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WO1992016529A1 - Nouveaux derives d'isoindole et medicaments les contenant - Google Patents

Nouveaux derives d'isoindole et medicaments les contenant 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
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrolo
tetrahydro
general formula
isoindol
compound
Prior art date
Application number
PCT/EP1992/000601
Other languages
German (de)
English (en)
Inventor
Herbert Leinert
Bernhard König
Ulrike Leser
Thomas Poll
Wolfgang Schäfer
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 WO1992016529A1 publication Critical patent/WO1992016529A1/fr

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Classifications

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

Abstract

Nouveaux dérivés d'isoindole, leur procédé de préparation et des médicaments contenant ces composés. Des dérivés d'isoindole ont la formule générale (I), dans laquelle R1 désigne un noyau phényle, substitué le cas échéant une ou plusieurs fois, ou un noyau carbocyclique, bicyclique ou tricyclique ayant 3 à 15 atomes de carbone ou un système à noyau hétérocyclique; R2 et R3 désignent un atome d'hydrogène, un résidu aliphatique saturé ou insaturé à chaîne droite ou ramifiée ayant 1 à 6 atomes de carbone ou alcoxy C¿1?-C6, alkylmercapto C1-C6, alkylsulfinyle C1-C6, alkylsulfonyle C1-C6, amino, alkylamino C1-C6, dialkylamino C1-C6, alcoxycarbonyle C1-C6, carboxy, halogène, hydroxy, nitro, cyano, trifluorométhyle, phényle ou benzyloxy; X désigne un atome d'oxygène ou de soufre, ou les groupes alkyle NH- ou N-C1-C5; et Y désigne -CH2-, CH2-CH2-, ou -CH=CH-. L'invention concerne également les tautomères, énantiomères, diastéréomères ou sels physiologiquement acceptables de ces composés.
PCT/EP1992/000601 1991-03-25 1992-03-19 Nouveaux derives d'isoindole et medicaments les contenant WO1992016529A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4109737.8 1991-03-25
DE19914109737 DE4109737A1 (de) 1991-03-25 1991-03-25 Neue isoindol-derivate und diese enthaltende arzneimittel

Publications (1)

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WO1992016529A1 true WO1992016529A1 (fr) 1992-10-01

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DE (1) DE4109737A1 (fr)
WO (1) WO1992016529A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994024109A1 (fr) * 1993-04-09 1994-10-27 Boehringer Mannheim Gmbh Derives d'indazole et medicaments antiviraux contenant ces derives
CN108003160A (zh) * 2016-10-28 2018-05-08 南京理工大学 一种合成[a]-环化吲哚类衍生物的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Keine einschl{gigen Dokumente gefunden *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994024109A1 (fr) * 1993-04-09 1994-10-27 Boehringer Mannheim Gmbh Derives d'indazole et medicaments antiviraux contenant ces derives
CN108003160A (zh) * 2016-10-28 2018-05-08 南京理工大学 一种合成[a]-环化吲哚类衍生物的方法
CN108003160B (zh) * 2016-10-28 2020-05-19 南京理工大学 一种合成[a]-环化吲哚类衍生物的方法

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AU1559392A (en) 1992-10-21
DE4109737A1 (de) 1992-10-01

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