EP0682523A1

EP0682523A1 - Use of tricyclic isoindolinones as antiviral drugs, and new, optically active isoindolinones

Info

Publication number: EP0682523A1
Application number: EP92904953A
Authority: EP
Inventors: Harald Zilch; Thomas Poll; Wolfgang Schäfer; Bernhard König; Ulrike Leser
Original assignee: Roche Diagnostics GmbH; Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1991-02-28
Filing date: 1992-02-22
Publication date: 1995-11-22
Also published as: AU1251192A; WO1992015310A1; JPH06505017A; CA2104963A1

Abstract

The invention concerns the use of tricyclic isoindole derivatives of general formula (I) to manufacture antiviral drugs. In formula (I), X stands for an oxygen or a sulphur atom, the imino group =NH or an N-C1-C5 alkylimino group, Y stands for an oxygen or a sulphur atom, or an NH-, C1-C5 alkylamino group, C1-C5-alkylocarbonylamino, sulphinyl or sulphonyl group, R stands for a hydrogen atom, an aliphatic residue with 1-9 carbon atoms, optionally substituted with phenyl, a phenyl ring, a carbocyclic ring with 7-15 carbon atoms or a heterocyclic ring system in which each ring has 5 or 6 atoms, R?1 and R2¿ stand for a hydrogen atom, an aliphatic residue with 1-6 carbon atoms or C¿1?-C6 alkoxy, C1-C6 alkymercapto, C1-C6 alkylsulphinyl, C1-C6 alkylsulphonyl, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, sulphonamido, C1-C6 alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy, R?3 and R4¿ stand for hydrogen, C¿1?-C6 alkyl, C1-C6 alkoxy, C1-C6 alkymercapto, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, halogen, cyano, hydroxy, carboxy or C1-C6 alkoxycarbonyl. The invention also concerns the physiologically acceptable salts and the optically active derivatives of the compounds of the formula (I).

Description

Use of tricyclic isoindolinones as antiviral drugs, as well as new optically active isoindolinones

The present invention relates to the use of tricyclic isoindole derivatives as antiviral drugs and new optically active isoindolinones.

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

for the production of medicaments with antiviral or anti-retroviral activity, wherein in formula I

X is an oxygen or sulfur atom, which can be imino group = NH or an NC ₁ -C ₅ alkylimino group,

Y can be an oxygen or sulfur atom or the NH, C ₁ -C ₅ alkylamino, C ₁ -C ₅ alkylcarbonylamino, sulfinyl or sulfonyl group,

R is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-9 C atoms, which is substituted by phenyl can be, or a C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl or C ₁ - C ₆ alkylmercapto-C ₁ -C ₆ alkyl radical, or a phenyl ring which may be one or more times is substituted by C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylmercapto, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkenyloxy, C ₂ -C ₆ alkenylmercapto, C ₂ -C ₆ alkynyloxy, C ₂ - C ₆ alkynylmercapto, amino, C ₁ -C ₆ alkylamino , Di-C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonylamino, C ₁ -C ₆ alkylaminocarbonyl, aminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano , Halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl, or a mono-, bi- or tricyclic carbocyclic ring with a total of 7-15 carbon atoms or a heterocyclic mono-, bi- or tricyclic ring system, where 5 or 6 each Ring atoms are present per ring system and in the case of heterocyc len contain 1-4 or 1-5 heteroatoms and the heteroatoms can be nitrogen, sulfur or oxygen,

R ^{1 is} a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C atoms or C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylmercapto, C ₁ -C ₆ alkylsulfinyl, C ₁ - C ₆ alkylsulfonyl, amino, C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, sulfonamido, C ₁ -C ₆ alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy means

R ^{2 has} the same meaning as R ¹ , where the radicals R ¹ and R ^{2 can,} independently of one another, be the same or different,

R ^{3 is} hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylmercapto, amino, C ₁ -C ₆ -alkylamino, di-C ₁ -C ₆ -alkylamino, Is halogen, cyano, hydroxy, carboxy or C ₁ -C ₆ -alkoxycarbonyl,

R ^{4 has} the same meaning as R ³ , the radicals

R ³ and R ^{4 can} independently be the same or different, as well as their tautomers, enantiomers, diastereomers and physiologically tolerable salts.

Compounds of the formula I in which Y is a sulfur atom and X is an oxygen atom are known from BE-A-659,528 (cf. also US Pat. No. 3,646,022) and have an anti-inflammatory, anticonvulsive and analgesic effect.

Isoindolinone derivatives of the formula I in which Y is the NH group are described in the patents GB-1,059,175 (Chem. Abstr. 72, 121 531 u) and DE-A-1,445,443; Neth. Appl. 6,613,264 (Chem. Abstr. 67, 82 204 g) or US 3,590,043 with anti-inflammatory, analgesic, hypotensive, spasmolytic and antitussive activity, as well as in the publications An. 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 instructions.

Compounds of the formula I in which Y represents an oxygen atom are described, inter alia, in J. Heterocycl. Chem. 2j5, 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 3,336,306, such derivatives are attributed an anticonvulsive effect. Compounds with a similar structure and spectrum of activity as compounds of formula I are known from the earlier German patent application P 40 35 809.7. The compounds described there are tricyclic isoindolinone derivatives in which the ring fused in the 2,3-position of the isoindolinone ring is a thiazole ring (thiazolo [2,3-a] isoindolinone derivatives). The corresponding optically active forms are described in the earlier German application P 40 37 674.5.

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 simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or

Epstein-Barr virus or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, and the lentiviruses Visna and human immunodeficiency virus HIV-1 and -2, are caused.

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.

The compounds of general formula I according to the invention have a pronounced antiviral effect and are particularly suitable for the treatment of viral or retro-viral infections. Viral infections in mammals, especially humans, are common. Despite intensive efforts, it has so far not been possible to provide chemotherapeutic agents which interfere causally or symptomatically with the viral or retroviral-related disease process with recognizable substantial success. It is not possible today to diagnose certain viral diseases, such as that Acquired Immune Deficiency Syndrome (AIDS), the AIDS-related complex (ARC) and its preliminary stages, to cure herpes, cytomegalovirus (CMV), influenza and other viral infections or to chemically influence their symptoms favorably. Currently, for example, the treatment of AIDS is almost exclusively 3'-azido-3'-deoxy-thymidine

(AZT), known as Zidovudine ^R or Retrovir ^R , are available. However, AZT is characterized by a very narrow therapeutic range or by very severe toxicities already occurring in the therapeutic field (Hirsch, MS (1988) J. Infec. Dis. 157, 427-431). The compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being in pharmacologically relevant doses

to be cytotoxic.

It has now been demonstrated that compounds of the 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 by inhibiting the enzyme reverse transcriptase (cf. Proc. Natl. Acad. Sci. USA .83., 1911, 1986 or 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 mentioned could advantageously be used prophylactically or therapeutically in the treatment of diseases in which a retroviral Infection is of pathophysiological, symptomatic or clinical relevance.

The present invention relates in particular to those compounds of the formula I in which Y denotes a sulfur atom or the groups -SO- or -SO ₂ -. It has been shows that these compounds show particularly good antiviral or anti-retroviral activity.

Compounds of the formula I have hitherto been known only as racemates. The optically active forms, in particular the R enantiomers, have a higher pharmacological activity than the racemates and are also an object of the present invention.

The racemates can be separated into the enantiomers

analytical, semi-preparative and preparative chromatographic on suitable optically active phases with common eluents. Suitable optically active phases are, for example, optically active polyacrylamides or polymethacrylamides, in some cases. also on silica gel (e.g. ChiraSpher (R) from Merck, Chiralpak (R) OT / OP from Baker), cellulose esters / carbamates (e.g. Chiracel (R) OB / OY from Baker / Daicel), phases based on cyclodextrin or crown ether (e.g. Crownpak (R) from Daicel) or microcrystalline cellulose triacetate

(Merck).

In the definition of R, R ¹ and R ² , an aliphatic radical means a straight-chain or branched alkyl, alkenyl or alkynyl radical with 1-9 or 2-9, preferably 2-7 carbon atoms, such as, for example, propyl, isopropyl or butyl -,

Isobutyl, pentyl, hexyl or heptyl. Suitable unsaturated radicals are C ₂ -C ₇ alkenyl and alkynyl radicals, preferably C ₂ -C ₅ , such as, for example, the allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propinyl radical.

In the definition of R is an aliphatic radical which can be substituted by phenyl, in particular a phenyl-C ₁ -C ₆ -alkyl group, such as, for example, the benzyl, phenethyl, phenylpropyl or phenylbutyl radical. If R is a phenyl ring, this can be mono-, di- or trisubstituted. The substituents can be in the o, m or p position independently of one another. Doubly substituted phenyl rings are preferably the 2,4- and 3,5-substituted derivatives.

A carbocyclic ring with 7-15 C atoms can be mono-, bi- or tricyclic and have 5 or 6 C atoms per ring. This ring can be saturated, unsaturated, partially saturated or aromatic. The following ring systems may be mentioned as examples: the naphthyl, anthracenyl,

Phenanthrenyl, fluorenyl, indenyl, indanyl, acenaphthylenyl, norbornyl, adamantyl ring or a C ₃ -C ₇ cycloalkyl or C ₅ -C ₆ 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. The following ring systems may be mentioned by way of example: 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, where the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated.

R preferably denotes unsubstituted phenyl or phenyl mono- or disubstituted by C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylmercapto, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ -Alkyl-sulfonyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -alkenyloxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -dialkylamino-, C ₁ -C _6- alkylcarbonylamino, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl-, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen. The abovementioned “alkyl” parts preferably contain up to 4, in particular up to 3, carbon atoms in the respective definitions.

Carbocyclic rings are preferably phenyl, biphenyl,

Naphthyl, anthracenyl, indenyl, indanyl, fluorenyl, acenaphthylenyl, phenanthrenyl, norbornyl, adamantyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₈ cycloalkenyl, especially phenyl, naphthyl and indanyl.

Heterocyclic ring systems are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole and pyrid, acridyl and phenothiaziazine .

For the radicals R ¹ and R ² are hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylmercapto , C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkoxycarbonyl, amino, halogen,

Hydroxy, cyano and azido are preferred, the “alkyl” parts in the definitions given above preferably containing up to 4, in particular up to 3, carbon atoms.

Preferred substituents for R ³ and R ⁴ are hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl mercapto, carboxy, C ₁ -C ₆ alkoxycarbonyl, halogen, cyano and hydroxy , the

"Alkyl" parts in the definitions given above preferably contain up to 4, in particular up to 3, carbon atoms. «

X and Y are preferably oxygen or sulfur. Halogen generally means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

Particularly preferred radicals for R are C ₃ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₄ alkynyl, benzyl, phenethyl, phenyl, by C ₁ -C ₆ alkyl, C ₁ -C ₆ -Alkoxy, C ₁ -C ₆ -Alkylmercapto, allyl, allyloxy, C ₁ -C ₆ -alkylamino, di-C ₁ -C ₆ -alkylamino, amino, hydroxy, azido, trifluoromethyl, cyano or halogen mono- or disubstituted phenyl or phenyl, naphthyl, anthracenyl, indenyl, indanyl-, acenaphthylenyl, phenanthrenyl, adamantyl, cyclohexyl, cyclohexenyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, indolyl, quinolinyl, methylimidazolylazylylazolylazolylazolylazolylazolylphenylphenylphenylphenyl, phenol, by methyl or halogen .

For R ¹ and R ² , independently of one another, hydrogen, methyl, ethyl, isopropyl, allyl, methoxy,

Ethoxy, methylmercapto, ethylmercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, nitro, azido, cyano, hydroxy and halogen, chlorine and bromine being very particularly preferred for halogen.

For R ³ and R ⁴ , methyl, ethyl, isopropyl, methoxy, ethoxy, methyl mercapto, ethyl mercapto, methylamino, amino, chlorine, bromine and cyano are particularly preferred.

Particularly preferred are compounds of the general formula I in which R, R ¹ , X have the meaning given above and R ² , R ³ and R ⁴ are hydrogen, methyl, ethyl, chlorine, bromine, methoxy or ethoxy, where R ² to R ⁴ particularly preferably hydrogen and R ^{1 is} hydrogen or

Represent halogen.

The following meanings of the radicals X, Y, R and R ¹ -R ⁴ are, independently of one another, particularly suitable for the purposes of the invention: X is an oxygen atom; Y is a sulfur or

Oxygen atom; R is a C ₁ -C ₆ alkyl, naphthyl, indanyl, Pyridyl, thienyl or phenyl group, where the phenyl group can be mono- or disubstituted by C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen; R ^{1 is} a hydrogen or halogen atom; R ² -R ^{4 is} a hydrogen 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. Here, the usual forms of application come into question, such as tablets, capsules, coated tablets,

Syrups, solutions or suspensions. Water is preferably used as the injection medium

Injection solutions contains common additives such as stabilizers, solubilizers and buffers. such

Additions are e.g. Tartrate and citrate buffers, ethanol,

Complexing agents, such as ethylenediaminetetraacetic acid and its non-toxic salts, high-molecular polymers, such as liquid polyethylene oxide for viscosity regulation. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids, such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers, such as polyethylene glycols, etc. For Preparations suitable for oral applications can, if desired, contain flavoring or sweetening agents. To manufacture the ready-to-use packaging units, the appropriate dosage forms, such as. B. capsules,

Tablets, dragees, in the appropriate number

assembled and packaged into appropriate units, the packaging units thus produced with the

Information for use as an antiviral or anti-retroviral agent can be provided, for example in the form of the prescribed package insert. To produce physiologically compatible salts, compounds of the formula I which carry a basic group are reacted with inorganic or organic acids, such as, for example, 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, the physiologically tolerable salts are obtained by reaction with alkali or alkaline earth hydroxides, such as, for example, sodium hydroxide, potassium hydroxide or calcium hydroxide, or with other basic groups, such as, for example, with amines.

The dosage can depend on various factors, such as the mode of administration, species, age or individual condition

depend. The compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 tablets with an active ingredient content of 0.5-500 mg being administered with each application. The tablets can also be delayed, which increases the number of

Applications per day reduced 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, with the amounts of 5-1000 mg per day usually being sufficient.

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

in which R, R ¹ and R ^{2 have} the meaning given above and A is -COOH or C = N, with substituted or

unsubstituted aminoalkyl mercaptans of the general formula III

or diamines of the general formula IV

in which R ³ and R ^{4 have} the meaning given above, in a suitable inert solvent at room temperature to reflux temperature, if appropriate in the presence of catalytic amounts of acid, for example p-toluenesulfonic acid, or if that Y = O, arylmagnesium bromides with N- (3-bromopropyl) phthalimide to react at -10 ° C to reflux temperature in an inert solvent, as exemplified in J. Heterocycl. Chem. 26, 1441 (1989) and subsequently subsequently converting compounds of the formula I into other compounds of the formula I and then purifying them by chromatography or by recrystallization. Racemates can by chromatography on suitable optically active phases, such as cellulose triacetate, in the

Antipodes are separated.

The subsequent conversions of compounds of the formula I into other compounds of the formula I relate to the preparation of derivatives with X = S or N-alkylimine. Compounds with X = S are made by reacting compounds of

Formula I, in which X represents an oxygen atom, with

sulfur group transferring compounds such as e.g.

Lawesson's reagent. Compounds with X = N-alkylimino are prepared by reacting the corresponding imino compounds of the general formula I with alkylamines by methods known per se. Compounds of formula I with Y = N-alkylimino are prepared by alkylation of compounds of formula I in which Y represents a nitrogen atom.

Furthermore, the subsequent conversion relates, for example, to the oxidation of compounds of the general formula I with Y = s to the corresponding sulfinyl and sulfonyl derivatives with Y = SO, SO ₂ by methods known per se.

The benzoic acid derivatives of the general formula II are known from the literature and are, for example, 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 V

R-MgBr (V),

in which R, with the exception of hydrogen, has the meaning given above, with phthalic anhydride, which is optionally substituted, in suitable inert solvents at low temperatures.

Compounds of formula III, such as. B. 3-mercaptopropylamine (Helv. Chim. Acta 46., 752, 1963) and IV are known compounds and can be prepared according to literature rules or are commercially available.

The compounds of the formula I are prepared analogously to the preparation of the thiazolo- [2,3-a] isoindolinones which are known from the prior art (cf. US Pat. No. 3,334,113; US Pat. No. 3,646,022; US 2,860,985, Belgian Patent Application 564,592 ; J. Org. Chem. 30, 1506 (1965) and J. Org. Chem. 34, 165 (1969)).

For the purposes of the present invention, in addition to the compounds mentioned in the examples and the combination of all the meanings of the substituents mentioned in the claims, the following compounds of the formula I are suitable, which are used as racemic mixtures or in optically active form or as pure R and S enantiomers can 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] thiazino- [2,3-a] isoindole-6 (10-bH) -one

4. 10b- (4-chlorophenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10-bH) -one

5. 10b- (4-methoxyphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-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] isoindole-6 (2H) -one

9. 10b- (4-methylmercaptophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindole-6 (2H) -one

10. 10b- (4-ethoxyphenyl) -1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole-6 (2H) -one

11. 10b- (4-fluorophenyl) -1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole-6 (2H) -one

12. 1-Methyl-10b-phenyl-1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole-6 (2H) -one

13. 1-Methyl-10b- (4-chlorophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindole-6 (2H) -one 14. 1-Propyl-10b-phenyl-1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole-6 (2H) -one

15. 1-Ethyl-10b-phenyl-1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole-6 (2H) -one

16. 3-Hydroxy-10b-phenyl-1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole-6 (2H) -one

17. 3-Hydroxy-10b-benzyl-1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole-6 (2H) -one

18. 9-Nitro-10b-phenyl-l, 3,4,10b-tetrahydropyrimido [2,1-a] isoindole-6 (2H) -one

19. 10b- (2-thienyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindole-6 (2H) -one

20. 3-Methyl-10b- (4-chlorophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindole-6 (2H) -one

21. 10b- (4-Chloro-3-aminophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindole-6 (2H) -one

22. 2-Methyl-10b- (4-chlorophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindole-6 (2H) -one

23. 1-Methyl-10b- (3-nitrophenyl) -1,3,4,10b-tetrahydropyrimido- [2,1-a] isoindole-6 (2H) -one

24. 1-Ethyl-10b- (4-methoxyphenyl) -1,3,4,10b-tetrahydropyrimido [2,1-a] isoindole-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] isoindole-6 (10bH) -one

27. 10b- (3-methylphenyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

28. 10b- (4-methylphenyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

29. 10b- (4-fluorophenyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

30. 10b-phenylethenyl-3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

31. 10b-phenylethynyl-3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

32. 10b- (4-methoxyphenyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

33. 10b- (1-Piperazinyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

34. 10b- (1H-Imidazol-l-yl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

35. 10b- (4-Morpholinyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

36. 10b-Propynyloxy-3,4-dihydro-2H- [1,3] oxazino - «[2,3-a] isoindole-6 (10bH) -one

37. 10b- (4-chlorophenyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one 38. 10b- (1-piperidine) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

39. 10b- (3-methylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

40. 10b- (1-Naphthyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

41. 9-Methyl-10b-phenyl-3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

42. 9-Chloro-10b-phenyl-3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

43. 9-Chloro-10b- (3-methylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

44. 10b- (3,4-Dimethylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-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] isoindole-6 (10bH) -one

47. 9-Methyl-10b- (3,5-dimethylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

48. 9-Chloro-10b- (1-naphthyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

49. 10b- (2-Naphthyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one 50. 10b- (Anthracen-1-yl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

51. 10b- (Anthracen-9-yl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

52. 9-Methyl-10b- (3-trfluoromethylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

53. 9-Methoxy-10b-phenyl-3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

54. 10b- (3-Ethylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-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] isoindole-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] isoindole-6 (10bH) -one

61. 10b- (Phenanthren-1-yl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) thione 62. 10b- (Phenanthren-9-yl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) thione

63. 9-Chloro-10b- (3-methylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) thione

64. 10b- (2-Naphthyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) thione

65. 10b- (Cyclohexen-3-yl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

66. 10b- (2-furyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

67. 10b- (3-furyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

68. 10b- (2-Thienyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

69. 10b- (3-Thienyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

70. 10b- (3-pyridyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one

71. 10b- (Pyrimidin-4-yl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-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] isoindole-6 (10bH) -one

80. 10b- (2-pyridyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-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-oxide

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 in 80 ml abs. Toluene dissolved and after adding 1.92 g (21 mmol) 3- Mercaptopropylamine and a catalytic amount of p-toluenesulfonic acid heated under reflux for one hour on a water separator. The solvent was then removed in vacuo and the residue was purified by column chromatography on silica gel 60 using ether / isohexane 2/1 as the eluent. Educ. 3.02 g (51% of theory), mp. 164-167 ° C after recrystallization from ethanol.

The 3-mercaptopropylamine (formula III) used was based on Helv. Chim. Acta 46., 752 (1963) by reacting commercially available 3-bromopropylamine hydrobromide with carbon disulfide to 2-mercaptohydrothiazine, cleavage with hydrobromic acid and release of the base with sodium hydroxide solution in 21% yield.

Example 2

10b- (1-Naphthyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one was prepared analogously to Example 1 in 56% yield. Mp 218 - 220 ° C (decomp.) After stirring with

Ether.

Example 3

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

Example 4

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

Example 5

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

Example 6

10b- (3-methoxyphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] isoindole-6 (10bH) -one was prepared analogously to Example 1 in 49% yield. Mp 165 ° C after stirring with ether.

Example 7

10b- (3,5-dimethylphenyl) -3,4-dihydro-2H- [1,3] thiazino- [2,3-a] -isoindol-6 (10bH) -one was analogous to Example 1 in 41%

Yield made. Mp. 200 ° C after stirring with ether.

Example 8

10b-phenyl-3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one

4.8 g (21 mmol) 2-benzoylbenzoic acid were dissolved in 80 ml abs, Toluene dissolved and after adding 3.76 g (50 mmol) of 3-amino-l-propanol and a batalytic amount of p-toluenesulfonic acid heated under reflux for three hours on a water separator.

Then the solvent was removed in vacuo and the

The residue was purified by column chromatography on silica gel 60 using ether / isohexane 3/2 as the eluent. Educ. 3.4 g (61% of theory), mp. 129-130 ° C after recrystallization from ethanol.

Example 9

10b-methyl-3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) -one was prepared analogously to Example 9 in 26% yield.

Mp 86-89 ° C after stirring with ether.

Example 10

10b- (3-methylphenyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] iso-indole-6 (2H) -one was obtained analogously to Example 9 in 32% yield

manufactured. Mp 110-114 ° C after recrystallization from ethanol.

Example 11

10b- (1-Naphthyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] iso-indole-6 (2H) -one was obtained analogously to Example 9 in 53% yield manufactured.

Mp 153-158 ° C after recrystallization from ethanol. Example 12

10b- (2-thienyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] iso-indole-6 (2H) -one was analogous to Ex. 9 in 39% yield manufactured. Mp 110 ° C after recrystallization from ethanol.

Example 13

10b- (4-indanyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] iso-indole-6 (2H) -one was obtained analogously to Ex. 9 in 30% yield manufactured. Mp 67-70 ° C after stirring with ether.

Example 14

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

Example 15

10b- (2-pyridyl) -3,4-dihydro-2H- [1,3] oxazino- [2,3-a] iso-indole-6 (2H) -one was obtained analogously to Ex. 9 in 27% yield manufactured. Mp 169 ° C after stirring with ether.

Example 16

10b-phenyl-1,3,4,10b-tetrahydropyrimido- [2,1-a] ispindol-6 (2H) -one

4.8 g (21 mmol) of 2-benzoylbenzoic acid in 80 ml abs.

Toluene dissolved and after adding 3.7 g (50 mmol) of 1,3-diaminopropane and a catalytic amount of p-toluenesulfonic acid for three hours on a water separator under reflux heated. The solvent was then removed in vacuo and the residue was purified by column chromatography on silica gel 60 using ether / isohexane 2/1 as the eluent. Educ. 3.1 g (56% of theory), mp. 183-187 ° C. after recrystallization

Ethanol.

Example 17

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

Example 18

10b-phenyl-3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10bH) thione

2 g of 10b-phenyl-3,4-dihydro-2H- [1,3] oxazino- [2,3-a] isoindole-6 (10b) -one (see Ex. 9) in 200 ml of dioxane were mixed with 3.35 g Lawesson's reagent was added and the mixture was stirred at 60 ° C. for 7 h (TLC control). After cooling, the precipitate

filtered off, the filtrate evaporated in vacuo and the

The residue was purified by column chromatography on silica gel 60 using heptane / methyl ethyl ketone 6/1 as the eluent. Educ.

1.72 g (81% of theory), mp. 148-152 ° C after

Recrystallization from ethanol.

Example 19

Inhibition of reverse transcriptase (RT)

The screening test system 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 Site complementary 18mer oligonucleotide as a primer. The [ ³ H] -thymidine-5'-triphosphate incorporation was measured by counting in the ß-counter. The following table shows the IC ₅₀ value for the compounds tested. This value corresponds to the concentration of the test substance which causes an inhibition of the reverse transcriptase activity by 50%. The value for AZT was determined accordingly as a reference substance.

Claims

1. Use of tricyclic isoindole derivatives of the general formula I

Y is an oxygen or sulfur atom, or -NH-, C ₁ - C ₅ alkylamino, C ₁ -C ₅ may be -alkylcarbonylamino-, sulphinyl or sulphonyl group,

R is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-9 C atoms, which can be substituted by phenyl, or a C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl or C ₁ -C ₆ alkylmercapto-C ₁ -C ₆ alkyl group means, or means a phenyl ring which is optionally mono- or polysubstituted by C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, C ₁ -C ₆ Alkyl mercapto, C ₁ -C ₆ alkyl sulfinyl, C ₁ -C ₆ alkyl sulfonyl, _C2 -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₂ - C ₆ alkenyloxy, C ₂ -C ₆ alkenyl mercapto, C ₂ -C ₆ alkynyl oxy, C ₂ -C ₆ -alkynylmercapto, amino, C ₁ -C ₆ -alkylamino, di-C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylamino-carbonyl, aminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl, or a mono-, bi- or tricyclic carbocyclic ring with 7-15 C. -Atoms or a heterocyclic mono-, bi- or tricyclic ring system with 5 or 6 ring atoms each and 1-4 or 1-5 heteroatoms can be contained per ring system, the

Heteroatoms are nitrogen, sulfur or oxygen,

R ^{1 is} a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C atoms or C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylmercapto, C ₁ -C ₆ alkylsulfinyl, C ₁ - C ₆ -alkylsulfonyl, amino, C ₁ -C ₆ -alkylamino, di-C ₁ -C ₆ -alkylamino, sulfonamido, C ₁ -C ₆ -alkoxycarbonyl, carboxy, halogen,

Means hydroxy, nitro, cyano, azido, phenyl or benzyloxy,

R ^{3 is} hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylmercapto, amino, C ₁ -C ₆ -alkylamino, di-Cl-C6-alkylamino, halogen, Means cyano, hydroxy, carboxy or C ₁ -C ₆ -alkoxycarbonyl,

R ^{4 has} the same meaning as R ³ , where the radicals R ³ and R ^{4 can} independently of one another be the same or different. as well as 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 -SO ₂ group.

3. Use according to claim 1, characterized in that R is a carbocyclic ring having 7-15 C atoms, selected from the group naphthyl, anthracenyl,

Phenanthrenyl, fluorenyl, indenyl, acenaphthylenyl, norbornyl, adamantyl, C ₃ -C ₇ cycloalkyl or C ₅ -C ₆ cycloalkenyl, it being possible for the unsaturated or aromatic carbocycles to be partially or completely hydrogenated.

4. Use according to claim 1, characterized in that R represents a heterocyclic ring selected from the group pyridine, pyrimidine, pyridazine, pyrazine,

Triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazan, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzothiazole, indazole, benzimidazole, benztriazole, quinoline, chromen Quinoxaline, methylenedioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine, it being possible for the unsaturated or aromatic heterocycles to be partially or completely hydrogenated.

5. Optically active tricyclic isoindole derivatives of gen my formula I

in the

Y is an oxygen or sulfur atom, or -NH-, C ₁ - C ₅ alkylamino, C ₁ -C ₅ may be -alkylcarbonylamino-, sulfinyl or Sulfonylgmppe,

R is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-9 C atoms, which can be substituted by phenyl, or a C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl or C ₁ -C ₆ alkylmercapto-C ₁ -C ₆ alkyl group means, or means a phenyl ring which is optionally mono- or polysubstituted by C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, C ₁ -C ₆ -Alkyl mercapto, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C2-C ₆ -alkenyloxy, C ₂ -C ₆ -alkenylmercapto, C ₂ -C ₆ alkynyloxy, C ₂ -C ₆ alkynylmercapto, amino, C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonylamino, C ₁ -C ₆ - alkylamino-carbonyl, aminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl, or is a mono-, bi- or tricyclic carbocyclic ring with 7-15 C atoms or a heterocyclic mono-, bi- or tricyclic ring system with 5 or 6 ring atoms each and can contain 1-4 or 1-5 heteroatoms per ring system , where the heteroatoms are nitrogen, sulfur or oxygen,

R ^{3 is} hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylmercapto, amino, C ₁ -C ₆ -alkylamino, di-C1-C6-alkylamino, halogen, cyano, Is hydroxyl, carboxy or C ₁ -C ₆ -alkoxycarbonyl,

R ^{4 has} the same meaning as R ³ , where the radicals R ³ and R ^{4 can} independently of one another be the same or different, and their tautomers and physiologically tolerable salts.

6. Medicament containing at least one compound of the formula I according to claim 5 and pharmaceutically customary excipients or auxiliaries.

7. Use of compounds of formula I according to claim 5 for the manufacture of medicaments with antiviral or anti-retroviral activity.

8. A process for the preparation of compounds of the formula I according to claim 5, characterized in that the racemates of the formula I are separated chromatographically on suitable optically active phases into the optically active compounds.

9. A process for the preparation of medicaments with anti-viral or anti-retroviral activity, characterized in that a compound of the formula I according to any one of claims 1-5 is mixed together with customary pharmaceutical auxiliaries and processed to pharmaceutical forms.