DE4117358A1 - New tri:cyclic isoindole derivs. - Google Patents

Abstract

Tricyclic isoindole derivs. of formula (I), and their tautomers, and salts are new. Where X = O, S, NH or N-(1-5C)alkylimino; Y = S, NH, SO, SO2, 1-5C alkylamino or 1-5C alkylcarbonylamino (sic); R = (a) H, 1-9C aliphatic gp. (opt. substd. by phenyl) R'OA or R'SA; (b) mono-, bi- or tricyclic carbocyclic ring contg. 7-15C or a heterocyclic mono-, bi- or tricyclic system contg. 5-6 atoms including 1-4 or 1-5 O, S or N atoms, respectively, in each ring. (C) Phenyl opt. substd. by one or more R', R'O, R'S, R'SO, R'SO2, Q, QO, QS, NH2, R'NH, (R)2n, R'CONH, R'NHCO, NH2CO, R'OCO, OH, PhCH2O, PhS, PhO, NO2, CN, halo, CF3, N2, HCONH, COOH OR Ph; R1, R2 = H, 1-6C aliphatic gp., R'O, R'S, R'SO, R'SO2, NH2, R'NH, (R')2NH, sulphonamido, R'OCO, COOH, halo, OH, NO2, CN, N3, Ph or PhCH2O; R3,R4 = H, R', R'O, R'S, NH2, R'NH,(R')2NH, halo, CN, OH, COOH or R'OCO; R' = 1-6C alkyl; A = 1-6C alkylene; Q = 2-6C alkynyl or 2-6C alkenyl; Ph = phenyl.

Description

The present invention is the use of tricyclic isoindole derivatives as antiviral drugs as well as new optically active isoindolinones.

The invention relates to the use of tricyclic Isoindole derivatives of the general formula I.

for the manufacture of medicaments with antiviral activity, where in formula I

X is an oxygen or sulfur atom which may be imino = NH or an N-C₁-C₅-alkylimino group,
Y can be an oxygen or sulfur atom or the NH, C₁-C₅-alkylamino, C₁-C₅-alkylcarbonylamino, sulfinyl or sulfonyl group,
R is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-9 C atoms, which may be substituted by phenyl, or a C₁-C₆-alkoxy-C₁-C₆-alkyl or C₁-C₆-alkylmercapto C₁-C₆-alkyl radical or
a phenyl ring which is optionally mono- or polysubstituted by C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₂-C₆-alkenyl, C₂ -C₆-alkynyl, C₂-C₆ alkenyloxy, C₂-C₆ alkenylmercapto, C₂-C₆ alkynyloxy, C₂-C₆ alkynylmercapto, amino, C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₁-C₆ alkylcarbonylamino , C₁-C₆-alkylamino-carbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl or
a mono-, bi- or tricyclic carbocyclic ring having 7-15 C atoms or a heterocyclic mono-, bi- or tricyclic ring system having in each case 5 or 6 ring atoms and per ring system may contain 1-4 or 1-5 heteroatoms where the heteroatoms are nitrogen, sulfur or oxygen,
R¹ is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms or C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, amino, C₁- C₆-alkylamino, di-C₁-C₆-alkylamino, sulfonamido, C₁-C₆-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy,
R 2 has the same meaning as R 1, wherein R 1 and R 2 may be the same or different independently of each other,
R³ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, halogen, cyano, hydroxy, carboxy or C₁-C₆-alkoxycarbonyl means
R⁴ has the same meaning as R³, where the radicals R³ and R⁴ can be identical or different independently of one another,

and their tautomers, enantiomers, diastereomers and physiological compatible salts.

Isoindolinone derivatives of the formula I in which Y is the NH group means are described in the patents GB 10 59 175 (Chem. Abstr. 72, 121 531 u) or DE-A 14 45 443; Neth. Appl. 66 13 264 (Chem. Abstr. 67, 82 204 q) or US 35 90 043 with anti-inflammatory, analgesic, hypotensive, spasmolytic and antitussive activity, as well as in to the publications. Asoc. Quim. Argent. 70, 651 (1982) (cf. Chem. Abstr. 97, 127 596 g), J. Heterocycl. Chem. 17, 23 (1980) and Chem. Pharm. Bull. 20, 69 (1972) with corresponding Synthesis regulations.

Compounds of the formula I in which Y is an oxygen atom, are u. a. in J. Heterocycl. Chem. 26, 1441 (1989), J. Heterocycl. Chem. 21, 293 (1984), J. Am. Chem. Soc. 96, 499 (1974) and J. Am. Chem. Soc. 96, 507 (1974). In US 33 36 306 such derivatives is an anticonvulsive Attributed effect.

Compounds with similar structures and similar spectrum of activity like compounds of the formula I are from the earlier German Patent Application P 40 35 809.7 known. The ones described there Compounds represent tricyclic isoindolinone derivatives, in which the condensed in the 2,3-position of the isoindolinone ring Ring is a thiazole ring (thiazolo [2,3-a] isoindolinone derivatives). The corresponding optically active forms are in the earlier German application P 40 37 674.5 described.

The compounds of the present invention are valuable pharmacological properties. In particular, they are suitable to therapy and prophylaxis of infections by DNA viruses, such. Herpes simplex virus, the cytomegalovirus, Papilloma virus, the varicella-zoster virus or  Epstein-Barr virus or RNA viruses such as toga viruses or in particular Retroviruses such as the onco-viruses HTLV-I and II, as well as the Lentivirus Visna and Human Immunodeficiency Virus HIV-1 and -2, caused.

Particularly suitable appear the compounds of formula I for Treatment of clinical manifestations of retroviral HIV infection in humans, as the persistent, generalized Lymphadenopathy (PGL), the advanced stage of the AIDS-related Complex (ARC) and the clinical picture of AIDS.

The compounds of general formula I according to the invention have a pronounced antiviral effect and are suitable in particular for the treatment of viral or retro-viral Infections. Viral infections of mammals, in particular of the People, are widespread. Despite intensive efforts it has not yet been possible to provide chemotherapeutic agents, the causative or symptomatic with the viral or retroviral conditional illness with recognizable substantial Interfere with success. It is not possible these days, certain Viral diseases, such as the Aquired Immune Deficiency Syndrome (AIDS) the AIDS-related-complex (ARC) and their precursors, herpes, cytomegalovirus (CMV), influenza and cure other viral infections or chemotherapy to influence their symptoms favorably. Currently stands, for example almost exclusively for the treatment of AIDS 3'-azido-3'-deoxy-thymidine (AZT), known as Zidovudine® or Retrovir® available. AZT, however, is by a very close therapeutic width or by already in the therapeutic Characterized by very severe toxicities (Hirsch, M.S. [1988], J. Infec. Dis., 157, 427-431). The connections of general formula I do not have these disadvantages. They work antivirally, without pharmacologically relevant doses to be cytotoxic.

It has now been demonstrated that compounds of the general Formula I, the proliferation of DNA or RNA viruses on the Inhibit level of virus-specific DNA or RNA transcription. The substances can reverse via the inhibition of the enzyme  Transcriptase influence the proliferation of retroviruses (cf. Proc. Natl. Acad. Sci. USA 83, 1911, 1986, or Nature 325, 773, 1987).

Because there is a huge need for chemotherapeutics, the as specific as possible with retroviral diseases or their symptoms interfere without the normal ones could affect the natural body functions, the mentioned compounds advantageously prophylactic or therapeutic be used in the treatment of diseases, in which a retroviral infection of pathophysiological, symptomatic or clinical relevance.

The present invention particularly relates to such Compounds of formula I in which Y is a sulfur atom or the Groups -SO- or -SO₂- means. It has been shown that these compounds have a particularly good antiviral activity demonstrate.

Compounds of the formula I are hitherto known only as racemates. The optically active forms have opposite to the racemates a higher pharmacological efficacy and provide as well an object of the present invention.

The separation of the racemates into the enantiomers can be analytical, semi-preparative and preparative chromatographic on suitable optically active phases carried out with common eluents become. Examples of suitable optically active phases are optically active polyacrylamides or Polymethacrylamides, e.g. T. also on silica gel (eg ChiraSpher® from Merck, Chiralpak® OT / OP from Baker), cellulose esters / carbamates (eg Chiracel® OB / OY from Baker / Daicel), phases based on cyclodextrin or crown ether (eg Crownpak® of Daicel) or microcrystalline cellulose triacetate (Merck).

In the definition of R and R¹ means an aliphatic A straight-chain or branched alkyl, alkenyl or Alkynyl radical having 1-9, preferably 2-7 carbon atoms, such as z. As the propyl, isopropyl, butyl, isobutyl, pentyl,  Hexyl or heptyl radical. Unsaturated radicals are C₂-C₇-alkenyl and alkynyl radicals in question, preferably C₂-C₅, such as. B. the allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propynyl radical.

In the definition of R is an aliphatic radical, which by Phenyl, in particular a phenyl-C₁-C₆-alkyl group, such as B. the benzyl, phenethyl, phenylpropyl or phenylbutyl radical.

If R is a phenyl ring, it may be one, two or three be substituted three times. The substituents can be independent stand each other in o, m or p position.

A carbocyclic ring with 7-15 C atoms can mono-, bi- or be tricyclic and each have 5 or 6 carbon atoms per ring. This ring can be saturated, unsaturated, partially be saturated or aromatic. Examples are the following ring systems: the naphthyl, anthracenyl, Phenanthrenyl, fluorenyl, indenyl, acenaphthylenyl, Norbornyl, adamantyl or a C₃-C₇-cycloalkyl or C₅-C₈-cycloalkenyl group.

The heterocyclic mono-, bi- or tricyclic ring systems contain 5 or 6 carbon atoms per ring system, with 1-4 or 1-5 C atoms through the heteroatoms oxygen, sulfur and / or nitrogen can be replaced. The ring systems can be aromatic, partially or fully hydrogenated. exemplary mention may be made of the following ring systems: the pyridine, Pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, Imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, Furazane, furan, thiophene, indole, quinoline, isoquinoline, Coumarone, thionaphthene, benzoxazole, benzthiazole, indazole, Benzimidazole, benzotriazole, chromene, phthalazine, Quinazoline, quinoxaline, methylenedioxybenzene, carbazole, Acridine, phenoxazine, phenothiazine, phenazine or purine system, wherein the unsaturated or aromatic Carbo- and Heterocycles may be partially or fully hydrogenated.  

R is preferably unsubstituted phenyl or phenyl or monosubstituted by C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₂-C₆-alkenyl, C₂-C₆ alkynyl, C₃-C₆ alkenyloxy, C₁-C₆ alkylamino, C₁-C₆-dialkylamino, C₁-C₆-alkylcarbonylamino, C₁-C₆-alkylaminocarbonyl, C₁-C₆ alkoxycarbonyl, amino, hydroxy, nitro, Azido, trifluoromethyl, cyano or halogen. Preferably included the aforementioned "alkyl" parts in the respective Definitions up to 4, in particular up to 3 C-atoms.

Carbocyclic rings are preferably biphenyl, naphthyl, Anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthrenyl, Norbornyl, adamantyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalkenyl.

Heterocyclic ring systems are preferably pyrrole, imidazole, Furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, Quinoline, isoquinoline, coumarone, thionaphthene, benzimidazole, Quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, Acridine and phenothiazine.

R¹ and R² are hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ alkylmercapto, C₁-C₆ alkylamino, C₁-C₆ alkoxycarbonyl, amino, halogen, hydroxy, Cyano and azido are preferred, the "alkyl" parts in the aforementioned definitions preferably up to 4, in particular contain up to 3 carbon atoms.

Preferred substituents for R³ and R⁴ are hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, carboxy, C₁-C₆-alkoxycarbonyl, Halogen, cyano and hydroxy, wherein the "alkyl" parts in the aforementioned definitions, preferably up to 4, in particular up to 3 carbon atoms.

X is preferably oxygen or sulfur, n is preferably 0.

Halogen is generally fluorine, chlorine, bromine or iodine understand, prefers fluorine, chlorine and bromine.  

Particularly preferred radicals for R are C₃-C₅-alkyl, C₂-C₅-alkenyl, C₂-C₄alkynyl, benzyl, phenethyl, phenyl, by C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, allyl, allyloxy, C₁-C₆-alkylamino, Di-C₁-C₆-alkylamino, amino, hydroxy, azido, Trifluoromethyl, cyano or halogen mono- or disubstituted Phenyl or phenyl which is trisubstituted by methyl or halogen, Naphthyl, anthracenyl, indenyl, acenaphthylenyl, phenanthrenyl, Adamantyl, cyclohexyl, cyclohexenyl, furyl, thienyl, pyridyl, Pyrimidinyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, Methylenedioxyphenyl, carbazolyl and phenothiazinyl.

For R¹ and R² are independently particularly preferred Hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, Methylmercapto, ethylmercapto, methylamino, methoxycarbonyl, Ethoxycarbonyl, amino, azido, cyano, hydroxy and halogen, wherein Chlorine and bromine are very particularly preferred for halogen.

For R³ and R⁴ are methyl, ethyl, isopropyl, methoxy, ethoxy, Methylmercapto, ethylmercapto, methylamino, amino, chloro, bromo and cyano especially preferred.

Particular preference is given to compounds of the general formula I, in which R, R¹, X and n have the abovementioned meaning and R², R³ and R⁴ are hydrogen, methyl, ethyl, chlorine, Bromine, methoxy or ethoxy, wherein R² to R⁴ particularly preferably represent hydrogen.

The medicaments containing at least one compound of Formula I for the treatment of viral infections, can be found in liquid or solid form administered enterally or parenterally become. Here are the usual forms of application in Question, such as tablets, capsules, drag'es, syrups, Solutions or suspensions. As the injection medium is preferably Water for use, which in the case of injection solutions usual additives such as stabilizers, solubilizers and contains buffer. Such additives are z. B. tartrate and Citrate buffer, ethanol, complexing agents, such as ethylene-diaminetetraacetic acid and their non-toxic salts, high molecular weight  Polymers such as liquid polyethylene oxide for viscosity control. Liquid carriers for injection solutions need be sterile and are preferably filled into ampoules. Solid carriers are, for example, starch, lactose, mannitol, Methyl cellulose, talc, fumed silicas, higher molecular fatty acids, such as stearic acid, gelatin, agar-agar, Calcium phosphate, magnesium stearate, animal and vegetable Fats, solid high molecular weight polymers, such as polyethylene glycols, etc. For oral applications suitable preparations if desired, flavorings or sweeteners.

For the preparation of physiologically acceptable salts Compounds of formula I, which carry a basic group, with implemented inorganic or organic acids, such as. B. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid or maleic acid, and the acid addition salts isolated. If the compounds of the formula I contain an acid group, see above the physiologically acceptable salts are obtained by reaction with alkali or alkaline earth metal hydroxides, such as. For example, sodium hydroxide, Potassium hydroxide or calcium hydroxide, or with others basic groups, such as. B. with amines.

The dosage may depend on various factors, such as the mode of administration, Species, age or individual condition, depend. The compounds of the invention are commonly used in Amounts of 0.1-100 mg, preferably 0.2-80 mg per day and applied per kg of body weight. It is preferable to the daily dose to distribute 2-5 applications, with each Application 1-2 tablets with an active ingredient content of 0.5-500 mg be administered. The tablets can also be retarded be, which increases the number of applications per day to 1-3 reduced. The active substance content of the retarded tablets can 2-1000 mg. The active ingredient can also be obtained by continuous infusion be given, the amounts of 5-1000 mg per Normally sufficient.

The compounds of general formula I according to the invention are prepared by methods known per se, by  optionally substituted benzoic acid derivatives of the general Formula II

in which R, R¹ and R² have the abovementioned meaning and A is equal to -COOH or C≡N, with substituted or unsubstituted ones Aminoalkylmercaptans of the general formula III

or diamines of the general formula IV

in which R³ and R⁴ have the abovementioned meaning, in a suitable inert solvent at room temperature until Reflux temperature possibly in the presence of catalytic amounts Acid, e.g. As p-toluenesulfonic acid, or in the event that Y = O represents arylmagnesium bromides with N- (3-bromopropyl) phthalamide at -10 ° C to reflux temperature in an inert Solvent reacts, as exemplified in  J. Heterocycl. Chem. 26, 1441 (1989), and optionally then compounds of the formula I in others Subsequently converted compounds of formula I and then chromatographically or by recrystallization cleans. Racemates can be purified by chromatography at appropriate optically active phases, z. As cellulose triacetate, in the antipodes be separated.

The subsequent conversions of compounds of the formula I. in other compounds of formula I relate to the preparation of derivatives with X = S or N-alkylimine. Connections with X = S are prepared by reacting compounds of the formula I, in which X represents an oxygen atom, with sulfur group-transmitting Compounds, such. B. Lawesson's reagent. links with X = N-alkylimino are prepared by Reaction of the corresponding imino compounds of the general Formula I with alkylamines according to known methods. Compounds of formula I with Y = N-alkylimino are prepared by alkylation of compounds of the formula I, in where Y represents a nitrogen atom.

Furthermore, the subsequent conversion, z. As the oxidation of compounds of general formula I with n = 0 to the corresponding sulfinyl and sulfonyl derivatives with n = 1 or 2 according to known methods.

The benzoic acid derivatives of the general formula II are known from the literature and are z. By Friedel-Crafts acylation of substituted or unsubstituted phthalic anhydride with optionally substituted arenes in the presence of a Lewis acid (eg aluminum chloride) or by reaction of Grignard reagents the general formula V

R-MgBr (V)

in the R except for hydrogen, the above Meaning, with phthalic anhydride, if necessary  is substituted in suitable inert solvents produced at low temperatures.

Compounds of the formula III and IV are known compounds and can be produced according to the literature are or are available commercially.

The compounds of the formula I are prepared analogously for the preparation of thiazolo [2,3-a] isoindolinones, which are known from the Prior art are known (see US Patent 33 34 113, US Patent 36 46 022; U.S. 28 60 985, Belgian patent application 5,664,592; J. Org. Chem. 30, 1506 [1965], and J. Org. Chem. 34, 165 [1969]).

For the purposes of the present invention except those in the Examples of compounds and by combination all meanings of the substituents mentioned in the claims the following compounds of the formula I in question, as racemic mixtures or in optically active form or as pure R and S enantiomers may be present:

• 1. 10b-Methyl-3,4-dihydro-2H- [1,3] thiazino [2,3-a] isoindole 6 (10-bH) -one
• 2. 10b-Phenyl-3,4-dihydro-2H- [1,3] thiazino [2,3-a] isoindole 6 (10-bH) -one
• 3. 10b- (3-trifluoromethylphenyl) -3,4-dihydro-2H- [1,3] thiazine [2,3-a] isoindol-6 (10-bH) -one
• 4. 10b- (4-chlorophenyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10-bH) -one
• 5. 10b- (4-methoxyphenyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10-bH) -one  
• 6. 10b-phenyl-1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole 6 (2H) -one
• 7. 10b-Benzyl-1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole 6 (2H) -one
• 8. 10b- (4-chlorophenyl) -1,3,4,10b-tetrahydropyrimido- [2.1- a] isoindol-6 (2H) -one
• 9. 10b- (4-methylmercaptophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindol-6 (2H) -one
• 10. 10b- (4-Ethoxyphenyl) -1,3,4,10b-tetrahydropyrimido- [2.1- a] isoindol-6 (2H) -one
• 11. 10b- (4-fluorophenyl) -1,3,4,10b-tetrahydropyrimido- [2.1- a] isoindol-6 (2H) -one
• 12. 1-methyl-10b-phenyl-1,3,4,10b-tetrahydropyrimido- [2,1- a] isoindol-6 (2H) -one
• 13. 1-methyl-10b- (4-chlorophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindol-6 (2H) -one
• 14. 1-Propyl-10b-phenyl-1,3,4,10b-tetrahydropyrimido- [2.1- a] isoindol-6 (2H) -one
• 15. 1-ethyl-10b-phenyl-1,3,4,10b-tetrahydropyrimido- [2.1- a] isoindol-6 (2H) -one
• 16. 3-Hydroxy-10b-phenyl-1,3,4,10b-tetrahydropyrimido- [2.1- a] isoindol-6 (2H) -one
• 17. 3-hydroxy-10b-benzyl-1,3,4,10b-tetrahydropyrimido- [2.1- a] isoindol-6 (2H) -one
• 18. 9-nitro-10b-phenyl-1,3,4,10b-tetrahydropyrimido- [2.1- a] isoindol-6 (2H) -one  
• 19. 10b- (2-Thienyl) -1,3,4,10b-tetrahydropyrimido- [2.1- a] isoindol-6 (2H) -one
• 20. 3-Methyl-10b- (4-chlorophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindol-6 (2H) -one
• 21. 10b- (4-chloro-3-aminophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindol-6 (2H) -one
• 22. 2-methyl-10b- (4-chlorophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindol-6 (2H) -one
• 23. 1-Methyl-10b- (3-nitrophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindol-6 (2H) -one
• 24. 1-Ethyl-10b- (4-methoxyphenyl) -1,3,4,10b-tetrahydro pyrimido [2,1-a] isoindol-6 (2H) -one
• 25. 10b-Phenyl-3,4-dihydro-2H- [1,3] oxazino [2,3-a] isoindole 6 (10BH) -one
• 26. 10b- (4-t-butylphenyl) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 27. 10b- (3-methylphenyl) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 28. 10b- (4-methylphenyl) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 29. 10b- (4-fluorophenyl) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 30. 10b-phenylethenyl-3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 31. 10b-phenylethynyl-3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one  
• 32. 10b- (4-methoxyphenyl) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 33. 10b- (1-piperazinyl) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 34. 10b- (1H-imidazol-1-yl) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 35. 10b- (4-morpholinyl) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 36. 10b-propynyloxy-3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 37. 10b- (4-chlorophenyl) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 38. 10b- (1-piperidine) -3,4-dihydro-2H- [1,3] oxazino [2,3- a] isoindol-6 (10BH) -one
• 39. 10b- (3-methylphenyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 40. 10b- (1-naphthyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 41. 9-methyl-10b-phenyl-3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 42. 9-Chloro-10b-phenyl-3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 43. 9-chloro-10b- (3-methylphenyl) -3,4-dihydro-2H- [1,3] thiazine [2,3-a] isoindol-6 (10BH) -one
• 44. 10b- (3,4-dimethylphenyl) -3,4-dihydro-2H- [1,3] thiazine [2,3-a] isoindol-6 (10BH) -one  
• 45. 10b-phenyl-3,4-dihydro-2H- [1,3] thiazino [2,3-a] isoindole 6 (10BH) -thione
• 46. 10b- (3-chlorophenyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 47. 9-Methyl-10b- (3,5-dimethylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindol-6 (10BH) -one
• 48. 9-chloro-10b- (1-naphthyl) -3,4-dihydro-2H- [1,3] thiazine [2,3-a] isoindol-6 (10BH) -one
• 49. 10b- (2-naphthyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 50. 10b- (anthracene-1-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 51. 10b- (anthracene-9-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 52. 9-methyl-10b- (3-trifluoromethylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindol-6 (10BH) -one
• 53. 9-Methoxy-10b-phenyl-3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 54. 10b- (3-ethylphenyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 55. 10b-Benzyl-3,4-dihydro-2H- [1,3] thiazino [2,3-a] isoindole 6 (10BH) -one
• 56,3,3-dimethyl-10b-phenyl-3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 57. 10b-Allyl-3,4-dihydro-2H- [1,3] thiazino [2,3-a] isoindole 6 (10BH) -one  
• 58. 10b- (inden-1-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 59. 10b- (inden-3-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 60. 10b- (inden-4-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 61. 10b- (phenanthrene-1-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -thione
• 62. 10b- (phenanthrene-9-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -thione
• 63. 9-chloro-10b- (3-methylphenyl) -3,4-dihydro-2H- [1,3] thiazine [2,3-a] isoindol-6 (10BH) -thione
• 64. 10b- (2-naphthyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -thione
• 65. 10b- (cyclohexen-3-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 66. 10b- (2-furyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 67. 10b- (3-furyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 68. 10b- (2-thienyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 69. 10b- (3-Thienyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 70. 10b- (3-pyridyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one  
• 71. 10b- (pyrimidin-4-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 72. 10b- (thiazol-4-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 73. 10b- (indol-3-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 74. 10b- (indol-7-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 75. 10b- (Quinolin-5-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 76. 10b- (benzimidazol-4-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 77. 10b- (Carbazol-4-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 78. 10b- (Phenothiazin-4-yl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 79. 10b- (4-pyridyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 80. 10b- (2-pyridyl) -3,4-dihydro-2H- [1,3] thiazino [2,3- a] isoindol-6 (10BH) -one
• 81. 10b- (phenyl) -3,4-dihydro-2H- [1,3] thiazino [2,3-a] isoindole 6 (10BH) -one-1-oxide
• 82. 10b- (phenyl) -3,4-dihydro-2H- [1,3] thiazino [2,3-a] isoindole 6 (10BH) -one-1,1-dioxide

example 1 10b-phenyl-3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole 6 (10BH) -one

4.8 g (21 mmol) of 2-benzoylbenzoic acid were dissolved in 80 ml of abs. Toluene dissolved and after addition of 1.92 g (21 mmol) of 3-mercaptopropylamine and a catalytic amount of p-toluenesulfonic acid heated under reflux for one hour on a water separator. Then the solvent was removed in vacuo and the residue by column chromatography on silica gel 60 with ether / isohexane 2/1 cleaned as eluent. Y. 3.02 g (51% of theory), m.p. 164-167 ° C after recrystallization from ethanol.

The 3-mercaptopropylamine (Formula III) used was in Based on Helv. Chim. Acta 46, 752 (1963), by reaction of commercially available 3-bromopropylamine hydrobromide with Carbon disulfide to 2-mercaptohydrothiazine, cleavage with Hydrobromic acid and release of the base with sodium hydroxide solution produced in 21% yield.

Example 2 Inhibition of reverse transcriptase (RT)

The screening test system contains the purified RT from HIV-1, expressed by genetic engineering methods in E. coli was, as well as the components of the initiation complex, as the in vitro transcripts of the HIV LTR with the adjacent primer Binding site as a template and a primer binding site complementary 18mer oligonucleotide as a primer. Was measured [³H] -thymidine-5'-triphosphate incorporation by counting in the β-counter. The following table is for the examined Compounds of IC₅₀ value indicated. This value corresponds  that concentration of the test substance which inhibits the Reverse transcriptase activity caused by 50%. When Comparative substance was the value for AZT accordingly certainly.

Results substance Inhibition of HIV-RT IC₅₀ [M] 3'-azido-3'-deoxythymidine-5'-triphosphate [AZT-TP] | 6.0 × 10⁻⁶ 10b-phenyl-3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10BH) -one 2.2 x 10⁻⁶

Example 3

10B (1-naphthyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindol-6 (10BH -) - on was prepared analogously to Ex. 1 in 56% yield. Mp. 218-220 ° C (dec.) After stirring with ether.

Example 4

10B (3-methylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindol-6 (-10bH) -one was analogous to Ex. 1 in 41% yield manufactured. Mp. 149-153 ° C after stirring with ether.  

Example 5

10B (4-fluorophenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindol-6 (1-0bH) -one was analogous to Ex. 1 in 63% yield manufactured. Mp 161-163 ° C after stirring with ether.

Example 6

9-Chloro-10b-phenyl-3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindol-6 (10-bH) -one was analogous to Ex. 1 in 37% yield manufactured. Mp 173-175 ° C after stirring with ether.

Example 7

10B (3-methoxyphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindol-6- (10BH) -one was analogous to Ex. 1 in 49% yield manufactured. Mp. 165 ° C after stirring with ether.

Example 8

10B (3,5-dimethylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindol-l-6 (10BH) -one was analogous to Ex. 1 in 41% yield manufactured. Mp. 200 ° C after stirring with ether.

Example 9 10b-phenyl-3,4-dihydro-2H- [1,3] oxazino [2,3-a] isoindol-6 (10BH) - on

4.8 g (21 mmol) of 2-benzoylbenzoic acid were dissolved in 80 ml of abs. Toluene and after addition of 3.76 g (50 mmol) of 3-amino-1-propanol  and a catalytic amount of p-toluenesulfonic acid heated under reflux for three hours on a water separator. Then the solvent was removed in vacuo and the Residue by column chromatography on silica gel 60 with Ether / isohexane 3/2 purified as eluent. Y. 3.4 g (61% of theory), Mp 129-130 ° C after recrystallization from ethanol.

Example 10

10b-methyl-3,4-dihydro-2H- [1,3] oxazino [2,3-a] isoindol-6 (10BH) -one was prepared analogously to Ex. 9 in 26% yield. Mp. 86-89 ° C after stirring with ether.

Example 11

10B (3-methylphenyl) -3,4-dihydro-2H- [1,3] oxazino [2,3-a] isoindol-6 (2 H) -one was analogous to Ex. 9 in 32% yield manufactured. Melting point 110-114 ° C after recrystallization Ethanol.

Example 12

10B (1-naphthyl) -3,4-dihydro-2H- [1,3] oxazino [2,3-a] iso-indol-6 (2H) - one was prepared analogously to Ex. 9 in 53% yield. Mp. 153-158 ° C after recrystallization from ethanol.

Example 13

10B (2-thienyl) -3,4-dihydro-2H- [1,3] oxazino [2,3-a] iso-indol-6 (2H) -o-n was prepared analogously to Ex. 9 in 39% yield. Mp 110 ° C after recrystallization from ethanol.  

Example 14

10B (4-indanyl) -3,4-dihydro-2H- [1,3] oxazino [2,3-a] iso-indol-6 (2H) -o-n was prepared analogously to Ex. 9 in 30% yield. Mp. 67-70 ° C after stirring with ether.

Example 15

9-Chloro-10b-phenyl-3,4-dihydro-2H- [1,3] oxazino [2,3-a] iso-indol-6 (2H -) - on was analogous to Ex. 9 in 45% yield manufactured. Mp 131-134 ° C after stirring with ether.

Example 16

10B (2-pyridyl) -3,4-dihydro-2H- [1,3] oxazino [2,3-a] iso-indol-6 (2H) -o-n was prepared analogously to Ex. 9 in 27% yield. Mp 169 ° C after stirring with ether.

Example 17 10b-phenyl-1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindol-6 (2H) - on

4.8 g (21 mmol) of 2-benzoylbenzoic acid were dissolved in 80 ml of abs. Toluene and after addition of 3.7 g (50 mmol) of 1,3-diaminopropane and a catalytic amount of p-toluenesulfonic acid heated under reflux for three hours on a water separator. Then the solvent was removed in vacuo and the Residue by column chromatography on silica gel 60 with Ether / isohexane 2/1 purified as eluent. Y. 3.1 g (56% of theory), Mp 183-187 ° C after recrystallization from ethanol.  

Example 18

10B (3-methylphenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] iso-indol-6 (2H) -one was prepared analogously to Ex. 17 in 43% yield. Mp 128 ° C after stirring with ether.

Example 19

10b-phenyl-3,4-dihydro-2H- [1,3] oxazino [2,3-a] isoindol-6 (10BH) -thione 2 g of 10b-phenyl-3,4-dihydro-2H- [1,3] oxazino [2,3-a] isoindole-6 (10b) -one (see Example 9) in 200 ml of dioxane were with Added 3.35 g of Lawesson's reagent and stirred at 60 ° C for 7 h (TLC). After cooling, it was precipitated filtered off, the filtrate was evaporated in vacuo and the Residue by column chromatography on silica gel 60 with Heptane / methyl ethyl ketone 6/1 purified as eluent. Y. 1.72 g (81% of theory), mp 148-152 ° C after recrystallization from Ethanol.

Claims (8)

1. Use of tricyclic isoindole derivatives of the general formula I. for the preparation of medicaments with antiviral activity, wherein in formula I
X is an oxygen or sulfur atom which may be imino = NH or an N-C₁-C₅-alkylimino group,
Y can be an oxygen or sulfur atom or the NH, C₁-C₅-alkylamino, C₁-C₅-alkylcarbonylamino, sulfinyl or sulfonyl group,
R is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-9 C atoms, which may be substituted by phenyl, or a C₁-C₆-alkoxy-C₁-C₆-alkyl or C₁-C₆-alkylmercapto C₁-C₆-alkyl radical or
a phenyl ring which is optionally mono- or polysubstituted by C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₂-C₆-alkenyl, C₂ -C₆-alkynyl, C₂-C₆ alkenyloxy, C₂-C₆ alkenylmercapto, C₂-C₆ alkynyloxy, C₂-C₆ alkynylmercapto, amino, C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₁-C₆ alkylcarbonylamino , C₁-C₆-alkylamino-carbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl or
a mono-, bi- or tricyclic carbocyclic ring having 7-15 C atoms or a heterocyclic mono-, bi- or tricyclic ring system having in each case 5 or 6 ring atoms and per ring system 1-4 to 1-5 heteroatoms may be contained, where the heteroatoms are nitrogen, sulfur or oxygen,
R¹ is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms or C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, amino, C₁- C₆-alkylamino, di-C₁-C₆-alkylamino, sulfonamido, C₁-C₆-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy,
R 2 has the same meaning as R 1, wherein R 1 and R 2 may be the same or different independently of each other,
R³ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, halogen, cyano, hydroxy, carboxy or C₁-C₆-alkoxycarbonyl means
R⁴ has the same meaning as R³, where the radicals R³ and R⁴ can be identical or different independently of one another,
and their tautomers, enantiomers, diastereomers and physiologically acceptable salts. 2. Use according to claim 1, characterized in that Y represents a sulfur atom or an -SO- or -SO₂ group.   3. Use according to claim 1, characterized in that R denotes a carbocyclic ring having 7-15 C atoms, selected from the group naphthyl, anthracenyl, Phenanthrenyl, fluorenyl, indenyl, acenaphthylenyl, Norbornyl, adamantyl, C₃-C₇cycloalkyl or C₅-C₈cycloalkenyl, where the unsaturated or aromatic carbocycles may be partially or fully hydrogenated. 4. Use according to claim 1, characterized in that R represents a heterocyclic ring selected from Group pyridine, pyrimidine, pyridazine, pyrazine, triazine, Pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, Isoxazole, oxadiazole, furazane, furan, thiophene, indole, Quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, Benzothiazole, indazole, benzimidazole, benzotriazole, chromene, Phthalazine, quinazoline, quinoxaline, methylenedioxybenzene, Carbazole, acridine, phenoxazine, phenothiazine, phenazine or Purine, wherein the unsaturated or aromatic heterocycles may be partially or fully hydrogenated. 5. optically active tricyclic isoindole derivatives of general formula I. in the
X is an oxygen or sulfur atom which may be imino = NH or an N-C₁-C₅-alkylimino group,
Y can be an oxygen or sulfur atom or the NH, C₁-C₅-alkylamino, C₁-C₅-alkylcarbonylamino, sulfinyl or sulfonyl group,
R is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-9 C atoms, which may be substituted by phenyl, or a C₁-C₆-alkoxy-C₁-C₆-alkyl or C₁-C₆-alkylmercapto C₁-C₆-alkyl radical or
a phenyl ring which is optionally mono- or polysubstituted by C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₂-C₆-alkenyl, C₂ -C₆-alkynyl, C₂-C₆ alkenyloxy, C₂-C₆ alkenylmercapto, C₂-C₆ alkynyloxy, C₂-C₆ alkynylmercapto, amino, C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₁-C₆ alkylcarbonylamino , C₁-C₆-alkylaminocarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl or
a mono-, bi- or tricyclic carbocyclic ring having 7-15 C atoms or a heterocyclic mono-, bi- or tricyclic ring system having in each case 5 or 6 ring atoms and per ring system 1-4 to 1-5 heteroatoms may be contained, where the heteroatoms are nitrogen, sulfur or oxygen,
R¹ is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms or C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, amino, C₁- C₆-alkylamino, di-C₁-C₆-alkylamino, sulfonamido, C₁-C₆-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy,
R 2 has the same meaning as R 1, wherein R 1 and R 2 may be the same or different independently of each other,
R³ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, halogen, cyano, hydroxy, carboxy or C₁-C₆-alkoxycarbonyl means
R⁴ has the same meaning as R³, where the radicals R³ and R⁴ can be identical or different independently of one another,
and their tautomers and physiologically acceptable salts. 6. Medicaments containing at least one compound of Formula I according to claim 5 and pharmaceutically customary Carrier or excipients. 7. Use of compounds of the formula I according to claim 5 for the manufacture of medicaments with antiviral activity. 8. Process for the preparation of compounds of the formula I. according to claim 5, characterized in that the Racemates of the formula I chromatographically on suitable optically active phases in the optically active compounds separates.