EP0593536A1

EP0593536A1 - DIBENZ b,e]AZEPINE DERIVATIVES AND DRUGS CONTAINING THEM

Info

Publication number: EP0593536A1
Application number: EP92913494A
Authority: EP
Inventors: Walter-Gunar Friebe; Herbert Leinert; Alfred Mertens; Wolfgang Schäfer; Harald Zilch
Original assignee: Roche Diagnostics GmbH; Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1991-07-05
Filing date: 1992-06-30
Publication date: 1994-04-27
Also published as: AU2194292A; CA2111710A1; JPH06508840A; DE4122240A1; WO1993001195A1

Abstract

L'invention a pour objet des dérivés dibenz[b,e]azépines de formule (I), dans laquelle A désigne un groupe méthylène, carbonyle, thiocarbonyle, carbimino, N-hydroxycarbimino ou sulfonyle, X est une liaison de valence ou un atome d'oxygène ou un atome de soufre, un groupe sulfinyle ou sulfonyle, un groupe CH2S ou un groupe NH, n est un nombre entier de 1 à 3, et R1 à R4, qui peuvent être identiques ou différents indépendamment l'un de l'autre, représentent chacun un atome d'hydrogène, un reste aliphatique de 1 à 6 atomes de carbone, ainsi que leurs tautomères, énantiomères, diastéréomères et leurs sels physiologiquement compatibles. En outre, l'invention concerne des médicaments renfermant des composés de formule (I), notamment pour le traitement d'infections virales.The subject of the invention is dibenz [b, e] azepine derivatives of formula (I), in which A denotes a methylene, carbonyl, thiocarbonyl, carbimino, N-hydroxycarbimino or sulfonyl group, X is a valence bond or an atom. of oxygen or a sulfur atom, a sulfinyl or sulfonyl group, a CH2S group or an NH group, n is an integer from 1 to 3, and R1 to R4, which may be the same or different independently of one of l 'other, each represents a hydrogen atom, an aliphatic residue of 1 to 6 carbon atoms, as well as their tautomers, enantiomers, diastereomers and their physiologically compatible salts. In addition, the invention relates to medicaments containing compounds of formula (I), in particular for the treatment of viral infections.

Description

Dibenzrb.elazepine derivatives and medicinal products containing them

The present invention relates to

Dibenz [b, e] azepine derivatives, processes for their preparation and medicaments containing these compounds.

The invention relates to dibenz [b, e] azepine derivatives of the general formula I

in the

A is a methylene, carbonyl, thiocarbonyl, carbimino, N-hydroxycarbimino or sulfonyl group,

X is a valence bond or an oxygen or sulfur atom, a sulfinyl or sulfonyl group, a CH2S group or an NH group,

n is an integer from 1 to 3 and

R ¹ to R ³ , which can be the same or different independently of one another, are each a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C-ato or C -C ₆ -alkoxy, Cx-Cg-alkylmercapto, C ₁ -Cs-alkylsulfinyl, Ci-Cg-alkylsulfonyl, A ino, C ₁ -Cg-alkylamino, di- Ci-Cs-alkylamino, sulfonamido, C ^ -Cg alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy and

R ^{4 is} hydrogen or a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms

mean,

their tautomers, enantiomers, diastereomers and physiologically acceptable salts.

The object of the present invention was to provide new dibenz [b, e] azepine derivatives. These compounds are used in particular for the production of medicaments.

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-Vl üs or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and the human immunodeficiency virus HIV-1 and -2.

The compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS. 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 Che otherapeutics which cause causally or symptomatically to interfere with the viral or retroviral-related illness with evidently substantial success. It is not possible today to diagnose certain viral diseases such as Acquired Immune Deficiency Syndro (AIDS), the AIDS-related complex (ARC) and its pre-stages, herpes, cytomegalovirus (CMV), influenza and other viral infections to heal or to chemically influence the symptoms favorably. For the treatment of AIDS, for example, 3 '-azido-3' deoxythymidine (AZT), known as Zidovudine or Retrovir ^R , is available almost exclusively. However, AZT is characterized by a very narrow therapeutic range or by very severe toxicities already occurring in the therapeutic area (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 cytotoxic in pharmacologically relevant doses.

It has now been shown that compounds of general formula I inhibit the multiplication of DNA or RNA viruses at the level of virus-specific DNA or RNA transcription. The substances can influence the multiplication of retroviruses by inhibiting the enzyme reverse transcriptase (cf. Proc. Natl. Acad. Sci. USA 81, 1911, 1986 and Nature 325, 773 1987).

Since there is a very great need for chemotherapeutics that interfere as specifically as possible with retroviral-related diseases or their symptoms without affecting the normal natural body functions, the mentioned compounds are advantageously used prophylactically or therapeutically in the treatment of diseases in which a retroviral infection is of pathophysiological, symptomatic or clinical relevance.

The separation of the race ate into the enantiomers can be carried out analytically, semi-preparatively and preparatively chromatographically on suitable optically active phases with common eluents.

Suitable optically active phases are, for example, optically active polyacrylamides or polyethacrylamides, some 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 (for example Crownpak ^(R) from Daicel) or microcrystalline cellulose triacetate (Merck).

In the general formula I, A denotes in particular a carbonyl, methylene or thiocarbonyl group, the carbonyl group being preferred.

X represents in particular an oxygen or sulfur atom or a sulfinyl or sulfonyl group.

n is preferably the number 1 or 2.

For the radicals R ¹ to R ³ are hydrogen, C] _- C3-alkyl, C2-C4-alkenyl, C2-C -alkynyl, Cι ~ C3-alkoxy, C_-C ₃ -alkylmercapto, Cι ~ C ₃ -alkylamino , C _] _-C ₃ alkoxycarbonyl, amino, halogen, hydroxy, cyano and azido preferred. The ring system can be substituted in the 7-, 8-, 9- or 10-position by R ¹ , the 8- and 9-position being preferred. In particular, R ^{1 represents} a halogen atom or a Ci-Cg-alkyl group.

The substituents R ² and R ³ can be in the 1-, 2-, 3- or 4- position of the ring system, the 3- and 4-position are preferred. In particular, R ^{2 represents} a hydrogen atom and R ^{3 represents} a hydrogen or halogen atom, a Ci-Cg-alkyl or Ci-Cg-alkoxy group. In this sense, R ^{3 is} in particular a chlorine atom, or a methyl or methoxy group.

For the radical R ⁴ , hydrogen, C 1 -C ³ -alkyl, C ² -C ⁴ -alkenyl and C ² -C ⁴ -alkynyl are preferred.

For R ¹ to R ³ , independently of one another, hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methyl ercapto, ethyl mercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, amino, azido, cyano, hydroxy and halogen, with chlorine and bromine are preferred for halogen. For R ⁴ , hydrogen, methyl, ethyl, isopropyl and allyl are particularly preferred.

The aliphatic radical in the definition of R ¹ -R ⁴ can be straight-chain or branched, saturated or unsaturated and contain a total of up to six carbon atoms. Ci-Cg-alkyl groups are possible as saturated residues, such as. B. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. Unsaturated radicals are in particular C2-Cg-alkenyl and C2-C ₆ -alkynyl groups, which can also be branched, such as. As allyl, vinyl, 2-butenyl or propargyl.

The medicaments containing at least one compound of the formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form. Here, the usual forms of application come into question, such as tablets, capsules, dragees, syrups, solutions or suspensions. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, solubilizers and buffers. Such additives are tartrate and Citrate buffer, ethanol, complexing agents such as ethylene diamine tetraacetic acid and its non-toxic salts, high molecular weight 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 oral Preparations suitable for applications can, if desired, contain flavorings or sweeteners.

Pharmacologically acceptable salts are the acid addition salts with inorganic or organic acids, such as. B. halogen acids (HC1, HBr, etc.), sulfuric acid, phosphoric acid, tartaric acid, succinic acid, oxalic acid, acetic acid.

The dosage can depend on various factors, such as the mode of application, species, age or individual condition. 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 applications with an active ingredient content of 0.5-500 mg being administered for each application. The tablets can also be delayed, which reduces the number of applications per day to 1-3. The ^~ content of active substance of the retarded tablets can be 2 - mg 1000th The active ingredient can also be given by continuous infusion, the amounts of 5-1000 mg per day being normally sufficient.

The compounds of general formula I according to the invention are prepared by processes known per se by either a) a compound of formula II

in which A, X, n and R ¹ to R ^{4 have} the meaning given above and Y represents a reactive radical, or

b) a compound of formula III

in which A, X, n, R ¹ to R ⁴ and Y have the meaning given above.

cyclized with elimination of HY, or c) a compound of formula IV

in which A, X and R ¹ to R ^{4 have} the meaning given above, with a compound of the formula (V),

ϊ ^, - ⁽ CH ₂ ) nY "(V),

wherein n has the meaning given above and Y 'and Y ", which are the same or different, have the meaning of Y,

with the splitting off of HY ¹ and HY ", or

d) a compound of formula VI

in which A, X, n and R ¹ to R ^{4 have} the meaning given above and Z represents a reactive radical, cyclizes or

e) converting a compound of formula (I) in which one or more of the n CH2 groups has been replaced by CO or a derivative thereof by reduction into a compound of formula I,

and, if appropriate, then subsequently converting compounds of the formula I into other compounds of the formula I and, if desired, converting them into salts by titration with pharmacologically acceptable acids or bases. Racemates can be separated into the antipodes, for example, by chromatography on suitable optically active phases such as cellulose triacetate.

Easily removable residues, in particular halogen atoms and the mesyloxy and tosyloxy group, are suitable as reactive residues, X, Y, Y ¹ and Y ". The groups HY, HY ¹ and HY" are advantageously eliminated in a solvent in the presence of a base such as for example an alkali alcoholate in the corresponding alcohol, potassium carbonate in acetone or butanone, sodium hydride in toluene or dimethylformamide. In addition to those mentioned for Y, reactive radicals Z can also be lower alkoxy groups, optionally substituted phenoxy groups or the azide radical.

The reduction of a carbonyl group to a CH2 group is advantageously carried out using complex metal hydrides such as lithium aluminum hydride or sodium borohydride or using catalytically excited hydrogen.

The starting materials of the formulas II to VI are known from the literature or can be prepared from the substances described by known processes.

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 formula I in question, which can be present as racemic mixtures or in optically active form or as pure R and S enantiomers:

1. 5,6-dihydro-ll, 5-thiomethano-llH-dibenz [b, e] azepin-6-one

2. l-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one

3. 2-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one

4. 3-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one

5. 4-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one

6. 3-chloro-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin- 6-one

7. 4-chloro-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin- 6-one

8. 3-methoxy-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one

9. 4-methoxy = 5 ^" , 6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one

10. 8-chloro-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin- 6-one

11. 9-chloro-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one 12. 9-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one

13. 9-methoxy-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one

14. 5,6-Dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepine

15. 6-imino-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepine

16. 6-oximino-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepine

17. 5,6-Dihydro-ll, 5-thioethano-IIH-dibenz [b, e] azepine-6-thione

18. 6,11-Dihydro-ll, 6-thioethano-dibenzo [c, f] [1,2] thiazepine-5,5-dioxide

19. ll-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz- [b, e] azepin-6-one

20. 5,6-Dihydro-5,11-propano-IIH-dibenz [b, e] azepin-6-one

21. 5,6-Dihydro-ll, 5-epoxyethano-llH-dibenz [b, e] azepin-6-one

22. 5,6-Dihydro-ll, 5-iminoethano-llH-dibenz [b, e] azepin-6-one

23. 5,6-Dihydro-5,11-ethano-IIH-dibenz [b, e] azepin-6-one

24. 5,6-Dihydro-ll, 5-thiopropano-llH-dibenz [b, e] azepin-6-one

25. 5,6-Dihydro-ll, 5-methanothioethano-IIH-dibenz [b, e] azepin- 6-one

26. 5,6-Dihydro-ll, 5-thioethano-IIH-dibenz [b, e] azepin-6-one-12-oxide 27. 5,6-Dihydro-ll, 5-thioethano-IIH-dibenz [b, e] azepin-6-one, 12,12-dioxide

example 1

5,6-Dihvdro-ll.5-thioethano-llH-dibenzfb, eiazepin-6-one

To a suspension of 240 mg 50 percent. Sodium hydride (white oil dispersion) in 20 ml of N, N-dimethylformamide (DMF), the solution of 1.5 g (5 mmol) of ll- (2-chloroethylthio) -5,6-dihydro-HH- is dropped at 70 ° C. dibenz [b, e] azepin-6-one in 10 ml DMF, stirred for 1 h at 70 ^β C, concentrated, taken up in dichloromethane, washed with water, dried, concentrated and purified by chromatography on silica gel RP18 (Merck ). After elution with methanol / water / acetic acid 40: 60: 1, 680 mg (51% of theory) of the title compound of mp 201-202 ^β C. are obtained after trituration with ether.

The ll- (2-chloroethylthio) -5,6-dihydro-HH-dibenz [b, e] azepin-6-one used as starting material can be obtained as follows:

a) A mixture of 8.0 g (33 mmol) ll-chloro-5,6-dihydro-HH-dibenz [b, e] azepin-6-one (J.Pharm.Pharmako1. 21, 520 (1969)), 75 ml of dichloromethane and 2.6 g (33 mmol) of mercaptoethanol is 4 h at room temperature. touched. The mixture is concentrated in vacuo and the resulting ll- (2-hydroxyethylthio) -5,6-dihydro-HH-dibenz [b, e] azepin-6-one (9.5 g oil, quantitative) is reacted further as a crude product.

b) A mixture of 14.2 g (50 mmol) of the crude product described above, 70 ml of dichloromethane and 5.5 ml of thionyl chloride is heated to reflux for 2 h. The mixture is concentrated, triturated with ether and filtered. There remain 13.8 g of ll- (2-chloroethylthio) -5,6-dihydro-HH-dibenz [b, e] azepin-6-one (91% of theory), mp. 170-172 ° C. Example 2

5,6-dihydro-ll.5-thioethano-llH-dibenzrb, eiazepin-6-one

0.43 ml (5 mmol) of 1,2-dibromoethane are added dropwise to the solution of 1.2 g (5 mmol) of II-mercapto-5,6-dihydro-IIH-dibenz [b, e] azepin-6-one in 20 ml of DMF , stirred for 30 min at room temperature, heated to 70 ° C., a suspension of 0.48 g of 50 percent sodium hydride in 20 ml of DMF is added dropwise, the mixture is stirred for 1 h, concentrated, taken up in dichloromethane, washed with water, dried, concentrated and cleans as described in Example 1.

420 mg (31% of theory) of the title compound of mp 196-198 ^β C. are obtained.

The ll-mercapto-5,6-dihydro-IIH-dibenz [b, e] azepin-6-one used as the starting material can be obtained as follows:

A mixture of 7.2 g (30 mmol) ll-chloro-5,6-dihydro-IIH-dibenz [b, e] azepin-6-one, 2.7 g thiourea and 60 ml ethanol is heated under reflux for 6 h under nitrogen. Then 18 ml of 5 N sodium hydroxide solution are added, the mixture is heated under reflux for 2 h, acidified with hydrochloric acid, concentrated, taken up in water, extracted with dichloromethane, dried and concentrated. After the residue has been triturated with ether, 4.5 g (62% of theory) of ll-mercapto-5,6-dihydro-IIH-dibenz [b, e] azepin-6-one, mp. 188-190 ^β C. Example 3

Enantiomer separation of rac-5,6-dihvdro-ll, 5-thioethano-llH-dibenzfb, eiazepin-6-one

For the separation of the antipodes, 300 mg of the racemate were dissolved in 30 ml of methanol, placed on a column with an inner diameter of 50 mm and a length of 300 mm (corresponding to 250 g of cellulose triacetate, 15-25 / um grain size, Merck 16326) and with 80 percent. aqueous methanol eluted (flow 7.5 ml / min, approx. 1.5 bar).

After concentration of the appropriate fractions and trituration with isohexane, the following were obtained:

a) from fraction 1: 90 mg (-) - 5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one with mp. 177-178 "C, [OL] D ²⁰ - 121 ^β .

b) from fraction 2: 90 mg (+) - 5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one, mp. 178-179 ° C, [^] D ²⁰ + 117 ° C.

3Example 4

5,6-dihvdro-ll, 5-thioethano-llH-dibenzTb, eiazepine-hvdrochloride

2.6 g of aluminum chloride are added at room temperature to a solution of 1.4 g (5 mmol) of the compound of Example 1 in 20 ml of 1,2-dimethoxyethane, the mixture is stirred for a further 30 minutes, 0.74 g of sodium borohydride is added within 1 h, and the mixture is stirred for 3 hours, decomposes with ice water, makes alkaline, extracts with dichloromethane and cleans on silica gel. After elution with isohexane: ethyl acetate 3: 1, 0.5 g of the desired compound (40% of theory) is obtained, which is converted into the hydrochloride with a melting point of 220-222 ° C. using an ethereal hydrogen chloride solution. Example 5

5,6-Dihvdro-ll.5-thioethano-llH-dibenzfb, eiazepine-thione

A mixture of 2.1 g (7.9 mmol) of compound from Example 1, 60 ml of toluene and 1.5 g of Lawesson's reagent is heated to reflux for 6 h, a further 1.5 g of Lawesson's reagent are added, the mixture is boiled under reflux for 6 h, concentrated and purified on silica gel. After elution with isohexane: ethyl acetate 3: 1, 0.6 g of the title compound (27% of theory) is isolated, which melts at 192-193 ° C. after trituration with ether.

Example 6

5,6-Dihvdro-ll.5-thiopropano-llH-dibenzTb, eiazepin-6-one

In an analogous manner to that described in Example 1, the title compound is obtained in 23% yield, mp. 222-224 ° C. from 11- (3-chloropropylthio) 5,6-dihydro-IIH-dibenz [b, e] azepine 6-one and natriu hyrid.

The above-mentioned starting material can be obtained as follows:

a) A mixture of 14.6 g (60 mmol) ll-chloro-5,6-dihydro-HH-dibenz [b, e] azepin-6-one, 200 ml dichloromethane and 5.4 ml (60 mmol) 3-mercapto-propionic acid is stirred for 4 h at room temperature, extracted with soda solution, the extract acidified and the product filtered off.

15.9 g of 3- (5,6-dihydro-IIH-dibenz [b, e] azepin-6-on-II-yl) mercaptopropionic acid (85% of theory), mp. 185-187 ° C., are isolated. b) A solution of 15.6 g (50 mmol) of the above-described acid in 125 ml of tetrahydrofuran is added dropwise to a suspension of 2.66 g of lithium aluminum hydride in 75 ml of tetrahydrofuran, heated to reflux for 5 h, decomposed with brine, extracted with ethyl acetate and purified on silica gel . After elution with isohexane: ethyl acetate 3: 1, 8.1 g of ll- (3-hydroypropylthio) -5,6-dihydro-IIH-dibenz [b, e] azepin-6-one (54% of theory) of

Mp 113-135 ° C.

c) In a manner analogous to that described in Example 1b, the above intermediate and thionyl chloride give the ll- (3-chloropropylthio) -5,6-dihydro-HH-dibenz [b, e] azepine in 68% yield 6-one with a melting point of 110-112 ° C (from ether).

Example 7

5,6-Dihvdro-ll.5-thioethano-llH-dibenzTb, eiazepin-6-one-12-oxide

A solution of 1.3 g (5 mmol) of compound from Example 1, 50 ml of acetone and 1.2 ml of 30% hydrogen peroxide is stirred for 2 hours at 50 ° C., mixed with water and extracted with ethyl acetate. After concentrating the extract and triturating with ether, 0.8 g of the title compound (53% of theory), mp. 108-109 ° C., remains as a monohydrate.

Example 8

5,6-Dihvdro-ll, 5-thioethano-llH-dibenzrb, e1azepin-6-one-12,12-dioxide

A solution of 1.3 g (5 mmol) of the compound from Example 1 in 30 ml of chloroform is mixed with a solution of 2.1 g of 3-chloroperoxybenzoic acid in 30 ml of chloroform, and the mixture is stirred for 1 hour Room temperature, washes with sodium bicarbonate solution and concentrated the organic phase. After trituration with ether, 0.9 g of the title compound (60% of theory) of mp. 244-246 ° C. remain.

Example 9

Inhibition of reverse transcriptase (RT) by derivatives of dibenzTb, eiazepine.

The test system contains the purified RT from HIV-1, which was expressed by genetic engineering methods in E. coli, as well as the components of the initiation complex, such as the in vitro transcripts of the HIV-LTR with the neighboring primer binding site as a template and one for Primer binding site complementary 18mer oligonucleotide as a primer. The [ ³ H] -thymidine-5'-triphosphate incorporation was measured by counting in the ß-counter. The table below shows the ICsoth for the compounds examined. This value corresponds to the concentration of the test substance which causes an inhibition of the reverse transcriptase activity by 50%.

Results

Claims

Dibenz [b, e] azepine derivatives of the formula I.

in the

X is a valence bond or an oxygen or

Sulfur atom, a sulfinyl or sulfonyl group, a CH2S group or a NH group,

n is an integer from 1 to 3 and

R ¹ to R ³ , which can be the same or different independently of one another, each represent a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms or Ci-Cg-alkoxy, Ci-Cg-alkyl mercapto , C -_- C _Q - alkylsulfinyl, Ci-Cg-alkylsulfonyl, amino, C1-C5-alkylamino, di-Ci-Cg-alkylamino, sulfonamido, C -_- C _Q - alkoxycarbonyl, carboxy, halogen, hydroxy, nitro , Cyano, azido, phenyl or benzyloxy and R ^{4 is} hydrogen or a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms

mean,

their tautomers, enantiomers, diastereomers and physiologically compatible salts.

Dibenz [b, e] azepine derivatives according to claim 1, characterized in that

R ¹ to R ^{3 are} hydrogen, C] _- C3-alkyl, C2 "C4-alkenyl, C2-C4-alkynyl, C_-C ₃ -alkoxy, Cι-C ₃ -alkylmercapto, C _] _-C3- alkylamino, Cι -C ₃ -alkoxycarbonyl, amino, halogen, hydroxy, cyano and azido.

3. dibenz [b, e] azepine derivatives according to claim 1 or 2, characterized in that

R ^{4 is} hydrogen, C! -C3-al yl, C2-C-alkenyl or C ₂ -C - alkynyl.

4. A process for the preparation of dibenz [b, e] azepine derivatives of the formula I according to claims 1, 2 or 3, characterized in that

a) a compound of formula II

b) a compound of formula III

in which A, X, n, R ¹ to R ⁴ and Y have the meaning given above,

cyclized with elimination of HY, or c) a compound of formula IV

Y ^, - ^(C H ₂ ) n-ϊ "(V),

with the splitting off of HY 'and HY ", or

d) a compound of formula VI

e) converting a compound of the formula (I) in which one or more of the n CH2 groups has been replaced by CO or a derivative thereof into a compound of the formula I by reduction,

and, if appropriate, then subsequently converting compounds of the formula I into other compounds of the formula I and, if desired, converting them into salts by titration with pharmacologically acceptable acids or bases.

Medicaments containing at least one dibenz [b, e] azepine derivative of the formula I according to Claims 1, 2 or 3, and also conventional carriers or auxiliaries.

6. Use of dibenz [b, e] azepine derivatives of the formula I according to claim 1, 2 or 3 for the preparation of medicaments for the treatment of diseases caused by viruses or retroviruses.