WO1992016529A1 - Novel isoindole derivatives and medicaments containing them - Google Patents

Novel isoindole derivatives and medicaments containing them Download PDF

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Publication number
WO1992016529A1
WO1992016529A1 PCT/EP1992/000601 EP9200601W WO9216529A1 WO 1992016529 A1 WO1992016529 A1 WO 1992016529A1 EP 9200601 W EP9200601 W EP 9200601W WO 9216529 A1 WO9216529 A1 WO 9216529A1
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Prior art keywords
pyrrolo
tetrahydro
general formula
isoindol
compound
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PCT/EP1992/000601
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German (de)
French (fr)
Inventor
Herbert Leinert
Bernhard König
Ulrike Leser
Thomas Poll
Wolfgang Schäfer
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Boehringer Mannheim Gmbh
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Publication of WO1992016529A1 publication Critical patent/WO1992016529A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to new isoindole derivatives, processes for their preparation and medicaments which contain these compounds.
  • the invention relates to isoindole derivatives of the general formula I.
  • R 1 represents a phenyl ring which is optionally mono- or polysubstituted by C- L -Cg-alkyl, C 3 -C5-cycloalkyl, C -] _- Cg-alkoxy, C ⁇ .-Cg-alkylmercapto, C- L - Cg-alkylsulfinyl, C -] _- Cg-alkylsulfonyl, C2-Cg-alkenyl, C 2 - Cg-alkynyl, C2-Cg-alkenyloxy, C2-Cg-alkenylmercapto, C2-Cg-alkynyloxy, C2-Cg-alkynylmercapto, Amino, C -__- Cg-Alkyla ino, Di-C -] _- Cg-alkylamino, Ci-Cg-alkylcarbonylamino, Ci-Cg-alkylamino-carbony
  • R 2 is a hydrogen atom, a straight-chain or branched saturated or unsaturated aliphatic radical with 1-6 C atoms or Ci-Cg-alkoxy, Ci-Cg-alkylmer- ⁇ apto, C ⁇ _-Cg-alkylsulfinyl, C ⁇ -Cg-alkylsulfonyl, Amino, C ⁇ _-Cg-alkylamino, di-C ⁇ -Cg-alkylamino, Ci-Cg-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, trifluoromethyl, phenyl or benzyloxy means,
  • R 3 has the same meaning as R 2 , where the radicals R 2 and R 3 can independently of one another be the same or different,
  • X represents an oxygen or sulfur atom or the NH or N-C ⁇ _-C5-alkyl group
  • the object of the present invention was to provide new isoindole derivatives which, in particular can be used to manufacture medicinal products. This object is achieved by the present invention.
  • the compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes si plex virus, the cytomegalovirus, papilloma viruses, the Epstein-Barr virus, the varicella-zoster virus or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II , as well as the lentiviruses and human immunodeficiency virus HIV-1 and HIV-2.
  • the compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS.
  • PDL generalized lymphadenopathy
  • ARC advanced stage of the AIDS-related complex
  • the compounds of the general formula I according to the invention have a pronounced antiviral activity and are particularly suitable for the treatment of viral and retroviral infections.
  • Viral infections in mammals, especially humans, are common.
  • chemotherapeutic agents which cause causally or symptomatically to interfere with the viral or retroviral-related illness with recognizable substantial success.
  • AIDS Acguired Immune Deficiency Syndrome
  • ARC AIDS-related complex
  • CMV cytomegalovirus
  • AZT 3 'azido-3' deoxy-thymidine
  • Zidovudine R or Retrovir R 3 'azido-3' deoxy-thymidine
  • Zidovudine R or Retrovir R 3 'azido-3' deoxy-thymidine
  • AZT is characterized by a very narrow therapeutic breadth or by already occurring in the therapeutic field, characterized very severe toxicities (Hirsch, MS (1988) J. nfec. Dis. 157, 427-431).
  • the compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacologically relevant doses.
  • compounds of general formula I inhibit the multiplication of DNA or RNA viruses at the level of virus-specific DNA or RNA transcription.
  • the substances can influence the multiplication of retroviruses (cf. Proc. Natl. Acad. Sci. USA 83, 1911 (1986) and Nature 325, 773 (1987)). Since there is a very great need for chemotherapeutics which interfere as specifically as possible with retroviral-related diseases or their symptoms without influencing the normal natural body functions, the compounds according to the invention can advantageously be used prophylactically or therapeutically in the treatment of diseases, in which a retroviral infection is of pathophysiological, symptomatic or clinical relevance.
  • optically active phases are, for example, optically active polyamide amides, some also on silica gel (for example ChiraSpehr R from Merck, Chirapak R OT / OP from Baker), cellulose ester / carbamates (for example Chiracel R OB / OY from Baker / Daicel, phases based on cyclodextrin or crown ether (for example Crownpak R from Daicel) or microcrystalline cellulose triacetate from Merck.
  • silica gel for example ChiraSpehr R from Merck, Chirapak R OT / OP from Baker
  • cellulose ester / carbamates for example Chiracel R OB / OY from Baker / Daicel
  • phases based on cyclodextrin or crown ether for example Crownpak R from Daicel
  • microcrystalline cellulose triacetate from Merck.
  • alkyl "alkenyl” or “alkynyl” parts of the various groups mentioned in the definitions of R 1 -R 3 and X, such as, for example, alkyl, alkoxy, alkylmercapto, alkenyl, alkenyloxy, etc.
  • R 1 -R 3 and X can be straight or branched in all cases, such as z.
  • B. the methyl, ethyl, n-propyl, i-propyl, n-butyl or tert-butyl radical.
  • C3-Cg-cycloalkyl rings are in particular the cyclopentyl and cyclohexyl ring.
  • an aliphatic radical means a straight-chain or branched alkyl, alkenyl or alkynyl radical with 1-6, preferably 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl -, Pentyl or Hexylrest.
  • Possible unsaturated radicals are C2-Cg-alkenyl and alkynyl radicals, preferably C2-C5, such as, for example, the allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propinyl radical.
  • R 1 is a phenyl ring, this can be mono-, di- or trisubstituted.
  • the substituents can stand independently of one another in the o, m or p position to one another.
  • R 1 is a carbocyclic ring with 5-15 C atoms, this can be mono-, bi- or tricyclic and each have 5 or 6 C atoms. This can be saturated, unsaturated, partially saturated or aromatic.
  • ring systems may be mentioned as examples: the naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, indanyl, acenaphthylene, norbonyl and adamantyl ring or a C 3 -C 7 -cycloalkyl or Cs-Cs-cycloalkenyl group.
  • the heterocyclic mono-, bi- or tricyclic ring systems contain 5 or 6 carbon atoms per ring system, where 1-4 or 1-5 carbon atoms can be replaced by the heteroatoms oxygen, sulfur and / or nitrogen.
  • the ring systems can be aromatic, partially or completely hydrogenated.
  • ring systems may be mentioned by way of example: the pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadizole, furazane, Furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzothiazole, indazole, benzimidazole, benzotriazole, chromene, phthalazine, quinazoline, methylenedioxybenzene, Carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system, where the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated.
  • R- 1 preferably denotes phenyl or phenyl mono- or disubstituted by Ci-Cg-alkyl, C3-Cg-cycloalkyl, C ⁇ -Cg-alkoxy, C ⁇ -Cg-alkylmer ⁇ apto, C ⁇ -Cg-alkylsulfinyl, C ⁇ -Cg-alkylsulfonyl, C 2 -Cg-alkenyl A C2-Cg-alkynyl, C3-Cg-alkenyl-oxy, C ⁇ -Cg-alkylamino, C ⁇ -Cg-dialkylamino, C ⁇ -Cg-alkyl ⁇ arbonylamino, C ⁇ -Cg-alkylaminocarbonyl, C ⁇ -Cg -Alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen.
  • the “alkyl” parts mentioned above preferably contain up to 4,
  • Carbocyclic rings are preferably biphenyl, naphthyl, anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthrenyl, norbonyl and adamantyl.
  • Heterocyclic ring systems are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, coumarone, thionapthene, benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, acridine and phenidine.
  • radicals for R 1 are the phenyl, the 3-methylphenyl, the 3-methoxyphenyl, the 3-chlorophenyl, the 3-trifluoromethylphenyl and the 3,5-dimethyl phenyl-, 3,5-dichlorophenyl-, 3-cyclopropyl-phenyl-, 3-cyclobutyl-phenyl-, 3-cyclopentyl-phenyl-, 3-cyclohexyl-phenyl-, naphthyl- the pyridyl, the thienyl and the furanyl radical.
  • radicals R 2 and R 3 are hydrogen, C ⁇ -Cg-alkyl, C2-C - alkenyl, C2 ⁇ Cg-alkynyl, C ⁇ -Cg-alkoxy, C ⁇ -Cg-alkylmercapto, C ⁇ -Cg-alkylamino, C ⁇ -Cg Alkoxycarbonyl, amino, halogen, Hydroxy, cyano, trifluoromethyl and azido are preferred.
  • the "alkyl" parts of the abovementioned radicals preferably contain up to 4, in particular up to 3, carbon atoms.
  • radicals for R 2 and R 3 are, independently of one another, hydrogen, methyl, ethyl, propyl, isopropyl, allyl, methoxy, ethoxy, propoxy, methylmercapto, ethylmercapto, methyl ino, ethylamino, methoxycarbonyl, ethoxycarbonyl, amino , Azido, cyano, trifluoromethyl, hydroxy and halogen, with fluorine, chlorine and bromine being particularly preferred for halogen.
  • X preferably represents a sulfur or an oxygen atom.
  • the medicaments containing at least one compound 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 come into question, 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, for example, tartrate and citrate buffers, ethanol, complexing agents such as ethylenedia intetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity control.
  • 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 silicic acid, higher molecular fatty acids, such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal fats, solid high molecular polymers, polyethylene glycols etc.
  • Preparations suitable for oral applications can, if desired Contain flavorings or sweeteners.
  • the corresponding pharmaceutical forms such as, for. B. tablets, capsules, Drag ⁇ es, made up in the appropriate number, z. B. packed in blister strips, and packaged into corresponding units, the ready-to-sell packagings thus produced being provided with the information for use as an antiviral or antiretroviral agent, for example in the form of the prescribed package insert or a label print.
  • physiologically tolerable salts For the preparation of physiologically tolerable salts, compounds of formula I which carry "a basic group, is reacted with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid or maleic acid, and if the compounds of the formula I contain an acid group, the physiologically tolerable salts are obtained by reaction with alkali or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or calcium hydroxide, or with other basic groups, such as with amines, for example. for example triethylamine.
  • organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid or maleic acid
  • alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or
  • the dosage can depend on various factors, such as method of application, species, age or individual condition.
  • the compounds according to the invention are usually administered in amounts of 0.1-100 mg, preferably in amounts of 0.2-80 mg per day and per kilogram of body weight. It is preferred to distribute the daily dose over 2-5 applications.
  • the tablets can also be retarded, which reduces the number of applications 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 being normally sufficient.
  • the compounds of general formula I according to the invention are prepared by using a compound of general formula II
  • Y has the meaning given and A represents a reactive, easily removable group, such as a halogen atom or a sulfonic ester group, in an inert solvent such as toluene or dimethylformamide in the presence of an alkaline condensing agent such as sodium hydride at temperatures between room temperature and the reflux temperature of the solvent, preferably between 40 and 80 ° C.
  • an alkaline condensing agent such as sodium hydride at temperatures between room temperature and the reflux temperature of the solvent, preferably between 40 and 80 ° C.
  • the reaction of a compound of the general formula II with a compound of the general formula III can also be carried out in a two-phase mixture in the presence of a phase transfer catalyst, for example in the presence of a tert-alkylammonium salt.
  • the racemic mixtures obtained in the preparation of the compounds of the general formula I can be separated into the optically active isomers by chromatography on suitable optically active phases, for example cellulose triacetate.
  • suitable optically active phases for example cellulose triacetate.
  • the compounds of the general formula I in which X denotes an oxygen atom can subsequently be converted into compounds of the general formula I in which X denotes a sulfur atom by reactions with sulfur-transferring compounds, such as Lawesson's reagent or with sulfur pentasulfide.
  • the compounds of the general formula II are known from the literature or can be obtained from known compounds of the general formula IV by processes known from the literature
  • R 1 , R 2 , R 3 and X have the meanings given above, are obtained by reaction with ammonia.
  • the compounds of general formula IV are obtained by reaction with reducing agents according to known methods, e.g. by reduction with sodium borohydride, from compounds of the general formula V
  • the benzoic acid derivatives of the general formula V are known in the literature and are obtained by Friedel-Crafts acylation of substituted or unsubstituted phthalic anhydride with optionally substituted arenes in the presence of a Lewis acid (for example aluminum chloride) or by reaction of Grignard reagents of the general formula VI
  • R 1 has the meaning given above, with substituted or unsubstituted phthalic anhydride in the presence of an inert solvent.
  • the compounds of the general formula I can also be prepared by using a compound of the general formula II in which R 1 , R 2 and R 3 have the meanings given above and X is an oxygen atom, by known processes Meerwein reagent in a compound of the general formula VII
  • R 1 , R 2 and R 3 have the meanings given and R 4 is a C ⁇ -Cg-alkyl group, such as the methyl or ethyl group, transferred and this with a compound of the general my Formula VIII
  • a and Y have the meanings given and Z is a protective group, e.g. represents a benzyl group in the presence of an alkaline condensing agent such as e.g. Sodium hydride, in an inert solvent, e.g. Dimethylformamide or toluene, brings to reaction and the compound of general formula IX obtained
  • R 1 , R 2 , R 3 , R 4 and Z have the meanings given, by treatment with acid in a compound of the general formula X.
  • phenylphthalimidine 500 mg are dissolved in 3 ml of dimethylformamide. 630 mg of potassium hydroxide, 80 mg of tetrabutylammonium bromide and 0.3 ml of l-bromo-3-chloropropane are added to this solution. The mixture is stirred intensively for 6 hours at 60 ° C., then diluted with water and shaken out with ethyl acetate. The ethyl acetate phase is washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column for purification. (Eluent: isohexane / ethyl acetate 1: 2). The column fractions obtained are evaporated and recrystallized from ether. 350 mg of the title compound of mp: 97 ° C. are obtained.
  • the test system for determining the inhibitory effect of the compounds according to the invention on the HIV-RT contains the purified RT from HIV-1, which was expressed by genetic engineering methods in E. coli, and the components of the initiation complex, such as the in vitro Transcripts of the HIV-LTR with the neighboring primer binding site as template and an 18mer oligonucleotide complementary to the primer binding site as primer.
  • the [ 3 H] -thymidine-5'-triphosphate incorporation was measured by counting in the ⁇ -counter.
  • the table below shows the ICsother for the compounds examined. This value corresponds to the concentration of the test substance which causes an inhibition of the RT activity by 50%.

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Abstract

The present invention relates to novel isoindole derivatives, a process for producing them and medicaments containing these compounds. The invention relates to isoindole derivatives of the general formula (I) in which: R1 is a phenyl ring which may be singly or multiply substituted, or a mono, bi or tricyclic carbocyclic ring with 3 to 15 C atoms or a heterocyclic ring system, R?2 and R3¿ are a hydrogen atom, a straight or branched-chain saturated or unsaturated aliphatic radical with 1 to 6 C atoms or C¿1?-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsuphinyl, C1-C6 alkylsulphonyl, amino, C1-C6 alkylamino, Di-C1-C6 alkylamino, C1-C6 alkoxy carbonyl, carboxy, halogen, hydroxy, nitro, cyano, trifluoromethyl, phenyl or benzyloxy, X is an oxygen or sulphur atom or the NH or N-C1-C5 alkyl group, and Y is -CH2-, CH2-CH2- or -CH=CH-, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts.

Description

Neue Isoindol-Derivate und diese enthaltende ArzneimittelNew isoindole derivatives and medicinal products containing them
Gegenstand der vorliegenden Erfindung sind neue Isoindol- Derivate, Verfahren zu deren Herstellung und Arzneimittel, die diese Verbindungen enthalten.The present invention relates to new isoindole derivatives, processes for their preparation and medicaments which contain these compounds.
Die Erfindung betrifft Isoindol-Derivate der allgemeinen Formel IThe invention relates to isoindole derivatives of the general formula I.
Figure imgf000003_0001
Figure imgf000003_0001
in derin the
R1 einen Phenylring bedeutet, der gegebenenfalls ein- oder mehrfach substituiert ist durch C-L-Cg-Alkyl, C3-C5- Cycloalkyl, C-]_-Cg-Alkoxy, Cτ.-Cg-Alkylmercapto, C-L-Cg- Alkylsulfinyl, C-]_-Cg-Alkylsulfonyl, C2-Cg-Alkenyl, C2- Cg-Alkinyl, C2-Cg-Alkenyloxy, C2-Cg-Alkenylmercapto, C2- Cg-Alkinyloxy, C2-Cg-Alkinylmercapto, Amino, C-__-Cg- Alkyla ino, Di-C-]_-Cg-alkylamino, Ci-Cg-Alkylcarbonyl- amino, Ci-Cg-Alkylamino-carbonyl, C-L-Cg-Alkoxycarbonyl, Hydroxy, Benzyloxy, Phenylmercapto, Phenyloxy, Nitro, Cyano, Halogen, Trifluormethyl, Azido, Formylamino oder Phenyl,R 1 represents a phenyl ring which is optionally mono- or polysubstituted by C- L -Cg-alkyl, C 3 -C5-cycloalkyl, C -] _- Cg-alkoxy, Cτ.-Cg-alkylmercapto, C- L - Cg-alkylsulfinyl, C -] _- Cg-alkylsulfonyl, C2-Cg-alkenyl, C 2 - Cg-alkynyl, C2-Cg-alkenyloxy, C2-Cg-alkenylmercapto, C2-Cg-alkynyloxy, C2-Cg-alkynylmercapto, Amino, C -__- Cg-Alkyla ino, Di-C -] _- Cg-alkylamino, Ci-Cg-alkylcarbonylamino, Ci-Cg-alkylamino-carbonyl, CL-Cg-alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, Phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino or phenyl,
oder einen mono-, bi- oder triσyclischen carbocyclischen Ring mit 3-15 C-Atomen oder ein heterocylisches mono-, bi-oder tricyclisches Ringsystem mit jeweils 5 oder 6 Ringatomen bedeutet und pro Ringsystem 1-4 bzw 1-5 Heteroato e enthalten sein können, wobei die Heteroatome Stickstoff, Sauerstoff oder Schwefel sind,or a mono-, bi- or tricyclic carbocyclic ring with 3-15 C atoms or a heterocyclic mono-, bi- or tricyclic ring system with 5 or 6 each Means ring atoms and can contain 1-4 or 1-5 heteroatoms per ring system, the heteroatoms being nitrogen, oxygen or sulfur,
R2 ein Wasserstoffatom, einen geradkettigen oder ver¬ zweigten gesättigten oder ungesättigten aliphatischen Rest mit 1-6 C-Atomen oder Ci-Cg-Alkoxy, Ci-Cg-Alkylmer- σapto, Cτ_-Cg-Alkylsufinyl, Cχ-Cg-Alkylsulfonyl, Amino, Cτ_-Cg-Alkylamino, Di-Cχ-Cg-Alkylamino, Ci-Cg-Alkoxycar- bonyl, Carboxy, Halogen, Hydroxy, Nitro, Cyano, Tri- fluormethyl, Phenyl oder Benzyloxy bedeutet,R 2 is a hydrogen atom, a straight-chain or branched saturated or unsaturated aliphatic radical with 1-6 C atoms or Ci-Cg-alkoxy, Ci-Cg-alkylmer-σapto, Cτ_-Cg-alkylsulfinyl, Cχ-Cg-alkylsulfonyl, Amino, Cτ_-Cg-alkylamino, di-Cχ-Cg-alkylamino, Ci-Cg-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, trifluoromethyl, phenyl or benzyloxy means,
R3 die gleiche Bedeutung wie R2 hat, wobei die Reste R2 und R3 unabhängig voneinander gleich oder verschieden sein können,R 3 has the same meaning as R 2 , where the radicals R 2 and R 3 can independently of one another be the same or different,
X ein Sauerstoff- oder Schwefelatom bzw. die NH- oder N- Cτ_-C5-Alkylgruppe darstellt undX represents an oxygen or sulfur atom or the NH or N-Cτ_-C5-alkyl group and
Y -CH2-, CH2-CH2-, oder -CH=CH- bedeutet,Y denotes -CH 2 -, CH 2 -CH 2 -, or -CH = CH-,
sowie deren Tautomere, Enantio ere, Diastereomere oder physiologisch verträgliche Salze.and their tautomers, enantiomers, diastereomers or physiologically acceptable salts.
Verbindungen ähnlicher Struktur mit antiviraler Wirkung sind bekannt aus den Deutschen Patentanmeldungen P 40 35 809.7, P 41 03 177.6, P 41 06 283.3 und P 41 08 395.4 und den dort zitierten Literaturstellen. Die erfindungsgemäßen Ver¬ bindungen unterscheiden sich strukturell von den dort be¬ schriebenen Verbindungen unter anderem dadurch, daß Y eine -CH2~, -CH2-CH2- oder -CH=CH-Gruppe bedeutet, während die aus dem Stand der Technik bekannten Derivate Verbindungen dar¬ stellen, in denen Y ein Sauerstoff-, Schwefel- oder Stick¬ stoffatom darstellt.Compounds of similar structure with antiviral activity are known from German patent applications P 40 35 809.7, P 41 03 177.6, P 41 06 283.3 and P 41 08 395.4 and the references cited therein. The compounds according to the invention differ structurally from the compounds described therein, inter alia in that Y denotes a —CH 2,, —CH 2 -CH 2 or —CH =CH group, while the derivatives known from the prior art are compounds represent in which Y represents an oxygen, sulfur or nitrogen atom.
Der vorliegenden Erfindung lag die Aufgabe zugrunde, neue Isoindol-Derivate zur Verfuegung zu stellen, die insbesondere zur Herstellung von Arzneimitteln verwendet werden können. Diese Aufgabe wird durch die vorliegende Erfindung gelöst.The object of the present invention was to provide new isoindole derivatives which, in particular can be used to manufacture medicinal products. This object is achieved by the present invention.
Die Verbindungen der vorliegenden Erfindung weisen wertvolle pharmakologische Eigenschaften auf. Insbesondere eignen sie sich zur Therapie und Prophylaxe von Infektionen, die durch DNA-Viren wie z.B. das Herpes-Si plex-Virus, das Zytomegalie- Virus, Papilloma Viren, das Epstein-Barr-Virus, das Varicella-Zoster-Virus oder RNA-Viren wie Toga-Viren oder insbesondere Retroviren wie die Onko-Viren HTLV-I und II, sowie die Lentiviren und Humanes-Immunschwäche-Virus HIV-1 und HIV-2 verursacht werden. Insbesondere geeignet erscheinen die Verbindungen der Formel I zur Behandlung der klinischen Manifestationen der retroviralen HIV-Infektion beim Menschen, wie der anhaltenden, generalisierten Lymphadenopathie (PGL) , dem fortgeschrittenen Stadium des AIDS-verwandten Komplex (ARC) und dem klinischen Vollbild von AIDS.The compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes si plex virus, the cytomegalovirus, papilloma viruses, the Epstein-Barr virus, the varicella-zoster virus or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II , as well as the lentiviruses and human immunodeficiency virus HIV-1 and HIV-2. The compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS.
Die erfindungsge ässen Verbindungen der allgemeinen Formel I besitzen eine ausgeprägte antivirale Wirkung und eignen sich insbesondere zur Behandlung von viralen und retroviralen Infektionen. Virale Infektionen von Säugern, insbesondere des Menschen sind weit verbreitet. Trotz intensiver Bemühungen ist es bisher nicht gelungen, Chemotherapeutica bereitzu¬ stellen, die ursächlich oder symptomatisch mit dem viral oder retroviral bedingten Krankheitsgeschehen mit erkennbar sub¬ stantiellem Erfolg interferieren. Es ist heutzutage nicht möglich, bestimmte Viruserkrankungen, wie z.B. das Acguired Immune Deficiency Syndrom (AIDS) , den AIDS-related Komplex (ARC) und deren Vorstadien, Herpes-, Cytomegalie-Virus (CMV) , Influenza- und andere Viruserkrankungen zu heilen oder chemo¬ therapeutisch deren Symptome günstig zu beeinflussen. Derzeit steht bespielsweise für die Behandlung von AIDS fast aus- schliesslich das 3 '-Azido-3 '-deoxy-thymidin zur Verfügung (AZT) , bekannt als ZidovudineR oder RetrovirR, zur Verfügung. AZT ist jedoch durch eine sehr enge therapeutische Breite bzw. durch bereits im therapeutischen Bereich auftretende, sehr schwere Toxizitäten charakterisiert (Hirsch, M.S. (1988) J. nfec. Dis. 157, 427-431) . Die Verbindungen der allge¬ meinen Formel I besitzen diese Nachteile nicht. Sie wirken antiviral, ohne in pharmakolgisch relevanten Dosen cytotoxisch zu sein.The compounds of the general formula I according to the invention have a pronounced antiviral activity and are particularly suitable for the treatment of viral and retroviral infections. Viral infections in mammals, especially humans, are common. Despite intensive efforts, it has so far not been possible to provide chemotherapeutic agents which cause causally or symptomatically to interfere with the viral or retroviral-related illness with recognizable substantial success. Nowadays it is not possible to cure certain viral diseases, such as the Acguired Immune Deficiency Syndrome (AIDS), the AIDS-related complex (ARC) and its pre-stages, herpes, cytomegalovirus (CMV), influenza and other viral diseases or to influence their symptoms chemo-therapeutically. For example, 3 'azido-3' deoxy-thymidine (AZT), known as Zidovudine R or Retrovir R , is almost exclusively available for the treatment of AIDS. However, AZT is characterized by a very narrow therapeutic breadth or by already occurring in the therapeutic field, characterized very severe toxicities (Hirsch, MS (1988) J. nfec. Dis. 157, 427-431). The compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacologically relevant doses.
Es konnte nachgewiesen werden, daß Verbindungen der allge¬ meinen Formel I die Vermehrung von DNA- bzw. RNA-Viren auf der Stufe der virusspezischen DNA- bzw. RNA-Transkription hemmen. Die Substanzen können über die Inhibierung des Enzyms Reverse Transkriptase die Vermehrung von Retroviren beein¬ flussen (vgl. Proc. Natl. Acad. Sei. USA 83, 1911 ( 1986) bzw. Nature 325, 773 (1987)). Da ein sehr großer Bedarf an Chemotherapeutcia besteht, die möglichst spezifisch mit retroviral bedingten Erkrankungen oder deren Symptomen inter¬ ferieren, ohne die normal ablaufenden natürlichen Körper¬ funktionen zu beeinflussen, können die erfindungsgemässen Verbindungen vorteilhaft prophylaktisch oder therapeutisch bei der Behandlung von Krankheiten eingesetzt werden, bei denen eine retrovirale Infektion von pathophysiologischer, symptomatischer oder klinischer Relevanz ist.It has been demonstrated that compounds of general formula I inhibit the multiplication of DNA or RNA viruses at the level of virus-specific DNA or RNA transcription. By inhibiting the enzyme reverse transcriptase, the substances can influence the multiplication of retroviruses (cf. Proc. Natl. Acad. Sci. USA 83, 1911 (1986) and Nature 325, 773 (1987)). Since there is a very great need for chemotherapeutics which interfere as specifically as possible with retroviral-related diseases or their symptoms without influencing the normal natural body functions, the compounds according to the invention can advantageously be used prophylactically or therapeutically in the treatment of diseases, in which a retroviral infection is of pathophysiological, symptomatic or clinical relevance.
Die Trennung der Racemate in die Enantiomeren kann analytisch, semipräparativ und präparativ chromatographisch an geeigneten optisch aktiven Phasen mit gängigen Elutionsmitteln durchgeführt werden. Als optisch aktive Phasen eignen sich beispielsweise optisch aktive Polyaσryl- amide, z.T. auch an Kieselgel (z.B. ChiraSpehrR von Merck, ChirapakR OT/OP von Baker), Celluloseester-/carbamate (z.B. ChiracelR OB/OY von Baker/Daicel, Phasen auf Cyclodextrin- oder Kronenetherbasis (z.B. CrownpakR von Daicel) oder mikro¬ kristallines Cellulosetriacetat von Merck.The separation of the racemates into the enantiomers can be carried out analytically, semi-preparatively and preparatively chromatographically on suitable optically active phases with common eluents. Optically active phases are, for example, optically active polyamide amides, some also on silica gel (for example ChiraSpehr R from Merck, Chirapak R OT / OP from Baker), cellulose ester / carbamates (for example Chiracel R OB / OY from Baker / Daicel, phases based on cyclodextrin or crown ether (for example Crownpak R from Daicel) or microcrystalline cellulose triacetate from Merck.
Die in den Definitionen von R1-R3 und X genannten "Alkyl-", "Alkenyl-" oder "Alkinyl-'-teile der diversen Gruppen, wie z. B. Alkyl, Alkoxy, Alkylmercapto, Alkenyl, Alkenyloxy, etc., können in allen Fällen geradkettig oder verzweigt sein, wie z. B. der Methyl-, Ethyl-, n-Propyl-, i-Propyl-, n-Butyl- oder tert.-Butylrest. C3-Cg-Cycloalkylringe sind insbesondere der Cyclopentyl- und Cyclohexylring.The "alkyl", "alkenyl" or "alkynyl" parts of the various groups mentioned in the definitions of R 1 -R 3 and X, such as, for example, alkyl, alkoxy, alkylmercapto, alkenyl, alkenyloxy, etc. , can be straight or branched in all cases, such as z. B. the methyl, ethyl, n-propyl, i-propyl, n-butyl or tert-butyl radical. C3-Cg-cycloalkyl rings are in particular the cyclopentyl and cyclohexyl ring.
In der Definition von R2 bedeutet ein aliphatischer Rest einen geradkettigen oder verzweigten Alkyl-, Alkenyl- oder Alkinylrest mit 1-6, vorzugsweise 1-4 Kohlenstoffatomen, wie z.B. Methyl-, Ethyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl-, Pentyl- oder Hexylrest. Als ungesättigte Reste kommen C2-Cg- Alkenyl- und Alkinylreste in Frage, bevorzugt C2-C5, wie z.B. der Allyl-, Dimethylallyl-, Butenyl-, Isobutenyl-, Pentenyl- oder Propinylrest.In the definition of R 2 , an aliphatic radical means a straight-chain or branched alkyl, alkenyl or alkynyl radical with 1-6, preferably 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl -, Pentyl or Hexylrest. Possible unsaturated radicals are C2-Cg-alkenyl and alkynyl radicals, preferably C2-C5, such as, for example, the allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propinyl radical.
Bedeutet R1 einen Phenylring, so kann dieser ein-, zwei oder dreifach substituiert sein. Die Substituenten können unabhän¬ gig voneiander in o-, m- oder p-Stellung zueinander stehen. Bedeutet R1 einen carbocyclischen Ring mit 5-15 C-Atomen, so kann dieser mono-, bi- oder tricyclisch sein und pro Ring jeweils 5 oder 6 C-Atome besitzen. Dieser kann gesättigt, ungesättigt, teilweise gesättigt oder aromatisch sein. Bei¬ spielhaft genannt seien die folgende Ringsysteme: der Naphthyl-, Anthracenyl, Phenanthrenyl-, Fluorenyl-, Indenyl-, Indanyl-, Acenaphthylen-, Norbonyl- und Adamantylring oder eine C3-C7-cycloalkyl- oder Cs-Cs-Cycloalkenylgruppe.If R 1 is a phenyl ring, this can be mono-, di- or trisubstituted. The substituents can stand independently of one another in the o, m or p position to one another. If R 1 is a carbocyclic ring with 5-15 C atoms, this can be mono-, bi- or tricyclic and each have 5 or 6 C atoms. This can be saturated, unsaturated, partially saturated or aromatic. The following ring systems may be mentioned as examples: the naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, indanyl, acenaphthylene, norbonyl and adamantyl ring or a C 3 -C 7 -cycloalkyl or Cs-Cs-cycloalkenyl group.
Die heterocyclischen mono-, bi- oder tricyclischen Ring¬ systeme enthalten pro Ringsystem 5 oder 6 C-Atome, wobei 1-4 bzw. 1-5 C-Atome durch die Heteroatome Sauerstoff, Schwefel und/oder Stickstoff ersetzt sein können. Die Ringsysteme können aromatisch, partiell oder vollständig hydriert sein. Beispielhaft genannt seien die folgenden Ringsysteme: das Pyridin-, Pyrimidin-, Pyridazin-, Pyrazin-, Triazin-, Pyrrol-, Pyrazol-, Imidazol-, Triazol-, Thiazol-, Oxazol-, Isoxazol-, Oxadizol-, Furazan-, Furan-, Thiophen-, Indol-, Chinolin-, Isochinolin-, Cumaron-, Thionaphthen-, Benzoxa- zol-, Benzthiazol-, Indazol-, Benzimidazol-, Benztriazol-, Chromen-, Phthalazin-, Chinazolin-, Methylendioxybenzol-, Carbazol-, Acridin-, Phenoxazin-, Phenothiazin-, Phenazin- oder Purinsystem, wobei die ungesättigten bzw. aromatischen Carbo- und Heterocyclen partiell oder vollständig hydriert sein können.The heterocyclic mono-, bi- or tricyclic ring systems contain 5 or 6 carbon atoms per ring system, where 1-4 or 1-5 carbon atoms can be replaced by the heteroatoms oxygen, sulfur and / or nitrogen. The ring systems can be aromatic, partially or completely hydrogenated. The following ring systems may be mentioned by way of example: the pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadizole, furazane, Furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzothiazole, indazole, benzimidazole, benzotriazole, chromene, phthalazine, quinazoline, methylenedioxybenzene, Carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system, where the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated.
R-1 bedeutet bevorzugt Phenyl oder Phenyl ein- oder zweifach substituiert durch Ci-Cg-Alkyl, C3-Cg-Cyσloalkyl, Cχ-Cg- Alkoxy, Cχ-Cg-Alkylmerσapto, Cχ-Cg-Alkylsulfinyl, Cχ-Cg- Alkylsulfonyl, C2-Cg-AlkenylA C2-Cg-Alkinyl, C3-Cg-Alkenyl- oxy, Cχ-Cg-Alkylamino, Cχ-Cg-Dialkylamino, Cχ-Cg-Alkylσarbo- nylamino, Cχ-Cg-Alkylaminocarbonyl, Cχ-Cg-Alkoxycarbonyl, Amino, Hydroxy, Nitro, Azido, Trifluormethyl, Cyano oder Halogen. Bevorzugt enthalten die zuvor genannten "Alkyl"- teile in den jeweiligen Definitionen bis zu 4, insbesondere bis zu 3 C-Atome.R- 1 preferably denotes phenyl or phenyl mono- or disubstituted by Ci-Cg-alkyl, C3-Cg-cycloalkyl, Cχ-Cg-alkoxy, Cχ-Cg-alkylmerσapto, Cχ-Cg-alkylsulfinyl, Cχ-Cg-alkylsulfonyl, C 2 -Cg-alkenyl A C2-Cg-alkynyl, C3-Cg-alkenyl-oxy, Cχ-Cg-alkylamino, Cχ-Cg-dialkylamino, Cχ-Cg-alkylσarbonylamino, Cχ-Cg-alkylaminocarbonyl, Cχ-Cg -Alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen. The “alkyl” parts mentioned above preferably contain up to 4, in particular up to 3, carbon atoms in the respective definitions.
Carbocyclische Ringe sind bevorzugt Biphenyl, Naphthyl, Anthracenyl, Indenyl, Fluorenyl, Acenaphthylenyl, Phen- anthrenyl, Norbonyl und Adamantyl.Carbocyclic rings are preferably biphenyl, naphthyl, anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthrenyl, norbonyl and adamantyl.
Heterocyclische Ringsysteme sind bevorzugt Pyrrol, Imidazol, Furan, Thiophen, Pyridin, Pyrimidin, Thiazol, Triazin, Indol, Chinolin, Isochinolin, Cumaron, Thionapthen, Benzimidazol, Chinazolin, Methylendioxybenzol, Ethylendioxybenzol, Carba¬ zol, Acridin und Phenothiazin.Heterocyclic ring systems are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, coumarone, thionapthene, benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, acridine and phenidine.
Besonders bevorzugte Reste für R1 sind der Phenyl-, der 3- Methyl-phenyl-, der 3-Methoxy-phenyl-, der 3-Chlor-phenyl-, der 3-Trifluormethyl-phenyl-, der 3,5-Dimethyl-phenyl-, der 3,5-Dichlor-phenyl-, der 3-Cyclopropyl-phenyl-, der 3-Cyclo- butyl-phenyl-, der 3-Cyclopentyl-phenyl-, der 3-Cyclohexyl- phenyl-, der Naphthyl- der Pyridyl-, der Thienyl- und der Furanyl-Rest.Particularly preferred radicals for R 1 are the phenyl, the 3-methylphenyl, the 3-methoxyphenyl, the 3-chlorophenyl, the 3-trifluoromethylphenyl and the 3,5-dimethyl phenyl-, 3,5-dichlorophenyl-, 3-cyclopropyl-phenyl-, 3-cyclobutyl-phenyl-, 3-cyclopentyl-phenyl-, 3-cyclohexyl-phenyl-, naphthyl- the pyridyl, the thienyl and the furanyl radical.
Für die Reste R2 und R3 sind Wasserstoff, Cχ-Cg-Alkyl, C2-C - Alkenyl, C2~Cg-Alkinyl, Cχ-Cg-Alkoxy, Cχ-Cg-Alkylmercapto, Cχ-Cg-Alkylamino, Cχ-Cg-Alkoxycarbonyl, Amino, Halogen, Hydroxy, Cyano, Trifluormethyl und Azido bevorzugt. Bevorzugt enthalten die "Alkyl"-teile der zuvor genannten Reste bis zu 4, insbesondere bis zu 3 C-Atome.For the radicals R 2 and R 3 are hydrogen, Cχ-Cg-alkyl, C2-C - alkenyl, C2 ~ Cg-alkynyl, Cχ-Cg-alkoxy, Cχ-Cg-alkylmercapto, Cχ-Cg-alkylamino, Cχ-Cg Alkoxycarbonyl, amino, halogen, Hydroxy, cyano, trifluoromethyl and azido are preferred. The "alkyl" parts of the abovementioned radicals preferably contain up to 4, in particular up to 3, carbon atoms.
Besonders bevorzugte Reste für R2 und R3 sind unabhängig von¬ einander Wasserstoff, Methyl, Ethyl, Propyl, Isopropyl, Allyl, Methoxy, Ethoxy, Propoxy, Methylmercapto, Ethylmer- capto, Methyla ino, Ethylamino, Methoxycarbonyl, Ethoxycar- bonyl, Amino, Azido, Cyano, Trifluormethyl, Hydroxy und Halogen, wobei für Halogen Fluor, Chlor und Brom besonders bevorzugt sind.Particularly preferred radicals for R 2 and R 3 are, independently of one another, hydrogen, methyl, ethyl, propyl, isopropyl, allyl, methoxy, ethoxy, propoxy, methylmercapto, ethylmercapto, methyl ino, ethylamino, methoxycarbonyl, ethoxycarbonyl, amino , Azido, cyano, trifluoromethyl, hydroxy and halogen, with fluorine, chlorine and bromine being particularly preferred for halogen.
X bedeutet bevorzugt ein Schwefel- oder ein Sauerstoffatom.X preferably represents a sulfur or an oxygen atom.
Y ist bevorzugt eine -CH2- oder -CH=CH-Gruppe.Y is preferably a -CH2 or -CH = CH group.
Die Arzneimittel enthaltend mindestens eine Verbindung 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 beispielsweise Tabletten, Kapseln, Dragees, Sirupe, Lösungen oder Suspensionen. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, das die bei Injektionslösungen üblichen Zusätze wie Stabilisierungs¬ mittel, Lösungsvermittler und Puffer enthält. Derartige Zusätze sind z.B. Tartrat- und Zitratpuffer, Ethanol, Komplexbildner, wie Ethylendia intetraessigsäure und deren nichtoxischen Salze, hochmolekulare Polymere wie flüssiges Polyethylenoxid zur Viskositätsregelung. Flüssige Träger¬ stoffe für Injektionslösungen müssen steril sein und werden vorzugsweise in Ampullen abgefüllt. Feste TrägerStoffe sind beispielsweise Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäure, höher molekulare Fett¬ säuren, wie z.B. Stearinsäure, Gelatine, Agar-Agar, Calcium- phosphat, Magnesiumstearat, tierische Fette, feste hoch molekulare Polymere, Polyethylenglykole etc.. Für orale An Wendungen geeignete Zubereitungen können gewünschtenfalls Geschmacks- oder Süßstoffe enthalten. Zur Herstellung von gebrauchsfertigen Verpackungseinheiten werden die ent¬ sprechenden Arzneiformen, wie z. B. Tabletten, Kapseln, Dragόes, in der entsprechenden Stückzahl konfektioniert, z. B. in Blisterstreifen, und zu entsprechenden Einheiten ver¬ packt, wobei die so hergestellten Verkaufsfertigen Ver¬ packungseinheiten mit der Information zur Anwendung als antivirales oder antiretrovirales Mittel versehen werden, beispielsweise in Form des vorgeschriebenen Beipackzettels oder eines Etikettenaufdruσkes.The medicaments containing at least one compound of the formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form. Here, the usual forms of application come into question, 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, for example, tartrate and citrate buffers, ethanol, complexing agents such as ethylenedia intetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity control. 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 silicic acid, higher molecular fatty acids, such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal fats, solid high molecular polymers, polyethylene glycols etc. Preparations suitable for oral applications can, if desired Contain flavorings or sweeteners. For the production of ready-to-use packaging units, the corresponding pharmaceutical forms, such as, for. B. tablets, capsules, Dragόes, made up in the appropriate number, z. B. packed in blister strips, and packaged into corresponding units, the ready-to-sell packagings thus produced being provided with the information for use as an antiviral or antiretroviral agent, for example in the form of the prescribed package insert or a label print.
Zur Herstellung der physiologisch verträglichen Salze werden Verbindungen der Formel I, die"eine basische Gruppe tragen, mit organischen oder anorganischen Säuren umgesetzt, wie z.B. Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphor¬ säure, Fumarsäure, Bernsteinsäure, Weinsäure, Zitronensäure, Milchsäure oder Maleinsäure, und die Säureadditionssalze isoliert. Enthalten die Verbindungen der Formel I eine Säure¬ gruppe, so erhält man die physiologisch verträglichen Salze durch Umsetzung mit Alkali- oder Erdalkalihydroxiden, wie z.B. Natriumhydroxid, Kaliumhydroxid oder Calciumhydroxid, oder mit anderen basischen Gruppen, wie z.B. mit Aminen, beispielsweise Triethylamin.For the preparation of physiologically tolerable salts, compounds of formula I which carry "a basic group, is reacted with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid or maleic acid, and if the compounds of the formula I contain an acid group, the physiologically tolerable salts are obtained by reaction with alkali or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or calcium hydroxide, or with other basic groups, such as with amines, for example. for example triethylamine.
Die Dosierung kann von verschiedenen Faktoren, wie Applikati¬ onsweise, Spezies, Alter oder individuellem Zustand abhängen. Die erfindungsgemässen Verbindungen werden üblicherweise in Mengen von 0,1 - 100 mg, vorzugsweise in Mengen von 0,2 - 80 mg pro Tag und pro Kilogramm Körpergewicht verabreicht. Bevorzugt ist es, die Tagesdosis auf 2 - 5 Applikationen zu verteilen. Die Tabletten können auch retardiert sein, wodurch sich die Anzahl der Applikationen auf 1 - 3 verringert. 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 normaler¬ weise ausreichen. Die erfindungsgemässen Verbindungen der allgemeinen Formel I werden dargestellt, indem man eine Verbindung der allgemeinen Formel IIThe dosage can depend on various factors, such as method of application, species, age or individual condition. The compounds according to the invention are usually administered in amounts of 0.1-100 mg, preferably in amounts of 0.2-80 mg per day and per kilogram of body weight. It is preferred to distribute the daily dose over 2-5 applications. The tablets can also be retarded, which reduces the number of applications 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 being normally sufficient. The compounds of general formula I according to the invention are prepared by using a compound of general formula II
Figure imgf000011_0001
Figure imgf000011_0001
in der R1, R , R3 und X die oben angegebenen Bedeutungen besitzen, mit einer Verbindung der allgemeinen Formel IIIin which R 1 , R, R 3 and X have the meanings given above, with a compound of the general formula III
A-Y-CH2-CH2-A (III) •AY-CH 2 -CH 2 -A (III) •
in der Y die angegebene Bedeutung besitzt und A eine reaktionsfähige, leicht abspaltbare Gruppe, wie z.B. ein Halogenatom oder eine Sulfönestergruppe darstellt, in einem inerten Lösungsmittel, wie z.B Toluol oder Dimethylformamid, in Gegenwart eines alkalischen Kondensationsmittels, wie z.B. Natriumhydrid, bei Temperaturen zwischen Raumtemperatur und Rückflusstemperatur des Lösungsmittels, vorzugsweise zwischen 40 und 80 °C zur Reaktion bringt. Die Umsetzung einer Ver¬ bindung der allgemeinen Formel II mit einer Verbindung der allgemeinen Formel III kann auch im Zweiphasengemisch in Gegenwart eines Phasentransferkatalysators, z.B. in Gegenwart eines tert.-Alkylammonium-Salzes, durchgeführt werden. Die bei der Darstellung der Verbindungen der allgemeinen Formel I anfallenden racemischen Gemische können durch Chromatographie an geeigneten optisch aktiven Phasen, z.B. Cellulosetri- acetat, in die optisch aktiven Isomere getrennt werden. Die Verbindungen der allgemeinen Formel I, in denen X ein SauerStoffatom bedeutet, können nachträglich in Verbindungen der allgemeinen Formel I, in denen X ein Schwefelatom be¬ deutet, umgewandelt werden durch Umsetzungen mit schwefel¬ übertragenden Verbindungen, wie z.B. Lawesson's Reagenz oder mit Schwefelpentasulfid. Verbindungen mit X = N-Alkyl-imino werden hergestellt durch Umsetzung der entsprechenden Imino- verbindungen der allgemeinen Formel I mit Alkylaminen nach an sich bekannten Verfahren.in which Y has the meaning given and A represents a reactive, easily removable group, such as a halogen atom or a sulfonic ester group, in an inert solvent such as toluene or dimethylformamide in the presence of an alkaline condensing agent such as sodium hydride at temperatures between room temperature and the reflux temperature of the solvent, preferably between 40 and 80 ° C. The reaction of a compound of the general formula II with a compound of the general formula III can also be carried out in a two-phase mixture in the presence of a phase transfer catalyst, for example in the presence of a tert-alkylammonium salt. The racemic mixtures obtained in the preparation of the compounds of the general formula I can be separated into the optically active isomers by chromatography on suitable optically active phases, for example cellulose triacetate. The compounds of the general formula I in which X denotes an oxygen atom can subsequently be converted into compounds of the general formula I in which X denotes a sulfur atom by reactions with sulfur-transferring compounds, such as Lawesson's reagent or with sulfur pentasulfide. Compounds with X = N-alkylimino are prepared by reacting the corresponding imino compounds of the general formula I with alkylamines by methods known per se.
Die Verbindungen der allgemeinen Formel II sind literaturbe¬ kannt oder können nach literaturbekannten Verfahren aus literaturbekannten Verbindungen der allgemeinen Formel IVThe compounds of the general formula II are known from the literature or can be obtained from known compounds of the general formula IV by processes known from the literature
Figure imgf000012_0001
Figure imgf000012_0001
in der R1, R2, R3 und X die oben genannten Bedeutungen besit¬ zen, durch Umsetzung mit Ammoniak erhalten werden.in which R 1 , R 2 , R 3 and X have the meanings given above, are obtained by reaction with ammonia.
Die Verbindungen der allgemeinen Formel IV werden durch Umsetzung mit Reduktionsmitteln nach bekannten Verfahren, z.B. durch Reduktion mit Natriumborhydrid, aus Verbindungen der allgemeinen Formel VThe compounds of general formula IV are obtained by reaction with reducing agents according to known methods, e.g. by reduction with sodium borohydride, from compounds of the general formula V
E-E-
Figure imgf000012_0002
hergestellt. Die Benzoesäurederivate der allgemeinen Formel V sind litera¬ turbekannt und werden durch Friedel-Crafts Acylierung von substituiertem oder unsubstituiertem Phthalsaureanhydrid mit gegebenenfalls substituierten Arenen in Gegenwart einer Lewis-Säure (z.B.Aluminiumchlorid) oder durch Reaktion von Grignardreagenzien der allgemeinen Formel VI
Figure imgf000012_0002
manufactured. The benzoic acid derivatives of the general formula V are known in the literature and are obtained by Friedel-Crafts acylation of substituted or unsubstituted phthalic anhydride with optionally substituted arenes in the presence of a Lewis acid (for example aluminum chloride) or by reaction of Grignard reagents of the general formula VI
R-J-MgBr (VI) ,R-J-MgBr (VI),
in der R1 die oben angegebene Bedeutung hat, mit substitu¬ iertem oder unsubstituiertem Phthalsaureanhydrid in Gegenwart eines inerten Lösungsmittels dargestellt.in which R 1 has the meaning given above, with substituted or unsubstituted phthalic anhydride in the presence of an inert solvent.
Die Verbindungen der allgemeinen Formel I können auch herge¬ stellt werden, indem man eine Verbindung der allgemeinen Formel II, in der R1, R2 und R3 die oben angegebenen Be¬ deutungen besitzen und X ein Sauerstoffatom darstellt, nach bekannten Verfahren mit einem Meerwein-Reagenz in eine Ver¬ bindung der allgemeinen Formel VIIThe compounds of the general formula I can also be prepared by using a compound of the general formula II in which R 1 , R 2 and R 3 have the meanings given above and X is an oxygen atom, by known processes Meerwein reagent in a compound of the general formula VII
Figure imgf000013_0001
Figure imgf000013_0001
in der R1, R2 und R3 die angegebenen Bedeutungen besitzen und R4 eine Cχ-Cg-Alkylgruppe, wie die Methyl- oder Ethylgruppe, bedeutet, überführt und diese mit einer Verbindung der allge- meinen Formel VIIIin which R 1 , R 2 and R 3 have the meanings given and R 4 is a Cχ-Cg-alkyl group, such as the methyl or ethyl group, transferred and this with a compound of the general my Formula VIII
A-Y-CH2-CH2-0-Z (VIII)AY-CH 2 -CH 2 -0-Z (VIII)
in der A und Y die angegebenen Bedeutungen besitzen und Z eine Schutzgruppe, wie z.B. eine Benzylgruppe, darstellt, in Gegenwart eines alkalischen Kondensationsmittels, wie z.B. Natriumhydrid, in einem inerten Lösungsmittel, wie z.B. Dimethylformamid oder Toluol, zur Reaktion bringt und die erhaltene Verbindung der allgemeinen Formel IXin which A and Y have the meanings given and Z is a protective group, e.g. represents a benzyl group in the presence of an alkaline condensing agent such as e.g. Sodium hydride, in an inert solvent, e.g. Dimethylformamide or toluene, brings to reaction and the compound of general formula IX obtained
Figure imgf000014_0001
Figure imgf000014_0001
R-R-
in der R1, R2, R3, R4 und Z die angegebenen Bedeutungen besitzen, durch Behandlung mit Säure in eine Verbindung der allgemeinen Formel Xin which R 1 , R 2 , R 3 , R 4 and Z have the meanings given, by treatment with acid in a compound of the general formula X.
(X),
Figure imgf000014_0002
in der R1, R2, R3, Y und Z die angegebenen Bedeutungen besit¬ zen, überführt. Nach Abspaltung der Sauerstoffschutzgruppe Z und Überführung der alkoholischen OH-Gruppe in ein Halogenid oder Sulfonsäureester-Derivat erhält man hieraus durch Be¬ handlung mit einem alkalischen Kondensationsmittel, wie z.B. Natriumhydrid, in einem inerten Lösungsmittel, wie z.B. Di ethylformamid oder Toluol, die erfindungsgemässen Ver¬ bindungen der allgemeinen Formel I.(X),
Figure imgf000014_0002
in which R 1 , R 2 , R 3 , Y and Z have the meanings given, transferred. After the oxygen protecting group Z has been split off and the alcoholic OH group has been converted into a halide or sulfonic acid ester derivative, the ver. According to the invention are obtained from this by treatment with an alkaline condensing agent, such as, for example, sodium hydride, in an inert solvent, such as, for example, diethylformamide or toluene ¬ bonds of the general formula I.
Im Sinne der vorliegenden Verbindung kommen ausser den in den Beispielen genannten Verbindungen und der durch Kombination aller in den Ansprüchen genannten Bedeutungen der Substitu- enten die folgenden Verbindungen der Formel I in Frage, die als racemische Gemische oder in optisch reiner Form als R- oder S-Enantiomere vorliegen können.For the purposes of the present compound, in addition to the compounds mentioned in the examples and the combination of all the meanings of the substituents mentioned in the claims, the following compounds of the formula I are suitable, which are used as racemic mixtures or in optically pure form as R or S Enantiomers can be present.
1. 9b-(4-Fluor-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a] isoindol-5-on1. 9b- (4-fluorophenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
2. 9b-(4-Chlor-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a] isoindol-5-on2. 9b- (4-chlorophenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
3. 9b-(4-Methoxy-phenyl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on3. 9b- (4-methoxyphenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
4. 9b-(4-Methyl-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2 ,1- a] isoindol-5-on4. 9b- (4-methylphenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2, 1- a] isoindol-5-one
5. 9b-(4-Trifluormethyl-phenyl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on5. 9b- (4-Trifluoromethyl-phenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
6. 9b-(3-Fluor-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a] isoindol-5-on 7. 9b-(3-Chlor-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a] isoindol-5-on6. 9b- (3-fluorophenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one 7. 9b- (3-chlorophenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
8. 9b-(4-Methoxy-phenyl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on8. 9b- (4-methoxyphenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
9. 9b-(3-Methyl-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a] isoindol-5-on9. 9b- (3-methylphenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
10. 9b-(3-Trifluormethyl-phenyl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on10. 9b- (3-trifluoromethyl-phenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
11. 9b-(2-Fluor-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2 ,1- a] isoindol-5-on11. 9b- (2-fluorophenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2, 1- a] isoindol-5-one
12. 9b-(2-Chlor-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a] isoindol-5-on12. 9b- (2-chlorophenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
13. 9b-(2-Methoxy-phenyl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on13. 9b- (2-methoxyphenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
14. 9b-(2-Methyl-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a] isoindol-5-on14. 9b- (2-methylphenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
15. 9b-(2,3-Dimethyl-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a]isoindol-5-on15. 9b- (2,3-Dimethylphenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
16. 9b-(3.4-Dimethyl-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a]isoindol-5-on16. 9b- (3,4-Dimethyl-phenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
17. 9b-(3.5-Dichlor-phenyl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,l-a]isoindol-5-on17. 9b- (3,5-dichlorophenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2, l-a] isoindol-5-one
18. 9b-(3.4-Dimethoxy-phenyl)-l,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a]isoindol-5-on 19. 9b-Phenyl-7-fluor-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on18. 9b- (3,4-Dimethoxyphenyl) -1, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one 19. 9b-phenyl-7-fluoro-1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
20. 9b-Phenyl-7-chlor-l,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on20. 9b-phenyl-7-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
21. 9b-Phenyl-7-methoxy-l,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on21. 9b-phenyl-7-methoxy-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
22. 9b-Phenyl-7-methyl-l,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on22. 9b-phenyl-7-methyl-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
23. 9b-Phenyl-7-trifluormethyl-1,2,3,9b-tetrahydro-5H- pyrrolo [2,l-a]isoindol-5-on23. 9b-phenyl-7-trifluoromethyl-1,2,3,9b-tetrahydro-5H-pyrrolo [2, l-a] isoindol-5-one
24. 9b-Phenyl-8-fluor-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on24. 9b-phenyl-8-fluoro-1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
25. 9b-Phenyl-8-chlor-l,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on25. 9b-phenyl-8-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
26. 9b-Phenyl-8-methoxy-l,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on26. 9b-phenyl-8-methoxy-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
27. 9b-Phenyl-8-methyl-l,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on27. 9b-phenyl-8-methyl-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
28. 9b-(4-Fluor-phenyl)-7-chlor-l,2,3 ,9b-tetrahydro-5H- pyrrolo[2,l-a]isoindol-5-on28. 9b- (4-fluoro-phenyl) -7-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2, l-a] isoindol-5-one
29. 9b-(4-Methoxy-phenyl)-7-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on29. 9b- (4-methoxyphenyl) -7-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
30. 9b-(4-Methyl-phenyl)-7-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on 31. 9b-(4-Chlor-phenyl)-7-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2 ,1-a]isoindol-5-on30. 9b- (4-methylphenyl) -7-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one 31. 9b- (4-chlorophenyl) -7-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2, 1-a] isoindol-5-one
32. 9b-(4-Trifluormethyl-phenyl)-7-chlor-l,2,3,9b-tetra- hydro-5H-pyrrolo[2,1-a]isoindol-5-on32. 9b- (4-trifluoromethylphenyl) -7-chloro-l, 2,3,9b-tetra-hydro-5H-pyrrolo [2,1-a] isoindol-5-one
33. 9b-(3-Fluor-phenyl)-7-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on33. 9b- (3-fluorophenyl) -7-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
34. 9b-(3-Methoxy-phenyl)-7-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isόindol-5-on34. 9b- (3-methoxyphenyl) -7-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isόindol-5-one
35. 9b-(3-Methyl-phenyl)-7-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on35. 9b- (3-Methylphenyl) -7-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
36. 9b-(3-Chlor-phenyl)-7-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on36. 9b- (3-chlorophenyl) -7-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
37. 9b-(3-Trifluormethyl-phenyl)-7-chlor-l,2,3,9b-tetra- hydro-5H-pyrrolo[2 ,1-a]isoindol-5-on37. 9b- (3-Trifluoromethyl-phenyl) -7-chloro-l, 2,3,9b-tetra-hydro-5H-pyrrolo [2, 1-a] isoindol-5-one
38. 9b-(4-Fluor-phenyl)-8-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on38. 9b- (4-fluorophenyl) -8-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
39. 9b-(4-Methoxy-phenyl)-8-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2 ,1-a]isoindol-5-on39. 9b- (4-methoxyphenyl) -8-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2, 1-a] isoindol-5-one
40. 9b-(4-Methyl-phenyl)-8-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2 ,1-a]isoindol-5-on40. 9b- (4-methylphenyl) -8-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2, 1-a] isoindol-5-one
41. 9b-(4-Chlor-phenyl)-8-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,l-a]isoindol-5-on41. 9b- (4-chlorophenyl) -8-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2, l-a] isoindol-5-one
42. 9b-(4-Trifluormethyl-phenyl)-8-chlor-l,2,3,9b-tetra- hydro-5H-pyrrolo[2,1-a]isoindol-5-on 43. 9b-(3-Fluor-phenyl)-8-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,l-a]isoindol-5-on42. 9b- (4-Trifluoromethyl-phenyl) -8-chloro-l, 2,3,9b-tetra-hydro-5H-pyrrolo [2,1-a] isoindol-5-one 43. 9b- (3-fluorophenyl) -8-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2, la] isoindol-5-one
44. 9b-(3-Methoxy-phenyl)-8-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on44. 9b- (3-methoxyphenyl) -8-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
45. 9b-(3-Methyl-phenyl)-8-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,l-a]isoindol-5-on45. 9b- (3-Methylphenyl) -8-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2, l-a] isoindol-5-one
46. 9b-(3-Chlor-phenyl)-8-chlor-l,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on46. 9b- (3-chlorophenyl) -8-chloro-l, 2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
47. 9b-(3-Trifluormethyl-phenyl)-8-chlor-l,2,3,9b-tetra- hydro-5H-pyrrolo[2,l-a]isoindol-5-on47. 9b- (3-Trifluoromethyl-phenyl) -8-chloro-l, 2,3,9b-tetra-hydro-5H-pyrrolo [2, l-a] isoindol-5-one
48. 9b-(Naphth-1-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a] isoindol-5-on48. 9b- (Naphth-1-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
49. 9b-(Naphth-2-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a] isoindol-5-on49. 9b- (Naphth-2-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
50. 9b-(2-Thienyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a] isoindol-5-on50. 9b- (2-Thienyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
51. 9b-(1-Thienyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a] isoindol-5-on51. 9b- (1-Thienyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
52. 9b-(2-Furyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on52. 9b- (2-furyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
53. 9b-(Carbazol-4-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a] isoindol-5-on53. 9b- (Carbazol-4-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
54. 9b-(Carbazol-9-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a] isoindol-5-on 55. 9b-(Phenothiazin-4-yl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on54. 9b- (Carbazol-9-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one 55. 9b- (Phenothiazin-4-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
56. 9b-(Phenothiazin-1-yl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,1-a]isoindol-5-on56. 9b- (Phenothiazin-1-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
57. 9b-(Thiazol-2-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on57. 9b- (Thiazol-2-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
58. 9b-(Thiazol-4-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on58. 9b- (Thiazol-4-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
59. 9b-(Indol-4-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on59. 9b- (Indol-4-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
60. 9b-(Indol-3-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on60. 9b- (Indol-3-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
61. 9b-(Indol-7-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on61. 9b- (Indol-7-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
62. 9b-(Chinolin-4-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on62. 9b- (Quinolin-4-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
63. 9b-(Chinolin-5-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on63. 9b- (Quinolin-5-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
64. 9b-(Pyrimdin-4-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on64. 9b- (Pyrimdin-4-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
65. 9b-(Pyridin-2-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on65. 9b- (Pyridin-2-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
66. 9b-(Pyridin-3-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on 67. 9b-(Pyridin-4-yl)-1,2,3 ,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on66. 9b- (Pyridin-3-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one 67. 9b- (Pyridin-4-yl) -1,2,3, 9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one
68. 10b-(3-Fluor-phenyl)-1,3,4,lOb-tetrahydro-pyrido[2,1-a] isoindol-6(2H)-on68. 10b- (3-Fluoro-phenyl) -1,3,4, 10B-tetrahydro-pyrido [2,1-a] isoindole-6 (2H) -one
69. 10b-(3-Chlor-phenyl)-1,3,4,lOb-tetrahydro-pyrido[2,1-a] isoindol-6(2H)-on69. 10b- (3-Chlorophenyl) -1,3,4, 10B-tetrahydro-pyrido [2,1-a] isoindole-6 (2H) -one
70. 10b-(3-Methyl-phenyl)-1,3,4,lOb-tetrahydro-pyrido[2,1-a] isoindol-6(2H)-on70. 10b- (3-Methylphenyl) -1,3,4, 10B-tetrahydro-pyrido [2,1-a] isoindole-6 (2H) -one
71. 10b-(3-Trifluor-methyl-phenyl)-1,3,4,lOb-tetrahydro- pyrido[2,1-a]isoindol-6(2H)-on71. 10b- (3-Trifluoromethylphenyl) -1,3,4, 10B-tetrahydropyrido [2,1-a] isoindole-6 (2H) -one
Beispiel 1example 1
9b-Phenyl-l,2 -3,9b-tetrahydro-5H-Pyrrolor2,1-alisoindol-5-on9b-phenyl-1,2,3,9b-tetrahydro-5H-pyrrolor2,1-alisoindol-5-one
500 mg Phenylphthalimidin werden in 3 ml Dimethylformamid gelöst. Zu dieser Lösung gibt man 630 mg Kaliumhydroxid, 80 mg Tetrabutylammoniumbromid und 0,3 ml l-Brom-3-chlor- propan. Man rührt die Mischung intensiv 6 Stdn. bei 60 °C, verdünnt dann mit Wasser und schüttelt mit Essigester aus. Die Essigesterphase wird mit Wasser gewaschen, über Natrium¬ sulfat getrocknet und eingedampft. Der Rückstand wird zur Reinigung an einer Kieselgelsäule chromatographiert. (Elutionsmittel: Isohexan/Essigester 1:2). Die erhaltenen Säulenfraktionen werden eingedampft und aus Ether um¬ kristallisiert. Man erhält 350 mg der Titelverbindung vom Schmp. : 97 °C.500 mg of phenylphthalimidine are dissolved in 3 ml of dimethylformamide. 630 mg of potassium hydroxide, 80 mg of tetrabutylammonium bromide and 0.3 ml of l-bromo-3-chloropropane are added to this solution. The mixture is stirred intensively for 6 hours at 60 ° C., then diluted with water and shaken out with ethyl acetate. The ethyl acetate phase is washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column for purification. (Eluent: isohexane / ethyl acetate 1: 2). The column fractions obtained are evaporated and recrystallized from ether. 350 mg of the title compound of mp: 97 ° C. are obtained.
Analog zu Beispiel 1 werden die folgenden Verbindungen herge¬ stellt: 1.1 9b-(3-Fluor-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on, Schmelzpunkt 143° CThe following compounds are produced analogously to Example 1: 1.1 9b- (3-fluoro-phenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one, melting point 143 ° C.
1.2 9b-(3-Methoxy-phenyl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,l-a]isoindol-5-on, Schmelzpunkt 130° C1.2 9b- (3-methoxyphenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2, l-a] isoindol-5-one, melting point 130 ° C
1.3 9b-(3-Methyl-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on, Schmelzpunkt 125° C1.3 9b- (3-methylphenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one, melting point 125 ° C
1.4 9b-(3-Trifluormethyl-phenyl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,l-a]isoindol-5-on, Schmelzpunkt 136° C1.4 9b- (3-trifluoromethyl-phenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2, l-a] isoindol-5-one, melting point 136 ° C.
1.5 9b-(4-Fluor-phenyl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on, öl1.5 9b- (4-fluorophenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one, oil
1.6 9b-(3.5-Dichlor-phenyl)-1,2,3,9b-tetrahydro-5H- pyrrolo[2,l-a]isoindol-5-on, Schmelzpunkt 190° C1.6 9b- (3,5-dichlorophenyl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2, l-a] isoindol-5-one, melting point 190 ° C.
1.7 9b-(Naphth-1-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1- a]isoindol-5-on, Schmelzpunkt 168° C1.7 9b- (Naphth-1-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo [2,1-a] isoindol-5-one, melting point 168 ° C
1.8 9b-(Anthracen-9-yl)-1,2,3,9b-tetrahydro-5H-pyrrolo-[2,1- a]isoindol-5-on, Schmelzpunkt 190° C1.8 9b- (Anthracen-9-yl) -1,2,3,9b-tetrahydro-5H-pyrrolo- [2,1- a] isoindol-5-one, melting point 190 ° C
Beispiel 2Example 2
10b-Phenyl-l.3,4.10-tetrahvdro-pγrido- \2 ,1-alisoindol-6C2H) on10b-phenyl-1,3,4,10-tetrahvdro-pγrido-2, 1-alisoindole-6C2H) on
700 mg Phenylphthalimidin werden in einer Mischung aus 15 ml Toluol und 1 ml Dirnethylforma id gelöst. Hierzu gibt man 0.5 ml 1,4-Dibrombutan und 100 mg Natriumhydrid. Die Mischung wird 3 Stdn. auf 130"C erhitzt, abgekühlt, mit Wasser ver¬ dünnt und mit Essigester ausgeschüttelt. Die Essigesterphase wird über Natriumsulfat getrocknet und eingedampft. Der Rückstand wird an einer Kieselgelsäule chromatographiert. (Elutionsmittel: Essigester/Isohexan 1:1). Die Säulenfraktion werden eingedampft und der Rückstand aus Essigester um¬ kristallisiert. Ausbeute: 200 mg; Schmp. : 162-164βC.700 mg of phenylphthalimidine are dissolved in a mixture of 15 ml of toluene and 1 ml of Dirnethylforma id. 0.5 ml of 1,4-dibromobutane and 100 mg of sodium hydride are added. The mixture is heated to 130 ° C. for 3 hours, cooled, diluted with water and shaken out with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and evaporated The residue is chromatographed on a silica gel column. (Eluent: ethyl acetate / isohexane 1: 1). The column fraction is evaporated and the residue is recrystallized from ethyl acetate. Yield: 200 mg; Mp: 162-164 β C.
Beispiel 3Example 3
Hemmung der HIV Reversen Transkriptase (RT)Inhibition of HIV reverse transcriptase (RT)
Das Testsystem zur Bestimmung der Hemmwirkung der erfindungs¬ gemäßen Verbindungen auf die HIV-RT beinhaltet die gereinigte RT aus HIV-1, die durch gentechnologische Methoden in E. coli exprimiert wurde, sowie die Komponenten des Initiationskom¬ plexes, wie die in-vitro-Transkripte des HIV-LTR's mit der benachbarten Primer Binding Site als Template und einem zur Primer Binding Site komplementären 18mer Oligonukleotid als Primer. Gemessen wurde der [3H]-Thymidin-5'-triphosphat- Einbau durch Auszählen im ß-Counter. In der folgenden Tabelle wird für die untersuchten Verbindungen der ICso- ert angege¬ ben. Dieser Wert entspricht derjenigen Konzentration der Testsubstanz, die eine Hemmung der RT-Aktivität um 50 % bewirkt.The test system for determining the inhibitory effect of the compounds according to the invention on the HIV-RT contains the purified RT from HIV-1, which was expressed by genetic engineering methods in E. coli, and the components of the initiation complex, such as the in vitro Transcripts of the HIV-LTR with the neighboring primer binding site as template and an 18mer oligonucleotide complementary to the primer binding site as primer. The [ 3 H] -thymidine-5'-triphosphate incorporation was measured by counting in the β-counter. The table below shows the ICsother for the compounds examined. This value corresponds to the concentration of the test substance which causes an inhibition of the RT activity by 50%.
Ergebnisse:Results:
Substanz Hemmung der HIV-RTSubstance inhibition of HIV RT
Figure imgf000023_0001
Figure imgf000023_0001

Claims

Patentansprüche Claims
1. Isoindol-Derivate der allgemeinen Formel I1. Isoindole derivatives of the general formula I
Figure imgf000024_0001
Figure imgf000024_0001
in derin the
R1 einen Phenylring bedeutet, der gegebenenfalls ein- oder mehrfach substituiert ist durch Cχ-Cg-Alkyl, C3- Cg-Cycloalkyl, Cχ-Cg-Alkoxy, Cχ-Cg-Alkylmercapto, Cχ~ Cg-Alkylsulfinyl, Cχ-Cg-Alkylsulfonyl, C2-Cg-Alkenyl, C2-Cg-Alkinyl, C -Cg-Alkenyloxy, C2-Cg-Alkenyl- mercapto, C2-Cg-Alkinyloxy, C2-Cg-Alkinylmercapto, Amino, Cχ-Cg-Alkylamino, Di-Cχ-Cg-alkylamino, Cχ-Cg- Alkylcarbonylamino, Cχ-Cg-Alkylamino-carbonyl, Cχ-Cg- Alkoxycarbonyl , Hydroxy, Benzyloxy, Phenylmercapto, Phenyloxy, Nitro, Cyano, Halogen, Trifluormethyl, Azido, Formylamino oder Phenyl,R 1 represents a phenyl ring which is optionally mono- or polysubstituted by Cχ-Cg-alkyl, C3-Cg-cycloalkyl, Cχ-Cg-alkoxy, Cχ-Cg-alkylmercapto, Cχ-Cg-alkylsulfinyl, Cχ-Cg-alkylsulfonyl , C2-Cg-alkenyl, C 2 -Cg-alkynyl, C -C -g alkenyloxy, C 2 -Cg-alkenyl-mercapto, C 2 -Cg-alkynyloxy, C 2 -Cg-alkynylmercapto, amino, Cχ-Cg-alkylamino , Di-Cχ-Cg-alkylamino, Cχ-Cg-alkylcarbonylamino, Cχ-Cg-alkylamino-carbonyl, Cχ-Cg- alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino or phenyl ,
oder einen mono-, bi- oder tricyclischen carbocycli- schen Ring mit 3-15 C-Atomen oder ein heterocylisches mono-, bi- oder tricyclisσhes Ringsystem mit jeweils 5 oder 6 Ringatomen bedeutet und pro Ringsystem 1-4 bzw 1-5 Heteroatome enthalten sein können, wobei die Heteroatome Stickstoff, Sauerstoff oder Schwefel sind.or a mono-, bi- or tricyclic carbocyclic ring with 3-15 C atoms or a heterocyclic mono-, bi- or tricyclic ring system with 5 or 6 ring atoms each and containing 1-4 or 1-5 heteroatoms per ring system can be, wherein the heteroatoms are nitrogen, oxygen or sulfur.
R2 ein Wasserstoffatom, einen geradkettigen oder ver¬ zweigten gesättigten oder ungesättigten aliphatischen Rest mit 1-6 C-Atomen oder Cχ-Cg-Alkoxy, Cχ-Cg-Alkyl- mercapto, Cχ-Cg-Alkylsufinyl, Cχ-Cg-Alkylsulfonyl, Amino, Cχ-Cg-Alkylamino, Di-Cχ-Cg-Alkylamino, Cχ-Cg- Alkoxycarbonyl , Carboxy, Halogen, Hydroxy, Nitro, Cyano, Trilfuormethyl, Phenyl oder Benzyloxy be¬ deutet,R 2 is a hydrogen atom, a straight-chain or branched saturated or unsaturated aliphatic Radical with 1-6 C-atoms or Cχ-Cg-alkoxy, Cχ-Cg-alkyl mercapto, Cχ-Cg-alkylsufinyl, Cχ-Cg-alkylsulfonyl, amino, Cχ-Cg-alkylamino, di-Cχ-Cg-alkylamino , Cχ-Cg-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, trilfuormethyl, phenyl or benzyloxy means,
R3 die gleiche Bedeutung wie R2 hat, wobei die Reste R2 und R3 unabhängig voneinander gleich oder verschieden sein können,R 3 has the same meaning as R 2 , where the radicals R 2 and R 3 can independently of one another be the same or different,
X ein Sauerstoff- oder Schwefelatom bzw. die NH- oder N-Cχ-C5-Alkylgruppe darstellt undX represents an oxygen or sulfur atom or the NH or N-Cχ-C5-alkyl group and
Y -CH2-, CH2-CH2-, oder -CH-CH- bedeutet,Y denotes -CH 2 -, CH 2 -CH 2 -, or -CH-CH-,
sowie deren Tautomere, Enantiomere, Diastereomere oder physiologisch verträgliche Salze.and their tautomers, enantiomers, diastereomers or physiologically acceptable salts.
2. Isoindol-Derivate gemäß Anspruch 1, dadurch gekenn¬ zeichnet, daß2. Isoindole derivatives according to claim 1, characterized gekenn¬ characterized in that
R1 einen carbocyclischen Ring mit 5-15 C-Atomen be¬ deutet, ausgewählt aus der Gruppe Naphthyl-, Anthracenyl-, Phenanthrenyl-, Fluorenyl-, Indenyl-, Acenaphthylen-, Norbonyl- und Adamantyl-, wobei diese gesättigt, ungesättigt, teilweise gesättigt oder aromatisch sein können, oder R1 eine C3-C7-Cyclo- alkyl- oder Cs-Cs-Cycloalkenylgruppe bedeutet.R 1 denotes a carbocyclic ring with 5-15 C atoms, selected from the group of naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, acenaphthylene, norbonyl and adamantyl, these being saturated, unsaturated, can be partially saturated or aromatic, or R 1 represents a C3-C7-cycloalkyl or Cs-Cs-cycloalkenyl group.
3. Isoindol-Derivate gemäß Anspruch 1, dadurch gekenn¬ zeichnet, daß3. isoindole derivatives according to claim 1, characterized gekenn¬ characterized in that
R1 ein heterocyclisches mono-, bi- oder tricyclisches Ringsystem bedeutet, ausgewählt aus der■Gruppe Pyridinyl-, Pyrimidinyl-, Pyridazinyl-, Pyrazinyl-, Triazinyl-, Pyrrolyl-, Pyrazolyl-, I idazolyl-, Triazolyl-, Thiazolyl-, Oxazolyl-, Isoxazolyl-, Oxadiazolyl-, Furazanyl-, Furanyl-, Thiophenyl-, Indolyl-, Chinolinyl-, Isochinolinyl-, Cumaronyl-, Thionaphthyl-, Benzoxazolyl-, Benzthiazolyl-, Indazolyl-, Benzimidazolyl-, Benztriazolyl-, Chromenyl-, Phthalazinyl-, Chinazolinyl-, Methylen- dioxybenzyl-, Carbazolyl-, Aσridinyl-, Phenoxazinyl-, Phenothiazinyl-, Phenazinyl- oder Purinyl-, wobei diese Heterocyσlen partiell oder vollständig hydriert sein können.R 1 denotes a heterocyclic mono-, bi- or tricyclic ring system, selected from the group ■ pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, idazolyl, Triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, furazanyl, furanyl, thiophenyl, indolyl, quinolinyl, isoquinolinyl, coumaronyl, thionaphthyl, benzoxazolyl, benzthiazolyl, indimidazolyl , Benztriazolyl-, Chromenyl-, Phthalazinyl-, Quinazolinyl-, Methylen- dioxybenzyl-, Carbazolyl-, Aσridinyl-, Phenoxazinyl-, Phenothiazinyl-, Phenazinyl- or Purinyl-, whereby these heterocycles can be partially or completely hydrogenated.
4. Isoindol-Derivate gemäß Anspruch 1, dadurch gekenn¬ zeichnet, daß4. isoindole derivatives according to claim 1, characterized gekenn¬ characterized in that
R1 einen Phenylring bedeutet, der ein- oder zweifach substituiert sein kann durch Cχ-Cg-Alkyl, C3~C - Cycloalkyl, Cχ-Cg-Alkoxy, Cχ-Cg-Alkylmercapto, Cχ-Cg- Alkylsulfinyl, Cχ-Cg-Alkylsulfonyl, C2-Cg-Alkenyl. C2-Cg-Alkinyl, C3-Cg-Alkenyloxy, Cχ-Cg-Alkylamino, Cχ-C6-Dialkylamino, Cχ-Cg-Alkylcarbonylamino, Cχ-Cg- Alkylaminocarbonyl, Cχ-Cg-Alkoxycarbonyl, Amino, Hydroxy, Nitro, Azido, Trifluormethyl, Cyano oder Halogen.R 1 represents a phenyl ring which can be mono- or disubstituted by Cχ-Cg-alkyl, C3 ~ C - cycloalkyl, Cχ-Cg-alkoxy, Cχ-Cg-alkylmercapto, Cχ-Cg-alkylsulfinyl, Cχ-Cg-alkylsulfonyl , C 2 -Cg alkenyl. C2-Cg-alkynyl, C 3 -Cg-alkenyloxy, Cχ-Cg-alkylamino, Cχ-C 6 -dialkylamino, Cχ-Cg-alkylcarbonylamino, Cχ-Cg-alkylaminocarbonyl, Cχ-Cg-alkoxycarbonyl, amino, hydroxy, nitro, Azido, trifluoromethyl, cyano or halogen.
5. Isoindol-Derivate gemäß einem der Ansprüche 1-4, dadurch gekennzeichnet, daß R2 oder R3 Wasserstoff, Cχ-Cg-Alkyl, C2-Cg-Alkenyl, C -Cg-Alkinyl, Cχ-Cg-Alkoxy, Cχ-Cg- Alkyl ercapto, Cχ-Cg-Alkylamino, Cχ-Cg-Alkoxycarbonyl, Amino, Halogen, Hydroxy, Cyano, Trifluormethyl oder Azido bedeuten.5. isoindole derivatives according to any one of claims 1-4, characterized in that R 2 or R 3 is hydrogen, Cχ-Cg-alkyl, C 2 -Cg-alkenyl, C-Cg-alkynyl, Cχ-Cg-alkoxy, Cχ -Cg- alkyl ercapto, Cχ-Cg-alkylamino, Cχ-Cg-alkoxycarbonyl, amino, halogen, hydroxy, cyano, trifluoromethyl or azido mean.
6. Isoindol-Derivate gemäß einem der Ansprüche 1-5, dadurch gekennzeichnet, daß X ein Schwefel- oder ein Sauerstoff- atom bedeutet. 6. isoindole derivatives according to any one of claims 1-5, characterized in that X represents a sulfur or an oxygen atom.
7. Isoindol-Derivate gemäß einem der Ansprüche 1-6, dadurch gekennzeichnet, daß Y eine -CH2- oder -CH2-CH2-Gruppe bedeutet.7. isoindole derivatives according to any one of claims 1-6, characterized in that Y represents a -CH 2 - or -CH 2 -CH 2 group.
8. Verfahren zur Herstellung von Isoindol-Derivaten gemäß einem der Ansprüche 1-7, dadurch gekennzeichnet, daß man a) eine Verbindung der Formel II8. A process for the preparation of isoindole derivatives according to any one of claims 1-7, characterized in that a) a compound of formula II
Figure imgf000027_0001
Figure imgf000027_0001
mit einer Verbindung der Formel IIIwith a compound of formula III
A-Y-CH2-CH2-A (III) ,AY-CH 2 -CH 2 -A (III),
in der A eine reaktionsfähige, leicht abspaltbare Gruppe darstellt, in einem inerten Lösungsmittel in Gegenwart eines Kondensationsmittels umsetzt, oderin which A represents a reactive, easily removable group, reacted in an inert solvent in the presence of a condensing agent, or
b) eine Verbindung der allgemeinen Formel IIb) a compound of the general formula II
(II), ( II ) ,
Figure imgf000027_0002
in der X ein Sauerstoffatom darstellt, nach bekannten Verfahren mit einem Meerwein-Reagenz in eine Verbindung der allgemeinen Formel VII
Figure imgf000027_0002
in which X represents an oxygen atom, according to known methods with a Meerwein reagent into a compound of general formula VII
Figure imgf000028_0001
Figure imgf000028_0001
\\
in der R4 eine Cχ-Cg-Alkylgruppe bedeutet, überführt, und diese mit einer Verbindung der allgemeinen Formel VIIIin which R 4 is a Cχ-Cg alkyl group, transferred, and this with a compound of general formula VIII
A-Y-CH2-CH2-0-Z (VIII),AY-CH 2 -CH 2 -0-Z (VIII),
in der A die oben angegebene Bedeutung besitzt und Z eine Schutzgruppe darstellt, in Gegenwart eines alkalischen Kondensationsmittels in einem inerten Lösungsmittel zur Reaktion bringt, und die so erhaltene Verbindung der allgemeinen Formel IXin which A has the meaning given above and Z represents a protective group, is reacted in the presence of an alkaline condensing agent in an inert solvent, and the compound of general formula IX thus obtained
Figure imgf000028_0002
Figure imgf000028_0002
\ in der R1, R2, R3, R4 und Z die angegebenen Bedeutungen besitzen, durch Behandlung mit Säure in eine Verbindung der allgemeinen Formel X\ in which R 1 , R 2 , R 3 , R 4 and Z have the meanings given, by treatment with acid in a compound of the general formula X.
Figure imgf000029_0001
Figure imgf000029_0001
überführt, und nach Abspaltung der Sauerstoffschutzgruppe Z und Überführung der alkoholischen OH-Gruppe in ein Halogenid oder Sulfonsäureester-Derivat und anschlie߬ ender Behandlung mit einem alkalischen Kondensations¬ mittel in einem inerten Lösungsmittel Verbindungen der allgemeinen Formel I isoliert.transferred, and after splitting off the oxygen protecting group Z and converting the alcoholic OH group into a halide or sulfonic ester derivative and subsequent treatment with an alkaline condensing agent in an inert solvent, compounds of the general formula I are isolated.
9. Arzneimittel enthaltend.mindestens ein Isoindol-Derivat gemäß einem der Ansprüche 1-7 neben pharmakologisch verträglichen Träger- oder Hilfsstoffen.9. Medicament containing at least one isoindole derivative according to any one of claims 1-7 in addition to pharmacologically acceptable carriers or excipients.
10. Verwendung von Isoindol-Derivaten gemäß einem der An¬ sprüche 1-7 zur Herstellung von Arzneimitteln zur Behandlung oder Prophylaxe von viralen oder retroviralen Infektionen oder von durch diese Infektionen verursachte Erkrankungen.10. Use of isoindole derivatives according to one of claims 1-7 for the manufacture of medicaments for the treatment or prophylaxis of viral or retroviral infections or of diseases caused by these infections.
11. Verfahren zur Herstellung von Arzneimitteln enthaltend mindestens eine Verbindung der Formel I gemäß einem der Ansprüche 1-7 neben pharmazeutisch üblichen Träger- oder Hilfsstoffen, dadurch gekennzeichnet, daß man eine Ver¬ bindung der Formel I mit den Träger- oder Hilfsstoffen vermischt und zu geeigneten Darreichungsformen ver¬ arbeitet. 11. A process for the preparation of medicaments comprising at least one compound of the formula I according to one of claims 1-7 in addition to pharmaceutically customary carriers or Excipients, characterized in that a compound of the formula I is mixed with the carriers or auxiliaries and processed into suitable dosage forms.
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WO1994024109A1 (en) * 1993-04-09 1994-10-27 Boehringer Mannheim Gmbh Indazole derivatives and antiviral drugs that contain them
CN108003160A (en) * 2016-10-28 2018-05-08 南京理工大学 The method of one kind synthesis [a]-ring annulated indole analog derivative

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* Cited by examiner, † Cited by third party
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WO1994024109A1 (en) * 1993-04-09 1994-10-27 Boehringer Mannheim Gmbh Indazole derivatives and antiviral drugs that contain them
CN108003160A (en) * 2016-10-28 2018-05-08 南京理工大学 The method of one kind synthesis [a]-ring annulated indole analog derivative
CN108003160B (en) * 2016-10-28 2020-05-19 南京理工大学 Method for synthesizing [ a ] -cyclized indole derivative

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