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WO
WIPO (PCT)
Prior art keywords
4c
alkyl
phenyl
substituted
hydrogen
Prior art date
Application number
PCT/EP1997/000404
Other languages
German (de)
French (fr)
Inventor
Wolf-Rüdiger Ulrich
Thomas Bär
Peter Zimmermann
Rainer Boer
Volker Gekeler
Wolfgang Ise
Hildegard Boss
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gmbh
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Priority to DE19603508.2 priority Critical
Priority to DE19603508 priority
Priority to EP96101790 priority
Priority to EP96101790.2 priority
Application filed by Byk Gulden Lomberg Chemische Fabrik Gmbh filed Critical Byk Gulden Lomberg Chemische Fabrik Gmbh
Publication of WO1997028166A1 publication Critical patent/WO1997028166A1/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic 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
    • C07D495/04Ortho-condensed systems

Abstract

Compositions of the formula (I), in which the substituents and the symbols have the meanings given in the description, are interesting resistance modulators.

Description

Thienochinoline

Field of the Invention

The invention relates to novel Thienochinoline, process extension in the pharmaceutical industry for their preparation and their Verwen¬ the preparation of medicaments.

Description of the Invention

It has now been found that the new Thienochinoline described in detail below have surprising and particularly advantageous properties.

The invention relates to compounds of formula (I) are thus (see attached Formel¬ leaf) in which the subsequently labeled (A) partial structure 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, wherein Z is hydrogen or 1-4C-alkyl,

E 1-4C-alkylene,

R3 is hydrogen or 1 -4C-alkyl,

R4 is aryl-1-4C-alkyl, where aryl means bedeu¬ tet by R41, R42 and R43 represents substituted phenyl and R41, R42 and R43 are independently hydrogen, 1-4C-alkyl or 1-4C-alkoxy, or

R3 and R4, represent an unsubstituted or substituted 1,2,3,4-tetrahydroisoquinoline, together and including the nitrogen atom to which both are attached, it being possible for a substituted 1,2,3,4-Tetrahydroisochinoiinrest at positions 1, may be substituted 3 and / or 4 by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, carboxy, phenyl, substituted phenyl by R31 and R32, phenyl-1-4C-alkyl and R31 and R32 may be substituted in the phenyl radical sub¬ stituiertes phenyl-1-4C-alkyl, and in the benzo moiety by 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 mean independently hydrogen, hydroxy, 1-4C-alkyl, 1-4C-alkoxy, halogen or 1-4C-alkylamino, R5 and R6 are independently hydrogen, halogen, 1-4C-alkoxy, nitro, di-1 -4C-alkyl aminocarbonyl, 1-4C-Alkylaminocarbonyi. carbamoyl, carboxy, amino, 1-4C-alkyl, 1-4C-alkoxycarbonyl, cyano, phenyl, substituted phenyl or R7 is 1-4C-alkylthio, or, if they are adjacent, R5 and R6, together and including the Kohlenstoffato ¬ me to which they are attached can also represent a cyclohexene ring,

R7 is halogen, and their salts.

An embodiment of the invention are compounds of formula (I) wherein the bezeich¬ with (A) designated partial structure has the meaning (C) and the other substituents and symbols have the meanings given oben¬.

1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Spielsweise be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

Halogen within the meaning of the present invention is bromine, chlorine and fluorine.

1-4C-alkoxy is a radical which contains one of the 1-4C-alkyl radicals genann¬ th addition to the oxygen atom. For example, the methoxy and ethoxy may be mentioned.

1-4C-Alkylene represents straight-chain or branched 1-4C-alkylene radicals, for example the methylene (-CH r). Ethylene (-CH 2 -CH r), trimethylene (-CH CH r r CHr), tetramethylene (-CH 2 -CH 2 -CH 2 -CH 2 -). 1 2-dimethylethylene [-CH (CH 3) -CH (CH 3 R 1,1-dimethylethylene [-C (CH 3) CH r r], 2,2-dimethylethylene [-CH r C (CH 3) r l, isopropylidene [-C (CH 3) 2 -], 1-methyl ethylene [-CH (CH 3) -CH 2 -], and 2-methyl ethylene radical [-CH 2 -CH (CH 3 ) -].

Aryl-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by R41, R42 and R43 substituted phenyl. Examples include the benzyl, the phen- are ethyl, 3,4-dimethoxybenzyl, 2- (3,4-dimethoxyphenyl) ethyl, 4-methoxybenzyl, 4-methylphenyl, 2-methoxybenzyl -, the 2- (4-methoxyphenyl) ethyl, 2- (4-methylphenyl) - ethyl, 3-methoxybenzyl and 3,4,5-Trimethoxybenzylrest.

As exemplary, and R32 by R31 substituted phenyl radicals are the radicals 3,4-dihydroxy, 3-hydroxy-4-methoxy-, 3,4-dimethoxy-, 2-methoxy-, 2-ethoxy-, 3-methoxy-, 4-methoxy, 2-hy- droxy-, 3-hydroxy, 4-hydroxy, 4-fluoro, 4-chloro, 2-chloro-, 3-chloro-, 3,4-dichloro-, 2- mentioned 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 represents one of the abovementioned, phenyl-substituted 1-4C-alkyl radicals. For example, the phenethyl and the benzyl may be mentioned.

By R31 and R32 in the phenyl radical substituted phenyl-1-4C-alkyl represents one of the obenge¬ called 1-4C-alkyl radicals which is substituted by R31 and R32 substituted phenyl. game be mentioned Bei¬ the 3,4-dihydroxybenzyl, 3-hydroxy-4-methoxybenzyl and 3,4-dimethoxybenzyl may be.

Di-1-4C-alkylamino represents an amino radical which is substituted by two identical or different of the abovementioned 1-4C-alkyl radicals. For example, the Dimethylami¬ were no-, the diethylamino and the di-isopropylaminorest called.

As the substituted-1.2,3,4 Tetrahydroisochinolinreste include for example the 1-methyl-6,7-dihydroxydiphenyl droxy-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-tetrahydro-2-isoquinolinyl, 1-benzyl-1, 2,3,4-tetrahydro-2-isochiπolinyl-, 1- (3-hydroxy-4-methoxy-benzyl) -6-dimethylamino -1,2,3,4-tetrahydro-2-isoquinolinyl, 3-tert-butyl-6-methoxy-4-phenyl-1, 2 t 3,4-tetrahydro-2-isoquinolinyl, 1 - (3 , 4-dimethoxy-benzyl) -6,7-dimethoxy-1, 2,3,4-tetrahydro-2-isoquinolinyl, 1- (3,4-dihydroxybenzyl) -6,7-dihydroxy-1,2,3,4 tetrahydro-2-isoquinolinyl,

6,7-dihydroxy-1, 2,3.4-tetrahydro-2-isoquinolinyl, 6,7-dimethoxy-1-methyl-1, 2,3,4-tetrahydro-2-isoquinolinyl, 6,7-dihydroxy- 1-methyl-1, 2,3,4-tetrahydro-2-isoquinolinyl, 6-hydroxy-7-methoxy-1 -methyH, 2,3,4-tetrahydro-2-isoquinolinyl, and the 1- (5- chloro-2-methylaminophenyl) -1, 2,3,4-called tetrahydro-2-isoquinolinyl radical.

1-4C-Alkoxycarbonyl represents a carbonyl group, is bonded to the one of the abovementioned 1-4C-alkoxy radicals. For example, the methoxycarbonyl (CH 3 0-CO-) which may be (CH 2 CH 3 0-CO-) and the ethoxycarbonyl called.

1-4C-Alkylthio represents a radical, which contains one of the ge called 1-4C-alkyl radicals in addition to the sulfur atom. For example, the methylthio and ethylthio be mentioned are.

Di-1-4C-alkylamiπocarbonyl represents a radical which, in addition to the carbonyl group one of the vor¬-mentioned di-1-4C-alkylamino groups. For example, the dimethyl thylcarbamoyl- and Diethylcarbamoylrest be mentioned. 1-4C-alkylaminocarbonyl represents a radical which, in addition to the carbonyl group one of the abovementioned 1-4C-alkylamino unten¬. For example, the Methyicarbamoyl- and Ethylcarbamoylrest be mentioned.

1-4C-alkylamino represents an amino radical which is substituted by one of the abovementioned 1-4C-alkyl radicals.

Exemplary by R7 substituted phenyl are 4-Chlorphenyf-, 3-chlorophenyl, 2-chlorophenyl, der4-Fluoφhenyl-, the 3-Fluoφhenyl- and 2-fluorophenyl.

Suitable salts of compounds of formula (I) - depending on the substitution • proposition all Säureadditions¬ or all salts with bases. The pharmacologically tolerable salts of the inorganic and organi¬ rule acids and bases customarily used in pharmacy. As such, on the one hand water-soluble and wasserunlöslich- e acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric phoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, Benzoe¬ acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid are acid, sulfosalicylic acid, maleic acid, Laurin¬ acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, Stea¬ rinsäure, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is is a mono- or polybasic acid and depending on which salt is desired - in an equimolar or one of them ab¬ retreating amount ratio.

On the other hand, salts with bases. Examples of salts with bases sei¬ en alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, Am¬ monium-, ammonium, meglumine or guanidinium salts, where here too in the wer¬ salt preparation the bases in an equimolar quantitative ratio or one differing therefrom used to.

Pharmacologically intolerable salts which can be obtained for example in the preparation of the compounds according to the invention on an industrial scale as process products, are converted by methods known to those skilled in the pharmacologically acceptable salts thereof.

Compounds of the formula (I) are those in which the partial structure (A) the oben¬ meanings mentioned (B), (C) or (D), R1 is hydrogen or 1-4C-alkyl, R2 is hydrogen,

D is oxygen or a bond,

E 1-4C- alkylene,

R3 is hydrogen or 1-4C-alkyl,

R4 is aryl-1-4C-alkyl, where aryl means bedeu¬ tet by R41, R42 and R43 represents substituted phenyl and R41, R42 and R43 are independently hydrogen, 1-4C-alkyl or 1-4C-alkoxy, or

R3 and R4, represent an unsubstituted or substituted 1, 2,3,4-tetrahydroisoquinoline, together and including the nitrogen atom to which both are attached, it being possible for a substituted 1,2,3,4-Tetrahydroisochinotinrest at positions 1, can with one or two identical or different substituents selected from the group be substituted 3 and / or 4 consisting of 1 -4 C alkyl, phenyl, R32 through R31 and substi¬ tuiertes phenyl, phenyl-1-4C-alkyl and R31 and R32 is substituted in the phenyl may be phenyl-1-4C-alkyl, and substituted on the benzo moiety by one or two identical or different substituents selected from the group consisting of hydroxy and 1-4C-alkoxy, wherein

R31 and R32 mean independently hydrogen, hydroxy, 1-4C-alkyl, 1-4C-alkoxy, halogen or 1-4C-alkylamino,

R5 and R6 are independently hydrogen, halogen, 1-4C-alkoxy, carbamoyl, 1-4C-alkyl, cyano, phenyl, substituted phenyl or R7 is 1-4C-alkylthio, or, if they are adjacent, R5 and R6 together and including the Kohlenstoffa¬ tome to which they are attached can also represent a cyclohexene ring,

R7 is halogen, and their salts.

Particularly to be emphasized compounds of the formula (I) are those in which the partial structure (A) as defined above (B), (C) or (D),

R1 is hydrogen or 1 -4C-alkyl,

R2 is hydrogen,

D is oxygen or a bond,

E 1-4C-alkylene,

R3 C 1 -4 alkyl,

R4 is aryl-1-4C-alkyl, where aryl means bedeu¬ tet by R41, R42 and R43 represents substituted phenyl and R41, R42 and R43 are independently hydrogen, 1-4C-alkyl or 1-4C-alkoxy, or R3 and R4 together and including the nitrogen atom to which both are bonded, represent an unsubstituted or substituted 1,2,3,4-tetrahydroisoquinoline, it being possible for a substituted 1, 2,3,4-tetrahydroisoquinoline may be substituted on the benzo moiety with one or two identical or different 1-4C-alkoxy,

R5 and R6 are independently hydrogen, halogen, 1-4C-Alkyi, cyano, phenyl, substituted phenyl or R7 is 1-4C-alkylthio, or, if they are adjacent, R5 and R6, together and including the tome of Kohlenstoffa¬ which they are attached can also represent a cyclohexene ring,

R7 is halogen, and their salts.

Preferred compounds of formula (I) are those in which the partial structure (A) the obengenann¬ th meanings (B), (C) or (D),

R1 and R2 are hydrogen,

D represents a bond,

E 1-4C-alkylene,

R3 1-4C- alkyl,

R4 is aryl-1-4C-alkyl, where aryl means bedeu¬ tet by R41, R42 and R43 represents substituted phenyl and R41, R42 and R43 are independently hydrogen, 1-4C-alkyl or 1-4C-alkoxy, or

R3 and R4 represent a substituted 1,2,3,4-tetrahydroisoquinoline, together and including the nitrogen atom to which both are bonded, wherein a substituted 1, 2,3,4-tetrahydroisoquinoline may be substituted on the benzo moiety with one or two identical or different 1-4C-alkoxy,

R5 and R6 are independently hydrogen, halogen, 1-4C-alkyl, phenyl, sub¬ stituiertes by R7, phenyl or 1-4C-alkylthio, or, if they are adjacent, R5 and R6, together and including the tome of Kohlenstoffa¬ which they are attached can also represent a cyclohexene ring,

R7 is halogen, and their salts.

One embodiment of the preferred compounds of formula (I) are those compounds of formula (I) wherein the partial structure (A) as defined above (B), (C) or (D),

R1 and R2 are hydrogen, D is a bond, E is 1-4C-alkylene,

R3 is 1-4C-alkyl,

R4 is benzyl, 3,4-dimethoxybenzyl, 2- (3,4-dimethoxyphenyl) ethyl, 4-methylbenzyl or 4-meth- means oxybeπzyl, or

R3 and R4, the 6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl represent, together and including the nitrogen atom to which both are bonded,

R5 and R6 are independently hydrogen, halogen, 1-4C-alkyl, phenyl, R7 mean by sub¬ stituiertes phenyl or 1-4C-alkylthio, or, if they are adjacent, R5 and R6, together and including the me to Kohlenstoffato¬ which they are attached can also represent a cyclohexene ring,

R7 is halogen, and their salts.

Particularly preferred compounds of formula (I) are those in which has the partial structure (A) as defined above (C) or (D),

R1 and R2 are hydrogen,

D represents a bond,

E 1-2C-alkylene,

R3 and R4, together and including the nitrogen atom to which both are bonded, the, 2,3,4-tetrahydro-2-isoquinolinyl represent 6,7-dimethoxy-1, R5 and R6 are independently hydrogen or 1-4C-alkyl mean, and their salts.

Emphasized particularly preferred compounds of formula (I) are those wherein the

has a partial structure (A) as defined above (C),

R1 and R2 are hydrogen,

D represents a bond,

E 1-2C-alkylene,

R3 and R4, together and including the nitrogen atom to which both are bonded, the 6,7-dimethoxy-1, 2,3,4-tetrahydro-2-isochinoiinylrest represent, R5 and R6 are independently hydrogen or alkyl 1-4C- mean, and their salts.

The invention further relates to a process for preparing the compounds of formula (I) (see attached formula sheet) in which R1, R2, D, E, R3 and R4 have the above angegebe- NEN meanings and the partial structure (A) (the meanings has B), (C) or (D), and ih¬ rer salts.

The method is characterized in that in which they have compounds of formula (II) (see bei¬ gefügtes formula sheet) R1 and R2 are as defined above and the partial structure (A), the meanings (B), (C) or (D) has, with compounds of formula (III) (see attached Fonmelblatt) in which, R3 and R4 ben ha¬ D e have the meanings given above. Compounds of formula (I) thus obtained are, if desired, on closing into their salts, or obtained salts of the compounds of formula (I) gewünschten¬ optionally converted into the free compounds.

The reaction of the compounds of formulas (II) and (III) takes place in a known in the art per se, preferably using a coupling reagent. As geeig¬ designated coupling reagents, for example N, N'-carbonyldiimidazole, phosphoric acid diphenyl ester-azide or 1 are benzotriazolyloxy-tris (dimethylamino) -phosphoniumhexafluoro- phosphate (BOP) called, but preferably NN-dicyclohexylcarbodiimide (DCC). Gewünsch¬ case scenario, the reaction can be promoted by the addition of 1-hydroxy-1-H-benzotriazole.

The reaction is preferably temperatures between 0 "C and the boiling point of the solvent used, with the addition of or in the absence of water and at Reaktions¬ but preferably at room temperature in polar, aprotic or protic solvents (for example in dimethylformamide).

The isolation and purification of the substances according to the invention carried out in known manner, for example in such a manner per se, by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or supply methods of the usual Reini¬, such as column chromatography on suitable Trägermateri¬ al, subjects.

Salts are obtained by dissolving the free compound in a suitable solvent, for example or 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 to which the desired acid . base is then added. The salts are obtained by filtering, drop, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted kön¬ NEN, which in turn can be converted into salts by alkalization or by acidification into the free compounds. In this way not acceptable salts can be pharmako¬ logically into pharmacologically acceptable salts to convert.

Compounds of formula (III) are known per se, for example from the international application WO 92/12132 Patentanmel¬ or prepared from J. Med. Chem. 1995, 38, 2418-2426, or can in an analogous manner.

has Compounds of formula (II) may be prepared from the corresponding compounds of formula (IV) (see attached formula sheet) in which R1 and R2 have the abovementioned meanings, the partial structure (A), the meanings (B), (C) or (D) and X expediently hydroxy (OH), can be obtained. These are compounds of the formula (IV), for example, similar to a the expert from A. Albert, The Acridines, pp 29-56, Second Edition, Edward Arnold (Pubiishers) LTD London 1966 known method, preferably as in the examples be¬ wrote implemented.

has the compounds of formula (IV) in which R1, R2 and X have the abovementioned meanings and the partial structure (A), the meanings (B), (C) or (D), can be (by saponification of the corresponding compounds of formula IV ) in which X is suitably (the meaning of alkoxy preferably methoxy), has represent. The reaction can be carried out as a well-known to the expert method, such as in SR Sandler, W. Caro, Organic Functio¬ nal Group Preparations, Volume I, pp 230-232, Academic Press 1968..

has the compounds of formula (IV) in which ben R1 and R2 have the meanings given above ha¬, X has the meaning alkoxy the partial structure (A), the meanings (B), (C) or (D) may be prepared by reaction of appropriately substituted compounds of formula (V) (see attached formula sheet) in which R1 and X are as defined above and the partial structure (A), the meanings (B), (C) or (D), with the appropriately substituted Dipheπyiiodonium -2-carboxylates of the formula (VI) (see attached formula sheet) in which R2 has the abovementioned meaning, are prepared. The reaction may be described in a manner known to the expert (for example, analogously as described by RO Scheπrer HR and Beatty, J. Org. Chem. 1980, 45, 2127-2131 or by GW Rewcastle and Denny WA in Synthesis 1985, 220-222 be carried out).

has Compounds of formula (V) wherein R1 have the abovementioned meanings and X and the partial structure (A), the meanings (B), (C) or (D), are known, eg from Chem. Ber. 1965, 98, 3571-3577 and EP-B-0298542 or can be prepared in an analogous manner. Diphenyliodonium-2-carboxylates of the formula (VI), in which the Bedeutun¬ above has gen R2, are either known, for example from LF. Fieser, MJ Haddadin, Org. Syn. Collect. Vol. V, 1037 (1973), RA Scherrer, HR Beatty, J. Org. Chem. 1980, 45, 2127-2131 or GW Re¬ wcastle, WA Denny, Synthesis 1985, 220-222 or may be prepared in an analogous manner ,

The following examples eriäutem the invention without limiting it. The compounds mentioned in the examples and their salts are preferred subject of the Erfin dung. The abbreviation RT stands for room temperature, h stands for hour (s), min for minute (s), y. for yield, mp. for melting point, dec. for decomposition, DMF for Dimethylforma¬ mid and THF for tetrahydrofuran and DMSO for dimethylsulphoxide.

Examples

end products

1. 4-oxo-4.9-dihydro-thienor2.3-b1chinolin-8-carboxylic acid f4-f2-f6.7-dimethoxy-3,4-dihydro-1 H-2-ιsochιnolin viι-ethvπ-phenylι-am8d

2.88 g (11.8 mmol) of 4-oxo-4,9-dihydro-thieno [2,3-b] quinoline-8-carboxylic acid, 1, 8 g (11.8 mmol) of hydroxybenzotriazole and 3.15 g (15.2 mmol) of dicyclohexylcarbodiimide are stirred in 130 ml DMF trocke¬ nem 3 h at RT. Then 3.8 g (11.8 mmol) of 4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] aniline was added and stirred for 16 h at RT , The reaction solution is concentrated, treated with 2 I of boiling THF and aspirated. The filtrate is concentrated, treated with 1 I of dichloromethane and 500 ml of water, and the phases separated. The water phase is saturated with sodium chloride, filtered off with suction the precipitated substance and the residue washed three times with 50 ml of water. After recrystallization in 30 ml of isopropanol 1.1 g of the Titeiverbindung with mp. Obtained> 300 ° C.

2. 3-Methyl-9-oxo-4.9-dihydro-thienor3.4-b1chinolin-5-carboxylic acid f4-r2- (6.7-dimethacrylate oxy-3,4-dihydro-1H-isoquinoline-2-phenyl-ethvn-ylι > amide

1.27 g (4.8 mmol) of 3-methyl-9-oxo-4,9-dihydro-thieno [3,4-b] quinoline-5-carboxylic acid, 0.73 g (4.8 mmol) of hydroxybenzotriazole and 1, 28 g (6.2 mmol) of dicyclohexylcarbodiimide are stirred in 50 ml of dry DMF for 1 h at RT. Then 1.53 g (4.8 mmol) of 4- [2- (6,7-dimethacrylate oxy-3,4-dihydro-1H-isoquinolin-2-yl) -ethyl] -aniline in added and 16 h RT. The Reak¬ tion solution is concentrated and chromatographed on silica gel [ethyl acetate / triethylamine (100: 1)]. Add to 200 ml of ethyl acetate and 100 ml of 0.1 N Natroniauge and vacuum. The phases separate and dry the organic phase over magnesium sulfate. After Einen¬ gen ethanol is recrystallized from 15 ml. This gives the title compound of m.p.. 215-218'C.

3. 1.3-Dimethvi-9-oxo-4.9-dihydro-thienor3.4-b1chinoiin-5-carboxylic acid f4-r2- (6.7-di- methoxy-3,4-dihydro-1H-isoquinoline-2-vh-ethvπ-phenvπ amide

1, 09 g (4 mmol) of 1 t 3-dimethyl-9-oxo-4,9-dihydro-thieno [3,4-b] quinoline-5-carboxylic acid, 0.61 g (4 mmol) of hydroxybenzotriazole and 1, 03 g (5 mmol) of dicyclohexylcarbodiimide are stirred in 40 ml of dry DMF for 2 h at RT. Then 1 29 g (4 mmol) of 4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] aniline was added and stirred for 16 h at RT. The reaction solution is concentrated and chromatographed on silica gel (ethyl acetate / triethylamine (100: 1).] In 30 ml record dichloromethane and aspirate After concentration of the mother liquor of ethanol is from 50 ml recrystallized to give the title compound of m.p. 219-... 222'C.

starting compounds

A1. 4-oxo ~ 4.9-dihydro-thienor2.3-b1chinolin-8-carboxylic acid

4.35 g (16.5 mmol) of 2- (2-carboxy-phenylamino) -thiophene-3-carboxylic acid are phosphoric acid in 116 g of poly stirred for 4 h at 55 ° C. Under cooling 200 ml of water are added dropwise to the reaction solution so that the temperature is not over 60 C β increases. The resulting precipitate is filtered off and washed twice with 20 ml of water. This gives 2.88 g (71%) of the title compound are obtained as amoφhen solid.

B1. 3-methyl-9-oxo-4,9-dihydro-thienor3.4-5-carboxylic acid b1chinolin-

7.9 g (28.5 mmol) of 3- (2-carboxy-phenylamino) -2-methylthiophene-4-carboπsäure are stirred in 200 g polyphosphoric acid for 3 h at 65 ° C.. Under cooling 400 ml of water are added dropwise to the reaction solution so that the temperature does not exceed 35 * C increases. The resulting Nie¬ Derschlag is suctioned off and chromatographed on silica gel [ethanol / triethylamine (50: 1)]. Add to 40 ml of water, acidified at RT with 2 N hydrochloric acid and with 100 ml of 50% dilute Et¬ HANOL. saturate, vacuum and nach¬ washing twice 10 ml of water with sodium chloride. This gives 1, 4 g (19%) of the title compound of m.p., 286 ° C (dec.).

C1. 1.3-dimethyl-9-oxo-4.9-dihydro-thienor3.4-b1chinolin-5-carboxylic acid

4.4 g (15 mmol) of 3- (2-carboxyphenylamino) -2,5-dimethylthiophene-4-carboxylic acid are stirred in 150 g polyphosphoric acid for 3 h at 60 ° C. Under cooling 200 ml of water are added dropwise to the reaction solution so that the temperature is not above 40 C β increases. The resulting Nie¬ Derschlag is suctioned off, dissolved in 200 ml of 2 N sodium hydroxide, filtered and heated to 50 * C. With conc. Hydrochloric acid to acidify, vacuum again and washed twice with 30 ml of water. One er¬ 3.5 g stops (85%) of the title compound with mp. 246 'C (dec.).

DI. 2-i2-Carfaoxy-Dhenylamino) -thiophene-3-carboxylic acid

4.4 g (15.9 mmol) are heated in 70 ml of 2 N sodium hydroxide for 15 min. At reflux 2- (2-carboxy-pheπylamino) -thiophene-3-carbonsäuremethylester. The still warm reaction solution is acidified with 6 N hydrochloric acid, the resulting precipitate is filtered off with suction and washed twice with 30 ml of water. This gives 4.2 g (quantitative) of the title compound as amoψhen solid.

E1. 3- / 2-carboxy-phenylaminoi-2-methvithiophen-4-carboxylic acid

8.5 g (29 mmol) of 3- (2-carboxy-phenylamino) -2-methylthiophene-4-caΦonsäuremethyiester wer¬ heated to h in 100 ml of 2 N sodium hydroxide 1 under reflux. The still warm reaction solution is acidified with 6-n-sentence acid, the resulting precipitate is filtered off with suction and washed twice 50 ml of water mK. This gives 7.9 g (98%) of the title compound of m.p., 270 "C (dec.).

F1. 3-f2-Carboxy-phenylamino) -2.S-dimethylthiophene-4-carboxylic acid

9.3 g (30 mmol) of 3- (2-CaΦoxy-phenylamino) -2,5-dimethylthiophene-4-caΦonsäuremethylester are heated in 100 ml of 2 N sodium hydroxide for 45 min. Under reflux. The still warm Reaktions¬ solution is acidified with 6 N hydrochloric acid, the resulting precipitate is filtered off with suction and washed twice with 30 ml of water. This gives 7.9 g (89%) of the title compound as amoφhen solid.

G1. 2- (2-carboxy-3-phenylaminoMhiophen carbonsäuremethylester

6 g (38 mmol) of 2-aminothiophene-3-carbonsäuremethylester, 11.8 g (34 mmol) umcarboxylat Diphenyliodoni- and 0.28 g (1.4 mmol) of copper (II) acetate hydrate are dissolved in 100 ml of isopropanol 2 heated under reflux. The reaction solution is concentrated, aufgenom¬ in 1 I of 0.1 N sodium hydroxide solution men, washed twice with 200 ml of diethyl ether and acidified with 6 N hydrochloric acid. The amor¬ phe precipitate is filtered off. This gives 4.8 g (50%) of the title compound as amoφhen solid.

H1. 3-l2-carboxy-phenylaminol-2-methylthiophene-4-carbonsäuremethylester

5.6 g (33 mmol) of 3-amino-2-methylthiophene-4-caΦonsäuremethylester, 10.3 g (30 mmol) diphenyl nyliodoniumcarboxylat and 0.25 g (1.25 mmol) of copper (II) acetate hydrate are in 100 ml Iso¬ propanol heated for 2 hours under reflux. The reaction solution is concentrated, taken up, washed with twice 50 ml of diethyl ether and ange¬ with 6 N hydrochloric acid is acidified in 150 ml of 1N-sodium hydroxide solution. vacuum the amoφhen precipitation and wash twice with 50 ml of water. This gives 8.5 g (97%) of the TitelveΦindung mp. 185 "C (dec.). 11. 3-J2-carboxy-phenylaminoι-2.5-dimethylthiophene-4-carbonsäuremethylester

6.2 g (34 mmol) of 3-amino-2,5-dimethyKhiophen-4-carϋonsäuremethylester, 13.4 g (39 mmol) di- phenyliodoniumcarboxylat and 0.4 g (2 mmol) of copper (II) acetate hydrate are dissolved in 80 ml propanol Isopro¬ 90 min. under reflux. The reaction solution is concentrated, dissolved in 100 ml of 1N-sodium hydroxide solution was added, mK washed twice 50 ml of diethyl ether and mK ange¬ 6 N hydrochloric acid is acidified. vacuum the amoφhen precipitation and wash twice with 50 ml of water. This gives 9.3 g (91%) of the title compound of m.p., 176-177 * C.

K1. 2-aminothiophene-3-carbonsäuremethylester

The title compound is known from the literature.

Ll. 3-amino-2-methylthiophene-4-carbonsäuremethylester

The title compound is known from the literature.

MI. 3-Amino-2.5-dimethylthiophene-4-carbonsäuremethylester

The title compound is HteratuΦekannt.

I

N1. 4-T2- (6.7-Dimethoxy-3.4-dihydro-1H-isoquinoline-2-vπ-ethvn-aniiin

The title compound is known from the literature.

01. diphenyliodonium-2-carboxylate

The title compound is known from the literature.

commercial Applications

The VeΦindungen of formula (I) and their salts have valuable properties that make them ge advertising recyclable. You veΦessem the effect of antibiotics and / or cytostatic agents in a synergistic manner, and they are furthermore able to squirm to über¬ existing or in the course of therapy occurring resistance to antibiotics and / or cytostatics. They can not only be used in combination with other cytotoxic drugs or antibiotics to overcome the so-called "drug resistance" or "multidrug resistance". Rather, they are, due to its antineoplastic properties per se senbildung to Behand¬ development of tumor diseases, for example, to reduce or eliminate the Metasta¬ and tumor growth in mammals, and due to its antiproliferative properties Eigen¬ example for the treatment of dermatoses.

In their excellent efficacy, which manifests itself in a pronounced resistance to overcome and that is coupled with low toxicity, good bioavailability and lack of undesirable side effects, is VeΦindungen of formula (I) and their Sal¬ differ ze in a surprising and advantageous way of known resistance modulators and cancer chemotherapeutic agents.

The excellent activity of VeΦindungen of formula (I) and their salts allows their use in human medicine as the sole or concomitant chemotherapeutic agents for the treatment of tumors, including leukemia, ovarian cancer, testicular tumors, Prostatakarzi¬ noun, bladder tumors, kidney tumors, ösophaguskarziπomen and other malicious Ge - websneubildungen, especially colon cancer, breast cancer, lung cancer and Lun¬ genkarzinomen. In the same way as VeΦindungen the invention can overcome the "drυg resi¬ stance" of tumor cells and resistance to certain Mala¬ can riamittel, such as chloroquine, are canceled by the invention VeΦindungen. In overcoming resistance to antibiotics is to overcome the resistance to chloroquine of particular importance, since the increasing in some parts of the world development of resistance of Plasmodium falciparum berei¬ increasing difficulties in combating malaria (the causative agent of malaria tropica) against this proven antimalarials tet , The compounds of the invention are also suitable not only to overcome the resistance to antibiotics. Rather, they may as beispiels¬ as malaria, sleeping sickness, filariasis and onchocerciasis, are used for their anti-parasitic properties for the treatment of parasitic, in particular tropical parasitic diseases. In improving the effect of or overcoming the resistance development gegen¬ cytotoxic drugs is particularly important that the dose of the administered cytotoxic drugs can be reduced, resulting in a significant Vemngerung the toxic side effects, and that the number of usable cytostatics increases so that the voted for the be¬ tumor and the particular patient optimally suitable cytostatic can be ausgewähH targeted.

It should be noted in this connection that pressure due to the low influence of the compounds of formula (I) on the cardiovascular system, for example on the Blut¬ and heart rate, these compounds in therapeutically effective doses without the housing driving of undesirable side effects on the cardiovascular system be administered NEN kön¬.

If the compounds of formula (I) and / or their pharmacologically acceptable salts administered as resistance modulators in the antibiotic and cytostatic therapy, the compounds of formula (I) can together with the antibiotics or cytostatics in a dose in the form of th festgeleg¬ Kombinationspräparateπ be administered, or the VeΦindungen of formula (I) may be employed in any dosage form and a suitable Darreichungs¬ as an accompanying and supporting active ingredients in the antibiotic or cytostatic therapy separately.

The ratio of compounds of formula (I) to antibiotic or cytostatic agent will depend on the disease being treated, the disease state of the patient and the antibiotic or a cytostatic agent used. Here, it has been found in general to be advantageous to VeΦindungen of formula (I) upon oral administration in a daily dose of about 0.5 to 30 mg / kg of body weight, when administered intravenously in a daily dose of about 0.1 to 10 mg / Köφerge- kg weight, if desired, be administered in the form of several individual doses or as a continuous infusion to achieve the desired result. The antibiotics or cytostatics are, however, administered in the amounts customary for them, preferably at lower doses.

Also subject of the invention, the VeΦindungen of formula (I) and their pharmako¬ logically tolerable salts for use in the treatment of tumor diseases.

The invention likewise comprises the use of VeΦindungen of formula (I) and their phar¬ a pharmacologically acceptable salt thereof in the manufacture of medicaments which are employed for the control of tumor diseases. The invention further relates to the use of compounds of formula (I) in combination with antibiotics or cytostatics in the antibiotic and / or cytostatic therapy.

The invention also relates to the use of VeΦindungen of formula (I) for the preparation of medicaments which biotika- in combination with antibiotics or cytostatics in the Anti¬ and / or cytostatic therapy to be used.

Another object of the invention are medicaments which receive one or more VeΦindungen of the general formula (I) and / or their pharmacologically tolerable salts.

The pharmaceutical compositions are prepared according to known per se to the person skilled in the art methods manufactured. As medicaments, the pharmacologically active VeΦindungen of formula (I) and their salts (= active compounds) star either as such, or preferably in combination with suitable pharmaceutical excipients in the form of tablets, coated tablets, capsules, suppositories, Pfla¬ (for transdermal drug application) , emulsions, suspensions, aerosols, sprays, ointments, creams, gels or solutions, the active compound content advantageously being between 0.1 and 95%.

The auxiliaries which are suitable for the desired pharmaceutical formulations are familiar to the expert on the basis of his expert knowledge. Besides solvents, Gelbiidnem, suppositories bases, tablet excipients and other active compound, for example, Anti¬ oxidants, dispersants, emulsifiers, defoamers, flavor, Konservie¬ insurance agents, solubilizers, colorants or in particular permeation promoters and complexing agents (eg cyclodextrins).

The active compounds can be administered by inhalation, parenterally (perlingually, intravenously, percutaneously) or orally rectally.

pharmacology

The ability of compounds of formula (I), the resistance of tumor cells to cytotoxic drugs to overcome has been demonstrated in various tests.

1. Measurement of Resistenzüberwindunα to chemotherapeutic agents

The measurement of the resistance was performed on overcoming the human T-lymphoblastoid Zel- line CCRF-CEM and derived resident lines (Niethammer et al, Advances in enzyme regulation, G. Weber (ed) 29, 231-245, Pergamon Press:.. Oxford , New York, 1989) in the three-day MTT assay.

With the help of the tetrazolium salt MTT (3- (4,5) -Dimethylthiazol-2-yl) -2,5Diphenyltetrazoliumbro- mid) can be the activity of cells via mitochondrial succinate dehydrogenase by the reduction of the tetrazolium salt to blue Foπmazaπ determine (Mosmann, Br J. Cancer., 52: 205-214, 1983). may then be closed to the respective cell number on the metabolic activity.

For "screening" exponentially growing cultures after trypan count in 96-well Microtiteφlatten (flat bottom) were seeded. The optimal seeding density was determined for each cell line in upstream growth experiments to a exponentielies growth wäh¬ rend the 3-day incubation to be granted plump.

Cells were in 80 ul medium (RPM1 1640 containing 50% human serum) were plated with the help of an automatic pipette (Elektrapette, Tecπomara). The modulators to be tested were dissolved in 100% DMSO and then diluted further with medium. The DMSO final concentration was 0.1% in all batches. 10 ul cytostatic solution and 10 ul modulator solution of ZellkuKur were added. When the control 20 ul of medium was pipetted accordingly.

After 3 days incubation in an incubator at 37 C and 5% COrAtmosphäre 10 ul MTT (final concentration 0.5 mg / ml) were pipetted. The plates were then further 4 h cubed in¬. After 5 min centrifugation at 200 xg (Labofuge 6000, Heraeus) 60 .mu.l of the supernatant were removed and 150 .mu.l of DMSO. The plates were to the formazan Solubilisieruπg 1 h formed on a Mikrotitβφlattenschüttler (Vibrax-VXR, Ika) shaken.

Quantification of the formazan formed was carried out using an automatic microtiter teφlatteπ reader (EL 311, Bio-tea Instruments) at 540 nm. The reference wavelength was 690 nm. The Absoφtionsdaten were angege¬ as averages of 3X determining + -SEM ben. Dose-response curves were obtained by plotting the percentage of formazan Kontrol¬ le against the respective Zytostatikumkonzentration.

In the following Table 1 Determined Erten test results are reproduced. As Zeliinie were each CCRF-VCR 1000 used as a cytostatic agent vincristine. The Konzentrati¬ on the corresponding VeΦindungen were respectively 3 microns and 10 microns. The numbers of the un¬ ters lights compounds correspond to the numbers in the Examples. As a result Untersuchungser¬ the RMF value (Resistenzmoduiationsfaktor) is specified. The RMF value is the Quo¬ tient of ICs-rvalue (ng / ml) cytostatic drug alone and IC50 cytostatic + examined Ver¬ bond.

Table 1

Determination of the resistance modulation factor

Figure imgf000021_0001

RMF value = IC50 (ng / ml) cytostatic / 1C50 (ng / ml) cytostatic + respective compound.

2. Measurement of P-Glvkoprotein-Hemmunα

"Multi Drug" resistant and sensitive cells of the T lymphoblastoid leukemia cell lines CCRF-CEM VCR1000 and CCRF-be removed from the cell culture and harvested by Zentrifuga¬ tion. The cells are taken up in RPMI medium (pH = 7.3 or 7.8) without fetal calf serum and incubated for 30 min with increasing concentrations of resistance modulators at 37 * C. Then incubated rhodamine 123 was added (final concentration 0.8 mg / I), and another hour at 37 * C. The cellular Rhodamine 123 fluorescence is measured using a fluorescence activated cell sorter. The excitation wavelength is 488 nm. The rhodamine 123 fluorescence is measured at 520 nm. Dose-response curves whose ECSO value is used as a measure of the potency of a modulator for the abolition of P-glycoprotein-mediated Rhodamine 123 accumulation minder are created from the eΦaltenen data.

In Table 2 below the determined ECsσ values ​​for some examined VeΦindungen are shown. The Nummem of the tested compounds correspond to the numbers in the Examples.

table 2

Measurement of P-Glykoproteiπ inhibition

Figure imgf000022_0001

Claims

claims
1. VeΦindungen of formula (I)
^
Figure imgf000023_0001
wherein the subsequently labeled (A) partial structure has the meanings (B), (C) or (D),
Figure imgf000023_0002
c
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, wherein Z is hydrogen or 1-4C-alkyl,
E 1-4C-alkylene,
R3 is hydrogen or 1-4C-alkyl,
R4 is aryl-1-4C-alkyl, where aryl means bedeu¬ tet by R41, R42 and R43 represents substituted phenyl and R41, R42 and R43 are independently hydrogen, 1-4C- alkyl or 1-4C-alkoxy, or
R3 and R4, represent an unsubstituted or substituted 1,2,3,4-tetrahydroisoquinoline, together and including the nitrogen atom to which both are bonded, a substituted 1,2,3,4-WO in Tetrahydroisochinoiinrest at positions 1, may be substituted 3 and / or 4 by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, carboxy, phenyl, substituted phenyl by R31 and R32, phenyl-1-4C-alkyl and R31 and R32 may be substituted in the phenyl radical sub¬ stKuiertes phenyl-1-4C-alkyl, and in the benzo moiety by one or two identical or different SubstKuenten ausgewähK from the group consisting of hydroxy, 1-4C-alkoxy and di-1-4C-alkylamino, in which
R31 and R32 mean independently hydrogen, hydroxy, 1-4C-alkyl, 1-4C-alkoxy, halogen or 1-4C-alkylamino,
R5 and R6 are independently hydrogen, halogen, 1-4C-alkoxy, nitro, di-1-4C-alkyl- aminocarbonyl, 1-4C-AlkylaminocaΦonyl, CaΦamoyl, CaΦoxy, amino, 1-4C-alkyl, 1-4C- alkoxycarbonyl , cyano, phenyl, bedeu¬ th through R7 substituted phenyl or 1-4C-Alkytthio, or, if they are adjacent, R5 and R6, together and including the Kohlenstoffa¬ tome to which they are attached can also represent a cyclohexene ring,
R7 is halogen, and their salts.
2. VeΦindungen of formula (I) according to claim 1, wherein the partial structure (A), the meanings (B) mentioned in claim 1, (C) or (D),
R1 is hydrogen or 1 -4C-alkyl,
R2 is hydrogen,
D is oxygen or a bond,
E 1-4C-alkylene,
R3 1-4C- alkyl,
R4 is aryl-1-4C-alkyl, where aryl means bedeu¬ tet by R41, R42 and R43 represents substituted phenyl and R41, R42 and R43 are independently hydrogen, 1-4C-alkyl or 1-4C- alkoxy, or
may be bound R3 and R4, together and including the nitrogen atom to which both represent an unsubstituted or substituted 1,2,3,4-Tetrahydroisochinoiinrest, it being possible for a substituted 1, 2,3,4-Tetrahydroisochinoliπrest the benzo moiety substituted with one or two identical or different 1-4C-alkoxy,
R5 and R6 are independently hydrogen, halogen, 1-4C-alkyl, cyano, phenyl, substituted phenyl or R7 is 1-4C-alkylthio, or, if they are adjacent, R5 and R6, together and including the tome of Kohlenstoffa¬ which they are attached can also represent a cyclohexene ring,
R7 is halogen, and their salts.
3. VeΦindungen of formula (I) according to claim 1, wherein the partial structure (A), the meanings (B) mentioned in claim 1, (C) or (D),
R1 and R2 are hydrogen,
D represents a bond,
E 1-4C-alkylene,
R3 is 1-4C-alkyl,
R4 is benzyl, 3,4-dimethoxybenzyl, 2- (3,4-dimethoxyphenyl) ethyl, 4-methylbenzyl or 4-meth- oxybenzyl means, or
R3 and R4, together and including the nitrogen atom to which both are bonded, the 6.7-dimethoxy-1, 2,3,4-tetrahydro-2-isoquinolinyl represent
R5 and R6 are independently hydrogen, halogen, 1-4C-alkyl, phenyl, R7 mean by sub¬ stituiertes phenyl or 1-4C-alkylthio, or, if they are adjacent, R5 and R6, together and including the me to Kohlenstoffato¬ which they are attached can also represent a cyclohexene ring,
R7 is halogen, and their salts.
4 has the compounds of formula (I) according to claim 1, wherein the partial structure (A) as defined in claim 1 (C) or (D),
R1 and R2 are hydrogen,
D represents a bond,
E-1-2C Aikylen means
R3 and R4, together and including the nitrogen atom they are both attached to the, the 6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl represent, R5 and R6 are independently hydrogen or 1-4C-alkyl mean, and their salts.
5. VeΦindungen of formula (I) according to claim 1, wherein the partial structure (A) as defined in claim 1 (C) has
R1 and R2 are hydrogen,
D represents a bond,
E 1-2C-alkylene,
R3 and R4, together and including the nitrogen atom they are both attached to the, the 6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl represent, R5 and R6 are independently hydrogen or 1-4C-alkyl mean, and their salts.
6. Use of VeΦindungen of formula (I) according to claim 1 for the preparation of Arz¬ neimitteln for the treatment or prophylaxis of tumor diseases.
7. A medicament comprising one or more compounds of formula (I) according to claim 1 and / or their pharmacologically acceptable salts, together mK usual pharmaceutical auxiliaries and / or excipients.
8. The medicament for improving the effect of antibiotics and / or cytostatics and / or to overcome the resistance to antibiotics and / or cytostatic agents containing one or more compounds of claim 1 and / or their pharmacologically tolerable salts.
9. The pharmaceutical enthaKend one or more VeΦindungen according to claim 1 and / or their pharmacologically acceptable salts in combination with a cytostatic agent.
10. A medicament comprising one or more VeΦindungen according to claim 1 and / or their pharmacologically acceptable salts in combination with an antibiotic.
PCT/EP1997/000404 1996-02-01 1997-01-30 Thienoquinolines WO1997028166A1 (en)

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Cited By (4)

* 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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012132A1 (en) * 1991-01-11 1992-07-23 Laboratoires Glaxo S.A. Acridine derivatives
WO1994001408A1 (en) * 1992-07-10 1994-01-20 Laboratoires Glaxo S.A. Anilide derivatives
WO1995026337A1 (en) * 1994-03-25 1995-10-05 Vertex Pharmaceuticals Incorporated Novel carbamates and ureas as modifiers of multi-drug resistance

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012132A1 (en) * 1991-01-11 1992-07-23 Laboratoires Glaxo S.A. Acridine derivatives
WO1994001408A1 (en) * 1992-07-10 1994-01-20 Laboratoires Glaxo S.A. Anilide derivatives
WO1995026337A1 (en) * 1994-03-25 1995-10-05 Vertex Pharmaceuticals Incorporated Novel carbamates and ureas as modifiers of multi-drug resistance

Cited By (4)

* 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

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