EP0777481A1 - Use of n-substituted phenothiazines - Google Patents

Use of n-substituted phenothiazines

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Publication number
EP0777481A1
EP0777481A1 EP95929864A EP95929864A EP0777481A1 EP 0777481 A1 EP0777481 A1 EP 0777481A1 EP 95929864 A EP95929864 A EP 95929864A EP 95929864 A EP95929864 A EP 95929864A EP 0777481 A1 EP0777481 A1 EP 0777481A1
Authority
EP
European Patent Office
Prior art keywords
phenothiazine
carbon atoms
straight
chain
substituted
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.)
Ceased
Application number
EP95929864A
Other languages
German (de)
French (fr)
Inventor
Klaus Urbahns
Hans-Georg Heine
Bodo Junge
Rudolf Schohe-Loop
Henning Sommermeyer
Thomas Glaser
Reilinde Wittka
Jean-Marie-Viktor De Vry
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Bayer AG
Original Assignee
Bayer AG
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Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP0777481A1 publication Critical patent/EP0777481A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, ***e
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
    • C07D279/26—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom without other substituents attached to the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
    • C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/30—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with acyl radicals attached to the ring nitrogen atom

Definitions

  • the present invention relates to the use of N-substituted phenothiazines for the production of medicaments, new active ingredients, a process for their preparation, in particular the use as a cerebrally active agent.
  • R 1 represents a radical of the formula - (CH 2 ) a -CO-R 6 , - (CH 2 ) a -CO-NR 7 R 8 or - (CH 2 ) b -R 9 ,
  • a represents a number 0, 1 or 2
  • R 6 denotes hydrogen or straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms, the latter being able to be substituted by halogen or hydroxy,
  • R 7 is hydrogen or straight-chain or branched alkyl with up to 6
  • R 8 is hydrogen, cycloalkyl with 3 to 6 carbon atoms, pyridyl, phenyl, amino or straight-chain or branched alkyl with up to
  • R 7 and R 8 together with the nitrogen atom form a piperidine, morpholine, azacycloheptyl or pyrrolidinyl ring,
  • R 9 denotes cyano or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms
  • R 2 , R 3 , R 4 and R 5 are identical or different and represent hydrogen, halogen or trifluoromethyl
  • Physiologically acceptable salts are generally salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are preferred, or salts with organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid. acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are preferred, or salts with organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid. acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanes
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or which do not behave like image and mirror image (diastereomers).
  • the invention relates to both the antipodes and the racemic forms as well as the diastereomer mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • R 1 represents a radical of the formula - (CH 2 ) a -CO-R 6 , - (CH 2 ) a -CO-NR 7 R 8 or - (CH 2 ) b -R 9 ,
  • a represents a number 0, 1 or 2
  • b represents a number 1 or 2
  • R 6 denotes hydrogen or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms, the latter being able to be substituted by fluorine, chlorine or hydroxy,
  • R 7 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by chlorine,
  • R 8 is hydrogen, pyridyl, phenyl, amino, cyclopropyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl with up to 4 Means carbon atoms which is optionally substituted by hydroxy or pyridyl,
  • R 7 and R 8 together with the nitrogen atom form a piperidine, morpholine, azacycloheptyl or pyrrolidinyl ring,
  • R 9 denotes cyano or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms
  • R 2 and R 5 are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl
  • R 3 and R 4 represent hydrogen
  • R 1 represents a radical of the formula - (CH 2 ) a -CO-R 6 , - (CH 2 ) a -CO-NR 7 R 8 or - (CH 2 ) b -R 9 ,
  • a represents a number 0, 1 or 2
  • R 6 denotes hydrogen or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms, the latter being able to be substituted by fluorine, chlorine or hydroxy,
  • R 7 is hydrogen or straight-chain or branched alkyl with up to 4
  • R 8 is hydrogen, pyridyl, phenyl, amino, cyclopropyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl with up to 4
  • R 7 and R 8 together with the nitrogen atom form a piperidine, morpholine, azacycloheptyl or pyrrolidinyl ring,
  • R 9 denotes cyano or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms
  • R 2 and R 5 are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl
  • R 3 and R 4 represent hydrogen
  • BK (Ca) channels calcium-dependent potassium channels of high conductivity channels
  • MID multi-infarct dementia
  • PDD primarily degenerative dementia
  • senile dementia of the type of Alzheimer's disease
  • HIV dementia HIV dementia
  • Dementia forms are also suitable for the treatment of Parkinson's disease or amyotrophic lateral sclerosis and multiple sclerosis.
  • the active ingredients are also suitable for the treatment of brain performance disorders in old age, organic brain psychosyndrome (HOPS, Organic Brain Syndrome, OBS) and age-related memory disorders (AAMI).
  • HOPS organic brain psychosyndrome
  • OBS Organic Brain Syndrome
  • AAMI age-related memory disorders
  • the active compounds are also suitable for treating disorders of the immune system, in particular T lymphocyte proliferation and for influencing smooth muscles, in particular the uterus, urinary bladder and bronchial tract and for treating related diseases such as e.g. Asthma and urinary incontinence and used to treat hypertension, arrhythmia, angina and diabetes.
  • the invention also relates to new compounds of the general formula (Ia) and their salts
  • E represents a typical leaving group, such as chlorine or iodine, preferably chlorine,
  • R 7 and R 8 have the specified scope
  • solvents which do not change under the reaction conditions are suitable as solvents.
  • solvents preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether, acetonitrile, or amides such as hexamethylphosphoric triamide or dimethylformamide, or halogenated hydrocarbons such as methylene chloride or hydrocarbons such as benzene Toluene. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is particularly preferred.
  • Suitable bases are generally alkali metal hydrides or alcoholates, such as sodium hydride or potassium tert-butoxide, or cyclic amines such as piperidine, dimethylaminopyridine or C j -C 4 alkylamines, such as triethylamine. Triethylamine and sodium hydride are preferred depending on the respective reaction steps.
  • the ratio of the substances involved in the reaction is arbitrary. In general, however, one works with molar amounts of the reactants.
  • the reaction temperatures can be varied over a wide range. In general, between -10 ° C and + 150 ° C, preferably between 0 ° C and + 100 ° C, especially at the boiling point of the solvent.
  • the reactions can be carried out at normal pressure, but also at elevated or reduced pressure (for example 0.5 to 3 bar). Generally one works at normal pressure.
  • reaction under an inert gas atmosphere is appropriate.
  • customary reagents such as inorganic halides, for example thionyl chloride, phosphorus trichloride or phosphorus pentachloride, or carbonyldiimidazole, carbodiimides such as cyclohexylcarbodiimide or 1-cyclohexyl-3- [2- (N-methylmo holino) ethyl] carbodiimide are suitable for activating the carboxylic acid -p- toluenesulfonate or N-hydroxyphthalimide or N-hydroxy-benzotriazole.
  • inorganic halides for example thionyl chloride, phosphorus trichloride or phosphorus pentachloride, or carbonyldiimidazole
  • carbodiimides such as cyclohexylcarbodiimide or 1-cyclohexyl-3- [2- (N-methylmo holino) ethyl] carbodiimide are suitable for activ
  • the enantiomerically pure compounds can also be obtained by chromatography of the racemic esters on chiral phases.
  • phenothiazine-10-carboxylic acid chlorides of the general formula (Ia) are known or new and can then be prepared, for example, as described above by reacting phenothiazine with the corresponding acid chlorides.
  • Nomenclature names phenothiazine-10-carboxylic acid-NN-di-n-propyla ⁇ id are known (US 4,833,138); Nomiglaturname 3- (Phenothiazin-10-yl) methyl propynate
  • Rats C6-BU1 glioma cells are used for this.
  • the present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds of the general formulas (I) / (Ia) / (Ib) or which consist of one or more active ingredients , such as
  • the active substances should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture.
  • the pharmaceutical preparations can also contain other pharmaceutical active ingredients.
  • the pharmaceutical preparations listed above can be prepared in a conventional manner by known methods, for example using the auxiliary agent or excipients.
  • the active ingredient (s) in total amounts of about 0.01 to about 100 mg / kg, preferably in total amounts of about 1 mg / kg to 50 mg kg body weight per 24 hours, optionally in the form of several individual doses to deliver the desired result.
  • the active ingredient (s) may be advantageous to deviate from the amounts mentioned, depending on the type and body weight of the object being treated, on the individual behavior towards the medication, the type and severity of the disease, the type of preparation and application, and the Time or interval at which the administration takes place.

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  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Otolaryngology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

The invention concerns the use of N-substituted phenothiazines for producing drugs for treating cerebral disorders. The invention also concerns novel active substances prepared by reacting phenothiazine with the appropriate acids, esters or amides or by reacting phenothiazine carboxylic acid halides with amines. The active substances are in particular suitable for treating dementia, depression and learning and memory disorders caused by old age.

Description

Verwendung von N-substituierten PhenothiazinenUse of N-substituted phenothiazines
Die vorliegende Erfindung betrifft die Verwendung von N-substituierten Phenothiazinen zur Herstellung von Arzneimitteln, neue Wirkstoffe, ein Verfahren zu deren Herstellung, insbesondere die Verwendung als cerebral wirksame Mittel.The present invention relates to the use of N-substituted phenothiazines for the production of medicaments, new active ingredients, a process for their preparation, in particular the use as a cerebrally active agent.
Es ist bereits bekannt, daß 10-Carboxamidsubstituierte Phenothiazine eine Antitumor Wirkung besitzen [vgl. JP 561 66 183 A2 , 1981]. Außerdem werden in der Publikation US 4 833 138 Phenothiazinderivate zur Behandlung von neurotoxischen Erkrankungen beschrieben. Weiterhin werden in der Publikation [Arch. Int. Pharmacodyn. Ther. 173 (1), 44 - 55, (1968)] Effekte einiger Phenothiazine in dem intrapleural fluid Test aufgeführt.It is already known that 10-carboxamide-substituted phenothiazines have an anti-tumor effect [cf. JP 561 66 183 A2, 1981]. The publication US Pat. No. 4,833,138 also describes phenothiazine derivatives for the treatment of neurotoxic diseases. Furthermore, in the publication [Arch. Int. Pharmacodyn. Ther. 173 (1), 44-55, (1968)] Effects of some phenothiazines listed in the intrapleural fluid test.
Es wurde nun gefunden, daß N-substituierte Phenothiazine der allgemeinen Formel (I).It has now been found that N-substituted phenothiazines of the general formula (I).
in welcher in which
R1 für einen Rest der Formel -(CH2)a-CO-R6, -(CH2)a-CO-NR7R8 oder -(CH2)b-R9 steht,R 1 represents a radical of the formula - (CH 2 ) a -CO-R 6 , - (CH 2 ) a -CO-NR 7 R 8 or - (CH 2 ) b -R 9 ,
woπnwoπn
a eine Zahl 0, 1 oder 2 bedeutet,a represents a number 0, 1 or 2,
b eine Zahl 1 oder 2 bedeutet, R6 Wasserstoff oder geradkettiges oder verzweigtes Alkoxy oder Alkyl mit jeweils bis zu 6 Kohlenstoffatomen bedeutet, wobei letzteres durch Halogen oder Hydroxy substituiert sein kann,b represents a number 1 or 2, R 6 denotes hydrogen or straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms, the latter being able to be substituted by halogen or hydroxy,
R7 Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 6R 7 is hydrogen or straight-chain or branched alkyl with up to 6
Kohlenstoffatomen bedeutet, das gegebenenfalls durch Halogen substituiert ist,Means carbon atoms which is optionally substituted by halogen,
R8 Wasserstoff, Cycloalkyl mit 3 bis 6 Kohlenstoffatomen, Pyridyl, Phenyl, Amino oder geradkettiges oder verzweigtes Alkyl mit bis zuR 8 is hydrogen, cycloalkyl with 3 to 6 carbon atoms, pyridyl, phenyl, amino or straight-chain or branched alkyl with up to
6 Kohlenstoffatomen bedeutet, das gegebenenfalls durch Hydroxy oder Pyridyl substituiert ist,6 carbon atoms, which is optionally substituted by hydroxy or pyridyl,
oderor
R7 und R8 gemeinsam mit dem Stickstoffatom einen Piperidin-, Morpholin-, Azacycloheptyl- oder Pyrrolidinylring bilden,R 7 and R 8 together with the nitrogen atom form a piperidine, morpholine, azacycloheptyl or pyrrolidinyl ring,
R9 Cyano oder geradkettiges oder verzweigtes Alkoxycarbonyl mit bis zu 6 Kohlenstoffatomen bedeutet,R 9 denotes cyano or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms,
R2, R3, R4 und R5 gleich oder verschieden sind und für Wasserstoff, Halogen oder Trifluormethyl stehen,R 2 , R 3 , R 4 and R 5 are identical or different and represent hydrogen, halogen or trifluoromethyl,
und deren Salze überraschenderweise eine modulierende Wirkung auf Kalium¬ kanäle besitzen vmd somit geeignet sind zur Verwendung bei der Bekämpfung von Erkrankungen des Zentralen Nerven Systems (ZNS) und der S i chel ze l l en - anämi e .and their salts surprisingly have a modulating effect on potassium channels and are therefore suitable for use in combating diseases of the central nervous system (CNS) and of the sick cell anemia.
Im Rahmen der Erfindung sind physiologisch unbedenkliche Salze bevorzugt.Physiologically acceptable salts are preferred in the context of the invention.
Physiologisch unbedenkliche Salze sind im allgemeinen Salze der erfindungs¬ gemäßen Verbindungen mit anorganischen oder organischen Säuren. Bevorzugt werden Salze mit anorganischen Säuren wie beispielsweise Salzsäure, Brom¬ wasserstoffsäure, Phosphorsäure oder Schwefelsäure, oder Salze mit organischen Carbon- oder Sulfonsäuren wie beispielsweise Essigsäure, Maleinsäure, Fumar- säure, Äpfelsäure, Zitronensäure, Weinsäure, Milchsäure, Benzoesäure, oder Methansulfonsäure, Ethansulfonsäure, Phenylsulfonsäure, Toluolsulfonsäure oder Naphthalindisulfonsäure.Physiologically acceptable salts are generally salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are preferred, or salts with organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid. acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
Die erfindungsgemäßen Verbindungen können in stereoisomeren Formen existie¬ ren, die sich entweder wie Bild und Spiegelbild (Enantiomere), oder die sich nicht wie Bild und Spiegelbild (Diastereomere) verhalten. Die Erfindung betrifft sowohl die Antipoden als auch die Racemformen sowie die Diastereomerengemische. Die Racemformen lassen sich ebenso wie die Diastereomeren in bekannter Weise in die stereoisomer einheitlichen Bestandteile trennen.The compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or which do not behave like image and mirror image (diastereomers). The invention relates to both the antipodes and the racemic forms as well as the diastereomer mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
Bevorzugt sind Verbindungen der allgemeinen Formel (I),Compounds of the general formula (I) are preferred
in welcherin which
R1 für einen Rest der Formel -(CH2)a-CO-R6, -(CH2)a-CO-NR7R8 oder -(CH2)b-R9 steht,R 1 represents a radical of the formula - (CH 2 ) a -CO-R 6 , - (CH 2 ) a -CO-NR 7 R 8 or - (CH 2 ) b -R 9 ,
worinwherein
a eine Zahl 0, 1 oder 2 bedeutet,a represents a number 0, 1 or 2,
b eine Zahl 1 oder 2 bedeutet,b represents a number 1 or 2,
R6 Wasserstoff oder geradkettiges oder verzweigtes Alkoxy oder Alkyl mit jeweils bis zu.4 Kohlenstoffatomen bedeutet, wobei letzteres durch Fluor, Chlor oder Hydroxy substituiert sein kann,R 6 denotes hydrogen or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms, the latter being able to be substituted by fluorine, chlorine or hydroxy,
R7 Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoffatomen bedeutet, das gegebenenfalls durch Chlor substituiert ist,R 7 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by chlorine,
R8 Wasserstoff, Pyridyl, Phenyl, Amino, Cyclopropyl, Cyclopentyl, Cyclohexyl oder geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoffatomen bedeutet, das gegebenenfalls durch Hydroxy oder Pyridyl substituiert ist,R 8 is hydrogen, pyridyl, phenyl, amino, cyclopropyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl with up to 4 Means carbon atoms which is optionally substituted by hydroxy or pyridyl,
oderor
R7 und R8 gemeinsam mit dem Stickstoffatom einen Piperidin-, Morpholin-, Azacycloheptyl- oder Pyrrolidinylring bilden,R 7 and R 8 together with the nitrogen atom form a piperidine, morpholine, azacycloheptyl or pyrrolidinyl ring,
R9 Cyano oder geradkettiges oder verzweigtes Alkoxycarbonyl mit bis zu 4 Kohlenstoffatomen bedeutet,R 9 denotes cyano or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms,
R2 und R5 gleich oder verschieden sind und für Wasserstoff, Fluor, Chlor, Brom oder Trifluormethyl stehen,R 2 and R 5 are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,
R3 und R4 für Wasserstoff stehen,R 3 and R 4 represent hydrogen,
und deren Salze,and their salts,
bei der Bekämpfung von Erkrankungen des ZNS.in combating diseases of the CNS.
Besonders bevorzugt sind Verbindungen der allgemeinen Formel (I),Compounds of the general formula (I) are particularly preferred
in welcherin which
R1 für einen Rest der Formel -(CH2)a-CO-R6, -(CH2)a-CO-NR7R8 oder -(CH2)b-R9 steht,R 1 represents a radical of the formula - (CH 2 ) a -CO-R 6 , - (CH 2 ) a -CO-NR 7 R 8 or - (CH 2 ) b -R 9 ,
worinwherein
a eine Zahl 0, 1 oder 2 bedeutet,a represents a number 0, 1 or 2,
b eine Zahl 1 oder 2 bedeutet, R6 Wasserstoff oder geradkettiges oder verzweigtes Alkoxy oder Alkyl mit jeweils bis zu 4 Kohlenstoffatomen bedeutet, wobei letzteres durch Fluor, Chlor oder Hydroxy substituiert sein kann,b represents a number 1 or 2, R 6 denotes hydrogen or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms, the latter being able to be substituted by fluorine, chlorine or hydroxy,
R7 Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 4R 7 is hydrogen or straight-chain or branched alkyl with up to 4
Kohlenstoffatomen bedeutet, das gegebenenfalls durch Chlor substituiert ist,Means carbon atoms which is optionally substituted by chlorine,
R8 Wasserstoff, Pyridyl, Phenyl, Amino, Cyclopropyl, Cyclopentyl, Cyclohexyl oder geradkettiges oder verzweigtes Alkyl mit bis zu 4R 8 is hydrogen, pyridyl, phenyl, amino, cyclopropyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl with up to 4
Kohlenstoffatomen bedeutet, das gegebenenfalls durch Hydroxy oder Pyridyl substituiert ist,Means carbon atoms which is optionally substituted by hydroxy or pyridyl,
oderor
R7 und R8 gemeinsam mit dem Stickstoffatom einen Piperidin-, Morpholin-, Azacycloheptyl- oder Pyrrolidinylring bilden,R 7 and R 8 together with the nitrogen atom form a piperidine, morpholine, azacycloheptyl or pyrrolidinyl ring,
R9 Cyano oder geradkettiges oder verzweigtes Alkoxycarbonyl mit bis zu 4 Kohienstoffatomen bedeutet,R 9 denotes cyano or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms,
R2 und R5 gleich oder verschieden sind und für Wasserstoff, Fluor, Chlor, Brom oder Trifluormethyl stehen,R 2 and R 5 are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,
R3und R4 für Wasserstoff stehen,R 3 and R 4 represent hydrogen,
und deren Salze,and their salts,
bei der Bekämpfung von Erkrankungen des ZNS.in combating diseases of the CNS.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) zeigen ein nicht vorhersehbares, wertvolles pharmakologisches Wirkspektrum.The compounds of general formula (I) according to the invention show an unforeseeable, valuable pharmacological spectrum of action.
Sie sind Kanalmodulatoren mit Selektivität für Calciumabhängige Kalium-Kanäle großer Leitfähigkeit (BK(Ca)-Kanäle), insbesondere des zentralen Nervensystems. Aufgrund ihrer pharmakologischen Eigenschaften können sie für die Herstellung von Arzneimitteln zur Behandlung von zentral degenerativen Erkrankungen eingesetzt werden, wie zum Beispiel bei Auftreten von Demenzen wie Multiinfarktdemenz (MID), primär degenerativer Demenz (PDD), präseniler und seniler Demenz vom Typ der Alzheimerschen Krankheit, HIV-Demenz und andereThey are channel modulators with selectivity for calcium-dependent potassium channels of high conductivity (BK (Ca) channels), especially of the central nervous system. Due to their pharmacological properties, they can be used in the manufacture of medicinal products for the treatment of central degenerative diseases, such as, for example, when dementias such as multi-infarct dementia (MID), primarily degenerative dementia (PDD), presence and senile dementia of the type of Alzheimer's disease, HIV dementia and others
Demenzformen. Ferner sind sie geeignet zur Behandlung von Parkinsonscher Krankheit oder amyotrophischer Lateralsklerose sowie multipler Sklerose.Dementia forms. They are also suitable for the treatment of Parkinson's disease or amyotrophic lateral sclerosis and multiple sclerosis.
Weiterhin eignen sich die Wirkstoffe zur Behandlung von Hirnleistungsstörungen im Alter, des hirnorganischen Psychosyndroms (HOPS, Organic Brain Syndrom, OBS) und von altersbedingten Gedächtnisstörungen (age associated memory impairment, AAMI).The active ingredients are also suitable for the treatment of brain performance disorders in old age, organic brain psychosyndrome (HOPS, Organic Brain Syndrome, OBS) and age-related memory disorders (AAMI).
Sie sind geeignet zur Prophylaxe, zur Behandlung und zur Bekämpfung der Folgen cerebraler Durchblutungsstörungen wie cerebraler Ischämien, Schlaganfallen,They are suitable for prophylaxis, treatment and combating the consequences of cerebral circulatory disorders such as cerebral ischemia, strokes,
Schädel-Hirn-Traumata und von Subarachnoidalblutungen.Traumatic brain injury and subarachnoid hemorrhage.
Sie sind wertvoll zur Behandlung von Depressionen und Psychosen, z.B. Schizophrenie. Außerdem eignen sie sich zur Behandlung von Störungen der neuroendokrinen Sekretion sowie der Neurotransmittersekretion und damit zu¬ sammenhängenden gesundheitlichen Störungen wie Manie, Alkoholismus, Drogen¬ mißbrauch, Sucht oder krankhaftem Eßverhalten. Weitere Anwendungsgebiete sind die Behandlung von Migräne, Schlafstörungen und von Neuropathien. Darüber hinaus sind sie als Schmerzmittel geeignet.They are valuable for the treatment of depression and psychoses, e.g. Schizophrenia. They are also suitable for the treatment of disorders of neuroendocrine secretion and of neurotransmitter secretion and related health disorders such as mania, alcoholism, drug abuse, addiction or pathological eating behavior. Other areas of application are the treatment of migraines, sleep disorders and neuropathies. They are also suitable as pain relievers.
Die Wirkstoffe sind ferner geeignet zur Behandlung von Störungen des Immun¬ systems, insbesondere der T-Lymphocyten-Proliferation und zur Beeinflussung der glatten Muskulatur, insbesondere von Uterus, Harnblase und Bronchialtrakt und zur Behandlung damit zusammenhängender Krankheiten wie z.B. Asthma und urinärer Inkontinenz und zur Behandlung von Bluthochdruck, Arrhythmie, Angina und Diabetes.The active compounds are also suitable for treating disorders of the immune system, in particular T lymphocyte proliferation and for influencing smooth muscles, in particular the uterus, urinary bladder and bronchial tract and for treating related diseases such as e.g. Asthma and urinary incontinence and used to treat hypertension, arrhythmia, angina and diabetes.
Die Erfindung betrifft außerdem neue Verbindungen der allgemeinen Formel (Ia) und deren SalzeThe invention also relates to new compounds of the general formula (Ia) and their salts
mit den in der folgenden Tabelle angegebenen Substituentenbedeutungen:with the substituent meanings given in the following table:
R1 R2 R 1 R 2
-CO-N(CH3)-C6H5 H-CO-N (CH 3 ) -C 6 H 5 H
-CO-(CH2)3-Cl Cl-CO- (CH 2 ) 3 -Cl Cl
-CO-(CH2)3-Cl H-CO- (CH 2 ) 3 -Cl H
-CO-N((CH2)3CH3)2 H-CO-N ((CH 2 ) 3 CH 3 ) 2 H
-CO-N(CH3)-C6Hπ H-CO-N (CH 3 ) -C 6 H π H
-(CH2)2-CO-NH-C2H5 Cl- (CH 2 ) 2 -CO-NH-C 2 H 5 Cl
-(CH2)2-CO-NH(CH2)3-CH3 Cl- (CH 2 ) 2 -CO-NH (CH 2 ) 3 -CH 3 Cl
-(CH2)2-CO-NH-(CH2)3-CH3 H- (CH 2 ) 2 -CO-NH- (CH 2 ) 3 -CH 3 H
-(CH2)2-CO-NH-(CH2)2CH3 H- (CH 2 ) 2 -CO-NH- (CH 2 ) 2 CH 3 H
-(CH2)-CO-N(CH2CH3)2 H- (CH 2 ) -CO-N (CH 2 CH 3 ) 2 H
R1 R2 R 1 R 2
HH
-CO-N-CO-N
-CH2-CO-NH-(CH2)3CH3 H-CH 2 -CO-NH- (CH 2 ) 3 CH 3 H
-CH2-CO-NH-(CH2)2CH3 H -CH2-CO-NH-C2H5 H-CH 2 -CO-NH- (CH 2 ) 2 CH 3 H -CH 2 -CO-NH-C 2 H 5 H
-CH2-CO-NH((CH2)2CH3)2 H-CH 2 -CO-NH ((CH 2 ) 2 CH 3 ) 2 H
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) werden herge¬ stellt, indem manThe compounds of general formula (I) according to the invention are prepared by:
entweder direkt Phenothiazin mit den entsprechenden Säuren, Estern oder Amiden der allgemeinen Formel (II)either directly phenothiazine with the corresponding acids, esters or amides of the general formula (II)
E-R1 (H.)ER 1 (H.)
in welcherin which
E für eine typische Abgangsgruppe, wie beispielsweise Chlor oder Iod, bevorzugt für Chlor steht,E represents a typical leaving group, such as chlorine or iodine, preferably chlorine,
in inerten Lösemitteln und in Anwesenheit einer Base, gegebenenfalls unter Schutzgasatmosphäre umsetztin inert solvents and in the presence of a base, if appropriate under an inert gas atmosphere
oder im Falle der Amide -(CH2)a-CO-NR7R8 ausgehend von den entsprechenden Säurechloriden der allgemeinen Formel (Ib)or in the case of the amides - (CH 2 ) a -CO-NR 7 R 8 starting from the corresponding acid chlorides of the general formula (Ib)
in welcher CO-CI in which CO-CI
R bis R und a die angegebene Bedeutung haben,R to R and a have the meaning given,
mit Aminen der allgemeinen Formel (HI)with amines of the general formula (HI)
H-NR7R8 (HI)H-NR 7 R 8 (HI)
in welcherin which
R7 und R8 den angegebenen Bedeutungsumfang haben,R 7 and R 8 have the specified scope,
in inerten Lösemitteln, gegebenenfalls in Anwesenheit einer weiteren Base und gegebenenfalls unter Schutzgasatmosphäre umsetzt.in inert solvents, if appropriate in the presence of a further base and if appropriate under a protective gas atmosphere.
Das erfindungsgemäße Verfahren kann durch folgendes Formelschema beispielhaft erläutert werden: The process according to the invention can be illustrated by the following formula scheme:
Als Lösemittel eignen sich hierbei alle inerten organischen Lösemittel, die sich unter den Reaktionsbedingungen nicht verändern. Hierzu gehören bevorzugt Alkohole wie Methanol, Ethanol, Propanol oder Isopropanol, oder Ether wie Diethylether, Dioxan, Tetrahydrofüran, Glykoldimethylether, oder Diethylenglykol- dimethylether, Acetonitril, oder Amide wie Hexamethylphosphorsäuretriamid oder Dimethylformamid, oder halogenierte Kohlenwasserstoffe wie Methylenchlorid, Tetrachlorkohlenstoff oder Kohlenwasserstoffe wie Benzol oder Toluol. Ebenso ist es möglich, Gemische der genannten Lösemittel zu verwenden. Besonders bevorzugt ist Dimethylformamid.All inert organic solvents which do not change under the reaction conditions are suitable as solvents. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether, acetonitrile, or amides such as hexamethylphosphoric triamide or dimethylformamide, or halogenated hydrocarbons such as methylene chloride or hydrocarbons such as benzene Toluene. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is particularly preferred.
Als Basen eignen sich im allgemeinen Alkalihydride oder -alkoholate, wie beispielsweise Natriumhydrid oder Kalium-tert.butylat, oder cyclische Amine, wie beispielsweise Piperidin, Dimethylaminopyridin oder Cj-C4-Alkylamine, wie beispielsweise Triethylamin. Bevorzugt sind in Abhängigkeit der jeweiligen Reaktionsschritte Triethylamin und Natriumhydrid.Suitable bases are generally alkali metal hydrides or alcoholates, such as sodium hydride or potassium tert-butoxide, or cyclic amines such as piperidine, dimethylaminopyridine or C j -C 4 alkylamines, such as triethylamine. Triethylamine and sodium hydride are preferred depending on the respective reaction steps.
Bei der Durchführung der erfindungsgemäßen Verfahren ist das Verhältnis der an der Reaktion beteiligten Stoffe beliebig. Im allgemeinen arbeitet man jedoch bei molaren Mengen der Reaktanden.When carrying out the process according to the invention, the ratio of the substances involved in the reaction is arbitrary. In general, however, one works with molar amounts of the reactants.
Die Reaktionstemperaturen können in einem größeren Bereich variiert werden. Im allgemeinen arbeitet man zwischen -10°C und +150°C, vorzugsweise zwischen 0°C und +100°C, insbesondere bei der Siedetemperatur des jeweiligen Lösemittels. Die Umsetzungen können bei Normaldruck, aber auch bei erhöhtem oder ernie¬ drigtem Druck (z.B. 0,5 bis 3 bar) durchgeführt werden. Im allgemeinen arbeitet man bei Normaldruck.The reaction temperatures can be varied over a wide range. In general, between -10 ° C and + 150 ° C, preferably between 0 ° C and + 100 ° C, especially at the boiling point of the solvent. The reactions can be carried out at normal pressure, but also at elevated or reduced pressure (for example 0.5 to 3 bar). Generally one works at normal pressure.
Für einige Reaktionsschritte ist die Umsetzung unter Schutzgasatmosphäre angebracht.For some reaction steps, the reaction under an inert gas atmosphere is appropriate.
Zur Aktivierung der Carbonsäure eignen sich die üblichen Reagenzien wie an¬ organische Halogenide, beispielsweise Thionylchlorid, Phosphortrichlorid oder Phosphorpentachlorid, oder Carbonyldiimidazol, Carbodiimide wie Cyclohexyl- carbodiimid oder 1 -Cyclohexyl-3-[2-(N-methylmo holino)ethyl]-carbodiimid-p- toluolsulfonat oder N-Hydroxyphthalimid oder N-Hydroxy-benztriazol.The customary reagents such as inorganic halides, for example thionyl chloride, phosphorus trichloride or phosphorus pentachloride, or carbonyldiimidazole, carbodiimides such as cyclohexylcarbodiimide or 1-cyclohexyl-3- [2- (N-methylmo holino) ethyl] carbodiimide are suitable for activating the carboxylic acid -p- toluenesulfonate or N-hydroxyphthalimide or N-hydroxy-benzotriazole.
Die enantiomerenreinen Verbindungen sind auch zugänglich durch Chromato- graphie der racemischen Ester auf chiralen Phasen.The enantiomerically pure compounds can also be obtained by chromatography of the racemic esters on chiral phases.
Die Verbindungen der allgemeinen Formeln (II) und (HI) sind bekannt.The compounds of the general formulas (II) and (HI) are known.
Die Phenothiazin- 10-carbonsäurechloride der allgemeinen Formel (Ia) sind teil- weise bekannt oder neu und können dann beispielsweise wie oben beschrieben durch Umsetzung von Phenothiazin mit den entsprechenden Säurechloriden her¬ gestellt werden.Some of the phenothiazine-10-carboxylic acid chlorides of the general formula (Ia) are known or new and can then be prepared, for example, as described above by reacting phenothiazine with the corresponding acid chlorides.
Bekannt sind Nomenklaturname Phenothiazin- 10-carbonsäure-NN-di-n-propylaήιid (US 4 833 138); Nomiglaturname 3-(Phenothiazin-10-yl)propinsäuremethylesterNomenclature names phenothiazine-10-carboxylic acid-NN-di-n-propylaήιid are known (US 4,833,138); Nomiglaturname 3- (Phenothiazin-10-yl) methyl propynate
(WO 9 412 621; WO 9 412 619) und Nomenklaturname 3-(2-Chlorphenthiazin- 10-yl)propionsäuremethylester (US 2 820 031(1953)). (WO 9 412 621; WO 9 412 619) and nomenclature name 3- (2-chlorophenthiazin- 10-yl) propionic acid methyl ester (US 2,820,031 (1953)).
^Rubidium-Efflux aus C6-BUl-Glioma-Zellen^ Rubidium efflux from C6-BUl glioma cells
Die Versuche wurden mit geringfügigen Veränderungen entsprechend der von Tas et al. (Neurosci. Lett. 94, 279-284, (1988)) beschriebenen Methode durchgeführt. Dazu werden Ratten C6-BUl-Glioma-Zellen verwendet.The experiments were carried out with minor changes in accordance with that of Tas et al. (Neurosci. Lett. 94, 279-284, (1988)). Rats C6-BU1 glioma cells are used for this.
Aus den durch Flüssigkeitszintillation gewonnenen Daten wird die durch Ionomycin hervorgerufene Erhöhung des Rb-Effluxes über den Basalefflux berechnet und als 100 % gesetzt. Die Stimulationen in Gegenwart von Prüfsubstanzen werden dann auf diesen Wert bezogen.From the data obtained by liquid scintillation, the increase in Rb efflux caused by ionomycin above basal flow is calculated and set as 100%. The stimulations in the presence of test substances are then related to this value.
Zur vorliegenden Erfindung gehören auch pharmazeutische Zubereitungen, die neben inerten, nicht-toxischen, pharmazeutisch geeigneten Hilfs- und Trägerstoffen eine oder mehrere Verbindungen der allgemeinen Formeln (I) / (Ia) / (Ib) enthalten, oder die aus einem oder mehreren Wirkstoffen bestehen, sowieThe present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds of the general formulas (I) / (Ia) / (Ib) or which consist of one or more active ingredients , such as
Verfahren zur Herstellung dieser Zubereitungen.Process for the preparation of these preparations.
Die Wirkstoffe sollen in diesen Zubereitungen in einer Konzentration von 0,1 bis 99,5 Gew.-%, bevorzugt von 0,5 bis 95 Gew.-% der Gesamtmischung vorhanden sein.The active substances should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture.
Neben den Wirkstoffen können die pharmazeutischen Zubereitungen auch andere pharmazeutische Wirkstoffe enthalten.In addition to the active ingredients, the pharmaceutical preparations can also contain other pharmaceutical active ingredients.
Die oben aufgeführten pharmazeutischen Zubereitungen können in üblicher Weise nach bekannten Methoden hergestellt werden, beispielsweise mit dem oder den Hilfs- oder Trägerstoffen.The pharmaceutical preparations listed above can be prepared in a conventional manner by known methods, for example using the auxiliary agent or excipients.
Im allgemeinen hat es sich als vorteilhaft erwiesen, den oder die Wirkstoffe in Gesamtmengen von etwa 0,01 bis etwa 100 mg/kg, bevorzugt in Gesamtmengen von etwa 1 mg/kg bis 50 mg kg Körpergewicht je 24 Stunden, gegebenenfalls in Form mehrerer Einzelgaben, zur Erzielung des gewünschten Ergebnisses zu verabreichen. Es kann aber gegebenenfalls vorteilhaft sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit von der Art und vom Körpergewicht des behandelten Objekts, vom individuellen Verhalten gegenüber dem Medikament, der Art und Schwere der Erkrankung, der Art der Zubereitung und Applikation, sowie dem Zeitpunkt bzw. Intervall, zu welchem die Verabreichung erfolgt.In general, it has proven to be advantageous to use the active ingredient (s) in total amounts of about 0.01 to about 100 mg / kg, preferably in total amounts of about 1 mg / kg to 50 mg kg body weight per 24 hours, optionally in the form of several individual doses to deliver the desired result. However, it may be advantageous to deviate from the amounts mentioned, depending on the type and body weight of the object being treated, on the individual behavior towards the medication, the type and severity of the disease, the type of preparation and application, and the Time or interval at which the administration takes place.
Schlüssel für die DC-Laufmittelgemische:Key for the DC solvent mixtures:
a) Ammoniak MeOH/CHCl3/AcOEt/n-Hexan 1 : 10: 100: 1,7:3 b) Toluol / AcOEt 10: 1 c) Toluol / AcOEt 3:1 d) Toluol / AcOEt 1:1 a) Ammonia MeOH / CHCl 3 / AcOEt / n-hexane 1: 10: 100: 1.7: 3 b) Toluene / AcOEt 10: 1 c) Toluene / AcOEt 3: 1 d) Toluene / AcOEt 1: 1
HerstellungsbeispieleManufacturing examples
Beispiel 1example 1
(Phenothiazin- 10-yl)-essigsäure-N,N-diethylamid(Phenothiazine-10-yl) acetic acid-N, N-diethylamide
29,9 g (150 mmol) Phenothiazin werden in 400 ml Dimethylformamid unter Stickstoff bei 25°C portionsweise mit insgesamt 3,9 g (160 mmol) Natriumhydrid versetzt. Nach 30 min. Nachrühren werden 25,0 g (160 mmol) 2-Chlor-N,N'- diethylacetamid (97%) in 50 ml Dimethylformamid innerhalb von 30 Minuten zugetropft. Nach Rühren über Nacht bei 25°C wird der Ansatz auf Eis gegeben und mit Dichlormethan extrahiert. Die organische Phase wird 2 mal mit Kochsalzlösung gewaschen, über wasserfreiem Natriumsulfat getrocknet und im29.9 g (150 mmol) of phenothiazine are added in portions in 400 ml of dimethylformamide under nitrogen at 25 ° C. with a total of 3.9 g (160 mmol) of sodium hydride. After 30 min. After stirring, 25.0 g (160 mmol) of 2-chloro-N, N'-diethylacetamide (97%) in 50 ml of dimethylformamide are added dropwise within 30 minutes. After stirring overnight at 25 ° C., the mixture is poured onto ice and extracted with dichloromethane. The organic phase is washed twice with brine, dried over anhydrous sodium sulfate and in
Vakuum eingeengt. Der Rückstand wird an 1000 g Kieselgel mit Toluol/Ethylacetat (Gradient) chromatographiert und liefert 18,8 g farblose Kristalle. Schmp. 129-130°C (aus Dichlormethan Diethylether).Vacuum concentrated. The residue is chromatographed on 1000 g of silica gel using toluene / ethyl acetate (gradient) and gives 18.8 g of colorless crystals. Mp 129-130 ° C (from dichloromethane diethyl ether).
Beispiel 2Example 2
Phenothiazin- 10-carbonsäure-N,N-di-n-butylamidPhenothiazine-10-carboxylic acid-N, N-di-n-butylamide
5,3 g (20 mmol) Phenothiazin- 10-carbonsäurechlorid werden in 80 ml Dichlormethan bei 0°C nacheinander mit 2,6 g (20 mmol) Di-n-butylamin sowie 2,8 g (20 mmol) Triethylamin versetzt und 72 h bei 25°C gerührt. Die Reaktionslösung wird mit 1 n Salzsäure versetzt, anschließend mit Wasser gewaschen, über wasserfreiem Natriumsulfat getrocknet und im Vakuum eingedampft. Der Rückstand wird an Kieselgel chromatographiert (Blitzchromatographie) und ergibt 4,5 g (63%) farblose Kristalle. Schmp. 42-43 °C (aus Petrolether, Sdp. 40°C).5.3 g (20 mmol) of phenothiazine-10-carboxylic acid chloride are mixed in succession in 80 ml of dichloromethane at 0 ° C with 2.6 g (20 mmol) of di-n-butylamine and 2.8 g (20 mmol) of triethylamine, and 72 h at 25 ° C stirred. The The reaction solution is mixed with 1N hydrochloric acid, then washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel (flash chromatography) and gives 4.5 g (63%) of colorless crystals. 42-43 ° C (from petroleum ether, bp 40 ° C).
Beispiel 3Example 3
3-(Phenothiazin- 10-yl)-propionsäure-N-n-butylamid3- (phenothiazine-10-yl) propionic acid-N-n-butylamide
4,2 g (150 mmol) 3 -(Phenothiazin- 10-yl)-propionsäuremethylester und 2,2 g (30 mmol) n-Butylamin werden unter Stickstoff 18 h auf 100°C erhitzt. Das in 60 ml Methylenchlorid aufgenommene Reaktionsprodukt wird mit 1 N Salzsäure und anschließend mit Wasser gewaschen, über wasserfreiem Natriumsulfat getrocknet und im Vakuum eingedampft. Der Rückstand (4,9 g ) wird über Kieselgel (Blitzchromatographie) filtriert. Man erhält 4,8 g (98% d.Th.) farblose Kristalle. Schmp. 106-107°C (aus Dichlormethan/Petrolether).4.2 g (150 mmol) of methyl 3 - (phenothiazin-10-yl) propionate and 2.2 g (30 mmol) of n-butylamine are heated at 100 ° C. under nitrogen for 18 h. The reaction product taken up in 60 ml of methylene chloride is washed with 1 N hydrochloric acid and then with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue (4.9 g) is filtered through silica gel (flash chromatography). 4.8 g (98% of theory) of colorless crystals are obtained. M.p. 106-107 ° C (from dichloromethane / petroleum ether).
Beispiel 4Example 4
3 -(2-Chlor-phenothiazin- 10-yl)-propionsäure-N-n-butylamid3 - (2-chlorophenothiazine-10-yl) propionic acid-N-n-butylamide
Zu 5,1 g (16 mmol) 3-(2-Chlor-phenothiazin-10-yl)-propionsäurechlorid in 100 ml Dichlormethan werden unter Eiskühlung und Rühren nacheinander 1,2 g (16 mmol) n-Butylamin und 1,6 g (2,2 ml, 16 mmol) Triethylamin zugegeben. Nach 20 h Rühren bei 25°C wird die Reaktionslösung in Eiswasser eingetragen und mit Ammoniakwasser alkalisch gestellt (pH 9). Extrahieren mit Dichlormethan, Waschen der Dichlormethanextrakte mit Wasser und anschließendes Trocknen über wasserfreiem Natriumsulfat liefern nach Eindampfen im Vakuum und Chromatographie des Rückstands an Kieselgel (100 g) mit Toluol/Ethylacetat 5,3 g kristallines Produkt. Kristallisation aus Dichlormethan/Petrolether ergibt 4,2 g (36% d.Th.) der Titelverbindung. Schmp. 89-91°C. To 5.1 g (16 mmol) of 3- (2-chlorophenothiazin-10-yl) propionic acid chloride in 100 ml of dichloromethane are added 1.2 g (16 mmol) of n-butylamine and 1.6 g in succession with ice cooling and stirring (2.2 ml, 16 mmol) triethylamine added. After stirring for 20 h at 25 ° C., the reaction solution is introduced into ice water and made alkaline with ammonia water (pH 9). Extracting with dichloromethane, washing the dichloromethane extracts with water and then drying over anhydrous sodium sulfate yield, after evaporation in vacuo and chromatography of the residue on silica gel (100 g) with toluene / ethyl acetate, 5.3 g of crystalline product. Crystallization from dichloromethane / petroleum ether gives 4.2 g (36% of theory) of the title compound. Mp 89-91 ° C.
In Analogie zu den oben aufgeführten Herstellungsvorschriften werden die in den Tabellen 1, 2 und 3 aufgeführten Verbindungen hergestellt. The compounds listed in Tables 1, 2 and 3 are prepared in analogy to the production instructions listed above.
Tabelle 1:Table 1:

Claims

PatentansprücheClaims
1. Verwendung von N-substituierten Phenothiazinen der allgemeinen Formel 0) 1. Use of N-substituted phenothiazines of the general formula 0 )
in welcher in which
R1 für einen Rest der Formel -(CH2)a-CO-R6, -(CH2)a-CO-NR7R8 oderR 1 for a radical of the formula - (CH 2 ) a -CO-R 6 , - (CH 2 ) a -CO-NR 7 R 8 or
-(CH2)b-R9 steht,- (CH 2 ) b -R 9 ,
worinwherein
a eine Zahl 0, 1 oder 2 bedeutet,a represents a number 0, 1 or 2,
b eine Zahl 1 oder 2 bedeutet,b represents a number 1 or 2,
R6 Wasserstoff oder geradkettiges oder verzweigtes Alkoxy oder Alkyl mit jeweils bis zu 6 Kohlenstoffatomen bedeutet, wobei letzteres durch Halogen oder Hydroxy substituiert sein kann,R 6 denotes hydrogen or straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms, the latter being able to be substituted by halogen or hydroxy,
R7 Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoffatomen bedeutet, das gegebenenfalls durch Halogen substituiert ist,R 7 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen,
R8 Wasserstoff, Cycloalkyl mit 3 bis 6 Koblenstoffatomen,R 8 is hydrogen, cycloalkyl having 3 to 6 coblene atoms,
Pyridyl, Phenyl, Amino oder geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoffatomen bedeutet, das gegebenenfalls durch Hydroxy oder Pyridyl substituiert ist, oderMeans pyridyl, phenyl, amino or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy or pyridyl, or
R7 und R8 gemeinsam mit dem Stickstoffatom einen Piperidin-, Morpholin-, Azacycloheptyl- oder Pyrrolidinylring bilden,R 7 and R 8 together with the nitrogen atom form a piperidine, morpholine, azacycloheptyl or pyrrolidinyl ring,
R9 Cyano oder geradkettiges oder verzweigtes Alkoxycarbonyl mit bis zu 6 Kohlenstoffatomen bedeutet,R 9 denotes cyano or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms,
R2, R3, R4 und R5 gleich oder verschieden sind und für Wasserstoff, Halogen oder Trifluormethyl stehen,R 2 , R 3 , R 4 and R 5 are identical or different and represent hydrogen, halogen or trifluoromethyl,
und deren Salzeand their salts
zur Herstellung von Arzneimitteln zur Behandlung von Erkrankungen des ZNS.for the manufacture of medicinal products for the treatment of diseases of the CNS.
2. Verwendung von N-substituierten Phenothiazinen der Formel (I) nach Anspruch 1, worin2. Use of N-substituted phenothiazines of the formula (I) according to Claim 1, in which
R1 für einen Rest der Formel -(CH2)a-CO-R6, -(CH2)a-CO-NR7R8 oder -(CH2)b-R9 steht,R 1 represents a radical of the formula - (CH 2 ) a -CO-R 6 , - (CH 2 ) a -CO-NR 7 R 8 or - (CH 2 ) b -R 9 ,
worinwherein
a eine Zahl 0, 1 oder 2 bedeutet,a represents a number 0, 1 or 2,
b eine Zahl 1 oder 2 bedeutet,b represents a number 1 or 2,
R6 Wasserstoff oder geradkettiges oder verzweigtes Alkoxy oder Alkyl mit jeweils bis zu 4 Kohlenstoffatomen bedeutet, wobei letzteres durch Fluor, Chlor oder Hydroxy substituiert sein kann, R Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoffatomen bedeutet, das gegebenenfalls durch Chlor substituiert ist,R 6 denotes hydrogen or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms, the latter being able to be substituted by fluorine, chlorine or hydroxy, R is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by chlorine,
R8 Wasserstoff, Pyridyl, Phenyl, Amino, Cyclopropyl, Cyclo- pentyl, Cyclohexyl oder geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoffatomen bedeutet, das gegebenenfalls durch Hydroxy oder Pyridyl substituiert ist,R 8 denotes hydrogen, pyridyl, phenyl, amino, cyclopropyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy or pyridyl,
oderor
R7 und R8 gemeinsam mit dem Stickstoffatom einen Piperidin-, Morpholin-, Azacycloheptyl- oder Pyrrolidinylring bilden,R 7 and R 8 together with the nitrogen atom form a piperidine, morpholine, azacycloheptyl or pyrrolidinyl ring,
R9 Cyano oder geradkettiges oder verzweigtes Alkoxycarbonyl mit bis zu 4 Kohlenstoffatomen bedeutet,R 9 denotes cyano or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms,
R2 und R5 gleich oder verschieden sind und für Wasserstoff, Fluor, Chlor, Brom oder Trifluormethyl stehen,R 2 and R 5 are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,
R3 und R4 für Wasserstoff stehen,R 3 and R 4 represent hydrogen,
und deren Salze,and their salts,
zur Herstellung von Arzneimitteln zur Behandlung von Erkrankungen desfor the manufacture of medicaments for the treatment of diseases of the
ZNS.CNS.
3. Verwendung von N-substituierten Phenothiazinen der Formel (I) nach Anspruch 1, worin3. Use of N-substituted phenothiazines of the formula (I) according to claim 1, wherein
R1 für einen Rest der Formel -(CH2)a-CO-R6, -(CH2)a-CO-NR7R8 oder -(CH2)b-R9 steht,R 1 represents a radical of the formula - (CH 2 ) a -CO-R 6 , - (CH 2 ) a -CO-NR 7 R 8 or - (CH 2 ) b -R 9 ,
woπn a eine Zahl 0, 1 oder 2 bedeutet,woπn a represents a number 0, 1 or 2,
b eine Zahl 1 oder 2 bedeutet,b represents a number 1 or 2,
R6 Wasserstoff oder geradkettiges oder verzweigtes Alkoxy oderR 6 is hydrogen or straight-chain or branched alkoxy or
Alkyl mit jeweils bis zu 4 Kohlenstoffatomen bedeutet, wobei letzteres durch Fluor, Chlor oder Hydroxy substituiert sein kann,Alkyl with up to 4 carbon atoms each, the latter being substituted by fluorine, chlorine or hydroxy,
R7 Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoffatomen bedeutet, das gegebenenfalls durch Chlor substituiert ist,R 7 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by chlorine,
R8 Wasserstoff, Pyridyl, Phenyl, Amino, Cyclopropyl, Cyclo- pentyl, Cyclohexyl oder geradkettiges oder verzweigtesR 8 is hydrogen, pyridyl, phenyl, amino, cyclopropyl, cyclopentyl, cyclohexyl or straight-chain or branched
Alkyl mit bis zu 4 Kohlenstoffatomen bedeutet, das gegebenenfalls durch Hydroxy oder Pyridyl substituiert ist,Means alkyl with up to 4 carbon atoms, which is optionally substituted by hydroxy or pyridyl,
oderor
R7 und R8 gemeinsam mit dem Stickstoffatom einen Piperidin-, Morpholin-, Azacycloheptyl- oder Pyrrolidinylring bilden,R 7 and R 8 together with the nitrogen atom form a piperidine, morpholine, azacycloheptyl or pyrrolidinyl ring,
R9 Cyano oder geradkettiges oder verzweigtes Alkoxycarbonyl mit bis zu 4 Kohlenstoffatomen bedeutet,R 9 denotes cyano or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms,
R2 und R5 gleich oder verschieden sind und für Wasserstoff, Fluor, Chlor, Brom oder Trifluormethyl stehen,R 2 and R 5 are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,
R3 und R4 für Wasserstoff stehen,R 3 and R 4 represent hydrogen,
und deren Salze,and their salts,
zur Herstellung von Arzneimitteln zur Bekämpfung von Erkrankungen des ZNS. 4. Verwendung nach Anspruch 1 bis 3 zur Herstellung von Arzneimitteln zur Behandlung von zentral degenerativen Erkrankungen.for the manufacture of medicinal products for combating diseases of the CNS. 4. Use according to claim 1 to 3 for the manufacture of medicaments for the treatment of central degenerative diseases.
5. Verwendung nach Anspruch 1 bis 3 zur Herstellung von Arzneimitteln zur Behandlung von Hirnleistungsstörungen im Alter.5. Use according to claim 1 to 3 for the manufacture of medicaments for the treatment of brain disorders in old age.
6. Verwendung nach Anspruch 1 bis 3 zur Herstellung von Arzneimitteln zur Behandlung und Prophylaxe der Folgen cerebraler Durchblutungsstörungen.6. Use according to claim 1 to 3 for the manufacture of medicaments for the treatment and prophylaxis of the consequences of cerebral circulatory disorders.
7. Verwendung nach Anspruch 1 bis 3 zur Herstellung von Arzneimitteln zur7. Use according to claim 1 to 3 for the manufacture of medicaments for
Behandlung von Depressionen und Psychosen.Treatment of depression and psychosis.
8. N-substituierte Phenothiazine der Reihe8. N-substituted phenothiazines of the series
- Phenothiazin- 10-carbonsäure-N-(pyrid-4-yl)amid- Phenothiazine-10-carboxylic acid N- (pyrid-4-yl) amide
Phenothiazin- 10-carbonsäure-(N-methyl-N-phenyl)amid Phenothiazin- 10-carbonsäure-(N,N-di-n-butyl)amid Phenothiazin- 10-carbonsäure-(N-cyclohexyl-N-methyl)amid 3-(2-Chlor-phenothiazin-l 0-yl)-propionsäure-N-ethylamid - 3-(2-Chlor-phenothiazin-10-yl)-propionsäure-(N-propyl)amidPhenothiazine 10-carboxylic acid (N-methyl-N-phenyl) amide phenothiazine 10-carboxylic acid (N, N-di-n-butyl) amide phenothiazine 10-carboxylic acid (N-cyclohexyl-N-methyl) amide 3- (2-chlorophenothiazin-10-yl) propionic acid-N-ethylamide - 3- (2-chlorophenothiazin-10-yl) propionic acid (N-propyl) amide
3-(2-Chlor-phenothiazin-10-yl)-propionsäure-(N-(pyridin-4- ylmethyl))-amid3- (2-chlorophenothiazin-10-yl) propionic acid (N- (pyridin-4-ylmethyl)) amide
3-(Phenothiazin- 10-yl)-propionsäure-(N-propyl)amid3- (phenothiazine-10-yl) propionic acid (N-propyl) amide
Phenothiazin- 10-essigsäure-diethylamid - Phenothiazin- 10-carbonsäure-pyrolianimidPhenothiazine-10-acetic acid-diethylamide - phenothiazine-10-carboxylic acid pyrolianimide
Phenothiazin- 10-carbonsäure-morpholinimid (Phenothiazin- 10-yl)-carbonsäure-azacy cloheptylimid (Phenothiazin- 10-yl)-essigsäure-n-propylamid (Phenothiazin- 10-yl)-essigsäure-ethylamid - (Phenothiazin- 10-yl)-essigsäure-di-n-propylamidPhenothiazine-10-carboxylic acid-morpholineimide (phenothiazine-10-yl) -carboxylic acid-azacy cloheptylimide (phenothiazine-10-yl) -acetic acid-n-propylamide (phenothiazine-10-yl) -acetic acid-ethylamide - (phenothiazine-10-yl ) -acetic acid-di-n-propylamide
Phenothiazin- 10-propinsäure-N-n-butylamid 4-Chl or- 1 -(2-Chl orphenothiazin- 10-yl)butan- 1 -on 4-Chlor- 1 -(phenothiazin- 10-yl)butan- 1 -on Phenothiazin- 10-essigsäure-n-butylamid - 3-(2-Chlorphenothiazin-10-yl)-N-n-butylamid. Verfahren zur Herstellung von N-substituierten Phenothiazinen nach Anspruch 8, dadurch gekennzeichnet, daß manPhenothiazine-10-propynoic acid-Nn-butylamide 4-chloro-1 - (2-chloro-orphenothiazine-10-yl) butane-1-one 4-chloro-1 - (phenothiazine-10-yl) butane-1-one phenothiazine - 10-acetic acid-n-butylamide - 3- (2-chlorophenothiazin-10-yl) -Nn-butylamide. Process for the preparation of N-substituted phenothiazines according to Claim 8, characterized in that
Phenothiazin direkt mit den entsprechenden Säuren, Estern oder Amiden in inerten Lösemitteln und in Anwesenheit einer Base gegebenenfalls unter Schutzgasatmosphäre umsetztPhenothiazine directly with the corresponding acids, esters or amides in inert solvents and in the presence of a base, if appropriate under a protective gas atmosphere
oder die entsprechenden Phenothiazinsäurechloride mit Aminen in inerten Lösemitteln gegebenenfalls in Anwesenheit einer weiteren Base umsetzt.or the corresponding phenothiazinoyl chlorides are reacted with amines in inert solvents, if appropriate in the presence of a further base.
10. Arzneimittel enthaltend mindestens ein N-substituiertes Phenothiazin nach Anspruch 8 sowie übliche Formulierungshilfsmittel. 10. Medicament containing at least one N-substituted phenothiazine according to claim 8 and conventional formulation auxiliaries.
EP95929864A 1994-08-25 1995-08-14 Use of n-substituted phenothiazines Ceased EP0777481A1 (en)

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US7790881B2 (en) 2004-09-23 2010-09-07 Wista Laboratories Ltd. Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (MTC)
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