DE4320347A1 - Quinazoline derivatives and medicaments containing them - Google Patents

Abstract

The invention relates to quinazoline derivatives of the formula I <IMAGE> in which R is a phenyl ring or a carbocyclic ring having 7-15 C atoms or a heterocyclic ring system in each case having 5 or 6 ring atoms and these are optionally mono- or polysubstituted by C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylmercapto, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkylcarbonylamino, hydroxyl, nitro, halogen, trifluoromethyl or azido, R<1> is a hydrogen atom, an aliphatic radical having 1-6 C atoms or C1-C6-alkoxy, C1-C6-alkylmercapto, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, sulphonamido, C1-C6-alkoxycarbonyl, carboxyl, halogen, hydroxyl, nitro, cyano or azido, R<2> is C1-C8-alkyl, C2-C8-alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, where the alkyl or alkenyl radicals can optionally be substituted by fluorine, chlorine, hydroxyl and mercapto or interrupted by an oxygen or sulphur atom, R<3> is hydrogen or a C1-C6-alkyl group which can be substituted by one, two or three halogen atoms, X is an oxygen or sulphur atom, Y is a nitrogen atom or CR<1>, and their tautomers, enantiomers, diastereomers and physiologically tolerable salts.

Description

The present invention relates to quinazoline derivatives, Process for their manufacture and medicinal products containing them Connections included.

The invention relates to quinazoline 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 1-4 or 1- per ring system 5 heteroatoms can be contained, the heteroatoms being nitrogen, sulfur or oxygen, the aforementioned phenyl rings, the mono-, bi- or tricyclic carbocyclic rings or the heterocyclic mono-, bi- or tricyclic ring system optionally being substituted one or more times is by C₁-C₆- alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxy, nitro, halogen, trifluoromethyl or Azido,
R¹ is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C atoms or C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, amino, C₁- C₆-alkyl amino, di-C₁-C₆-alkylamino, sulfonamido, C₁-C₆-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano or azido,
R² C₁-C₈-alkyl, C₂-C₈-alkenyl, C₃-C₈-cycloalkyl, C₃-C₈-cyclo alkenyl, the above-mentioned alkyl or alkenyl radicals being optionally substituted with fluorine, chlorine, hydroxy and mercapto or interrupted by an oxygen or sulfur atom could be,
R³ is hydrogen or a C₁-C₆ alkyl group which can be substituted by one, two or three halogen atoms,
X is an oxygen or sulfur atom,
Y represents a nitrogen atom or CR¹,
as well as their tautomers, enantiomers, diastereomers and physiologically compatible salts.

Quinazoline derivatives with a similar structure are from the Inter national patent application WO 93/04047 known. The be there Derivatives written are reverse inhibitors Transcriptase and can be used to manufacture drugs be used. Quinazoline derivatives are also in the Patent literature for various medical applications already described. This is especially true for such deri vate zu, in which the radical R is an unsubstituted phenyl ring and R1 is hydrogen or chlorine. The Japanese application JP 7214183 describes China substituted in the 3-position zolin-2-one with anti-inflammatory and analgesic Effect. In the German Offenlegungsschrift 2508543  Quinazoline as an intermediate for the production of anti depressive drugs related. Antidepressants, anti-inflammatory, analgesic and bactericidal effect 3-substituted quinazolin-2-ones in German Offenlegun gen 2162327 and 2166327. As intermediates for Manufacture of drugs with hypotensive and platelets 3-substituted quinazolines are inhibitory in the Japanese application called JP 7844592. The synthesis of this Quinazoline derivatives is described in detail in Chem. Pharm. Bull. 29, 2135, 1981. Antiviral activity has been reported in however, these derivatives have not yet been demonstrated.

The object of the present invention was to create new ones Quinazoline is available for the manufacture of medicines too put.

The compounds of the present invention have valuable pharmacological properties. In particular, they own an antiviral effect and are suitable for therapy and pro prevention of infections caused by DNA viruses such as B. that Herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr virus or RNA Viruses like toga viruses or especially retroviruses like the oncology HTLV-I and II viruses, as well as the lentiviruses Visna and Humanes- Immunodeficiency virus HIV-1 and -2.

The compounds of the formula I appear to be particularly suitable for Treatment of clinical manifestations of retroviral HIV Human infection, such as the persistent, generalized Lymphadenopathy (PGL), the advanced stage of AIDS related complex (ARC) and the clinical picture of AIDS.

The compounds of general formula I according to the invention have a pronounced antiviral effect and are suitable especially for the treatment of viral or retroviral Infections. Viral infections in mammals, especially the People are common. Despite intensive efforts  it has so far not been possible to provide chemotherapy drugs, the causal or symptomatic with the viral or retroviral conditioned illnesses with recognizable substantial Interfering Success. It is not possible these days to determine te viral diseases, such as the acquired immune Deficiency Syndrome (AIDS), the AIDS-related complex (ARC) and their pre-stages, herpes, cytomegalovirus (CMV) -, influenza and cure other viral infections or chemotherapy to influence their symptoms favorably. Is currently at for example for the treatment of AIDS almost exclusively that 3'-azido-3'-deoxy-thymidine (AZT), known as zidovudine or Retrovir®, available. AZT is, however, very tight therapeutic breadth or already in therapeutic Characterized very severe toxicities (Hirsch, M.S. (1988) J.Infec. Dis. 157, 427-431). The connection gene 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 connections of the general Formula I mean the multiplication of DNA or RNA viruses on the Level of virus-specific DNA or RNA transcription hem men. The substances can inhibit the enzyme Reverse transcriptase affects retrovirus proliferation sen (see Proc. Natl. Acad. Sci. USA 83, 1911, 1986 and Nature 325, 773 1987).

Since there is a very great need for chemotherapeutics, the as specifically as possible with retroviral diseases or their symptoms interfere without the normal ones could influence natural bodily functions mentioned compounds advantageously prophylactically or thera used in the treatment of diseases in which a retroviral infection of pathophysiological, is symptomatic or clinical relevance.  

The separation of the racemates into the enantiomers can be carried out analytically, semi-preparative and preparative chromatographic on suitable optically active phases with common eluents leads.

Optically active phases are, for example, optically suitable active polyacrylamides or polymethacrylamides, e.g. T. also on Silica gel (e.g. ChiraSpher® from Merck, Chiralpak® OT / OP from Baker), cellulose esters / carbamates (e.g. Chiracel® OB / OY from Baker / Daicel), phases on cyclodextrin or crown ether base (e.g. Crownpak® from Daicel) or microcrystalline Cellulose triacetate (Merck).

A carbocyclic ring R with 7-15 C atoms can be mono-, bi- or be tricyclic and 5 or 6 carbon atoms per ring exhibit. This ring can be saturated, unsaturated, partial be saturated or aromatic. Examples include those following ring systems: the naphthyl, anthracenyl, phenanthre nyl, flourenyl, indenyl, acenaphthylenyl, norbornyl, Adamantyl ring or a C₃-C₇ cycloalkyl or C₅-C₈ cycloalke nyl group. The carbocyclic ring can also be mono- or be disubstituted, the substituents being independent can preferably be 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, where 1-4 or 1-5 carbon atoms through the heteroatoms oxygen, Sulfur and / or nitrogen can be replaced. The ring systems can be aromatic, partially or fully hydrogenated his. The following ring systems may be mentioned as examples: Pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, Pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, Oxadiazole, furazane, furan, thiophene, indole, quinoline, Isoquinoline, coumarone, thionaphthene, benzoxazole, benzthia zole, indazole, benzimidazole, benzotriazole, chromene, phthalate tin, quinazoline, quinoxaline, methylenedioxybenzene, Carbazole, acridine, phenoxazine, phenothiazine, phenazine or  Purine system, the unsaturated or aromatic carbo- and heterocycles can be partially or fully hydrogenated nen. The heterocyclic ring system can also be mono- or be disubstituted, the substituents being independent can preferably be in the o- or m-position.

R preferably denotes unsubstituted phenyl or phenyl mono- or substituted twice by C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁- C₃-alkylmercapto, C₁-C₃-alkylamino, C₁-C₃-dialkylamino-, C₁-C₃- Alkylcarbonylamino, amino, hydroxy, nitro, azido, tri fluoromethyl or halogen, the aforementioned aliphati rule radicals preferably contain up to 3 carbon atoms.

Carbocyclic rings R are preferably biphenyl, naphthyl, Anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthre nyl, norbornyl, adamantyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalke nyl, the carbocyclic rings being one or two can be substituted by C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁- C₃-alkyl mercapto, C₁-C₃-alkylamino, C₁-C₃-dialkylamino-, C₁-C₃- Alkylcarbonylamino, amino, hydroxy, nitro, azido, tri fluoromethyl or halogen, the aforementioned aliphati rule radicals preferably contain up to 3 carbon atoms.

Heterocyclic ring systems R are preferably pyrrole, imidazole, Furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, Quinoline, isoquinoline, coumarone, thionaphthene, benzimidazole, Quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, Acridine and phenothiazine, with the heterocyclic rings or can be substituted twice by C₁-C₃-alkyl, C₁- C₃-alkoxy, C₁-C₃-alkyl mercapto, C₁-C₃-alkylamino, C₁-C₃-di alkylamino, C₁-C₃ alkylcarbonylamino, amino, hydroxy, nitro, Azido, trifluoromethyl or halogen.

For the rest R¹ is hydrogen, C₁-C₃-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₃-alkoxy, C₁-C₃-alkylmercapto, C₁-C₃-alkyl amino, C₁-C₃ alkoxycarbonyl, amino, halogen, hydroxy, nitro, Cyano and azido preferred.  

Preferred for R² are C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃- Alkylthiomethyl, C₁-C₃-alkylthioethyl, C₁-C₃-alkylthioethyl, C₁-C₃-alkylthiopropyl, C₁-C₃-alkoxymethyl, C₁-C₃-alkoxyethyl and C₁-C₃ alkoxypropyl.

R³ means in particular an alkyl group with up to 4 C atoms, which can be straight-chain or branched, preferred have a methyl, ethyl, propyl or butyl group, the Alkyl group on one or more carbon atoms by one or two or three halogen atoms is substituted and in total up to three halogen substituents may be present. Halogen atoms are in particular the fluorine, chlorine or bromine atom. Especially the trifluoromethyl and trichloromethyl groups are preferred Question.

X is preferably oxygen.

Halogen generally includes fluorine, chlorine, bromine and iodine understand, preferably fluorine, chlorine and bromine.

Y is preferably a nitrogen atom or the group CH.

Particularly preferred radicals for R are phenyl, by C₁-C₃- Alkyl, C₁-C₃-alkoxy, C₁-C₃-alkylmercapto, C₁-C₃-alkylamino, di- C₁-C₃-alkylamino, amino, hydroxy, azido, trifluoromethyl or Halogen mono- or disubstituted phenyl or by methyl or halogen trisubstituted phenyl, naphthyl, anthracenyl, Indenyl, acenaphthylenyl, phenanthrenyl, adamantyl, cyclohexyl, Cyclohexenyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, Indolyl, quinolinyl, benzimidazolyl, methylenedioxyphenyl, Carbazolyl and phenothiazinyl and by methyl or halogen mono- or disubstituted derivatives of the aforementioned carbo cyclic or heterocyclic rings.

R 1 is particularly preferably hydrogen, methyl, ethyl, Isopropyl, allyl, methoxy, ethoxy, methylmercapto, ethylmer capto, methylamino, methoxycarbonyl, ethoxycarbonyl, amino,  Azido, Cyano, Hydroxy and Halogen, whereby chlorine and bromine for Halogen is preferred.

For R², methyl, ethyl and isopropyl are particularly preferred.

Compounds of the general are particularly preferred Formula I in which R, R¹, X and Y have the meaning given above tion and R² is methyl or ethyl.

Trichloromethyl is particularly preferred for R³.

The medicinal products contain at least one compound of Formula I for the treatment of viral infections and can be used in liquid or solid form applied enterally or parenterally become. The usual forms of application come into play here Question such as tablets, capsules, drag'es, syrups, Solutions or suspensions. Preference is given as the injection medium wise water to use, which is the case with injection solutions usual additives such as stabilizers, solubilizers and contains buffers. Such additives are e.g. B. tartrate and Citrate buffer, ethanol, complexing agents, such as ethylene diamine tetra acetic acid and its non-toxic salts, high molecular weight Polymers such as liquid polyethylene oxide for viscosity control tion. 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, Calcium phosphate, magnesium stearate, animal and vegetable Fat, solid, high molecular weight polymers, such as polyethylene glycols, etc. Suitable preparations for oral applications if desired contain flavorings or sweeteners.

The dosage can depend on various factors, such as appliques manner, species, age or individual condition. The compounds according to the invention are usually described in Amounts of 0.1-100 mg, preferably 0.2-80 mg per day and  applied per kg body weight. It is preferred the day distribute dose over 2-5 applications, with each Application 1-2 tablets with an active ingredient content of 0.5-500 mg can be administered. The tablets can also be delayed be, which brings the number of applications per day to 1-3 reduced. The active substance content of the prolonged-release tablets can Amount to 2-1000 mg. The active ingredient can also last through be given infusion, the amounts of 5-1000 mg per Day is usually sufficient.

The compounds of the present invention and their pharmazeu Table preparations can also be used in combination with others Medicines for the treatment and prophylaxis of the above Infections are used. Examples of these other medic neimittmittel include agents used for treatment and prophylaxis HIV infection or disease accompanying this disease gene can be used like 3'-azido-3'deoxythymidine, 2 ', 3'-dide soxynucleosides such as B. 2 ', 3'-dideoxycytidine, 2', 3'- Dideoxyadenosine and 2 ′, 3 ′ -dideoxyinosine, acyclic nucleosi de (e.g. acyclovir), interferons such as e.g. B. alpha interferon, renal excretion inhibitors such as B. probenicid, nucleo sid transport inhibitors such as B. dipyridamole, as well Immunomodulators such as B. Interleukin II or stimulation Factors such as B. the granulocyte-macrophage colony factor. The compounds of the present invention and the other Medicines can be given individually, at the same time if in a single or two separate formulations or administered at different times, so that a synergistic effect is achieved.

The compounds of general formula I according to the invention are based on methods known from the literature (Chem. Pharm. Bull. 29, 2135, 1981 or Heterocycles 29, 1317, 1989), by using compounds of the general formula II

in which R and R¹ have the meaning given above and R³, C₁-₆-alkyl, CBr₃, CCl₃ or CF₃ can be with an amine general formula III

H₂N-R² III,

in which R² has the meaning given above, in a suitable ten inert solvent at room temperature to reflux temperature temperature in the presence of catalytic amounts of acid, e.g. B. p- Toluene sulfonic acid or hydrochloric acid and optionally then compounds of the formula I into other compounds of the formula I subsequently converted and then chromato cleaned graphically or by recrystallization. Racemate can by chromatography on suitable optically active phases, e.g. B. cellulose triacetate, are separated into the antipodes.

The subsequent conversion of compounds of formula I into other compounds of formula I relate to e.g. B. the manufacture of compounds with R³ equal to hydrogen. These connections z. B. prepared from compounds of formula I with R² = Trihalomethyl by reaction with a reducing agent such as e.g. B. NaBH₄ or LiAlH₄ in an inert solvent Temperatures between -20 ° C and 150 ° C.

Compounds of the general formula I with X = S are obtained represents by reacting compounds of formula I in which X means an oxygen atom with sulfur group transferring Connections such as B. Lawesson's reagent.  

The compounds of the general used as starting material NEN Formula II are based on methods known from the literature Aminobenzophenone derivatives obtained by acylation. The substituted or unsubstituted 2-aminobenzophenone derivatives te can be advantageous according to those of David A. Walsh produce the written method (Synthesis, 677, 1980).

For the purposes of the present invention come in addition to the in Examples mentioned compounds and the combination all the meanings of the substituents mentioned in the claims the following compounds of the formula in question as racemi mixtures or in optically active form or as pure R- and S enantiomers can be present:

1. 3-ethyl-4-phenyl-3,4-dihydroquinazolin-2 (1H) one
2. 3-ethyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) thione
3. 3-ethyl-4- (3-methylphenyl) -3,4-dihydroguinazolin-2 (1H) one
4. 3-ethyl-4- (3-chlorophenyl) -3,4-dihydroguinazolin-2 (1H) one
5. 3-ethyl-4- (4-methoxyphenyl) -3,4-dihydroguinazolin-2 (1H) one
6. 3-ethyl-4- (2,3-dimethylphenyl) -3,4-dihydroquinazolin-2 (1H) one
7. 3-ethyl-4- (3,5-dimethylphenyl) -3,4-dihydroquinazolin-2 (1H) one
8. 3-ethyl-4- (1-naphthyl) -3,4-dihydroguinazolin-2 (1H) one
9. 3-ethyl-4- (4-indonyl) -3,4-dihydroguinazolin-2 (1H) one
10. 3-ethyl-4- (2-amino-5-methylphenyl) -3,4-dihydroguinazolin-2 (1H) one
11. 3-Ethyl-4- (3,5-dichlorophenyl) -3,4-dihydroguinazolin-2 (1H) one
12. 3-ethyl-4- (6-methyl-2-pyridyl) -3,4-dihydroguinazolin-2 (1H) one
13. 3-Ethyl-4- (4-methyl-2-pyridiyl) -3,4-dihydroguinazolin-2 (1H) one
14. 3-Ethyl-4- (2-thienyl) -3,4-dihydroquinazolin-2 (1H) one
15. 3-Ethyl-4- (2-furanyl) -3,4-dihydroquinazolin-2 (1H) one
16. 3-Ethyl-4-phenyl-6-chloro-3,4-dihydroguinazolin-2 (1H) one
17. 3-ethyl-4-phenyl-6-methyl-3,4-dihydroguinazolin-2 (1H) one
18. 3-ethyl-4-phenyl-6-methoxy-3,4-dihydroguinazolin-2 (1H) one
19. 3-ethyl-4-phenyl-5-chloro-3,4-dihydroquinazolin-2 (1H) one
20. 3-ethyl-4-phenyl-5-nitro-3,4-dihydroguinazolin-2 (1H) one
21. 3-Ethyl-4-phenyl-8-methyl-3,4-dihydroguinazolin-2 (1H) one
22. 3-Ethyl-4-phenyl-7-methyl-3,4-dihydroguinazolin-2 (1H) one
23. 3-ethyl-4-phenyl-3,4-dihydropyrido [3,2-b] pyrimidin-2 (1H) one
24. 3-Ethyl-4- (3-methylphenyl) -3,4-dihydropyrido [3,2- b] pyrimidin-2 (1H) one
25. 3-Ethyl-4- (3-chlorophenyl) -3,4-dihydropyrido [3,2- b] pyrimidin-2 (1H) one
26. 3-ethyl-4- (6-methyl-2-pyridyl) -3,4-dihydropyrido [3,2-b] pyrimidin-2 (1H) one
27. 3-Ethyl-4- (4-methyl-2-pyridyl) -3,4-dihydropyrido [3,2-b] pyrimidin-2 (1H) one
28. 3-ethyl-4-methyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
29. 3-ethyl-4-trichloromethyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
30. 3-ethyl-4-trifluoromethyl-4-phenyl-3,4-dihydroquinazolin-2 (1H) one
31. 3-Methyl-4-phenyl-3,4-dihydroquinazolin-2 (1H) one
32. 3-Methylthioethyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
33. 3- (2-hydroxypropyl) -4-phenyl-3,4-dihydroguinazolin-2 (1H) one
34. 3-Allyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
35. 3-Cyclopropyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
36. 3- (1-Cyclopentyl) -4-phenyl-3,4-dihydroquinazolin-2 (1H) one
37. 3- (3-Chloropropyl) -4-phenyl-3,4-dihydroquinazolin-2 (1H) one
38. 3- (Ethoxyethyl) -4-phenyl-3,4-dihydroguinazolin-2 (1H) one

example 1 4-trichloromethyl-4-phenyl-3,4-dihydrocuinazolin-2 (1H) one

• a) To 5 g (25 mmol) of 2-aminobenzophenone in 50 ml of toluene and 2.2 ml of pyridine are added dropwise 3.1 ml (27.5 mmol) of trichloroacetyl chloride in 10 ml of toluene at 10 ° C. with stirring. After one hour, the mixture is shaken 3 × with water, the organic phase is separated off, dried and evaporated. The oil obtained is rubbed with isohexane and the crystals are filtered off with suction.
  7.7 g of 2-trichloroacetylaminobenzophenone with a melting point of 103-105 ° C. are obtained.
• b) 1 g (2.9 mmol) 2-trichloroacetylaminobenzophenone, 1.6 g (11.7 mmol) triethylamine and 1.84 g (23.4 mmol) ethylamine Hydrochloride, stick in 5 ml of DMSO for 24 hours stuff stirred. Then it is diluted with water and the crystals are suctioned off. Obtained after recrystallization 0.7 g of the title compound of mp. 223-225 ° C.

Example 2

The following products are obtained analogously to Example 1:

Example 3 3-ethyl-4-phenyl-3,4-dihydroquinazolin-2 (1H) one

1.4 g (3.8 mmol) of the compound obtained in Example 1 was dissolved in 20 ml DMF and at 25 ° C with 0.3 g (7.6 mmol) NaBH₄ transferred. After 16 hours it was diluted with water, carefully treated with 2 N HCl and the precipitate is suction filtered. You get 0.85 g of the title compound of mp 170-172 ° C.  

Example 4

The following products are obtained analogously to Example 3:

Example 5 3-ethyl-4-phenyl-3,4-dihydroquinazoline-2 (1H) thione

0.5 g (1.9 mmol) of the compound obtained in Example 3 was with 0.75 g (1.9 mmol) of Lawesson's reagent in 25 ml of toluene 90 ° C stirred. After 4 and 8 hours the same thing happened again Amount of Lawessons reagent added. After 24 hours it was Washed toluene with water, dried, evaporated and the Residue on silica gel (mobile phase: 60% isohexane-40% vinegar ester) cleaned. After evaporating the desired fractions the residue was crystallized from ethanol. You get 110 mg of the title compound of mp 160-62 ° C.

Example 6

The following products are obtained analogously to Example 5:

Claims (11)

1. Quinazoline 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 1-4 or 1- per ring system 5 heteroatoms can be contained, the heteroatoms being nitrogen, sulfur or oxygen, the aforementioned phenyl rings, the mono-, bi- or tricyclic carbocyclic rings or the heterocyclic mono-, bi- or tricyclic ring system optionally being substituted one or more times is by C₁-C₆- alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonyl amino, hydroxy, nitro, halogen, trifluoromethyl or azido,
R¹ is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms or C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, amino, C₁ -C₆- alkylamino, di-C₁-C₆-alkylamino, sulfonamido, C₁-C₆- alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano or azido,
R² C₁-C₈-alkyl, C₂-C₈-alkenyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, where the aforementioned alkyl or alkenyl radicals are optionally substituted with fluorine, chlorine, hydroxy and mercapto or interrupted by an oxygen or sulfur atom could be,
R³ is hydrogen or a C₁-C₆ alkyl group which can be substituted by one, two or three halogen atoms,
X is an oxygen or sulfur atom,
Y represents a nitrogen atom or CR¹,
as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts. 2. Quinazoline derivatives of the formula I according to claim 1, characterized characterized in that R represents a phenyl ring which is unsub is substituted or mono- or disubstituted by C₁- C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-alkylmercapto, C₁-C₃-alkyl amino, C₁-C₃-dialkylamino, C₁-C₃-alkylcarbonylamino, amino, Hydroxy, nitro, azido, trifluoromethyl or halogen. 3. Quinazoline derivatives of the formula I according to claim 1, characterized characterized in that R represents a carbocyclic ring selected from the group biphenyl, naphthyl, anthracenyl, Indenyl, fluorenyl, acenaphthylenyl, phenanthrenyl, norbor nyl, adamantyl, C₃-C₆-cycloalkyl and C₅-C₈-cycloalkenyl, the carbocyclic rings one or two substi can be tuiert by C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃- Alkylmercapto, C₁-C₃-alkylamino, C₁-C₃-dialkylamino-, C₁-C₃- Alkylcarbonylamino, amino, hydroxy, nitro, azido, trifluor methyl or halogen. 4. Quinazoline derivatives of the formula I according to claim 1, characterized characterized in that R represents a heterocyclic ring selected from the group pyrrole, imidazole, furan, thiophene,  Pyridine, pyrimidine, thiazole, triazine, indole, quinoline, Isoquinoline, coumarone, thionaphthene, benzimidazole, quinazo lin, methylenedioxybenzene, ethylenedioxybenzene, carbazole, Acridine and phenothiazine, with the heterocyclic rings can be mono- or disubstituted by C₁-C₃- Alkyl, C₁-C₃-alkoxy, C₁-C₃-alkylmercapto, C₁-C₃-alkylamino, C₁-C₃-dialkylamino, C₁-C₃-alkylcarbonylamino, amino, Hydroxy, nitro, azido, trifluoromethyl or halogen. 5. Quinazoline derivatives of the formula I according to one of the claims 1-4, characterized in that R¹ is hydrogen, C₁-C₃- Alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₃-alkoxy, C₁-C₃- Alkylmercapto, C₁-C₃-alkylamino, C₁-C₃-alkoxycarbonyl, Amino, halogen, hydroxy, nitro, cyano or azido means. 6. Quinazoline derivatives of the formula I according to one of the claims 1-5, characterized in that R² is C₁-C₃-alkyl, C₁-C₃- Hydroxyalkyl, C₁-C₃-alkylthiomethyl-, C₁-C₃-alkylthioethyl, C₁-C₃-alkylthioethyl, C₁-C₃-alkylthiopropyl, C₁-C₃-alkoxy methyl, C₁-C₃-alkoxyethyl or C₁-C₃-alkoxypropyl. 7. Quinazoline derivatives of the formula I according to one of the claims 1-6, characterized in that R³ is a methyl, ethyl, Represents propyl or butyl group on one or more Ren carbon atoms by one, two or three halogen atoms is tuiert and a total of up to three halogen substituents can be present. 8. Quinazoline derivatives of the formula I according to claim 7, characterized characterized in that R³ trifluoromethyl or trichloromethyl means. 9. A process for the preparation of quinazoline derivatives of the formula I according to any one of claims 1-8, characterized in that compounds of the general formula II in which R and R¹ have the meaning given above and R³, C₁-Alkyl-alkyl, CBr₃, CCl₃ or CF₃, with an amine of the general formula IIIH₂N-R² III, in which R² has the meaning given, in a suitable inert Reacts solvent at room temperature to reflux temperature, possibly in the presence of catalytic amounts of acid and, if appropriate, subsequently subsequently converts compounds of the formula I into other compounds of the formula I. 10. Medicament containing at least one compound of Formula I according to any one of claims 1-8 and pharmacologically compatible auxiliaries or carriers. 11. Use of compounds of formula I according to one of the Claims 1-8 for the manufacture of medicaments for Treatment of viral or retroviral infections.