EP0612247A1 - Use of sulphonyl compounds - Google Patents

Use of sulphonyl compounds

Info

Publication number
EP0612247A1
EP0612247A1 EP92923587A EP92923587A EP0612247A1 EP 0612247 A1 EP0612247 A1 EP 0612247A1 EP 92923587 A EP92923587 A EP 92923587A EP 92923587 A EP92923587 A EP 92923587A EP 0612247 A1 EP0612247 A1 EP 0612247A1
Authority
EP
European Patent Office
Prior art keywords
compounds
methyl
formula
hydrogen
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP92923587A
Other languages
German (de)
French (fr)
Inventor
Dieter Flockerzi
Christian Schudt
Hermann Amschler
Rolf Beume
Richard Riedel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
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
Publication of EP0612247A1 publication Critical patent/EP0612247A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines

Definitions

  • the invention relates to the use of sulfonyl compounds for the manufacture of new drugs.
  • the invention relates to the use of compounds of the formula I.
  • R2 is hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy
  • R3 is hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy
  • R4 is hydrogen (H), methyl or methoxy
  • R5 is hydrogen (H) or 1-4C-alkyl
  • 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially methyl est.
  • 1-4C-Al oxy radicals contain, in addition to the oxygen atom, one of the above-mentioned I-4C-alkyl radicals.
  • the methoxy radical is preferred.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • substituted phenyl radicals R6 which may be mentioned are: 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,5-dichloropheny and 4-hydroxyphenyl.
  • Suitable pharmacologically acceptable salts for compounds of the formula I are preferably all acid addition salts with inorganic acids customarily used in galenics. Suitable as such are 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, maleinosalicylic acid ⁇ acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, e bonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is a one or polyacid acts and, depending on which salt is desired - be used in an e
  • proliferative, inflammatory and allergic skin diseases are mentioned as dermatoses.
  • the compounds of the formula I can be used for the prevention and treatment of the following skin diseases. The following are used: psoriasis vulgaris, toxic and allergic contact dermatitis, atopic dermatitis, seborrheic dermatitis, follicular and extensive pyoderma, endogenous and exogenous acne, rosacea and other proliferative, inflammatory and allergic skin diseases.
  • Another object of the invention is thus the use of compounds of formula I and their pharmacologically acceptable salts for the treatment of such individuals who are suffering from dermatoses.
  • the compounds of the formula I are used in particular in the form of those medicaments which are suitable for topical application.
  • suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions in which the active substance content is advantageously between 0.1 and 99%.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
  • R4 is hydrogen or methyl
  • R5 is hydrogen or 1-4C-alkyl
  • R6 denotes 1-4C-A1kyl, phenyl or substituted phenyl with a substituent from the group 1-4C-A1kyl, 1-4C-alkoxy and halogen, and their pharmacologically acceptable salts. Of particular note is the use of such in accordance with the invention
  • R4 is hydrogen or methyl
  • the radical -N (R5) SC R6 is in the 4-position on the phenyl radical bonded in the 6-position on the benzo-naphthyridine ring
  • R5 is hydrogen, methyl or ethyl
  • R6 is methyl, 4-methylphenyl, 4-methoxyphenyl or 4-fluorophenyl, and their pharmacologically acceptable salts.
  • the benzo-naphthyridine cycle has (at positions 4a and 10b) two centers of chirality.
  • the invention therefore includes all conceivable enantiomers and diastereomers as well as the racemates and mixtures thereof.
  • Preferred compounds of the formula I are those in which the hydrogen atoms in positions 4a and 10b are in the cis position.
  • the separation of the trans compounds from the (additionally diastereomeric) cis compounds is carried out - as is the separation of the (+) - and (-) - enantiomers - in a manner familiar to the person skilled in the art, e.g. as described in European patent application 247971.
  • the compounds of formula I and their salts are prepared by a process which is characterized in that a) Compounds of the formula II (see attached formula sheet), in which Rl, R2, R3, R4 and R5 have the meanings indicated above, with sulfonyl compounds of the formula III (see attached formula sheet), in which R6 has the meaning indicated above and X represents a suitable leaving group, um ⁇ , or that one
  • the reaction of the compounds II with the compounds III takes place in inert solvents in a manner known to the person skilled in the art for the production of sulfonates.
  • the leaving group X is preferably a halogen atom, in particular a chlorine atom.
  • the implementation is preferably carried out in the presence of an auxiliary base, e.g. an organic amine such as triethylamine or pyridine, or e.g. a carbonate, such as potassium carbonate or sodium carbonate.
  • the deprotonating agents that can be used are those agents for which the acidity of the proton on the nitrogen is high enough to achieve anion formation.
  • organometallic compounds such as, for example, butyl lithium
  • metal hydrides in particular sodium hydride, or alkali metal alcoholates, for example sodium methylate or potassium tert-butoxide, or Alihydroxide, such as sodium hydroxide or potassium hydroxide, or alkali carbonates, such as sodium carbonate mentioned.
  • the leaving group Y of the compounds IV is a group which is easily split off when Y-R5 is reacted with the deprotonated I, for example a halogen atom, such as chlorine, bromine or iodine, or the alkyl sulfate group.
  • the deprotonation and subsequent N-alkylation is carried out in inert, water-free solvents, such as are suitable for working with strong deprotonating agents, or in water-solvent mixtures, such as are used when working under phase transfer conditions.
  • inert, water-free solvents such as are suitable for working with strong deprotonating agents, or in water-solvent mixtures, such as are used when working under phase transfer conditions.
  • examples include open-chain or cyclic ethers, such as diethyl ether, doxane or tetrahydrofuran, or solvents such as DMF or DMSO.
  • water / solvent mixtures are the mixtures of water with chloroform, dichloromethane or benzene.
  • the reaction is preferably carried out under mild reaction conditions at temperatures around or below 0 ⁇ C.
  • cyclocondensation according to process variant c) is carried out in a manner known per se to the person skilled in the art according to Bisch! Er-Napieralski in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus pentoxide or preferably phosphorus oxychloride, in a suitable inert solvent, e.g.
  • a chlorinated hydrocarbon such as chloroform
  • a cyclic hydrocarbon such as toluene or xylene
  • another inert solvent such as acetonitrile
  • an excess of condensing agent preferably at elevated temperature, especially at Boiling temperature of the solvent or condensation agent used.
  • the compounds of the formula V are obtained in a manner known per se from the compounds VI and VII (see reaction scheme of the formula sheet) in which R 1, R 2, R 3, R 4, R 5 and R 6 have the meanings indicated above and Z is a suitable leaving group, for example represents a chlorine atom.
  • Compounds VI are e.g. known from DE-OS 21 23 328 or EP-A-247 971 or they can be prepared in an analogous manner.
  • the compounds VII are also known or can be prepared in a manner known to the person skilled in the art.
  • the trans compounds are separated from the cis compounds and the (+) and (-) enantiomers are advantageously separated at the stage of the preliminary and intermediate products prepared analogously to EP-A-247 971 .
  • the starting compound rac-cis-3- (3,4-dimethoxyphenyl) -l-methl-4- [4-methyl-3- (p-toluenesulfonamido) -benzamido] -piperidine is obtained by reacting 4, 6 g of 4-methyl-3- (p-toluenesulfonamido) -benzoic acid chloride with 3.0 g of rac-cis-4-amino-3- (3,4-dimethoxyphenyl) -l-methylpiperidine (produced in a manner analogous to that in DE -OS 21 23328 described procedure) and 4 ml of triethylamine in 50 ml of anhydrous dichloromethane. After shaking out with NaHCO 3 solution, drying the organic phase over sodium sulfate and concentrating, the residue is recrystallized in methanol. Yield: 4.2 g, mp 142-146 ° C.
  • the starting compound rac-cis-3- (3,4-dimethoxyphenyl) -l-methyl-4- [2- (p-toluenesulfonamido) -benzamido] -piperidine is obtained analogously to Example 3 from 2- (p-toluo! Sulfonamido) -benzoic acid chloride and the corresponding piperidine. Yield: 70%.
  • Example 2 The title compound is obtained analogously to Example 1 when p-methoxyphenylsulfonic acid chloride is used. Yield: 66%, mp. 210-217 ° C (crystallized as carbonate hydrate from methanol).
  • the title compound is obtained analogously to Example 3 if rac-cis- -3- (3,4-dimethoxyphenyl) -1-methyl-4 - [(4-p-methoxyphenylsulfonamido) benzamido] piperidine is cyclocondensed.
  • This starting compound is obtained Analogously to Example 3, if 4- (p-methoxyphenylsulfonamido) benzoic acid chloride is used.
  • Example 3 Analogously to Example 3, the title compound is obtained when rac-cis-3- (3,4-dimethoxyphenyl) -1-methyl-4 - [(p-fluorophenylsulfonamido) benzamido] piperidine is used. Yield: 69%, mp 163-165 ⁇ C.
  • the starting compound is obtainable analogously to Example 3 from 4- (p-fluorophenylsulfonamido) benzoic acid chloride. Yield: 60%, m.p. 108-113'C.
  • Example 3 Analogously to Example 3, the title compound is obtained from rac-cis-3- (3,4-dimethoxyphenyl) -1-methyl-4 - [(p-toluenesulfone-N-methylamido) benzamido] piperidine; Yield: 53%, mp. 157-158 ⁇ C (from methanol / ether).
  • the starting compound is obtainable analogously to Example 3 from 4- (p-toluenesulfone-N-methylamido) benzoic acid chloride.

Abstract

L'invention concerne l'utilisation de composés répondant à la formule (I), dans laquelle les substituants ont les propriétés énoncées dans la description, ainsi que de leurs sels compatibles sur le plan pharmacologique, pour fabriquer des médicaments destinés au traitement de dermatoses.The invention relates to the use of compounds having the formula (I), in which the substituents have the properties stated in the description, as well as their pharmacologically compatible salts, for the manufacture of medicaments for the treatment of dermatoses.

Description

Verwendung von SulfonylVerbindungen Use of sulfonyl compounds
Anwendungsgebiet der ErfindungField of application of the invention
Die Erfindung betrifft die Verwendung von SulfonylVerbindungen zur Herstel lung neuer Arzneimittel.The invention relates to the use of sulfonyl compounds for the manufacture of new drugs.
Bekannter technischer HintergrundKnown technical background
In einer Reihe von Patentanmeldungen und Patenten wird die Eignung von Verbindungen verschiedener Substanzklassen zur Behandlung proliferativer Hauterkrankungen beschrieben. So sollen sich beispielsweise bestimmte Xan- thinderivate (siehe z.B. EP 389 282, EP 267 676, EP 260 127, WO 87/04435 und EP 195 496) und bestimmte Imidazo-chinazolinderivate (siehe z.B. US 4,837,239, US 4,690,925, US 4,663,320, EP 212 647, EP 153 152 und EP 116 948) zur Behandlung entzündlicher Hauterkrankungen eignen. - In der internationalen Patentanmeldung PCT/EP91/00895 werden Verbindungen be¬ schrieben, die sich aufgrund ihrer bronchospasmolytisehen Wirkung zur Be¬ handlung von Atemwegserkrankungen eignen sollen.A number of patent applications and patents describe the suitability of compounds of different classes of substances for the treatment of proliferative skin diseases. For example, certain xanthine derivatives (see, for example, EP 389 282, EP 267 676, EP 260 127, WO 87/04435 and EP 195 496) and certain imidazo-quinazoline derivatives (see, for example, US 4,837,239, US 4,690,925, US 4,663,320, EP) 212 647, EP 153 152 and EP 116 948) are suitable for the treatment of inflammatory skin diseases. The international patent application PCT / EP91 / 00895 describes compounds which, owing to their bronchospasmolytic action, are said to be suitable for the treatment of respiratory diseases.
Beschreibung der ErfindungDescription of the invention
Es wurde gefunden, daß die unten näher beschriebenen Verbindungen zur Be¬ handlung von Der atosen in hervorragender Weise geeignet sind.It has been found that the compounds described in more detail below are outstandingly suitable for the treatment of doses.
Gegenstand der Erfindung ist die Verwendung von Verbindungen der Formel IThe invention relates to the use of compounds of the formula I.
(siehe beigefügtes Formelblatt), worin(see attached formula sheet), where
Rl 1-4C-Alkyl,Rl 1-4C-alkyl,
R2 Wasserstoff (H), 1-4C-Alkyl oder l-4C-Alkoxy,R2 is hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy,
R3 Wasserstoff (H), 1-4C-Alkyl oder l-4C-Alkoxy,R3 is hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy,
R4 Wasserstoff (H), Methyl oder Methoxy,R4 is hydrogen (H), methyl or methoxy,
*>*>
R5 Wasserstoff (H) oder 1-4C-Alkyl undR5 is hydrogen (H) or 1-4C-alkyl and
R6 1-4C-Alkyl, Phenyl oder substituiertes Phenyl mit einem oder zwei gleichen oder verschiedenen Substituenten aus der Gruppe 1-4C-Alkyl, l-4C-Alkoxy, Hydroxy und Halogen bedeutet, und ihren pharmakologisch verträglichen Salzen mit Säuren zur Herstellung von Arzneimitteln für die Behandlung von Dermatosen.R6 1-4C-alkyl, phenyl or substituted phenyl with one or two the same or different substituents from the group 1-4C-alkyl, 1-4C-alkoxy, hydroxy and halogen, and their pharmacologically acceptable salts with acids for the preparation of medicaments for the treatment of dermatoses.
1-4C-Alkyl steht für geradkettige oder verzweigte Alkylreste mit 1 bis 4 Kohlenstoffatomen. Beispielsweise seien genannt der Butyl-, iso-Butyl-, sec.-Butyl-, tert.-Butyl-, Propyl-, Isopropyl-, Ethyl- und insbesondere der Methyl est.1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially methyl est.
l-4C-Al oxyreste enthalten neben dem Sauerstoffato einen der vorstehend genannten I-4C-Alkylreste. Bevorzugt ist der Methoxyrest.1-4C-Al oxy radicals contain, in addition to the oxygen atom, one of the above-mentioned I-4C-alkyl radicals. The methoxy radical is preferred.
Halogen im Sinne der vorliegenden Erfindung ist Brom, Chlor und Fluor.Halogen in the sense of the present invention is bromine, chlorine and fluorine.
Als beispielhafte substituierte Phenylreste R6 seien genannt die Reste: 4-Methylphenyl , 4-tert.-Butylphenyl, 4-Methoxyphenyl , 4-Fluorphenyl , 4-Chlorphenyl, 2,5-Dichlorpheny und 4-Hydroxyphenyl .Examples of substituted phenyl radicals R6 which may be mentioned are: 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,5-dichloropheny and 4-hydroxyphenyl.
Als pharmakologisch verträgliche Salze kommen für Verbindungen der Formel I bevorzugt alle Säureadditionssalze mit in der in der Galenik üblicherwei¬ se verwendeten anorganischen Säuren mit Betracht. Als solche eignen sich wasserlösliche und wasserunlösl che Säureadditionssalze mit Säuren wie bei¬ spielsweise Salzsäure, Bromwasserstoffsäure, Phosphorsäure, Salpetersäure, Schwefelsäure, Essigsäure, Zitronensäure, D-Gluconsäure, Benzoesäure, 2-(4-Hydroxybenzoyl)-benzoesäure, Buttersäure, Sulfosalicylsäure, Malein¬ säure, Laurinsäure, Äpfelsäure, Fumarsäure, Bernsteinsäure, Oxalsäure, Weinsäure, E bonsäure, Stearinsäure, Toluolsulfonsäure, Methansulfonsäure oder 3-Hydroxy-2-naphtoesäure, wobei die Säuren bei der Salzherstellung - je nachdem, ob es sich um eine ein- oder mehrbasige Säure handelt und je nachdem, welches Salz gewünscht wird - im äquimolaren oder einem davon abweichenden Mengenverhältnis eingesetzt werden.Suitable pharmacologically acceptable salts for compounds of the formula I are preferably all acid addition salts with inorganic acids customarily used in galenics. Suitable as such are 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, maleinosalicylic acid ¬ acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, e bonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is a one or polyacid acts and, depending on which salt is desired - be used in an equimolar or a different quantity ratio.
Als Dermatosen seien insbesondere prol ferative, entzündliche und allergi¬ sche Hauterkrankungen erwähnt. So können die Verbindungen der Formel I bei¬ spielsweise zur Verhütung und Behandlung folgender Hauterkrankungen einge- setzt werden: Psoriasis vulgaris, toxisches und allergisches Kontaktekzem, atopisches Ekzem, seborrhoisches Ekzem, follikuläre und flächenhafte Pyo- dermien, endogene und exogene Akne, Akne rosacea sowie andere proliferati- ve, entzündliche und allergische Hauterkrankungen. Weiterer Gegenstand der Erfindung ist somit die Verwendung von Verbindungen der Formel I und ihren pharmakologisch verträglichen Salzen zur Behandlung von solchen Individuen, die an Dermatosen erkrankt sind.In particular, proliferative, inflammatory and allergic skin diseases are mentioned as dermatoses. For example, the compounds of the formula I can be used for the prevention and treatment of the following skin diseases. The following are used: psoriasis vulgaris, toxic and allergic contact dermatitis, atopic dermatitis, seborrheic dermatitis, follicular and extensive pyoderma, endogenous and exogenous acne, rosacea and other proliferative, inflammatory and allergic skin diseases. Another object of the invention is thus the use of compounds of formula I and their pharmacologically acceptable salts for the treatment of such individuals who are suffering from dermatoses.
Die Anwendung der Verbindungen der Formel I erfolgt insbesondere in Form solcher Arzneimittel, die für eine topische Applikation geeignet sind. Für die Herstellung der Arzneimittel werden die Verbindungen der Formel I und/oder ihre pharmakologisch verträglichen Salze (= Wirkstoffe) vorzugs¬ weise mit geeigneten pharmazeutischen Hilfsstoffen vermischt und zu geeig¬ neten Arzneifor ulierungen weiterverarbeitet. Als geeignete Arzneiformu¬ lierungen seien beispielsweise Puder, Emulsionen, Suspensionen, Sprays, Öle, Salben, Fettsalben, Cremes, Pasten, Gele oder Lösungen genannt, in de¬ nen der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 99 % beträgt.The compounds of the formula I are used in particular in the form of those medicaments which are suitable for topical application. For the preparation of the pharmaceuticals, the compounds of the formula I and / or their pharmacologically acceptable salts (= active ingredients) are preferably mixed with suitable pharmaceutical auxiliaries and processed further to give suitable pharmaceutical formulations. Suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions in which the active substance content is advantageously between 0.1 and 99%.
Welche Hilfsstoffe für die gewünschten Arzneiformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Salbengrundlagen und anderen Wirkstoffträgern können bei¬ spielsweise Antioxidantien, Dispergiermittel, E ulgatoren, Konservierungs¬ mittel, Lösungsvermittler oder Permeationspromotoren verwendet werden.The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, ointment bases and other active substance carriers, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
Hervorzuheben ist die erfindungsgemäße Verwendung von solchen Verbindungen der Formel I, in denenThe use according to the invention of compounds of the formula I in which
Rl 1-4C-Alkyl,Rl 1-4C-alkyl,
R2 l-4C-Alkoxy,R2 1-4C alkoxy,
R3 l-4C-Alkoxy,R3 1-4C-alkoxy,
R4 Wasserstoff oder Methyl ,R4 is hydrogen or methyl,
R5 Wasserstoff oder 1-4C-Alkyl,R5 is hydrogen or 1-4C-alkyl,
R6 1-4C-A1kyl , Phenyl oder substituiertes Phenyl mit einem Substituenten aus der Gruppe 1-4C-A1kyl , l-4C-Alkoxy und Halogen bedeutet, und ihren pharmakologisch verträglichen Salzen. Besonders hervorzuheben ist die erfindungsgemäße Verwendung von solchenR6 denotes 1-4C-A1kyl, phenyl or substituted phenyl with a substituent from the group 1-4C-A1kyl, 1-4C-alkoxy and halogen, and their pharmacologically acceptable salts. Of particular note is the use of such in accordance with the invention
Verbindungen der Formel I, in denenCompounds of formula I in which
Rl Methyl,Rl methyl,
R2 Methoxy,R2 methoxy,
R3 Methoxy undR3 methoxy and
R4 Wasserstoff oder Methyl bedeutet, der Rest -N(R5)SC R6 in 4-Position an dem in 6-Stellung am Benzo-naphthyri- dinring gebundenen Phenylrest steht,R4 is hydrogen or methyl, the radical -N (R5) SC R6 is in the 4-position on the phenyl radical bonded in the 6-position on the benzo-naphthyridine ring,
R5 Wasserstoff, Methyl oder Ethyl undR5 is hydrogen, methyl or ethyl and
R6 Methyl, 4-Methylphenyl , 4-Methoxyphenyl oder 4-Fluorphenyl bedeutet, und ihren pharmakologisch verträglichen Salzen.R6 is methyl, 4-methylphenyl, 4-methoxyphenyl or 4-fluorophenyl, and their pharmacologically acceptable salts.
Der Benzo-naphthyridincyclus besitzt (an den Positionen 4a und 10b) zwei Chiralitätszentren. Die Erfindung umfaßt daher alle denkbaren Enantiomeren und Diastereomeren sowie die Racemate und Gemische davon. Bevorzugt sind jene Verbindungen der Formel I, in denen die Wasserstoffatome in den Posi¬ tionen 4a und 10b cis-ständig sind.The benzo-naphthyridine cycle has (at positions 4a and 10b) two centers of chirality. The invention therefore includes all conceivable enantiomers and diastereomers as well as the racemates and mixtures thereof. Preferred compounds of the formula I are those in which the hydrogen atoms in positions 4a and 10b are in the cis position.
Bevorzugt ist die erfindungsgemäße Verwendung der enantiomer reinen, zuein¬ ander spiegelbildlichen Cis-Verbindungen, die das linear polarisierte Licht in (+)- bzw. (-)-Richtung drehen [(+)-Enantiomer und (-)-Enantiomer]. Die Trennung der trans-Verbindungen von den (dazu diastereomeren) Cis-Verbin¬ dungen erfolgt - ebenso wie die Trennung der (+)- und (-)-Enantiomeren - auf eine dem Fachmann vertraute Weise, z.B. so wie in der Europäischen Patentanmeldung 247971 beschrieben.Preferred is the use according to the invention of the enantiomerically pure, mutually mirror-image cis compounds which rotate the linearly polarized light in the (+) or (-) direction [(+) - enantiomer and (-) - enantiomer]. The separation of the trans compounds from the (additionally diastereomeric) cis compounds is carried out - as is the separation of the (+) - and (-) - enantiomers - in a manner familiar to the person skilled in the art, e.g. as described in European patent application 247971.
Besonders bevorzugt ist in diesem Zusammenhang die Verwendung solcher Ver¬ bindungen der Formel I, die sich von Verbindungen der Formel II herleiten, die die gleiche absolute Konfiguration haben wie die .Verbindung (-)-cis-6-In this context, particular preference is given to the use of compounds of the formula I which derive from compounds of the formula II which have the same absolute configuration as the compound (-) - cis-6-
(4-Aminophenyl)-8,9-dimethoxy-l,2,3,4,4a,10b-hexahydro-2-methyl-benzo[c]-(4-aminophenyl) -8,9-dimethoxy-l, 2,3,4,4a, 10b-hexahydro-2-methyl-benzo [c] -
22 [l,6]-naphthyridin mit dem optischen Drehwert Mryguπ = -213° (c=l,22 [l, 6] -naphthyridine with the optical rotation value M r yguπ = -213 ° (c = l,
Chloroform).Chloroform).
Die Verbindungen der Formel I und ihre Salze werden nach einem Verfahren hergestellt, das dadurch gekennzeichnet ist, daß man a) Verbindungen der Formel II (siehe beigefügtes Formelblatt), worin Rl, R2, R3, R4 und R5 die oben angegebenen Bedeutungen haben, mit Sulfonylver- bindungen der Formel III (siehe beigefügtes Formelblatt), worin R6 die oben angegebene Bedeutung hat und X eine geeignete Abgangsgruppe darstellt, um¬ setzt, oder daß manThe compounds of formula I and their salts are prepared by a process which is characterized in that a) Compounds of the formula II (see attached formula sheet), in which Rl, R2, R3, R4 and R5 have the meanings indicated above, with sulfonyl compounds of the formula III (see attached formula sheet), in which R6 has the meaning indicated above and X represents a suitable leaving group, um¬, or that one
b) zur Herstellung von Verbindungen I, in denen R5 1-4C-A1kyl bedeutet, Verbindungen der Formel I, in denen R5 Wasserstoff bedeutet, mit einem Al- kylierungsmittel der Formel IV (siehe beigefügtes Formelblatt), worin R5 1-4C-Alkyl und Y eine Abgangsgruppe bedeutet, alkyliert, oder daß manb) for the preparation of compounds I in which R5 is 1-4C-alkyl, compounds of the formula I in which R5 is hydrogen with an alkylating agent of the formula IV (see attached formula sheet), in which R5 is 1-4C-alkyl and Y represents a leaving group, alkylated or that one
c) Verbindungen der Formel V (siehe beigefügtes Formelblatt), worin Rl, R2, R3, R4, R5 und R6 die oben angegebenen Bedeutungen haben, cyclokondensiert und daß man gewünschtenfalls anschließend die nach a), b) oder c) erhalte¬ nen Verbindungen I in ihre Salze überführt, oder daß man gewünschtenfalls anschließend aus erhaltenen Salzen der Verbindungen I die Verbindungen I freisetzt.c) Compounds of the formula V (see attached formula sheet), in which R 1, R 2, R 3, R 4, R 5 and R 6 have the meanings given above, cyclocondensed and that, if desired, the compounds obtained according to a), b) or c) are subsequently obtained I converted into their salts, or that, if desired, the compounds I are subsequently released from the salts of the compounds I obtained.
Die Umsetzung der Verbindungen II mit den Verbindungen III erfolgt in iner¬ ten Lösungsmitteln auf eine Weise, wie sie dem Fachmann für die Herstellung von Sulfona iden bekannt ist. Die Abgangsgruppe X ist bevorzugt ein Halo¬ genatom, insbesondere ein .Chloratom. Die Umsetzung erfolgt bevorzugt in Ge¬ genwart einer Hilfsbase, z.B. eines organischen Amins, wie Triethylamin oder Pyridin, oder z.B. eines Carbonates, wie Kaliumcarbonat oder Natrium- carbonat.The reaction of the compounds II with the compounds III takes place in inert solvents in a manner known to the person skilled in the art for the production of sulfonates. The leaving group X is preferably a halogen atom, in particular a chlorine atom. The implementation is preferably carried out in the presence of an auxiliary base, e.g. an organic amine such as triethylamine or pyridine, or e.g. a carbonate, such as potassium carbonate or sodium carbonate.
Die N-Alkylierung gemäß Verfahrensvariante b) wird in einer dem Fachmann an sich vertrauten Weise, gegebenenfalls unter Phasentransfer-Bedingungen, be¬ vorzugt in Gegenwart geeigneter Basen oder nach vorheriger Deprotonierung der Verbindungen I mit R5 = Wasserstoff durchgeführt.The N-alkylation according to process variant b) is carried out in a manner known per se to the person skilled in the art, if appropriate under phase transfer conditions, preferably in the presence of suitable bases or after prior deprotonation of the compounds I with R5 = hydrogen.
Als Deprotonierungsmittel kommen vor allem solche Agenzien in Frage, für die die Acidität des Protons am Stickstoff groß genug ist, um eine Anion- bildung zu erzielen. Neben metallorganischen Verbindungen, wie z.B. Butyl- lithiu , seien beispielsweise Metallhydride, insbesondere Natriumhydrid, oder Alkalialkoholate, z.B. Natriummethylat oder Kaiium-tert.-butylat, oder Al alihydroxide, z.B. Natriumhydroxid oder Kaliumhydroxid, oder Alkalicar- bonate, z.B. Natriumcarbonat erwähnt.The deprotonating agents that can be used are those agents for which the acidity of the proton on the nitrogen is high enough to achieve anion formation. In addition to organometallic compounds, such as, for example, butyl lithium, there may be, for example, metal hydrides, in particular sodium hydride, or alkali metal alcoholates, for example sodium methylate or potassium tert-butoxide, or Alihydroxide, such as sodium hydroxide or potassium hydroxide, or alkali carbonates, such as sodium carbonate mentioned.
Die Abgangsgruppe Y der Verbindungen IV ist eine Gruppe, die bei der Umset¬ zung von Y - R5 mit dem deprotonierten I leicht abgespalten wird, bei¬ spielsweise ein Halogenatom, wie Chlor, Brom oder Jod, oder die Alkylsul- fatgruppe.The leaving group Y of the compounds IV is a group which is easily split off when Y-R5 is reacted with the deprotonated I, for example a halogen atom, such as chlorine, bromine or iodine, or the alkyl sulfate group.
Die Deprotonierung und anschließende N-Alkyl erung wird in inerten, wasser¬ freien Lösungsmitteln vorgenommen, wie sie für das Arbeiten mit starken De- protonierungsmitteln geeignet sind, oder in Wasser-Lösungsmittelgemisehen, wie sie beim Arbeiten unter Phasentransfer-Bediηgungen eingesetzt werden. Beispielsweise seien offenkettige oder cyclische Ether, wie Diethylether, D oxan oder Tetrahydrofuran, oder Lösungsmittel wie DMF oder DMSO genannt. Als Wasser/Lösungsmittelmischungen seien beispielsweise die Mischungen von Wasser mit Chloroform, Dichlormethan oder Benzol genannt. Die Umsetzung er¬ folgt bevorzugt unter schonenden Reaktionsbedingungen bei Temperaturen um oder unter 0βC.The deprotonation and subsequent N-alkylation is carried out in inert, water-free solvents, such as are suitable for working with strong deprotonating agents, or in water-solvent mixtures, such as are used when working under phase transfer conditions. Examples include open-chain or cyclic ethers, such as diethyl ether, doxane or tetrahydrofuran, or solvents such as DMF or DMSO. Examples of water / solvent mixtures are the mixtures of water with chloroform, dichloromethane or benzene. The reaction is preferably carried out under mild reaction conditions at temperatures around or below 0 β C.
Die Cyclokondensation gemäß Vefahrenvariante c) erfolgt auf eine dem Fach¬ mann an sich bekannte Weise gemäß Bisch!er-Napieralski in Gegenwart eines geeigneten Kondensationsmittels, wie beispielsweise Pol phosphorsäure, Phosphorpentachlorid, Phosphorpentoxid oder bevorzugt PhosphoroxytriChlo¬ rid, in einem geeigneten inerten Lösungsmittel, z.B. in einem chlorierten Kohlenwasserstoff wie Chloroform, oder in einem cyclischen Kohlenwasser¬ stoff wie Toluol oder Xylol, oder einem sonstigen inerten Lösungsmittel wie Acetonitril, oder ohne weiteres Lösungsmittel unter Verwendung eines Über¬ schusses an Kondensationsmittel, vorzugsweise bei erhöhter Temperatur, ins¬ besondere bei der Siedetemperatur des verwendeten Lösungs- bzw. Kondensa¬ tionsmittels.The cyclocondensation according to process variant c) is carried out in a manner known per se to the person skilled in the art according to Bisch! Er-Napieralski in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus pentoxide or preferably phosphorus oxychloride, in a suitable inert solvent, e.g. in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon such as toluene or xylene, or another inert solvent such as acetonitrile, or without further solvent using an excess of condensing agent, preferably at elevated temperature, especially at Boiling temperature of the solvent or condensation agent used.
Die Verbindungen der Formel II mit R5 = Wasserstoff sind aus den Schriften DE-OS 2123328, USP 3,899,494 und EP-A-247 971 bekannt bzw. sie können in analoger Weise hergestellt werden. Verbindungen II mit R5 = 1-4C-Alkyl kön¬ nen aus den Verbindungen II mit R5 = Wasserstoff durch Alkylierung auf eine dem Fachmann vertraute Weise hergestellt werden. Die Verbindungen der Formel V erhält man in an sich bekannter Weise aus den Verbindungen VI und VII (siehe Reaktionsschema des Formelblattes) worin Rl, R2, R3, R4, R5 und R6 die oben angegebenen Bedeutungen haben und Z eine ge¬ eignete Abgangsgruppe, beispielsweise ein Chloratom darstellt.The compounds of formula II with R5 = hydrogen are known from the documents DE-OS 2123328, USP 3,899,494 and EP-A-247 971 or they can be prepared in an analogous manner. Compounds II with R5 = 1-4C-alkyl can be prepared from the compounds II with R5 = hydrogen by alkylation in a manner familiar to those skilled in the art. The compounds of the formula V are obtained in a manner known per se from the compounds VI and VII (see reaction scheme of the formula sheet) in which R 1, R 2, R 3, R 4, R 5 and R 6 have the meanings indicated above and Z is a suitable leaving group, for example represents a chlorine atom.
Die Verbindungen VI sind z.B. aus der DE-OS 21 23 328 oder der EP-A-247 971 bekannt oder sie können auf analoge Weise hergestellt werden.Compounds VI are e.g. known from DE-OS 21 23 328 or EP-A-247 971 or they can be prepared in an analogous manner.
Die Verbindungen VII sind ebenfalls bekannt oder auf eine dem Fachmann be¬ kannte Weise herstellbar.The compounds VII are also known or can be prepared in a manner known to the person skilled in the art.
Zur Herstellung der enantiomer reinen Verbindungen I erfolgt die Trennung der trans-Verbindungen von den cis-Verbindungen sowie die Trennung der (+)- und (-)-Enantiomeren vorteilhafterweise auf der Stufe der analog EP-A-247 971 hergestellten Vor- und Zwischenprodukte.To prepare the enantiomerically pure compounds I, the trans compounds are separated from the cis compounds and the (+) and (-) enantiomers are advantageously separated at the stage of the preliminary and intermediate products prepared analogously to EP-A-247 971 .
Die folgenden Beispiele erläutern die Herstellung der Verbindungen I näher. Die erfindungsgemäße Verwendung der in den Beispielen namentlich aufgeführ¬ ten Verbindungen der allgemeinen Formel I sowie ihrer pharmakologisch ver¬ träglichen Salze ist bevorzugter Gegenstand der Erfindung. Schmp. bedeutet Schmelzpunkt, für Stunde(n) wird die Abkürzung h und für Minuten die Abkür¬ zung Min. verwendet. Zers. steht für Zersetzung. Unter "Ether" wird Di- ethylether verstanden. The following examples explain the preparation of the compounds I in more detail. The use according to the invention of the compounds of the general formula I mentioned by name in the examples and their pharmacologically tolerable salts is a preferred subject of the invention. Mp. Means melting point, the abbreviation h is used for hour (s) and the abbreviation Min. For minutes. Decay stands for decomposition. “Ether” means diethyl ether.
BeispieleExamples
1. rac-cis-8,9-Dimethoxy-l,2,3,4,4a,10b-hexahvdro-2-methyl-6-f4-methylsul- fonamidophenyl )-benzoTelfl,βlnaphthyridin1. rac-cis-8,9-dimethoxy-l, 2,3,4,4a, 10b-hexahvdro-2-methyl-6-f4-methylsulfonamidophenyl) -benzoTelfl, βlnaphthyridine
Zur Lösung von 2,1 g rac-cis-6-(4-Aminophenyl)-8,9-dimethoxy-l,2,3,4,4a,- 10b-hexahydro-2-methyl-benzo[c][l,6]naphthyridin in 20 ml absolutem Pyridin tropft man eine Lösung von 0,6 ml Methansulfonsäurechlorid in 3 ml absolu¬ tem Dioxan und rührt anschließend das Gemisch noch 3 h bei 60"C. Nach dem Abkühlen gießt man den Ansatz auf 100 ml Eis/Wassergemisch, alkalisiert mit verdünnter Natronlauge und extrahiert mit n-Butanol. Nach dem Abdampfen des n-Butanols wird der verbleibende Rückstand mit Dichlormethan extrahiert und die organische Phase über Natriumsulfat getrocknet und anschließend einge¬ engt. Man erhält als Rückstand 2,4 g der TitelVerbindung, die mit etheri- scher HC1 ins D hydrochlorid überführt und aus nicht getrocknetem Methanol umkristallisiert wird. Schmp. 239-240°C (Zers.).To dissolve 2.1 g of rac-cis-6- (4-aminophenyl) -8,9-dimethoxy-l, 2,3,4,4a, - 10b-hexahydro-2-methyl-benzo [c] [l , 6] naphthyridine in 20 ml of absolute pyridine, a solution of 0.6 ml of methanesulfonyl chloride in 3 ml of absolute dioxane is added dropwise and the mixture is then stirred for a further 3 hours at 60 ° C. After cooling, the mixture is poured onto 100 ml of ice / Water mixture, alkalized with dilute sodium hydroxide solution and extracted with n-butanol After evaporation of the n-butanol, the remaining residue is extracted with dichloromethane and the organic phase is dried over sodium sulfate and then concentrated to give 2.4 g of the residue Title compound which is converted into the D hydrochloride using ethereal HC1 and recrystallized from undried methanol, mp 239-240 ° C. (dec.).
2. rac-cis-8,9-Dimethoxy-l,2.3,4, a.10b-hexahydro-2-methyl-6-f4-(p-tolu- olsulfonamido)-phenyl1-benzoTelπ,61naphthyridin2. rac-cis-8,9-dimethoxy-l, 2,3,4, a.10b-hexahydro-2-methyl-6-f4- (p-toluenesulfonamido) -phenyl1-benzoTelπ, 61naphthyridine
Analog Beispiel 1 erhält man die TitelVerbindung, wenn p-Toluolsulfonsäu- rechlorid anstelle von Methansulfonsäurechlorid eingesetzt wird. Schmp. 219-221βC (Dihydrochlorid-hydrat) .The title compound is obtained analogously to Example 1 if p-toluenesulfonic acid chloride is used instead of methanesulfonic acid chloride. M.p. 219-221 β C (dihydrochloride hydrate).
3. rac-cis-8.,9-Dimethoxy-l,2.3-r4,4a,10b-hexahvdro-2-methv1-6-r4-methv1- 3-fp-toluolsulfonamidol-phenyl1-benzofein,61naphthyridin3. rac-cis-8., 9-dimethoxy-l, 2.3- r 4,4a, 10b-hexahvdro-2-methv1-6-r4-methv1-3-fp-toluenesulfonamidol-phenyl1-benzofein, 61naphthyridine
4,0 g rac-cis-l-Cyclopropylmethyl-3-(3,4-dimethoxyphenyl)-4-[4-methyl-3- (p-toluolsulfonamido)-benzamido]-piperidin werden in 50 ml Phosphoroxytri- chlorϊd 3 h unter Rückfluß zum Sieden erhitzt. Nach Abdestiliieren des überschüssigen PhosphoroxytriChlorids verteilt man den Rückstand zwischen Dichlormethan und 2N Natronlauge, wäscht die organische Phase mit Wasser und trocknet sie über Natriumsulfat. Nach dem Abdestillieren des Dichlorme- thans reinigt man den Rückstand durch KieselgelChromatographie. Die sepa- rierte Hauptproduktfraktion wird eingeengt und der feste Rückstand in Es- sigsäureethylester/Petrolether umkristallisiert. Man erhält 2,6 g der Ti¬ telverbindung als gelbliche Kristalle vom Schmp. 206-210"C (Zers.).4.0 g of rac-cis-l-cyclopropylmethyl-3- (3,4-dimethoxyphenyl) -4- [4-methyl-3- (p-toluenesulfonamido) -benzamido] -piperidine are in 50 ml of phosphorus oxychloroϊd for 3 h heated to boiling under reflux. After the excess phosphorus oxychloride has been distilled off, the residue is partitioned between dichloromethane and 2N sodium hydroxide solution, the organic phase is washed with water and dried over sodium sulfate. After the dichloromethane has been distilled off, the residue is purified by silica gel chromatography. The separate The main product fraction is concentrated and the solid residue is recrystallized from ethyl acetate / petroleum ether. 2.6 g of the titanium compound are obtained as yellowish crystals of mp. 206-210 "C. (dec.).
Die Ausgangsverbindung rac-cis-3-(3,4-Dimethoxyphenyl)-l-methl-4-[4-me- thyl-3-(p-toluolsulfonamido)-benzamido]-piperidin erhält man durch Umset¬ zung von 4,6 g 4-Methyl-3-(p-toluolsulfonamido)-benzoesäurechlorid mit 3,0 g rac-cis-4-Amino-3-(3,4-dimethoxyphenyl)-l-methylpiperidin (herge¬ stellt analog der in der DE-OS 21 23328 beschriebenen Arbeitsweise) und 4 ml Triethylamin in 50 ml wasserfreiem Dichlormethan. Nach Ausschütteln mit NaHC03-Lösung, Trocknen der organischen Phase über Natriumsulfat und Ein¬ engen kristallisiert man den Rückstand in Methanol um. Ausbeute: 4,2 g, Schmp. 142-146°C.The starting compound rac-cis-3- (3,4-dimethoxyphenyl) -l-methl-4- [4-methyl-3- (p-toluenesulfonamido) -benzamido] -piperidine is obtained by reacting 4, 6 g of 4-methyl-3- (p-toluenesulfonamido) -benzoic acid chloride with 3.0 g of rac-cis-4-amino-3- (3,4-dimethoxyphenyl) -l-methylpiperidine (produced in a manner analogous to that in DE -OS 21 23328 described procedure) and 4 ml of triethylamine in 50 ml of anhydrous dichloromethane. After shaking out with NaHCO 3 solution, drying the organic phase over sodium sulfate and concentrating, the residue is recrystallized in methanol. Yield: 4.2 g, mp 142-146 ° C.
4. rac-cis-8,9-Di ethoχy-l,2,3,4,4a,10b-hexahydro-2-methy1-6-r2-(p-tolu- olsulfona ido)-phenyl!-benzoTelfl,61naphthyridin4. rac-cis-8,9-di ethoχy-l, 2,3,4,4a, 10b-hexahydro-2-methy1-6-r2- (p-toluenesulfona ido) -phenyl! -BenzoTelfl, 61naphthyridine
Analog Beispie! 3 erhält man die Titelverbindung aus 4,5 g rac-cis-3-(3,4- Dimethoxphenyl)-1-methyl-4-[2-(p-toluolsulfonamido)-benzamido]-piperidin und 30 ml Phosphoroxytrichlorid. Ausbeute: 3,3 g bräunliche Kristalle.Analogous example! 3, the title compound is obtained from 4.5 g of rac-cis-3- (3,4-dimethoxphenyl) -1-methyl-4- [2- (p-toluenesulfonamido) benzamido] piperidine and 30 ml of phosphorus oxytrichloride. Yield: 3.3 g of brownish crystals.
Die Ausgangsverbindung rac-cis-3-(3,4-Dimethoxyphenyl)-l-methyl-4-[2-(p- toluolsulfonamido)-benzamido]-piperidin erhält man analog Beispiel 3 aus 2-(p-Toluo!sulfonamido)-benzoesäurechlorid und dem entsprechenden Piperi¬ din. Ausbeute: 70 %.The starting compound rac-cis-3- (3,4-dimethoxyphenyl) -l-methyl-4- [2- (p-toluenesulfonamido) -benzamido] -piperidine is obtained analogously to Example 3 from 2- (p-toluo! Sulfonamido) -benzoic acid chloride and the corresponding piperidine. Yield: 70%.
5. rac-cis-8,9-Dimethoxy-l,2,3,4,4a,10b-hexahydro-2-methy1-6-r4-(p-meth- oxy-phenv!sulfonamido)-phenyl!-benzofein,61naphthyridin5. rac-cis-8,9-dimethoxy-l, 2,3,4,4a, 10b-hexahydro-2-methy1-6-r4- (p-meth-oxy-phenv! Sulfonamido) -phenyl! -Benzofine , 61naphthyridine
Analog Beispiel 1 erhält man die TitelVerbindung, wenn p-Methoxyphenylsul- fonsäurechlorid eingesetzt wird. Ausbeute: 66 %, Schmp. 210-217°C (als Car- bonathydrat aus Methanol kristallisiert).The title compound is obtained analogously to Example 1 when p-methoxyphenylsulfonic acid chloride is used. Yield: 66%, mp. 210-217 ° C (crystallized as carbonate hydrate from methanol).
Alternativ erhält man die Titelverbindung analog Beispiel 3, wenn rac-cis- -3-(3,4-Dimethoxyphenyl)-l-methyl-4-[(4-p-methoxyphenylsulfonamido)-benz- amido]-piperidin cyclokondensiert wird. Diese Ausgangsverbindung erhält man analog Beispiel 3, wenn 4-(p-Methoxyphenylsulfonamido)-benzoesäurechlorid eingesetzt wird.Alternatively, the title compound is obtained analogously to Example 3 if rac-cis- -3- (3,4-dimethoxyphenyl) -1-methyl-4 - [(4-p-methoxyphenylsulfonamido) benzamido] piperidine is cyclocondensed. This starting compound is obtained Analogously to Example 3, if 4- (p-methoxyphenylsulfonamido) benzoic acid chloride is used.
6. ra-cis-8.9-Dimethoχy-1.2.3,4,4a,10b-hexahydro-2-methv1-6-r4-(p-fluor- phenylsulfonamido)-phenyl1-benzofein,61naphthyridin6. ra-cis-8.9-Dimethoχy-1.2.3,4,4a, 10b-hexahydro-2-methv1-6-r4- (p-fluorophenylsulfonamido) -phenyl1-benzofein, 61naphthyridine
Analog Beispiel 3 erhält man die TitelVerbindung wenn rac-cis-3-(3,4-Di- methoxyphenyl)-l-methyl-4-[(p-fluorphenylsulfonamido)-benzamido]-piperidin eingesetzt wird. Ausbeute: 69 %, Schmp. 163-165βC.Analogously to Example 3, the title compound is obtained when rac-cis-3- (3,4-dimethoxyphenyl) -1-methyl-4 - [(p-fluorophenylsulfonamido) benzamido] piperidine is used. Yield: 69%, mp 163-165 β C.
Die Ausgangsverbindung ist analog Beispiel 3 aus 4-(p-Fluorphenylsulfon- amido)-benzoesäurechlorid erhältlich. Aubeute: 60 %, Schmp. 108-113'C.The starting compound is obtainable analogously to Example 3 from 4- (p-fluorophenylsulfonamido) benzoic acid chloride. Yield: 60%, m.p. 108-113'C.
7. rac-cis-8.9-Dimethoχy-l,2,3,4,4a,10b-hexahydro-2-methy1-6-r4-(p-tolu- olsulfon-N-methylamido)-phenyl!-benzofein,61naphthyridin7. rac-cis-8.9-Dimethoχy-l, 2,3,4,4a, 10b-hexahydro-2-methy1-6-r4- (p-toluenesulfone-N-methylamido) -phenyl! -Benzofein, 61naphthyridine
Analog Beispiel 3 erhält man die TitelVerbindung aus rac-cis-3-(3,4-Dimeth- oxyphenyl)-l-methyl-4-[(p-toluolsulfon-N-methylamido)-benzamido]-piperidin; Ausbeute: 53 %, Schmp. 157-158βC (aus Methanol/Ether).Analogously to Example 3, the title compound is obtained from rac-cis-3- (3,4-dimethoxyphenyl) -1-methyl-4 - [(p-toluenesulfone-N-methylamido) benzamido] piperidine; Yield: 53%, mp. 157-158 β C (from methanol / ether).
Die Ausgangsverbindung ist analog Beispiel 3 aus 4-(p-Toluolsulfon-N-me¬ thylamido)-benzoesäurechlorid erhältlich.The starting compound is obtainable analogously to Example 3 from 4- (p-toluenesulfone-N-methylamido) benzoic acid chloride.
8. rac-cis-8,9-Dimethoχy-l, ,3,4,4a.10b-hexahydro-2-methyl-6-T4-(p-tolu- olsulfon-N-ethylamido)-phenyl!-benzoTelπ,61naphthyridin8. rac-cis-8,9-Dimethoχy-l,, 3,4,4a.10b-hexahydro-2-methyl-6-T4- (p-toluenesulfone-N-ethylamido) -phenyl! -BenzoTelπ, 61naphthyridine
Analog dem vorstehenden Beispiel erhält man die TitelVerbindung, wenn statt der N-methyl- die entsprechenden N-ethyl-Verbindungen eingesetzt werden. Ausbeute: 71 %, Schmp. 160-166T (Carbonat).Analogously to the example above, the title compound is obtained if the corresponding N-ethyl compounds are used instead of the N-methyl compounds. Yield: 71%, mp 160-166T (carbonate).
9. f-)-cis-8.9-Dimethoχy-1.2.3.4.4a,10b-hexahvdro-2-methyl-6-r4-fp-tolu- olsulfonamido)-phenyl1-benzoTelT1,61naphthyridin9. f- ) -cis-8.9-Dimetho χ y-1.2.3.4.4a, 10b-hexahvdro-2-methyl-6-r4-fp-toluenesulfonamido) -phenyl1-benzoTelT1,61naphthyridine
Analog Beispiel 1 wird die TitelVerbindung erhalten, wenn (-)-cis-6-(4-Ami-. nophenyl-8,9-dimethoxy-l,2,3,4,4a,10b-hexahydro-2-methyl-benzo[c][l,6]naph- thyridin CHC13) mit p-Toluolsulfonsäurechlorid umgesetzt wird. Ausbeute 82 %, Schmp. 178-183°C (gelbliche Kristalle aus Essigsäureethylester/Methanol); [α]22 = -81,6°, [α]^^ = -81,1°, (je c=l, Methanol) .Analogously to Example 1, the title compound is obtained when (-) - cis-6- (4-ami-. Nophenyl-8,9-dimethoxy-l, 2,3,4,4a, 10b-hexahydro-2-methyl-benzo [c] [1,6] naphthyridine CHC1 3 ) with p-toluenesulfonic acid chloride is implemented. Yield 82%, mp. 178-183 ° C (yellowish crystals from ethyl acetate / methanol); [α] 22 = -81.6 °, [α] ^^ = -81.1 °, (each c = 1, methanol).
10. (+)-cis-8,9-Dimethoχy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-T4-fp-tolu¬ olsulfonamido)-phenyl1-benzofeif1,61naphthyridin10. (+) - cis-8,9-Dimethoχy-1,2,3,4,4a, 10b-hexahydro-2-methyl-6-T4-fp-toluenesulfonamido) -phenyl1-benzofeif1,61naphthyridine
Die Titelverbindung wird analog Beispiel 9 erhalten, wenn (+)-cis-6-(4-Ami- nophenyl)-8,9-dimethoxy-l,2,3,4,4a,10b-hexahydro-2-methyl-benzo[c][l,6]-The title compound is obtained analogously to Example 9 when (+) - cis-6- (4-aminophenyl) -8,9-dimethoxy-l, 2,3,4,4a, 10b-hexahydro-2-methyl-benzo [c] [1,6] -
22 naphthyridin [αlcyoug = +210° (c=l, CHCl,) eingesetzt wird. Ausbeute:22 naphthyridine [αlcy o u g = + 210 ° (c = 1, CHCl,) is used. Yield:
81 %, Schmp. 180-181°C (gelbliche Kristalle aus Essigsäureethylester/Me¬ thanol); [α]22 = +84,2" (c=l, Methanol).81%, mp. 180-181 ° C (yellowish crystals of ethyl acetate / methanol); [α] 22 = +84.2 "(c = 1, methanol).
Die Ausgangsverbindungen (+)-cis- und (-)-cis-6-(4-Aminophenyl)-8,9-dimeth- oxy-1,2,3,4,4a,10b-hexahydro-2-methyl -benzo[c][1,6]naphthyridin sind bekannt aus EP-A-247 971. The starting compounds (+) - cis- and (-) - cis-6- (4-aminophenyl) -8,9-dimethoxy-1,2,3,4,4a, 10b-hexahydro-2-methyl-benzo [c] [1,6] naphthyridine are known from EP-A-247 971.

Claims

Patentansprüche Claims
1. Verwendung von Verbindungen der Formel I ,1. Use of compounds of the formula I,
worin wherein
Rl 1-4C-Alkyl,Rl 1-4C-alkyl,
R2 Wasserstoff (H), 1-4C-A1ky1 oder l-4C-A1koxy,R2 hydrogen (H), 1-4C-A1ky1 or l-4C-A1koxy,
R3 Wasserstoff (H), 1-4C-Al yl oder l-4C-Alkoxy,R3 is hydrogen (H), 1-4C-al yl or 1-4C-alkoxy,
R4 Wasserstoff (H), Methyl oder Methoxy,R4 is hydrogen (H), methyl or methoxy,
R5 Wasserstoff (H) oder 1-4C-Alkyl undR5 is hydrogen (H) or 1-4C-alkyl and
R6 1-4C-Alkyl, Phenyl oder substituiertes Phenyl mit einem oder zwei gleichen oder verschiedenen Substituenten aus der Gruppe 1-4C-Alkyl, l-4C-Al oxy, Hydroxy und Halogen bedeutet, und ihren pharmakologisch verträglichen Salzen zur Herstellung von Arznei mitteln für die Behandlung von Dermatosen.R6 means 1-4C-alkyl, phenyl or substituted phenyl with one or two identical or different substituents from the group 1-4C-alkyl, 1-4C-Al oxy, hydroxy and halogen, and their pharmacologically acceptable salts for the preparation of medicaments for the treatment of dermatoses.
2. Verwendung gemäß Anspruch 1 von Verbindungen der Formel I nach Anspruch2. Use according to claim 1 of compounds of formula I according to claim
1, in denen1 in which
Rl 1-4C-Al yl,Rl 1-4C-Al yl,
R2 l-4C-Alkoxy,R2 1-4C alkoxy,
R3 l-4C-Alkoxy,R3 1-4C-alkoxy,
R4 Wasserstoff oder Methyl,R4 is hydrogen or methyl,
R5 Wasserstoff oder 1-4C-Al yl, R6 1-4C-Alky1, Phenyl oder substituiertes Phenyl mit einem Substituenten aus der Gruppe 1-4C-A1kyl , l-4C-Alkoxy und Halogen bedeutet, und ihren pharmakologisch verträglichen Salzen.R5 is hydrogen or 1-4C-Al yl, R6 denotes 1-4C-alkyl, phenyl or substituted phenyl with a substituent from the group 1-4C-alkyl, 1-4C-alkoxy and halogen, and their pharmacologically acceptable salts.
3. Verwendung gemäß Anspruch 1 von Verbindungen der Formel I nach Anspruch 1, in denen3. Use according to claim 1 of compounds of formula I according to claim 1, in which
Rl Methyl ,Rl methyl,
R2 Methoxy,R2 methoxy,
R3 Methoxy undR3 methoxy and
R4 Wasserstoff oder Methyl bedeutet, der Rest -N(R5)S02R6 in 4-Position an dem in 6-Stellung am Benzo-naphthyri- dinring gebundenen Phenylrest steht, R5 Wasserstoff, Methyl oder Ethyl undR4 is hydrogen or methyl, the radical -N (R5) S0 2 R6 is in the 4-position on the phenyl radical bonded in the 6-position on the benzo-naphthyridine ring, R5 is hydrogen, methyl or ethyl and
R6 Methyl, 4-Methylphenyl , 4-Methoxyphenyl oder 4-Fluorphenyl bedeutet, und ihren pharmakologisch verträglichen Salzen.R6 is methyl, 4-methylphenyl, 4-methoxyphenyl or 4-fluorophenyl, and their pharmacologically acceptable salts.
4. Verwendung gemäß Anspruch 1 der Verbindung (-)-cis-8,9-Dimethoxy-l,2,3,- 4,4a,10b-hexahydro-2-methyl-6-[4-(p-toluolsulfonamido)-phenyl]-benzo[c]- [l,6]naphthyridin und ihrer pharmakologisch verträglichen Salze.4. Use according to claim 1 of the compound (-) - cis-8,9-dimethoxy-l, 2,3, - 4,4a, 10b-hexahydro-2-methyl-6- [4- (p-toluenesulfonamido) - phenyl] -benzo [c] - [1,6] naphthyridine and their pharmacologically acceptable salts.
5. Verwendung von Verbindungen der Formel I und ihren pharmakologisch ver¬ träglichen Salzen zur Behandlung von Dermatosen bei Säugern, insbesondere Menschen.5. Use of compounds of the formula I and their pharmacologically tolerable salts for the treatment of dermatoses in mammals, in particular humans.
6. Verwendung gemäß Anspruch 1 von Verbindungen der Formel I und ihren pharmakologisch verträglichen Salzen, dadurch gekennzeichnet, daß es sich bei den zu behandelnden Dermatosen um pro! iferative, entzündliche oder al¬ lergische Hauterkrankungen handelt.6. Use according to claim 1 of compounds of formula I and their pharmacologically tolerable salts, characterized in that the dermatoses to be treated are pro! iferative, inflammatory or allergic skin diseases.
7. Verwendung gemäß Anspruch 1 von Verbindungen der Formel I und ihren pharmakologisch verträglichen Salzen, dadurch gekennzeichnet, daß es sich bei den zu behandelnden Dermatosen um Psoriasis oder atopische Der atitis handelt. 7. Use according to claim 1 of compounds of formula I and their pharmacologically tolerable salts, characterized in that the dermatoses to be treated are psoriasis or atopic deritis.
EP92923587A 1991-11-15 1992-11-11 Use of sulphonyl compounds Withdrawn EP0612247A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH33344/91 1991-11-15
CH334491 1991-11-15
PCT/EP1992/002583 WO1993009780A1 (en) 1991-11-15 1992-11-11 Use of sulphonyl compounds

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Publication number Priority date Publication date Assignee Title
EP0988302B1 (en) 1997-06-03 2003-02-19 ALTANA Pharma AG Benzonaphthyridines
KR20050010018A (en) 2002-05-31 2005-01-26 다케다 야쿠힌 고교 가부시키가이샤 Piperidine derivative, process for producing the same, and use
JP2004285038A (en) * 2002-05-31 2004-10-14 Takeda Chem Ind Ltd Piperidine derivative, its production method and application
US7932252B2 (en) 2004-05-12 2011-04-26 Chemocentryx, Inc. Aryl sulfonamides
AU2007272972B2 (en) 2006-07-14 2011-12-01 Chemocentryx, Inc. Triazolyl pyridyl benzenesulfonamides as CCR2 or CCR9 modulators for the treatment of atherosclerosis
US7718683B2 (en) 2006-07-14 2010-05-18 Chemocentryx, Inc. Triazolyl phenyl benzenesulfonamides
US7776877B2 (en) 2007-06-22 2010-08-17 Chemocentryx, Inc. N-(2-(hetaryl)aryl) arylsulfonamides and N-(2-(hetaryl) hetaryl arylsulfonamides

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US3899494A (en) * 1970-05-13 1975-08-12 Sandoz Ltd Substituted 6-phenyl benzo-naphthyridines
EP0247971A3 (en) * 1986-05-29 1990-01-17 Sandoz Ag Novel pharmaceutical compositions comprising and use of cis-6-(4-acetanilido)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridin
MY105344A (en) * 1990-05-16 1994-09-30 Byk Gulden Lomberg Chemische Fabrik New sulphonyl compounds

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