WO1994024109A1

WO1994024109A1 - Indazole derivatives and antiviral drugs that contain them

Info

Publication number: WO1994024109A1
Application number: PCT/EP1994/001094
Authority: WO
Inventors: Alfred Mertens; Bernhard König; Ulrike Leser
Original assignee: Boehringer Mannheim Gmbh
Priority date: 1993-04-09
Filing date: 1994-04-08
Publication date: 1994-10-27
Also published as: DE4311782A1; AU6566394A

Abstract

The present invention pertains to indazole derivatives of formula (I), methods of preparing them and drugs containing these compounds. The invention particularly pertains to indazole derivatives of formula (I), in which R is a phenyl ring or a carbocyclic ring with 7-15 C atoms or a heterocyclic ring, and the aforementioned rings may be substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl mercapto, amino, C1-C6 alkyl amino, di-C1-C6 alkyl amino, C1-C6 alkyl carbonyl amino, hydroxy, nitro, halogen, trifluoremethyl or azido, R1 is a hydrogen atom, a straight-chained or branched, saturated or unsaturated aliphatic group with 1-6 C atoms, R2 is C1-C8 alkyl, C2-C8 alkenyl, C4-C8 cycloalkyl, C3-C8 cycloalkenyl, X is an oxygen or sulfur atom, Y is a nitrogen atom or CR1, as well as their tautomers, enantiomers, diastereoisomers and physiologically tolerable salts.

Description

Indazole derivatives and antimalarial drugs containing them

The present invention relates to new indazole derivatives of the formula I, processes for their preparation and medicaments which contain these compounds. The invention also relates to the use of indazole derivatives for the production of medicaments with antiviral activity.

The invention relates to indazole derivatives of the formula I.

in the

R denotes a phenyl ring 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 per ring system -5 heteroatoms may be present, the heteroatoms being nitrogen, sulfur or oxygen, and the aforementioned phenyl rings, the mono-, bi- or tricyclic carbocyclic rings or the heterocyclic mono-, bi- or tricyclic ring systems, if appropriate or are substituted several times by C _.- Cg-alkyl, C1-C5-alkoxy, C _.- Cg-alkylmercapto, amino, C -.- Cg-alkylamino, di-Cη-Cg-alkylamino, C _, - Cg- Alkylcarbonylamino, hydroxy, nitro, halogen, trifluoromethyl or azido, R 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 -Cg alkylmercapto, C _j -Cg alkylsulfinyl, C _j -Cg alkylsulfonyl, amino,

C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, sulfonamido, C 1 -C 10 -alkoxycarbonyl, carboxy, halogen, hydroxyl, nitro, cyano or azido,

R ^{2 is} Cf-Cg-alkyl, C ₂ -Cg-alkenyl, C ₄ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl meaning, the above-mentioned alkyl or alkenyl radicals optionally being substituted with fluorine, chlorine, hydroxy and mercapto or can be interrupted by an oxygen or sulfur atom,

X represents an oxygen or sulfur atom and i Y represents a nitrogen atom or CR,

with the proviso that R is not an unsubstituted phenyl ring or a 3-trifluorophenyl ring if R is a C 1 -C 6 -alkyl group which may be substituted by halogen,

as well as their tautomers, enantiomers, diastereomers and physiologically compatible salts.

In addition, the present invention relates to indazole derivatives of the formula I for the production of medicaments for the treatment of viral or retroviral infections or the diseases caused by these infections, where R in addition to the meanings mentioned above also has an unsubstituted phenyl ring or

2 denotes a 3-trifluoromethylphenyl ring when R represents a C 1 -C ₃ -alkyl group which can be substituted by halogen.

Indazoles of the formula I in which R is an unsubstituted phenyl ring or a 3-trifluoromethylphenyl ring and R is a C ₁ -C ₃ -alkyl group which can be substituted by halogen are already known from the prior art. Japanese patent application JP 8245157 describes indazoles with an antithrombotic effect. Anti-allergic activity is attributed to indazoles in German patent application DE 3132916. The synthesis of some indazole derivatives will be in Boll. Chim. Farm. 107, 598, 1968. However, no antiviral activity of indazoles of the formula I has been demonstrated to date.

The object of the present invention was to provide new indazole derivatives and to find a further use for the previously known indazole derivatives in the pharmaceutical industry.

It has surprisingly been found that the indazole derivatives of the formula I have valuable pharmacological properties. In particular, they have an antiviral effect and are 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, as well as the lentiviruses Visna and the human immunodeficiency virus HIV-1 and -2. They are also suitable for the treatment of diseases caused by viruses or retroviruses.

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 retroviral infections. Viral infections in mammals, especially humans, are common. Despite intensive efforts, it has so far not been possible to provide chemotherapeutic agents which cause causally or symptomatically interfering with the viral or retroviral-related illness with recognizable substantial success. It is not possible today to diagnose certain viral diseases, such as, for example, the Acquired Immune Deficiency Syndrome (AIDS), the AIDS-related complex (ARC) and its pre-stages, herpes, cytomegalovirus (CMV), influenza and to cure other viral infections or to chemically influence their symptoms favorably. For example, 3'-azido-3'-deoxy-thymidine (AZT), known as zidovudine or retrovir, is almost exclusively available for the treatment of AIDS. However, AZT is through one very narrow therapeutic range or characterized 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 cytotoxic in pharmacologically relevant doses.

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 and Nature 325, 773 1987).

Since there is a very great need for chemotherapeutics which interfere as specifically as possible with retroviral-related diseases or their symptoms without influencing the normal natural body functions, the compounds mentioned can advantageously be 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 racemates into the enantiomers can be carried out analytically, semi-preparatively and preparatively chromatographically on suitable optically active phases using common eluents.

Suitable optically active phases are, for example, optically active polyacrylamides or polymethacrylamides, some also on silica gel (e.g. ChiraSpher - '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 '' from Daicel) or microcrystalline cellulose triacetate (Merck).

1 The radicals R, R, specified in the definition of the compounds of the formula I

2

R, X or Y are explained in more detail below.

A carbocyclic ring R 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 by way of example: the naphthyl, anthracenyl, phenanthrenyl, flourenyl, Indenyl, acenaphthylenyl, norbomyl, adamantyl ring or a C ₃ -C cycloalkyl or Cς-Cg cycloalkenyl group. The carbocyclic ring can moreover be mono- or disubstituted, it being possible for the substituents to be, independently of one another, preferably in the o- or m-position.

The heterocyclic mono-, bi- or tricyclic ring systems of the radical R contain 5 or 6 carbon atoms per ring, it being possible for 1-4 or 1-5 C atoms to 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, benzothiazole, 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. The heterocyclic ring system can moreover be mono- or disubstituted, where the substituents can independently of one another preferably be in the o- or m-position.

R is preferably unsubstituted phenyl or phenyl mono- or disubstituted by C_ _j -CG alkyl, C_-Cg alkoxy, C _j -CG-alkylmercapto, Ci-CSS alkyl amino, C _j -CG-dialkylamino, C _j -Cg-alkylcarbonylamino, amino, hydroxyl, nitro, azido, trifluoromethyl or halogen, the abovementioned aliphatic radicals preferably containing up to 3 carbon atoms.

Carbocyclic rings R are preferably biphenyl, naphthyl, anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthrenyl, norbomyl, adamantyl, Cs-Cß-cycloalkyl, Cc-Cg-cycloalkenyl, where the carbocyclic rings can be mono- or disubstituted by C_ .-Cg-alkyl, C _.- Cg-A.koxy, C _.- Cg-alkylmercapto, C _j- Cg-alkylamino, C- _j- Cg-dialkylamino-, C ^ Cg-alkylcarbonylamino, amino, hydroxy, nitro, Azido, trifluoromethyl or halogen, the aforementioned aliphatic radicals preferably containing up to 3 carbon atoms.

Heterocyclic ring systems R are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, coumarone, thionaph- then, benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, acridine and phenothiazine, where the heterocyclic rings can be mono- or disubstituted by C.-Cg-alkyl, C ^ -Cg-alkoxy, C.-Cg-alkylmercapto , C _j -Cg alkylamino, C _j -Cg dialkylamino, C ^ -Cg alkylcarbonylamino, amino, hydroxy, nitro, azido, trifluoromethyl or halogen, the aforementioned radicals preferably containing up to 3 carbon atoms.

For the radical R is hydrogen, Cj-Cg-alkyl, C ₂ -Cg-alkenyl, C ₂ -Cg-alkynyl, C_ _| -Cg alkoxy, C _j -Cg alkylmercapto, C_ _| -Cg-alkylamino, C _j -Cg-alkoxy-carbonyl, amino, halogen, hydroxy, nitro, cyano and azido are preferred, the above-mentioned radicals preferably containing up to 3 carbon atoms.

2 Preferred substituents for R are C _j -Cg-alkyl, C.-Cg-hydroxyalkyl.

C ^ Cg-alkylthiomethyl-, C ^ Cg-alkylthioethyl, C _, - C ₆ -alkylthioethyl,

C _j -cg-Alkylthiopropyl, C_ _| -Cg-alkoxymethyi, C _j -Cg-alkoxyethyl and

C_ _j -Cg alkoxypropyl, the aforementioned radicals preferably up to

Contain 3 carbon atoms.

X is preferably oxygen. Halogen generally means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

Y is preferably a nitrogen atom or the group CH.

Particularly preferred radicals for R are phenyl, by C _.- C ₃ alkyl, C ^ -C ₃ alkoxy, C. _| -C ₃ -Alkylmercapto, C _.- C ₃ -alkylamino, di-C -.- C ₃ -alkylamino, amino, hydroxy, azido, trifluoromethyl, or halogen mono- or disubstituted phenyl or phenyl trisubstituted by methyl or halogen, naphthyl , anthracenyl, indenyl, acenaphthylenyl, phenanthrenyl, adamantyl, cyclohexyl, cyclohexenyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, methylenedioxyphenyl, carbazolyl and phenothiazinyl and mono- or di-substituted by methyl or halogen derivatives of the aforementioned carbocychschen or heterocyclic rings.

R is particularly preferably hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methylmercapto, ethylmercapto, methylamino, methoxycarbonyl, Ethoxycarbonyl, amino, azido, cyano, hydroxy and halogen, chlorine and bromine being preferred for halogen.

2 For R, methyl, ethyl and isopropyl are particularly preferred.

Compounds of the general formula I in which R,

1 2

R, X and Y have the meaning given above and R is methyl or ethyl.

The medicaments contain at least one compound of the formula I for the treatment of viral infections and can be administered in liquid or solid form enterally or parenterally. The usual forms of application are possible, such as tablets, capsules, dragees, syrups, solutions or suspensions. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers. Such additives are e.g. Tartrate and citrate buffers, 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 silicic acids, 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. Preparations suitable for oral applications can, if desired, contain flavorings or sweeteners.

The dosage can depend on various factors, such as the mode of administration, species, age or individual condition. The compounds of the invention are usually administered 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 retarded, whereby the number of applications per day is 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 the present invention and their pharmaceutical preparations can also be used in combination with other medicaments for the treatment and prophylaxis of the above-mentioned infections. Examples of these further drugs include agents that can be used for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as S'-azido-S'desoxythymidine, 2 \ 3'-dideoxynucleosides such as, for. B. 2 \ 3'-dideoxycytidine, 2 ', 3'-dideoxyadenosine and 2', 3'-dideoxyinosine, acyclic nucleosides (e.g. acyclovir), interferons such as alpha-interferon, renal excretion inhibitors such as probenicide, Nucleoside transport inhibitors such as dipyridamole, as well as immunomodulators such. B. Interleukin II or stimulation factors such as the granulocyte-macrophage colony factor. The compounds of the present invention and the other medicament can each be administered individually, simultaneously, if appropriate in a single or two separate formulations or at different times.

The compounds of the general formula I according to the invention are prepared by processes known from the literature by

a) Compounds of the general formula II

Λ in which R, R and Y have the meaning given above, with a compound of the general formula III

Z - R2 (III),

2 in which R has the meaning given, and Z is an easily removable

Group such as Halogen or tosylate means in a suitable

Reacts solvent at room temperature to reflux temperature, possibly in the presence of a base such as NaH, alcoholate or NaNH ₂ , or b) compounds of the general formula IV

1 4 in which R has the meaning given, R is a leaving group such as

5 e.g. Halogen and R is a hydrogen atom or an alkyl, benzyl or phenyl derivative, with a hydrazine derivative of the general formula V,

R-NH-NH-R '(V),

in which R and R have the meaning given, to hydrazone of the general formula VI

Λ Λ in which R, R, R, R, X and Y have the meaning given, implemented and then cyclized to give compounds of the general formula I.

Hydrazone formation is advantageously carried out in a protic or aprotic solvent at temperatures between -50 ° C and the boiling point of the solvent, possibly with the addition of an acid, such as e.g. p-Toluoisutfonic acid, glacial acetic acid or hydrochloric acid.

The hydrazones are advantageously cyclized in protic solvents at temperatures between 20 ° C. and 250 ° C., if appropriate under pressure, with the addition of a base such as K ZO- _* , pyridine or collidine in the presence of copper powder. Compounds of the general formula I can also be subsequently converted into other compounds of the general formula I. Thus, compounds of the general formula I with X = S can be prepared by reacting compounds of the formula I in which X is an oxygen atom with compounds which transfer sulfur groups, such as Lawesson's reagent.

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 are suitable, which are used as racemic mixtures or in optically active form or as pure R- and S enantiomers can be present:

1. 2-ethyl-1-phenyl-1, 2-dihydroindazol-3 (3H) one

2. 2-ethyl-1-phenyl-1,2-dihydroindazole-3 (3H) thione

3. 2-ethyl-1 - (3-methylphenyl) -1, 2-dihydroindazol-3 (3H) one

4. 2-ethyl-1 - (3-chlorophenyl) -1, 2-dihydroindazol-3 (3H) one

5. 2-ethyl-1 - (4-methoxyphenyl) -1, 2-dihydroindazol-3 (3H) one

6. 2-ethyl-1 - (2,3-dimethylphenyl) -1, 2-dihydroindazol-3 (3H) one

7. 2-Ethyl-1 - (3,5-dimethylphenyl) -1, 2-dihydroindazol-3 (3H) one

8. 2-ethyl-1 - (1-naphthyl) -1, 2-dihydroindazol-3 (3H) one

9. 2-ethyl-1 - (4-indolyl) -1, 2-dihydroindazol-3 (3H) one

10. 2-ethyl-1 - (2-amino-5-methylphenyl) -1, 2-dihydroindazol-3 (3H) one

11. 2-ethyl-1 - (3,5-dichlorophenyl) -1, 2-dihydroindazol-3 (3H) one

12. 2-ethyl-1 - (6-methyl-2-pyridyl) -1, 2-dihydroindazol-3 (3H) one 13. 2-ethyl-1 - (4-methyl-2-pyridiyl) -1, 2-dihydroindazol-3 (3H) one

1 . 2-ethyl-1 - (2-thienyl) -1, 2-dihydroindazol-3 (3H) one

15. 2-ethyl-1 - (2-furanyl) -1, 2-dihydroindazol-3 (3H) one

16. 2-Ethyl-1-phenyl-6-chloro-1,2-dihydroindazol-3 (3H) one

17. 2-ethyl-1-phenyl-6-methyl-1, 2-dihydroindazol-3 (3H) one

18. 2-ethyl-1-phenyl-6-methoxy-1,2-dihydroindazol-3 (3H) one

19. 2-ethyl-1-phenyl-7-chloro-1,2-dihydroindazol-3 (3H) one

20. 2-ethyl-1-phenyl-7-nitro-1,2-dihydroindazol-3 (3H) one

21. 2-Ethyl-1-phenyl-8-methyl-1,2-dihydroindazol-3 (3H) one

22. 2-ethyl-1-phenyl-7-methyl-1, 2-dihydroindazol-3 (3H) one

23. 2-ethyl-1-phenyl-1,2-dihydropyrazolo [3,4-b] pyridin-3 (3H) one

24. 2-ethyl-1 - (3-methylphenyl) -1, 2-dihydropyrazolo [3,4-b] pyridin-3 (3H) one

25. 2-ethyl-1 - (3-chlorophenyl) -1, 2-dihydropyrazolo [3,4-b] pyridin-3 (3H) one

26. 2-ethyl-1 - (6-methyl-2-pyridyl) -1, 2-dihydropyrazolo [3,4-b] pyridine-3 (3H)

27. 2-Ethyl-1 - (4-methyl-2-pyridyl) -1, 2-dihydropyrazolo [3,4-b] ρyridin-3 (3H) one

28. 2-Methyl-1-phenyl-1,2-dihydroindazol-3 (3H) one

29. 2-methylthioethyl-1-phenyl-1, 2-dihydroindazol-3 (3H) one

30. 2- (2-hydroxypropyl) -1-phenyl-1,2-dihydroindazol-3 (3H) one 31. 2-allyl-1-phenyl-1,2-dihydroindazol-3 (3H) one

32. 2-Cyclopropyl-1-phenyl-1, 2-dihydroindazol-3 (3H) one

33. 2- (1-Cyclopentyl) -1-phenyl-1,2-dihydroindazol-3 (3H) one

34. 2- (3-chloropropyl) -1-phenyl-1,2-dihydroindazol-3 (3H) one

35. 2- (2-ethoxyethyl) -1-phenyl-1,2-dihydroindazol-3 (3H) one

example 1

2-ethyl-1- (3-methyldhenyl) -1.2-dihvdropyrazolof3.4-blpyridin-3f3H) on

a) 13.2 g (108 mmol) of 3-methylphenylhydrazine and 15 ml (108 mmol) of NEW are mixed with 100 ml of CH ₂ Cl ₂ and 19 g (108 mmol) of 2-chloromotinic acid chloride are slowly added dropwise with stirring. After 1 hour the methylene chloride was washed with 2N NaOH, 2N HCl and water, dried and evaporated. After trituration with ether, 12.1 g of crude 2-chloro nicotinic acid 3-methylphenylhydrazone are obtained. 1.9 g of this crude product were heated without stirring to 200 ° C. for 10 minutes, cooled and the residue was crystallized from toluene. 1.0 g of 1- (3-methylphenyl) -1,2-dihydropyrazolo [3,4-b] pyridin-3 (3H) one of mp 169-175 ° C. is obtained.

b) 0.5 g (2.2 mmol) of the previous compound are dissolved in 10 ml of DMF, 80 mg (3.3 mmol) of NaH are added, and 0.1 ml (2.7 mmol) of ethyl bromide are then added dropwise. After 5 hours, the mixture is evaporated, water is added, the mixture is slightly acidified (pH 5.5) and extracted with CH ₂ CL. After the solvent has been stripped off, the O-alkyl derivative which occurs as a by-product can largely be separated off by crystallization from ethanol. The ethanolic mother liquor is evaporated and the residue is purified by chromatography (RP 18, eluent 30% water - 70% methanol). After the desired fractions have been evaporated, 85 mg of the titanium compound are obtained. IR spectrum, CO = 1690 cm ^"1 . Example 2

2-ethyl-1 - (3-methylphenyl) -1,2-dihydroindazol-3 (3H) one

a) 21 g (0.17 mol) of 3-methylphenylhydrazine are dissolved in 100 ml of ether and 32.4 ml (0.34 mol) of acetic anhydride in 100 ml of ether are slowly added dropwise at 0 ° C. After the addition is complete, stirring is continued for 1 hour, the crystals are filtered off with suction and washed with ether. 20.4 g of acetic acid 3-methylphenylhydrazone of mp 114-116 ° C. are obtained.

b) 8.7 g (53 mmol) of the aforementioned compound in 70 ml of THF were mixed with 10 ml (106 mmol) of acetic anhydride and heated to reflux for 4 hours. The mixture was then evaporated at 50 ° C./10 mbar. 10 g of N- (3-methylphenyl) -N, N ^' -diacetylhydrazine are obtained as an oil. HPLC (RP 18): methanol / buffer (pH 2.3) = 80:20, retention time: 1.1 minutes.

c) 1.7 g of sodium are dissolved in 50 ml of ethanol and 10 g (48 mmol) of the preceding compound are added. 8 ml of diethyl sulfate are added to this solution and the mixture is stirred at 25 ° C. for 6 hours. The evaporated residue was taken up in ether, washed with water, dried and evaporated. 6.9 g of N-ethyl-N ^' - (3-methylphenyl) -N, N ^' - diacetylhydrazine are obtained as an oil. HPLC (RP 18): methanol / buffer (pH 2.3) = 80:20, retention time: 1.29 minutes.

d) 6.4 g of the preceding compounds were refluxed with 100 ml of 2N NaOH and 100 ml of ethanol under nitrogen for 6 hours. After the ethanol had been evaporated off, the water phase was extracted with ether and the ether was dried and evaporated. 5.8 g of N-ethyl-N ^' - (3-methylphenyl) -N-acetylhydrazine are obtained as a light red oil. HPLC (RP 18): methanol / buffer (pH 2.3) = 80:20, retention time: 1.61 minutes.

e) 2.0 g of the preceding compounds were mixed with 10 ml of 2N HCl and 10 ml of ethanol and refluxed for 5 hours under nitrogen. The solvent is then completely removed at 50 ° C./10 mbar. 2.1 g of N-ethyl-N '- (3-methylphenyl) hydrazine hydrochloride are obtained as an oil. HPLC (RP 18): methanol / buffer (pH 2.3) = 80:20, retention time: 1.32 minutes.

f) 2.4 g of the previous compound, 3.9 ml of triethylamine and 2.7 g of 2-chlorobenzoyl chloride were in 25 ml of methylene chloride under nitrogen

Stirred for 1 hour. Then it is shaken once with dilute hydrochloric acid and dilute sodium hydroxide solution, dried and evaporated. The residue is purified by chromatography on silica gel with toluene / ethyl acetate = 9: 1. After evaporation of the desired fraction, 1.7 g of N-ethyl-N '- (3-methylphenyl) -N- (2-chlorobenzoyl) hydrazine are obtained as an oil. HPLC (RP 18): methanol / buffer (pH 2.3) = 80:20, retention time: 1.88 minutes.

g) 0.5 g of the preceding compound, 0.24 g of K2CO3, 4.3 mg of copper powder and 5 ml of isoamyl alcohol are heated to 200 ° C. in an autoclave for 48 hours. The alcohol is then distilled off in vacuo and the residue is taken up in dichloromethane, washed with water, dried and concentrated. The residue is purified by chromatography on silica gel with isohexane / ethyl acetate = 8: 2. After evaporation of the desired fractions, 100 mg of the title compound are obtained as an oil. HPLC (RP 18): methanol / buffer (pH 2.3) = 80:20, retention time: 2.23 minutes.

Example 3

The following end products are obtained analogously to Example 2:

3 a) 2-ethyl-1-phenyl-1, 2-dihydroindazol-3 (3H) one

3 b) 2-ethyl-1 - (3,5-dimethylphenyl) -1, 2-dihydroindazol-3 (3H) one

3 c) 2-ethyl-1- (3-chlorophenyl) -1,2-dihydroindazol-3 (3H) one

3 d) 1-methyl- (3-methylphenyl) -1, 2-dihydroindazol-3 (3H) one

3 e) 2-ethyl- (6-methyl-2-pyridinyl) -1, 2-dihydroindazol-3 (3H) one f) 2-ethyl- (4-methyl-2-pyridinyl) -1, 2-dihydroindazol-3 (3H) one

g) 2-ethyl-6-chloro-1-phenyl-1, 2-dihydroindazol-3 (3H) one

Claims

1. Indazole derivatives of the formula I.

in the

R is a phenyl ring 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 means 1-4 or 1-5 heteroatoms can be present, the heteroatoms being nitrogen, sulfur or oxygen, and the aforementioned phenyl rings, the mono-, bi- or tricyclic carbocyclic rings or the heterocyclic mono-, bi- or tri-cyclic ring systems, if appropriate are substituted one or more times by C _j -Cg alkyl, C _| -Cg alkoxy, C _j -Cg alkyl mercapto, amino, C- _| -Cg-alkylamino, di-C _, - Cg-aikylamino, C _, - Cg-alkylcarbonylamino, hydroxy, nitro, halogen, trifluoromethyl or azido,

R is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C atoms or C _j -Cg alkoxy, C _j -Cg alkyl mercapto, C _j -Cg alkyl sulfinyl, C <| -C6 Alkylsulfonyl, amino, C _.- Cg-alkylamino, di-C ..- Cg-alkylamino, sulfonamido, C _.- Cg-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano or azido,

R ² is C _j -CG alkyl, C ₂ -CG-alkenyl, C ₄ -C ₈ cycloalkyl, C ₃ is -CG-cycloalkenyl, where the abovementioned alkyl or alkenyl radical if appropriate with fluorine, chlorine, hydroxyl and mercapto substituted or can be interrupted by an oxygen or sulfur atom, represents an oxygen or sulfur atom, and

-1 represents a nitrogen atom or CR,

with the proviso that R is not an unsubstituted phenyl ring or a

2 3-Tr ^' ιfluorphenyiring means when R is a C_ _| -C ₃ alkyl group through

Halogen may be substituted,

as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts.

Indazole derivatives of the formula I according to claim 1, characterized in that R is a phenyl ring or a carbocyclic radical selected from the group naphthyl, anthracenyl, phenanthrenyl, flourenyl, indenyl, acenaphthylenyl, norbomyl, adamantyl, C ₃ -C cycloalkyl or C ₅ -Cg-cycloalkenyl, which can be substituted by C _j -Cg-alkyl, C.-Cg-alkoxy, Ci-Cg-alkylmercapto, C _, - Cg-alkylamino, C _j -Cg-dialkylamino-, Ci Cß-alkylcarbonylamino, amino, hydroxy, nitro, azido, trifluoromethyl or halogen.

Indazole derivatives of the formula I according to claim 1, characterized in that R is a heterocyclic mono-, bi- or tricyclic ring selected from the group pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, Oxazolyl, isoxazolyl, oxadiazolyl, furazanyl, furanyl, thiophenyl, indolyl, quinolinyl, isoquinolinyl, coumaronyl, thionaphthenyl, benzoxazolyl, benzthiazolyl, indazolyl, benzimidazolyl, benztriazoiyl, chromenyl, phthalazylyl, methylzylazylyl, carbolnylazylylyl, methylzylazylyl, carbolnylazylyl, methylphenylyl, methyazolylyl, methazolylyl, methazolylyl, methazolylyl, acrolazyl, methylazylyl, methacylazylyl, carbolnylazylyl, carbolnylazylyl, methacylazolyl, carbolnylazylyl phen- oxazinyl, phenothiazinyl, phenazinyl or purinyl, wherein the heterogeneously cyciische ring may be substituted by C _j -CG alkyl, C, -. Cg-alkoxy, C _.- Cg alkylmercapto, C _.- Cg-alkylamino, C ^ -Cg-dialkylamino-, C- | -C6- alkylcarbonylamino, amino, hydroxy, nitro, azido, trifluoromethyl or halogen.

Indazole derivatives of the formula I according to claim 1 or 2, characterized gekenn¬ characterized in that R is an unsubstituted phenyl ring or a phenyl ring means that is mono- or disubstituted by C _.- Cg-alkyl, C_j-Cg-alkoxy, Cj-Cg-alkylmercapto, Cj-Cg-alkylamino, C ^« | -C6-dialkylamino-, C ^ Cg- Alkylcarbonylamino, amino, hydroxy, nitro, azido, trifluoromethyl or halogen.

5. indazole derivatives of the formula I according to any one of claims 1-4, characterized in that the radical R is hydrogen, C.-Cg-alkyl, C ₂ -Cg-alkenyl, C ₂ -Cg-alkynyl, C _, - Cg- Alkoxy, C _, - Cg-alkylmercapto, C _, - Cg-alkylamino, C ^ Cg-alkoxy carbonyl, amino, halogen, hydroxy, nitro, cyano or azido means.

6. indazole derivatives of the formula I according to one of claims 1-5, characterized in that R ² is C _j -CG alkyl, C _j -CG-hydroxyalkyl, Ci-CSS alkylthiomethyl, C_ _j -CG-alkylthioethyl, C _j -cg-alkylthioethyl, C- | -C6- Alkylthiopropyl, C _j -cg-alkoxymethyl, C_ _j -cg-alkoxyethyl or C Cβ- alkoxypropyl means.

7. indazole derivatives of the formula I according to any one of claims 1-6, characterized ge indicates that X is oxygen.

8. indazole derivatives of the formula I according to any one of claims 1-7, characterized ge indicates that Y represents a nitrogen atom or the group CH.

9. Use of indazole derivatives of the formula I according to any one of claims 1-8 for the manufacture of medicaments for the treatment of viral or retroviral infections or the diseases caused by these infections.

10. Use of indazole derivatives of the formula I.

/ Y - R

N

> 1 l ^'

LN © for the manufacture of medicaments for the treatment of viral or retro-viral infections or the diseases caused by these infections, wherein

R denotes a phenyl ring 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 in each case and 1-4 or 1-5 heteroatoms may be present, the heteroatoms being nitrogen, sulfur or oxygen, and the aforementioned phenyl rings, the mono-, bi- or tri-cyclic carbocyclic rings or the heterocyclic mono-, bi- or tricychic ring systems or polysubstituted by C _j -CG alkyl, C- _j -CG-alkoxy, C_ _| -Cg-alkyl-mercapto, amino, C _.- Cg-alkylamino, di-C _j -Cg-alkylamino, C- | -C6-alkylcarbonylamino, hydroxy, nitro, halogen, trifluoromethyl or azido,

R is a hydrogen atom, a linear or branched, saturated or unsaturated gesät¬ aliphatic radical having 1-6 C atoms or C _j -CG-alkoxy, C _j -CG-alkylmercapto, C _j -CG-alkylsulfinyl, Cη-Cβ- Means alkylsulfonyl, amino, C _j -Cg-alkylamino, di-C _j -Cg-alkylamino, sulfonamido, C _, - Cg-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano or azido,

R ^{2 is} C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₄ -C ₈ -cycloalkyl, C ₃ -Cg -cycloalkenyl, the aforementioned alkyl or alkenyl radicals optionally being substituted with fluorine, chlorine, hydroxyl and mercapto or can be interrupted by an oxygen or sulfur atom,

X represents an oxygen or sulfur atom,

Y represents a nitrogen atom or CR,

as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts. 11. A process for the preparation of compounds of formula I according to any one of claims 1-9, characterized in that

a) Compounds of the general formula II

in which R, R and Y have the meaning given above, with a compound of the general formula III

Z - R ² (III),

in which R has the meaning given, and Z means an easily removable group, such as halogen or tosylate, in a suitable solvent at room temperature to reflux temperature, possibly in the presence of a base such as NaH, alcoholate or NaNH ₂ , or

b) compounds of the general formula IV

in which R 1 has the meaning given, R 4 is a leaving group such as

5 e.g. Halogen and R is a hydrogen atom or an alkyl, benzyl or

Phenyl derivative is, with a hydrazine derivative of the general formula

(V)

R-NH-NH-R (V), in which R and R have the meaning given, to hydrazone of the general formula VI

1 2 4 in which R, R, R, R, X and Y have the meaning given, converted and then cyclized to give compounds of the general formula I.