IE920334A1 - THE USE OF THIAZOLO-[2,3-a]-ISOINDOLE DERIVATIVES AS¹ANTIVIRAL PHARMACEUTICALS AND NEW THIAZOLO-[2,3-a]-ISOINDOLE¹DERIVATIVES - Google Patents

Abstract

The object of the present invention is the use of thiazolo-[2,3-a]isoindole derivatives for the production of antiviral medicaments and novel thiazolo-[2,3-a]isoindole derivatives. The invention relates in particular to the use of thiazolo-[2,3-a]isoindole derivatives of general formula (I) for the production of medicaments for the treatment of viral or retroviral infections, wherein: X may be an oxygen or sulphur atom, the imino group =NH or an N-C1?-C5?-alkylimino group; n is 0, 1 or 2; R is a hydrogen atom, an aliphatic radical or an optionally substituted carbocyclic or heterocyclic ring; R?1 to R?6 have the meaning given in the description; and their tautomers, enantiomers, diastereomers and physiologically acceptable salts. The present invention also discloses novel thiazolo-[2,3-a]isoindoles of formula (I) in which R is a heterocyclic mono, bi or tricyclic ring.

Description

The present invention is concerned with the use of thiazolo-/2,$^7-isoindole derivatives for the preparation of anti-viral pharmaceutical compositions and is also concerned with new thiazolo-/2,3-a7-indole derivatives.

In particular, the present invention is concerned with the use of thiazolo—3-a7—isoindole derivatives of the general formula:- for the preparation of pharmaceutical compositions for the treatment of viral and retroviral infections, wherein X is an oxygen or sulphur atom, an imino group =NH or an N-C^-C^-alkylimino radical, n is 0,; 1 or 2, R is a hydrogen atom, a straight-chained or branched, saturated or unsaturated aliphatic radical containing up to 9 carbon atoms, which can be substituted by phenyl,· or a C^-Cg-alkoxy-C^-C^alkyl or C^-Gg-elkylmercapto-G^-Gg-alkyl radical or is a phenyl ring which is optionally substituted one or more times by C^-C^-alkyl, C^-C^-alkoxy, C1-C6-alkylmercapto, G^-G^-alkylsulphinyl, C^-Ggalkylsulphonyl, Cg-Cg-alkenyl» G2C6"alkyn71’ -5C2-Cg-alken;yloxy , G2"Gg-alkenylmercapto, ^2~^6~ alkynyloxy, G2~Cg-alkynylmercapto, amino, C^-Όθalkylamino, di-G^-Gg-allylamino, C^-C^-alkylcarbonylamino, C^-Cg-alkylaminocarbonyl, Ο^-Οθalkoxycarbonyl, aminocarbonyl, hydroxyl, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxyl or phenyl or is a mono-, bi- or tricyclic carbocyclic ring with 7 to 15 carbon atoms or is a heterocyclic mono—, bi or tricyclic ring system with, in each case, 5 or 6 ring atoms and can contain per ring system 1 to 4 or 1 to 5 heteroatoms, respectively, the heteroatoms being nitrogen, sulphur or oxygen, and these rings can be substituted by C^-Cg-elkyl, C^-Cg-alkoxy, nitro, amino or halogen, E^ is a hydrogen atom, a straight-chained or branched, saturated or unsaturated aliphatic radical containing up to 6 carbon atoms or C^-G^-alkoxy, C^-Όθ-θIkylmercapto, C^-Cθ-alkyIsulphihyl, C^-Cgalkylsulphohyl, amino, Ο^-Οθ-elkylamino, di-σ^-Οθalkylamino, sulphonamide, C-j-C^-a lkoxy carbonyl,. carboxyl, halogen, hydroxyl, nitro, cyano, azido, 1 phenyl or benzyloxy, B has the same meaning as E , whereby, independently of one another, the radicals 3 B and E can be the same or different, R is a hydrogen atom or a Ο^-Οθ-elkyl, C^-Οθ-alkoxy, C1-C6-alkylmercapto, amino, Οχ-Cθ-alkylamino, -4di-C1-Cg-alkylamino, aminocarbonyl, C^-G^-alkylaminocarbonyl, di-G^-G^-alkylaminocarbonyl, morpbolinocarbonyl, halogen, cyano, hydroxyl, carboxyl, G^-Cθ-alkoxycarbonyl, aryloxycarbonyl, he taryloxycarbony1, aryl-C ^-Οθ-aIkoxyca rbony1, hetaryl-G^-Cg-alkoxycarbonyl, C1-Cg~aIkoxy-Ο^-Οθalkoxycarbonyl or hydroxy-G^-G^-alkoxycarbonyl, whereby- the aryl and hetaryl radicals can, in each case, dan be substituted by C-|-C6-alkyl, C,-C6-alkoxy or halogen and R , R^ and R have the same meanings as R^, whereby, independently of one another, R^, R^, R^ and R^ can be the same or different, as well as the tautomers, enantiomers, diastereomers and physiologically acceptable salts thereof, with the proviso that when R^, R^, R^, R^, R^ and R^ are hydrogen atoms, π is 0 or 1 and X is an oxygen atom, R cannot be a hydrogen atom, an aliphatic radical containing up to 7 carbon atoms, which can be substituted hy phenyl, or phenyl which is substituted one or more times by C^-C^-alkyl, G^-G^— alkoxy, hydroxyl, trifluoromethyl, methylsulphonyl or halogen.

The present invention also provides new thiazaGlo-^iJ-eT-isoindoles of general formula I, wherein R is a heterocyclic φοηο-, bi- or tricyclic ring with, in each case, 5 or δ ring atoms and which, per ring, system can contain 1 to 4 or 1 to 5 heteroatoms, respectively, the heteroatoms -5being oxygen,, sulphur or nitrogen, and these rings can be substituted by C^-C^-alkyl, C^-C^-alkoxy, nitro, amino or halogen.

Thiazaolo-/5,3-a/-isoindoles of the general formula I in which X is an oxygen atom, n is 0 or 1, each of R to R is a hydrogen atom and R is a hydrogen atom or an aliphatic radical containing up to 7 carbon atoms, which can be substituted by phenyl, or R is a phenyl which can be substituted one or more times by alkyl, alkoxy, hydroxyl, trifluoromethyl, methylsulphonyl or halogen, are known from the earlier German Patent Application P AO 35 809.7 as anti-viral medicaments.

Furthermore, individual compounds of the general formula I, in which R is a hydrogen atom, are known from J. Org. Chem., 1506-1508/1965; J.A.C.S.T 80. 702-707/1958 and Liebigs Ann. Chem., A, 657-672/1985. Compounds in which X is an oxygen atom and R is a phenyl or naphthyl radical are known from British Patent Specification No. 1,.039,117 as medicaments with anti-inflammatory,: anti-convulsive and analgesic action.

The task forming the basis of the present invention is to find a further medical indication for known compounds of general formula I and to provide new thiazaolo-/5,3-a7-isoindoles with antiviral action. This task is solved by the features characterised in the claims. -6The compounds of general formula I have valuable pharmacological properties. In particular, they can be used for the therapy and prophylaxis of infections which are caused by DNA viruses, for example herpes simplex virus, cytomegalovirus, Papillomaviruses, varicella-zoster virus and Epstein-Barr virus, or RNA viruses,· such as togaviruses, and especially retroviruses, such as the oncoviruses HTLV-I and II, as well as the lentiviruses visna and human immune deficiency viruses HIV-1 and 2, The compounds of general formula I appear to be especially suitable for the treatment of the clinical manifestations of the retroviral HIV infection in humans, such as persistent generalised lymphadenopathy (PGL), the advanced stage of the AIDS_related complex (ARC) and the clinical complete picture of AIDS, The compounds of general formula I according to the present invention possess an outstanding antiviral action and are especially suitable for the treatment of viral and retroviral infections. Viral infections of mammals and especially of humans are very widespread, In spite of intensive efforts, hitherto it has not beenpossible to provide chemotherapeutics which interfere causally or symptomatically with the virally or retrovirally caused appearances of diseases with β recognisable substantial success. At present, it is not possible to cure certain viral diseases, for example the acquired immune deficiency syndrom (AIDS), the AIDS-related complex (AEG) end the preliminary stages thereof, infections by herpes virus, cytomegalovirus (COV)}influenzal viruses and other viruses, or chemotherapeutically favourable to influence the symptoms thereof. At present, for example, for the treatment of AIDS there is available almost exclusively 3’-azido-3’deoxythymidine (AZT), known as Zidovudine or Retrovir However, AZT is characterised by a very narrow therapeutic range or by very severe toxicities which already appear in the therapeutic range (see M.S. Hirsch, J. Infec. Dis.. 157- 427-431/1988). The compounds of general formula I do not possess these disadvantages. They act anti-virally without, being cytotoxic in the pharmacologically relevant doses.

We have now been able to show that compounds of general formula I inhibit the multiplication of DNA and RNA viruses at the stafge of the virusspecific DNA or RNA transcription. Via the inhibition of the enzyme reverse transcriptase, the compounds can influence the multiplication of retroviruses (cf. Proc. Natl. Acad. Sci. USA, 83, 1911/1986 and Nature, 325. 775/1987).

Since there is a very great need for chemotherapeutics which interfere as specifically as possible with retrovirally-caused diseases or the -8symptoms thereof without influencing the normally occurring natural body functions, the abovedescribed compounds can be advantageously used prophylactically or therapeutically in the treatment of diseases in which a retroviral infection is of pathophysiological, symptomatic or clinical relevance.

The compounds of general formula 1 possess a centre of chirality and can be used not only in the form of their racemates but also in the form of their enantiomers and diastereomers. The separation of the racemates into the enantiomers can be carried out analytically, semi-preparatively and preparatively by chromatography on appropriate optically-active phases with conventional elution agents. As opticallyactive phases there can be used, for example, optically-active polyacrylamides or polymethacryl— amides, in some cases also on silica gel (for example ChiraSpher ® of Merck, C^iralpak® OT/OP of Baker), cellulose eaters/carbamates (for example Chipacel® OB/OT of Baker/Daicel), phases based on (s) cyclodextrin and crown ethers (for example Crownpak^ of Daicel) or microcrystalline cellulose triacetate.

An aliphatic radical means a straight-chained or branched alkyl, alkenyl or alkynyl radical with 1 to 9 and preferably 2 to 7 carbon atoms, for example the propyl, isopropyl* butyl, isobutyl, -9pentyl, hexyl or heptyl radical. Unsaturated radicals can he alkenyl and alkynyl radicals containing 2 to 7 and preferably 2 to 5 carbon atoms, for example the allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propynyl radical.

An aliphatic radical which can he substituted by phenyl is especially a phenyl-C^-C^-aIky1 radical, for example the benzyl, phenethyl, phenylpropyl or phenylhutyl radical..

If S is a phenyl ring, this can be substituted once, twice or three times. Independently of one another, the substituents can be in the o-r m- or ^-position.

A carbocyclic ring with 7 to 15 carbon atoms can be mono—, di- or tricyclic and, in each case, contain 5 or 6 carbon atoms per ring. This ring can he saturated, unsaturated, partly saturated or aromatic. By way of example, there may be mentioned the following ring systemss the naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, indanyl, acenaphthylenyl, horbomyl, adamantyl ring or a Cj-C^-cycloalkyl or C^-Cg-cycloalkenyl radical, whereby, in the last two cases, the corresponding 5- or 6-membered rings are preferred.

The heterocyclic mono—, di- and tricyclic ring systems contain 5 or 6 carbon atoms per ring system, whereby 1 - 4 or 1 - 5 carbon atoms, respectively, can be replaced by the heteroatoms oxygen, sulphur -10and/or nitrogen. The ring systems can be aromatic or partly or completely hydrogenated. By way of example, the following ring systems may be mentioned: the pyridine, pyrimidine,; pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazane, furan, thiophene, indole, quinoline, isoquinoline, cumarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxybenzene, carbazole:, acridine, phenoxazine, phenothiazine, phenazine or purine systems, whereby the unsaturated or aromatic carbocycles and heterocycles can be partly oT completely hydrogenated.

As aryl and hetaryl radicals in the definition of Ί3? - Ηθ, the phenyl, naphthyl and pyridyl radicals are preferred, whereby, in particular, these radicals can be substituted once or twice by C^-Cyalkyl, C^-C^-alkoxy or halogen. β is preferably unsubstituted phenyl or phenyl substituted once or twice by C^-C^-alkyl, C^-C^alkoxy, G^-G^-alkylmercapto, C^-C^-alkylsulphinyl, C^-C^-alkylsulphonyl, CgJ^-alkenyl, CyCy alkynyl, C^-C^-alkenyloxy, C^-C^-alkylamino, C^-G^-dialkylamino, C^-C^-aIkylearbonylamino, C^-Cy a Iky lamino— carbonyl, CyCy alkoxy carbonyl, amino, hydroxyl, nitro, azido, trifluoromethyl, cyano or halogen. -11Carbocyclic rings are preferably biphenyl, naphthyl, anthracenyl, indanyl, fluorenyl, acenaphthylenyl, phenanthrenyl, norbornyl, adamantyl, C^-Cg-cycloalkyl, C^-Cg-cycloaelkenyl. Heterocyclic ring systems are preferably pyrrole, imidazole, furan,, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, cumarone, thionaphthene, benzimidazole, quinazoline, methylenedioxy benzene, ethylenedioxybenzene, carbazole, acridine and phenothiazine. 2 The radicals R and R are preferably hydrogen atoms, Cj-C^-alkyl, CIkenyl·, G2"*G4"elk7ny1»’ C-j—C^-alkoxy, C^-G^-alkylmercapto, C^-C^-a Iky lamino, Cj-Cyalkoxycarbonyl, sulphonamide, amino, halogen, hydroxyl, cyano and azido, these radicals being especially in the 7-, 8- or 9-position of the thiazoloZ2,3-a.7-isoindole ring.

Preferred substituents for r\ R^ and R° are hydrogen, C^-C^-alkyl, C^-C^-alkoxy, G^-G^— alkylmercapto, carboxyl, C^-G^-alkoxycarbonyl, morpholinocarbonyl, aminocarbonyl, C^-C^-alkylaminocarbonyl, di-G^-G^-alkylaminocarbonyl, C^-C^-alkoxyC^-C^-alkoxy ca rbony1, pyridy1-C^-C^-alkoxycarbony1, II halogen, cyano and hydroxyl, R and R being χ 6 especially hydrogen. The radicals R - R can be the same or different but those compounds ere preferred in which at least two and preferably three of these radicals are hydrogen. -12X is preferably oxygen or sulphur end n is preferably 0» By halogen is generally to be understood fluorine, chlorine, bromine or iodine, fluorine, chlorine and bromine being preferred.

Especially preferred radicals for R are G^-C^alkyl, C2-Ccj-alkeny 1, C2-C^-alkynyl, benzyl, phenethyl, phenyl;, phenyl mono- or disubstituted by G^-G^-alkyl, G^-G^-alkoxy, C^-C^-alkylmercapto, allyl, allyloxy, Cj-C^-elkylamino, di-C^-G^-alkylaminq., amino, hydroxyl, azido, nitro, trifluoromethyl, cyano or halogen or phenyl trisubstituted by methyl or halogen^, naphthyl, anthracenyl, indanyl, acenaphthylenyl, phensnthrenyl, adamantyl, cyclohexyl, cyclohexenyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, methylenedioxyphenyl, carbazolyl and phenothiazinyl, 2 For R and-R , independently of one another, there are especially preferred hydrogen,, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methy1mercapto, ethylmercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, amino, azido, cyano, hydroxyl and halogen, whereby halogen is especially chlorine or bromine.

Eor r\ R4, R^ and Κθ are especially preferred methyl, ethyl, isopropyl, methoxy, ethoxy, methy1mercapto, ethylmercapto, methylamino, amino, chlorine, bromine and cyano. -13Especially preferred are compounds of the general formula I in which R, R1, X and n have the abovegiven meanings and R^, R^, r\ R^ and R^ are hydrogen, methyl, ethyl, chlorine, bromine, methoxy or ethoxy, the radicals R to R preferably being hydrogen.

The new compounds of general formula I in which S is a heterocyclic radical are especially those derivatives in which R is thienyl, furyl, pyridyl, thionaphthenyl or indolyl, whereby these radicals can be especially substituted by C^-C^-alkyl and halogen.

The pharmaceutical compositions containing at least one compound of the general formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form. There can hereby be used the conventional forms of administration, for example tablets* capsules, dragees* syrups, solutions and suspensions. As injection medium, it is preferred to use water which contains the additives usual in the case of injection solutions* such as stabilising agents, solubilising agents and buffers. Such additives include, for example, tartrate and citrate buffers, ethanol, complex formers, such as ethylenediaminetetraacetic acid and the non-toxic salts thereof, high molecular weight polymers, such as liquid polyethylene oxide,for viscosity regulation. Liquid carrier materials for injection solutions must be -14sterile and are preferably filled into ampoules.

Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids, such as stearic acid, gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers, such as polyethylene glycols and the like. Compositions which are suitable for oral administration can, if desired,, contain flavouring and sweetening agents.

The dosaging can depend upon various factors, such as mode of administration, species, age or individual state of health. The compounds according to the present invention are usually administered in amounts of from 0.1 to 100 mg and preferably of from 0.2 to 80 mg per day and per kg of body weight. It is preferred to divide up the daily dose into 2 to ,5 administrations, whereby, in the case of each administration, there are given 1 or 2 tablets with a content of active material of from 0.5 to 500 mg.

The tablets can also he retarded, whereby the number of administrations can be reduced to 1 to 5. The active material content of the retarded tablets can be from 2 to 1000 mg.The active materials can also he given by continuous infusion, in which case amounts of from 5 to 10Q0 mg per day normally suffice. -15The compounds of general formula I can also be used iri the form of their physiologically acceptable salts, for example the alkali metal or alkaline earth metal salts insofar as these compounds have acid groups, for example a free carboxyl group. If basic groups are present,, then the compounds of general formula I can he converted into the corresponding physiologically acceptable acid addition salts with the help of organic or inorganic acids.

The compounds of general formula I according to the present invention can be prepared by processes known from the literature in that optionally substituted benzoic acid derivatives of the general formula:- and A is a carboxyl or cyano group, are reacted with unsubstituted or substituted cysteamines of the general formula:— -165 4 5 6 in which R, R , R and S have the above-given meanings, in an appropriate inert solvent at a temperature from ambient temperature to reflux temperature, optionally in the presence of catalytic amounts of an acid, for example p-toluene— sulphonic acid, and subsequently optionally converts the compounds obtained of general formula I into other compounds of general formula I and subsequently purifies by chromatography or recrystallisation. Racemates can be separated by chromatography on a.n appropriate optically-active phase, for example cellulose triacetate, into the antipodes.

The subsequent conversions of compounds of general formula I into other compounds of general formula I concerns the preparation of thiazolo/S/^-aZ-isoindole derivatives in which X is a sulphur atom or N-alkylimine radical. Compbunds in which X is a sulphur atom are prepared by reacting compounds of general formula I, in which X is an oxygen atom, with sulphur group-transferring compounds, for example Lawesson*s reagent.

Compounds which X is an N-alkylimino radical are prepared by reacting the corresponding imino compounds of general formula I with alkylamines according to known methods.

The benzoic acid derivatives of general formula I are also known from the literature and are prepared., -17for example, by Friedel-Crafts acylation of unsubstituted or substituted phthalic anhydride with optionally substituted arenes in the presence of a Lewis acid, for example aluminium chloride, or by reaction of Grignard reagents of the general formula :R-MgBr (IV), in which R has the above-given meaning with the exception of hydrogen, with phthalic anhydride which is optionally substituted, in appropriate inert solvents at low temperatures.

The processes for the preparation of the compounds of general formula I according to the present invention can also be taken from the patent specifications and literature references mentioned in the prior art (cf. U.S. Patent Specification No. 3,334,113, Swiss Patent Specification No. 469,733* Belgian Patent Application No. 659,528, U.S. Patent Specification No. 3,646,022, U.S. Patent Specification No. 2,860,985, Belgian Patent Application No. 564,592, J. Org. Ghem., 30. 1506/ 1965, 39 well as J. Org, Chem., 34, 165/1969).

Within the meaning of the present invention, apart from the compounds mentioned in the Examples and those obtained by combination of all of the meanings of the substituents mentioned in the claims, the following compounds of general formula I also come into consideration, which can be present as racemic mixtures or in optically-active form or as pure R— and S-enantiomers: -181. 8,9b-dimethy1-2,3-dihydrothia zolo-/2,3-a7-isoind.ol-5(9bH)-one 2. 8-chloro-9h-pheny1-2,3-dihydrothiazolo-/S, 3-8,7i so indol-5(9bH)-one 3. 8-fluoro-9h-(4-methylphenyl)-2,3-dihydrothiazoloZZ, 3-a.7-isoindol-5(9bH3-one . 8-chloro-9h—( 3-me thy lpheny l) —2,3-dihydrothia zolo— /2,3-3.7—iso indol-5 (9 bH)-one . 3-nie thy l-9b-(4-ethy lphenyl)-2 r3-dihydro thia zolo/2,3-£Z-isoindol-5(9bH)-one 6. 9b-(2,3-dimethylphenyl)-2,3-dihydrothiazoloJ/2’,3-a7-isoindol-5(9bH)-thione 7. 8-chloro-9b-(3»4-dimethylphenyl)-2,3-dihydrothiazolo-/2,3-a7-isoindol-5(9bH)-thione 8. 2-ethyl-9b-(2,5-dimethyIphenyl)-2,3-dihydrothiazolo-/2,3-£Z-isoindol-5(9bH)-one 9. 8-chloro-9b-(3-trifluoromethylpheny1)-2,3-dihydrothiazolo-/?, 3-aZ-isoindol-5(9bH)-one . 6-methoxy-9b-(4-trifluoromethylphenyl)-2,3-dihydro thia zolo-/?,3-a7-isoindol-5(9bH)-one 11. 9b-(4-hydroxypheny1)-2,3-dihydrothiazolo-/?,3-a7isoindole-5(9hH)-thione 12. 8-chloro-9h-(3-hydroxypheny1)-2,3-dihydro thia zolo/2,3-aZ-i so indol-5(9bH)-one 13. 7-methylmercapto-9b-(4-ethoxyphenyl)-2,3-dihycfirothiazolo-Z?,3-aZ"isoindol-5(9bH)-one 14. 9-methyl-9b-(3-methoxypheny1)-2,3-dihydrothiazolo/2,3-£7-isoindol-5(9bH)-one -1915. 8-fluoro-9b-(3-fluo.rophenyl)-2,.3-dihydrothiazolo/2,3-a7-isoindol-5(9bH)-one 16. 9b-(4-chlorophenyl)-2r3-dihydrothiazolo-/?,3-a7isoindol-5(9bH)-'bhione 17. 8-methyl-9b-(5-metbylsulphonylpheny1)-2r3-dibydzo thia zolo-/2,3-s7>-isoindol-5(9bH)-one 18. 8-chloro-9b-phenyl-2*3-dihydrothiazolo-/?,3-a/isoindol-5(9bH)-one 1-oxide 19. 8-chloro-9b-benzyl-2*3-one . 2,2-dimθthyl·-9b-phenethyl-2*3-dihydΓothiazolo/?,3-ai7-isoindol-5(9bH)-one 21. 9b-(3-methylmercaptophenyl)-2*3- 22. 9b-(3-methylaminophenyl)-2r,3-dihydrothiazolo3-aZ-isoindol-5(9bH)-one 23. 9b-(3-azidophenyl)-2,.3-dihydrothiazolo-/?, 3-a7isoindol-5(9bH)-one 24. 8-methyl-9b-ally1-2,3-dibydrothiazolo-/?, 3-®7isoindol-5(9bH)-one . 8-chloro-9b-(3,5-dimethylpheny1)-2,3-dihydrothiazolo-/2,3-s7-isoindol-5(9bH)-one 26. 8-me thyl-9b-(1-naphthy1)-2,3-dihydro thia zolo/2,3-a/-isoindol-5(9bH)-one 27. 9h-(anthracen-l-yl)-2, 3-d.ihydro thiaΖ0Ι0-/Σ, 3-a/isoindol-5(9bH)-one 28. 9b-(anthracen-9-yl)-2,3-dihydrothiazolo-/2,3-^7isoindol-5(9bH)-one -2029. 9b-(inden-l-yl)-2,3-dihydrothiazolo-/2,3-aZisoindol-5(9bH)-one ., 9b- (inden-3-y 1)-2,3-dihydro thia zolo-/2,3-a.Zisoindol-5(9bH)-one 31. 9b-(inden-4-yl)-2,3- 32. 9b-(phenanthren-l-y1)-2,3-dihydrothiazolo/2,3-£Z-isoindol—5(9bH)-one 33- 9b—(phenanthren-9-yl)-2,3- 34. 9b-(cy clohexen-3-yl)-2,3-dihydrothia zolo-/2,3-aZ isoindole-5(9bH)-thione - 9b-(2-fury1)-2,3-dihydrothiazolo-/2,3-a/-i soindole-5(9bH)-thione 36. 9b-(3-f uryl)-2,3-dibydro thia zolo-/2,3-a/-iso— indol-5(9bH)-one - 9b-( 2-thienyl) -2,3-d.ihy dro thia z olo-/3,3-a/isoindole-5(9bH)-thione 38. 9b-(3-thienyl)-2,3-cLihydrothiazolo-/2,3-£Zisoindol-5(9bH)-one 39. 9b-(pyrimidin-4-yl)-2,3- 40. 9b-(thiazol-2-y1)-2,3-dihydrothiazolo-/2,3-£/is0indo1-5(9bH)-one 41. 9b-(thiazol-4-yl)-2,!3-dihydrothiazolo-/2,3-a>Zisoindole-5(9^H)—thione 42. 9b-(indol-3-yl)-2,3-cLihydrothiazolo-/2,3-aZisoindol-5(9bH)-one -2143. 9b-(indol-7-yl)-2,3-dihydrothiazolo-/2,3-a7isoindol-5(9bH)-one 44. 9h-(quinolin-4-y1)-2,3-dihydrothiazolo-/2,3-a7 isoindol-5(9t>H)-one 45. 9b-(quinolin-5-y 1)-2 r3-dihydrothiazolo-/2,3-3.7 isoindol-5-(9LH)-thione 46. 9h-(henzimidazol-4-yl)-2,3-dihydrothiazolo/2,3-3.7-isoindol—5-(9LH)-one 47. 9b-( carbazol-l-y 1)-2,3-dihy dro thia zolo-/2,3-aiZ isoindol-5(9bH)-one 48. 9b-(carbazol-4-yl)-2,3-dihydro thiazolo-/2,3-a.Z· isoindole-5(9bH)—thione 49. 9b-(phenothiazin-l-y1)-2,3-dihydro thia zolo/2,3-a7-isoindole-5(9bH)-thione 50. 9b-(pheno thiaz in-4-y1)-2,3-dihydro thia zolo/a, 3-3.7—isoindol-5(9bH)-one 51. 9b—(4-quinazolin-4-yl)-2,3-dihydrothiazolo/2,5-a/-isoindol-5(9bH)-one 52. 8-chloro-9b-(inden-3-yl)-2r3-dihydrothiazolo/2,3-a7-isoindol-5(9bH)-one 53- 8-me thyl-9b-(isoquinolin-l-y1)-2,3-dihydrothiazolo-/2,3-a7-isoindole-5(9bH)-thione 54. 9-methoxy-9b-(l-naphthyl)-2,3-dihydrothiazolo/2,3-87-isoindol-5(9bH)-one 55. 9b-(c umaron-3-y1)-2,3-dihydro thia zolo-/2,3-^7isoindol-5(9bH)-one 56. 9b-(l-naphthyl)-2,3-dihydrothiazolo-/2,3-a7isoindol-5(9bH)-one 1,1-dioxide -2257. 9b- (1-naphthy 1)-2,3-dihydro thia zolo-/2,3-a7isoindol-5(9bH)-one 1-oxide The following Examples are given for the purpose of illustrating the present invention: Example 1. 9b-(l-Naphthyl)-2,5-dihydrothiazolo-/g,3-a7-isoindol-5(9bH)-pne. 2.76 g (10 mmol) 2-(l-naphthoyl)-benzoic acid were dissolved in 100 ml xylene and, after the addition of l. 54 g (20 mmol) cysteamine, as well as of a catalytic amount of £-toluenesulphonic acid, heated under reflux for 1 hour on a water separator. The solvent was then removed in a vacuum and the residue recrystallised from ethenol. Yield 1.54 g (67ft of theory); m. p. 151-152°C.

The 2-(l-naphthoyX)-benzoic acid used was prepared by the slow dropwise addition of IL-naphthyl magnesium bromide in diethyl ether/toluene at -10°C -to a solution of phthalic anhydride in toluene, then stirring for 2 hours, followed by the addition of a saturated solution of ammonium chloride, extraction with ethyl acetate, shaking out of the ethyl acetate phase with 2N sodium carbonate solution and again exracting the acidified sodium carbonate phase with ethyl acetate. Yield after recrystallisation from ethanol 64ft of theory; m.p. 17Q°C.

The following compounds were prepared analogously to Example 1: -251.1 9b— (2-naphthyl)-2,5-dihydrothiazolo-/?, 5-a7isoindol-5(9bH)-0ne; amorphous; Rf = 0.5 (ethyl acetate/isohexane 1:5 v/v) from 2-(2-naphthoyl)benzoic acid and cysteamine (yield 66% of theory) 1.2 9b-(anthr3cen-9-yl)-2,5-dihydrothiazolo-/2,.5-a7isoindol-5(9t>H)-oney m.p. 198°G, from 2-(9anthracenoyl)-benzoic acid and cysteamine (yield 49% of theory) 1.5 7-chloro-9b-phenyl-2,5-dihydrothiazolo-/5,5-a/— isoindol-5(9bH)-one; m.p. 125°C, from 5-chloro2-benzoylbenzoic acid and cysteamine (yield 61% of theory) 1.4 7-®e thy l-9b-pheny 1-2,5-dihydro thia zolo-^/3,5-^7isoindol-5(9bH)-one; m.p, 98°G, from 5-methyl-2benzoylbenzoic acid and cysteamine (yield 59% of theory) 1.5 6-methyl-9b-pheny 1-2,5-dihydrothiazolo-/2,5-a/isoindol-5(9bH)-one; m.p. 185°C, from 6-methyl2-benzoylhenzoic acid and cysteamine (yield 79% of theory) 1.6 7-me thoxy -9b-pheny 1-2,5-dihydro thia z o lo-/2,5-3/isoindol-5(9^H)-one? R^ « 0.55 (ethyl acetate/ isohexane 1:5 v/v) from 5-methoxy-2-benzoylbenzoic acid and cysteamine (yield 55% of theory) 1.7 7»8-dichloro-9b-phenyl-2,.5-dihydrothiazolo-/5,5-®7 isoindol-5(9bH)-one; m.p. 112-114°C, from 4,5dichloro-2-benzoylbenzoic acid and cysteamine (yield 67% of theory) -241.8 9b-( 2-thieny1)-2,3-dihydrothiazolo-/2,3-a7isoindol-5(9bH)-one; m.p. 151°C after recrystallisation from aqueous ethanol; from 2-(2thienoyl)-benzoic acid and cysteamine (yield 63% of theory) 1.9 9b-(2-furyl)-2,3-dihydrothiazolo-/?,3-a7-iso— indol-5(9bH)-one; m.p. 114°C, after recrystall— isation from etheno1/diethyl ether; from 2-(2furoyl)-benzoic acid and cysteamine (yield 70% of theory) 1.10 9'b-cyclopentyl-2,.3-dihydrothiazolo-/2,3-a7isoindol-5(9bH)-one; oil; R^ = 0.85 (dichlerometh ’.ane/methanol 9=1 v/v); from 2-cyclopentoylbenzoic acid and cysteamine (yield 81% of theory); the purification of this compound took place by column chromatography with ethyl acetate/ isohexane 1»1 v/v 1.11 8-chloro-7-sulphonamido-9b-pheny1-2,3-dihydrothiazolo-/2,3-aZ-isoindol-5-(9'bH)-one; m.p. 245-246°G, from 4-chloro-5-sulphonamido-2benzoylbenzoic acid and cysteamine (yield 54% of theory) 1.12 8-chloro-9b-pheny1-2,3-dihydrothia zol©-/2,3-a7— isoindol-5(9bH)-one; m.p. 113-136°C, from 4chloro-2-benzoylbenzoic acid and cysteamine (yield 68% of theory) -251.13 S-methyl-9b-phenyl-2,3-dihydrothiazolo-/2,3-a.7_ isoindol-5(9bH)-one; m.p. 115-118°C; from 4methyl-2-benzoylbenzoic acid and cysteamine (yield 75ft of theory) 1.14 9b-(4-pyridyl)-2,3-dihydrothiazolo-/5,3-a7isoindol-5(9t»H)-one; m.p. 114°C;. from 2-(4pyridoyl)-benzoic acid and cysteamine (yield 68ft of theory} 1.15 9b-(2-pyridyl)-2,3- 61ft of theory) 1.16 9b-( 3-pyridyl)_2 ,,3-dihy dro thiazolo-/?, 3-3.7isoindol-5(9t>H)—on®» m.p. 149-152°C^ from 2(3-pyridoyl)-benzoic acid and cysteamine (yield 57ft of theory) 1.17 9b-cyclohexyl-2,3-dihydrothiazolo-/2’,3-a.7isoindol-5(9bH)-one; oil; R^ = 0.55 (ethyl acetate/isohexane 1:3 v/v); from 2-cyclohexoylbenzoic acid and cysteamine (yield 79ft of theory) 1.18 91-(2-aminopheny 1)-2,3-one;'m.p. 147-151°G after recrystallisation from isopropanol; from 2-(2aminobenzoyl)-benzoic acid and cysteamine (yield 43ft of theory) -261.19 9t»-(4-aminopheny1)-2,5-dihydrothiazolo-/2,5-a7— · isoindol-5(9bH)-one; m.p. 179-185°Ct after recrystallisation from isopropanol; from 2-(4aminobenzoyl)-benzoic acid and cysteamine (yield 49% of theory) 1.20 9b-(indan-4—y 1)-2,3-dihydrothiazolo-/2,3-a7— isoindol-5(9t»H)-one; m.p. 151-153°O; from 2(indan-4-ylcarbonyl)-benzoic acid and cysteamine (yield 65% of theory) 1.21 9b-(2-nitro-5-methylpheny1)-2,5-dihydrothiazolo/2,5-£7-isoindol-5(9DH)-one; m.p. 161-164°, after recrystallisation from ethyl acetate/ isohexane; from 2-(2-nitro-5-methylbenzoyl)benzoic acid and cysteamine (yield 70% of theory) 1.22 8-me thoxy-9b-pheny1-2,5-dihydro thia z olo-/2,5-a7isoindol—5(9bH)-one; oil; from 4-methoxybenzoylbenzoic acid and cysteamine (yield 56% of theory) 1.25 9b-(5-nitrophenyl)-2,5-dihydrothiazolo-/2r5-a7isoindol-5(9t>H).one; m.p. 91-97°C; from 2-(5nitrobenzoyl)-benzoic acid and cysteamine (yield 55% of theory) 1.24 8-ehloro-9b-(l-naphthyl)-2,5-dihydrothiazolo/2,5-a7-isoindol—5(9bH)-one; m.p. 156-159°C, after recrystallisation from methanol; from 4chloro-2-(l-naphthoyl)-benzoic acid and cysteamine (yield 28% of theory) -271.25 9b-(3-dime thylaminopheny1)-2, 3-d ihydro thiazolo/2,3-a7-isoindol-5(9tfl)-one; m.p. 149-151°0, after recrystallisation from methanol; from 2(3-dimethylaminobenzoyl)-benzoic acid and cysteamine (yield 27# of theory) 1.26 9b-(9-phenanthrenyl)-2r3-dihydrothiazolo-/2,3-a7 isoindol-5(9bH)-one; m.,p. 17O-172°Cr after recrystallisation from ethyl ecetate/isohexane; from 2-(9-phenanthrenoyl)-benzoic acid and cysteamine (yield 64# of theory) 1.27 9b-(3-amino-4-chlorophenyl)-2„3-dihydrothiazolo—/?,3-s/-isoindol-5(9bH)-one; m.p. 180°C,, after recrystallisation from isopropanol; from 2-(3-amino-4-chlorobenzoyl)-benzoic acid and cysteamine (yield 41# of theory) 1.28 9b-(5-fluoro-l-naphthyl)-2r3-dihydrothiazolo— /2,3-a7-isoindol-5(9bH)-one; m.p. 157°0; from 2-(5-fluoro-l-naphthoyl)-benzoic acid and cysteamine (yield 85# of theory) 1.29 8-chloro-9b-(3-chlorophenyl)-2,3-dihydrothiazolo-/2,3-a>7-isoindol-5(9bH)-one; m.p. 162°C; from 4-chloro-2-(3-chlorobenzoyl)-benzoic acid and cysteamine (yield 75# of theory) 1.30 6-methoxy-9b-pheny1-2,3-dihydrothiazolo-/?,5-a7isoindol-5(9bH)-one; m.p. 187°θ, after recrystallisation from isopropanol; from 6-methoxy-2benzoylbenzoic acid and cysteamine (yield 42# of theory) -281.31 8-chloro-9b-(3-methylpheny1)-2,3-dihydrothiazolo-/2,3-.a7-isoindol-5(9bH)-one; m.p. 129-132°C, after recrystallisation from diethyl ether; from 4-chloro-2-(3-niethylbenzoyl)-benzoic acid and cysteamine (yield 24% of theory) 1.32 7-cbloro-9b-(3-methylpheny1)-2,3-dihydrothiazolo-/2,3-e7-is°indol-5(9bH)-one; m.p. 76-80°G, after recrystallisation from diethyl ether;· from 5-Qhloro-2-(3-methylbenzoyl)-benzoic acid and cysteamine (yield 27% of theory) 1.33 9b-(4-methylpyridin-2-yl)_2,3-dihydrothiazolo/2,3-a7-isoindol-5(9bH)-qne; oil; from 2-/2-(4methylpyridoyl27-benzbic acid and cysteamine (yield 53% of theory) 1.34 9b-(2-thionaphthenyl)-2,3-dihydrothiazolo/2,3-.a7-isoindol-5(9bH)-one; m.p. 13O-133°C; from 2-(2-thionaphthenoyl)-benzoic acid and cysteamine (yield 62% of theory) 1.35 9b-(3-tbionaphtheny 1)-2,3-d.ihydrothiazolo/?,3-a7-is°indol-5(9bH)-one; m.p. 2O6-217°C; from 2-(3-thionaphthenoyl)’-benzoic acid and cysteamine (yield 5Q% of theory) 1.36 9b-(indol-3-yl)-2,3-dihydrothiazol®-/?, 3-^7isoindol-5(9bE)-one; m.p. 272-275°θ, efter recrystallisation from methanol; from 2-(indol3-ylcarbonyl)-benzoic acid and cysteamine (yield 42% of theory) The compounds were, in each case, recrystallised from ethanol insofar as nothing otherwise is stated. -29Example 2,. 9b-Phenyi-2.3-dihydrothiazolo-/2,5-a7-isoindole5(9hH)-thione. g (7.5 mmol) 9b-pheny1-2,3-dihydrothiazolo/2,3-a7-isoindol-5(9bH)-0ne (J. Org. Chem., 34, 165/1969) in 100 ml anhydrous dioxane were mixed with 3.8 g (9.4 mmol) Lawesson's reagent (2,4-bis(4-methoxyphenyl)—l,3-dithia-2,4-diphosphetaneE' 2,4-disulphide) and stirred for 5 hours at 60°C (TLC control). After cooling, the precipitate is filtered off, the filtrate is evaporated in a vacuum and the residue is purified hy flash column chromatography with heptane/methyl ethyl ketone (6:1 v/v) as eluent. Tield 1.24 g (58$o of theory); m.p. 152-155°C.

The following compound was prepared analogously: 2.1 9h-(1-naphthy1)-2,3-dihydro thia zolo-/2,3-aZisoindole-5(9hH) ..thione was prepared from the corresponding oxo compound (see Example 1). Tield 71» of theory; m.p. ° C. Example 3.

Enantiomer separation of rac-9b-(l-naphthyl)-2.3dihydrothiazolo-/2.3-aZ’-igoindole-5(9bH)-one on cellulose triacetate.

For the separation of the antipodes, 200 mg of the racemate were dissolved in 15 ml methanol, applied to a column of 5θ mm inner diameter and 300 mm length (corresponding to 250 g cellulose -30triacetate, 15-25 /x grain size, Merck 16326) and eluted with methanol (flow 7.5 ml/min, about 1.5 bar).

Peak I peak II UV detection /nm7 run time /ΉΙη7 m.p. 254 110 -4540¼ 5 175-176°C 254 255 454 + 5 175-176°C absolute configuration k ' ' The enantiomers were recrystallised from methanol. +- enantiomer purity according to HPLC in each case > 99.-6½ ee The following compounds were prepared analogously to Example 3: 3.1 ( —) -8-chloro-9b-phenyl-2 , 3-dihy dro thia zolcrZ^,3-£7-isoindole-5(9bH)-one m.p. 87-93°C 3.2 (+)-8-chloro-9b-phenyl-2,3-dihydrothiazoloj/2,3-®7-isoindol—5(9bH.)-one m.p. 97-93°C,- with ethanol as eluent 3.3 (-)-8-chloro-9b-<3-chlorophenyl)-2,3-dihydrothiazolo-/2,3-a7-iaoindol-5(9bH)-one m.p. 138°C, recrystallised from ethanol; otjj = -236°C/c - l/CHClj 3.4 (+)-8-chloro-9b-( 3-cbloropheny1)-2,.3-dihydrothiazolo-/2,3-a7"isoindol-5(9bH)-one m.p. 138°C, recrystallised from ethanol; = +236°C/c, with methanol as eluent. -31Example 4. 9b-(4-A7,idop1ien.yl-)..2.5- 2.1 g (7.-4 mmol) 9b-(4-aminophenyl)-2,3-dihydrothiazolo-/2,3-a,7-isoindol-5(9bH)-one were suspended in L2 ml. 2N hydrochloric acid, mixed at 0 - 5°C within the course of 15 minutes with a solution of 0.55 g (8 mmol) sodium nitrite in 3 ml water and stirred for 3θ minutes at 0°C. A solution of 0.6 g (9.2 mmol) sodium azide in 8 ml water was then added dropwise thereto in the course of 10 minutes, followed by stirring for 30 minutes. The resultant precipitate was then filtered off with suction. The crude product was purified by column chromatography on silica gel 60 with diethyl ether/isohexane (1:2 v/v) as eluent. Yield 1.62 g (71% of theory); m.p. > 140°C (decomp.). 4.1 9b-(3-azidophenyl)-2,3-dihydrothiazolo-/2,3-a7isoindol-5(9bH)-one was prepared analogously to Example 4 from 9b(3-aminopheny1)-2,3-dihydro thia zolo-/2,3-aZisoindol-5(9bH)-one in a yield of 86% of theory; m.p. 100-101°C, after recrystallisation from diethyl ether.

Example 5, 9b-(3-Aminnnheny1)-2,3-dihydrothiazolo-/?, 3-a7isoindol-5(9bS)-one. 11.2 g (35.7 mmol) 9b-<5-nitrophenyl)-2,3dihydrothiazolo-/S\3-a7-isoindole-5(9bH)-one in -3290 ml ethanol was mixed at the boiling point with 23 g sodium hydrosulphite in 90 ml water within the course of 5 minutes and then heated under reflux for 1 hour. The ethanol was then evaporated off in a vacuum, the aqueous phase was extracted several times with dichloromethane and the organic phase was dried over anhydrous sodium sulphate.

After removal of the solvent on a rotary evaporator, the residue was recrystallised from dichloromethane. Yield 6..02 g (60# of theory); m.p. 184—186°C. .1 9b-(2-amino-5-methylphenyl)-2,3-dihydrothia z olo-/2,3-3,7-iso indol-5(9hH ) -one was prepared analogously to Example 5 from 9b(2-nitro-5-methylphenyl)-2,3-dihydrothiazolo— /2,3-a7-isoindol-5(9bH)-one in a yield of 55ft of theory; m.p. 153-156°θ, after recrystall— isation from dichloromethane.

Example 6.. 9b—Phen;? 1-2.5-dihydrothiazolo-/2\ 5-aZ-isoindol5(9bH)-one-3-carboxylic acid methyl ester. 1.7 g (9.9 mmol) L-cysteine methyl ester hydrochloride and 1.35 5 sodium acetate were introduced portionwise at 100°C over a period of time of 10 hours into a solution of 1 g (4.4 mmol) 2-benzoylbenzoic acid in W ml xylene. After a further 3 hours at 100°G, the xylene was distilled off, the residue was taken up in dichloromethane and washed -33with a solution of sodium hydrogen carbonate, as well as with water. The ester was isolated by removal of the solvent and used without further purification in the next reaction; /"a= -57°C/c = 1/MeOH). Exam£leJ^ 9b-Phenyl-2,3-dihydco thiazolo-/?,5-a7-*isoindol5-(9bH)—one-5-carboxyiic acid.

The crude product from the last reaction was dissolved in 5 ml. ethanol, mixed with 2 ml 2N sodium hydroxide solution and stirred for 2 hours at 40°G. The ethanol was then distilled off, the aqueous phase was acidified with 6N hydrochloric acid and the free acid was filtered off with suction. Yield 0.6 g (44# of theory, referred to the 2benzoylbenzoic acid used); m. p. 96-98°G, after recrystallisation from ethanol; /"o_7q = -211°/c = 0.89/Me0H.

Example 8. 9b-Phenyl-2 ,.3-dihydro thiazolo-/?, 3-a7-igoindole5(qbH)-one-5-carboxylic acid morpholide. 311 mg (1 mmol) 9b-pheny1-2,3-dihydrothiazolo/2,3-a7-isoind°l-5(9kH)-one-3-carboxylic acid (see Example 7) in Ιθ ml anhydrous dichloromethane were mixed at -15°C with 101 mg (1 mmol) 4-methylmarpholine and subsequently with 155 mg (1.1 mmol) isobutyl chloroformate and stirred for 15 minutes. mg (1.1 mmol) morpholine were then added thereto, the reaction mixture was wanned to room temperature -J4and then stirred for 4 hours at room temperature.

After the addition of a further 20 ml dichloromethane, the solution was shaken out with a solution of sodium hydrogen carbonate and with water, dried over anhydrous sodium sulphate and freed from solvent.

The residue was purified hy chromatography on silica gel with ethyl acetate as eluent, field 158 mg (519b of theory); m..p. 138—141°C. 8.1 9b-phenyl-2,3-dihydrothiazolo-/2,3-aZ-isoindol5(9hH)-one-3-carhoxylic acid amide was prepared analogously to Example 8 in a yield of 57$ of theory;· m.p. 164°G< after recrystallisation from ethyl acetate. 8.2 9h-pheny1-2,3-dihydrothiezolo-/?,-3-aZ-isoindole5(9bH)-one-3-carboxylic acid methylamide was prepared analogously to Example 8 in a yield of 41$ of theory; m.p. 160-162°Cr after recrystallisation from ethyl acetate 8.3 9b-pheny 1-2,3-dihydrothiazolo-/2,3-.a7-isoindol5(9bH)-one-3-carhoxylic acid dimethylamide was prepared analogously to Example 8 in a yield of 59$ of theory; m.p. 178°C, after recrystallisation from ethyl acetate 8.4 9b-phenyl-2,3-dihydrothiazolo-/?,3-aZ-isoindol5(9bH)-one-3-carboxylic acid propyl ester was prepared analogously to Example 8 hy reaction of the active ester with η-propanol in a yield of 27$ of theory; m.p. 103-106°C. -358. 5 9b-phenyl-2,3-dihydrothiazolo-/2,3-a.7-isoindol5(9bH)-one-3-carboxylic acid isopropyl ester was prepared analogously to Example 8 by reaction of the active ester with propan-2-ol in a yield of 51% of theory; m.p. 88-9θ°0 8.6 9b-pheny1—2,3-dihydrothiazolo-/2,3-^7-isoindol5(9bH)-one-3-carboxylic acid methoxyethyl ester was prepared analogously to Example 8 by reaction of the active ester with 2-methoxyethanol in a yield of 303» of theory; oil 8.7 9b-phenyl-2i3-dihydrothiazolo-/2,3-a7"isoindol·5(9bH)-one-3-carboxylic acid isobutyl ester was prepared analogously to Example 8 by reaction of the active ester with 2-methylpropan—l-ol in a yield of 42% of theory; oil 8.8 9b-phenyl-2,3-dihydrothiazolo-/2,3-a.7-isoindol5(9bH)-one-3-carboxylic acid 2-pyridylmethyl ester was prepared analogously to Example 8 by reaction of the active ester with 2-(hydroxymethyl)-pyridine in a yield of 42% of theory 8.9 9b-pheny1—2,3-dihydrothiazolo-/2,3-£7-isoindol5(9bH)-one-3-carboxylic acid 3-pyridyImethyl ester was prepared analogously to Example 8 by reaction of the active ester with 3-(hydroxymethyl)pyridine in a yield of 60% of theory; m.p. 119—121°C -568.10 9b-pheny1-2,3-dihydrothiazolo-/2,3-aZ-isoindol5(9bH)-one-3-®arboxylic acid 4-pyridylmethyl ester· was prepared analogously to Example 8 by reaction of the active ester with 4-(hydroxymethyl·)pyridine in a yield of 37% of theory; m.p. 125-128°C.

Example 9.

Inhibition of reverse transcriptase (RT) by derivatives of 9b-phenyl—2,3-dihydrothiazolo-/?,5-a7isoindol·-5(9bH)-nne;..

The screening test system contains the purified RT from HIV-1, which was expressed by gene-technological methods in Escherichia coli, as well as the components of the initiation complex, such as the in vitro transcripts of the HIV-LTR's with the neighbouring primer binding site as template and an 18mer oligonucleotide complementary to the primer hind site as primer. The /"^HZ-thymidine5'-triphosphate incorporation was measured by counting in a β-counter·. In the following Table, there are given the IC^q values for the compounds investigated. These values correspond to those concentrations of the test compounds which bring about an inhibition of the reverse transcriptase activity of 50%. As comparative compound, the value for AZT was determined in a corresponding manner -37Results: compound tested inhibition of the HIV-RT IC5Q _7 3'-azido-3-'-desoxythymidine5'-triphosphate 6.0 x IO"6 9b-phenyl-2,3-dihydrothia zolo-/2,3-a7-isoindole5(9bH)-thione 3.5 x 10"6 7,8-dichloro-9b-pheny1-2,3- dihydrothiazolo-/2,3-a.7- isoindol-5(9bH)-one 4.5 x 106 9b-(2-thieny1)-2,3-dihydro- thiazolo-/2,3-e7-isoindol- 5(9bH)-one 2.7 x 10-6 9b-(2-furyl)-2,3-dihydro- thiazolo-/2,3-£7-isoindol- 5(9bH)-one 1.4 x IO"6

Claims (14)

1. Patent Claims

1. The use of thiazolo—/2,3-a7-isoindole derivatives of the general formulat- for the preparation of pharmaceutical compositions with anti-viral action, wherein X is an oxygen or sulphur atom, an imino group =NH or an N-C^-C^alkylimino radical, n is 0, 1 or 2, R is q hydrogen atom, a straight-chained or branched, saturated or unsaturated aliphatic radical containing up to 9 carbon atoms, which can be substituted by phenyl, or a C^-Cg-alkoxy-C^-Cg-alkyl or C^-Cg-alkylmercapto-C^-Cg-alkyl radical or is a phenyl ring which is optionally substituted one or more times by C^-Οθ—alkyl,. -alkoxy, C^-C^-alkylmercapto, C^-Cg-alkylsulphinyl, C^-Gg-alkylsulphonyl, G 2” G 6“ alkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyloxy, Ο 2 -ΰθalkenylmercapto, C 2 -Cg-alkynyloxy, C 2 -Cg-alkynylmercapto, amino, C^-Cθ-alkylamino, di-C^-Cgalkylamino, C^-Cg-alkylcarbonylamino, C 1 -Cg-alkylaminocarbonyl, C^-Cg-slkoxycarbonyl, aminocarbonyl, hydroxyl, benzyloxy, phenylmercspto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, -59formylamino, carboxyl or phenyl or is a mono-, bior tricyclic carbocyclic ring containing 7 to 15 carbon atoms or a heterocyclic mono-, bi- or tricyclic ring system with, in each case* 5 or 6 ring atoms and, per ring system, can contain 1 to 4 or 1 to 5 heteroatoms, respectively, whereby the heteroatoms are nitrogen, sulphur or oxygen, and these rings can be substituted by G^-Gg-alkyl* G^-Cg-alkoxy, nitro, amino or halogen, R^ is a hydrogen atom, a straight-chained or branched* saturated or unsaturated aliphatic radical containing up to 6 carbon atoms or G^-Cg-alkoxy* G^-Cg-alkylmercapto, G^-Gg-aIky1sulphinyl, C^-Gg-alkylsulphonyl, amino* C^-Cg-aIkylamino, di-G^-Cg-aIkylamino* sulphonamido* C^-Cg-alkoxycarbonyl, carboxyl, halogen, hydroxyl* nitro, cyano* azido* phenyl or benzyloxy, 2. 1 R has the same meaning as R , whereby the radicals 1 2 R and R , independently of one another, can be the same or different, R^ is a hydrogen atom, C^-Cgalkyl* G^-Gg-alkoxy, G^-Cg-alkylmercapto* amino, C^-Cg-alky lamino,, di-G^-Gg-aIkylamino, aminocarbonyl, Ci-Gg-alkylaminocarbonyl, di-C^-Cg-alkylaminocarbonyl, morpholinocarbonyl, halogen, cyano, hydroxyl, carboxyl* C^-Cg-alkoxycarbony1, aryloxycarbonyl, hetaryloxycarbonyl* ary 1-C^-Cg-alkoxycarbonyl, he ta ry1-C ^-Gg-alkoxyca rbony1, C ^-C g-alkoxy ~ σ χ“ σ θalkoxycarbonyl or hydroxy-C^-C^-elkoxycarbonyl, whereby the aryl and hetaryl radicals can, in each -40case, be substituted by C^-Cg-alkyl, C^-Cg-aIkoxy 4 5 6 or halogen and R , R and R have the same meaning 5 5 4 5 6 as R , whereby the radicals R , R , Rz and R , independently of one another, can be the same or different, as well as the tautomers, enantiomers, diastereomers and physiologically acceptable salts 12 5 4 thereof, with the proviso that, when R , R , R , R , C (Z R · and R are hydrogen atoms, n is 0 or 1 and X is an oxygen atom, the radical R cannot be a hydrogen atom, an aliphatic radical containing up to 7 carbon atoms, which can be substituted by phenyl, or phenyl alkyl, C^-C^-alkoxy, hydroxyl, trifluoromethyl, methylsulphonyl or halogen.

2. The use according to claim 1, wherein R is a carbocyclic ring containing 7 to 15 carbon atoms selected from naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, indenyl, acenaphthylenyl, norbornyl, adamantyl,. G^-G^-cycloalkyl and C^-Ggcycloalkenyl.

3. The use according to claim 1,. wherein R is a heterocyclic mono-, hi- or tricyclic 1-, 2- or 3ring system with, in each case, 5 or 6 ring atoms and, per ring system, can contain 1 to 4 or 1 to 5 heteroatoms, respectively, whereby the heterostoms are nitrogen, sulphur or oxygen, selected from pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, -41oxazole, isoxazole, oxadiazole, furazane, furan, thiophene, indole, quinoline, isoquinoline, cuinarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or a purine system, whereby the unsaturated or aromatic heterocycles can be partly or completely hydrogenated.

4. The use according to any of the preceding claims, wherein R^ is a hydrogen atom or C^-Cg-alkyl, Ο^-Οθalkocxy, sulphonamide, amino, hydroxyl or halogen and p R is a hydrogen or halogen atom.

5.. The use according to any of the preceding claims, wherein R y and R are hydrogen atoms.

6. The use according to any of the preceding claims, wherein R^ is a hydrogen atom or G^-C^-alkyl, carboxyl, C^-Cg-alkoxycarbonyl, morpholinocarbonyl, aminocarbonyl, CIkyla minoca rbony 1, di-C^-C^-aIkylaminoc a rbony1, Cj-Cg-alkoxy-Cj-Cg-alkoxycarbony1, pyridyl-C^-Οθalkoxycarbonyl or halogen and R is a hydrogen atom.

7. The use according to claim 1, substantially as hereinbeforedescribed and exemplified.

8. Thiazolo-/2,3“£7-i9oindole derivatives of the general formula:IE 920334 wherein Ϊ is 3 sulphur or oxygen.atom, an imino group =NH or an N-X3^-C^-8lkylimino radical, n is Ο, 1 or 2, S is a heterocyclic mono-, bi- or tricyclic ring system with, in each case, 5 or 6 ring atoms and, per ring system, can contain 1 to 4 or 1 to 5 heteroatoms, respectively, whereby the heteroatoms are nitrogen, sulphur or oxygen, and these rings can he substituted by G^-C^-alkyl, C^-Cg-alkoxy, nitro, amino or halogen, R 1 is a hydrogen atom, a straight-chained or braaiched, saturated or unsaturated aliphatic radical containing up to 6 carbon atoms or C^-C^-alkoxy, C^-Cg-alkylmercapto,. C^-C^-alkylsulphinyl, alkylsulphonyl, amino, C^-Cg-aIkylamino, di-C^-C^alkylamino, sulphonamido, G 1 -Οθ-alkoxycarbonyl, carboxyl, halogen, hydroxyl, nitro, cyano, azido, 2 1 phenyl or benzyloxy, R has the same meaning as R , 1 2 whereby the radicals R and R , independently of z one another, can be the same or different, R is a hydrogen atom, C^-Οθ-alkyl, C^-Cg-alkoxy, C^-Οθalkylmercapto, amino, G^-C^-aIkylamino, di-C^-C^alkylamino, aminocarbonyl, C^-C^—alkylaminocarbonyl, -43di-G^-Cg-alkylaminocarbonyl, morpholinocarbonyl, halogen, cyano, hydroxyl, cerboxyl, C-L-Cg-alkoxycarbonyl, aryloxycarbonyl, hetaryloxycarbonyl, a ry1-C lkoxyc a rbony1, he ta ryl-C^-C^-alkoxycarbonyl, G^-Cg-alkoxy-C^-C^-alkoxycarbonyl or hydroxy-C-^-Cg-alkoxycarbonyl, whereby the aryl and hetaryl radicals can each be substituted by C-^-Cg-alkyl, C^-C^-alkoxy or halogen, R^, R^ and 6 3 R have the same meaning as R , whereby the radicals 3 4 5 6 R , R , R and R , independently of one another, can be the same or different, as well as the tautomers, enantiomers, diasteromers and physiologically acceptable salts thereof.

9. Thiazolo—/2,3-eT-isoindole derivatives according to claim 8, wherein R is a thienyl, furyl, pyridyl, thionaphthenyl or indolyl radical optionally substituted by C^-Cg-alkyl or halogen.

10. Thiazolo-/2,3-a/—isoindole derivatives according to claim 8 which are hereinbefore specifically exemplified.

11. Process for the preparation of thiazolo-Z2,3-a7— isoindole derivatives according to any of claims 8 to 10, wherein an optionally substituted benzoic acid derivative of the general formula:IE 920334 (II) 1 2 in which R, R and R have the same meaning as in claim 8 and A is a carboxyl or cyano group, is reached with an unsubstituted or substituted cysteamine of the general formula:- (III) in which R^, r\ R^ and Εθ have the same meanings as in claim 8, in an appropriate inert solvent at a temperature from room temperature to reflux temperature, optionally in the presence of a catalytic amount of an acid, a compound of general formula I is isolated and optionally a compound of general formula I is converted into anahher compound of general formula I and the racemate obtained is optionally separated into the optically active forms.

12. Process for the preparation of thiazolo-/2,3-a7 isoindole derivatives according to any of claims 8 to 10, substantially as hereinbefore described and exemplified.

13. Thiazolo-/?,3-8,7-isomndole derivatives according to any of claims 8 to 10, whenever prepared by the process according to claim 11 or 12.

14. Pharmaceutical compositions containing at least one compound of general formula I according to any of claims 8 to 10.