SK131193A3 - Heterocyclic compounds with antiasthmatic/antialergic, antiinflammatic positive inotropic and blood pressure lowering effect - Google Patents

Abstract

Compounds of the triazinone type having the general formula 1, which have antiasthmatic, antiallergic and cardiovascular activities, and process variants for their preparation were described.

Description

The triazinone-type compounds of formula I, wherein the meaning of the substituents is given in the claims, with antiasthmatic, antiallergic and blood pressure-influencing effects, as well as process variants for their preparation.

Novel heterocyclic compounds with anti-asthmatic / antiallergic, anti-inflammatory, positively isotropic and blood pressure reducing effects

The present invention provides novel aryltriazinones and aryltriazinophthalazines, processes for their preparation and use of the compounds of the invention for the treatment of bronchial asthma, allergies of various origins, inflammatory processes, cardiac insufficiency and hypertension.

For example, the compounds of the invention are potent and selective inhibitors of 5-lipoxygenase and can therefore be used in the treatment of diseases in which the participation of 5-lipoxygenase or iucotrienes in pathological processes is important. Sayed et al. (Chinese Journal of Chemistry, No. 1 (1991? P. 45) describes the synthesis of substituted phthalazinone derivatives by reacting phthalides or substituted benzoylbenzoic esters with hydrazine. Another reaction results in 7- (p-ethylphenyl) -2H- 1,2,4-triazino- [3,4-a] phthalazine-3 (4H-by-products). Camparini et al. (J. Heterocyclic. Chem. 15. 1271 (1975) describe the reaction of iminoesters and substituted hydrazines to 2 5-Dihydro-1,2,4-triazin-6 (1H-ones). The reaction proceeds in good yield.

EP-0 522 422 describes triazinones which are substituted in position 6 by a substituted aromatic ring. The compounds exhibit cardiotonic properties and are additionally useful. for the treatment of Parkinson's disease.

European Patent Application 80 296 describes oxadiazole from _TT Zinon, triazinones and Thiadiazinones substituted at the 4-position of the aromatic residues that have cardiotonic and antihypertensive effect.

The compounds of the invention may be described by the formula:

^R 2 ° ^R 1

N. N Z - / -

The compounds of the invention may also exist in tautomeric forms.

Since X contains an asymmetric carbon atom, there are two optically active forms of the mirror-image structure of the compounds of the invention. Furthermore, the compounds of the invention may exist in two enantiomers of the (r) - or (S) - form or in the form of a racemic mixture or even mixtures of any composition.

Synthesis of compounds

All three described process variants lead to the compounds of formula (1).

Procedure 1

7-Phenyl-2H-triazine (3,4, a) phthalazin-3- (4H) -one

The corresponding phenylthiazinophthalazinones of formula IV can be prepared from Scheme I.

The meanings of X and Y correspond to the above definitions.

Based on methods known in the literature, 4-arylphthalazinones of formula I (prepared according to J. Pharmaceutical Soc. Jpn 86, 578 (1966) and USP J., 694, 422 and alkylation (according to J. Organic. Ghem. 50. 1967 (1985)) alkyl-4-arylphthalazinoacetates of formula II. Suitable solvents in the process from Compound II to Compound III according to Scheme 1 are aromatic hydrocarbons which are liquid and which may be substituted by one or more alxy groups such as e.g. benzene, toluene and isomeric xylenes.

After conversion to the thioamides of formula III (with or Lawesson's reagent?), It is cyclized with hydrazine or substituted hydrazine derivatives in alcohols at 50 ° C - 80 ° C.

Lawesson's reagent is 2,4- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphonethane-2,4-disulfide, which may be prepared according to Synthesis, p. 941 (1979) or by T. P. Anderson et al., Tetrahedron, 39 (20), 2419 (1983).

The alcohols which may be used are aliphatic alcohols which do not have one or more hydroxyl groups and whose chain length consists of 1 to 4 carbon atoms. It fits eg. methanol, ethanol, propanol, isopropanol and isomer not butanols.

Example 1

7-Phenyl-2H-triazine (3,4a) phthalazin-3 (4K) -one (D-19509);

g (0.032 mol) of 4-phenylphthalazinone (melting point 232-234 ° C) is dissolved in 100 ml of toluene and 0.8 g is added in portions

Synthesis of aryltriazinophthalazine

ΓΊ x _u y

Lawesson /

Toluene.

ri

I

N

.N ^l 7 ^l R ₂ N HVALkohol

N-CH, CO ₂ Et t

N

X Y (V

(0.130 mol) of sodium hydride at room temperature. It is then refluxed for 1 hour and treated with bromoacetic acid ester after cooling to 50 ° C with 5.4 g (0.032 mol ·). After refluxing for 5 hours, the precipitate was collected and the solution was concentrated. The crystals formed are dissolved in 203 ml of toluene and the solution is mixed with 9 g (0.022 mol) of Lawesson's reagent f 2,4-bis (4-methoxyphenyl) -2,4-dithiooxo-1,3,2,4-dithiophosphoethane. }.

After 24 hours at 30 ° C, the solution is concentrated in vacuo and the precipitated thioamide is isolated. 8 g (0.025 mol) of thioamide are dissolved in 100 ml of ethanol, 1.5 g (0.03 mol) of hydrazine hydrate are added and refluxed for 18 hours. The precipitate is filtered off with suction, suspended in water and dried. Melting point: 251-252 ° C.

Thin-layer chromatography in chloroform / methanol> 1 /% ammonia solution 95/5/1? = 0.69.

The compounds listed in Table L of Formula IV were prepared according to Formula IV.

Procedure 2

3-phenyl-4,5-dihydro-1,2,4-triazin-6-one

V v

Compounds of the invention may be prepared according to Scheme II. Substituted 4-hydroxy esters, respectively. The 4-aminobenzoylamino acids of formula V serve as a precursor (preparation according to the literature, e.g. E-422191 or Buil. Chem. Soc. Chim. Belg., 92 (11?, 1024 (1983)).

IN

Table 1

no. Formula IV

X Y

2 3-Me Toxy 4-Methoxy 3 3-Me Toxy 4- Methoxy 4 3-0xetylén 4- Oxes of flax 5 3-PLuóŕ 4-1 Fluorine 6 4-fluoro H 7 4-methoxy H 8 4-OBzl H 9 . ^N ( ^CH3 > 2 H 10 _4-S-CH3 H 11 3-Cl 4-OH 12 4-OH H 13 4- (2-hydroxydimethyl) oxy Cl 14 4- (2-Pyridylmethyl-oxy) 3-Cl 15 4- (2-Cholylmethyl) oxy 3-Cl

IN ^Y 1 crystals -... point žacia z mp H H Metahol 249-252 ’C H 7-Me Those 1-Me Dancing 237-239 ’C U . ..H acid. · Acetic 266'C H • “H ethanol '  269 ’C H H butanol 257-259 ’C H H dioxane 266 ’C H H dioxane 272'C H H dioxane 268 ^e C H H acid. acid 282 ’C H H methanol 275-277 ’C H Ή butanol 308 ’C H H acid. acid 263-264'C H H -. ^u - > 300'C H H __ tt _ > 300 ’C.

benzoylamino acid esters of formula V with aryl resp. h.Ateroarylalkyl halides in organic solvents such as toluene or DMA or mixtures thereof are converted to the corresponding arylalkyl- and / or mixtures thereof using an auxiliary base. heteroalkyl ether, thioethers or amines of type VI.

The alkali metal carbonates, alkaline earth metal carbonates, and aliphatic amines, e.g. sodium carbonate, potassium carbonate or triethylamine.

Activation of the formation of the amides according to formula VI by formation of the imide chlorides (using Pögl ^ / ^ FGL or SOCl? As agent), or ^- preparation of thioamides (using P2S5 or Lawesson's reagent.) Gives intermediates VII.

With hydrazine or substituted hydrazine derivatives in C1-alcohols, in particular ethanol or butanol, compounds of type VII of the invention can be obtained at temperatures of 40 ° C - 50 ^σ C. Suitable substituted hydrazine derivatives are alkylhydrazines such as e.g. methyl-, ethylhydrazine and also benzylhydrazine.

Example 16

2- {j-chloro-4 - [(2-quinolyl) methoxyphenyl] -4-methyl-4,5-dihydro-1,2,4-triazin-6-one (D-20783) / N- (3- (ethyl) ethyl ester) chloro-4-hydroxy) benzoyl-sarcosine

Example for a compound of formula V.

1-72.6 g (1 mol) of 3-chloro-4-hydroxybenzoic acid,

153.6 g (1 mol) of sarcosine ethyl ester hydrochloride and 3 mol. triethylamine was dissolved in 1.5 L of dichloromethane and cooled to -10 C. 60 g (0.4 mol) of 1-hydroxybenzotriazole hydrate and 211 g (1.1 mol) of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride were added and 1 hour Stir at -10 ° C. The mixture is then stirred at room temperature until no more traces are visible on the thin-layer chromatogram. The organic solution is then poured onto 4 l of water and the separated aqueous phase is extracted twice more with 300 ml of dichloromethane each time. The organic phase was then combined, dried over sodium sulfate and concentrated.

The prepared product (yellow oil) is dried under vacuum using an oil pump and then further processed as raw material.

b) N- p-chloro-4- (2-quinolyl) methoxybenzoyl-sarcosine ethyl ester (2)

Example for a compound of formula VT

271-, 7 g (1 mol) (1) and 195.4 g (1.1 mol) of chloromethylchonolinus are dissolved in 600 ml of toluene and 200 ml of dimethylacidamud. 1.2 mol of powdery potassium carbonate is then added and the suspension is refluxed for 6 hours, after completion of the reaction, the residue is filtered off with suction and washed with toluene. The filtrate was concentrated to give a dark oil.

c / N- (4-chloro-4- (2-quinolyl) methoxy) phenylthioxosarcosine ethyl ester (3y)

Example for compound of formula (VII)

412.5 g (1 mol) (2) are dissolved in 1 liter of toluene and then mixed with 202.2 g (0.5 mol) of Lawesson's reagent (= 2,4 bis- (4-methoxyphenyl) -2,4-dithiooxo-1). , 3,2,4 'dithiadiphosphetane). Heat the mixture at 80 ° C for four hours. The solution was concentrated in a rotary evaporator. A brown, thickened oil is obtained, which is then further processed as a raw material.

á /

3- [i-chloro-4 - ((2-quinolyl) methoxy) phenyl] methyl-4,5-dihydro-1,2,4-triazin-6-one (D-40783)

428.9 g fl mol? (3 L dissolve a 1 L of ethanol and mix with 65 g (1 · 3 small hydrazine hydrate), then heat the mixture under reflux for 6 to 10 hours. Concentrate the reaction mixture on a rotary evaporator. Dissolve in 1.5 L of acetone and stir at room temperature for 1 hour.

Yield: 39.89 g (12%), mp 205-209 ° C.

The data of NMR, (500 MHz, d ₆ -DMS0? (Ppm? 10,4.5 (s, IH, NH?, 7.6-8.5 (m, GH, quinolyl radical?

7.55 (s, 1H, 2H aromatic, 7.4 f d, 1H, GH aromatic)

7.35 (a, 1H, 5H-aromatic, 5.55 (s, 2H, 00 '))

3.8 (s, 2H, N-CH3), 2.75 (s, 3H, N-CH3).

The compounds of the following step 2 can be prepared as in Example 16.

The compounds of the invention type 3 3-aryl-4,5'-dihydro-1,2,4-triazin-6-one can also be prepared according to alternative synthesis methods. These methods can be derived from Schemes IIb and Faces and can be considered as examples.

Scheme Ila

Synthesis of 3-aryl-4,5-dihydro-1,2,4-triazin-6-one

He! / - Ar-2! £ kyLhilo enid

OR ₂ 'vi = Het-alkyl / Ar-alkyl-S / O / N.

+ H ₂ NNKR ³ x H ₂ O / Alcohol

Scheme Ilb

\ V = OH _% SH, NH,

X = Het-alkyl / Ar-alkyl-S / O / NH

.) bases

inherited means

VNI

A = Alkyl C ₍ -C ₄ , Benzyl R 1 = H, Alkyl, Benzyl R 1 = H, Alkyl, Benzyl

Scheme obverse

W = OH, SH, NH

R = Alkyl

Z = S / O / NH

Ary I ilky LHe te ary I hilojcnid

-Lr * 'csson /? 2S4 <-

X

VIII

A = Alkyl C 1 -C 3, Benzyl R ₁ = H, Alkyl, Bcnzyl R, = H, Alkyl, Bcnzyl

13th

Table 2, compounds of formula VII

no. X • Y · A ^R 1 : ^r 2 solvent point mp 17 OH no ₂ H H H kys.octová 242-244 ’C 18 OH nh ₂ H H H acetone 213-215'C 19 OH H H H H methanol 249-251 ’C 20 OH Cl ^CH 3 H H acetone 228-231 ’C 21 OH Cl. H H H isopropanol / Methanol. 236-239 ’C 22 OH OCH H H · Isopropanol / ' 256-258 ’C 3 methanol 23 OH OCH 3 ^H H H isopropanol / 261-264'C 24 OH OCH 3 ^{H CH} 3 H Methanol. isopropanol 244-247'C 25 Bzl-0 H H H H methanol 199-202'C 26 3-Cl- (2-Methoxyphenyl) -piperazine- H H H H isopropanol / methanol 133-135'C . nylj-propýloxl 27 3- [1- (2-Methoxy- H H H H isopropanol / 139-141'C phenyl) piperazinyl-ethoxy methanol 28 (2-Fyridylme- t.oxy) H H H H isopropanol 178-182'C 29 Bzl-0 H CH H H IzoproDanol /. 163-171'C 3 methanol 31 J-Γΐ- (2-methoxyphenyl) -piperazi- Cl ^CH 3 H H isopropanol 113-115 ’C

nyl] -ethoxy

Continuation of Table 2

no. X A ^R 2 solvent point mp 32 Bzl-0 OCH H o H · Isopropanol / Me.tanol Mp 231-233 ° C 33 Bzl-0 c. ch ₃ H isopropanol 252-2S4 ’C 34 Bzl-0 Cl H H isopropanol 241-243'C 35 Bzl-0 OCH ₃ ^CH 3 H isopropanol / methanol 212-214 ^e C 36 3-Pyridylme- acetoxy Cl H H. isopropanol /  methanol · Mp 246-249 ° C 37 3? Yridylme- acetoxy OCH H 0 H methanol Mp 243-245 ° C 38 3-ŕyridylae- acetoxy Cl, CH about H isopropanol Mp 158-162 ° C 39 3-Pyridylrae acetoxy OCH H 3 H isopropanol 186-188 ^e C 40 (4-fluoro) -Bzl-0 OCH H ABOUT H isopropanol 189-191 ^e C 41 Bzl-0 OCH H ^CH 3 isopropanol / methanol 228-231 ^e C 42 S-Bzl F H H isopropanol / Me tanol Mp 244-247 ° C 43 S-Bzl H H H isopropanol 250-252 ^e C 44 NH-Bzl och ₃ ^ch 3 H isopropanol 181-183 ° C 45 NH-Bzl H H H . methanol &Gt; 250 ° C 46 S-Bzl F CH ₃ H isopropanol 138 ^e C 47 S-Bzl nh ₂ ch ₃ H isopropanol / methanol 245-247 ° C 43 NH-Bzl och ₃ ch ₃ H isopropanol 252-254 ^e C 49 3-ryridylme- methylamine H CH ₃ H isopropanol Mp 238-241 ° C 50 3-hyridylme- methylamine · OCH CH H · Isopropanol / methanol 229-232 ° C

- 15 Continuation of Table 2 point

no. X AR _ľ ^R 2 rozpúätadlo mp 51 (4-Methoxy) ben- OCH H H isopropanol 198-201 «C benzyloxy 3 52 (4-Methoxy) benzyl Cl H H isopropanol 181-183'C zyioxy 53 3-Pyridylme- OCH H H methanol 73-75 ^e C methylamine 3 ⁵⁴ 3-Pyridylme- methylamine H H H isopropanol 231-233 “C 55 (2,3,4-tri- Cl H H isopropanol / '194-197' C methoxy) benzyloxy methanol 56 2-ChinolyI- or CH ₃ OCH CH H isopropanol / 205-209 ° C 57 H methanol 238-241 ^e C 58 acetoxy 3 3 H Z-Chinaiy Ime Cl H isopropanol / 203-205 ^e C acetoxy methanol

Procedure 3 r-Reap 59 59-Methyl-3-oxo-3,4-dihydro-2H-1,2,4-triazine [4,3-c] quinazoline (D-19749)

Based on the known quinazolin-4-yl-3-yl-acetic acid ethyl ester derivatives of formula IX (see M. Suisse,

5. Johme, J. Prakt. Chem. (2), 326, 342 (1984), respectively.

Clark RH, EC Wagner J, Org. Chem. 9, 55 (1944), the corresponding ethyl esters of quinolin-4-thion-1-yl acetic acid according to formula X were prepared by sulfuric acid using P ₂ S 4 and Lawesson reagent, respectively.

in

In order to prepare the triazinoquinazoline of formula XI, thioamides of formula X are converted to compounds of formula XI with hydrazine hydrate in an alcohol.

Suitable alcohols are all O-aliphatic alcohols, e.g. methanol, ethanol, propanol, isopropanol. and isomeric butanols.

and o-methylquinazolin-4-thion-j-yl acetic acid ethyl ester

A suspension of 20 g (0.081 mol) of ethyl ester, 6-methylquinazolin-4-one-3-yl-acetic acid and 17.1 g (0.042 mol) of Lawesson's reagent is dissolved in 300 ml of toluene and stirred for 33 hours at temperature 80 ° - 105 ° C, forming a slowly orange to dark red solution. After completion of the reaction, the solution was cooled, concentrated, and the residue was washed with a little cold toluene and then with petroleum ether and crystallized from dichloromethane / methanol. Mp 130-13 ° C, b / 10-methyl-3-oxo-1,4-dihydro-2H [1,2,4] triazine [4,3-c] quinazoline

8.7 g (0.133 mol) of thiamide are suspended in 200 ml of ethanol and mixed with 10.1 g (0.2 mol) of nydrazine hyurate and the mixture is heated to reflux. After four hours, the precipitate is filtered off with suction, washed with ethanol and the product is crystallized from ethanol-acetic acid. Melting point: 298 - 304 ° C - decomposition

According to Example 59, the compounds shown in the following table can be prepared.

Scheme 3

Lawesson respp2 ^ 5

R ₂ N-NH 2

Table 3 - formula XII

point

no. X in ^R i ... . r solvent mp 60 ^CH 3 H H H Ethanol / acetic acid Mp 293-204 ° C 61 ^CH 3 H ^CH 3 H Ethanol / acetic acid 265-269 [deg.] C 62- och ₃ och ₃ och ₃ H Ethanol / acetic acid Mp 273-275 ° C 63 Cl H H H Dichloromethane / Me- &Gt; 300 ° C butanol; 64 Cl H Cl H Ethanol / acetic acid &Gt; 200 ^e C 65 Cl H H CH Ethanol / acetic acid 0 > 300'C 66 Cl H Cl CH ethanol · / acetic acid> 300 ° C 0 67 H H ’ • H H Ethanol > 300 ° C

The compounds of the present invention have an anti-inflammatory effect (lipoxygenase inhibition), a cast bronchorelaxant effect (guinea pig tracheal-over-extracted carbachol model).

In addition, these compounds have effects on blood pressure (increased camventricular contractility, lowered blood pressure ?.

The compounds also have an inhibitory effect on histamine-induced rat rhinitis as well as on the release of histamine from cells.

Pharmacological testing of the effect in allergic-induced histamine release of sensitive rats was performed as prescribed σ in experiments P, A. Shore et al., I. Pharmacol. Exp. Then. 127, 1959, p. 182nd

Further, the relaxing effect of these compounds on carbachol over-extracted guinea pig trachea chain was found by T'allandria et al., Manual of Pharmacological Calcuations with Computer Programs, Springer, 1981.

Inhibition of the production of downstream lipoxygenase products was tested on rat macrophages under the order of Murphy et al., Methods in Enzymology 86, p. 409 41-6 ·

The compounds of Example 1 show the following values:

Allergic induced histamine release at 10yumol / l concentration exhibits 25% inhibition of release ·

The compound of Example 16 showed an in

hibiscus delayed oesinophilic phase in guinea pigs according to Cartwright's prescription, Diagnostic Laboratory Hematology, 1968, p. 48 and Mac Fortare et al., Eosinophil Counting, Brit., Mes., 2, 1187 (1951) at a dosage of 30 mg per kg body weight, administered p.o. with a value of 80%. Inhibition of LTD-4 receptor binding by Borbe and Zierenberg, Harmacopsycniatry 18, 314-319 (1985) resulted in an inhibition of 50% activity at a concentration of 8.4 µmol / L.

? In 1311-73

Claims (10)

Compounds according to formula I wherein e R .. and R may be _the same or different, are hydrogen or alkyl groups with chain lengths G ^ - C ^, which can also be branched., A benzyl group which may be substituted e.g. fluorine, chlorine or bromine, whereby the substituent of the zyl group may be -CH 2, -NO ₂ , amino and substituted amino, further -CF 3; if R6 = benzyl or substituted benzyl, R2 can also be fused, A - E can be or Whereby R is alkyl, branched chain alkyl of up to C 4, phenyl, halo-enid and / or nitro substituted one or more times phenyl, C 3 -C 6 -alkyloxy groups and substituted phenyl, which may be straight or branched, alkoxy, cyclic alkoxy , thiaaikyl-quinuclide, Phenyl substituted with aryl or heteroarylmethoxy, A may be straight or branched alkyl with a chain length from. 1-6 carbon atoms or benzyl or halogen substituted benzyl, B can be hydrogen when there is no bond between A and B, X may be aryl or heteroaryl, aryl or heteroaryimethoxy, heteroarylmethyl, or heteroarylmethylthio, Y may be halogen, hydroxy, O-alkyl having a chain length of from 1 to 6 carbon atoms, NC 6, NR 6 R 8, wherein R 6 and R 8 may be the same or different, and may be hydrogen, alkyl, branched alkyl 1-6 carbon atoms, X and Y may also occur multiple times. 2. Preparation of the compounds of formula 1, characterized in that a compound of formula I with compounds of formula Z - GH ₂ 'G00 Et converted to the compound of formula II, then treated with Lawesson's reagent or P ₂ S ^ the compound of formula III and with substituted hydrazines are converted to compounds of formula IV. Process for the preparation of the compounds of formula I, characterized in that the compounds of the formula VI are converted to compounds of the formula VII with the aid of Lawesson's reagent or P ₂ S 2 and then by substituted hydrazines to the compounds of the formula VIII. tnaziao 4. A process for the preparation of compounds according to formula I, characterized in that:. the compounds of formula IX are reacted with Lawesson's reagent or P.S.RTM. ^{to form} compounds of formula X and further substituted compounds of formula XI with substituted hydrazines. Use of compounds of formula L for the preparation of medicaments. 6 '. Medicaments, characterized in that they contain a compound of the formula I in an amount of from 1 mg to 1000 mg and other additives and auxiliaries. A process for the preparation of medicaments, which comprises formulating the compounds of the formula I in an amount of between 1 and 100 mg with conventional carriers, compounds and excipients. S. Substance selected from 7-phenyl-2H-triazino [3,4-b] zin-j (4E) on, 7- (i, i-difluorophenes and phthalszine-3 (4 $ on, 7- [4- (2-Pyridyimethoxy) phenyl] 2H-triszino [3,4-a] phthalazine-3 (4H) -one, 3-p-Methoxy-4- (3-pyridylmethylamino) phenyl-4-methyl-4,5-dihydro-g, 4-triazin-6-one, 3- [3-chloro-4- (3-pyridylmethoxy) phenyl] -4-methyl-4,5-dihydro-1,2,4-triazin-6-one; 3- [3-Chloro-4- (3-pyridyimethoxy) -phenyl] -4,5-dihydro-1,2,4-triazin-6-one, 3 [i-methoxy-4- ( ^'3, pyridylmethoxy) fenyiJ -4,5-dihydro-2,4-triazin-6-one; 3- [3-Methoxy-4- β-benzyloxy? - phenyl-4-methyl-4,5-dihydro-1,2,4-triazin-6-one, 3- [3-Methoxy-4- (1'-benzylmercapto} phenyl) -4-methyl-4,5-dihydro-1,2,4-triazin-6-one; LO-methyl-3-oxo-1,4-dihydro-2H- [1,2,4] triazine [4,3-c] quinazoline, 3- [3-chloro-4- (2-quinolylmexoxy) phenyl] methyl-4,5-dihydro-1,2,4-triazin-6-one, 3- [3-Methoxy-4- (2-quinolylmethoxy) -phenyl] -4-methyl-4,5-dihydro-1,2,4-triazin-6-one; Use of the compounds according to claim 8 for the preparation of medicaments. Medicaments, characterized in that they contain one or more compounds according to claim 8 in an amount of between 1 mg and 1000 mg, as well as other additives and excipients. Pharmaceutical preparation process, characterized in that one or more compounds according to claim 6 in an amount of between 1 mg to 1000 mg are treated with customary carriers, preservatives and drug adjuvants.