CA2134200A1 - New tricyclic thiazolo and thiazino derivatives and pharmaceutical agents containing them - Google Patents

Abstract

Abstract The present invention concerns tricyclic thiazolo and thiazino derivatives of formula I
(I) in which A represents a carbocyclic or heterocyclic ring, X can be an oxygen or sulphur atom or the group =NH, =N-C1-C6-alkyl or =S(O)2, R denotes an aliphatic residue with 1-9 C atoms which can be substituted by phenyl or a carbocyclic ring with 7-15 C atoms or a heterocyclic ring system, R1 denotes a hydrogen atom, an aliphatic residue with 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, azido, phenyl or benzyloxy, R2, R3, R4 and R5 can denote hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, cyano, carboxy or C1-C6 alkoxy-carbonyl or R2 and R4 can denote a further bond between the C atoms to which they are bound, R6 denotes hydrogen or C1-C6 alkyl, n denotes 0, 1 or 2 and m denotes 0 or 1 as well as tautomers, enantiomers, diastereomers and physiologically tolerated salts thereof.

The invention in addition concerns pharmaceutical agents that contain compounds of formula I in particular for the treatment of viral infections.

Description

213~2QQ

Boehringer Mannheim Gmb~ ~ :

New tricyclic thiazolo and thi~zino derivatives nnd pharmaceutical agents containing them The present invention concerns tricyclic thiazolo and thiazino derivatives, processes for their production and pharmaceutical agents that contain these compounds. ~ ~ ~

The invention concerns tricyclic thiazolo[3,2-c]- -pyrimidine and thiazino[3,2-c]pyrimidine derivatives of formula I

(I) ~

6,N ~ N~ ~ ~ :

X ^, . ~
, in which A represents a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic ring with a maximum of 4 heteroatoms in which the heteroatoms can be the same or different and denote oxygen, nitrogen or sulphur and, if desired, the heterocycles can carry an oxygen atom on one or several nitrogen atoms and A is substituted, if desired, by one or several , . , . ~. ~ ~ : .. - .
~, - :. : :

- :

. ~ . , ... ~ 2134200 : ~

~ , .. ' residues R1 which can be the same or different, X can be an oxygen or sulphur atom or the group =NH, =N-cl-c6-alkyl or =S(0)2 R can be a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-9 C atoms which can be substituted by phenyl or it denotes a phenyl ring, .~
~ .~' ,'..
or it denotes 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 can contain 1-4 or 1-5 heteroatoms per ring system in which the heteroatoms are nitrogen, sulphur or oxygen and the aforementioned phenyl rings, the mono-, bi- or tricyclic carbocyclic rings or the heterocyclic mono-, bi- or tricyclic ring system is substituted, if desired, once or several times by Cl-C6 alkyl, Cl-C6 alkoxy, C1-C6 alkylmercapto, Cl-C6 alkylsulfinyl, Cl-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 -alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, Cl-C6 alkylamino, di-C1-C6 alkylamino, Cl-C6 alkylcarbonylamino, Cl-C6 ~-alkylaminocarbonyl, Cl-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl, R1 denotes a hydrogen atom, a straight-chained or - branched, saturated or unsaturated aliphatic -~ :- :
residue with 1-6 C atoms or Cl-C6 alkoxy, C1-C6 :: -~

: - ~ ~ .-: ~ .
' . ' ' -.. .. .
. ;, , ~ ~'' '~'. ;' ' ' ' `'` `

`- ~13~2QO~ ~

, ~ :

alkylmercapto, Cl-C6 alkylsulfinyl, Cl-C6 alkylsulfonyl, amino, C1-C6 alkylamino, di-Cl-C6 alkylamino, sulfonamido, C1-C6 alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, ~-phenyl or benzyloxy, R2, R3, R4 and R5 can, independently of each other, be the same or different and each denote hydrogen, Cl-C6 alkyl, C1-G6 hydroxyalkyl, cyano, carboxy or C1-C6 alkoxycarbonyl or R2 and R4 can denote a further bond between the C atoms to which they are bound, R6 denotes hydrogen or C1-C6 alkyl, n denotes 0, 1 or 2 and ~ ;
m denotes O or 1 as well as tautomers, enantiomers, diastereomers and physiologically tolerated salts thereof.
,~
Compounds of similar structure (quinazoline derivatives) are known as inhibitors of reverse transcriptase from the earlier European Patent Application EP O 530 994. In , the examples 5C - 5F and 101 described therein oxazolo-[3,2-c~pyrimidines which correspond to formula I are described in particular in which A represents a substituted phenyl ring and R represents a cyclopentyl, cyclopropyl or phenyl ring or a propyl group. In --comparison with these compounds the thiazolo[3,2-c]pyrimidines (m=O) and thiazino[3,2-c]pyrimidines (m=1) according to the invention exhibit an increased pharmacological efficacy.

. :. . , : . . .
1'~.;"~ ~.
.:~ .. . . - . , ,.,.:. :
.: . ; : . :

` ~13~00 The object of the present invention was to provide new `~
tricyclic thiazolo[3,2-c]pyrimidines and thiazino[3,2-c] ` ;
pyrimidines which can be used in particular as pharmaceutically active substances for the production of pharmaceutical agents.

The compounds of the present invention have valuable pharmacological properties. In particular they have an antiviral action and are suitable for the therapy and i~
prophylaxis of infections that are caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegaly virus, papilloma viruses, the varicella-zoster virus or ~;
Epstein-Barr virus or RNA viruses such as togaviruses or in particular retroviruses such as the oncoviruses HTLV-I and II as well as the lentiviruses visna and the human immunodeficiency viruses HIV-1 and 2.

The compounds of formula I appear to be particularly suitable for the treatment of clinical manifestations of retroviral HIV infections in humans such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the complete clinical picture of AIDS.

The compounds according to the invention of the general formula I have a pronounced antiviral action and are ~ `
particularly suitable for the treatment of viral and retroviral infections. Viral infections of mammals, in particular of humans, are widespread. Despite extensive efforts it has previously not been possible to provide `~
chemotherapeutic agents which interfere causally or symptcmatically with the viral or retroviral-dependent pathological process with a discernible substantial success. Nowadays it is not possible to heal certain ,~ ,." - : : ` ' ~. . , . ` .
, --- 213~200 viral diseases such as for example the acquired immune deficiency syndrome (AIDS), the AIDS-related complex (ARC) and early stages thereof, herpes, cytomegaly virus (CMV), influenza virus and other viral infections or to favourably influence their symptoms by chemotherapeutic ~ -means. At present for example 3'-azido-3'-deoxy-thymidine (AZT) known as Zidovudine or Retrovir~ is almost all that is available for the treatment of AIDS.
However, AZT is characterized by a very narrow therapeutic range and by very severe toxicities that already occur in the therapeutic range (Hirsch, M.S.
(1988) J. Infec. Dis. 157, 427-431). The compounds of the general formula I do not have these disadvantages.
They act antivirally without being cytotoxic in pharmacologically-relevant doses.

It has now been possible to demonstrate that compounds '-`
of the general formula I inhibit ~he multiplication of DNA and RNA viruses at the level of viral-specific DNA
and 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 chemotherapeutic agents which interfere as specifically as possible with diseases caused by retroviruses or the symptoms thereof without influencing the normal course of natural body functions, the said compounds can be used to advantage prophylactically or therapeutically in the treatment of diseases in which a retroviral infection is of patho-physiological, symptomatical or clinical relevance.

The compounds of formula I can be present as racemates : : .. ~ . . ::
:, . . .
: : . . , .

213~%o or as optically active derivatives.

The separation of the racemates into enantiomers can be carried out analytically, semi-preparatively and preparatively by chromatography on suitable optically-active phases using conventional eluting agents.

Suitable optically-active phases are for example optically active polyacrylamides or polymethacrylamides, some also on silica gel (e.g. ChiraSpher~ from Merck, Chiralpak~ OT/OP from Baker), cellulose esters/
cellulose carbamates (e.g. Chiracel~ OB/OY from Baker/Daicel), phases based on cyclodextrin or crown ethers (e.g. Crownpak~ from Daicel) or microcrystalline -~
cellulose triacetate (Merck).

In the definition of A, A denotes a carbocyclic ring, in particular a phenyl or cyclohexyl or cyclopentyl ring. ~ ~-The anellated aromatic heterocyclic ring A has 5-6 carbon atoms in which up to 4 of these ring atoms can be substituted by the heteroatoms oxygen, sulphur and/or nitrogen. The following heterocycles are mentioned as examples: 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 several, preferably one, two or three residues Rl where the substituents R1 can be the same or different.

An aliphatic residue R or Rl denotes a straight-chained or branched alkyl, alkenyl or alkinyl residue with 1-9, ,.':; '' . :: . , : , ' .
;-' , :
,:' .. .: ::
. .:`::

~13~200 preferably 2-7 carbon atoms such as e.g. a propyl, isopropyl, butyl, isobutyl, pentyl, hexyl or heptyl residue. C2-C7 alkenyl and alkinyl residues come into consideration as unsaturated residues, preferably C2-C
such as e.g. an allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propinyl residue.

An aliphatic residue R which can be substituted by phenyl is in particular a phenyl-C1-C6-alkyl group such as e.g. a benzyl, phenethyl, phenylpropyl, or ;~
phenylbutyl residue.

If the residues R or Rl contain a phenyl ring, this can then be substituted once, twice or three times. The substitutents can, independently of one another, be in the o, m or p position.

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 are mentioned as examples: a naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, indanyl, acenaphthylenyl, norbornyl, adamantyl ring or a C3-C7 cycloalkyl or C5-C8 cycloalkenyl group. In addition the carbocyclic ring can be mono- or disubstituted whereby in the case of phenyl rings the substituents can, independently of one another, be in the o or m position.

The heterocyclic mono-, bi- or tricyclic ring systems of the residue R contain 5 or 6 carbon atoms per ring in which 1-4 or 1-5 C atoms can be substituted by the heteroatoms oxygen, sulphur and/or nitrogen. The ring systems can be aromatic and partially or completely ;

,., :- ~ . : : :

2~342~

hydrogenated. The following ring systems are mentioned -as examples: the pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazan, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, ~ ~-chromene, phthalazine, quinazoline, quinoxaline, methylenedioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system in which the unsaturated or aromatic carbo and heterocycles can be partially or completely hydrogenated. If these heterocyclic rings contain a nitrogen atom, the ~;
corresponding heterocycles can also be present in the form of their N-oxides. In addition the heterocyclic ring system can be mono- or disubstituted in which case the substitutents can, independently of one another, preferably be in the o or m position.

R preferably denotes unsubstituted phenyl or phenyl which is substituted once or twice by C1-C6 alkyl, C1-C
alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 ~ `
alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6 alkenyloxy, C1-C6 alkylamino, Cl-C6 dialkylamino, C1-C6 ` ```
alkylcarbonylamino, Cl-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen in which the aforementioned aliphatic residues preferably contain up -to three carbon atoms.

Carbocyclic rings R are preferably biphenyl, naphthyl, anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthxenyl, norbornyl, adamantyl, C3-C6 cycloalkyl, C5-C8 cycloalkenyl in which the carbocyclic rings can be ~-substituted once or twice by Cl-C6 alkyl, Cl-C6 alkoxy, ~

~13 ~200 C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6 alkenyloxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoro-methyl, cyano or halogen in which the aforementioned aliphatic residues preferably contain up to three carbon atoms.

Heterocyclic ring systems are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, acridine and phenothiazine in which the heterocyclic rings can be substituted once or twice by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylmercapto, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, C2-C4 alkenyl, C2-C3 alkinyl, C3-C4 alkenyloxy, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkylcarbonylamino, C1-C3 alkylaminocarbonyl, C1-C3 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoro-methyl, cyano or halogen.

Hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkinyl, C1-C3 alkoxy, C1-C3 alkylmercapto, C1-C3 alkylamino, C1-C
alkoxycarbonyl, amino, halogen, hydroxy, nitro, cyano and azido are preferred for the residue R

Preferred substituents for R2, R3, R4 and R5 are -hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, carboxy, C1-C
alkoxycarbonyl and cyano or when R2 and R4 form an ~ ~
additional bond. ~ -X is preferably oxygen. Halogen is generally to be ': .` ` `
: , : ~ ::
~ ~.

21342~0 , .

- 10 ~

understood as fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

Preferred anellated heterocycles A are aromatic rings containing nitrogen with 5 or 6 ring atoms.

Preferred residues for R are C3-C5 alkyl, C2-C5 alkenyl, ;~
C2-C4 alkinyl, benzyl, phenethyl, phenyl, phenyl which is mono or disubstituted by C1-C3 alkylr Cl-C3 alkoxy, ;~
C1-C3 alkylmercaptor allylr allyloxyr C1-C3 alkylamino di-Cl-C3-alkylaminor aminor hydroxyr azidor trifluoro-methylr cyano or halogenr or phenylr naphthylr anthracenyl, indenylr acenaphthylenylr phenanthrenyl adamantylr cyclohexylr cyclohexenylr furylr thienylr ~ -pyridyl, pyrimidinylr thiazolylr indolylr quinolinyl benzimidazolylr methylenedioxyphenylr carbazolyl and -phenothiazinyl trisubstituted by methyl or halogenr and derivatives of the aforementioned carbocylic or heterocyclic rings which are mono- or disubstituted by ~ ~
methyl or halogen. ~ -.
Hydrogen, methylr ethylr isopropylr allylr methoxy ethoxyl methylmercaptor ethylmercaptor methylaminor ~ ~-methoxycarbonylr ethoxycarbonylr aminor azidor cyano hydroxy and halogen are particularly preferred for Rl wherein chlorine and bromine preferably come into consideration as the halogen.

Hydrogenr methylr ethylr isopropyl and cyano are particularly preferred for R2r R3r R4 and R5 or when R2 -and R4 denote an additional bond. Those compounds of formula I come particularly into consideration in which R2 and R4 simultaneously denote hydrogen.

:: .

Aromatic rings such as e.g. the phenyl, pyrrole, oxazole, thiophene, furan, isoxazole, thiazole, imidazole, pyridine, pyridazine, pyrimidine and pyrazine ring are particularly preferred for A. If A represents a carbocyclic or heterocyclic six-membered ring, those compounds are especially preferred which in relation to the nitrogen atom that is directly bound to the six~
membered ring of the condensed pyrimidine ring are -substituted in the para position of the six-membered -~
ring (position 9 of the tricyclic ring system).

Especially preferred are compounds of the general formula I in which R, R1, X, n and m have the meanings stated above and R2, R3, R4 and R5 are hydrogen, methyl or ethyl, in which three or four of the residues R2 to R5 are preferably hydrogen or R2 and R4 together represent a bond.

Hydrogen and C1-C3 alkyl are particularly preferred for R6. o is particularly preferred for n and m.

Compounds of formula I in which R1 is a hydrogen or halogen atom, in particular a chlorine atom, A is a phenyl or pyridine ring which is preferably substituted by R1 at the 9 position of the tricyclic ring system, -~
have a particularly well-pronounced pharmacological action. In this connection those compounds of formula I
are particularly preferred in which R2-R5 denote a hydrogen atom, m and n denote the number O and X denotes an oxygen or sulphur atom.

The pharmaceutical agents contain at least one compound of formula I for the treatment of viral infections and can be administered enterally or parenterally in a ~"``' ` ~

' : ' .:

' : ~, liquid or solid form. The usual forms of administration such as for example tablets, capsules, coated tablets, syrups, solutions or suspensions come into consideration ;~
as pharmaceutical forms of administration. Water is ;~
preferably used as an injection medium which contains the usual additives for injection solutions such as stabilizing agents, solubilizers and buffers. Such additives are for example tartrate and citrate buffer, ethanol, complexing agents such as ethylenediamine-tetraacetic acid and non-toxic salts thereof and high -molecular polymers such as li~uid polyethylene oxide to regulate viscosity. Liquid carrier substances for injection solutions must be sterile and are preferably dispensed into ampoulesO Solid carrier substances are -for example starch, lactose, mannitol, methylcsllulose, talcum, highly dispersed silicic acids, higher molecular ;~
fatty acids such as stearic acid, gelatins, agar-agar, calcium phosphate, magnesium stearate, animal and ~- -vegetable fats, solid high molecular polymers such as polyethylene glycols etc... Suitable formulations for -`~
oral administration can if desired, contain flavourings and sweeteners. `~
' ~: '''`',-`

The dosage can depend on various factors such as mode of application, species, age or individual condition. The compounds according to the invention are usually administered in amounts of 0.1 - 100 mg, preferably 0.2 - 80 mg per day and per kg body weight. It is preferable `~-to divide the daily dose into 2-5 administrations, 1-2 ~ ~ `
tablets with a content of active substance of 0.5 -500 mg being administered at each administration. The -~
tablets can also be retarded thus reducing the number of administrations to 1-3 per day. The content of active substance of the retarded tablets can be 2 - 1000 mg.
The active substance can also be administered by -`

-, i., ., ,. . . :

:: : ::, : - . :
:, : :, ::
'' ~ ;

, ~ ~

213~200 .

continuous infusion in which case amounts of 5 - 1000 mg -~
per day are usually adequate.

The compounds of the present invention and pharmaceutical preparations thereof can also be used in combination with other pharmaceutical agents for the ~ -~
treatment and prophylaxis of the infections mentioned above. Examples of these further agents containing other pharmaceutical agents which can be used for the treatment and prophylaxis of HIV infections and ~ -illnesses which accompany this disease are 3'-azido-3~
deoxyth,vmidine, 2,3'-dideoxynucleosides such as e.g. ;~ ~ -2',3'-dideoxycytidine, 2',3'-dideoxyadenosine and 2',3'- -dideoxyinosine or acyclic nucleosides (e.g. Acyclovir).

The compounds of the present invention and the other pharmaceutical agent can in each case be administered individually, simultaneously, if desired 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 produced according to methods known in the literature (Chem. Pharm. Bull. 29, 2135, 1981 or `~-~
Heterocycles 29, 1317, 1989), by reacting compounds of - `-the general formula II

Rl ~ R ~ -~=0 (II) --~
R~ ~ R
O
. ...

: . ~
. - , , ~ . , . .' .

. . ~

in which A, R, Rl and R6 have the meaning stated above and R7 denotes a readily cleavable group such as CCl3, CF3, oR3 or NR8R9 where R8 and R9 can be the same or different and can for example denote Cl-C6 alkyl or substituted or unsubstituted phenyl, phenylalkyl, hetaryl or hetarylalkyl, with a substituted or unsubstituted cysteamine or 3-mercapto-1-propanamine of the general formula III

H2N ( ~ ~ R `~
m RS

in which R2, R3, R4, R5 and m have the meaning stated above, in a suitable inert solvent at room temperature to reflux temperature, possibly in the presence of catalytic amounts of an acid such as p-toluenesulfonic acid or a base e.g. potassium hydroxide and if desired, compounds of formula I are subsequently converted into other compounds of formula I and subsequently purified by chromatography or by recrystallization. Racemates can be separated into the antipodes by chromatography on suitable optically active phases e.g. cellulose triacetate.

The subsequent conversions of compounds of formula I
into other compounds of formula I concerns for example the production of tricyclic thiazolo[3,2-c]pyrimidine and thiazino[3,2-c]pyrimidine derivatives in which X=S.

., . ~, . .. ~ - .

, ~ .
:
~:. ~; ..... - . . . ..

~121~Q

,:
Compounds in which X=S are produced by reacting compounds of formula I in which X denotes an oxygen atom with compounds carrying sulphur groups such as e.g. ~
Lawesson's reagent. ~ -. . :~,~''.
Compounds of the general formula I in which X=NH are produced by converting compounds of formula I in which X
denotes an oxygen atom by firstly producing the -~
chlorimine using a chlorination reagent such as e.g.
POCl3 and treating this with ammonia.

Compounds of the general formula I in which R2 and R4 denote an additional bond are produced in a Pummerer reaction by reacting compounds of the general formula I
in which n = 1 with an anhydride in an inert solvent -while heating if necessary, or compounds of the general formula I in which R2, R3, R4 or R5 denote a hydroxy~
methyl residue esterified with a carboxylic acid such as e.g. acetic acid or a sulfonic acid such as e.g.
. . ..
toluenesulfonic acid, are heated to 50-200C under pressure if necessary in an inert solvent in the presence of a base such as imidazole or sodium .: . -- . -:
hydroxide. -~
: ' ,: -, . .:'.

The compounds of the general formula II used as the ~ -starting material are obtained from aminobenzophenone derivatives according to methods known in the literature by acylation. The substituted or unsubstituted 2-amino-benzophenone derivatives can be preferably produced according to the method described by David A. Walsh ;
(Synthesis, 677, 1980).

In addition to the compounds mentioned in the examples -and compounds derived by combination of all meanings of ,: , ... ... . . . : . , -.: ~ ' - ~ . , ', ' ' . ' :' .
.

~13~200 the substituents stated in the claims, the following compounds of formula I come into consideration within the scope of the present invention which can be present as racemic mixtures or in an optically-active form or as :: ~:
pure R and S enantiomers~

1. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-quinazolin-5-one 2. lOb-Phenyl-2,3,6,1Ob-tetrahydro-5H-thiazolo[3,2-c]- ~ .
quinazolin-5-thione ~ .

3. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-quinazolin-5-imine `

4. 6-Methyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one 5. 9-Chloro-lOb-phenyl-2,3,6,10b-tetrahydro-5H- -"~
thiazolo[3,2-c]quinazolin-5-one :~

6. 9-Methyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one 7. 9-Methoxy-lOb-phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one . .

8. 10-Chloro-lOb-phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one 9. 10-Nitro-lOb-phenyl-2,3,6,10b-tetrahydro-5H- .~ .
thiazolo[3,2-c]quinazolin-5-one : :: ~: : , - . -.

.:: . :, , ~ :.

~13-~200 10. 7-Methyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H~
thiazolo[3,2-c]quinazolin-5-one .:

11. 8-Methyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one '''~;''; ;'''".'".'''''`' 12. lOb-(3-Methylphenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one 13. lOb-(3-Chlorophenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one ~ --, . ,,, .: - ~

14. lOb-(4-Methoxyphenyl)-2,3,6,10b-tetrahydro-5H-thiazoio[3,2-c]quinazolin-5-one .~

15. lOb-(2,3-Dimethylphenyl)-2,3,6,10b-tetrahydro-5H- ~ .
thiazolo[3,2-c]quinazolin-5-one 16. lOb-(3,5-Dimethylphenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one -~
.::

17. lOb-(l-Naphthyl)-2,3,6,10b-tetrahydro-5H-thiazolo- -~
[3,2-c]quinazolin-5-one ; ~--18. lOb-(4-Indanyl)-2,3,6,10b-tetrahydro-5H-thiazolo- ;~
[3,2-c]quinazolin-5-one 19. lOb-(2-Amino-5-methylphenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one - .

20. lOb-(6-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one `

' ' ~. " ' ' ' . , '' - 213~QQ

21. lOb-(4-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one 22. lOb-Thienyl-2,3,6,10b-tetrahydro-5H-thiazolo [3,2-c]quinazolin-5-one ,~
"";"' 23. lOb-Furanyl-2,3,6,10b-tetrahydro-5H-thiazolo -.
[3,2-c]quinazolin-5-one '~

24. llb-Phenyl-3,4,7,11b-tetrahydro-2H,6H-[1,3]~
thiazino[3,2-c~quinazolin-6-one ,;". .

25. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-pyrido[2,3-e]pyrimidin-5-one ~--26. lOb-(3-Methylphenyl)-2,3,6,1Ob-tetrahydro-5H-thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one 27. lOb-(3-Chlorophenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one 28. lOb-(6-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one 29. lOb-(4-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H- ~-thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one 30. 3-Ethoxycarbonyl-lOb-phenyl-2,3,6,1Ob-tetrahydro-5H-thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one 31. 3-Hydroxymethyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one ~: .
.~, , .

21342~0 ~

- 19 - ' 32. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-pyrido-[3,4-e]pyrimidin-5-one 33. lOb-(3-Ethylphenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]pyrido[3,4-e]pyrimidin-5-one " '.,,~' ~'':.','':

34. lOb-(3-Nitrophenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]pyrido[3,4-e]pyrimidin-5-one 35. lOb-(6-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]pyrido[3,4-e]pyrimidin-5-one 36. lOb-Methyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-pyrido[3,4-e]pyrimidin-5-one ' ~ ,~:'' 37. 9b-Phenyl-2,3,6,9b-tetrahydro-5H-thiazolo[3,2-c]-thieno[2,3-e]pyrimidin-5-one 38. 9b-(3-Methylphenyl)-2,3,6,9b-tetrahydro-5H-thiazolo[3,2-c]thieno[2,3-e]pyrimidin-5-one 39. 9b-(3,5-Dichlorophenyl)-2,3,6,9b-tetrahydro-5H-thiazolo[3,2-c]thieno[2,3-e]pyrimidin-5-one ~ :~

40. 9b-Phenyl-2,3,6,9b-tetrahydro-5H-thiazolo[3,2-c]- :~
furano[2,3-e]pyrimidin-5-one 41. 9b-(4-Methyl-2-pyridyl)-2,3,6,9b-tetrahydro-5H-thiazolo[3,2-c]furano[2,3-e]pyrimidin-5-one -.

42. lOb-Phenyl-2,3,6,1Ob-tetrahydro-5H-thiazolo[3,2-c]-quinazolin-5-one-1-oxide -::

`` 213~200 43. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]- ;~;
quinazolin-5-one-1,1-dioxide 44. lOb-Phenyl-6,10-dihydro-5H-thiazolo[3,2-c]~
quinazolin-5-one 45. lOb-(3-Methylphenyl)-6,10-dihydro-5H-thiazolo-[3,2-c]-quinazolin-5-one -~

46. 3-Methyl-lOb-phenyl-6,10-dihydro-5H-thiazolo-[3,2-c]-quinazolin-5-one 47. lOb-(3-Methylphenyl)-6,10-dihydro-5H-thiazolo-[3,2-c]pyrido[2,3-e]pyrimidin-5-one 48. 3-Methyl-lOb-(3-methylphenyl)-6,10-dihydro-5H-thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one ~
' :
Example ~............................................... ~:

lOb-Phenyl-2,3,6,1~-tetrahydro-5H-thiazolo-[3,2-c]quinazo~ -5-one ., ... -a) 5.8 ml (60.8 mmol) ethyl chloroformate in 25 ml toluene is added dropwise while stirring at 10C to -10 g (50.7 mmol) 2-aminobenzophenone in 125 ml toluene and 4.9 ml pyridine. After one hour the mixture is shaken three times with water, the ` ~-organic phase is separated, dried and evaporated.
The oil obtained is triturated with isohexane and the crystals are suction filtered.

, : ~ :

' .

2 1 3 ~ 2 0 0 12.3 g 2-ethoxycarbonylaminobenzophenone of melting point 73-75C is obtained. --b) 5 g (18.6 mmol) 2-ethoxycarbonylaminobenzophenone, ;
2.9 g (37.1 mmol) cysteamine and 0.5 g p-toluene~
sulfonic acid are heated in 100 ml dimethyl-formamide (DMF) to 140C for 52 hours under nitrogen. Subsequently the DMF is removed by distillation, the residue is dissolved in water and extracted twice by shaking with dichloromethane.
The organic phase is dried, evaporated and the ~ -residue is chromatographed over silica gel (mobile solvent: isohexane:ethyl acetate, 7:3). Evaporating the desired fractions and recrystallizing the residue from ethanol yields 3.5 g of the title compound of m.p. 212-215C.

~xample 2 llb-Phenyl-3,4,7,11b-tetrahydro-2H,6H-[1,3]thiazino-[3,2-c]quinazolin-6-one 5 g (18.6 mmol) 2-ethoxycarbonylaminobenzophenone (from example la), 3.4 g (37.1 mmol) 3-mercapto-1-propanamine and 0.5 g p-toluenesulfonic acid are heated in 100 ml dimethylformamide (DMF) to 140C for 52 hours under nitrogen. Subsequently the DMF is removed by distillation, the residue is dissolved in water and extracted twice by shaking with dichloromethane. The organic phase is dried, evaporated and the residue is i -~
chromatographed over silica gel (mobile solvent:
isohexane:ethyl acetate, 7:3). Evaporating the desired -fractions and recrystallizing the residue from ethanol yields 3.2 g of the title compound of m.p. 240-243C.

,:. ; . i .
,. ,. ~ . , Example 3 3-Hydroxymethyl-lOb-phenyl-2,3,6,10-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one a) 10 g (50.7 mmol) 2-aminobenzophenone is reacted with 8.6 g (55 mmol) phenyl chloroformate analogously to example 1 a. After processing and triturating with isohexane, 15.6 g 2-phenoxy-carbonylaminobenzophenone of m.p.115-117C is obtained. -.~ ' b) 22.19 g (70 mmol) 2-Phenoxycarbonylaminobenzo-phenone, 22 g (210 mmol) cysteinol and 2.2 g p-toluenesulfonic acid were refluxed in 500 ml toluene for 24 hours under nitrogen. Subsequently the toluene was removed by distillation and the oil was purified by column chromatography (mobile solvent: ethyl acetate/toluene = 80:20). The pooled fractions of the desired substance were concentrated by evaporation and the residue was crystallized from toluene. 3.5 g of the title compound of m.p. 188-190C is obtained.

Exam~le 4 -; -~

9-Chloro-lOb-phenyl-2,3,6,10b-tetrahydro-5H-thiazolo-[3,2-c]quinazolin-5-one In analogy to example 3 b 3.0 g (8.5 mmol) 2-phenoxy-carbonylamino-5-chlorobenzophenone, 1.3 g (17 mmol) cysteamine and 0.3 g p-toluenesulfonic acid in 150 ml toluene were boiled for 4 hours in a water separator.

.. - . .
. - , . .
-,~ -, :
;.. - . . .
::: . .

.. ~: . . .

- 23 - ~ ~
''~ ' '' ~ '' The toluene phase was shaken with 2 N hydrochloric acid and sodium carbonate solution, concentrated by evaporation and the residue was crystallized from ethanol. 2.1 g of the title compound of m.p. 187-194C
is obtained.

Ex~mple S

The following compounds are obtained analogously to example 4:
';
5 a) 10-Chloro-lOb-phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one of m.p. 264-265C
from ethanol 5 b) lOb-(3-Methylphenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one of m.p. 236-240C -from ethanol ~ ': .' .' 5 c) lOb-(3-Chlorophenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one of m.p. 226-227C
from ethanol 5 d) lOb-(3,5-Dimethylphenyl)-2,3,6,1Ob-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one of m.p. 243-256C
from ethanol . .
5 e) lOb-(3,5-Dichlorophenyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one of m.p. 260-261C
from ethanol ~; :

1 3 ~ 2 0 0 ~ ~ , 5 f) lOb-(6-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]quinazolin-5-one of m.p. 260-261C
from ethanol Ex mple 6 ~ ;

6-Methyl-lob-phenyl-2,3,6,10b-tetrahydro-5H-thiasolo-[3,2-c]quinazolin-5-one 0.5 g (1.8 mmol) of the compound obtained in example 1 b was dissolved in 10 ml DMF and admixed with 65 mg (2.7 mmol) NaH and 0.14 ml (2.2 mmol) methyl iodide. `
After 2 hours at 25C the DMF was removed by distillation, the residue was taken up in dichloro-methane, washed with water and the organic phase was dried and concentrated by evaporation. After crystallization from ethanol, 0.4 g of the title compound of m.p. 172-174C is obtained.
: :. ~ ::: ,:
~aople 7 lOb-Phenyl-2,3,6,1Ob-tetrahydro-5H-thiazolo[3,2-c]-quinazolin-5-thione 3.0 g (11 mmol) of the compound obtained in example 1 b and 8.8 g (22 mmol) ~awesson reagent were heated to reflux for 16 hours in 150 ml toluene. Subsequently ~;
water was added, undissolved material was separated and the organic phase was dried and concentrated by evaporation. The residue was purified over silica gel (mobile solvent: ethyl acetate/isohexane, 40:60). 1.5 g of the title compound of m.p. 208-215C is obtained ~`
aPter crystallization from ethanol.

~.. ,~., . ... . ~ .

:, :

.
: ~ :

~ 1 34 2 ~ 0 - 25 ~
,'' Exampl2 8 lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo-~3,2-c]quinazolin-5-imine -:

a) 0.25 g (0.84 mmol) of the compound obtained in example 7 was admixed in 5 ml DMF with 31 mg NaH and -~
0.06 ml methyl iodide. After 1 hour the DMF was removed ~
by distillation, methylene chloride and water were ~ ~;
added, it was acidified to pH 5 and the organic phase was separated. After drying and evaporating, 250 mg lOb- ;
phenyl-5-methylmercapto-2,3-dihydrothiazolo-[3,2-c]quinazoline is obtained as an oil, Rf=0.9 (toluene/dioxanetwater).

b) 250 mg of the previous compound was shaken for 9 hours in an autoclave at 80C with 15 ml ethanol and -~
10 ml liquid ammonia. After evaporation the residue was chromatographed over silica gel (mobile solvent: 80 %
ethyl acetate - 20 % isohexane). After concentrating the desired fractions by evaporation and crystallizing from -ethyl acetate, 75 mg of the title compound of m.p. 200-204C is obtained.

Bx~lmDle 9 ~ -:

Inhibition of reverse transcriptase (RT) '~
The screening test system consisted of purified RT from HIV-l which was expressed in E. coli by genetic engineering methods and the components of the initiation complex such as the in-vitro transcripts of the HIV-LTR's with the adjacent primer binding site as the ~' ' ' : ,, ! ': :

~ 1 3~

template and an 18mer oligonucleotide which is -complementary to the primer binding site as the primer.
The [3H~-thymidine-5'-triphosphate incorporation was ~ :.
measured by counting in a B-counter. ~:~

Results: .
ExampleInhibition of the HIV-RT ;:-:
IC50 tl~N
1 b 0.47 : .
2 0.51 _ ' 7 0.03 ~ :
4 O.C3 6 6.20 : ' 5 b 0.03 :~
~ ~:
5 f 0.20 : . . . .
:
.~ -, ,~;,

Claims (9)

Claims

1. Tricyclic thiazolo[3,2-c] pyrimidine and thiazino[3,2-c]pyrimidine derivatives of formula I

(I) in which A represents a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic ring with a maximum of 4 heteroatoms in which the heteroatoms can be the same or different and denote oxygen, nitrogen or sulphur and, if desired, the heterocycles can carry an oxygen atom on one or several nitrogen atoms, and A is substituted, if desired, by one or several residues R1 which can be the same or different, X can be an oxygen or sulphur atom or the group =NH, =N-C1-C6-alkyl or =S(O)2, R can be a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-9 C

atoms which can be substituted by phenyl or it denotes a phenyl ring, or R denotes 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 can contain 1-4 or 1-5 heteroatoms per ring system in which the heteroatoms are nitrogen, sulphur or oxygen and the aforementioned phenyl rings, the mono-, bi- or tricyclic carbocyclic rings or the heterocyclic mono-, bi- or tricyclic ring system is substituted, if desired, once or several times by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, C1-C6 alkylamino, di-C1-C6-alkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl, R1 denotes a hydrogen atom, a straight-chained or branched, saturated or unsaturated aliphatic residue with 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, azido, phenyl or benzyloxy, R2, R3, R4 and R5 can, independently of each other, be the same or different and each denote hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, cyano, carboxy or C1-C6 alkoxycarbonyl or R2 and R4 can denote a further bond between the C atoms to which they are bound, R6 denotes hydrogen or C1-C6 alkyl, n denotes 0, 1 or 2 and m denotes 0 or 1 as well as tautomers, enantiomers, diastereomers and physiologically tolerated salts thereof.

2. Tricyclic thiazolo[3,2-c]pyrimidine and thiazino-[3,2-c]pyrimidine derivatives as claimed in claim 1, wherein A denotes a single phenyl ring substituted by R1 or a heterocyclic ring selected from the group furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl ring.

3. Tricyclic thiazolo[3,2-c]pyrimidine and thiazino-[3,2-c]pyrimidine derivatives as claimed in claim 1 or 2, wherein R denotes a phenyl group or a carbocyclic ring from the group naphthyl, anthracenyl, phenanthrenyl, flourenyl, indenyl, indanyl, acenaphthylenyl, norbornyl, adamantyl, C3-C7 cycloalkyl or C5-C8 cycloalkenyl and these groups can be unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6 alkenyloxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkyl-carbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen.

4. Tricyclic thiazolo[3,2-c]pyrimidine and thiazino-[3,2-c]pyrimidine derivatives as claimed in claim 1 or 2, wherein R denotes a heterocyclic residue selected from the group pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazan, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system in which these heterocycles can be partially or completely hydrogenated and unsubstituted or substituted by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylmercapto, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, C2-C4 alkenyl, C2-C3 alkinyl, C3-C4 alkenyloxy, C1-C3 alkylamino, C1-C3 dialkyl-amino, C1-C3 alkylcarbonylamino, C1-C3 alkylamino-carbonyl, C1-C3 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen.

5. Tricyclic thiazolo[3,2-c]pyrimidine and thiazino-[3,2-c]pyrimidine derivatives as claimed in claims 1-4, wherein R1 denotes hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkinyl, C1-C3 alkoxy, C1-C3 alkyl-mercapto, C1-C3 alkylamino, C1-C3 alkoxycarbonyl, amino, halogen, hydroxy, nitro, cyano and azido.

6. Tricyclic thiazolo[3,2-c]pyrimidine and thiazino-[3,2-c]pyrimidine derivatives as claimed in claims 1-5, wherein A denotes a phenyl or pyridinyl ring which can be substituted by a halogen atom, R2-R6 each represent a hydrogen atom, m and n represent the number O and X represents an oxygen or sulphur atom.

7. Process for the production of tricyclic thiazolo-[3,2-c]pyrimidine and thiazino[3,2-c]pyrimidine derivatives as claimed in claims 1-6, wherein compounds of the general formula II
II

in which A, R, R1 and R6 have the meaning stated above and R7 is a readily cleavable group such as CCl3, CF3, OR8 or NR8R9 in which R8 and R9 can be the same or different and can for example denote C1-C6 alkyl or substituted or unsubstituted phenyl, phenylalkyl, hetaryl or hetarylalkyl, are reacted in a suitable inert solvent at room temperature to reflux temperature possibly in the presence of catalytic amounts of an acid or a base with a substituted or unsubstituted cysteamine or a 3-mercapto-1-propanamine of the general formula III

III
in which R2, R3, R4, R5 and m have the stated meaning and subsequently if desired, compounds of formula I in which X=O are converted into compounds of formula I in which X=S or X=NH.

7. Pharmaceutical agent containing at least one tricyclic thiazolo[3,2-c]pyrimidine or thiazino-[3,2-c]pyrimidine derivative of formula I as claimed in claims 1-6 as well as pharmacologically compatible auxiliary or carrier substances.

8. Use of tricyclic thiazolo[3,2-c]pyrimidine or thiazino[3,2-c]pyrimidine derivatives as claimed in claims 1-6 for the production of pharmaceutical agents having antiviral action.

9. Process for the production of pharmaceutical agents as claimed in claim 7, wherein at least one compound of formula I is mixed with pharmacologically compatible auxiliary substances and processed into pharmaceutical forms of administration.