CS208746B2 - Method of making the 3,6-disubstituted-1,2,4-triazin 5-ons - Google Patents

Description

(54) Production Method 3 _; 6-disubstituted-1,2,4-triazin-5-ones

The present invention relates to a process for the preparation of pharmacologically active triaznone derivatives. The compounds prepared by the process according to the invention may be acid addition salts, but for the sake of simplicity the following are always referred to exclusively as parent substances.

The biological manifestations of histamine which are inhibited by drugs commonly referred to as anti-hypersensics - and examples of which are meeyranine, diphenhydramine, and clphorpheniramine - are mediated by the action of histamine H-receptors, Ash and Schild, Brrt. J. Pharmac. 27, 427 (1966), and Xatltas with such efficacy are still discussed

As the histamine H 1 -antagonists. But other biological manifestations of histamine are not inhibited by the action of histamine H-antagonists, and the effects of this type, which are inhibited by a compound called burimamide - which poppaai Black et al., Nature 236: 385 (1972) - are mediated by receptors as defined by Black. spol. as histamine Hg receptors. Thus, H ₂ -receptors can be defined as those histamine receptors that are not blocked by meepranin, but are blocked by burimamide. Compounds that block histamine histamine receptors are referred to herein as histamine H2-antagonists.

Blocking -recepto ^ ^ hisaaminu is important in inhibiting the biological actions of histamine are not blocked when the H-hist antagonnsty amine, and therefore H ₂ -antagonnsty hisaaminu pouuiaelné iniibiasry example as a gastric acid secretion, as prsaizánёalivá and as agents ύδ ^ ^ Ι ί cardiovascular system, for example, as inhibitors of the blood pressure effects of histamine. When the treatment of certain conditions, for example inflammation and in inhibiting the effects hist-yne blood pressure suitable combination Hj and _H2 -antagonnstů hist amine.

(AND)

British Patent Specification No. 1,419,994 discloses, among other substances, compounds of formula I as histamine? -Agonists:

R-N-C

IH wherein in the general formula A is a chain of 3 to 4 atoms containing at least 1 carbon atom, which chain may also contain a sulfur atom, a nitrogen atom, 2 nitrogen atoms or a nitrogen and sulfur atom; and, if possible, a sulfone group, and may be substituted with one or two times lower alkyl, aryl, or aralkyl groups, or even in such a way that the resulting structure forms, with adjacent carbon and nitrogen atoms, a bicyclic system containing one a benzene core; R is in the above general formula) the structure of formula II,

Het-C ^ Z ^^^ (II) wherein

Het represents an imidazole, pyridine, thiazole, isothiazole or thiadiazole core, optionally substituted by a lower alkyl group, preferably methyl, furthermore an amino group, a hydroxyl group or a halogen, Z represents a sulfur or a methylene group, and δ represents 2 or 3;

It has now been found that a particular group of compounds, some of which fall within the scope of the above definition of compounds of formula (I), has some advantages over the whole group of compounds of formula (I). histamine diamines compared to the compounds of the general group of compounds of formula (I), and this novel group is characterized by an action in the presence of the histamine H-nitrites as well as in the histamine H 2 -antagonists.

This particular group of compounds set aside for the above-mentioned advantageous properties corresponds to the general formula III, (III)

H? -C? SC? C? NH A _N x ^N in which

Hee * represents a 5-methyl-4-imiadzolyl or 2-thiazolyl radical and

Ϊ is phenyl substituted with C 1 -C 4 alkoxy or pyridyl.

Also included within the scope of Formula III 'are the corresponding pharmaceutically acceptable salts.

The compounds of formula (III) are described as 2H-1,2,4-trazzinene derivatives that are in equilibrium with the 4H-tautomers, to a lesser extent as the hydrocytutomers. The triazine ring may exist in the following tautomeric forms:

ч

O

HfNA

-n = L jn ί \ Κ

AND

Η

OH

NA ^ N = L N

I H

Some of the Het * residues may also exist in several tautomeric forms, and it is intended that all of these tautomeric forms are within the scope of the present invention. Hydrates of the compounds of formula III, hydrated salts of the compounds of formula III, especially pharmaceutically acceptable salts, are also included.

Some specific compounds within the scope of this invention are:

3- (2- / 5-methyl-4-imidazolylmethylthio / ethylamino) -6- (3-methoxybenzyl) -1,2,4-triazin-5-one, 3- (2- / 5-methyl-4) Imidazooylmethyllhio / ethylamino) -6- (3-pyridylmethyl) -1,2,4-triazin-5-one.

Compounds of formula (III) may be prepared by a process characterized in that the triazine derivative of formula (IV),

in which

Has the meaning given for formula III and

Q is C 1 -C 4 alkylthio, with an amine of formula

He t -CH ₂ -S- (CH 2) ₂ NH ₂ in which

He * has the meaning given for formula III.

Preferably, the reaction is carried out without solvent at an elevated temperature, for example in the range of 150 to 180 ° C, or in the presence of three solvents, for example in boiling pyidine.

The triazinones of formula IV wherein Q is lower alkylthio may be prepared as follows

Y (CH ₂ ) _xl CHO (V)

water, acetone

O

Н1Ч ^ (СН ₂ ) _х У s = L im

AND

H (villa) \ HOOC

NH ₂ NHCNH ₂ ⁴ '

S is CHCH2CH3

NHAc (VII) wherein a carboxaldehyde of formula V is converted to an azlactone of formula VI which is partially hydrolyzed to acetEmidoacrylic acid of formula VII and reacted with 8 with thiosemicarbazide to give a compound of formula VIII which is converted to a triazinone derivative of formula IV by treatment with an alkyl halide or alkyl sulfate in an alkali environment.

Alternatively, the compounds of formula (VII) may be prepared by treating a pyruvic acid derivative of formula (Y) (CH2) _X ; COCOH- and this may be prepared by hydrolyzing the azlactone of formula (VI) in an acidic medium - or the corresponding ester with thiosemicarbazide and base.

Alternatively, compounds of formula VVII can be prepared by reacting azlactone of formula VI with thiosemicarbazide in an aqueous medium.

The compounds of formula (III) block the H2-receptors of heptimine, that is, they inhibit the biological actions of histimine which are not inhibited by H-antagonists of hdsttmin, such as mepyramine, but are inhibited by burimamide. For example, it has been found that the compounds of the invention inhibit histamine-stimulated gastric acid secretion in the case of perforated stomachs of urethnic anesthetized rats at doses ranging from 0.5 to 16 mol per kg intravenously. This procedure is referred to in the aforementioned work by Ash and Schild. The efficacy of these compounds as histamine β-antagonists has also been demonstrated by their ability to inhibit the further action of histamine, which according to Ashe and Schild, supra, are not inhibited by the histamine H 1 -receptors. For example, they inhibit the action of histimine on isolated guinea pig atrium and isolated rat uterus.

The compounds of the invention inhibit the basal secretion of gastric acid as well as that. is stimulated by pentagastrine or food.

Further, the compounds of the present invention are effective in conventional tests such as the rat paw edema test, when oedema is induced by the irritating compound, and the rat paw volume is reduced by subcutaneous injection of doses of the compound of formula III. is the measurement of the blood pressure of anesthetioovirus cats, the effect of the compounds of the invention at doses ranging from 0.5 to 256 mam may also be demonstrated. per kg intravenously with a view to inhibiting the vasodilating effect of histidine. The tubing of the compounds of this invention is exemplified as an effective dose at which 50% inhibition of gastric secretion in aesthetized rats is achieved, as well as a dose that achieves a 50% inhibition of tachycardia induced by histmiin on an isolated urinary atrium (less than 10 "5 M).

The compounds of formula (III) also block the histamine H-receptors, i.e., they inhibit the biological actions of histamine, which are inhibited by mepyrtmin, difhyrdmin, or chlorphenitmiin. For example, the compounds of the present invention have been found to inhibit the action of histimine on an isolated meal from flour. For many compounds of Formula III, a dose of 10 µM or less inhibits histamine-stimulated ileum contractions.

For many medical uses, usually the pharmacologically active compounds of the present invention may be administered in the form of pharmaceutical compositions, wherein at least one compound of the above type in the form of a base or a salt thereof with a pharmaceutically acceptable acid and a pharmaceutically acceptable carrier is present. Such addition salts include hydrochloric, hydrobromic, hydroiodic, sulfuric, and maleic salts, and these salts are generally prepared from the base of formula III by conventional methods, for example by reacting such a base with a lower alkane acid. or using ion exchange polystyrenes to produce the desired salt either directly from the base or from another addition salt.

Also described are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula III or a suitable acid addition salt thereof, as well as L methods for blocking Hg-histamine receptors by administering to an animal a compound of formula III or a pharmaceutically acceptable salt thereof. a suitable acid addition salt. Merely Pharmaceutically-supports can be, for example, BU3 solid or liquid. Exemplary of solid carriers include those ^ Ozu, taoHn, sucrose, talc, talattau, agar, ^p e ^e tin aka ^ i, tořečnatou stearate acid amide, stearic acid and alike. Examples of liquid carriers include syrups, oil, olive oil, water and the like.

As for the pharmaceutically acceptable forms, a variety of these forms can be handled. Thus, when the solid carrier is present, the preparation may be tabletted, inserted into a hard gelatin capsule in the form of a powder or tablets, or it may be offered in the form of a candy or any other. The bulk of the solid carrier generally varies greatly, but is preferably from about 25 mg to about 300 m, and if the liquid carrier is present, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule. , stellar, secretable capsules, e.g. contained in an ampoule or in an aqueous or non-aqueous liquid suspension.

The pharmaceutical compositions are made by conventional techniques using methods such as blending, granulating and compressing, or dissolving the ingredients as appropriate for this or that composition.

Effective ^and the number and ^ v ^ ^U sing preparation of u ^ min ^ rniém Tai, its ^Z is required for whipping and Hg Hj receptors histrminu. The compositions may be administered orally or parenterally.

Preferably, each dose contains the active ingredient in a ω 50 of from about 50 mg to about 250 mg.

The active ingredient is, after ^d RECOGNITION preferably one and ^f šesttoát Tonn. Mode varies with ^d ^ ávky ^either es preferably in the range from about 150 mg to about 1 500 mg.

Preferably, the formulation is formulated into a dosage form to be administered for this or that method, such as, for example, tablets, capsules, iodine solutions, or creams or ointments for topical administration.

The invention is further exemplified by the accompanying examples, which, however, are not intended to limit the scope of the invention in any way. All temperature values are given in degrees Ocesium.

Example 1

3- (2- / 5-Methyl-4-fluoro-tolyl-ethylthio / ethylthio) -6- (3-ueolylbutyl) -1,2,4-triazole (15i) A mixture of 25.9 g of m-anistlduhyde, 15.2 g of tert-ethyl-lycin and 7.8 g of sodium acetate are heated to 50 ml of acetic acid at reflux for 3/4 hours. The reaction mixture is then cooled, diluted with 150 ml of water and 27.7 g of crude azlactan, m.p. 145-150 °, are recovered by filtration. Hydrolysis using 450 ml of boiling 1N hydrochloric acid solution followed by cooling and extraction into ether gave 3-fluoroxy-pyruvic acid as a pale yellow oily solid which was isolated in a yield of 6.3 g.

ii) A mixture of 2.1 g of 3-methoxyphenylpyruvic acid, 0.98 g of thiosemicarbazide and 1.5 g of sodium hydroxide was heated in an atmosphere of 30 ml of water to 70-75 ° for one hour. Upon cooling, an oil is obtained upon acidification and 6- (3-methooybenzyl) -1,4,4-thiazine-3-thio-3,5-dione is isolated by pale yellow solid chromatography. Crystallization from ethyl acetate / benzene yields pure product, m.p. 140-141 °.

Analysis: Calculated: C 53.0%, H 4.5%, N 16.9%, S 12.9%.

Found: C 53.1%, H 4.6%, N 16.8%, S 12.6%.

iii) b 25 ml of ethanol was dissolved 0.34 g of sodium was added 3.5 g EE 6 t _(3-e m toxybenzyl) t t1 2,4ttгiazУn _J-3 th0o _З-L-5 and d0oУu knnenn, cooled ootooS ee After the addition of 2.1 g of methyl iodide, the reaction mixture was stirred for one hour at room temperature, after which an additional 0.5 g of methyl iodide and a sodium methoxide solution of 0.05 g of sodium were added. The reaction mixture is kept under refrigeration overnight, followed by filtration, 2.5 g of ^3-yl bthik Mee-6 t (3-mehoxybenyobl 1,2,4t ttгlazУn55-0Уu of mp 185-186 °. DAAS poddl this solid gave from mother liquors to dryness by addition of dilute hydrochloric acid to the residue.

iv) A mixture of 1.07 g of 3-menybthio-6- (3-metooχbenzyO) -112.4 triюin-5-OУu and 0.77 g of 2- (5-metylt4ti _ш: idlzolblmenylthik) etyllminu looks to 03.04 hours in an oil bath at 160-170 °. The solid obtained after the reaction is fortified under methanol (about 15 ml), all boiled for 5 minutes, after which the white solid is separated after cooling and crystallization from dimethylformamide is isolated, 0.65 g of compound, in the title. The substance is colorless and has a bt of 203 to 204 ^е5 .

Analysis: for C 18 ^H 22 ^N 6 ° 2 S calculated: 55.9% C, 5.7% H, 21.8% N, 8.3% S; Found: C 55.7%, H 5.7%, N 21.7%, S 8.3%.

Example 2

3- (2 t / Thiαzklylmetylthio / EB lадllno ^yl) -6- (t-πletoxyeenzyb) t1,2,4ttrlazУn-5-oyl

A mixture of 1.18 g of 3-methyl-6- (3-methylphenyl) -1,112,4-triloin-5-one and 0.87 g of 2- (2-thiloolylmethylthio) ethylamine was heated in an oil bath for 160 min. to 170 °. The resulting oil was chromatographed and the title compound was isolated from ethanol to give the title compound as a colorless solid in a yield of 0.88 g (m.p. 128-129 °).

Analysis: calculated for: C, 52.4; H, 4.9; N, 18.0; S, 16.5;

found: 52% C- 5.0% H- 18.0% N- 16.6% S.

Example 3

3- (2- / 5-Methyl-4-imidaloxybutylthioolyl) -1,6 (3-pyridylbutyl) -1,4-triazin-4-one

(i) A mixture of 92.6 g of pyrrolidine-3-carboxaladehyde, 86.0 g of N-acetylbenzin and 35.3 g of sodium acetate is heated under reflux for 1 hour in 150 ml of acetic anhydride. After cooling, 250 ml of water are added and 50.9 g of crude azlactone of m.p. 155-160 DEG C. are isolated by filtration. partial hydrolysis of 50 g of the thus prepared lactate by heating under reflux with 450 ml of acetone and 175 ml of water for 4 hours under reflux conditions gives a dark red solution after distilling off a major portion of acetone and adding 300 ml of water. The mixture is boiled for 10 minutes with activated charcoal, and then the solution is filtered. The filtrate was concentrated to dryness and the residue triturated with acetone. After washing the solid with acetone, 35 g of 2-acetamido-3- (3-acetyl) -acrtlic acid, m.p. 191 DEG-192 DEG, were isolated and further reduced.

ii) A mixture of 10.3 g knots ^3e lazy 2-acetamido-3- (3-pptidyl) akrtlové and 4.55 g of thiosemicarbazide were heated in 50 mL of water 42 hours to reflux. By removing the reaction mixture and subsequent filtration, 7.22 g of 6-Qp-tr are isolated. dy the mandrel tulle t) _12> 4 - triazine-3 · -thio-3,5-dione, mp about 280 DEG (decomposition), in the form of a pale brown solid.

iii) in 40 ml of ethanol was dissolved 1.73 g of sodium were added 6.6 g of 6- (3-pyridylmeeyl) -1,2 _R 4 triaznn-3-thio-3,5 '-dione and the mixture was cooled in ice. After the addition of 5.0 g of methyl iodide, the reaction mixture is stirred at room temperature for 30 minutes, then swallowed to dryness and the residue is dissolved in 50 ml of water. After filtration, the pH of the filtrate was adjusted to pH 6-7, and the reaction mixture was cooled overnight. The creamy solid obtained is filtered off, and 5.86 g of 3 ((methylthio-6 - ((3-pyridylmethyl) -1,2,4-triazin-5-one)) is isolated by crystallization from mS; bt 215 to 2169.

iv) A mixture of 2.34 g of - methyl-methyl-6- (3-acetylmethyl) (1,2,43-triazin-5-one) and 1.88 g of 2- (5-methyl-4-imidazolyl-methylthio) -thiamine is heated to After cooling, the reaction mixture was triturated with boiling methanol and crystallization of the solid from dimethylformamide to give the title compound, yielding the title compound as a white solid, mp 232-233 °, 2.53. G.

Analysis: calculated for C ^ HH N NN ^O OS: 53.8% C, found: 53.7% C,

H, 5.4; N, 27.4; S, 9.0;

5.4% li, 27.3% Ni, 8.8% S.

Example 4

3- (2- / 2-Thiazolylmethylthienylmethylmino) -6- (3-pyridylmethyl) -1,2,4-triazin-5-one

A mixture of 3.28 g of 3-methyl-6- (3-acetylmethyl) - (12,4-triazin-5-one) and 2.7 g of 2- (2-thiazol-4-yl-thiylthymyl) was heated in an oil bath for one hour. The precipitated reaction mixture was triturated with isopropanol and the solid was recrystallized twice from ethanol to give the title compound as a slightly yellowish solid, m.p. 158-159 °. Yield 3.1 g.

Analysis: for Oj H16 ^N 6 ^S 2 O calculated: found:

50.0% C,

50.0% C,

4.5% H,

4.6% H,

23.3% N,

23.5% N,

17.8% S;

17.6% S.

Example 5

Preparation of salts

0.5 g of the compound of Example 3 was dissolved in boiling ethanol to give a clear solution.

Ethanol saturated with dry hydrogen chloride was added and the solution was evaporated to a volume of about 10 ml. After cooling overnight, white crystals were obtained, which were collected by filtration, washed with isopropanol and dried in vacuo (yield of trihydric chloride salt 0.49 mg, mp 230-232 °).

21.00% N,

20.73% N,

6.87% N,

6.61% N,

208476

Aiolysis: for C8H18N4OS. 3HCl calculated: found:

41.16% C, 30% C,

4.75% H,

4.76% H,

22.79% Cl;

22.29% Cl. ·

Example 6

Pharmaceutical preparation

Folders Moss in mg 3- (2- / 5-methyl-4-imidazolylmethylthio) ethyl Emino) -6- (3-methoxybenzyl) -, 2,4-triazinone 100 ALIGN! sucrose 100 ALIGN! talc 30 stearic acid 2

The ingredients 3e are mixed after sieving and filled with hard gelatin capsules.

Example 7

Pharmaceutical preparation

Folders Moss in mg 3- (2- / 5-methyl-4-imidazolylmethylthio) ethyl Emino) -6- (3-methoxybenzyl) -1,2,4-triazonoo 150 lactose 100 ALIGN!

The ingredients are mixed after sieving and filled with hard gelatin capsules.

Claims (1)

SUBJECT OF THE INVENTION Preparation of _3> 6-diзubзtituovanýcha112,4-triazin-5-ones of general formula III wherein represents Het - CH ₂ CH ₂ CH ₂ NH O CH ₂ YN AND H Het * 5-methyl-4-imidazolyl or 2-thiazolyl residue and (III) Y females! substituted with (C 1 -C 4) alkoxy or pyridyl 208746 and pharmaceutically acceptable salts thereof, characterized in that the triazinone derivative of the general formula (IV): C 1 -C 4 alkylthio; Y is as defined above, with an amine of formula Het * -CH ₂ S- (CH ₂ ) ₂ NH ₂ in which Het * is as defined above, and the compound obtained is optionally converted to its pharmaceutically acceptable salt.