+

WO1992013860A1 - NEW 4,5,6,7-TETRAHYDRO-IMIDAZO-[4,5,lJK][1,4]-BENZODIAZEPINE-2-(1H)-THIONES, A METHOD OF PREPARING THEM AS WELL AS DRUGS CONTAINING THEM, AND INTERMEDIATES FOR THE PREPARATION OF THESE COMPOUNDS - Google Patents

NEW 4,5,6,7-TETRAHYDRO-IMIDAZO-[4,5,lJK][1,4]-BENZODIAZEPINE-2-(1H)-THIONES, A METHOD OF PREPARING THEM AS WELL AS DRUGS CONTAINING THEM, AND INTERMEDIATES FOR THE PREPARATION OF THESE COMPOUNDS Download PDF

Info

Publication number
WO1992013860A1
WO1992013860A1 PCT/EP1992/000261 EP9200261W WO9213860A1 WO 1992013860 A1 WO1992013860 A1 WO 1992013860A1 EP 9200261 W EP9200261 W EP 9200261W WO 9213860 A1 WO9213860 A1 WO 9213860A1
Authority
WO
WIPO (PCT)
Prior art keywords
tetrahydro
benzodiazepine
methyl
substituted
imidazo
Prior art date
Application number
PCT/EP1992/000261
Other languages
German (de)
French (fr)
Inventor
Herbert Leinert
Alfred Mertens
Original Assignee
Boehringer Mannheim 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 Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Publication of WO1992013860A1 publication Critical patent/WO1992013860A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines

Definitions

  • the invention relates to new 4,5,6,7-tetrahydro-imidazo- [4,5, ljk] [1,4] -benzodiazepine-2- (lH) -thiones, a process for their preparation, and medicaments and new ones Intermediates for the preparation of these compounds.
  • German patent specification P 40 36 552.2-44 describes a new, generally feasible process which involves the preparation of 4,5,6,7-tetrahydro-imidazo- [4,5, l, jk] [l, 4] -benzo- diazepine-2 (lH) -thions allowed in an economical manner.
  • the invention relates to new 4,5,6,7-tetrahydro-imidazo- [4, 5.1jk] [1.4] -benzodiazepine-2 (1H) -thiones of the general formula I
  • Rl is a hydrogen atom, a straight-chain or branched alkyl radical of 1-6 carbon atoms,
  • R2 is a straight-chain or branched Ci-Cg-alkyl radical, which can be substituted by one or more hydroxy, Ci-Cg-alkoxy, mercapto or Ci-Ce-alkyl mercapto groups or a substituted or unsubstituted phenyl radical; a C 3 -C7-C ⁇ cloalkyl residue, a substituted or unsubstituted phenyl residue, a substituted or unsubstituted aralkyl residue, a substituted or unsubstituted saturated hetero ⁇ yclic or an aromatic heterocyclic residue or a substituted or unsubstituted heteroarylalkyl residue, or together with R_- a C3-C7- Can form cycloalkyl ring, where the aforementioned substituted radicals can be mono-, di- or trisubstituted by Ci-Cg-alkyl, Ci-Cö- loxy, halogen, hydroxy, amino, Ci-C
  • R3 is a hydrogen atom, a straight-chain or branched C -Cg alkyl radical which is substituted by one or more hydroxyl or Ci-C ⁇ -alkoxy groups, a substituted or unsubstituted amino group or halogen may be substituted; a straight-chain or branched C2-C6 ⁇ alkenyl radical which can also carry one or more hydroxy or Ci-Cö alkoxy groups, a substituted or unsubstituted amino group or halogen; or a substituted or unsubstituted aralkyl or heteroarylalkyl radical, where one of the radicals R 1 or R 2 can also form a substituted or unsubstituted heterocyclic ring together with the radical R 3,
  • R4 is a hydrogen atom, a halogen atom, a hydroxy group, a Ci-Ce-alkoxy group, a Ci-Cg-alkylenedioxy group, a Ci-Cg-alkyl group, a mono- or polysubstituted amino group, or a substituted or unsubstituted benzyloxy group,
  • Rl represents a hydrogen atom, a straight-chain or branched alkyl radical of 1-6 carbon atoms, such as e.g. the methyl, ethyl, n-propyl, isopropyl, butyl, pentyl or hexyl radical.
  • R2 denotes a straight-chain or branched alkyl group of 1-6 carbon atoms, which can also be substituted by one or more hydroxyl, alkoxy, mercapto or alkyl erapto groups or by a substituted or unsubstituted phenyl radical.
  • the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl and isohexyl groups are preferred.
  • Alkoxy groups are generally understood to be methoxy or ethoxy groups.
  • the methyl mercapto or the ethyl mercapto group are suitable as alkyl mercapto groups.
  • the substituents of the phenyl radical can be a Ci-Cg-alkyl group such as the methyl or ethyl group, a Ci-Cg-alkoxy group such as the methoxy, ethoxy or propoxy group or a halogen atom such as chlorine, bromine or fluorine.
  • R2 represents a cycloalkyl radical, it means a cyclopentyl or cyclohexyl radical. If R2 is a substituted phenyl ring, one or more Ci-Cg-alkyl groups, such as methyl, ethyl, propyl, isopropyl or butyl groups, one or more hydroxyl groups, one or more Ci-Cg- Alkoxy groups, such as methoxy, ethoxy or propoxy groups, one or more halogen atoms, such as fluorine, chlorine, bromine or iodine or an unsubstituted or substituted by one or two Ci-Cg-alkyl groups, such as the methylamino, ethylamino, Dimethylamino or diethylamino group.
  • Ci-Cg-alkyl groups such as methyl, ethyl, propyl, isopropyl or butyl groups
  • R2 represents an unsubstituted aralkyl radical, this means the benzyl radical. If R2 is a substituted aralkyl radical, it means a substituted benzyl radical.
  • the substituents can be one or more alkyl groups, such as methyl, ethyl, n-propyl, isopropyl or butyl groups, a hydroxyl group or one or more alkoxy groups, such as methoxy or ethoxy groups, one or more halogen atoms, such as fluorine, Chlorine, bromine or iodine or an unsubstituted or substituted amino group, such as the methylamino, ethylamino, dimethylamino or diethylamino group.
  • R2 represents a saturated heterocyclic heterocyclic ring, it means a piperidine or pyrrolidine ring. If R2 represents an unsubstituted or substituted heteroaromatic radical, it means an unsubstituted Tuiert or substituted pyridine ring, which may be linked in the 2, 3 or 4-position, with substituents one or more halogen atoms, such as chlorine, bromine or fluorine, alkoxy groups such as the methoxy or ethoxy group or alkyl groups such as the methyl, ethyl or propyl group be considered.
  • substituents one or more halogen atoms, such as chlorine, bromine or fluorine, alkoxy groups such as the methoxy or ethoxy group or alkyl groups such as the methyl, ethyl or propyl group be considered.
  • a heteroarylalkyl radical for R2 is a pyridylmethyl radical, e.g. the pyridyl-2-methyl, pyridyl-3-methyl or the pyridyl-4-methyl radical, the indolyl-3-methyl radical or the imidazolyl-4-methyl radical.
  • R3 can denote a hydrogen atom or a straight-chain or branched Ci-Cg alkyl group, which can also be substituted by one or more hydroxyl, alkoxy or amino groups, or a halogen atom.
  • a halogen atom means chlorine or bromine.
  • the 2-chloroethyl, 2-bromoethyl, 3-chloropropyl, 3-bromopropyl, 4-chlorobutyl and 4-bromobutyl groups are preferred.
  • R3 can also mean a straight-chain or branched C2-Ce alkenyl group, which can also be substituted by a hydroxyl or alkoxy group or a halogen atom.
  • the vinyl, allyl, 2-methylallyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, 5-hydroxypenten-3-yl and the 5-methoxy-penten-3-yl group are preferred .
  • a halogen atom means chlorine or bromine.
  • R 3 is an aralkyl radical, it means a benzyl radical. If R3 is a substituted aralkyl radical, this means a substituted benzyl radical.
  • Suitable substituents are one or more hydroxyl groups, one or more alkoxy groups, such as methoxy, ethoxy or allyloxy groups, or one or more halogen atoms such as chlorine, bromine or fluorine or one or more alkyl groups, such as methyl or ethyl - or propyl groups.
  • R3 is a heteroarylalkyl radical, it means a 2-, 3- or 4-pyridylmethyl radical, which is also represented by one or more alkoxy groups, such as methoxy or ethoxy groups, by one or more alkyl groups, such as e.g. Methyl, ethyl or propyl groups or can be substituted by one or more halogen atoms, such as chlorine or bromine.
  • R4 can be hydrogen, a halogen atom, such as fluorine, chlorine or bromine, a hydroxyl group, an alkyl group, such as the methyl or ethyl group, an alkoxy group, such as the methoxy or ethoxy group, an alkylenedioxy group, such as the methylenedioxy group, or a substituted or unsubstituted group Benzyloxy group, where substituents are one or more alkoxy groups, such as methoxy or ethoxy groups, one or more Haigen atoms, such as chlorine, fluorine or bromine, and one or more alkyl groups, such as the methyl, ethyl or propyl group.
  • a halogen atom such as fluorine, chlorine or bromine
  • a hydroxyl group such as the methyl or ethyl group
  • an alkyl group such as the methyl or ethyl group
  • an alkoxy group such as the methoxy or e
  • radicals R 1 or R 2 forms a substituted or unsubstituted heterocyclic ring together with the radical R 3, this is understood to mean a pyrrolidine or hydroxypyrrolidine ring.
  • residues i and R 2 together form a C 3 ⁇ C 7- ing, this means a spiro-cyclopropyl, spiro-cyclobutyl, spiro-cyclopentyl, spiro-cyclohexyl or spiro-cycloheptyl ring.
  • substituted radicals such as. B. a substituted phenyl, aralkyl or heteroarylalkyl radical or a saturated or aromatic heterocyclic radical can in all cases be mono-, di- or trisubstituted by Ci-Cg-alkyl, Ci-Cg-alkoxy, halogen, hydroxy, amino, Ci-Cg-alkylamino or di-Ci-Cg-alkylamino.
  • the compounds of general formula I according to the invention can have one or more asymmetric carbon atoms.
  • the invention therefore also relates to all optically active and diastereomeric forms and racemic and diastereomeric mixtures.
  • R ⁇ , 2, R3 and R4 have the meanings given, according to a conventional method with a reagent which transfers the thiocarbonyl group, such as, for example, carbon disulfide, thiocarbonyldiimidazole, thiophosgene or thiourea.
  • a reagent which transfers the thiocarbonyl group such as, for example, carbon disulfide, thiocarbonyldiimidazole, thiophosgene or thiourea.
  • the compounds of the general formula II are prepared by, in a compound of the general formula III,
  • the compounds of general formula III can be prepared by using a compound of general formula IV,
  • X represents a halogen atom or a sulfonic ester grouping.
  • the compounds of general formula IV can be represented by using a compound of the general formula VI,
  • R 1, R 2 and R 4 have the meanings indicated and Y represents a halogen atom, is subjected to a cyclization reaction.
  • R_, R2, R4 and Y have the meanings given, and R5 denotes hydrogen or an alkyl radical, undergoes an amidation reaction by methods known to the person skilled in the art.
  • the compounds of general formula VIII can be prepared by using a compound of general formula IX,
  • R ] _ and R2 have the meanings given and one of the radicals R_ or R2 together with the amino group can, if appropriate, form a pyrrolidine or hydroxypyrrolidine ring and R5 is hydrogen or an alkyl radical, by a method known to those skilled in the art.
  • R5 is hydrogen or an alkyl radical, by a method known to those skilled in the art.
  • the compounds of the general formula IX are known from the literature or can be prepared by methods known from the literature.
  • the reactions of the compounds of general formula II with a reagent transferring a thiocarbonyl group to a compound of general formula I are carried out, e.g. reacting a compound of the general formula II with carbon disulphide in an aqueous-alcoholic solution in the presence of alkali by a method known to the person skilled in the art or by reacting a compound of the general formula II with thiocarbonyldiimidazole in an inert solvent, such as e.g. Dimethylformamide brings to reaction.
  • an inert solvent such as e.g. Dimethylformamide brings to reaction.
  • the compounds of the general formula II are prepared by converting the nitr group into an amine group in a compound of the general formula by a method known to those skilled in the art.
  • reaction of the compounds of the general formula IV with compounds of the general formula V to give compounds of the general formula III are carried out by reacting the compounds of the general formula IV with compounds of the general formula V in an inert solvent, such as, for example, dimethylformamide, di ethyl acetamide, acetone, methyl ethyl ketone or alcohol at temperatures between room temperature and reflux temperature of the solvent, means of, for example sodium carbonate or potassium carbonate to the skilled person by methods known brings preferably between 40 "C and 60 ⁇ C in the presence of an alkaline Kondensationsmit to the reaction.
  • an inert solvent such as, for example, dimethylformamide, di ethyl acetamide, acetone, methyl ethyl ketone or alcohol
  • the cyclization of a compound of the general formula VI to a compound of the general formula IV can be carried out by using a compound of the general formula VI in an inert solvent, such as, for example, dimethylformamide, dimethyl acetamide, acetone, methyl ethyl ketone or alcohol alkaline condensate, such as sodium carbonate or potassium carbonate at temperatures between room temperature and the reflux temperature of the solvent to react.
  • an inert solvent such as, for example, dimethylformamide, dimethyl acetamide, acetone, methyl ethyl ketone or alcohol alkaline condensate, such as sodium carbonate or potassium carbonate at temperatures between room temperature and the reflux temperature of the solvent to react.
  • the cyclization reaction of a compound of the general formula VI to a compound of the general formula IV can also be carried out by reacting a compound of the general formula IV in the presence of an alkaline condensing agent, such as, for example, sodium carbonate or potassium carbonate, at temperatures between 100 ⁇ C and 200 * C, preferably between 130'C and 170 ⁇ C heated.
  • an alkaline condensing agent such as, for example, sodium carbonate or potassium carbonate
  • the compounds of the general formula VI are shown by reacting a compound of the general formula VII with hydrogen boron or diborane in an inert solvent, such as e.g. Tetrahydrofuran, dioxane, diethyl ether or methylene chloride at temperatures between room temperature and reflux temperature of the solvent or by reacting a compound of general formula VI in an inert solvent such as e.g. Subjects methylene chloride reduction with a tetraalkylammonium borohydride.
  • an inert solvent such as e.g. Tetrahydrofuran, dioxane, diethyl ether or methylene chloride
  • the compounds of the general formula VII are prepared by subjecting a compound of the general formula VIII to an amide formation reaction according to the person skilled in the art and methods known from the literature.
  • the compounds of general formula VIII can be prepared by reacting a compound of general formula IX with a compound of general formula X by methods known to those skilled in the art.
  • the following compounds are particularly preferred compounds of the general formula I:
  • the invention also relates to medicaments which contain these compounds.
  • the compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of diseases which are caused by the human immunodeficiency virus HIV-1.
  • the compounds of the formula I appear to be particularly suitable for the treatment of the clinical manipulation of retroviral HIV infection in humans and the clinical full picture of AIDS.
  • the compounds of the general formula I inhibit the multiplication of HIV-1 on the virus-specific RNA transcription. They inhibit the multiplication of retroviruses by inhibiting the enzyme reverse transcriptase and are therefore particularly suitable for the treatment of the immune deficiency disease AIDS.
  • the compounds of the present invention and their pharmaceutical preparations can also be used in combination with other medicaments for the treatment and prophylaxis of the above-mentioned infections.
  • these further drugs include agents which can be used for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as 3'-azido-3 'deoxythymidine, 2 ! , 3'-dideoxynucleosides such as 2 ', 3' -dideoxycytidine, 2 •, 3'-di-deoxyadenosine and 2 ', 3'-dideoxyinosine, acyclic nucleosides (e.g.
  • acyclovir interferons
  • interferons such as A-interfero
  • renal excretion Inhibitors such as B. probenicid
  • nucleoside transport inhibitors such as B. Dipyridamol
  • Immunomodulators such as B. Interleukin II or stimulation factors
  • B. the granulocyte-macrophage colony factor can each be administered individually, at the same time optionally in a single or two separate formulations or at different times, so that a synergistic effect is achieved.
  • the compounds of the general formula I contain basic groups which can be converted into acid addition salts using suitable acids.
  • suitable acids for this purpose are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.
  • the medicaments containing compounds of the formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form.
  • the usual forms of application are possible here, such as tablets, capsules, dragees, syrups, solutions or suspensions.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers.
  • additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation.
  • Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules.
  • Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers, such as polyethylene glycols, etc.
  • Preparations suitable for oral applications can, if desired, contain flavorings or sweeteners.
  • the dosage can depend on various factors, such as the type of application, species, age or individual condition.
  • the compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight.
  • the tablets can also be delayed, which reduces the number of applications per day to 1-3.
  • the active substance content of the retarded tablets can be 2-1000 mg.
  • the active ingredient can also be given by continuous infusion, the amounts of 5-1000 mg per day are usually sufficient.
  • the invention further relates to intermediates of the general formula II.
  • the invention also relates to compounds of the general formula III in which R 1 -R 4 has the meanings mentioned above.
  • the invention also relates to compounds of the general formula IV in which R 1 , R 2 and R 4 have the meanings mentioned above:
  • a solution of 250 mg of potassium hydroxide in a mixture of 1 ml of water and 5 ml of ethanol is added to the evaporation residue and, after the addition of 0.25 ml of carbon disulfide, the mixture is heated under reflux for 3 hours.
  • the reaction solution is cooled, acidified with hydrochloric acid and extracted with ethyl acetate.
  • the ethyl acetate phase is discarded.
  • the hydrochloric acid solution is made alkaline and extracted with ethyl acetate.
  • the ethyl acetate phase is dried over sodium sulfate and evaporated.
  • the residue is chromatographed on a silica gel column for purification. 600 mg of the title compound of mp 166-168 "C. are obtained. The following were represented in an analogous manner:

Landscapes

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

Abstract

The invention concerns compounds of the formula (I), in which R1?, R2?, R3? and R4? represent groups defined in the claims. The invention also concerns a method of preparing these compounds, drugs containing them for the treatment of viral illnesses, and intermediates uses in the preparation of compounds of formula (I).

Description

Neue 4.5.6.7-Tetrahvdro-imidazo-f4.5.lik] r1.41-benzodiazepin-2- (1H)-thione. Verfahren zu ihrer Herstellung sowie Arzneimittel und Zwischenprodukte zur Herstellung dieser VerbindungenNew 4.5.6.7-tetrahvdro-imidazo-f4.5.lik] r1.41-benzodiazepine-2- (1H) -thione. Processes for their preparation and pharmaceuticals and intermediates for the preparation of these compounds
Gegenstand der Erfindung.sind neue 4,5,6,7-Tetrahydro-imidazo- [4,5,ljk] [l.4]-benzodiazepin-2-(lH)-thione, ein Verfahren zu deren Herstellung sowie Arzneimittel und neue Zwischenprodukte zur Herstellung dieser Verbindungen.The invention relates to new 4,5,6,7-tetrahydro-imidazo- [4,5, ljk] [1,4] -benzodiazepine-2- (lH) -thiones, a process for their preparation, and medicaments and new ones Intermediates for the preparation of these compounds.
In der Zeitschrift Nature, Vol. 343. S. 470 wird die Wirkung von 4,5,6,7-Tetrahydro-5-methyl-6-(3-methyl-2-butenyl)- imidazo-[4,5,ljk] [1.4]-benzodiazepin-2-(lH)-thion und dessen 9- Chlor-Derivat beschrieben. Diese Verbindungen hemmen die HIV-1 eplikation, aber nicht HIV-2 oder andere DNA- oder RNA-Viren, sodaß diese Verbindungen zur Behandlung von AIDS in Frage kommen. Diese Verbindungen sind auch Gegenstand der EP-A-0 384 522.In the journal Nature, Vol. 343, p. 470, the effect of 4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo- [4,5, ljk ] [1.4] -benzodiazepin-2- (lH) -thione and its 9-chloro derivative. These compounds inhibit HIV-1 replication, but not HIV-2 or other DNA or RNA viruses, so that these compounds are suitable for the treatment of AIDS. These compounds are also the subject of EP-A-0 384 522.
In der vorliegenden Erfindung werden nun neue 4,5,6,7-Tetra- hydroimidazo-[4,5,l,jk] [l,4]-benzodiozepin-2-(lH)-thione mit verbesserter Wirkung bezüglich der Hemmung der HIV-1 Replika¬ tion beschrieben.In the present invention, new 4,5,6,7-tetrahydroimidazo- [4,5, l, jk] [l, 4] -benzodiozepin-2- (lH) -thiones with improved effect with regard to the inhibition of HIV-1 replication described.
Eine Methode zur Herstellung von 4,5,6,7-Tetrahydro-imidazo- [4,5,1,jk] [1,4]-benzodiazepin-2(lH)-thione ist in der euro¬ päischen Patentschrift 0 384 522 beschrieben. Nach diesem Verfahren lassen sich die gewünschten Produkte jedoch nur in geringer Gesamtausbeute herstellen.A method for the preparation of 4,5,6,7-tetrahydro-imidazo- [4,5,1, jk] [1,4] -benzodiazepin-2 (1H) -thione is in European patent specification 0 384 522 described. However, the desired products can only be produced in this way in a low overall yield.
In der deutschen Patentschrift P 40 36 552.2-44 ist ein neues allgemein durchführbares Verfahren beschrieben, das die Her¬ stellung von 4,5,6,7-Tetrahydro-imidazo-[4,5,l,jk][l,4]-benzo- diazepin-2(lH)-thionen auf wirtschaftliche Art und Weise erlaubt. Gegenstand der Erfindung sind neue 4,5,6,7-Tetrahydro-imidazo- [4 ,5,1jk] [1.4]-benzodiazepin-2(1H)-thione der allgemeinen Formel IGerman patent specification P 40 36 552.2-44 describes a new, generally feasible process which involves the preparation of 4,5,6,7-tetrahydro-imidazo- [4,5, l, jk] [l, 4] -benzo- diazepine-2 (lH) -thions allowed in an economical manner. The invention relates to new 4,5,6,7-tetrahydro-imidazo- [4, 5.1jk] [1.4] -benzodiazepine-2 (1H) -thiones of the general formula I
Figure imgf000004_0001
Figure imgf000004_0001
in welcherin which
Rl ein Wasserstoffatom, einen geradkettigen oder verzweigten Alkylrest von 1-6 Kohlenstoffatomen,Rl is a hydrogen atom, a straight-chain or branched alkyl radical of 1-6 carbon atoms,
R2 einen geradkettigen oder verzweigten Ci-Cg-Alkylrest, der durch eine oder mehrere Hydroxy-, Ci-Cg-Alkoxy-, Mercapto oder Ci-Ce-Alkylmercaptogruppen oder einen substituierten oder unsubstitutierten Phenylrest substituiert sein kann; einen C3-C7-Cγcloalkylrest, einen substituierten oder unsubstituierten Phenylrest, einen substituierten oder unsubstituierten Aralkylrest, einen substituierten oder unsubstituierten gesättigten heteroσyclischen oder einen aromatischen heterocyclischen Rest oder einen substitu¬ ierten oder unsubstituierten Heteroarylalkylrest, oder zusammen mit R_- einen C3-C7-Cycloalkylring bilden kann, wobei die zuvor genannten substituierten Reste ein-, zwei- oder dreifach substituiert sein können durch Ci-Cg-Alkyl, Ci-Cö- l oxy, Halogen, Hydroxy, Amino, Ci-Cg-Alkylamino oder Di-Ci-Cg-Alkylamino,R2 is a straight-chain or branched Ci-Cg-alkyl radical, which can be substituted by one or more hydroxy, Ci-Cg-alkoxy, mercapto or Ci-Ce-alkyl mercapto groups or a substituted or unsubstituted phenyl radical; a C 3 -C7-Cγcloalkyl residue, a substituted or unsubstituted phenyl residue, a substituted or unsubstituted aralkyl residue, a substituted or unsubstituted saturated heteroσyclic or an aromatic heterocyclic residue or a substituted or unsubstituted heteroarylalkyl residue, or together with R_- a C3-C7- Can form cycloalkyl ring, where the aforementioned substituted radicals can be mono-, di- or trisubstituted by Ci-Cg-alkyl, Ci-Cö- loxy, halogen, hydroxy, amino, Ci-Cg-alkylamino or di-Ci Cg alkylamino,
R3 ein Wasserstoffatom, einen geradkettigen oder verzweigten C -Cg-Alkylrest, der durch eine oder mehrere Hydroxy- oder Ci-Cβ-Alkoxygruppen, eine substituierte oder unsubsti- tuierte Aminogruppe oder Halogen substituiert sein kann; einen geradkettigen oder verzweigten C2-C6~Alkenylrest, der noch eine oder mehrere Hydroxy- oder Ci-Cö-Alkoxy- gruppen, eine substituierte oder unsubstituierte Amino¬ gruppe oder Halogen tragen kann; oder einen substituierten oder unsubstituierten Aralkyl- oder Heteroarylalkylrest, wobei einer der Reste Ri oder R2 auch zusammen mit dem Rest R3 einen substituierten oder unsubstituierten hetero- cyclischen Ring bilden kann,R3 is a hydrogen atom, a straight-chain or branched C -Cg alkyl radical which is substituted by one or more hydroxyl or Ci-Cβ-alkoxy groups, a substituted or unsubstituted amino group or halogen may be substituted; a straight-chain or branched C2-C6 ~ alkenyl radical which can also carry one or more hydroxy or Ci-Cö alkoxy groups, a substituted or unsubstituted amino group or halogen; or a substituted or unsubstituted aralkyl or heteroarylalkyl radical, where one of the radicals R 1 or R 2 can also form a substituted or unsubstituted heterocyclic ring together with the radical R 3,
undand
R4 ein Wasserstoffatom, ein Halogenatom, eine Hydroxygruppe, eine Ci-Ce-Alkoxygruppe, eine Ci-Cg-Alkylendioxygruppe, eine Ci-Cg-Alkylgruppe, eine ein- oder mehrfach substi¬ tuierte Aminogruppe, oder eine substituierte oder un¬ substituierte Benzyloxygruppe,R4 is a hydrogen atom, a halogen atom, a hydroxy group, a Ci-Ce-alkoxy group, a Ci-Cg-alkylenedioxy group, a Ci-Cg-alkyl group, a mono- or polysubstituted amino group, or a substituted or unsubstituted benzyloxy group,
mit der Maßgabe, daß Ri nicht Wasserstoff bedeuten kann, wenn R2 einen unsubstituierten Ci-Cg-Alkylrest darstellt,with the proviso that Ri cannot be hydrogen if R 2 is an unsubstituted Ci-Cg-alkyl radical,
bedeuten, sowie deren pharmakologisch unbedenkliche Salze.mean, and their pharmacologically acceptable salts.
Rl bedeutet ein Wasserstoffatom, einen geradkettigen oder verzweigten Alkylrest von 1-6 Kohlenstoffatomen, wie z.B. den Methyl-, Ethyl-, n-Propyl-, Isopropyl-, Butyl-, Pentyl- oder Hexylrest.Rl represents a hydrogen atom, a straight-chain or branched alkyl radical of 1-6 carbon atoms, such as e.g. the methyl, ethyl, n-propyl, isopropyl, butyl, pentyl or hexyl radical.
R2 bedeutet eine geradkettige oder verzweigte Alkylgruppe von 1-6 Kohlenstoffatomen, die noch durch eine oder mehrere Hydroxy-, Alkoxy-, Mercapto- oder Alkyl ercaptogruppen oder durch einen substituierten oder unsubstituierten Phenylrest substituiert sein kann. Bevorzugt sind die Methyl-, Ethyl-, n- Propyl-, Isopropyl-, n-Butyl-, Isobutyl-, n-Pentyl-, Isopen- tyl-, n-Hexyl und die Isohexylgruppe. Unter Alkoxygruppen versteht man im allgemeinen Methoxy- oder Ethoxygruppen. Als Alkylmercaptogruppen kommen die Methyl- mercapto- oder die Ethylmercaptogruppe in Betracht. Die Substi- tuenten des Phenylrestes können sein, eine Ci-Cg-Alkylgruppe, wie die Methyl- oder Ethylgruppe, eine Ci-Cg-Alkoxygruppe wie die Methoxy-, Ethoxy- oder Propoxygruppe oder ein Halogenatom, wie Chlor, Brom oder Fluor.R2 denotes a straight-chain or branched alkyl group of 1-6 carbon atoms, which can also be substituted by one or more hydroxyl, alkoxy, mercapto or alkyl erapto groups or by a substituted or unsubstituted phenyl radical. The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl and isohexyl groups are preferred. Alkoxy groups are generally understood to be methoxy or ethoxy groups. The methyl mercapto or the ethyl mercapto group are suitable as alkyl mercapto groups. The substituents of the phenyl radical can be a Ci-Cg-alkyl group such as the methyl or ethyl group, a Ci-Cg-alkoxy group such as the methoxy, ethoxy or propoxy group or a halogen atom such as chlorine, bromine or fluorine.
Stellt R2 einen cycloalkylrest dar, versteht man darunter einen Cyclopentyl- oder Cyclohexylrest. Bedeutet R2 einen substi¬ tuierten Phenylring, so kommen als Substituenten in Betracht eine oder mehrere Ci-Cg-Alkylgruppen, wie Methyl-, Ethyl-, Propyl-, Isopropyl- oder Butylgruppen, eine oder mehrere Hydroxygruppen, eine oder mehrere Ci-Cg-Alkoxygruppen, wie Methoxy-, Ethoxy- oder Propoxygruppen, ein oder mehrere Halogenatome, wie Fluor, Chlor, Brom oder Jod oder eine unsub- stituierte oder durch eine oder zwei Ci-Cg-Alkylgruppen substituierte Aminoganippe, wie die Methylamino-, Ethylamino-, Dimethylamino- oder Diethylaminogruppe.If R2 represents a cycloalkyl radical, it means a cyclopentyl or cyclohexyl radical. If R2 is a substituted phenyl ring, one or more Ci-Cg-alkyl groups, such as methyl, ethyl, propyl, isopropyl or butyl groups, one or more hydroxyl groups, one or more Ci-Cg- Alkoxy groups, such as methoxy, ethoxy or propoxy groups, one or more halogen atoms, such as fluorine, chlorine, bromine or iodine or an unsubstituted or substituted by one or two Ci-Cg-alkyl groups, such as the methylamino, ethylamino, Dimethylamino or diethylamino group.
Stellt R2 einen unsubstituierten Aralkylrest dar, so versteht man darunter den Benzylrest. Bedeutet R2 einen substituierten Aralkylrest, so versteht man darunter einen substituierten Benzylrest. Die Substituenten können sein eine oder mehrere Alkylgruppen, wie Methyl-, Ethyl-, n-Propyl-, Isopropyl- oder Butylgruppen, eine Hydroxygruppe oder eine oder mehrere Alkoxy¬ gruppen, wie Methoxy- oder Ethoxygruppen, ein oder mehrere Halogenatome, wie Fluor, Chlor, Brom oder Jod oder eine unsub- stituierte oder substituierte Aminogruppe, wie die Methyl¬ amino-, Ethylamino-, Dimethylamino- oder Diethylaminogruppe.If R2 represents an unsubstituted aralkyl radical, this means the benzyl radical. If R2 is a substituted aralkyl radical, it means a substituted benzyl radical. The substituents can be one or more alkyl groups, such as methyl, ethyl, n-propyl, isopropyl or butyl groups, a hydroxyl group or one or more alkoxy groups, such as methoxy or ethoxy groups, one or more halogen atoms, such as fluorine, Chlorine, bromine or iodine or an unsubstituted or substituted amino group, such as the methylamino, ethylamino, dimethylamino or diethylamino group.
Stellt R2 einen gesättigten heterocyclischen heterocyclischen Ring dar, versteht man darunter einen Piperidin- oder Pyrroli- dinring. Bedeutet R2 einen unsubstituierten oder substituierten heteroaromatischen Rest, versteht man darunter einen unsubsti- tuierten oder substituierten Pyridinring, der in 2, 3 oder 4- Stellung verknüpft sein kann, wobei als Substituenten ein oder mehrere Halogenatome, wie Chlor, Brom oder Fluor, Alkoxygruppen wie die Methoxy- oder Ethoxygruppe oder Alkylgruppen wie die Methyl-, Ethyl oder Propylgruppe in Betracht kommen.If R2 represents a saturated heterocyclic heterocyclic ring, it means a piperidine or pyrrolidine ring. If R2 represents an unsubstituted or substituted heteroaromatic radical, it means an unsubstituted Tuiert or substituted pyridine ring, which may be linked in the 2, 3 or 4-position, with substituents one or more halogen atoms, such as chlorine, bromine or fluorine, alkoxy groups such as the methoxy or ethoxy group or alkyl groups such as the methyl, ethyl or propyl group be considered.
Unter einem Heteroarylalkylrest für R2 versteht man einen Pyridylmethylrest, z.B. den Pyridyl-2-methyl-, Pyridyl-3- methyl- oder den Pyridyl-4-methylrest, den Indolyl-3-methylrest oder den Imidazolyl-4-methylrest.A heteroarylalkyl radical for R2 is a pyridylmethyl radical, e.g. the pyridyl-2-methyl, pyridyl-3-methyl or the pyridyl-4-methyl radical, the indolyl-3-methyl radical or the imidazolyl-4-methyl radical.
R3 kann ein Wasserstoffatom oder eine geradkettige oder ver¬ zweigte Ci-Cg Alkylgruppe bedeuten, die noch durch eine oder mehrere Hydroxy-, Alkoxy oder Aminogruppen, oder ein Halogen¬ atom substituiert sein kann. Bevorzugt sind die Methyl-, Ethyl-, n-Propyl-, Isopropyl-, n-Butyl-, Isobutyl-, n-Pentyl-, Isopentyl-, n-Hexyl-, Isohexyl-, Hydroxyethyl-, Methoxymethyl-, Ethoxyethyl-, 2-Hydroxypropyl-, 2,3-Methylendioxypropyl-, Dimethyl ethylendioxypropyl , 2-Hydroxy-3-dimethyla inopropyl-, 2-Dimethylaminoethyl und die (2-Hydroxy-ethoxy)-methylgruppe. Unter einem Halogenatom versteht man Chlor oder Brom. Bevorzugt sind die 2-Chlorethyl-, 2-Bromethyl-, 3-Chlorpropyl-, 3-Brom- propyl-, 4-Chlorbutyl- und die 4-Brombutylgruppe.R3 can denote a hydrogen atom or a straight-chain or branched Ci-Cg alkyl group, which can also be substituted by one or more hydroxyl, alkoxy or amino groups, or a halogen atom. The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, hydroxyethyl, methoxymethyl, ethoxyethyl, 2-hydroxypropyl, 2,3-methylenedioxypropyl, dimethyl ethylenedioxypropyl, 2-hydroxy-3-dimethyla inopropyl, 2-dimethylaminoethyl and the (2-hydroxyethoxy) methyl group. A halogen atom means chlorine or bromine. The 2-chloroethyl, 2-bromoethyl, 3-chloropropyl, 3-bromopropyl, 4-chlorobutyl and 4-bromobutyl groups are preferred.
R3 kann auch eine geradkettige oder verzweigte C2-Ce-Alkenyl- gruppe bedeuten, die noch durch eine Hydroxy- oder Alkoxygruppe oder ein Halogenatom substituiert sein kann. Bevorzugt sind die Vinyl-, Allyl-, 2-Methylallyl, Isobutenyl-, Pentenyl-, Iso- pentenyl-, Hexenyl-, Isohexenyl-, 5-Hydroxy-penten-3-yl und die 5-Methoxy-penten-3-ylgruppe. Unter einem Halogenatom versteht man Chlor oder Brom.R3 can also mean a straight-chain or branched C2-Ce alkenyl group, which can also be substituted by a hydroxyl or alkoxy group or a halogen atom. The vinyl, allyl, 2-methylallyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, 5-hydroxypenten-3-yl and the 5-methoxy-penten-3-yl group are preferred . A halogen atom means chlorine or bromine.
Bedeutet R3 einen Aralkylrest, versteht man darunter einen Benzylrest. Bedeutet R3 einen substituierten Aralkylrest ver¬ steht man darunter einen substituierten Benzylrest. Als Substituenten kommen in Frage, eine oder mehrere Hydroxy- gruppen, eine oder mehrere Alkoxygruppen, wie z.B. Methoxy-, Ethoxy- oder Allyloxygruppen oder ein oder mehrere Halogenatome wie Chlor, Brom oder Fluor oder eine oder mehrere Alkylgruppen, wie z.B. Methyl-, Ethyl- oder Propylgruppen.If R 3 is an aralkyl radical, it means a benzyl radical. If R3 is a substituted aralkyl radical, this means a substituted benzyl radical. Suitable substituents are one or more hydroxyl groups, one or more alkoxy groups, such as methoxy, ethoxy or allyloxy groups, or one or more halogen atoms such as chlorine, bromine or fluorine or one or more alkyl groups, such as methyl or ethyl - or propyl groups.
Bedeutet R3 einen Heteroarylalkylrest versteht man darunter einen 2-,3- oder 4-Pyridylmethylrest, der noch durch eine oder mehrere Alkoxygruppen, wie Methoxy- oder Ethoxygruppen durch eine oder mehrere Alkylgruppen, wie z.B. Methyl-, Ethyl- oder Propylgruppen oder durch ein oder mehrere Halogenatome, wie Chlor oder Brom substituiert sein kann.If R3 is a heteroarylalkyl radical, it means a 2-, 3- or 4-pyridylmethyl radical, which is also represented by one or more alkoxy groups, such as methoxy or ethoxy groups, by one or more alkyl groups, such as e.g. Methyl, ethyl or propyl groups or can be substituted by one or more halogen atoms, such as chlorine or bromine.
R4 kann Wasserstoff, ein Halogenatom, wie Fluor, Chlor oder Brom, eine Hydroxygruppe, eine Alkylgruppe, wie die Methyl¬ oder Ethylgruppe, eine Alkoxygruppe, wie die Methoxy- oder Ethoxygruppe, eine Alkylendioxygruppe, wie die Methylendioxy- gruppe oder eine substituierte oder unsubstituierte Benzyloxy- gruppe bedeuten, wobei als Substituenten eine oder mehrere Alkoxygruppen, wie Methoxy- oder Ethoxygruppen, ein oder mehrere Haigenatome, wie Chlor, Fluor oder Brom und ein oder mehrere Alkylgruppen, wie die Methyl-, Ethyl- oder Propylgruppe in Frage kommen.R4 can be hydrogen, a halogen atom, such as fluorine, chlorine or bromine, a hydroxyl group, an alkyl group, such as the methyl or ethyl group, an alkoxy group, such as the methoxy or ethoxy group, an alkylenedioxy group, such as the methylenedioxy group, or a substituted or unsubstituted group Benzyloxy group, where substituents are one or more alkoxy groups, such as methoxy or ethoxy groups, one or more Haigen atoms, such as chlorine, fluorine or bromine, and one or more alkyl groups, such as the methyl, ethyl or propyl group.
Bildet einer der Reste Ri oder R2 zusammen mit dem Rest R3 einen substituierten oder unsubstituierten heterocyclischen Ring, versteht man darunter einen Pyrrolidin- oder Hydroxy- pyrrolidinring.If one of the radicals R 1 or R 2 forms a substituted or unsubstituted heterocyclic ring together with the radical R 3, this is understood to mean a pyrrolidine or hydroxypyrrolidine ring.
Bilden die Reste i und R2 zusammen einen C3~C7- ing, versteht man darunter einen Spiro-Cyclopropyl-, Spiro-Cyclobutyl-, Spiro-Cyclopentyl-, Spiro-Cyclohexyl- oder Spiro-Cycloheptyl- ring.If the residues i and R 2 together form a C 3 ~ C 7- ing, this means a spiro-cyclopropyl, spiro-cyclobutyl, spiro-cyclopentyl, spiro-cyclohexyl or spiro-cycloheptyl ring.
Die substituierten Reste, wie z. B. ein substituierter Phenyl-, Aralkyl- oder Heteroarylalkylrest oder ein gesättigter oder aromatischer heterocyclischer Rest, können in allen Fällen ein-, zwei- oder dreifach substituiert sein durch Ci-Cg-Alkyl, Ci-Cg-Alkoxy, Halogen, Hydroxy, Amino, Ci-Cg-Alkylamino oder Di-Ci-Cg-alkylamino.The substituted radicals, such as. B. a substituted phenyl, aralkyl or heteroarylalkyl radical or a saturated or aromatic heterocyclic radical can in all cases be mono-, di- or trisubstituted by Ci-Cg-alkyl, Ci-Cg-alkoxy, halogen, hydroxy, amino, Ci-Cg-alkylamino or di-Ci-Cg-alkylamino.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können ein oder mehrere asymmetrische Kohlenstoffatome be¬ sitzen. Gegenstand der Erfindung sind daher auch sämtliche optisch aktiven und diastereomeren Formen und racemische und diastereomeren Gemische.The compounds of general formula I according to the invention can have one or more asymmetric carbon atoms. The invention therefore also relates to all optically active and diastereomeric forms and racemic and diastereomeric mixtures.
Die Verbindungen der allgemeinen Formel I,The compounds of the general formula I
Figure imgf000009_0001
Figure imgf000009_0001
in der R , R , R3 und R4 die angegebenen Bedeutungen besitzen, werden hergestellt, indem man eine Verbindung der allgemeinen Formel II,in which R, R, R3 and R4 have the meanings given, are prepared by using a compound of the general formula II,
Figure imgf000009_0002
Figure imgf000009_0002
in der R^, 2, R3 und R4 die angegebenen Bedeutungen besitzen, nach einer herkömmlichen Methode mit einem die Thiocarbonyl- Gruppe übertragenden Reagenz, wie z.B. mit Schwefelkohlenstoff, Thiocarbonyl-diimidazol, Thiophosgen oder Thioharnstoff um¬ setzt. Die Verbindungen der allgemeinen Formel II werden hergestellt, indem man in einer Verbindung der allgemeinen Formel III,in which R ^, 2, R3 and R4 have the meanings given, according to a conventional method with a reagent which transfers the thiocarbonyl group, such as, for example, carbon disulfide, thiocarbonyldiimidazole, thiophosgene or thiourea. The compounds of the general formula II are prepared by, in a compound of the general formula III,
Figure imgf000010_0001
Figure imgf000010_0001
in der R_, R2, R3 und R4 die angegebenen Bedeutungen besitzen, nach einer dem Fachmann bekannten üblichen Methode die Nitro- gruppe in eine Aminogruppe überführt.in which R_, R2, R3 and R4 have the meanings given, the nitro group is converted into an amino group by a conventional method known to the person skilled in the art.
Die Verbindungen der allgemeinen Formel III können dargestellt werden, indem man eine Verbindung der allgemeinen Formel IV,The compounds of general formula III can be prepared by using a compound of general formula IV,
Figure imgf000010_0002
Figure imgf000010_0002
in der R_, R2 und R4 die angegebenen Bedeutungen besitzen, mit einer Verbindung der allgemeinen Formel V,in which R_, R2 and R4 have the meanings given, with a compound of the general formula V,
R3-X VR3-X V
in der X ein Halogenatom oder eine Sulfonestergruppierung darstellt, zur Reaktion bringt.in which X represents a halogen atom or a sulfonic ester grouping.
Die Verbindungen der allgemeinen Formel IV können dargestellt werden, indem man eine Verbindung der allgemeinen Formel VI,The compounds of general formula IV can be represented by using a compound of the general formula VI,
Figure imgf000011_0001
Figure imgf000011_0001
in der R^, R2 und R4 die angegebenen Bedeutungen besitzen und Y ein Halogenatom bedeutet, einer Cyclisierungsreaktion unter¬ wirft.in which R 1, R 2 and R 4 have the meanings indicated and Y represents a halogen atom, is subjected to a cyclization reaction.
Die Verbindungen der allgemeinen Formel VI werden dargestellt, indem man eine Verbindung der allgemeinen Formel VII,The compounds of general formula VI are prepared by using a compound of general formula VII,
Figure imgf000011_0002
Figure imgf000011_0002
in der ^, R2, R4 und Y die angegebenen Bedeutungen besitzen, einer Reduktion mit Borwasserstoff oder Diboran unterwirft. Die Verbindungen der allgemeinen Formel VII können dargestell werden, indem man eine Verbindung der allgemeinen Formel VIII,in which ^, R2, R4 and Y have the meanings given, subject to a reduction with hydrogen boron or diborane. The compounds of general formula VII can be prepared by using a compound of general formula VIII,
Figure imgf000012_0001
in der R_, R2, R4 und Y die angegebenen Bedeutungen besitzen, und R5 Wasserstoff oder einen Alkylrest bedeutet nach dem Fachmann bekannten Methoden einem Amidierungsreaktion unter¬ zieht.
Figure imgf000012_0001
in which R_, R2, R4 and Y have the meanings given, and R5 denotes hydrogen or an alkyl radical, undergoes an amidation reaction by methods known to the person skilled in the art.
Die Verbindungen der allgemeinen Formel VIII können dargestel werden, indem man eine Verbindung der allgemeinen Formel IX,The compounds of general formula VIII can be prepared by using a compound of general formula IX,
Figure imgf000012_0002
Figure imgf000012_0002
in der R4 und Y die angegebenen Bedeutungen besitzen mit einem Aminosäureester der allgemeinen Formel X,in which R4 and Y have the meanings given with an amino acid ester of the general formula X,
H2N C C02R5 X,H 2 NC C0 2 R 5 X,
/ \/ \
R2 Rχ R 2 R χ
in der R]_ und R2 die angegebenen Bedeutungen besitzen und eine der Reste R_ oder R2 mit der Aminogruppe zusammen gegebenen¬ falls einen Pyrrolidin oder Hydroxypyrrolidinring bilden kann und R5 Wasserstoff oder einen Alklyrest bedeutet nach einer d Fachmann bekannten Methoden zur Reaktion bringt. Die Verbindungen der allgemeinen Formel IX sind literatur¬ bekannt oder können nach literaturbekannten Methoden darge¬ stellt werden.in which R ] _ and R2 have the meanings given and one of the radicals R_ or R2 together with the amino group can, if appropriate, form a pyrrolidine or hydroxypyrrolidine ring and R5 is hydrogen or an alkyl radical, by a method known to those skilled in the art. The compounds of the general formula IX are known from the literature or can be prepared by methods known from the literature.
Die Verbindungen der allgemeinen Formel X sind literaturbekan oder können nach bekannten Methoden hergestellt werden.The compounds of general formula X are known from the literature or can be prepared by known methods.
Die Umsetzungen der Verbindungen der allgemeinen Formel II mi einem eine Thiocarbonylgruppe übertragenden Reagenz zu einer Verbindung der allgemeinen Formel I werden durchgeführt, inde man z.B. eine Verbindung der allgemeinen Formel II mit Schwefelkohlenstoff in einer wäßrig-alkoholischen Lösung in Gegenwart von Alkali nach einer dem Fachmann bekannten Method zur Reaktion bringt oder indem man eine Verbindung der allge¬ meinen Formel II mit Thiocarbonyldiimidazol in einem inerten Lösungsmittel, wie z.B. Dimethylformamid zur Reaktion bringt.The reactions of the compounds of general formula II with a reagent transferring a thiocarbonyl group to a compound of general formula I are carried out, e.g. reacting a compound of the general formula II with carbon disulphide in an aqueous-alcoholic solution in the presence of alkali by a method known to the person skilled in the art or by reacting a compound of the general formula II with thiocarbonyldiimidazole in an inert solvent, such as e.g. Dimethylformamide brings to reaction.
Die Verbindungen der allgemeinen Formel II werden hergestellt indem man in einer Verbindung der allgemeinen Formel die Nitr gruppe nach einer dem Fachmann bekannten Methode in eine Amin gruppe überführt.The compounds of the general formula II are prepared by converting the nitr group into an amine group in a compound of the general formula by a method known to those skilled in the art.
Die Umsetzung der Verbindungen der allgemeinen Formel IV mit Verbindungen der allgemeinen Formel V zu Verbindungen der allgemeinen Formel III werden durchgeführt, daß man die Verbi dungen der allgemeinen Formel IV mit Verbindungen der all¬ gemeinen Formel V in einem inerten Lösungsmittel, wie z.B. Dimethylformamid, Di ethylacetamid, Aceton, Methylethylketon oder Alkohol bei bei Temperaturen zwischen Raumtemperatur und Rückflußtemperatur des Lösungsmittels, vorzugsweise zwischen 40"C und 60βC in Gegenwart eines alkalischen Kondensationsmit tels, wie z.B. Natriumkarbonat oder Kaliumcarbonat nach dem Fachmann bekannten Methoden zur Reaktion bringt. Die Cyclisierung einer Verbindung der allgemeinen Formel VI zu einer Verbindung der allgemeinen Formel IV kann durchgeführt werden, indem man eine Verbindung der allgemeinen Formel VI in einem inerten Lösungsmittel, wie z.B. Dimethylformamid, Di- methylacetamid, Aceton, Methylethylketon oder Alkohol in Gegen¬ wart eines alkalischen Kondensatinsmittels, wie z.B. Natriumkarbonat oder Kaliumkarbonat bei Temperaturen zwischen Raumtemperatur und Rückflußtemperatur des Lösungsmittels zur Reaktion bringt.The reaction of the compounds of the general formula IV with compounds of the general formula V to give compounds of the general formula III are carried out by reacting the compounds of the general formula IV with compounds of the general formula V in an inert solvent, such as, for example, dimethylformamide, di ethyl acetamide, acetone, methyl ethyl ketone or alcohol at temperatures between room temperature and reflux temperature of the solvent, means of, for example sodium carbonate or potassium carbonate to the skilled person by methods known brings preferably between 40 "C and 60 β C in the presence of an alkaline Kondensationsmit to the reaction. The cyclization of a compound of the general formula VI to a compound of the general formula IV can be carried out by using a compound of the general formula VI in an inert solvent, such as, for example, dimethylformamide, dimethyl acetamide, acetone, methyl ethyl ketone or alcohol alkaline condensate, such as sodium carbonate or potassium carbonate at temperatures between room temperature and the reflux temperature of the solvent to react.
Die Cyclisierungsreaktion einer Verbindung der allgemeinen Formel VI zu einer Verbindung der allgemeinen Formel IV kann auch durchgeführt werden, daß man eine Verbindung der all¬ gemeinen Formel IV in Gegenwart eines alkalischen Kondensa¬ tionsmittels, wie z.B. Natriumkarbonat oder Kaliumkarbonat ohne Zusatz eines Lösungsmittels auf Temperaturen zwischen 100βC und 200*C, vorzugsweise zwischen 130'C und 170βC erhitzt.The cyclization reaction of a compound of the general formula VI to a compound of the general formula IV can also be carried out by reacting a compound of the general formula IV in the presence of an alkaline condensing agent, such as, for example, sodium carbonate or potassium carbonate, at temperatures between 100 β C and 200 * C, preferably between 130'C and 170 β C heated.
Die Verbindungen der allgemeinen Formel VI werden dargestellt, daß man eine Verbindung der allgemeinen Formel VII mit Bor¬ wasserstoff oder Diboran in einem inerten Lösungsmitel, wie z.B. Tetrahydrofuran, Dioxan, Diethylether oder Methylenchlorid bei Temperaturen zwischen Raumtemperatur und Rückflußtemperatur des Lösungsmittels zur Reaktion bringt oder indem man eine Verbindung der allgmeinen Formel VI in einem inerten Lösungs¬ mittel, wie z.B. Methylenchlorid der Reduktion mit einem Tetra- alkylammoniumborhydrid unterwirft.The compounds of the general formula VI are shown by reacting a compound of the general formula VII with hydrogen boron or diborane in an inert solvent, such as e.g. Tetrahydrofuran, dioxane, diethyl ether or methylene chloride at temperatures between room temperature and reflux temperature of the solvent or by reacting a compound of general formula VI in an inert solvent such as e.g. Subjects methylene chloride reduction with a tetraalkylammonium borohydride.
Die Verbindungen der allgemeinen Formel VII werden dargestellt, indem man eine Verbindung der allgemeinen Formel VIII nach dem Fachmann und literaturbekannten Methoden einer Amidbildungs- reaktion unterzieht.The compounds of the general formula VII are prepared by subjecting a compound of the general formula VIII to an amide formation reaction according to the person skilled in the art and methods known from the literature.
Die Verbindungen der allgemeinen Formel VIII können dargestellt werden, indem man eine Verbindung der allgemeinen Formel IX nach dem Fachmann bekannten Methoden mit einer Verbindung der allgemeinen Formel X zur Reaktion bringt. Besonders bevorzugte Verbindungen der allgemeinen Formel I sind folgende Verbindungen:The compounds of general formula VIII can be prepared by reacting a compound of general formula IX with a compound of general formula X by methods known to those skilled in the art. The following compounds are particularly preferred compounds of the general formula I:
4,5,6,7-Tetrahydro-5,5-dimethyl-6-(3-methyl-2-butenyl)-imidazo- [4,5,ljk][l,4]benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5,5-dimethyl-6- (3-methyl-2-butenyl) imidazo [4,5, ljk] [1,4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-5-phenyl-6-(3-methyl-2-butenyl)-imi¬ dazo[4,5,1jk] [1, ]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5-phenyl-6- (3-methyl-2-butenyl) -imi¬ dazo [4,5,1jk] [1,] -benzodiazepin-2 (1H) -thione
4,5,6,7-Tetrahydro-5-(4-chlor-phenyl)-6-(3-methyl-2-butenyl)- imidazo-[4,5,lj ][1.4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (4-chlorophenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, lj] [1.4] benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-5-(4-methyl-phenyl)-6-(3-methyl-2-butenyl)- imidazo[4,5,lj ][l,4]-benzodiazepin-2-(1H)-thion4,5,6,7-tetrahydro-5- (4-methylphenyl) -6- (3-methyl-2-butenyl) imidazo [4,5, lj] [1,4] benzodiazepine-2- (1H) -thione
4,5,6,7-Tetrahydro-5-(4-ethyl-phenyl)-6-(3-methyl-2-butenyl)- imidazo[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (4-ethylphenyl) -6- (3-methyl-2-butenyl) imidazo [4,5,1jk] [1,4] benzodiazepine-2 ( 1H) -thione
4,5,6,7-Tetrahydro-5-(4-Methoxy-phenyl)-6-(3-methyl-2-butenyl)- imidazo-[4,5,ljk][l,4]-benzodiazepin-2 (1H)-thion4,5,6,7-tetrahydro-5- (4-methoxyphenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-5-(3,4-dichlor-phenyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (3,4-dichlorophenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] benzodiazepine -2 (1H) thione
4,5,6,7-Tetrahydro-5-benzyl-6-(3-methyl-2-butenyl)-imidazo-4,5,6,7-tetrahydro-5-benzyl-6- (3-methyl-2-butenyl) imidazo
[4,5,1jk] [1,4]-benzodiazepin-2-(1H)-thion[4,5,1jk] [1,4] benzodiazepine-2- (1H) thione
4,5,6,7-Tetrahydro-5-(4-chlor-benzyl)-6-(3-methyl-2-butenyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (4-chlorobenzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1,4] benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-5-(4-Methoxy-benzyl)-6-(3-methyl-2-butenyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2 (1H)-thion4,5,6,7-tetrahydro-5- (4-methoxybenzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1,4] benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-5-(4-methyl-benzyl)-6-(3-methyl-2-butenyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion 4,5,6,-Tetrahydro-5-(3,4-dichlor-benzyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,lj ][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (4-methyl-benzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (1H) -thione 4,5,6, -Tetrahydro-5- (3,4-dichlorobenzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, lj] [1,4] benzodiazepine 2 (1H) thione
4,5,6,7-Tetrahydro-5-(3,4-dimethoxy-benzyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (3,4-dimethoxybenzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] benzodiazepine -2 (1H) thione
4,5,6,7-Tetrahydro-5-(3, -dimethoxy-phenyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (3, -dimethoxy-phenyl) -6- (3-methyl-2-butenyl) -imidazo- [4,5, ljk] [1,4] benzodiazepine 2 (1H) thione
4,5,6,7-Tetrahydro-9-chlor-5-phenyl-6-(3-methyl-2-butenyl)- imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5-phenyl-6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-chlor-phenyl)-6-(3-methyl-2- butenyl)-imidazo-[4 ,5,ljk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-chlorophenyl) -6- (3-methyl-2-butenyl) imidazo- [4, 5, ljk] [1,4] -benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-chlor-5-(4-methyl-phenyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-methylphenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-chlor-5-(4-ethyl-phenyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,lj ][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-ethylphenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, lj] [1,4] -benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-chlor-5-(4-methoxy-phenyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,ljk] [l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-methoxyphenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dimethoxy-phenyl)-6-(3- methyl-2-butenyl)-imidazo-[4,5,ljk] [l,4]-benzodiazepin-2(1H)- thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dimethoxyphenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [l, 4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dichlor-phenyl)-6-(3-methyl- 2-butenyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dichlorophenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1, 4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-9-chlor-5-benzyl-6-(3-methyl-2-butenyl)- imidazo-[4,5,ljk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5-benzyl-6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-methoxy-benzyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,ljk] [l,4]-benzodiazepin-2 (1H)-thion 4,5,6,7-Tetrahydro-9-chlor-5,5-dimethyl-6-(3-methyl-2-butenyl)- imidazo-[4,5,l,jk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-methoxy-benzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (1H) -thione 4,5,6,7-tetrahydro-9-chloro-5,5-dimethyl-6- (3-methyl-2-butenyl) imidazo- [4,5, l, jk] [l, 4] -benzodiazepine -2 (1H) thione
4,5,6,7-Tetrahydro-9-chlor-5-(4-chlor-benzyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,ljk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-chlorobenzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dichlor-benzyl)-6-(3-methyl- 2-butenyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dichlorobenzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [l, 4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dimethoxy-benzyl)-6-(3- methyl-2-butenyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)- thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dimethoxy-benzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1, 4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-9-brom-5,5-dimethyl-6-(3-methyl-2-butenyl)- imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5,5-dimethyl-6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-brom-5-phenyl-6-(3-methyl-2-butenyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5-phenyl-6- (3-methyl-2-butenyl) imidazo [4,5,1jk] [1,4] benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-9-brom-5-(4-chlorphenyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-chlorophenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] benzodiazepine -2 (1H) thione
4,5,6,7-Tetrahydro-9-brom-5-(4-methyl-phenyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-methylphenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-brom-5-(4-ethyl-phenyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,1jk] [1, ]-benzodiazepin-2 (1H)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-ethylphenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1,] - benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-9-brom-5-(4-methoxy-phenyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-methoxyphenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-brom-5-(3,4-dimethoxy-phenyl)-6-(3-methyl- 2-butenyl)-imidazo-[4,5,ljk] [l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5- (3,4-dimethoxyphenyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [l, 4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-9-brom-5-(3,4-dichlor-phenyl)-6-(3-methy1-2- butenyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion 4,5,6,7-Tetrahydro-9-brom-5-(benzyl)-6-(3-methyl-2-butenyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5- (3,4-dichlorophenyl) -6- (3-methy1-2-butenyl) imidazo- [4,5,1jk] [1, 4] benzodiazepine-2 (1H) thione 4,5,6,7-tetrahydro-9-bromo-5- (benzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1,4] benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-brom-5-(4-methoxy-benzyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-methoxy-benzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-brom-5-(4-chlor-benzyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-chlorobenzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-brom-5-(3,4-dichlor-benzyl)-6-(3-methyl-2- butenyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-bromo-5- (3,4-dichlorobenzyl) -6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [l, 4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-5,5-dimethyl-6-(3-methyl-butyl)-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(lH)-thion4,5,6,7-tetrahydro-5,5-dimethyl-6- (3-methylbutyl) imidazo [4,5, ljk] [1,4] benzodiazepine-2 (lH) thione
4,5,6,7-Tetrahydro-5-phenyl-6-(3-methyl-butyl)-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5-phenyl-6- (3-methylbutyl) imidazo [4,5, ljk] [1,4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-5-(4-chlor-phenyl)-6-(3-methyl-butyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (4-chlorophenyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-5-(4-methyl-phenyl)-6-(3-methyl-butyl)- imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (4-methylphenyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-5-( -ethyl-phenyl)-6-(3-methyl-butyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (-ethylphenyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine-2 (1H) -thion
4,5,6,7-Tetrahydro-5(4-methoxy-phenyl)-6-(3-methyl-butyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5 (4-methoxyphenyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine-2 (1H) -thion
4,5,6,7-Tetrahydro-5-(3,4-dimethoxy-phenyl)-6-(3-methyl-butyl)- imidazo-[4,5,lj ][l,4]-benzodiazepin-2 (1H)-thion4,5,6,7-tetrahydro-5- (3,4-dimethoxyphenyl) -6- (3-methylbutyl) imidazo- [4,5, lj] [1,4] benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-5-(3,4-dichlor-phenyl)-6-(3-methyl-butyl)- imidazo-[ ,5,1j ] [1,4]-benzodiazepin-2 (1H)-thion 4,5,6,7-Tetrahydro-5-benzyl-6-(3-methyl-butyl)-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (3,4-dichlorophenyl) -6- (3-methylbutyl) imidazo- [, 5.1j] [1,4] -benzodiazepine-2 ( 1H) -thione 4,5,6,7-tetrahydro-5-benzyl-6- (3-methylbutyl) imidazo [4,5, ljk] [1,4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-5-(4-chlor-benzyl)-6-(3-methyl-butyl)- imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (4-chlorobenzyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-5-(4-methoxy-benzyl)-6-(3-methyl-butyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (4-methoxybenzyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-5-(4-methyl-benzyl)-6-(3-methyl-butyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (4-methylbenzyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-5-(3,4-dichlor-benzyl)-6-(3-methyl-butyl)- imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (3,4-dichlorobenzyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-5-(3,4-dimethoxy-benzyl)-6-(3-methyl-butyl)- imidazo-[4,5,ljk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-5- (3,4-dimethoxybenzyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-9-chlor-5,5-dimethyl-6-(3-methyl-butyl)- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5,5-dimethyl-6- (3-methyl-butyl) imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (1H ) -thion
4,5,6,7-Tetrahydro-9-chlor-5-phenyl-6-(3-methyl-butyl)-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(lH)-thion4,5,6,7-tetrahydro-9-chloro-5-phenyl-6- (3-methylbutyl) imidazo [4,5, ljk] [1,4] benzodiazepine-2 (lH) - thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-chlor-ρhenyl)-6-(3-methyl- butyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-chlorophenyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine -2 (1H) thione
4,5,6,7-Tetrahydro-9-chlor-5-(4-methyl-phenyl)-6-(3-methyl- butyl)-imidazo-[4,5,ljk] [l,4]-benzodiazepin-2(1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-methylphenyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine -2 (1H) thione
4,5,6,7-Tetrahydro-9-chlor-5-(4-ethyl-phenyl)-6-(3-methyl- butyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2 (1H)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-ethylphenyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine -2 (1H) thione
4,5,6,7-Tetrahydro-9-chlor-5-(4-methoxy-phenyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2 (1H)-thion 4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dimethoxy-phenyl)-6-(3- methyl-butyl)-imidazo-[4,5,ljk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-methoxyphenyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine -2 (1H) thione 4,5,6,7-tetrahydro-9-chloro-5- (3,4-dimethoxyphenyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dichlor-phenyl)-6-(3-methyl- butyl)-imidazo-[4,5,ljk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dichlorophenyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-9-chlor-5-benzyl-6-(3-methyl-butyl)-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(lH)-thion4,5,6,7-tetrahydro-9-chloro-5-benzyl-6- (3-methylbutyl) imidazo [4,5, ljk] [1,4] benzodiazepine-2 (lH) - thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-chlor-benzyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-chlorobenzyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine -2 (IH) thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-methoxy-benzyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1 ,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-methoxy-benzyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine -2 (IH) thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-methyl-benzyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-methylbenzyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine -2 (IH) thion
4,5,6,7-Tetrahydro-9-chlor-5-(3 ,4-dichlor-benzyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dichlorobenzyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dimethoxy-benzyl)-6-(3- methyl-butyl)-imidazo-[ ,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dimethoxy-benzyl) -6- (3-methyl-butyl) imidazo- [, 5.1jk] [1.4] - benzodiazepine-2 (IH) thione
4,5,6,7-Tetrahydro-9-brom-5,5-dimethyl-6-(3-methyl-butyl)- imidazo-[4,5,ljk][l,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-bromo-5,5-dimethyl-6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine-2 (IH ) -thion
4,5,6,7-Tetrahydro-9-brom-5-phenyl-6-(3-methyl-butyl)-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-bromo-5-phenyl-6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine-2 (IH) - thion
4,5,6,7-Tetrahydro-9-brom-5-(4-chlor-phenyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-chlorophenyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine -2 (IH) thion
4,5,6,7-Tetrahydro-9-brom-5-(4-methyl-phenyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2-(IH)-thion 4,5,6,7-Tetrahydro-9-brom-5-(4-ethyl-phenyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2-(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-methylphenyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine -2- (IH) thion 4,5,6,7-tetrahydro-9-bromo-5- (4-ethylphenyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine -2- (IH) thion
4,5,6,7-Tetrahydro-9-brom-5-(4-methoxy-pheny1)-6-(3-methyl- butyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2-(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-methoxypheny1) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine -2- (IH) thion
4,5,6,7-Tetrahydro-9-brom-5-(3,4-dimethoxy-phenyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2-(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (3,4-dimethoxyphenyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] -benzodiazepine-2- (IH) -thione
4,5,6,7-Tetrahydro-9-brom-5-(3,4-dichlor-phenyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2-(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (3,4-dichlorophenyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] -benzodiazepine-2- (IH) -thione
4,5,6,7-Tetrahydro-9-brom-5-benzyl-6-(3-methyl-butyl)-imidazo- [4,5,ljk][l,4]-benzodiazepin-2-(IH)-thion4,5,6,7-tetrahydro-9-bromo-5-benzyl-6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4, -benzodiazepine-2- (IH) -thion
4,5,6,7-Tetrahydro-9-brom-5-(4-chlor-benzyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2-(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-chlorobenzyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine -2- (IH) thion
4,5,6,7-Tetrahydro-9-brom-5-(4-methoxy-benzyl)-6-(3-methyl- butyl)-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2-(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-methoxybenzyl) -6- (3-methylbutyl) imidazo- [4,5,1jk] [1,4] benzodiazepine -2- (IH) thion
4,5,6,7-Tetrahydro-9-brom-5-(4-methyl-benzyl)-6-(3-methyl- butyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2-(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (4-methylbenzyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] benzodiazepine -2- (IH) thion
4,5,6,7-Tetrahydro-9-brom-5-(3,4-dichlor-benzyl)-6-(3-methyl- butyl)-imidazo-[4,5,ljk][l,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (3,4-dichlorobenzyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-9-brom-5-(3,4-dimethoxy-benzyl)-6-(3-methyl- butyl)-imidazo-[4,5,ljk] [l,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-bromo-5- (3,4-dimethoxybenzyl) -6- (3-methylbutyl) imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-5,5-dimethyl-6-isopropyl-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5,5-dimethyl-6-isopropyl-imidazo- [4,5, ljk] [1,4, -benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-5-phenyl-6-isopropyl-imidazo-[4,5,lj ] [1,4]- benzodiazepin-2 (IH)-thion - 20 -4,5,6,7-tetrahydro-5-phenyl-6-isopropyl-imidazo- [4,5, lj] [1,4] - benzodiazepine-2 (IH) -thione - 20 -
4,5,6,7-Tetrahydro-5-(4-chlor-phenyl)-6-isopropyl-imidazo- [4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5- (4-chlorophenyl) -6-isopropyl-imidazo [4,5,1jk] [1,4] benzodiazepine-2 (IH) thione
4,5,6,7-Tetrahydro-5-(4-brom-phenyl)-6-isopropyl-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(lH)-thion4,5,6,7-tetrahydro-5- (4-bromo-phenyl) -6-isopropyl-imidazo [4,5, ljk] [1,4] benzodiazepine-2 (1H) -thione
4,5,6,7-Tetrahydro-5-(4-methoxy-phenyl)-6-isopropyl-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(lH)-thion4,5,6,7-tetrahydro-5- (4-methoxyphenyl) -6-isopropyl-imidazo [4,5, ljk] [1,4] benzodiazepine-2 (1H) thione
4,5,6,7-Tetrahydro-5-(3,4-dimethoxy-phenyl)-6-isopropyl- imidazo-[4,5,1j ] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5- (3,4-dimethoxyphenyl) -6-isopropylimidazo [4,5,1j] [1,4] benzodiazepine-2 (IH) thione
4,5,6,7-Tetrahydro-5-(3 ,4-dichlor-phenyl)-6-isopropyl-imidazo- [4,5,ljk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5- (3, 4-dichlorophenyl) -6-isopropyl-imidazo- [4,5, ljk] [1,4] -benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-5-benzyl-6-isopropyl-imidazo-[4,5,1jk] [1,4] benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5-benzyl-6-isopropyl-imidazo- [4,5,1jk] [1,4] benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-5-(4-chlor-benzyl)-6-isopropyl-imidazo- [4,5,1jk][1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5- (4-chlorobenzyl) -6-isopropyl-imidazo- [4,5,1jk] [1,4] -benzodiazepin-2 (IH) thione
4,5,6,7-Tetrahydro-5-(4-brom-benzyl)-6-isopropyl-imidazo- [ ,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5- (4-bromo-benzyl) -6-isopropyl-imidazo- [, 5.1jk] [1,4] -benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-5-(3,4-dichlor-benzyl)-6-isopropyl-imidazo- [4,5,lj ][l,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5- (3,4-dichlorobenzyl) -6-isopropyl-imidazo [4,5, lj] [1,4] benzodiazepine-2 (IH) thione
4,5,6,7-Tetrahydro-5-(4-methoxy-benzyl)-6-isopropyl-imidazo- [4,5,ljk] [l,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5- (4-methoxy-benzyl) -6-isopropyl-imidazo [4,5, ljk] [1,4] benzodiazepine-2 (IH) thione
4,5,6,7-Tetrahydro-5-(3,4-dimethoxy-benzyl)-6-isopropyl- imidazo-[4,5,1j ] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-5- (3,4-dimethoxybenzyl) -6-isopropylimidazo [4,5,1j] [1,4] benzodiazepine-2 (IH) thione
4,5,6,7-Tetrahydro-9-chlor-5,5-dimethyl-6-isopropyl-imidazo- [4,5,lj ] [1,4]-benzodiazepin-2(IH)-thion 4,5,6,7-Tetrahydro-9-chlor-5-phenyl-6-isopropyl-imidazo- [4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5,5-dimethyl-6-isopropyl-imidazo- [4,5, lj] [1,4] -benzodiazepin-2 (IH) thione 4,5,6,7-tetrahydro-9-chloro-5-phenyl-6-isopropyl-imidazo [4,5,1jk] [1,4] benzodiazepine-2 (IH) thione
4,5,6,7-Tetrahydro-9-chlor-5-(4-chlor-phenyl)-6-isopropyl- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-chlorophenyl) -6-isopropylimidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH) - thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-brom-phenyl)-6-isopropyl- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-bromo-phenyl) -6-isopropyl-imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH) - thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-methoxy-phenyl)-6-isopropyl- imidazo-[4,5,1jk] [1, ]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-methoxyphenyl) -6-isopropylimidazo- [4,5,1jk] [1,] -benzodiazepine-2 (IH) -thione
4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dichlor-phenyl)-6-isopropyl- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dichlorophenyl) -6-isopropylimidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH ) -thion
4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dimethoxy-phenyl)-6-iso- propyl-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dimethoxy-phenyl) -6-isopropyl-imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH) -thion
4,5,6,7-Tetrahydro-9-chlor-5-benzyl-6-isopropyl-imidazo- [4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5-benzyl-6-isopropyl-imidazo [4,5,1jk] [1,4] benzodiazepine-2 (IH) thione
4,5,6,7-Tetrahydro-9-chlor-5-(4-chlor-benzyl)-6-isopropyl- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-chloro-benzyl) -6-isopropyl-imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH) - thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-brom-benzyl)-6-isopropyl- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-bromo-benzyl) -6-isopropyl-imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH) - thion
4,5,6,7-Tetrahydro-9-chlor-5-(3,4-dichlor-benzyl)-6-isopropyl- imidazo-[4,5,1jk] [1,4]-benzodiazepin-2 (IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (3,4-dichlorobenzyl) -6-isopropylimidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH ) -thion
4,5,6,7-Tetrahydro-9-chlor-5-(4-methoxy-benzyl)-6-isopropyl- i idazo-[4,5,1jk] [1,4]-benzodiazepin-2 (IH)-thion4,5,6,7-tetrahydro-9-chloro-5- (4-methoxy-benzyl) -6-isopropyl-i idazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH) -thion
4,5,6,7-Tetrahydro-9-chlor-5-(3 ,4-dimethoxy-benzyl)-6-iso- propyl-imidazo-[4,5,1jk] [1,4]-benzodiazepin-2(IH)-thion . .4,5,6,7-tetrahydro-9-chloro-5- (3,4-dimethoxy-benzyl) -6-isopropyl-imidazo- [4,5,1jk] [1,4] -benzodiazepine-2 (IH) -thion , ,
- 22 -- 22 -
Gegenstand der Erfindung sind auch Arzneimittel, die diese Verbindungen enthalten. Die Verbindungen der vorliegenden Erfindung weisen wertvolle pharmakologische Eigenschaften auf. Insbesondere eignen sie sich zur Therapie und Prophylaxe von Krankheiten, die durch das Humanes-Immunschwäche-Virus HIV-l verursacht werden.The invention also relates to medicaments which contain these compounds. The compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of diseases which are caused by the human immunodeficiency virus HIV-1.
Besonders geeignet erscheinen die Verbindungen der Formel I zur Behandlung der klinischen Manifaktion der retroviralen HIV- Infektion beim Menschen und dem klinischen Vollbild von AIDS. Die Verbindungen der allgemeinen Formel I hemmen die Vermehrung von HIV-l auf der virusspezifischen RNA-Transkription. Sie hemmen über die Inhibierung des Enzyms Reverse Transkriptase die Vermehrung von Retroviren und sind daher besonders zur Behandlung der Immunschwäche-Erkrankung AIDS geeignet.The compounds of the formula I appear to be particularly suitable for the treatment of the clinical manipulation of retroviral HIV infection in humans and the clinical full picture of AIDS. The compounds of the general formula I inhibit the multiplication of HIV-1 on the virus-specific RNA transcription. They inhibit the multiplication of retroviruses by inhibiting the enzyme reverse transcriptase and are therefore particularly suitable for the treatment of the immune deficiency disease AIDS.
Zur Behandlung von AIDS ist heute nur 3'-Azido-3'desoxymidin (DE-A-3608606) bei AIDS Patienten zugelassen. Jedoch machen toxische Nebenwirkungen des 3'-Azido-3*-desoxythyidins auf das Knochenmark bei etwa 50 % der behandelten Patienten Bluttrans¬ fusionen erforderlich. Die Verbindungen der allgemeinen Formel I besitzten diese Nachteile nicht. Sie wirken antiviral, ohne in pharmakologisch relevanten Dosen cytotoxisch zu sein.Only 3'-azido-3'desoxymidine (DE-A-3608606) is currently approved for the treatment of AIDS in AIDS patients. However, toxic side effects of 3'-azido-3 * -deoxythyidine on the bone marrow require blood transfusions in about 50% of the patients treated. The compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacologically relevant doses.
Die Verbindungen der vorliegenden Erfindung und ihre pharmazeu¬ tischen Zubereitungen können auch in Kombination mit anderen Arzneimitteln zur Behandlung und Prophylaxe der oben genannten Infektionen eingesetzt werden. Beispiele dieser weiteren Arz¬ neimittel beinhalten Mittel, die zur Behandlung und Prophylaxe von HIV-Infektionen oder diese Krankheit begleitende Erkran¬ kungen einsetzbar sind wie 3'-Azido-3 '-desoxythymidin, 2! ,3'- Didesoxynukleoside wie z.B. 2' ,3 '-Didesoxycytidin, 2• ,3 '-Di- desoxyadenosin und 2' ,3'-Didesoxyinosin, acyclische Nukleoside (z.B. Acyclovir) , Interferone wie z.B. A-Interfero , renale Ausscheidungs-Inhibitoren wie z. B. Probenicid, Nukleosid- Transport-Inhibitoren wie z. B. Dipyridamol, als auch Immunmo¬ dulatoren wie z. B. Interleukin II oder Stimulierungs-Faktoren wie z. B. der Granulocyten-Makrophagen-Kolonie Faktor. Die Verbindungen der vorliegenden Erfindung und das andere Arznei¬ mittel können jeweils einzeln, gleichzeitig gegebenenfalls in einer einzigen oder zwei getrennten Formulierungen oder zu unterschiedlichen Zeiten verabreicht werden, so daß ein synergistischer Effekt erreicht wird.The compounds of the present invention and their pharmaceutical preparations can also be used in combination with other medicaments for the treatment and prophylaxis of the above-mentioned infections. Examples of these further drugs include agents which can be used for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as 3'-azido-3 'deoxythymidine, 2 ! , 3'-dideoxynucleosides such as 2 ', 3' -dideoxycytidine, 2 •, 3'-di-deoxyadenosine and 2 ', 3'-dideoxyinosine, acyclic nucleosides (e.g. acyclovir), interferons such as A-interfero, renal excretion Inhibitors such as B. probenicid, nucleoside transport inhibitors such. B. Dipyridamol, as well as Immunomodulators such. B. Interleukin II or stimulation factors such as B. the granulocyte-macrophage colony factor. The compounds of the present invention and the other medicament can each be administered individually, at the same time optionally in a single or two separate formulations or at different times, so that a synergistic effect is achieved.
Die Verbindungen der allgemeinen Formel I enthalten basische Gruppen, die mit geeigneten Säuren in Säureadditionssalze überführt werden können. Als Säuren kommen hierfür beispiels¬ weise in Betracht: Salzsäure Bromwassersäure, Schwefelsäure, Phosphorsäure, Fumarsäure, Bernsteinsäure, Weinsäure, Zitronen¬ säure, Milchsäure, Maleinsäure oder Methansulfonsäure.The compounds of the general formula I contain basic groups which can be converted into acid addition salts using suitable acids. Examples of suitable acids for this purpose are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.
Die Arzneimittel enthaltend Verbindungen der Formel I zur Behandlung von viralen Infektionen können in flüssiger oder fester Form enteral oder parenteral appliziert werden. Hierbei kommen die üblichen Applikationsformen in Frage, wie beispiels¬ weise Tabletten, Kapseln, Dragees, Sirupe, Lösungen oder Suspensionen. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, das die bei Injektionslösungen üblichen Zusätze wie Stabilisierungsmittel, Lösungsvermittler und Puffer ent¬ hält. Derartige Zusätze sind z. B. Tartrat- und Zitratpuffer, Ethanol, Komplexbildner, wie Ethylendiamintetraessigsäure und deren nichttoxischen Salze, hochmolekulare Polymere, wie flüssiges Polyethylenoxid zur Viskositätsregulierung. Flüssige Trägerstoffe für Injektionslösungen müssen steril sein und werden vorzugsweise in Ampullen abgefüllt. Feste Trägerstoffe sind beispielsweise Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäuren, höhermolekulare Fettsäuren, wie Stearinsäure, Gelatine, Agar-Agar, Calziumphosphat, Magnesiumstearat, tierische und pflanzliche Fette, fest hoch¬ molekulare polymere, wie Polyethylenglykole, etc.. Für orale Applikationen geeignete Zubereitungen können gewünschtenfalls Geschmacks- oder Süßstoffe enthalten. Die Dosierung kann von verschiedenen Faktoren, wie Appli¬ kationsweise, Spezies, Alter oder individuellem Zustand ab¬ hängen. Die erfindungsgemäßen Verbindungen werden üblicherweise in Mengen von 0,1 - 100 mg, vorzugsweise 0,2 - 80 mg pro Tag und pro kg Körpergewicht appliziert. Bevorzugt ist es, die Tagesdosis Auf 2-5 Applikationen zu verteilen, wobei bei jeder Applikation 1-2 Tabletten mit einem Wirkstoffgehalt von 0,5-500 mg verabreicht werden. Die Tabletten können auch retardiert sein, wodurch sich die .Anzahl der Applikationen pro Tag auf 1-3 vermindert. Der Wirkstoffgehalt der retardierten Tabletten kann 2-1000 mg betragen. Der Wirkstoff kann auch durch Dauerinfusion gegeben werden, wobei die Mengen von 5-1000 mg pro Tag normalerweise ausreichen.The medicaments containing compounds of the formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form. The usual forms of application are possible here, such as tablets, capsules, dragees, syrups, solutions or suspensions. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers. Such additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers, such as polyethylene glycols, etc. Preparations suitable for oral applications can, if desired, contain flavorings or sweeteners. The dosage can depend on various factors, such as the type of application, species, age or individual condition. The compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 applications with an active ingredient content of 0.5-500 mg being administered with each application. The tablets can also be delayed, which reduces the number of applications per day to 1-3. The active substance content of the retarded tablets can be 2-1000 mg. The active ingredient can also be given by continuous infusion, the amounts of 5-1000 mg per day are usually sufficient.
Weiterer Gegenstand der Erfindung sind Zwischenprodukte der allgemeinen Formel II.The invention further relates to intermediates of the general formula II.
Figure imgf000026_0001
Figure imgf000026_0001
Hierzu gehören insbesondere:These include in particular:
9-Amino-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methy1-2-butenyl) (lH)-l,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methy1-2-butenyl) (lH) -l, 4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-2-butenyl) - (lH)-l,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3-phenyl-4- (3-methyl-2-butenyl) - (lH) -l, 4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3-methyl-2- butenyl) -(IH) -1, -benzodiazepin 9-Amino-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-2-butenyl) - (IH) -1, -benzodiazepine 9-Amino-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3-methyl- 2-butenyl)-(lH)-l,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-2-butenyl) - (1H) -l, 4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4-(3- methyl-2-butenyl)-(lH)-l,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-methyl-2-butenyl) - (1H) -l, 4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-2-butenyl)- (lH)-l,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3-benzyl-4- (3-methyl-2-butenyl) - (lH) -l, 4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3-methyl-2- butenyl)-(lH)-l,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-methyl-2-butenyl) - (1H) -l, 4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3-methyl- 2-butenyl)-(lH)-l,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methyl-2-butenyl) - (1H) -l, 4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4-(3- methyl-2-butenyl)-(IH)-1, -benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1, -benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-ethyl-4-(3-methyl-2-butenyl)-(IH) 1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3-ethyl-4- (3-methyl-2-butenyl) - (IH) 1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3-phenyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin - 26 -9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine - 26 -
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-( methyl-2-butenyl)-(IH)-1, -benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (methyl-2-butenyl) - (IH) -1, -benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4 (3-methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4 (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-.Amino-7-chlor-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-.Amino-7-chloro-2,3,4,5-tetrahydro-3-benzyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3- methy1-2-butenyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-methy1-2-butenyl) - (IH) -1,4-benzodiazepine
9-.Amino-7-chlor-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-.Amino-7-chloro-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-.Amino-7-chlor-2,3,4,5-tetrahydro-3-(3, -dichlor-benzyl)-4-(3 methy1-2-butenyl)-(IH)-1,4-benzodiazepin9-.Amino-7-chloro-2,3,4,5-tetrahydro-3- (3, -dichlorobenzyl) -4- (3 methy1-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(3, -dimethoxy-benzyl)-4 (3-methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (3, -dimethoxy-benzyl) -4 (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-ethyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3-ethyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-.Amino-7-brom-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-.Amino-7-bromo-2,3,4,5-tetrahydro-3-phenyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3- methyl -2-butenyl)-(IH)-1,4-benzodiazepin 9-Amino-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methyl -2-butenyl) - (IH) -1,4-benzodiazepine 9-amino-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4- benzodiazepine
9-.Amino-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4- (3-methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-.Amino-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-methyl-2-butenyl) - (IH) -1.4 -benzodiazepine
9-.Amino-7-brom-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-.Amino-7-bromo-2,3,4,5-tetrahydro-3-benzyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-.Amino-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3- methyl-2-butenyl)-(lH)-l,4-benzodiazepin9-.Amino-7-bromo-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-methyl-2-butenyl) - (lH) -l, 4-benzodiazepine
9-.Amino-7-brom-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-.Amino-7-bromo-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3- methyl-2-butenyl)-(lH)-l,4-benzodiazepin9-amino-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methyl-2-butenyl) - (lH) -l, 4- benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4- (3-methyl-2-butenyl)-(lH)-l,4-benzodiazepin9-amino-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-2-butenyl) - (lH) -l, 4- benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl-butyl)- (lH)-l,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methyl-butyl) - (lH) -l, 4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-butyl)-(IH)- 1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3-phenyl-4- (3-methylbutyl) - (IH) - 1,4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3-methyl- butyl)-(lH)-l,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methylbutyl) - (1H) -l, 4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin 9-Amino-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4-(3- ethyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine 9-Amino-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-ethyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-butyl)-(IH)- 1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3-benzyl-4- (3-methyl-butyl) - (IH) - 1,4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (4-chlorobenzyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Amino-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-butyl)- (IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3-phenyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3- ethyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-ethyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4- (3-methyl-butyl)-(IH)-1,4-benzodiazepin 9-Amino-7-chlor-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-butyl)- (IH)-1, -benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine 9-Amino-7-chloro-2,3,4,5-tetrahydro-3-benzyl-4- (3-methylbutyl) - (IH) -1, -benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3- ethyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-ethyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3- methyl-butyl)-(lH)-l,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-butyl) - (1H) -l, 4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3- ethyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-ethyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4- (3-methyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-butyl)- (IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3-benzyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl- butyl)-(IH)-l,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methylbutyl) - (IH) -l, 4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-butyl)- (IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3-phenyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3- methyl-butyl)-(lH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-butyl) - (1H) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4- (3-methyl-butyl)-(IH)-1,4-benzodiazepin 9-Amino-7-brom-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-butyl)■ (IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine 9-Amino-7-bromo-2,3,4,5-tetrahydro-3-benzyl-4- (3-methyl-butyl) ■ (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-.Amino-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-.Amino-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4- (3-methyl-butyl)-(IH)-1,4-benzodiazepin9-Amino-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3,3-dimethyl-4-isopropyl- (IH)-1,4-benzodiazepin9-Amino-7-chloro-2,3,4,5-tetrahydro-3,3-dimethyl-4-isopropyl- (IH) -1,4-benzodiazepine
9-Amino-7-chlor-2,3,4,5-tetrahydro-3-benzyl-4-benzyl-(IH)-1,4- benzodiazepin9-amino-7-chloro-2,3,4,5-tetrahydro-3-benzyl-4-benzyl- (IH) -1,4-benzodiazepine
Gegenstand der Erfindung sind auch Verbindungen der allgemeinen Formel III, in der R1-R4 die zuvor genannten Bedeutungen be¬ sitzt.The invention also relates to compounds of the general formula III in which R 1 -R 4 has the meanings mentioned above.
n:n:
Figure imgf000032_0001
Hierzu gehören insbesondere:
Figure imgf000032_0001
These include in particular:
9-nitro-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl-2-butenyl)- (IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-2-butenyl)- (IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3-phenyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3-methyl-2- butenyl)-(lH)-l,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-2-butenyl) - (1H) -l, 4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3-methyl- 2-butenyl)-(lH)-l,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-2-butenyl) - (1H) -l, 4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-3,4-dimethoxy-phenyl)-4-(3-methyl- 2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3-3,4-dimethoxy-phenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-2-butenyl)- (IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3-benzyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3-methyl- 2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-nitro-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4-(3- methyl-2-butenyl)-(lH)-l,4-benzodiazepin 9-Nitro-7-chlor-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-2-butenyl) - (1H) -l, 4-benzodiazepine 9-nitro-7-chloro-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-σhlor-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3-phenyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4- benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4- benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4- (3-methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4- benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3-benzyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3- ethyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-ethyl-2-butenyl) - (IH) -1,4- benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin 9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4- (3-methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4- benzodiazepine 9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4- benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3-phenyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3- methyl-2-butenyl)-(lH)-l,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-2-butenyl) - (lH) -l, 4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3- methyl-2-butenyl)-(lH)-l,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-2-butenyl) - (lH) -l, 4- benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4- (3-methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-methyl-2-butenyl) - (IH) -1,4- benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-2- butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3-benzyl-4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3- methyl-2-butenyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4- benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4- (3-methyl-2-butenyl)-(IH)-1,4-benzodiazepin 9-Nitro-2,3,4,5-tetrahydro-3,3,-dimethyl-4-(3-methyl-butyl)- (IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-2-butenyl) - (IH) -1,4- benzodiazepine 9-nitro-2,3,4,5-tetrahydro-3,3, -dimethyl-4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahγdro-3-phenyl-4-(3-methyl-butyl)-(IH)- 1,4-benzodiazepin9-nitro-2,3,4,5-tetrahyro-3-phenyl-4- (3-methylbutyl) - (IH) - 1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-Nitro-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-butyl)-(IH)- 1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3-benzyl-4- (3-methyl-butyl) - (IH) - 1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-Nitro-2,3,4,5-tetrahydro-3- (4-chlorobenzyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-Nitro-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahγdro-3-(3,4-dimethoxy-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahyro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin 9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-butyl)- (IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine 9-nitro-7-chloro-2,3,4,5-tetrahydro-3-phenyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3- methyl-butyl)-(lH)-l,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-butyl) - (1H) -l, 4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3- methyl-butyl)-(lH)-l,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methylbutyl) - (1H) -l, 4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4- (3-methyl-butyl)-(IH)-1,4-benzodiazepin9-Nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-butyl)- (IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3-benzyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-σhlor-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4- (3-methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl- butyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-phenyl-4-(3-methyl-butyl)- (IH)-1,4-benzodiazepin 9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3-phenyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine 9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-chlorophenyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)-4- (3-methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) -4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-benzyl-4-(3-methyl-butyl)- (IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3-benzyl-4- (3-methylbutyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3, ,5-tetrahydro-3-(4-methoxy-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-Nitro-7-bromo-2,3,5,5-tetrahydro-3- (4-methoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-4-(3- methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-4- (3-methyl-butyl)-(IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) -4- (3-methyl-butyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3,3-dimethyl-4-isopropyl- (lH)-l,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3,3-dimethyl-4-isopropyl- (1H) -l, 4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-benzyl-4-benzyl-(IH)-1,4- benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3-benzyl-4-benzyl- (IH) -1,4-benzodiazepine
Gegenstand der Erfindung sind auch Verbindungen der allgemeine Formel IV, in der R1, R2 und R4 die zuvor genannten Bedeutunge besitzt:
Figure imgf000039_0001
The invention also relates to compounds of the general formula IV in which R 1 , R 2 and R 4 have the meanings mentioned above:
Figure imgf000039_0001
Hierzu gehören insbesondere:These include in particular:
9-Nitro-2,3,4,5-tetrahydro-3,3-dimethyl-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3,3-dimethyl- (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-phenyl-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3-phenyl- (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-(IH)-1,4-benzo- diazepin9-nitro-2,3,4,5-tetrahydro-3- (4-chlorophenyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-(IH)-1,4-benzo- diazepin9-nitro-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(3,4-dimetho.xy-phenyl)-(IH)-1,4- benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (3,4-dimetho.xy-phenyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(3,4-dichlor-penyl)-(IH)-1,4- benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (3,4-dichloropenyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-benzyl-(IH)-1,4-benzodiazepin9-nitro-2,3,4,5-tetrahydro-3-benzyl- (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-(IH)-1,4-benzo- diazepin9-nitro-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-(IH)-1,4-benzo- diazepin 9-Nitro-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-(IH)-1,4- benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) - (IH) -1,4-benzodiazepine 9-nitro-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) - (IH) -1,4-benzodiazepine
9-Nitro-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)-(IH)-1, - benzodiazepin9-nitro-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) - (IH) -1, - benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3,3-dimethyl-(IH)-1,4-benzo- diazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3,3-dimethyl- (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-phenyl-(IH)-1,4-benzodia- ze in9-nitro-7-chloro-2,3,4,5-tetrahydro-3-phenyl- (IH) -1,4-benzodiaze in
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-(IH)-1,4- benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-chlorophenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-(IH)- 1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) - (IH) - 1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)- (IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-(IH)- 1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) - (IH) - 1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-benzyl-(IH)-1,4-benzodia- zepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3-benzyl- (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-(IH)-1,4- benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-(IH)- 1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) - (IH) - 1,4-benzodiazepine
9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-(IH)- 1,4-benzodiazepin 9-Nitro-7-chlor-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)- (IH)-1,4-benzodiazepin9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) - (IH) - 1,4-benzodiazepine 9-nitro-7-chloro-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3,3-dimethyl-(IH)-1,4-benzo- diazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3,3-dimethyl- (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-phenyl-(IH)-1,4-benzodiaze- pin9-nitro-7-bromo-2,3,4,5-tetrahydro-3-phenyl- (IH) -1,4-benzodiazepin
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-phenyl)-(IH)-1,4- benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-chlorophenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-methoxy-phenyl)-(IH)- 1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-methoxyphenyl) - (IH) - 1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-phenyl)- (IH)-1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxyphenyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-phenyl)-(IH)- 1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorophenyl) - (IH) - 1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-benzyl-(IH)-1,4-benzodiaze- pin9-nitro-7-bromo-2,3,4,5-tetrahydro-3-benzyl- (IH) -1,4-benzodiazepin
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-chlor-benzyl)-(IH)-1,4- benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-chloro-benzyl) - (IH) -1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(4-methoxy-benzyl)-(IH)- 1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (4-methoxy-benzyl) - (IH) - 1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dichlor-benzyl)-(IH)- 1,4-benzodiazepin9-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dichlorobenzyl) - (IH) - 1,4-benzodiazepine
9-Nitro-7-brom-2,3,4,5-tetrahydro-3-(3,4-dimethoxy-benzyl)- (lH)-l,4-benzodiazepin Beispiel 19-nitro-7-bromo-2,3,4,5-tetrahydro-3- (3,4-dimethoxy-benzyl) - (lH) -l, 4-benzodiazepine example 1
4,5,6,7-Tetrahydro-5,5-dimethγl-6-(3-methyl-2-butenyl)-imidazo- [4,5,lj ][l,4]-benzodiazepin-2-(IH)-thion4,5,6,7-tetrahydro-5,5-dimethγl-6- (3-methyl-2-butenyl) imidazo- [4,5, lj] [1,4] benzodiazepine-2- (IH) -thion
a) 2-ff2-Brom-3-nitro-benzγl)-aminol-2.2-dimethyl-essigsäure- ethylestera) 2-ff2-bromo-3-nitro-benzγl) aminol-2,2-dimethyl-acetic acid, ethyl ester
2.9 g Ä-Aminoisobuttersäureethylester-Hydrochlorid werden in 30 ml Methylenchlorid suspendiert. Hierzu gibt man 5,2 ml Triethylamin und tropft anschließend unter Rühren eine Lösung von 4 g 2-Brom-3-nitro-benzoylchlorid in 20 ml Methylenchlorid bei Raumtemperatur zu. Man rührt noch 10 Stdn. bei Raumtemperatur weiter, säuert die Mischung mit verdünnter Salzsäure an und trennt die Phasen. Die organische Phase wird über Natriumsulfat getrocknet und eingedampft. Der Rückstand wird aus Essigester umkristal¬ lisiert. Man erhält 4,5 g weiße Kristalle vom Schmp. : 140- 141*C.2.9 g of ethyl Ä-aminoisobutyrate hydrochloride are suspended in 30 ml of methylene chloride. 5.2 ml of triethylamine are added and a solution of 4 g of 2-bromo-3-nitro-benzoyl chloride in 20 ml of methylene chloride is then added dropwise with stirring at room temperature. The mixture is stirred for a further 10 hours at room temperature, the mixture is acidified with dilute hydrochloric acid and the phases are separated. The organic phase is dried over sodium sulfate and evaporated. The residue is recrystallized from ethyl acetate. 4.5 g of white crystals of mp: 140-141 ° C. are obtained.
b) 2-r (2-Brom-3-nitro-benzyl)-amino]-2,2-dimethyl-acetamidb) 2-r (2-bromo-3-nitro-benzyl) amino] -2,2-dimethyl-acetamide
4,5 g N-(2-Brom-3-nitro-benzoyl-<-aminoisobutter- säureethylester werden in 100 ml konz. Ammoniak sus¬ pendiert und über Nacht bei Raumtemperatur geführt. Dann wird der Niederschlag abgesaugt und mit Alkohol und Ether gewaschen. Man erhält 3.8 g Kristalle vom Schmp.: 217- 220σC4.5 g of N- (2-bromo-3-nitro-benzoyl - <- aminoisobutyric acid ethyl ester are suspended in 100 ml of concentrated ammonia and passed overnight at room temperature. The precipitate is then filtered off with suction and washed with alcohol and ether 3.8 g of crystals with a melting point of 217-220 σ C are obtained
c) 2-f f2-Brom-3-nitro-benzyl)amino]2.2-dimethyl-ethylaminc) 2-f f2-bromo-3-nitro-benzyl) amino] 2,2-dimethyl-ethylamine
Zu 35 ml einer molaren Lösung von Borwasserstoff ein Tetrahydrofuran tropft man im Verlauf von 5 min eine Lösung von 1.65 g N-(2-Brom-3-nitro-benzoyl)-<^amino- isobuttersäureamid in 30 ml Tetrahydrofuran. Man rührt noch 1 Stunde bei Raumtemperatur weiter und erhitzt dann eine weitere Stunde auf Rückflußtemperatur. Man kühlt auf Raumtemperatur ab und versetzt die Mischung mit 10 ml 6 N Bromwasserstoffsäure. Dann wird das Tetrahydrofuran ab- edestilliert, der Rückstand mit verdünnter Natronlauge alkalisch gestellt und mit Essigester extrahiert. Die Essigesterphase wird über Natriumsulfat getrocknet und eingedampft. Man erhält 1,4 g eines amorphen Rückstandes von 2-[ (2-Brom-3-nitro-benzyl)-amino]-2,2-dimethyl-ethyl- amin.A solution of 1.65 g of N- (2-bromo-3-nitro-benzoyl) - <^ amino-isobutyric acid amide in 30 ml of tetrahydrofuran is added dropwise to 35 ml of a molar solution of hydrogen boron and tetrahydrofuran in the course of 5 minutes. You stir another 1 hour at room temperature and then heated to reflux for another hour. The mixture is cooled to room temperature and 10 ml of 6N hydrobromic acid are added to the mixture. Then the tetrahydrofuran is distilled off, the residue is made alkaline with dilute sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and evaporated. 1.4 g of an amorphous residue of 2- [(2-bromo-3-nitro-benzyl) amino] -2,2-dimethyl-ethylamine are obtained.
d) 9-Nitro-2.3.4.5-tetrahvdro-3.3-dimethyl- (IH)-1.4- benzodiazepind) 9-nitro-2.3.4.5-tetrahvdro-3.3-dimethyl- (IH) -1.4-benzodiazepine
1 g 2-(2-Brom-3-nitro-benzylamino)-2,2-dimethyl-ethylamin werden in 25 ml Dimethylformamid gelöst und die Lösung nach Zugabe von 1.5 g Kaliumkarbonat 3 Stunden auf 110"C erwärmt. Dann wird von Dimethylformamid i. Vak. ab¬ destilliert, der Rückstand mit Essigester extrahiert und die Essigesterlösung i. Vak. eingedampft. Das zurück¬ bleibende, rotbraune öl wird zur Reinigung an einer Kieselgelsäule chromatographiert. Laufmittel: Aceton/Toluol.Man erhält 320 mg (= 50 % d.Th.) 9-Nitro- 2,3,4,5-tetrahydro-3,3-dimethyl-(IH)-1,4-benzodiazepin als rotbraunes öl.1 g of 2- (2-bromo-3-nitro-benzylamino) -2,2-dimethyl-ethylamine is dissolved in 25 ml of dimethylformamide and, after adding 1.5 g of potassium carbonate, the solution is heated at 110 ° C. for 3 hours. Dimethylformamide is then removed distilled off in vacuo, the residue was extracted with ethyl acetate and the ethyl acetate solution was evaporated down in vacuo. The remaining red-brown oil was chromatographed on a silica gel column for cleaning. Mobile phase: acetone / toluene. 320 mg (= 50 % of theory) 9-nitro-2,3,4,5-tetrahydro-3,3-dimethyl- (IH) -1,4-benzodiazepine as red-brown oil.
e) 9-Nitro-2.3.4.5-tetrahvdro-3.3-dimethyl-4- (3-methyl-2- butenyl)- (IH)-1.4-benzodiazepine) 9-Nitro-2.3.4.5-tetrahvdro-3.3-dimethyl-4- (3-methyl-2-butenyl) - (IH) -1.4-benzodiazepine
310 mg 9-Nitro-2,3,4,5-tetrahydro-3,3-dimethyl-(lH)-l,4- benzodiazepin werden in 5 ml Dimethylformamid gelöst. Hierzu gibt man 1 g Kaliumkarbonat und 0.2 ml 3,3- Dimethylallylbromid und erwärmt die Mischung 1 Stunde auf 50 °C. Dann wird vom Dimethylformamid abdestilliert und der Rückstand zur Reinigung an einer Kieselgelsäule chromato- graphiert. Laufmittel: Ether/Isohexan (1:3). Die Säulen¬ fraktionen werden eingedampft und der Rückstand aus Methanol umkristallisiert. Man erhält 300 mg Kristalle vom Schmp. 125"C.310 mg of 9-nitro-2,3,4,5-tetrahydro-3,3-dimethyl- (1H) -l, 4-benzodiazepine are dissolved in 5 ml of dimethylformamide. 1 g of potassium carbonate and 0.2 ml of 3,3-dimethylallyl bromide are added and the mixture is warmed up for 1 hour 50 ° C. The dimethylformamide is then distilled off and the residue is chromatographed on a silica gel column for purification. Mobile solvent: ether / isohexane (1: 3). The column fractions are evaporated and the residue is recrystallized from methanol. 300 mg of crystals of mp 125 ° C. are obtained.
4,5.6.7-Tetrahydro-5.5-dimethγl-6-(3-methyl-2-butenyl)- imidazo-Λ.5.likl r1,41-benzodiazepin-2 (IH)-thion4,5.6.7-tetrahydro-5.5-dimethγl-6- (3-methyl-2-butenyl) - imidazo-Λ.5.likl r1,41-benzodiazepine-2 (IH) -thione
1 g 9-Nitro-2,3,4,5-tetrahydro-3,3-dimethyl-4-(3-methyl-2- butenyl)-(lH)-l,4-benzodiazepin werden in 10 ml konz. Salzsäure gelöst. Hierzu gibt man im Verlauf von einigen Minuten 2 g Zinkstaub, wobei sich die rote Lösung sofort entfärbt. Die Reduktionslösung wird unter Kühlung mit Natronlauge alkalisch gestellt und mit Essigester extra¬ hiert. Die Essigesterlösung wird über Natriumsulfat ge¬ trocknet und eingedampft. Der Eindampfrückstand wird mit einer Lösung von 250 mg Kaliumhydroxid in einer Mischung aus 1 ml Wasser und 5 ml Ethanol versetzt und nach Zugabe von 0.25 ml Schwefelkohlenstoff 3 Stunden am Rückfluß erhitzt. Die Reaktionslösung wird abgekühlt, mit Salzsäure angesäuert und mit Essigester extrahiert. Die Essigester¬ phase wird verworfen. Die salzsaure Lösung wird alkalisch gestellt und mit Essigester extrahiert. Die Essigester¬ phase wird über Natriumsulfat getrocknet und eingedampft. Der Rückstand wird zur Reinigung an einer Kieselgelsäule chromatographiert. Man erhält 600 mg der Titelverbindung vom Schmp. 166-168"C. Analog wurden dargestellt:1 g of 9-nitro-2,3,4,5-tetrahydro-3,3-dimethyl-4- (3-methyl-2-butenyl) - (lH) -l, 4-benzodiazepine are concentrated in 10 ml. Hydrochloric acid dissolved. To do this, add 2 g of zinc dust over the course of a few minutes, and the red solution immediately discolors. The cooling solution is made alkaline with cooling with sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate solution is dried over sodium sulfate and evaporated. A solution of 250 mg of potassium hydroxide in a mixture of 1 ml of water and 5 ml of ethanol is added to the evaporation residue and, after the addition of 0.25 ml of carbon disulfide, the mixture is heated under reflux for 3 hours. The reaction solution is cooled, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is discarded. The hydrochloric acid solution is made alkaline and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column for purification. 600 mg of the title compound of mp 166-168 "C. are obtained. The following were represented in an analogous manner:
Beispiel 2Example 2
4,5,6,7-Tetrahydro-5-benzyl-6-(3-methyl-2-butenyl)-imidazo- [4,5,1,jk] [1,4]-benzodiazepin-2(IH)-thion aus 2-Brom-3-nitro- benzolsäure und Phenylalanin.4,5,6,7-tetrahydro-5-benzyl-6- (3-methyl-2-butenyl) imidazo- [4,5,1, jk] [1,4] -benzodiazepine-2 (IH) - thione from 2-bromo-3-nitrobenzene acid and phenylalanine.
Beispiel 3Example 3
4,5,6,7-Tetrahydro-5-phenyl-6-(3-methyl-2-butenyl)-imidazo- [4,5,1,jk] [1,4]-benzodiazepin-2(lH)-thion aus 2-Brom-3-nitro- benzolsäure und Phenylglycin.4,5,6,7-tetrahydro-5-phenyl-6- (3-methyl-2-butenyl) imidazo- [4,5,1, jk] [1,4] -benzodiazepine-2 (1H) - thione from 2-bromo-3-nitrobenzene acid and phenylglycine.
Beispiel 4Example 4
4,5,6,7-Tetrahydro-9-chlor-5-benzyl-6-(3-methyl-2-butenyl)- imidazo-[4,5,l,jk] [1,4]-benzodiazepin-2(IH)-thion aus 2,5- Dichlor-5-nitrobenzolsäure und Phenylalanin.4,5,6,7-tetrahydro-9-chloro-5-benzyl-6- (3-methyl-2-butenyl) imidazo- [4,5, l, jk] [1,4] -benzodiazepine-2 (IH) -thione from 2,5-dichloro-5-nitrobenzenic acid and phenylalanine.
Beispiel 5Example 5
4,5,6,7-Tetrahydro-9-chlor-5-phenyl-6-(3-methyl-2- butenyl)imidazo-[4,5,l,jk][l,4]-benzodiazepin-2(IH)-thion aus4,5,6,7-tetrahydro-9-chloro-5-phenyl-6- (3-methyl-2-butenyl) imidazo- [4,5, l, jk] [l, 4] -benzodiazepine-2 ( IH) -thion
2,5-Dichlor-5-nitro-benzolsäure und Phenylglycin.2,5-dichloro-5-nitro-benzenic acid and phenylglycine.
Beispiel 6Example 6
[2,3,4,5]-Tetrahydro-[2,1c]-pyrrolo-[4,5,1,jk]-imidazo-[2,3,4,5] tetrahydro- [2,1c] pyrrolo- [4,5,1, jk] imidazo-
(4M) (9M) [1,4]-benzodiazepin-2(IH)-thion aus 2-Brom-3-nitro- benzolsäure und Prolin.(4M) (9M) [1,4] -benzodiazepin-2 (IH) -thione from 2-bromo-3-nitrobenzene acid and proline.
Beispiel 7Example 7
11-Chlor-[2,3,4,5]-tetrahydro-[2,1c]-pyrrolo-[4,5,1,jk]- imidazo-(4M) (9M) [1,4]-benzodiazepin-2(IM)-thion aus 2,5- Dichlor-3-nitrobenzolsäure und Prolin. 11-chloro [2,3,4,5] tetrahydro- [2,1c] pyrrolo- [4,5,1, jk] - imidazo- (4M) (9M) [1,4] benzodiazepine 2 (IM) -thione from 2,5-dichloro-3-nitrobenzenic acid and proline.

Claims

Patentansprüche Claims
1. Verbindungen der Formel I1. Compounds of formula I.
Figure imgf000046_0001
Figure imgf000046_0001
R,R,
in welcherin which
Rl ein Wasserstoffatom, einen geradkettigen oder ver¬ zweigten Alkylrest von 1-6 Kohlenstoffatomen,R1 is a hydrogen atom, a straight-chain or branched alkyl radical of 1-6 carbon atoms,
R2 einen geradkettigen oder verzweigten Ci-Cg-Alkylrest, der durch eine oder mehrere Hydroxy-, Ci-Cs-Alkoxy-, Mercapto oder Ci-Cg-Alkylmercaptogruppen oder einen substituierten oder unsubstitutierten Phenylrest sub¬ stituiert sein kann, einen C3-C7-Cycloalkylrest, einen substituierten oder unsubstituierten Phenylrest, einen substituierten oder unsubstituierten Aralkylrest, einen substituierten oder unsubstituierten gesättigten heterocyclischen oder einen aromatischen hetero¬ cyclischen Rest oder einen substituierten oder unsub¬ stituierten Heteroarylalkylrest, oder zusammen mit R^ einen C3-C7-Cycloalkylring bilden kann, wobei die zuvor genannten substituierten Reste ein-, zwei- oder drei¬ fach substituiert sein können durch Ci-Cg-Alkyl, C_-CQ- Alkoxy, Halogen, Hydroxy, Amino, Ci-Cg-Alkylamino oder Di-Ci-Cg-alkylamino, R3 ein Wasserstoffatom, einen geradkettigen oder ver¬ zweigten Ci-Cρ-Alkylrest, der durch eine oder mehrere Hydroxy- oder Ci-Cg-Alkoxygruppen, eine substituierte oder unsubstituierte Aminogruppe oder Halogen substi¬ tuiert sein kann; einen geradkettigen oder verzweigten C2-Ce-Alkenylrest, der noch eine oder mehrere Hydroxy- oder Ci-Cg-Alkoxygruppen, eine substituierte oder unsubstituierte Aminogruppe oder Halogen tragen kann oder einen substituierten oder unsubstituierten Aralkyl- oder Heteroarylalkylrest,R2 is a straight-chain or branched Ci-Cg-alkyl radical, which can be substituted by one or more hydroxy, Ci-Cs-alkoxy, mercapto or Ci-Cg-alkyl mercapto groups or a substituted or unsubstituted phenyl radical, a C3-C7- Cycloalkyl radical, a substituted or unsubstituted phenyl radical, a substituted or unsubstituted aralkyl radical, a substituted or unsubstituted saturated heterocyclic or an aromatic heterocyclic radical or a substituted or unsubstituted heteroarylalkyl radical, or together with R ^ can form a C 3 -C 7 cycloalkyl ring , where the aforementioned substituted radicals can be substituted once, twice or three times by Ci-Cg-alkyl, C_-C Q -alkoxy, halogen, hydroxy, amino, Ci-Cg-alkylamino or di-Ci-Cg -alkylamino, R3 is a hydrogen atom, a straight-chain or branched Ci-Cρ-alkyl radical which can be substituted by one or more hydroxy or Ci-Cg-alkoxy groups, a substituted or unsubstituted amino group or halogen; a straight-chain or branched C2-Ce-alkenyl radical which can also carry one or more hydroxy or Ci-Cg-alkoxy groups, a substituted or unsubstituted amino group or halogen or a substituted or unsubstituted aralkyl or heteroarylalkyl radical,
wobei einer der Reste R_ oder R2 auch zusammen mit Rest R3 einen substituierten oder unsubstituierten heterocyclischen Ring bilden kann,where one of the radicals R_ or R2 can also form a substituted or unsubstituted heterocyclic ring together with radical R 3 ,
R4 ein Wasserstoffatom, ein Halogenatom, eine Hydroxy- gruppe, eine Ci-Cg-Alkoxygruppe, eine Ci-Cg-Alkylendioxy- gruppe, eine Ci-Cß-Alkylgruppe, eine ein- oder mehrfach substituierte .Aminogruppe, oder eine substituierte oder unsubstituierte Benzyloxygruppe,R4 is a hydrogen atom, a halogen atom, a hydroxyl group, a Ci-Cg-alkoxy group, a Ci-Cg-alkylenedioxy group, a Ci-Cß-alkyl group, a mono- or polysubstituted .amino group, or a substituted or unsubstituted benzyloxy group ,
mit der Maßgabe, daß Ri nicht Wasserstoff bedeuten kann, wenn R2 einen unsubstituierten Ci-Cg-Alkylrest darstellt, undwith the proviso that Ri cannot be hydrogen if R2 is an unsubstituted Ci-Cg-alkyl radical, and
bedeuten, sowie deren pharmakologisch unbedenkliche Salze, optisch aktive und diastereomeren Formen.mean, and their pharmacologically acceptable salts, optically active and diastereomeric forms.
2. Verfahren zur Herstellung von Verbindungen der Formel I gemäß Anspruch 1, dadurch gekennzeichnet, daß man in an sich bekannter Weise a) eine Verbindung der Formel IX2. A process for the preparation of compounds of formula I according to claim 1, characterized in that in a manner known per se a) a compound of formula IX
Figure imgf000048_0001
Figure imgf000048_0001
in der R4 und Y die angegebenen Bedeutungen besitzen.in which R4 and Y have the meanings given.
mit einer Verbindung der Formel Xwith a compound of formula X
H2N — c — C02R5 H 2 N - c - C0 2 R 5
(X)(X)
/ N/ N
in der R_ und R2 die angegebenen Bedeutungen haben und einer der Reste R_ oder R2 mit der Aminogruppe zusammen gegebenenfalls einen Pyrrolidin oder Hydroxypyrrolidinring bilden kann und R5 Wasserstoff oder einen Alkylrest be¬ deutet, umsetztin which R_ and R2 have the meanings given and one of the radicals R_ or R2 together with the amino group can optionally form a pyrrolidine or hydroxypyrrolidine ring and R5 means hydrogen or an alkyl radical
b) die erhaltene Verbindung der Formel VIIIb) the compound of formula VIII obtained
Figure imgf000048_0002
Figure imgf000048_0002
R, in der Rχf R2 R4 und Y die angegebenen Bedeutungen besit¬ zen, und R5 Wasserstoff oder einen Alkylrest bedeutet, nach üblichen Methoden einer Amidierungsreaktion unterzieht,R, in which Rχ f R2 R4 and Y have the meanings given, and R5 is hydrogen or an alkyl radical, is subjected to an amidation reaction by customary methods,
c) die erhaltene Verbindung VIIc) the compound VII obtained
Figure imgf000049_0001
in der Ri, R2, R4 und Y die angegebenen Bedeutungen haben, mit Borwasserstoff oder Diboran reduziert,
Figure imgf000049_0001
in which R 1, R 2, R 4 and Y have the meanings given, reduced with hydrogen boride or diborane,
d) die erhaltene Verbindung der Formel VId) the compound of formula VI obtained
Figure imgf000049_0002
Figure imgf000049_0002
in der Rχ7 R2 und R4 die angegebenen Bedeutungen haben, und Y ein Halogenatom bedeutet, cyclisiert. in which Rχ 7 R2 and R4 have the meanings given, and Y represents a halogen atom, cyclizes.
e) die erhaltene Verbindung der Formel IVe) the compound of formula IV obtained
Figure imgf000050_0001
Figure imgf000050_0001
in der R_ , R2 und R4 die angegebene Bedeutung haben, mit einer Verbindung der Formel Vin which R_, R2 and R4 have the meaning given, with a compound of the formula V.
R3-X (V)R3-X (V)
in der R3 die angegebene Bedeutung hat und X ein Halogen¬ atom darstellt, umsetzt,in which R3 has the meaning given and X represents a halogen atom,
f) in der erhaltenen Verbindung der Formel IIIf) in the compound of formula III obtained
Figure imgf000050_0002
in der Rχf R2, R3 und R4 die angegebenen Bedeutungen haben, die Nitro-Gruppen in üblicher Weise in eine .Aminogruppe überführt und g) die erhaltene Verbindung der Formel II
Figure imgf000050_0002
in which Rχ f R2, R3 and R4 have the meanings given, the nitro groups are converted in the usual manner into an .amino group and g) the compound of formula II obtained
Figure imgf000051_0001
Figure imgf000051_0001
in der Ri, R2, R3 und R4 die angegebenen Bedeutungen haben mit Schwefelkohlenstoff, Thiocarbonyl-diimidazol, Thio- phosgen oder Thioharnstoff in eine Verbindung der allge¬ meinen Formel I überführt.in which R 1, R 2, R 3 and R 4 have the meanings given have converted to a compound of the general formula I using carbon disulphide, thiocarbonyldiimidazole, thiophosgene or thiourea.
3. Arzneimittel, enthaltend eine Verbindung gemäß Anspruch 1 neben üblichen Träger- und Hilfsstoffen.3. Medicament containing a compound according to claim 1 in addition to conventional carriers and auxiliaries.
4. Verwendung von Verbindungen gemäß Anspruch 1 zur Behandlung von viralen oder retroviralen Infektionen.4. Use of compounds according to claim 1 for the treatment of viral or retroviral infections.
5. Verbindungen der Formel II5. Compounds of formula II
Figure imgf000051_0002
in der 1- 4 die Bedeutungen gemäß Anspruch 1 besitzt
Figure imgf000051_0002
in which 1- 4 has the meanings according to claim 1
6. Verbindungen der Formel III6. Compounds of formula III
Figure imgf000052_0001
in welcher R1-R4 die Bedeutungen gemäß Anspruch 1 besitzt.
Figure imgf000052_0001
in which R1-R4 has the meanings according to claim 1.
7. Verbindungen der Formel IV7. Compounds of formula IV
Figure imgf000052_0002
Figure imgf000052_0002
in welcher Ri, R2 und R4 die Bedeutungen gemäß Anspruch 1 besitzt.in which Ri, R2 and R4 has the meanings according to claim 1.
8. Verfahren zur Herstellung von Arzneimitteln enthaltend als Wirkstoff mindestens eine Verbindung der Formel I gemäß Anspruch 1, dadurch gekennzeichnet, daß man den Wirkstoff zusammen mit pharmazeutischen Hilfs- und Trägerstoffen mischt und zu geeigneten Darreichungsformen verarbeitet. 8. A process for the preparation of medicaments containing as an active ingredient at least one compound of the formula I according to claim 1, characterized in that the active ingredient is mixed together with pharmaceutical auxiliaries and carriers and processed into suitable dosage forms.
PCT/EP1992/000261 1991-02-08 1992-02-05 NEW 4,5,6,7-TETRAHYDRO-IMIDAZO-[4,5,lJK][1,4]-BENZODIAZEPINE-2-(1H)-THIONES, A METHOD OF PREPARING THEM AS WELL AS DRUGS CONTAINING THEM, AND INTERMEDIATES FOR THE PREPARATION OF THESE COMPOUNDS WO1992013860A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4103803.7 1991-02-08
DE19914103803 DE4103803A1 (en) 1991-02-08 1991-02-08 NEW 4,5,6,7-TETRAHYDRO-IMIDAZO- (4,5, LJK) (1,4) - BENZODIAZEPIN-2- (1H) -THIONE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS AND INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF THESE COMPOUNDS

Publications (1)

Publication Number Publication Date
WO1992013860A1 true WO1992013860A1 (en) 1992-08-20

Family

ID=6424628

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/000261 WO1992013860A1 (en) 1991-02-08 1992-02-05 NEW 4,5,6,7-TETRAHYDRO-IMIDAZO-[4,5,lJK][1,4]-BENZODIAZEPINE-2-(1H)-THIONES, A METHOD OF PREPARING THEM AS WELL AS DRUGS CONTAINING THEM, AND INTERMEDIATES FOR THE PREPARATION OF THESE COMPOUNDS

Country Status (3)

Country Link
AU (1) AU1186292A (en)
DE (1) DE4103803A1 (en)
WO (1) WO1992013860A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5463049A (en) * 1991-09-24 1995-10-31 Janssen Pharmaceutica N.V. Process for preparing enantiomerically pure imidazo[4,5,1-JK][1,4]-benzodiazepin-2(1H)-thiones

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0384522A1 (en) * 1989-02-23 1990-08-29 Janssen Pharmaceutica N.V. Antiviral tetrahydroimidazo[1,4]benzodiazepin-2-thiones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0384522A1 (en) * 1989-02-23 1990-08-29 Janssen Pharmaceutica N.V. Antiviral tetrahydroimidazo[1,4]benzodiazepin-2-thiones

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5463049A (en) * 1991-09-24 1995-10-31 Janssen Pharmaceutica N.V. Process for preparing enantiomerically pure imidazo[4,5,1-JK][1,4]-benzodiazepin-2(1H)-thiones

Also Published As

Publication number Publication date
DE4103803A1 (en) 1992-08-13
AU1186292A (en) 1992-09-07

Similar Documents

Publication Publication Date Title
EP0005205B1 (en) Substituted 5.6-dimethylpyrrolo(2,3-d)pyrimidines, methods for their preparation and medicines containing them
EP0129128B1 (en) 2-pyrimidinyl-1-piperazine derivatives, process for their preparation and medicines containing them
EP0287907B1 (en) Pyrazolo[3,4-d]pyrimidines, process for their preparation and use as pharmaceutical compounds
DE2255172A1 (en) IMIDAZOTRIAZINONE, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS
DE2952279A1 (en) NEW 2-ACYLAMINOMETHYL-1,4-BENZODIAZEPINE AND ITS SALTS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
EP0053767B1 (en) Tricyclic cytosine derivatives for use in pharmaceutical preparations and process for their preparation
EP1296986A1 (en) 5-aminoalkyl-pyrazolo 4,3-d]pyrimidines with a phosphodiesterase v-inhibiting effect
DE2220906A1 (en) NEW SUBSTITUTED 2-PHENYLAMINOIMIDAZOLINE- (2), THEIR ACID-ADDITIONAL SALTS AND PROCESS FOR THEIR PRODUCTION
DE69908371T2 (en) DISTAMYCIN DERIVATIVES CONTAINING THIOETHER GROUPS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS ANTITUARY AGENTS
EP0556245B1 (en) Use of thiazolo-isoindolinone derivatives as antiviral medicaments
CH655116A5 (en) MITOMYCIN ANALOG COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM.
EP0602097A1 (en) New tricyclic thiazol and oxazol derivates with antiviral action.
DE2828261A1 (en) NEW PENICILLINE, ITS SALTS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
WO1992013860A1 (en) NEW 4,5,6,7-TETRAHYDRO-IMIDAZO-[4,5,lJK][1,4]-BENZODIAZEPINE-2-(1H)-THIONES, A METHOD OF PREPARING THEM AS WELL AS DRUGS CONTAINING THEM, AND INTERMEDIATES FOR THE PREPARATION OF THESE COMPOUNDS
DE2518032A1 (en) 2-AMINOIMIDAZOLE, PROCESS FOR THEIR PREPARATION AND COMPOUND CONTAINING THE SAME
DE69125962T2 (en) 3H, 6H-1,4,5a, 8a-tetraazaacenaphthylene-3,5- (4H) dione
DE3217236C2 (en) 5,6-Dihydro-11H-dibenzo [b, e] - azepin-6-one, and pharmaceutical compositions containing them
DE69026936T2 (en) 5-AMINOCARBONYL-5H-DIBENZO-A, D] CYCLOHEPTEN-5,10-IMINE FOR THE TREATMENT OF EPILEPSY AND COCOA ADDICTION
DE3900964A1 (en) NEW NUCLEOSIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
DE2259471A1 (en) NEW 6-AZA-3H-1,4-BENZODIAZEPINE
DE68911951T2 (en) 5- (Substituted amino) -8- (phenyl or substituted phenyl) -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one.
EP0711275B1 (en) (thio)carbimidinic acid derivatives and medicaments containing the same
DE2038922A1 (en) Organic thiazolopyrimidines
DE2733869C2 (en) 2-Carbamoyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-ones, processes for their preparation and pharmaceuticals containing them
EP0640088B1 (en) Novel tricyclic thiazolo and thiazino derivatives and anti-viral medicaments containing them

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BG BR CA CS FI HU JP KR NO PL RO RU US

AL Designated countries for regional patents

Kind code of ref document: A1

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

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载