WO1993023405A1

WO1993023405A1 - Use of tricyclic pyrimidine derivatives as anti-viral medicaments

Info

Publication number: WO1993023405A1
Application number: PCT/EP1993/001124
Authority: WO
Inventors: Alfred Mertens; Harald Zilch; Bernhard König; Ulrike Leser
Original assignee: Boehringer Mannheim Gmbh
Priority date: 1992-05-10
Filing date: 1993-05-07
Publication date: 1993-11-25
Also published as: EP0640087A1; JPH08500089A; DE4214829A1; AU4065493A; CA2134218A1

Abstract

The present invention relates to the novel use of tricyclic pyrimidine derivatives for the production of medicaments with an anti-viral effect. In addition, the object of the invention covers novel pyrimidine derivatives, a process for their production and medicaments containing these compounds. The invention relates to the use of tricyclic pyrimidine derivatives of general formula (I) for the production of medicaments with an anti-viral effect in which A is a carbocyclic or a heterocyclic ring, X may be an oxygen or sulphur atom or the group =NH, =N-C1?-C6? alkyl or =S(O)2?, Y may be an oxygen atom or the NH- or C1?-C5? alkylamino group, R is an aliphatic radical with 1-9 C atoms which may be substituted by phenyl, or a phenyl ring or a carbocyclic ring with 7-15 C atoms or a heterocyclic ring system, R?1 is a hydrogen atom, an aliphatic radical with 1-6 C atoms or C1?-C6? alkoxy, C1?-C6? alkylmercapto, C1?-C6? alkylsulphinyl, amino, C1?-C6? alkylamino, di-C1?-C6? alkylamino, sulphonamido, C1?-C6? alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy, R?2, R?3, R?4 and R?5 may be mutually independently the same or different and represent hydrogen, C1?-C6? alkyl, C1?-C6? hydroxyalkyl, cyano, carboxy or C1?-C6? alkoxycarbonyl or R?2 and R?4 are a further bond between the C atoms to which they are bonded, R?6 is hydrogen or C1?-C6? alkyl and m is 0 or 1, and their tautomers, enantiomers, diastereomers or physiological tolerable salts.

Description

Use of tricyclic pyrimidine derivatives as antiviral drugs

The present invention relates to the new use of tricyclic pyrimidine derivatives for the production of medicaments with an antiviral effect. The invention also relates to new pyrimidine derivatives, processes for their preparation and medicaments which contain these compounds.

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

for the manufacture of drugs with antiviral activity, wherein

A is a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic ring with max. 4 represents heteroatoms, where the heteroatoms can be the same or different and oxygen, nitrogen or sulfur mean, and the heterocycles can optionally carry an oxygen atom on one or more nitrogen atoms, and A is optionally substituted by one or more radicals R ¹ , which can be identical or different,

X can be an oxygen or sulfur atom or the group = NH, = N-Ci-Cg-alkyl or = S (0) 2,

Y can be an oxygen atom or the NH or Ci-Cs-alkylamino group,

R is a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-9 C atoms, which can be substituted by phenyl, or

means 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 1-5 heteroatoms per ring system may be contained, 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 system optionally being mono- or polysubstituted by Ci-Cg-alkyl, Ci-Cg-alkoxy, Ci-Cs-alkyl mercapto, Ci-Cg-alkylsulfinyl, Ci-Cg-alkylsulfonyl, C -C ₆ alkenyl, C ₂ -Cg alkynyl, C ₂ -C6 -Alkenyloxy, C ₂ -Cg-alkenylmercapto, C ₂ -Cg-alkynyloxy, C ₂ -Cg -alkynylmercapto, amino, C J_-CQ-alkylamino, di-Ci-Cg-alkylamino, Ci-Cg-alkylcarbonylamino, Cx -Cg-alkylamino-carbonyl, C -Cg -alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or he phenyl, R ^{1 is} a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C atoms or Ci-Cg-alkoxy, Ci-Cg-alkylmercapto, Ci-Cg-alkylsulfinyl, Ci-Cg-alkylsulfonyl, amino, Cj -Cs-alkylamino, di-Ci-Cs-alkylamino, sulfonamido, Ci-Cg-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy,

R, R ³ , R ⁴ and R ^{5 can,} independently of one another, be the same or different and each represent hydrogen, Ci-C _ß- alkyl, Ci-Cg-hydroxyalkyl, cyano, carboxy or Ci-Cg-alkoxycarbonyl, or R ² and R ^{4 represent} a further bond between the C atoms to which they are attached,

R ^{6 represents} hydrogen or Ci-Cg-alkyl,

m means 0 or 1,

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

In the earlier European patent application EP 0.530.994, compounds of a similar structure (quinazoline derivatives) are described as inhibitors of reverse transcriptase. In particular, examples 5C - 5F and 101 describe compounds of the formula I, where A is a chlorine atom substituted phenyl ring, R is a cyclopropyl, cyclopentyl or phenyl ring or a propyl group, X and Y are an oxygen atom, R ¹ , R ² , R ³ , R ⁵ and R ^{6 are} a hydrogen atom and R ^{4 is} a hydrogen atom or an isopropyl group.

Compounds of the general formula I in which A denotes an unsubstituted or substituted phenyl ring and X denotes an oxygen or sulfur atom or the group = NH have already been described in part in the literature. Thus, in US 3,891,638; US 3,812,257; DE 21 66 380; DE 23 07 808 and DE 21 41 616 compounds of this type with anti-inflammatory activity and improvement of the excretion of uric acid have been described.

In the application JP 47036758 substances were found which had an antispasmolytic effect.

Analgesic properties are ascribed to the compounds in the application DE 214 1616 and in the application US 3,329,679 compounds were found which act on the central nervous system.

The synthesis of some compounds of formula I is described in addition to the patent applications mentioned in Chem. Pharm. Bull. 29, 2135, 1981, Pharmazie 37, 379, 1982 and Yakugaku Zasshi 90. 629, 1970.

In particular, compounds of the general formula I in which A is an aromatic, heterocyclic ring with max. 4 heteroatoms, new and have not been described in the literature.

The object of the present invention was to find a further medical indication for the compounds known from the prior art. In addition, new tricyclic pyrimidine derivatives should be made available, which can be used in particular as active pharmaceutical ingredients for the production of pharmaceuticals. In particular, there has been the problem of finding such drugs that can be used in the treatment of viral or retroviral infections and the diseases caused by these infections. This object is achieved by the features characterized in the claims.

The compounds of formula I have valuable pharmacological properties. They are particularly suitable for therapy and prophylaxis of infections caused by DNA viruses such as, for example, the herpes simplex virus, the cytomegalovirus, papillo a 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 Che otherapeutics which cause causally or symptomatically to interfere with the viral or retroviral-related illness with evidently substantial success. It is not possible nowadays to diagnose certain viral diseases, such as the Acguired Immune Deficiency Syndro (AIDS), the AIDS-related complex (ARC) and its pre-stages, herpes, cytomegalovirus (CMV), and influenza to cure other viral infections or to chemically influence their symptoms favorably. Is currently spielsweise for the treatment of AIDS almost exclusively the 3 '-azido-3 ^■ deoxy-thymidine (AZT) known as Zidovudine 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 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 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 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 compounds of formula I can exist as racemates or as optically active derivatives.

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.

Optically active phases are, for example, optically active polyacrylics or polymethacrylamides, e.g. 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 A, A denotes a carbocyclic ring, in particular a fused phenyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclopentadienyl ring. The annealed aromatic heteroeyclic ring A has 5-6 carbon atoms, whereby up to 4 of these ring atoms can be replaced by the heteroatoms oxygen, sulfur and / or nitrogen. The following heterocycles may be mentioned by way of example: the furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, pyrazole, imidazole, oxadiazole, triazole, pyridine, pyridazine, pyrimidine or pyrazine ring . If a nitrogen atom is present in the heterocyclic ring A, the corresponding heterocycles can also be present in the form of their N-oxides. The ring A can be substituted by one or more, in particular by one or two, radicals R ¹ , it being possible for the substituents to be identical or different.

An aliphatic radical R or R ¹ denotes a straight-chain or branched alkyl, alkenyl or alkynyl radical with 1-9, preferably 2-7 carbon atoms, such as, for example, the propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or heptyl residue. Possible unsaturated radicals are C ₂ -C 7 alkenyl and alkynyl radicals, preferably C2-C5, such as, for example, the allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propinyl radical.

An aliphatic radical R which may be substituted by phenyl is in particular a phenyl-Ci-Cg-alkyl group, such as e.g. the benzyl, phenethyl, phenylpropyl or phenylbutyl radical.

If the radicals R or R ¹ contain a phenyl ring, this can be mono-, di- or trisubstituted. The substituents can be in o-, - or p-pitch independently of one another.

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, phenanthrhrenyl, flouryl, indenyl, indanyl, acenaphthylenyl, norbornyl, adamantyl ring or a C ₃ -C 7 -cycloalkyl or C5-Cg-cycloalkenyl group . The carbocyclic ring can also be mono- or disubstituted, where in the case of the phenyl rings the substituents can independently of one another 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 C 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, 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. If these heterocyclic rings contain a nitrogen atom, the corresponding heterocycles can also be in the form of their N-oxides. The heterocyclic ring system can moreover be mono- or disubstituted, and 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 --_- Cg-alkyl, Ci-Cg-alkoxy, C- _j _- Cg-alkylmercapto, Cχ-Cg-alkylsulfinγl, Ci-Cg-alkylsulfonyl, C ₂ - Cg-alkenyl, C ₂ -Cg-alkynyl, C ₃ ~ C -alkenyloxy, Ci-Cg-alkylamino, Ci-Cg-dialkylamino-, Ci-Cg-alkylcarbonylamino, Ci-Cg-alkylaminocarbonyl, C-] _-Cg-alkoxycarbonyl, amino, hydroxyl, nitro, azido, trifluoromethyl, cyano or halogen, the abovementioned aliphatic radicals preferably containing up to 3 carbon atoms. Carbocyclic rings R are preferably biphenyl, naphthyl, anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthanenyl, norbornyl, adamantyl, Cs-Cg-cycloalkyl, Cs-Cs-cycloalkenyl, where the carbocyclic rings can be mono- or disubstituted by C-j_-Cg-alkyl, Cj-Cg-alkoxy, C ^** _- Cg-alkylmercapto, Ci-Cg-alkylsulfinyl, C1-C5-alkylsulfonyl, C ₂ - Cg-alkenyl, C ₂ -Cg-alkynyl, C ₃ -C 4 alkenyloxy, C-j_-Cg-alkylamino, Cj-Cg-dialkylamino, Ci-Cg-alkylcarbonylamino, Ci-Cg-alkyl-a inocarbonyl, C ^ -Cg-alkoxycarbonyl, amino, hydroxy, nitro , Azido, trifluoromethyl, cyano or halogen, the aliphatic radicals mentioned above preferably containing up to 3 carbon atoms.

Heterocyclic ring systems R are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, cu aron, thionaphthene, benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, acridine and phenothiazine can be mono- or disubstituted by Cχ-Cg-alkyl, C --_- Cg-alkoxy, Ci-Cg-alkylmercapto, Ci-Cg-alkylsulfinyl, Ci-Cg-alkylsulfonyl, C ₂ -Cg-alkenyl, C ₂ -C ₆ -alkynyl, C ₂ -Cg-alkenyloxy, Ci-Cg-alkylamino, Cx-Cg-dialkylamino-, CL-Cg-alkylcarbonylamino, Ci-Cg-alkylaminocarbonyl, Ci-Cg-alkoxycarbonyl-, amino, hydroxy , Nitro, azido, trifluoromethyl, cyano or halogen, the aforementioned aliphatic radicals preferably containing up to 3 carbon atoms.

For the radical R ¹ is hydrogen, Ci-Cg-alkyl., C ₂ -C4-alkenyl, ^c 2 ~ ^c 4 ^_A alkynyl, C --_- Cg-alkoxy, Ci-Cg-alkyl ercapto, Ci-Cg- Alkyl¬ amino, C -Cg-alkoxycarbonyl, amino, halogen, hydroxy, nitro, cyano and azido are preferred, the aliphatic radicals mentioned above preferably containing up to 3 carbon atoms.

Preferred substituents for R ² , R ³ , R ⁴ and R ⁵ are hydrogen, C1-C ₃ -alkyl, Ci-Cg-hydroxyalkyl, carboxy, C _} .-Cg-alkoxycarbonyl and cyano or if R ² and R ^{4 form} an additional bond. X and Y is preferably oxygen. Halogen generally means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

Aromatic rings are particularly suitable for A. Preferred fused heterocycles A are aromatic nitrogen-containing rings with 5 or 6 ring atoms or the phenyl ring.

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 4 -alkyl, C ₁ -C 6 -alkoxy, c * L-Cg-alkylmercapto, allyl, allyloxy, c --_- Cg-alkylamino, di-C-j_-Cg-alkylamino, amino, hydroxy, azido, trifluoromethyl, cyano 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 or disazonyl or disazinylated carboxyl Derivatives of the aforementioned carbocyclic or heterocyclic rings.

For R ¹ , hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methylmercapto, ethyl mercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, amino, azido, cyano, hydroxy and halogen are particularly preferred, chlorine and bromine being very particular for halogen are preferred.

For R ² , R ³ , R ⁴ and R ⁵ , hydrogen, methyl, ethyl, isopropyl and cyano are particularly preferred, two or three of the radicals R ² -R ⁵ in particular representing a hydrogen atom. R ² and R ⁴ can preferably also mean a bond together.

Particularly preferred for A are the phenyl, pyrrole, pyrrole, oxazole, thiophene, furan, isoxazole, thiazole, imidazole, pyridine, pyridazine, pyrimidine and pyrazine ring. In the event that A represents a fused six-membered ring, particular preference is given to those compounds which relate to bear a substituent R ¹ , in particular a halogen atom, on the nitrogen atom of the fused pyrimidine ring bonded directly to the six ring A in the para position of the six ring A (9 position of the tricyclic ring system).

Particularly preferred are compounds of the general formula I in which R, R ¹ , X and m have the meaning given above, R ² , R ³ , R ⁴ and R ⁵ are hydrogen, methyl or ethyl, where R ² to R ⁵ preferably hydrogen or R ² and R ⁴ additionally represent a bond.

For R ⁶ , hydrogen and C1-C ₃ alkyl are particularly preferred. O is particularly preferred for m.

Compounds with a pronounced pharmacological activity are in particular those compounds of the formula I in which R represents a phenyl ring which is substituted in the meta position by Ci-Cg-alkyl, in particular by methyl or ethyl, and X represents a sulfur atom and R ^{1 represents} a halogen atom.

The medicaments contain at least one compound of the formula I for the treatment of viral infections and can be administered enterally or parenterally in liquid or solid form. The usual forms of administration are possible as pharmaceutical dosage forms, 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, for example, tartrate and citrate buffers, ethanol, complexing agents such as ethylene diamine tetraacetic acid and their 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. Preparations suitable for oral applications can, if desired, contain flavorings or sweeteners.

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 active substance content of the retarded tablets can be 2 - 1000 mg. The active ingredient can also be given by continuous infusion, the amounts of 5-1000 mg per day being normally 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 medicaments include agents which can be used for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as 3'-azido-3 ^' deoxythymidine,' 2 •, 3 '-dides oxynucleosides such as, for. B. 2 *, 3'-dideoxycytidine, 2 ', 3 • -dideoxy-adenosine and 2 ^■ , 3 ^■ -dideoxyinosine, acyclic nucleosides (e.g. acyclovir). The compounds of the present invention and the other medicament can each be administered individually, simultaneously, optionally in a single or two separate formulations or at different times, so that a synergistic effect is achieved.

The compounds of the general formula I according to the invention are prepared in particular by processes known per se, by using compounds of the general formula II

in which A, R, R ¹ and R ^{6 have} the meaning given above and R ^{7 is} an easily removable group, such as CCI ₃ , CF ₃ , OR ⁸ or NR ⁸ R ⁹ , where R ⁸ and R ^{9 can be} identical or different and can mean, for example, Ci-Cg-alkyl or substituted or unsubstituted phenyl, phenylalkyl, hetaryl or hetarylalkyl, with substituted or unsubstituted compounds of the general formula III

in which R ² , R ³ , R ⁴ , R ⁵ and m have the meaning given, in a suitable inert solvent at room temperature to reflux temperature, possibly in the presence of catalytic amounts of acid, for example p-toluenesulfonic acid, or base, for example potassium hydroxide, and if appropriate subsequently thereafter Compounds of formula I subsequently converted into other compounds of formula I. and then purified by chromatography or by recrystallization. Racemates can be separated into the anti-pods by chromatography on suitable optically active phases, for example cellulose triacetate.

The subsequent conversions of compounds of formula I into other compounds of formula I concern e.g. the production of tricyclic pyrimidine derivatives with X = S. Compounds with X = S are prepared by reacting compounds of the formula I, in which X is an oxygen atom, with compounds transferring sulfur groups, e.g. Lawesson's reagent.

Compounds of the general formula I with X = NH are prepared by reacting compounds of the formula I in which X is an oxygen atom by first preparing the chlorimine with a chlorinating reagent, such as POCI ₃ , and this with ammonia treated.

Compounds of the general formula I in which R ² and R ^{4 represent} an additional bond are prepared by compounds of the general formula I in which R ² , R ³ , R ⁴ or R ^{5 are} one with a carboxylic acid, such as. B. acetic acid, or sulfonic acid, such as. B. toluenesulfonic acid, esterified hydroxymethyl, means in an inert solvent in the presence of a base, such as. B. imidazole or sodium hydroxide, heated to 50-200 ^β C possibly under pressure.

The compounds of general formula II used as starting material are obtained from acobenzophenone derivatives by acylation using processes known from the literature. The substituted or unsubstituted 2-aminobenzophenone derivatives can advantageously be prepared by the processes described by David A. Walsh (Synthesis, 677, 1980).

For the purposes of the present invention, in addition to the compounds mentioned in the examples and those obtained by combination All the meanings of the substituents mentioned in the claims include the following compounds of the formula I, which can be present as racemic mixtures or in optically active form or as pure R and S enantiomers:

1. 10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazolin-5-one

2. 10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazolin-5-thione

3. 10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] guinazolin-5-imine

4. 6-methyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] guinazolin-5-one

5. 9-chloro-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

6. 9-methyl-10b-pheny1-2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] guinazolin-5-one

7. 9-methoxy-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

8. 10-chloro-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

9. 10-Nitro-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] guinazolin-5-one

10. 7-methyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

11. 8-Methyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one 12. 10b- (3-methylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

13. 10b- (3-chlorophenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

14. 10b- (4-methoxyphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

15. 10b- (2,3-Dimethylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

16. 10b- (3,5-Dimethylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

17. 10b- (1-naphthyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

18. 10b- (4-indanyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazolin-5-one

19. 10b- (2-Amino-5-methylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazolin-5-one

20. 10b- (6-methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] guinazolin-5-one

21. 10b- (4-methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5-one

22. 10b-Thienyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazolin-5-one

23. 10b-furanyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazolin-5-one

24. llb-phenyl-3,4,7, llb-tetrahydro-2H, 6H- [1,3] oxazino [3,2-c] ■ quinazolin-6-one 25. 10b-Phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] pyrido- [2,3-e] pyrimidin-5-one

26. 10b- (3-methylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] pyrido [2,3-e] pyrimidin-5-one

27. 10b- (3-chlorophenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] pyrido [2,3-e] pyrimidin-5-one

28. 10b- (6-methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] pyrido [2,3-e] pyrimidin-5-one

29. 10b- (4-methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] pyrido [2,3-e] pyrimidin-5-one

30. 3-ethoxycarbonyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] pyrido [2,3-e] yrimidin-5-one

31. 3-hydroxymethyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] pyrido [2,3-e] pyrimidin-5-one

32. 10b-Phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] pyrido- [3,4-e] pyrimidin-5-one

33. 10b- (3-Ethylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] pyrido [3,4-e] pyrimidin-5-one

34. 10b- (3-nitrophenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] pyrido [3,4-e] pyrimidin-5-one

35. 10b- (6-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] pyrido [3,4-e] pyrimidin-5-one

36. 10b-Methyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] pyrido- [3,4-e] pyrimidin-5-one

37. 9b-Phenyl-2,3,6,9b-tetrahydro-5H-oxazolo [3,2-c] thieno [2,3-e] pyrimidin-5-one 38. 9b- (3-methylphenyl) -2,3,6,9b-tetrahydro-5H-oxazolo [3,2-c] ^■ thieno [2,3-e] pyrimidin-5-one

39. 9b- (3,5-dichlorophenyl) -2,3,6,9b-tetrahydro-5H-oxazolo- [3,2-c] thieno [2,3-e] pyrimidin-5-one

40. 9b-Phenyl-2,3,6,9b-tetrahydro-5H-oxazolo [3,2-c] furano- [2,3-e] pyrimidin-5-one

41. 9b- (4-Methyl-2-pyridyl) -2,3,6,9b-tetrahydro-5H-oxazolo- [3,2-c] furano [2,3-e] pyrimidin-5-one

42. 10b-Phenyl-6,10-dihydro-5H-oxazolo [3,2-c] guinazolin-5-one

43. 10b- (3-methylphenyl) -6,10-dihydro-5H-oxazolo [3,2-c] guinazolin-5-one

44. 3-Methyl-10b-phenyl-6,10-dihydro-5H-oxazolo [3,2-c] quinazolin-5-one

45. 10b- (3-Methylphenyl) -6,10-dihydro-5H-oxazolo [3,2-c] pyrido [2,3-e] pyrimidin-5-one

46. 3-Methyl-10b- (3-methylphenyl) -6, 10-dihydro-5H-oxazolo- [3,2-c] pyrido [2,3-e] pyrimidin-5-one

la. 10b-phenyl-2,3,6, 10B-tetrahydro-imidazo [1,2-c] guinazolin-5 (1H) -one

2a. 10b-phenyl-2,3,6, 10B-tetrahydro-imidazo [1,2-c] quinazoline-5 (1H) thione

3a. 10b-phenyl-2,3,6, 10B-tetrahydro-imidazo [1,2-c] guinazoline-5 (1H) -imine

4a. 6-methyl-10b-phenyl-2,3,6, 10B-tetrahydro-imidazo [1,2-c] guinazolin-5 (1H) -one a. 9-Chloro-10b-phenyl-2,3,6, 10B-tetrahydro-imidazo [1,2-c] quinazolin-5 (1H) -one

6a. 9-methyl-10b-phenyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] quinazolin-5 (1H) -one

7a. 9-methoxy-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5 (1H) -one

8a. 10-chloro-10b-phenyl-2,3,6, 10-tetrahydro-imidazo [1,2-c] quinazolin-5 (1H) -one

9. 10-nitro-10b-phenyl-2,3,6, lOb-tetrahydro-imidazo [1,2-c] quinazolin-5 (1H) -one

10a. 7-methyl-10b-phenyl-2,3,6, 10B-tetrahydro-imidazo [1,2-c] guinazolin-5 (1H) -one

11a. 8-methyl-10b-pheny1-2,3,6, 10b-tetrahydro-imidazo [1,2-c] guinazolin-5 (1H) -one

12a. 10b- (3-methylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] guinazolin-5 (1H) -one

13a. 10b- (3-chlorophenyl) -2,3,6, 10B-tetrahydro-imidazo [1,2-c] quinazolin-5 (1H) -one

14a. 10b- (4-methoxyphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5 (1H) -one

15a. 10b- (2,3-dimethylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5 (1H) -one

16a. 10b- (3,5-dimethylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5 (1H) -one

17a. 10b- (1-naphthyl) -2,3,6, 10B-tetrahydro-imidazo [1,2-c] quinazolin-5 (1H) -one a. 10b- (4-indanyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] quinazolin-5 (1H) -one

a. 10b- (2-amino-5-methylphenyl) -2,3,6, 10B-tetrahydro-imidazo [1,2-c] quinazolin-5 (1H) -one

a. 10b- (6-methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5 (1H) -one

a. 10b- (4-methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo- [3,2-c] quinazolin-5 (1H) -one

a. 10b-thienyl-2,3,6,10b-tetrahydro-imidazo 1,2-c] quinazolin-5 (1H) -one

a. 10b-furanyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] quinazolin-5 (1H) -one

a. llb-phenyl-1,2,3,4,7, llb-hexahydro-6H-pyrimido [1,2-c] quinazolin-6-one

a. 10b-phenyl-2,3,6, lOb-tetrahydro-imidazo [1,2-c] pyrido- [2,3-e] pyrimidin-5 (1H) -one

a. 10b- (3-methylphenyl) -2,3,6, 10B-tetrahydro-imidazo [1,2-c] pyrido [2,3-e] pyrimidin-5 (1H) -one

a. 10b- (3-chlorophenyl) -2,3,6, 10B-tetrahydroimidazo [1,2-c] pyrido [2,3-e] pyrimidin-5 (1H) -one

a. 10b- (6-methyl-2-pyridyl) -2,3,6, 10B-tetrahydro-imidazo- [1,2-c] pyrido [2,3-e] pyrimidin-5 (1H) -one

a. 10b- (4-methyl-2-pyridyl) -2,3,6, 10B-tetrahydro-i idazo [1,2-c] pyrido [2,3-e] pyrimidin-5 (1H) -one

a. 3-ethoxycarbonyl-10b-phenyl-2,3,6, lOb-tetrahydro-imidazo [1,2-c] pyrido [2,3-e] pyrimidin-5 (1H) -one a. 3-hydroxymethyl-10b-phenyl-2,3,6, lOb-tetrahydro-i idazo [1,2-c] pyrido [2,3-e] pyrimidin-5 (IH) -one

a. 10b-phenyl-2,3,6, 10B-tetrahydro-imidazo [1,2-c] pyrido- [3,4-e] pyrimidin-5 (IH) -one

a. 10b- (3-ethylphenyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] pyrido [3,4-e] pyrimidin-5 (IH) -one

a. 10b- (3-nitrophenyl) -2,3,6, 10B-tetrahydro-imidazo [1,2-c] pyrido [3,4-e] pyrimidin-5 (IH) -one

a. 10b- (6-methyl-2-pyridyl) -2,3,6, 10B-tetrahydro-i idazo [1,2-c] pyrido [3,4-e] pyrimidin-5 (IH) -one

a. 1Ob-methyl-2,3,6, 10B-tetrahydro-imidazo [1,2-c] pyrido- [3,4-e] pyrimidin-5 (IH) -one

a. 9b-phenyl-2,3,6,9b-tetrahydro-imidazo [1,2-c] thieno [2,3-e] ■ pyrimidin-5 (IH) -one

a. 9b- (3-methylphenyl) -2,3,6,9b-tetrahydro-imidazo [1,2-c] thieno [2,3-e] pyrimidin-5 (1H) -one

a. 9b- (3,5-dichlorophenyl) -2,3,6,9b-tetrahydro-imidazo [1,2-c] • thieno [2,3-e] pyrimidin-5 (IH) -one

a. 9b-phenyl-2,3,6,9b-tetrahydro-imidazo [1,2-c] furano [2,3-e] pyrimidin-5 (IH) -one

a. 9b- (4-Methyl-2-pyridyl) -2,3,6,9b-tetrahydro-imidazo- [1,2-c] furano [2,3-e] pyrimidin-5 (IH) -one

a. 10b-phenyl-6,10-dihydro-imidazo [1,2-c] quinazolin-5 (IH) -one

a. 10b- (3-methylphenyl) -6,10-dihydro-imidazo [1,2-c] quinazolin-5 (IH) -one 4a. 3-methyl-10b-phenyl-6,10-dihydro-imidazo [1,2-c] quinazolin-5 (IH) -one

45a. 10b- (3-methylphenyl) -6, lθ-dihydro-imidazo [1,2-c] pyrido- [2,3-e] pyrimidin-5 (IH) -one

46a. 3-methyl-10b- (3-methylphenyl) -6,10-dihydro-5H-oxazolo- [3,2-c] pyrido [2,3-e] pyrimidin-5 (IH) -one

example 1

10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazolin-5-one

a) To 10 g (50.7 mmol) of 2-aminobenzophenone in 125 ml of toluene and 4.9 ml of pyridine, 5.8 ml (60.8 mmol) of ethyl chloroformate in 25 ml of toluene are added dropwise at 10 ° C. with stirring. After one hour, the mixture is mixed Shaken 3 times with water, the organic phase was separated off, dried and evaporated, the oil obtained was triturated with isohexane and the crystals were filtered off with suction.

This gives 12.3 g of 2-Ethoxycarbonylaminobenzophenon of mp. 73-75 C. ^β

b) 5 g (18.6 mmol) of 2-ethoxycarbonylaminobenzophenone, 2.3 g

(37.1 mmol) ethanolamine and 0.5 g p-toluenesulfonic acid are heated in 100 ml dimethylformamide (DMF) for 52 hours at 140 ° C under nitrogen. The DMF is then distilled off, the residue is dissolved in water and extracted twice with dichloromethane. The organic phase was dried and evaporated and the residue was chromatographed on silica gel (mobile phase: isohexane: ethyl acetate, 7: 3). Evaporation of the desired fractions and recrystallization of the residue 3.2 g of the title compound of mp 193-196 ° C. are obtained from ethanol.

Example 2

11b- (4-methyl-2-pyridyl) -3,4,7, 11b-tetrahydro-2H, 6H-r1,3] oxazinor3.2-clαuinazolin-6-one

Analogously to Example 1, the title compound of mp. Is obtained from l-ethoxycarbonylamino-2- (4-methyl-2-pyridinoyl) benzene and 3-hydroxy-l-propanamine.

Example 3

10b (3-methylphenyl) -2,3,6,10b-tetrahydro-imidazo [1,2-cl yrido \ 2.3-e1pyrimidin-5 (IH) -one

Analogously to Example 1, 3-ethoxycarbonylamino2- (3-methylbenzoyl) pyridine and ethylenediamine give the title compound of mp.

Example 4

Inhibition of reverse transcriptase (RT)

The screening test system contains the purified RT from HIV-1, which was expressed in E. coli using genetic engineering methods, and 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 18mer oligonucleotide complementary to the primer binding site as a primer. The [ ³ H] -thymidine-5'-triphosphate incorporation was measured by counting in the ß-counter. An IC _5Q value for the inhibition of reverse transcriptase (HIV-RT) in the order of magnitude of 0.01-10 / uM could be determined for the compounds of Examples 1-3 examined.

Claims

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

for the manufacture of drugs with antiviral activity, wherein

A is a fused carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic ring with max. 4 represents heteroatoms, where the heteroatoms can be the same or different and denote oxygen, nitrogen or sulfur, and the heterocycles can optionally carry an oxygen atom on one or more nitrogen atoms, and A is optionally substituted by one or more radicals R ¹ that can be the same or different,

X can be an oxygen or sulfur atom or the group = NH, = N-Ci-Cg-alkyl or = S (0) ₂ ,

Y can be an oxygen atom or the NH or Ci-Cs-alkylamino group,

R is a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-9 C atoms, which can be substituted by phenyl, or means 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 per ring system 1-5 heteroatoms can be included, 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 system, if appropriate - or more times is substituted by Cχ-Cg-alkyl, Cχ-Cg-alkoxy, Cχ-Cg-alkylmercapto, Cχ-Cg-alkylsulfinyl, Cχ ~ Cg-alkylsulfonyl, C C-Cg-alkenyl, C ₂ -Cg-alkynyl , C ₂ - Cg-alkenyloxy, C -Cg-alkenylmercapto, C ₂ -Cg-alkynyloxy, C-Cg-alkynylmercapto, amino, Cχ-Cg-alkylamino, di-Cχ-Cg-alkγlamino, Ci-Cg-alkylcarbonylamino , Cχ-Cg-alkylamino-carbonyl, Cχ-Cg-alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, Carboxy or phenyl,

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

R ² , R ³ , R ⁴ and R ^{5 can} independently of one another be the same or different and each represent hydrogen, Cχ ~ Cg-alkyl, Cχ-Cg-hydroxyalkyl, cyano, carboxy or Cχ-Cg-alkoxycarbonyl, or R ² and R ^{4 represent} a further bond between the carbon atoms to which they are attached, R ^{6 represents} hydrogen or Ci-Cg-alkyl,

m means 0 or 1,

and their tautomers, enantiomers, diastereomers or physiologically acceptable salts.

2. Use of compounds of formula I according to claim 1, characterized in that A is a phenyl ring or a heterocyclic ring selected from the group furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, pyrazole, imidazole , Oxadiazole, triazole, pyridine, pyridazine, pyrimidine or pyrazine ring.

3. Use of compounds of formula I according to claim 1 or 2, characterized in that R is a phenyl group or a carbocyclic ring selected from the group naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, indanyl, acenaphthylenyl, Norbornyl, adamantyl, C3-C7-cycloalkyl or Cs-Cg-cycloalkenyl group means, where these groups can be unsubstituted or substituted by Cχ-Cg-alkyl, Cχ-Cg-alkoxy, Cχ ~ Cg-alkyl mercapto , Ci-Cg-alkylsulfinyl, C --_- Cg-alkyl sulfonyl, C ₂ - Cg-alkenyl, C ₂ -Cg-alkynyl, C3-C-alkenyloxy, C -] _- Cg-alkylamino, Ci-Cg -Dialkylamino-, Cχ-Cg-alkylcarbonylamino, Cχ-Cg-alkylaminocarbonyl, Cχ-Cg-alkoxycarbonyl-, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen.

4. Use of compounds of the formula I according to claim 1 or 2, characterized in that R is a heterocyclic radical selected from the group pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, Pyrazole, imidazole, triazole, thiazole, oxazole, isoxa- zol, oxadiazole, furazane, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzothiazole, indazole, benzimidazole, benzotriazole, chromene, Phthalazine, quinazoline, quinoxaline, methylene-dioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system, where these heterocycles can be partially or completely hydrogenated and can be unsubstituted or substituted by Cχ-Cg-alkyl, Cχ-Cg-alkoxy, Cχ-Cg-alkylmercapto, Cj-Cg-alkylsulfinyl, Cχ-Cg-alkylsulfonyl, C ₂ -Cg-alkenyl, C ₂ -Cg-alkynyl, C ₃ -C4- Alkenyloxy, Cχ-Cg-alkylamino, Ci- Cg-dialkylamino-, Cχ-Cg- alkylcarbonylamino, Cχ-Cg-alkylaminocarbonγl, Cχ-Cg-alkoxycarbonyl-, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or Halogen"

5. Use of compounds of formula I according to claims 1-4, characterized in that R ^{1 is} hydrogen, Cx-C-alkyl, C ₂ -c ₄ -alkenyl, C ₂ -C -alkynyl, Cx-C - Alkoxy, Ci-Cg-alkylmercapto, Cχ-Cg-alkylamino, Cχ-Cg-alkoxycarbonyl, amino, halogen, hydroxy, nitro, cyano or azido means.

6. Pyrimidine derivatives of the general formula I

in the A is a fused carbocyclic ring with a total of 5 carbon atoms or a heterocyclic ring with max. 4 represents heteroatoms, where the heteroatoms can be the same or different and mean oxygen, nitrogen or sulfur, and the heterocycles can optionally carry an oxygen atom on one or more nitrogen atoms, and A is optionally substituted by one or more radicals R ¹ that can be the same or different,

Y can be an oxygen atom or the NH or Cχ-C5-alkylamino group,

R is a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-9 carbon atoms, which may be substituted by phenyl, or

means 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 per ring system 1-5 heteroatoms can be included, 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 system, if appropriate - or substituted several times by Cχ-Cg-alkyl, Cχ-Cg-alkoxy, Cχ-Cg-alkylmercapto, Cχ-Cg-alkylsulfinyl, c- _] _- Cg-alkylsulfonyl, C -Cg-alkenyl, C ₂ - C ₆ alkynyl, C ₂ - Cg-alkenyloxy, C ₂ -Cg-alkenylmercapto, C ₂ -Cg-alkynyloxy, C ₂ -Cg-alkynylmercapto, amino, Cχ-Cg-alkylamino, di-Cχ-Cg-alkylamino, Ci-Cg-alkylcarbonylamino, Cχ -Cg- alkylamino-carbonyl, Cχ-Cg-alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl,

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

R ² , R ³ , R ⁴ and R ^{5 can} independently of one another be the same or different and each represent hydrogen, Cχ ~ Cg-alkyl, Cχ-Cg-hydroxyalkyl, cyano, carboxy or Cχ-Cg-alkoxycarbonyl, or R ² and R ^{4 represent} a further bond between the carbon atoms to which they are attached,

R ^{6 represents} hydrogen or Cχ-Cg-alkyl,

m means 0 or 1,

7. pyrimidine derivatives of the formula I according to claim 6, characterized in that R represents a phenyl ring which is substituted in the meta position by Cχ-Cg-alkyl or halogen, X is a sulfur atom, Y is an oxygen atom, R ² - R ⁶ each have a hydrogen atom, and m is the number 0.

8. Process for the preparation of pyrimidine derivatives

Formula I according to claim 6 or 7, characterized in that compounds of the general formula II

in which A, R, R ¹ and R ^{6 have} the meanings given above and R ^{7 represents} an easily removable group, with substituted or unsubstituted compounds of the general formula III

in which R ² , R ³ , R ⁴ , R ⁵ and m have the meanings given above, in a suitable inert solvent at room temperature to reflux temperature, if appropriate in the presence of catalytic amounts of acid or base, and if appropriate subsequently compounds of the formula I with X = 0 subsequently converted into compounds of the formula I with X = S or X = NH.

9. Medicament containing at least one pyrimidine derivative of the formula I according to claim 7 or 8 and pharmaceutical excipient or carrier.

10. A process for the preparation of medicaments according to claim 9, characterized in that at least one compound of the formula I is mixed with pharmacologically acceptable auxiliaries and processed into pharmaceutical dosage forms.