SK88493A3 - Diazinediones, especially triazinediones, process of their production and their pharmaceutical compositions - Google Patents

Abstract

Novel di- and triazine diones of the formula I <IMAGE> in which R<1>, R<2>, R<3> and Z have the meaning indicated in Patent Claim 1, and their salts exhibit angiotensin II-antagonistic properties and can be used for the treatment of hypertension, aldosteronism, cardiac insufficiency and increased intraoccular pressure, and of disorders of the central nervous system.

Description

Technical field

SUMMARY OF THE INVENTION

The object of the invention

These are represented by the general formula ## STR2 ## wherein

CR ⁴

R ¹ represents (D (2) (3)

R ² represents - ° n ^H 2n - ^{C 8} · ^{8 τ τ} Γ v u u u u v * l n. , In _R 1 E, C6 ~ ^{_CnH2n C0_Ar} 'methods of making and optionally tri3zíndiónov, h compositions based on the diazíndióny groan or nitrogen atom (I)

-ch ₂

R ⁵ ,

-ch ₂

-u

F

C S -. ^ - He il-i · -

MR''R

^-1 - ^J 2 '-n-n-C _m H _2' -NR-CO-h (R) ₂ ;

R 'is H, A, alkenyl and 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, wherein one CH ₂ group is replaced by O or S, or represents cycloalkyl having 3 to 7 carbon atoms;

R @ 1 and the radicals R @ 1 independently of one another represent a hydrogen atom or a cycloalkyl group having from 3 to 7 carbon atoms. represents COCR, CN or 1H-5'tetrazolyl;

R ⁶ represents COCR, CN, NO ₂ , NH ₂ , NHCOCFβ, NHSO ₂ CF _3, or ΙΗ-5-tetrazolyl;

R? represents a hydrogen atom, -CC-R or -CO-CH / Ar ₁₂ ;

«*

R represents a hydrogen atom;

8

R 1 and R 2 together also represent -CO- (o-C 8 H 4) - CC-;

T is absent or represents -NR-CC-, -CO-NR- or

CH = CH;

U is -CE = C (CCCR) -, -CE = C (CN) -, -CH = C. (1H-5-tetrazolyl) -, -C-CH (CCOR 1) -, or -NR-CH.fCCOR. ) -;

m represents a number, 1, 2, 3, 4, 5, 6, 7, δ, 9 or 10;

n is 0, 1, 2, 3, 4, 5, 6, 7, 3, 9, or 10;

A represents alkyl of 1 to 6 carbon atoms;

Ar is phenyl or naphthyl which is unsubstituted or mono- or di-substituted by A, Hal, CF ₃ , ΟΗ, ΟΑ, COCH, COOA, CM, NO-, NH _; ,, NHA and / or N (A) -;

Het represents a five or six membered heteroaromatic radical having 1 to 4 nitrogen, oxygen and / or sulfur atoms, which is optionally fused to a benzene or pyridine ring and

Hal is F, Cl, B ^r, OMU or I;

It is an object of the invention to provide novel compounds with valuable properties, in particular those which can be used for the manufacture of medicaments.

The compounds of formula I and their salts have been found to possess valuable pharmacological properties of an angiotensin II antagonist and can therefore be used to treat angiotensin II-dependent hypertension, aldosteronism and cardiac insufficiency as well as central nervous system disorders. These effects can be verified in vitro or in vivo by conventional methods, as described, for example, in EP-A1-0 468 470, US 4,880,804 and in WO 91/14367, Still A.T. C’niu et al., J. Pharmacol. Exp. Therap. 250, 867-874 (1989) and P.C. Wong et al., Supra, 252, 719-725 (1990); in vivo, in rats.

The compounds of the formula I can be used as medicaments in human and veterinary medicine, in particular for the prophylaxis and / or treatment of cardiac, circulatory and vascular diseases, in particular hypertonia, cardiac insufficiency and hypereldosteronizine.

The present invention relates to compounds of the formula I and their salts as well as a process for the preparation of these compounds and their salts, characterized in that:

wherein it represents a chlorine, bromine or iodine atom or a free or reactive functionally modified hydroxy group, and

is as defined above, reacted with a compound of formula III

(III) where

Z, and R ⁴ are as defined above, or (b) in the preparation of a compound of formula (I) wherein:

T is -NR-CO- or -CO-NR-, reacting a compound of formula IV (IV)

or COOH and

R 'where q

R represents

X1 represents NH2

7 4

Z, R, R and R have the above-mentioned known or reactive derivative thereof with a compound of formula V

R ⁶ where

X ^ represents COOH (if X ^ · represents N ^) or represents ΝΗ - (if X ^ represents COOH) and

R1 is as defined above, or with a reactive derivative thereof;

or that (c) the compound of formula (I) is released from its functional derivatives by treatment with a solvolytic or hydrogerolytic agent;

and / or one in the compound of formula I is converted

2 or more R and / or R radicals to one or more other '2 R and / or R' radicals and / or the base or acid of formula I is converted into its salt.

In the preceding and following text, have residues, respectively, and i?

pad.e. the parameters Z, R and R ', R, T, U, m, n,, X', A, Ar, Het, Hal and E have the meanings given in formulas I to V, unless expressly stated otherwise.

In the above formulas, A represents especially alkyl having 1 to 6, preferably 1, 2, 3 or 4 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-diethylbutyl, 1- or 2-ethylbutyl, 1-ethyl 1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 or 1,2,2-trimethylpropyl.

Accordingly, the radical CA is preferably methoxy, further ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy and the radical SA is preferably methylthio and (more preferably ethylthio. COCA is preferably methoxycarbonyl or ethoxycarbonyl, other propyloxycarbonyl). The NHA group is preferably methylamino or ethylamino, and the N group (a ^ 2 is preferably dimethylamino or diethylamino), isopropyloxycarbonyl, butyl oxycarbonyl and isobutyloxycarbonyl.

Alkenyl is preferably vinyl, allyl or 1-propen-1-yl.

Alkyl group in which one CH ₂ group is replaced by O or S, is preferably OA, e.g., not acetoxy; or SA, for example, ethylthio; furthermore, for example, methoxymethyl, ethoxyethyl, 2-ethoxyethyl, 2-ethoxyethyl, methylthiomethyl, ethylthioethyl, 2-methylthioethyl or 2-ethylthioethyl.

Cycloalkyl is preferably cyclopropyl, furthermore cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, but also, for example, 4-methylcyclohexyl.

Hal is preferably fluorine, chlorine or bromine, but also iodine.

The radical Ar is preferably unsubstituted phenyl, furthermore phenyl and monosubstituted preferably in the para position, but also monosubstituted in the ortho or meta position. Preferred substituents are OA, COOH, COCA and NO ₂ . Accordingly, Ar is preferably phenyl, o-, m- or (especially) p-methoxyphenyl; o-, m- or / especially / p-carboxyphenyl, o-, m- or / mainly / p wetoxycarbonylphenyl, o-, m- or / especially / p-ethoxycarbonylphenyl, o-, m- or / especially / p-nitrophenyl further preferably o-, m- or / in particular / p-aminophenyl, o-, m- or / in particular / p-dimethylaminophenyl, o-, m- or / in particular / p-dimethylaminophenyl, o-, m- or p- tol.yl, o-, male- or p-trifluoromethylphenyl, o-, m- or p-hydroxyphenyl, o-, n- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p- bromophenyl, o-, m- or p-iodophenyl, o-, m- or p-cyanophenyl, o-, m- or p-methylaminophenyl, 1- or 2-naphthyl.

Het preferably contains one to four nitrogen atoms and / or one oxygen atom and / or one sulfur atom and is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2 or 3-pyrrolyl, 1-, 2-, 4- or 5-triazolyl, 1-, 3-,

4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-p-pyrimidinyl, further preferably 1,2,3-triazol-1,4- or -5-yl,

1,2,4-triazol-1-, -3- or -5-yl, 1,2,3-oxadiazol-4- or yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3, 4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 2,1,5-thiadiazol-3- or -4-yl, 3- or 4-pyridazinyl , pyrazinyl, 2-, 3-, 4-,

5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl , 1-, 2-, 4 or 5-benzimidazolyl, 1-, 3-, 4-, 5'-, 6- or 7-benzopvrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5 ', 6 or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5, 6- or 7benz-2-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-tolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-,

6-, 7- or 8-quinolyl, 2-, 4-, 5 -, 6-, 7 - or 8-quinazolyl, 1H-1-, -2-, -5-, -6- or -7-imidazole (4,5-b) pyridyl, 3H-2-, -3-, -5-, -6- or -7-imidazole / 4,5-b) pyridyl, 1H-1-, -2-, -4 -, -6- or -7-iodazole (4,5-c) pyridyl, 3H-2-, -3-, -4-, -6- or -7-iodazole / 4,5-c / pyridyl.

The term Het also includes homologous radicals in which the heteroarose ring is singly or multiply, preferably once or twice, substituted with A, preferably methyl and / or ethyl. Het is, for example, 3 ", 4- or 5 ^- ethyl-2-furyl, 2-, 4- or 5" ethyl-3-furyl, 2,4-dimethyl-3-furyl, 3 ", 4- or 5" ethyl-2-thienyl, 3-setyl-5-tert-butyl-2-thienyl, 2-, 4- or 5-ethyl-3-thienyl, 2 or 3-tetyl-1-pyrrolyl, 1-, 3- 4-, 5-methyl-2-pyrrolyl, 3,5-disethyl-4-ethyl-2-pyrrolyl, 2-, 4- or 5-methyl-1-iodazolyl, 4-methyl-5-pyrazolyl; - or 5-®etyl-3-isoxazolyl, ^{5-3alebo, j} and ethyl-4-isoxazolyl, 4-3alebo uetyl-5-isoxazolyl,

3,4-Dinethyl-5-isoxazolyl, 4- or 5-ethyl-2-thiazolyl, 4- or 5-ethyl-2-thiazolyl, 2- or 5-ethyl-4-thiazolyl , 2 or 4-methyl-5-thiazolyl, 2,4-dimethyl, 5-thiazolyl, 3-, 4-, 5- or 6-ethyl-2-pyrrolyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2- or 3 ^_ setyl-4-yl, 4 »ethyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2-, 5- or 6-methyl-4pyrirnidinyl, 2, 6-diethyl-4-p-pyrimidinyl, 3-, 4-, 5 -, or 7-methyl-2-benzofuryl, 2-ethyl-3-benzofuryl, 3 -, 4 -, 5-, 6- or 7-Methyl-2-benzothienyl, 3 ^- ethyl-2-benzothienyl, 1-, 2-, 4-, 5-, 6- or 7-ethyl-3-indolyl, 1-methyl-5 or -6 -benzimidazolyl, 1-ethyl-5- or -6-benzimidazolyl.

The radical Z is preferably CH3, more preferably CA, for example CCH3 or a nitrogen atom.

The radical T preferably is absent or preferably represents -NE-CC-, -N (CH 2) -CO-, -CC-NH-, -CO-N (CH 2) or -CH = CH-.

The radical U is preferably -CH = C, (CN) - or -CH = C (ΙΗ-5-tetrazolyl) -, further preferably -CH = C (CCCH) -, -CH = C (COOCH ₃ ) -, - CH = C (COCC ₂ H ₅ ) -, C-CH (COOH) -, -O-CH (COOCH-j) -, -O-CH (COOC ₂ H) -, - NH-CH (CCOH), -nf CH) -CHfCOOH) -, - NH-CHfC00CH ₃₎ -, -N _(CH3) -CH-ŕ'COOCH ₃₎ -, -NH-CH (CCOC ^) - ^ -NÍCH or -CHF ₂ H fCOOC ₅ ) -.

Preferably, R is independently from each other hydrogen, CH ₃ or C ₂ H 4.

(R) is preferably 2-cyanobiphenylyl-4-methyl, 2'-boxybiphenylyl-4-ethyl, 2 '- (1H-5-tetrazolyl) biphenylyl-4-ethyl, p- (2-cyano-) 2-phenylvinyl) benzyl, p- [2-phenyl-2- (1H-5-tetrazolyl) vinyl] benzyl or p-carboxybenzyl.

The radical R is preferably a hydrogen atom; A, in particular methyl, ethyl, propyl, isopropyl, butyl or isobutyl;

- (CH ₂ ) _n -COOR, especially -CH ₂ -COOR, especially carboxymethyl.

oethoxycarbonylmethyl or ethoxycarbonylsetyl, more preferably

-CCCOR, such as carboxy, setoxycarbonyl, ethoxycarbonyl or -C 1 -C 6 -COOR, in particular 2-carboxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl; -fCH₂Z -CN, especially cyano, cyanomethyl, 2-cyanethyl, -Ar, especially C 1-4 -Ar, such as benzyl, o-, m- or p -carbonylbenzyl, O-, m- or p-methoxycarbonylbenzyl, O-, α- or p-ethoxycarbonylbenzyl, more preferably -Ar, such as phenyl, O-, m- or p-carboxyphenyl, O-, m- or p-aethoxycarbonylphenyl, O-, m- or p-ethoxycarbonylphenyl or -Ar, such as 2 - (CH 2) -Het, especially -CH 8 -Het, such as 2- or 3-thienylmethyl, 2-, 3-, -phenylethyl, 2- (o-, 2-) or 2- (p-carboxyphenyl) ethyl; or 4-pyridylaethyl, 1H-5-tetrazolylmethyl, more preferably -Het such as 2- or 3'-thienyl, 2-, 3- or 4-pyridyl, ΙΗ-5-tetrazolyl or -C (CH 3) -Het such as 2 - (2- or 2- (3-thienyl) ethyl, 2- (2-, 2- (3or 2- (4-p-pyridyl) ethyl), 2- (ΙΗ-5-tetrazclyl) ethyl) --( CH₂-CH = CH-Ar, especially -CH₂"CH = CH-Ar, such as cinnaayl, more preferably -CH = CH-Ar, such as 2-phenylvinyl or -CH 2 -H"₉-CH = CH-Ar such as 4-phenyl-3-buten-1-yl; - (C 1-4) -CH = CH-Het, particularly -CH 2 -CH = = CH-Het, such as 3- (1H-5-tetrazolyl) -2-propen-1-yl. ; - (C ^ N Especially -C -C-CO-NÍR -C -C^andko carbamoylmethyl, N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, Ν, Ν-diethylcarbamoylmethyl, more preferably -CO-N, (R 12 as carbamoyl, N-methylcarbamoyl, γ-CH 2 -dimethylcarbamoyl,? CCN (R) 2, such as 2-carbamoylethyl, 2-M, N-diethylcarbamoylethyl;_n-CO-R, especially -C 1 -C 2 -C-R, such as formylaethyl, 2-oxopropyl, more preferably -CO-R, such as formyl, acetyl, propionyl or butyryl, or -CE 2 CH 2 -CO-R, such as 2-forwylethyl, 3-oxo-butyl; - (CH2)_n-CO-Ar, especially -C -C-CO-Ar, such as phenacyl, more preferably -CO-Ar, such as benzoyl, or -C ^-C ^-CO-Ar, such as 3-oxo-3-phenylpropyl; - (CH 2) 4 -O-CO-N (R 6, especially with -C 1-6 -O-CO-N (R) 2> such as carbomoyloxymethyl, N-methylcarbpheaoyloxymethyl, Ν, Ν-dimethylcarbamoyloxymethyl, or -C ^C N-O-CO-Nf R 6 such as 2-carbamoyloxyethyl, 2- (N-ethylcarbamoyloxy) ethyl, 2-N, N-dimethylcarbamoyloxy) ethyl; - (CH₂)_b-NR-CO-N ( 'R)₂ in particular -CEL, -NR-CO-NR1, such as ureidomethyl, N'-methylureidoethyl, N-aylureidomethyl, N, N'-diaethylureidomethyl, N ', N'-dimethylureidoethyl, N, N', Ν'-trimethylureidomethyl, or -CH₂CH₂-NR-CO-N ( 'R)₂such as 2-ureidoethyl.

The radical is preferably A, in particular ethyl, propyl, or butyl, or cycloalkyl, in particular cyclopropyl.

The radical is preferably a hydrogen atom, more preferably A, especially methyl or ethyl.

The residue is preferably COOH, COOCH ^ being preferred and preferably, COOC ₂ H _5, CN or ΙΗ-5-yl.

R is preferably hydrogen, acetyl or diphenylacetyl.

*

Preferably R is hydrogen

Ύ 8

The NR'R group represents Shaal preferably phthalimido.

The residue is preferably COOH, COOCH ^, CCOC ₂ H, CN or ΙΗ-5-yl.

Preferably, m is 1 or 2 and n is 0, 1 or 2. CH _? is preferably -CH ₂ -, especially -CH ₂ - or -CH ₂ CH ₂ -; CH _H "is preferably - _'O CH _O CH particular - or ^R R N N CN' 2

-CH ₂ CH ₂ -.

The compounds of formula (I) may contain one or more chiral centers and therefore exist in various optically active or optically inactive forms. Formula I includes all these forms.

The compounds of formula (I) preferably include uracils of formula (Ia) which correspond to formula (I), but wherein Z is Cr 1 R 1 '- 3-R 4 -5-R 6 -6-R 6 -1,2,3,4 -tetrahydro-1,3'-diazine-2,4-diones (as well as triazinediones of formula Ib), which corresponds to formula I but in which Z represents a nitrogen atom; 1-R -3-R -6-R -1,2,3,4-tetrahydro-1,3,5-triazine-2,4-dione].

Subject to. In particular, the invention relates to those compounds of the formula I, Ia and Ib in which at least one of the abovementioned radicals has the above-mentioned preferred meaning. Some preferred groups of compounds may be represented by the following sub-formulas T 1 to Ib, which correspond to the general formulas I, Ia or Ib and in which the unspecified residues have the meaning given in the general formula I, but in the sub-formulas Ic, Iac and Ibc

R ¹ represents 2 'cyanobiphenylyl-4-methyl, 2'-1H-5-tetrazolyl) biphenylyl-4-methyl, p-carboxybenzyl or p- (2-phenyl-2-1H-5-tetrazolylvinyl) benzyl;

in sub-formula Id, ice and Ibd

R 1 represents A, CH 2 CCOR, CH 2 CN, CH. _? (C 9 H-, o-COOR-benzyl, CH 2 (1 H-p-tetrazolyl)) or C 1 H 5 (R 1) in the sub-formulas Ie, Iae, and Ibe

R ¹ represents 2'-cyanobiphenylyl-4-methyl, 2'-1H-5-tetrazole, 4-methylbiphenylyl-4-methyl, p-carboxybenzyl or p- (2-phenyl-2- (1H-5-tetrazolyl) vinyl) benzyl; and

R 6 represents A, CH 2 COOR, CH 3 CN, CH p C 9 H 4, o-COORbenzyl, CH ₂ (ΙΗ-5-tetrazolyl) 'or CH ₂ CON (' R) ₂ .

Particular preference is given to compounds which correspond to all of the above general formulas, wherein in addition R 1 represents A or C 3 -C 7 cycloalkyl.

The compounds of the formula I as well as the starting materials which can be prepared in general by methods known per se, as described in the literature, for example in standard publications such as Houben-Weyl, Methoden der organischen Chemie, Georg.Thieme-Verlag, Stuttgart; in particular, in EP-A1-0 468 470 and US 4,880,804), under reaction conditions which are known and suitable for said reactions. It is also possible to use variants which are already known, not mentioned here in greater detail.

If desired, the starting materials can also be prepared in situ, so that they are not isolated from the reaction mixture, but are reacted directly to produce compounds of formula (I).

The compounds of formula I can preferably be obtained by reacting a compound of formula II with a compound of formula III.

In the compound of formula II, symbol is preferably a chlorine, bromine or iodine atom, or a reactive functionally modified hydroxy group such as a C 1 -C 6 alkylsulfonyloxy (preferably a 6-C 10 arylsulfonyloxy) or a 6-C 10 arylsulfonyloxy (preferably phenylaryl or p-tolyls) group.

The reaction of a compound of the formula II with a compound of the formula III is conveniently carried out by first converting the compound of the formula III with a base into a salt, for example with an alkali metal alkoxide such as sodium methoxide or tertiary potassium butoxide in an alcohol such as methanol. an ether such as tetrahydrofuran (THF) or in an amide such as dimethylformamide (DMF) or by treatment with an alkali metal hydride such as sodium hydride or an alkali metal alkoxide in DMF. This salt is then reacted in an inert solvent, for example an amide such as DMF or dimethylacetamide or a sulfoxide such as dimethylsulfoxide (DMSO), with a compound of formula II, suitably at a temperature of -20 to 100 ° C, preferably 10 to 30 ° C. Also suitable as bases are alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, or alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate. It is also possible to work in two phases, for example in a mixture of dichloromethane and water, whereby a phase transfer catalyst, for example tetrabutylammonium bromide, is expediently added.

When a compound of formula (III) is used wherein P is hydrogen, the reaction of a compound of formula (II) generally yields a mixture which can be easily separated, for example by chromatography. The ratio of the amount and the nature of the product can be controlled by changing the reaction conditions.

The acid amides of the formula I (where T is -NR-CO or -CO-NR-) can be further obtained by reacting a compound of the formula IV (or a reactive derivative thereof) with a compound of the formula V (or a reactive derivative thereof) .

As reactive derivatives of the carboxylic acids of formula IV and V / wherein X ^1, X ^ it is optionally COOH / are preferably the corresponding chlorides, bromides or anhydrides. The reaction is conveniently carried out in the presence of an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, chloroform, trichloroethene or 1,2-dichloroethane, or an ether such as THF or dioxane, at a temperature between 0 to 150 ° C, preferably between 20 to 80 ° C When acid halides are used for the reaction, it is recommended to add a base, for example a tertiary amine such as triethylamine, pyridine or 4-dimethylaminopyridine.

Further, the compounds of formula (I) may be released from their functional derivatives by treatment with solvolytic, for example hydrolytic or hydrogenolytic agents.

Thus, for example, give the carboxylic acid of formula I, wherein U is -O-CH (COOH) NH-CHFC), -NA-CH-fCOOH) 'or -CH = C (COOH), or R ⁵ and R ⁶ represents 2

COOH and / or R ~ ^{_CnH2n "CC0H and // alet,} ° ^Ar is phenyl or naphthyl which are substituted by one or two COOH, hydrolysis of the corresponding alkyl ester, for example with NaOH or KOH in aqueous solution, optionally in the adding an inert organic solvent such as methanol, ethanol, THF or dioxane at a temperature between 0 to 100 ° C; or by hydrogenolysis of the corresponding benzyl ester, for example in the presence of palladium on carbon at a pressure of between 1 and 20 MPa and at a temperature of between 0 and 100 ° C in any of the solvents mentioned above.

By the above-described methods, it is further possible to prepare compounds which correspond to the general formula I, but instead of the 5-tetrazolyl group they contain 1H- / or 2H / -5-tetrazo functionally modified in the 1-position, protecting them by suitable multiplication or 2-position. for example: triphenyl. hydrochloric acid or solvent is, for example, a mixture of ether, dichloromethane and ethyl, cleaved by reaction with sodium hydroxide THF; p-nitrobenzyl, cleaved by the action of Raney nickel in ethanol (see 3P-A2-0 lyl is not a protecting group). This splits. Methyl protecting groups which can be cleaved by metal or formic acid in an inert solvent of methanol; The reaction is carried out in a water / hydrogen mixture

IN? C

291,969 /.

those that are well known. If known by methods, similar to substance

The starting materials, in particular those of formulas (II) and (V), are absent and can be prepared by known methods.

Compounds of formula III (wherein Z is CR 4) may be prepared, for example, by reacting a ketoester of formula Fp-CO-CE 4 -COCA with urea of formula R -NHCONH? (see US 3,235,357), or by reacting this ketoester with thiourea to form δ-R 2 -2-thiouracil (t). (4-oxo-5-R-6-R'-2-thioxo-1,2,3,4-tetrahydropyrimidine) which is subsequently reacted with a compound of formula R -3 or dialkyl sulfate

9 Δ 7 to 4-oxo-2-R 'S-3-R' -5-R -6-R -3,4-dihydropyrimidine, which is then hydrolyzed, for example by treatment with hydrochloric acid

A compound of formula ZV can be obtained, for example, by reacting a compound of formula III with a q compound that corresponds to formula R -E, but the residue is protected such that amino groups are protected, for example, with an amino protecting group such as benzyl , AO-CQ- or benzyloxycarbonyl, or a carboxy group is protected by a carboxy protecting group, for example in the form of an ester group; then protecting groups are cleaved.

Further, the compounds of formula (I) may be converted to other compounds of formula (I) by converting one or more 12 to 9 R and / or R residues to another R and / or R residue. For example, the nitro group is reduced to an amino group, e.g. the presence of Raney nickel or palladium on carbon in an inert solvent such as methanol or ethanol and / or a free amino or hydroxy group is functionally modified and / or the functionally modified amino and / or hydroxy group is liberated solvolytically or hydrogenolytically and / or the nitrile atom is hydrolysed or a carboxy group and / or a nitrile group is reacted with a metal, for example, sodium azide with an N-methylpyrrolidone azide derivative or trimethylcinazide in toluene to form the tetrazolyl group.

Thus, for example, conventional ammonium can be acylated with free acid groups by reaction with an acid chloride or acid anhydride or alkylated with free hydroxy and / or imino groups with an unsubstituted or substituted alkyl halide or aldehyde such as formaldehyde in the presence of a reducing agent such as sodium borohydride or formic acid. an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethyl amine or pyridine at a temperature of -60 to 30 ° C.

If desired, a functionally modified amino and / or hydroxy group can be liberated solvolytically or hydrogenolytically in the compounds of formula I according to conventional methods. For example, a compound of formula I containing a COCA group can be converted to the corresponding compound of formula I, which instead contains the COOH group. Sister groups can, for example, be saponified by treatment with sodium or potassium hydroxide or water and dioxane in methanol, water and ethanol between

Reaction of nitriles of general formula

5 or R 'r ¹ / wherein R "or R ^-4 or 17 represents ON / s of tetrazole deprivation represented by ~ (' _n " 2n ^- ^^ 'azidic acid rivates leads to 2 3 of the general formula I / wherein R or R represents :

o · n-n trazolyl R or represents 1H-5-tetrazolyl) is used in a solvent, terlote between sodium azide in

Then take a trial

1G>

XIS by OOU column chromatography on ethyl acetate and methanol.

They are reacted with an acid, for example amounts of base and ethyl ether, which are then suitable for this reaction, in particular acids, of a suitable salt. Thus, it is possible to use sulfur, nitric, hydrogen halide or guitars by evaporating in an inert solvent. For which physiologically, for example, inorganic hydrogen chloride acid provides hydrogen bromide, equimolar acids, such as carboxylic or sulfonic acids, or acids derived from. sulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, melonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, acid ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acid, and lauryl sulfuric acid. Salts with acids that are not physiologically acceptable, for example picrates, can be used to isolate and / or purify the compounds of formula I.

On the other hand, compounds of the formula I which contain a carboxy or tetrazolyl group can be converted by treatment with bases, for example sodium or potassium hydroxide or sodium or potassium carbonate, into the corresponding salts with metals, in particular alkali or alkaline earth metals, or the corresponding ammonium salts. Potassium salts are particularly preferred.

The novel compounds of a suitable salt can be prepared. In this connection, the compounds of the formula I and their physiologically used compounds for the preparation of pharmaceutical preparations are treated together with at least one carrier or excipient and, if appropriate, one or more other active dosage forms. The compositions thus obtained are also desirable for use as medicaments in human or veterinary medicine by appropriate agents. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal) or parenteral administration or for administration in the form of an inhalation spray and which do not react with the novel compounds according to the invention. Such carriers are, for example, water, vegetable oils, benzyl alcohol, polyethylene glycols, glycerol triacetate of fatty acids, gelatin, soy lecithin and other glycerol hydrates such as or starches, magnesium stearate, talc or celloral administration, in particular tablets, dragees, capsules, juices; they deserve attention, they can be found with lacquer-coated or capsule-resistant capsules, solutions, especially oily or emulsions or implants. For sprays, it is possible to use sprays such as hepv micronisirups, coated tablets and capsules r for gastric juices, for parenteral administration of aqueous solutions, other suspensions, administration in lorm innal a nn c n c c. j c - which contain the active substance either. dissolved or suspended in a propellant or propellant mixture (such as, for example, hydrocarbons such as propane or butane or fluorinated hydrocarbons tafluoropropane). In this case, the active ingredient is used in a convenient form and one or more additional physiologically acceptable solvents, for example ethanol, may be present. The inhalation solutions may be administered by means of conventional inhalers. The novel compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the preparation of injectables. Said compositions may be sterilized and / or urine containing adjuvants such as preservatives or stabilizers and / or non-wetting agents, emulsifiers, salts for adjusting the osmotic pressure, buffers, coloring agents and / or flavoring agents. If desired, the compositions of the invention may also contain one or more other active ingredients, for example one or more vitamins, diuretics or anti-inflammatory drugs.

The compounds of the present invention may generally be other known commercially available formulations of the compound described in US 4,880-1 g, in particular 50-500 mg per kg, preferably between about 0.1 body weight, but depending on the particular compound, age the patient's administration, with a mg as a vein of about 50 mg / kg of the patient in the patient's condition, the time and route of administration, the speed of the drugs and the severity of the disease, gives oral administration.

should be administered similarly, but especially in analog 804. The preferred dose is a dosage unit. A dose of 100 mg / kg, in particular 1, and a dose for which one of its factors, for example, on body weight and body sex, diet, excretion, on the combination, is treated.

In the following examples, "common news" means the following:

If desired, water is added, depending on the nature of the final product, the pH is optionally adjusted to 2 to 10, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated and dried over sodium sulphate, evaporated and the residue purified by chromatography on silica gel and / or crystallization.

FAB = mass spectrum obtained by the fast atom bombardment method '.

An example of an embodiment of the invention

Example 1 which can be butylurea with thiourea in ethanol in the presence of sodium ethoxide to give 6-propyl-2-thiouracil (i.e. 4-oxo-6-propyl-2-thioxo-1,2,3,4-tetrahydropyrimidine, m.p. 279) (C) which is methylated by treatment of a mixture of dimethyl sulphate, sodium hydroxide and water with 3-methyl-2-methylthio-4-oxo-6-propyl-1,4-dihydropyrimidine to which is boiled with boiling concentrated hydrochloric acid] in 400 13.3 g of tetrabutylammonium bromide are added, followed by a solution of 8 g of sodium hydroxide in: 20 ml of water, followed by 27.2 g of 4-bronunethyl-2-cyanobiphenyl (compound IIIa). The mixture was stirred at 40 ° C for 32 hours, then subjected to the usual workup (silica gel; petroleum ether / ethyl acetate 6: 4) to give 1- (2'-cyanobiphenylyl-A-methyl) -3-methyl- Opropyl-uracil, m.p. 147 ° C.

In a similar way it is possible to:

from compound IIIa and p-bromomethylbenzoic acid methyl ester to give 1- (p-methoxycarbonylbenzyl) -3-methyl-6-propyluracil;

from compound H1a and p- (2-cyano-2-phenylvinyl) benzyl bromide to obtain 1- [p- (2-cyano-2-phenylvinyl) benzyl] -3-methyl-6-propyluracil;

(v) from compound IIIa and 4-bromomethyl-2-nitrobiphenyl

1- (2 & -nitrobifenylyl-4-methyl) -3-mety1-6-propyluracil,

FAB 380j from 6-butyl-3-methyluracil and Compound IIa to obtain 6-butyl-1- (2H ^- cyanobiphenylyl-4-methyl-3-methyluracil, FAB 374;

from 6-cycloporpyl-3-methyluracil and Compound IIa to obtain 1- (2'-cyanobiphenylyl-4-methyl) -c-cyclopropyl-3-methyluracil, FAB 358;

cyanbiphenylyl-4-methyl) -? - cyclohexyl-3-methyluracil, FAB 400;

from 3-, 6-dimethyl-c-propyluracil and IIa to obtain 1- (2'-cyanobiphenylyl-4-netyl) -3,5-dimethyl-6-propyluracil, FAB 374;

from 3-butyl-5-propyluracil and IIa

- (2'-cyanobiphenyl-4-methyl) -6-propyluracil

FAB 402;

from 3-phenyl-6-propyluracil and Compound IIa to obtain 1- (2'-cyanobiphenylyl-4-methyl) -3-phenyl-6-propyluracil, FAB 394;

from J-benzyl-6-propyluracil / mp 154 ° C; obtainable from ethylbuxyrylacetate and N-benzylurea and compound IIa to give 3-benzyl-1- (2'-cyanobiphenyl-4-methyl) -6-propyluracil, m.p. 196 ° C;

from 3'-methoxycarbonyl-ethyl-6-propyluracil and compound IIa to obtain 1- (2'-cyanobiphenyl-4-methyl) -3-methoxycarbonylmethyl-6-propyluracil, FAB 413;

from J-o-methoxycarbonylbenzyl-6-propyluracil and Compound IIa to obtain 1- (2'-cyanobiphenylyl-4-methyl) -3-o-methoxycarbonylbenzyl-6-propyluracil, FAB 494;

from 3-N, N-dimethylcarbamoylmethyl-6-propylaracil and IIa gave 1- (2'-cyanobiphenylyl-4-methyl) -3-N, N-dimethylcarbamyolmethyl-6-propyluracil, FAB 431;

from 3-allyl-o-propyluracil

- (2'-cyanobiphenylyl-4-methyl and compound IIa to obtain 3-allyl) -β-propyluracil, FAB 386; until . 3'-cyanomethyl-6-propyluracil and IIa obtained 1- (2'-cyanobenzenylyl-4-methyl-3-cyanomethyl-6-propylurscil, FAB 385).

A mixture of 0.01 mol of 6-butyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydra-1,3,5-triazine (obtainable by reacting Valeric anhydride) with dicyandiamide, the formation of 5-butyl-4-imine-2-oxo-1,2,3,4-tetrahydro-1,3,3-triazine is similar to that of F. Andreaschjononatshefe fr Onemie, 43, 145 et seq., 1927 , which is subjected to hydrolysis with sulfuric acid, and the thus-formed c-butyl-2,4-dioxo-1,2,3,4-tetrahydro-1,3,5-triazine is melted at 185 ° C with 0- methyl-N, N * -dicyclohexylisourea in DMF at 100 ° C /, 0.01 mol of the compound

IIIa, 0.011 mol of tert-butoxide and 400 ml of THF are stirred for 18 hours at 20 ° C. Then the mixture is evaporated and customary working up (silica gel, dichloromethane / methanol 95: 5) yields 3 6-butyl-1- (2). 3-methyl-2,4-dioxo-1,2,3,4-tetrshydro-1,3,5-triazine, m.p. 57 ° C.

Example 3

A mixture of 1 g of 1β-aminobenzyl-3-methyl-6-propyluracil (obtainable by reacting a Hla-type compound with p-BOC-aminobenzyl bromide to give 1β-BOC-aminobenzyl-3-methyl-6-propyluracil), and then deprotecting 0.6 g of phthalic anhydride and 40 ml of trichloromethane were stirred at 20 ° C for 16 hours. The precipitated mono-β-β-methyl-6-propyluracilyl-1-methyl-phthalic acid anilide was stirred for 16 hours. filtered.

Example 4

A mixture of 1.73 g of 1β-aminobenzyl-3-methyl-6-propyluracil, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 ml of dichloromethane is cooled to 5 ° C and treated dropwise with a solution of 2.88 g of o- trifluoromethanesulfonamido-oenzoyl chloride in 20 mL of dichloromethane. Stirring is continued for 16 hours at 20 ° C, then the mixture is evaporated. After usual work-up, 3-methyl-6-propyl-1- [4- (o-trifluoromethanesulfonamidobenzamido} benzyl) uracil is obtained.

Example 5

A mixture of 3.02 g of 1-p-carboxybenzyl-3-methyl-6-propyluracil, 12 g of thionyl chloride and 35 ml of trichloromethane is boiled for 6 hours and then evaporated. The crude acid chloride obtained is freed from thionyl chloride residues several times in toluene and evaporated and then dissolved in 80 ml. This solution was added dropwise to a solution of 1.37 g of anthranilic acid and 0.8 g of sodium hydroxide in 100 ml of water. The mixture was stirred for 24 hours and acidified to pH 5 by addition of hydrochloric acid. Conventional work-up gave 1- (4- (o-carboxyanilinocarbonyl) benzyl) -3-methyl-6-propyluracil.

EXAMPLE 6 (a) A solution of 16.3 g of 3-methyl-6-propyluracil (compound IIIa) in 300 ml of DMF is mixed with 11 g of potassium tert-butoxide and, after 30 minutes, with 54.5 g of 4 * -. bromomethyl-2- (1) or 27-triphenylmethyl-1H / or 2H (-5 'tetrazolyl) biphenyl (see, for example, ΞΡ-Α2-0 392 317); where it is designated as -1-triphenylmethyl-1H-, but this structure has not been proven. The mixture was stirred at 20 ° C for 3 hours. After usual work-up, 3-methyl-1- [2- (1-triphenylmethyl-1H-5-tetrazolyl) biphenylyl-4-methyl] -6-propyluracil was obtained.

A solution of 6.33 g of the compound obtained in (a) in 30 ml of dichloromethane and 30 ml of methanol is treated with 20 ml of ether

Example

A solution of 1 g of 1β-benzyloxycarbonylbenzyl-3-methyl-6-propyluracil (obtainable from compound IIIa and p-bromomethylbenzoic acid benzyl ester) in 25 ml of ethanol is hydrogenated in the presence of 0.5 g of 5¾ palladium on carbon at 20 ° C and a pressure of 0.1 MPa until the calculated amount of hydrogen was consumed. The resulting mixture was filtered and evaporated. After chromatographic? -Carboxybenzyl-3-methyl-6-propyl uracil

Example 8

A solution of 1 g of 3-methoxycarbonylmethyl-6-propyl-l- / ^/ 2 '' - (l 4-5-yl) biphenyl-4-methyl / uracil / see Example 10 / the $ ml of n sodium hydroxide solution and 60 ml of dioxane was stirred at 20 ° C for 48 hours. The solution was concentrated and the residue was taken up in water. The mixture was washed with dichloromethane and acidified by the addition of 1M hydrochloric acid. After usual work-up, 3-carboxymethyl-6-propyl-1- [2- (1H-5-tetrazolyl) biphenylyl-4-methyl] uracil is obtained.

Similarly, the saponification of the corresponding methyl esters yields:

3-o-carboxybenzyl-6-propyl-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) uracil and 1β-carboxybenzyl-4-methyl-6-propyluracil as monohydrate, m.p. 141 ° C.

Example 9 (a) A solution of 1- (2'-nitrobiphenylyl-4-methyl) -3-methyl-6-propyluracil (1 g) in ethanol (30 ml) was hydrogenated in the presence of Raney nickel (1 g) at 20 ° C until hydrogen uptake was complete. The mixture was filtered, the filtrate was evaporated to give 1- (2'-aminobiphenylyl-4-methyl) -3-methyl-6-propyluracil.

(b) A solution of 2.82 g of trifluoromethanesulfonic anhydride in 10 ml of dichloromethane was added dropwise to a solution of 3.49 g.

1- (2'-aminobiphenylyl-4-methyl) -3-methyl-6-propyluracil and 1.01 g of triethylamine in 30 ml of dichloromethane at -50 to -60 ° C. The mixture is warmed to 20 ° C and poured into dilute of acetic acid. After usual work-up, 3-methyl-6-propyl-1- (2'-trifluoromethanesulfonidobiphenylyl-4-methyl) uracil is obtained.

Example 10

A suspension of 3.59 g of 1- (2'-cyanobiphenylyl-4-methyl) -3-methyl-6-propyluracil and 6.2 g of trimethyltin azide in 140 ml of toluene is boiled for 9 days, then evaporated. The residue was dissolved in 1N sodium hydroxide solution. The solution is treated with concentrated hydrochloric acid and the resulting 3-methyl-6-propyl-1- [2- ((-5-tetrazolyl) biphenylyl-4-methyl] uracil is formed as a dihydrate, m.p. 119 ° C,

In a similar manner were obtained from the corresponding nitrites: 3-ιηΘί71-6-ρΓοργ1-1-, ^/ ρ- (2-ίθηγ1-2- (lH-5-yl) vinyl) -benzyl / uracil;

6-butyl-3-methyl-1- (2- ⁽ 1H-5-tetrazolyl) biphenylyl-4-methyl) uracil in the form of a nonahydrate, m.p. 74 ° C;

6-cyclopropyl-3-methyl-1- (2 * - (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) uracil as trihydrates, FAB 401;

6-cyclohexyl-3-methyl-1- (2 '- (1H-5-tetrolzolyl) biphenylyl-4-methyl) uracil;

3,5-dimethyl-6-propyl-1- [2 '- (η 5 -tetrazolyl) biphenylyl-4-methyl] uracil, RAB 417;

3-butyl-6-propyl-1- (2 ^z - (1H-5'tetrazolyl) biphenylyl-4-methyl) urscil, in the form of tetrahydrate, m.p. 147 ° C;

3-phenyl-6-propyl-1- [2- (1H-5-tetrazolyl) biphenylyl-4-methyl] uracil;

3-benzyl-6-propyl-1- (2 ^z - (1H-5-tetrazolyl) biphenynyl-4-methyl ⁾ uracil, in the form of the dihydrate, m.p. 107 ° C;

3-methoxycarbonylmethyl-6-propyl-1- (2 * - (E-5-tetrazolyl) biphenylyl-4-methyl) uracil;

3-o-methoxycarbonylbenzyl-6-propyl-1- [2- (1E-5-tetrazolyl) biphenylyl-4-methyl] uracil as monohydrate, m.p. 146 ° C; potassium salt as decahydrate, m.p. 227 ° C ;

3-N, N-dimethylcarbomoylmethyl 1-6-propyl-1- (2'-1H-5-tetrazolyl) biphenylyl-4-methyl] uracil as trihydrate, FAB 474; potassium salt in the form of monohydrate, m.p. 133 ° C;

3- allyl-6-propyl-1/2 ^from - (1H-5 ^- tetrazolyl) biphenylyl-4-methyl / uracil in the form of the monohydrate, m.p.

6-Butyl-3-methyl-2,4-dioxo-1- [2- (5-tetrazolyl) biphenylyl-4-methyl] -1,2,3,4-tetrahydro-1,3,5'-tri-zine as an octohydrate with temperature temperature 73 ° C.

Similar to the prime which is not substituted at the position following 1- (2 ') cyanobiphenylyl-4-me

3-methyl-c-ethyl-, FAB 346;

3-o-methoxycarbonylbenzyl-β-butyl-,

3- (2-phthalimidoethyl) -β-propyl-, FAB

71; »·

Example

To a solution of 7.9 g of 3- (2-phthalimidoethyl) -6-propyluracil, which can be obtained by reacting 1,6-dihydro-

2-methoxy-4-propylpyrimidin-6-one with 2-phthalidoethylbromidones in the presence of cesium carbonate to give 1,6-dihydro-2-methoxy-3- (2-phthalimidoethyl) -4-propylpyridin-6-one which is hydrochloric acid / in

100 ml of OMF was added with 7 g cesium carbonate.

The grains were stirred for 1 hour at 20 DEG C., 6.5 g of compound IZa was added thereto, and stirring was continued at 20 DEG C. for 18 hours. petroleum ether (ethyl acetate 1: 1) gave 1- (2'-cyanobiphenylyl-4-methyl) -3- (2-phthalimidoethyl) -6-propyluracil as an oil, FAB 519.

(b) A solution of 7.8 g of 1- (2'-cyanobiphenylyl-4-methyl) -3- (2-phthalimidoethyl) -6-propyluracil and 3 ml of hydrazine hydrate in 60 ml of methanol is stirred at 20 ° C for 18 hours. to give 1- (2'-cyanobiphenylyl-4-methyl) -3- (2-aminoethyl) -6-propyluracil (If), as an oil, FAB 389.

(c) A solution of 2.4 g of If and 0.76 ml of cyclohexyl isocyanate in 20 ml of dioxin was boiled for 3 hours, then evaporated. 1- (2'-Cyanobiphenylyl-4-methyl) -3- (2-N'-cyclohexylureidoethyl) -6-propyluracil, FAB 514, is obtained.

(a) g of compound If was stirred for 1 hour and 0.6 ml of acetic anhydride in 15 ml at 20 ° C then evaporated. obtained

uracil, FAB 431.

(e) A solution of 1 g of If, 0.55 g of diphenylacetic acid, 0> 5 g of N- (3-dimethylaninopropyl) -N'-ethylcarbodiimide hydrochloride and 0.53 g of N-methylmorpholine in 50 ml of DMF is stirred for 18 hours at The solution obtained is poured into water and the resulting 1- (2'-cyanobiphenylyl-4-methyl) -3- (2-diphenylacetamidoethyl) -6-propyluracil is separated by filtration,

FAB 583

Example 13

Similar to Example 10, the following 1- / 2 (1H-5-tetrazolyl) biphenylyl-4-methyl] uracils are obtained from the corresponding nitriles by treatment with trimethyltin azide:

3-methyl-6-ethyl-, in the form of the trihydrate, m.p. 180 ° C;

3-o-methoxycarbonylbenzyl-6-butyl-, in the form of a nonahydrate, m.p. 135 ° C;

3- (2-phthalimidoethyl) -6-propyl, mp 135 ° C;

3- (2-acetamidoethyl) -b-propyl-, in the form of tetrahydrate, m.p.

3- (2-diphenylacetamidoethyl) -6-propyl-, in the form of the dihydrate, m.p. 212 DEG C., and

3- (2-N-cyclohexylureidoethyl) -6-propyl, m.p.

The following examples relate to pharmaceutical preparations which contain as active ingredient a compound of the formula I or a salt thereof.

Example A

Pills and dragees

active ingredient of the formula I 100 microcrystalline cellulose 278.8 mg lactose 110 mg maize starch 11 mg magnesium stearate 5 mg silica-fine-grained silica n? - mg

Example B

Hard gelatine capsules

Conventional two-piece hard gelatine capsules are made such that each ninh contains a mixture of the following composition:

active substance general lactose cellulose magnesium stearate

of formula I 100 mg 150 mg 50 mg FROM· 0 mg

Example C light gelatin capsules

The usual soft gelatine capsules are filled with the mixture in

from

Example D

ampoule

A solution of 200 g of active ingredient in 2 kg of 1,2-propanediol is made up to 10 liters with water. The solution is filled into ampoules, each containing 20 mg of active ingredient.

-X

An aqueous suspension is prepared in a conventional manner, - One dose / 5 ml contains 100 mg of active substance, 100 mg of methyl cellulose sol, 5 mg of sodium benzoate and 100 mg of sorbine m-gt

Claims (7)

PATENT CLAIMS 1. Diazinediones of the formula I or triazinediones of general formula. (I) where represents CR ⁴ or a nitrogen atom R ¹ is (D (2)) -CH ₂ -QR ⁵ , or (3) -ch ₂ -QuQ) y R ¹ represents an atom C -COOR, -CH nm _of 'nm -CH = CH-Ar, -CH. up to 6 carbon atoms _A CH-CO-N, CH 2 n _with n 'm H 2 m, alkyl, -CN, -C -.-I, - »jx" nm n. _n . _{2 n} -CE = CE-Het, -C _n H ₂ -NR < -C _n H _2n -C 0-N (R) _2, -O-CON (R) _2, or -C -c R ³ represents a hydrogen atom, A, alkenyl group, one sulfur, n, oZ 1 alkyl group having 1 to 6 carbon atoms, the group CE- replaced by an oxygen atom, or represents a cycloalkyl having 3 to 7 att 6 carbon atoms in which the cm2mi carbon atom is j A R ' ^r and the radicals R are, independently of one another, a hydrogen atom A or a cycloalkyl of 3 to 7 carbon atoms R ⁵ represents COOR, CN or 1H-5'tetrazolyl; H ⁶ is COOR, CN, NC _2, NHCOCF ^, NHSCkCF., and ΙΗ-5-yl; II R? represents a hydrogen atom, -CO-H or -CO-CH 2 Ar 2; R represents a hydrogen atom; R? and R 8 together represent -CO-f-C (H 4) -CO-; T is absent or represents -NR-CC-, -CO-NR- or -CH = CH-; U represents -CH = C (COOR) -, -CH = C (CN) -, -CH = C (1H-5-tetraolyl) -, -O-CH (COOR) - or -NR-CH (COOR) -; b m. is number 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; < ' n is number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; A is alkyl C 1 -C 6; Ar is phenyl · - or naphthyl which is unsubstantiated bold or mono- or double-substituted A, Hal, CF _{3 /} OH, OA, COOH, 000A, CM, NO ₉ , NH 4, NHA and / or N (äJ ₂ ; Het represents a five or six membered heteroaromatic radical having 1 to 4 nitrogen, oxygen and / or sulfur atoms, which is optionally fused to a benzene or pyridine ring and Hal represents a fluorine atom of chlorine, bromine or iodine; as well as their salts. 2. (a) 3-Methyl-c-propyl-1- (2 '- (1H-5-tetrazolyl) -biphenyl-4-methyl) uracil and (b) 6-butyl-3-methyl-1 - [2- (1H-5-tetrazolyl) biphenylyl-4-methyl] uracil. 3. A process for producing diazinediones or triazinediones w of the formula Z according to claim 1, as well as their salts, characterized in that? váôOO ^ Cr ^ be in 9PO3 ⁷ * - * wherein the Cl, Br, I or a functionally modified volalebo hydroxyskupiau and AE are the 1Λ io is as defined above, with a compound of formula III J where "7 ti ' 31sbr / b / that from " 4., As is known in the art, the preparation of the compound is generally -NR-30- or -30 of the formula IV. CTI Of the formula I, v where T ce (III) (IV) where Ϊ? represents ω -θ-χι ^and represents NH ₂ or 300H and o? 4 ... Z, R ', R ^J and R have it. I know the above, IV or a reactive derivative thereof sq with a compound of formula V R ⁵ (V) wherein v 1 is OOOH (when X is N 4) or when X ⁴ is COOH / ^Z and is as defined above, or with a reactive derivative thereof; or that (c) the compound of formula (I) is released from its functional derivatives by treatment with a solvolytic or hydrogenolytic agent; and / or in a compound of formula I, one or two or more of R ^x and / or R is converted to one or more others The base or acid of the formula I is converted into its salt. 4. A process for the preparation of pharmaceutical preparations, characterized in that the compound of the formula I according to claim 1 and / or one of its physiologically acceptable salts is converted together with at least one solid, liquid or semi-liquid carrier or diseased substance into a suitable dosage form. . 5. A pharmaceutical composition comprising at least one compound of the formula I as claimed in claim 1 and / or one of its physiologically acceptable salts. Compounds of formula I according to claim 1 and physiologically acceptable salts thereof for the control of diseases. Use of the compounds of the general formula I according to claim 1 1 and / or their physiologically acceptable salts for the manufacture of medicaments.