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    • 专利摘要:
    Antiallergy and antiulcer agents having the formula (I), <IMAGE> and their pharmaceutically acceptable salts, wherein R1 and R2 taken separately are each hydrogen or C1-5 alkyl; and R1 and R2 taken together are alkylene of 3 - 9 carbon atoms or phenylalkylene of 9 - 11 carbon atoms, with the proviso that the ring so formed is between 5- and 8-membered; acids of the formula (II), <IMAGE> wherein R1 and R2 are as defined above and R3 is hydrogen, which are useful as intermediates for compounds of the formula (I), but in many instances also possess the same useful biological activity as do formula I compounds; and intermediates of the formula II wherein R1 and R2 are defined as above, and R3 is alkyl of 1 to 4 carbon atoms, carbalkoxy of 2 to 5 carbon atoms, carbophenoxy or carbobenzoxy, are described.
    公开号:SU1042620A3
    申请号:SU803212053
    申请日:1980-11-17
    公开日:1983-09-15
    发明作者:Бернард Кейдин Сол
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    pg

    R oV
    ohhhhhh

    one
    where R, H {and Rj have the indicated meanings, are reacted with one equivalent of 5-aminotetrazole; in dimethylacetamide at room temperature with subsequent separation; the desired product in free form or S salt. . ;
    This invention relates to a process for the preparation of new substituted N-tetrazolyl.) 1-ketr-1H-thiazole 3,2-aZ pyrmidine-2-carboxamides - biologically active compounds that can be used in medicine. A known method of forming an amide bond is by direct condection. compounds containing Kap6o (a kryl group with amino derivatives in the presence of a dehydration agent in the form of an agent N, N -carbonyldiimidazol). The amide formation process occurs already at room temperature with a good yield and is distinguished by the simplicity of the experiment and a slight tendency to racemization of lf. There is also known a method for producing amides by adsorbing Kapv amines with boonic acids by the method of anhydrides. The process proceeds under mild conditions, the formation of an amide bond is not accompanied by gradual reactions, the product yield is almost quantitative ij. The purpose of the invention is to obtain new compounds -substituted N-β-tetrazolyl) -1-keto-1H-thiazole (2,2-a) pyrimidine-2-carboxamides with pharmacological properties, and its variant. The goal is achieved (in the production of substituted (5-tetrazolyl) -1-keto-1H-thiazole pyrimidine-2-carboxamides of the formula l | Cgr 0 in C-a9y, where each and Rj. Denote water or alkyl C and - and Ig; together, means alkylene C or feil-alkylene C. - C, provided that the Yolza system is thus formed from 5-8 members or their salts, which means that the compounds of formula II.i where, the values I and R are as described above, are reacted with one L: the Gular equivalent of 5-aminotetrazole in the presence of one molar equivalent H, N-carbrnidiimylaeopa as a dehydrathion and on: -: zukvdego, an agent at 20-100 ° C in dimers with tkformamide followed by the desired product in free or in the form of salt. 1-keto-1H-thiazole (3,2-a) pyriknshn-2-ka p xami {formula: formulas where each ITf in I means hydrogen or apkyl C (- with $ f taken together, means 1F alkylene C or fenylalkshten C, provided that the Ring system thus formed is .5-8-hL. , .:. - / .-; OR OR them srley.;.: .-.:.,.:;, - v //; zaktochayMmb. in the way that myMyFormyJW jjft,,:;,. .c,., .- ;: ;; ::; ... where the values of H and K are higher, are reacted with a mole equivalent of the acid chloride of the formula where I is alkyl, benzyl, phenyl, in the presence of I. triethyl mine when in methyl chloride and the resulting compounds of Formula IV R where R, R and 2 have the indicated values, the interaction with one equivalent of 5-amino-tetrazole in dimethyl acetamide is introduced at room temperature followed by isolation of the target product in free form or in salt form . Example 2-AMINO-4-ETHYL5-metsh1thiazole. To a boiling solution of thiomo.chevin (20.9 gJ. 0.275 mol) in 250 ml of ethano is added dropwise a solution of 2-bromo methanol (41.3 g, 2.25 mol) in 50 m of ethanol over 25 min The mixture is then refluxed for 2 hours while the volume is reduced to 100 ml. Cool the slurry product by filtering off the potassium hydrobromide salt. Then it is dissolved, in water and re-precipitated from aqueous hydroxide. 2-amino-4-ethyl-5-methyl-tetrazole is obtained 15.1 g, m.p. 45-50 C t / C calculated 142, found 142. Using the same method, 1-bro 2 heptanone, 3-bromo-4-heptanone and 4-bromo-2 5-dimethyl-2-hexane converted to 2 -amino-4-pentylthiazole, 2-amino-4-ethyl-5-propylthiazole and 2-amino-4,5-diisopropylthiazole. accordingly. Example 2. 2-Amino-4,5-diethiazole hydrochloride diet. A mixture of thiourea (21.8 g, 0.286 MOL1,), 4-chloro-3-hexanone g {34.4 g, 0.26 mol) and 200 ml of ethanol is refluxed for 19 hours. The reaction mixture is cooled the solvent is distilled off to give a crude product as a white solid. The white crystals of 4,5-diethylthiazole hydrochloride are recrystallized from a mixture of ethyl acetate and ethanol, semi-crystallized 31 g, so pl. 154-156 ° C. Example 3. 2-Amino-cycloheptanthiazole. A mixture of thiourea (41.9 g 0.55 mol),. 2-Chlorocycloheptanone (72.3, 49 mol) and 500 ml of ethanol are refluxed for 7 hours. The solvent is distilled off and the resulting semi-solid is partitioned between ethyl acetate and water. Unreacted chloroketone is recovered by evaporation of the ethyl acetate phase, combined with 20 g of thiourea and, after boiling for 24 hours in ethanol under reflux, ethanol is removed and the additional crude product is partitioned between ethyl acetate and water, as indicated, In each case, the product is recovered by alkalizing with water. phases with ammonium hydroxide, extraction with ethyl acetate, drying over anhydrous sodium sulfate, removing the solvent to an oily residue, curing with trituration with hexane and filtering . The purified 2-aminocycloheptentiazole is recrystallized from cyclohexane (49.5 g, mp. 77-78.5 ° C). Example4. 2-AMINO-4-IZO-propyl thiazole. 1-Bromo-3-methyl-4-butanone (109.5 g, 0.66 mol) is added to a suspension of thiourea (52.5 g, 0.69 mol) in .400 MP of ethanol. An exothermic reaction takes place , the mixture is refluxed with external heating for 1 h, Solubility-. the solvent is distilled off and the resulting oil is crystallized on standing. Clean t 2-amino-4-isopropyl thiazole hydrobromide (104.4 g, mp. 74-76 ° C) by trituration with ether. The hydrobromide salt is converted: To a free base (58.6 g), dilute the salt in water, alkalize, excess with ammonium hydroxide, extract the free base with rhir, dry the ether over anhydrous sodium sulfate and remove the solvent to an oily residue. Example 5. 2-Amino-6-phenylcyclohexentiazole. To a suspension of thiourea (397.5 mg, 5.22 1 mmol) in 6 MP ethanol was added 2-bromo-4-phenylcyclohexanone (1.2, 74 mol), an exothermic reaction and dissolution occurred. The solution is boiled under reflux for 30 minutes, cooled, the solvent is removed, and the product is obtained in the form of hydrobromide. The crude salt is dissolved in warm. water, the solution is filtered and the free base is precipitated with ammonium hydroxide. The crude base is filtered off and purified by crystallization from a mixture of water.
    ethanol, get 2-amino-B-phenylclohexentaiaol (802,4 g. PL. 1811830C).
    Alternatively, on a large scale, using 8.2 g of thiourea, 24.6 g of 2-bromo-4-phenylcyclohexanone and 125 ml of ethanol, the reaction mixture was boiled under reflux for 30 minutes and cooled in an ice bath and the hydrobromide salt was filtered off . The hydrobromide salt is dissolved in water containing ethanol traces when heated and the free base (lO, 4 mp. 180182c) is precipitated by adding an excess of ammonium hydroxide.
    By the same method, 2-bromo-3-phenylcyclopentanone, 2 bromo-3,5-dimethylcyclohexanone, 2-bromo-3,; 5,5-trimethylcyclopentanone and 2-bromo-5-cyclooctanone are either converted to the hydrobromide salt or to the free base 2-amine-b-phenylcyclopentenyl & sol, 2-amine-5,7-dimethylcyclohexenthiazole, 2-amine-4, 4, 6-trimethyl-cyclopenteniazole, and 2-amine-7-methylcycloocentiathiazole, respectively.
    Example b. 2-amino-B-methylcyclohexenthiazole.
    To a suspension of thiourea (.22.3 g of 0.29 mol in 275 ml of ethanol. 2-bromo-4-methyldiclohexanone is added and the mixture is heated under reflux for 75 minutes. Then cooled to room temperature and the crude product is extracted as hydrobromide salt by filtration. The crude salt is dissolved in warm water and filtered and made basic with ammonium hydroxide to precipitate the free base as an oil, which is crystallized upon cooling. After recrystallization from cyclohexane, 2-amine-b-methylcyclohexenthiazole (25.2 g) is obtained with t mp.98100 ° C.
    Example 7. 2-Amin-b, b-dimethylcyclohexentiazole,
    2-Amin-b, b-dimethylcyclohexentiazole {9.8. Pl. 109-ljLl c) is obtained from. thiourea T, 2 g, 0.12 mol) and 2-bromo-4,4-dimethylcyclohexanone (22.6 g, 0.11 mol) in 100 ml of ethanol according to the method described in example b.
    Example 8. 2-Amin-4- (2-butyl) thiazole.
    Thiourea (16.7 g, 0.22 mol), 1-bromo-3 methyl-2-pentanone (36 g, 0.2 mol) and 100 ml of ethanol are combined and refluxed for 5 hours. potassium hydroxide solution (H, 100 ml) is heated and refluxed for an additional 0.5 h. The reaction mixture is cooled, acidified with hydrochloric; acid and impurities Extracted with ether.
    The aqueous phase is alkalinized with ammonium hydroxide and the product is extracted with ether. After washing with water and over anhydrous sodium sulfate, the ether is removed to give 10 g of 2-amino-4-2-butyl) thiazole as a dark brown viscous oil.
    Example 9. 2-.Amino-5-methylthiazole. .
    The mixture of thiourea (45.7 g
    -O, b mol) and propionaldehyde (7.4 g 0.3 mol) with 150 ml of chloroform are cooled in an ice bath. Sulfuryl chloride (44.5, 33 mol) is added over 15 minutes. Exothermic
    the reaction is carried out between 15-24 ° C. The evaporating, which occurs upon addition, within 1 hour after the addition, ends. Large
    part of the chloroform is evaporated on a steam bath. Ethanol (150 ml) was added and the mixture was heated under reflux for 3 hours. The solvent is distilled off, the oily residue is partitioned between water and ethyl acetate. The aqueous phase is alkalinized with ammonium hydroxide and the product is extracted with fresh ethyl acetate. The ethyl acetate extract is dried over anhydrous sodium sulfate and
    ethyl acetate is distilled off to obtain the product as a white solid. Purified 2-amine-5-methylthiazole (v, 36 g, mp. 94-95 ° C) is obtained by recrystallization from cyclohexane ..
    Example 10. 2-AMINO-5-ETYLTIAZOL.
    To a mixture of thiourea (, 5.7 gf 0.6 mol) and butyraldehyde (21.6 g 0.3 mol) in 150 ml of chloroform, cooled in an ice bath, sulfuryl chloride (44.5, 33 mole). Exothermic
    the reaction is carried out at 15-25 s. Gas release occurs in the process
    Add sulfonyl chloride for 1 hour after it. Ethanol is added to the mixture (400 MJ, chloroform yna-i is evaporated and the reaction mixture is heated under reflux for
    nights; (approximately 16. Dissolve the distilled off and the oily residue is recrystallized from cyclohexane to obtain 2-amine-5-ethylthiazo (11.7 g, mp 54-550 ° C).
    In the same way, penta al, 3methylbutanal and heptanal are converted to 2-amine-5-propylthiazole, 2-amine-5-isopropylthiazole and 2-amine-5-pentnIthiazole, respectively.
    Example 11. 2- (2,2-Likarb9Toku
    seethenylamino) -4,5-dimethylthiazo. i 2-Amine- "4,5-dimethylthiazrel (2.56 GD
    20 mmol. Diethyl ethoxlite was digest, nat (4; 8 t 22 mol) and ethanol (5 ml under reflux for 1 h. The reaction mixture
    cooled and the crude product precipitated with hexane. Purified 2- (2,2-dicarbethoxyethylamino-4, 5-dimethylthiazole (4.21 g, mp. 82-83.5 ° CJ) is obtained by recrystallization from hexane.
    Example 12. 2- (2,2-Dicarb ethoxyditenylamino) -4-ethyl-5-methylthiazole.
    2-Amin-4-ethyl-5-methylthiazole. (2.84 g, 2O) and diethyl ethoxymethylenemalonate (4.76 g, 22 1mol) are combined and heated on the steam bath for 3 hours. The product obtained in the form of oil is cooled and used without further purification in the next step.
    The same metol 2-amine-4-pentshgiazol, 2-amine-4-propyl-5-ethylthiazole,. 2-amine 4,5-diisopropylthiazole, 2-amine-5-propylthiazole, 2-amine-5isopropylthiazole, 2-amine-5-pentylthiazole, 2-amine-6-phenylcyclopentiazole, 2-amine-5,7-dimethylcyclohexenthiazole
    2-amine-4,6,6-trimethylcyclopenteniazole and 2-amine-7-methylcyclooctentazole are converted to the corresponding 2- (2 2-dicarbethoxyethylet ilamino) thiazole derivatives.
    In a similar way, the corresponding dimethyl dipropyl and diisopropyl esters are prepared using the corresponding dimethyl, dipropyl and diisopropylethoxymethylenemalonate instead of diethyl ethoxymethylenemalonate.
    Example 13. 2- (2,2-Dicarbethoxyethenylamino) -4-methyl-5-ethylthiazole.
    A mixture of diethylthiazole hydrochloride (15.4 g, 80 mmol), diethyl xymethylene malonate (19.0 g, 88 mmol triethylamine (8.1 g B0; mmol; and ethanol 125 ml) was heated under reflux for 2, 5 h. The reaction mixture is cooled and the solvent is removed. The resulting semi-solid product is partitioned between ethyl acetate and water. 2 (2,2-Dicarbethoxy ethenylamino) -4, 5 diethyl thiazole (28.6 g) is obtained as a golden oil from the ethyl acetate phase by drying over sodium sulfate anhydrate and remove any solvent.
    In a similar way, the hydrobromide salts of 5,7-dimethylcyclohexentiazole of 4,4,6-trimethylcyclopenteniazole and 7-methylcyclooctentiazole are converted to the corresponding 2- (2,2 dicarbethoxy ethenylamino) thiazole derivatives.
    In the same way. the corresponding dimethyl, dipropyl and diisopropyl esters are obtained by replacing diethyl ethoxymethylene malonate with the corresponding dimethyl, dipropyl or diisopropylethoxymethylene millsonate
    Example 15,2- (2,2-Dicarbethoxyethenylamino) cyclopentathiazole
    A mixture of 2-aminocyclopententhiazole (3.6 g, 34.5, mmol and diethyl ethoxymethylenemalonate C, 2 g, 38 milligrams) is heated on the steam bath for 100 minutes. The reaction mixture of ochlahsdayu and 2- (2, 2-dicarbethoxy ethylenylamino) -clopententhiazole (7.0 g in chromatography in a thin layer of silica gel in a mixture of chloroform / 1% ethanol8 (O. b) crystalline: from hexane.
    Example 16. 2- (2,2-Dicarb: ethoxyethenenlamino) cyclohexentiazo
    A mixture of 2-aminocyclohexentiazole (7.7 g, 50 mmol), diethyl ethoxime. Thylenemalonate (11.9 r 55: mmol and
    10ml the ethanol is refluxed for 50 minutes. The reaction, the mixture is cooled. The resulting 2- (2, .2-dicarbethoxyethenylamino) cyclohexenthiazole (15 g) is reprecipitated in the mixture from 50 ml of reKcaiHa. When chromatography in a thin layer of silica gel in a mixture of chloroform / 1% ethanol R-f O, 5.
    Alternatively, a mixture of 58.4 g of 2-amino-cyclohexentiazole, 89.82 g of diethyl ethoxymethylenemalonate and 584 ml of cyclohexane is refluxed under oxygen for 2.5 hours, cooled with and the product (.96 g, mp) is recovered by filtration.
    Example 17. 2- (2,2-Dicarbethoxyethenylamino) cyclooctene.thiazole.
    2-Aminocyclooctentiazole (2.0 g
    11 | MMOJa) H-diethylase, simethylenemalonate, (2, 22 g, 12.1 mmol) are combined and heated on a steam bath for 2.75 hours. The reaction mixture is cooled and 2- (2,2-dicarbate-6-xyethenyl-amino) cyclooctothiazole {3.18 chromatography in a thin layer of silica gel in a mixture of chloroform / 1% ethanol
    as eluant R- 0,6), reprecipitate by adding hexane.
    Example 18. 2- (2,2-Carbethoxyethenylamino) -4-methylthiazole,
    2-Amino-4-methylthiazole (4.57 g, 40 ylot) and diethylethrximeshonalonate (9.51 g, 44 mmole) are combined and heated on a steam 6-ana for 1 hour. The reaction mixture is cooled and 2- (2, 2-dicarbethoxyethenylamino) 4-methylthiaeol (9.8 r, R {0.5) by chromatography on a thin, layer of silica gel in chloroform / 1% ethanol) is precipitated by adding 60 ml; hexane.,.
    PRI m e. R 19. 2- (2,2-Dicarbetosyethenylamino) t-azol.
    A mixture of 2-aminothiazole (10.0 g 0.1 mol) and diethyl oxymethylenemalonate (23.8 g 0.11 mol) is heated on a steam bath for 1.25 hours; the reaction mixture is cooled and the resulting semi-solid is recrystallized from hexane, get pure 2- (2,2-dicarbethoxyethenylamino) thiazole fl7.2 g from double experience). Kf. 0.6 at thin-layer chromatography on silica gel in chloroform / 1% ethanol.
    Example 20. 2- (2,2-Dicarbethoxyethenylamino) -5-methylthiazole.
    2 -7 Amino-5-methylthiazole (b, 85 g, 60 mmol) and diethyl ethoxymethylenemalonate (14.3 g, 66 mmoles) are heated on the water bath for an hour. The reaction mixture is cooled and the product is precipitated by adding approximately 75 ml of hexane.
    Purified 2- (2,2-dicarbethoxyethenylamine) -5-metsh1thiazole (14.1 g in two experiments, Rf 0, 55-0.65 on thin-layer chromatography on silica gel in chloroform / 1% ethanol as eluant) is recrystallized from hexane,
    Example. 21. 2- (2,2-Dicarbethoxyethenylamino) -5-ethylthiazole.
    2-amino-5-ethylthiazole (11.7 g 91, .3 mmol J and diethyl ethoxymethylenemalonate (21.7 g, 100.43 MMoiibJ) are combined and heated on a steam bath for 45 minutes. 2- (2.2- Dicarbethoxyethenylamino-5-ethylthiazole, 27.2 g, 6, and 0.7, respectively, by thin-layer chromatography on silica gel in chloroform / 1% ethanol and hexane: ethyl acetate 2jl, the crude oil is cooled and used directly in the next stage.
    PRI me R 22. 2- (2,2-Dicarbethoxyethenylamino-4- (2-methyl-2propyl-thiazole.
    2-AMINO-4- (2-metsh1-2-propyl) chiazole (15.6, 1 mol) and diethyl ethoxymethylimalonate. (23.8, 11 mol) are combined and heated on a steam bath for 2 hours. 2- (2,2-DicarbethoxyethylnylMlO) -4- (2-metsh-2-propyl) thiazole are obtained as a wet solid product. which, after cooling, is used directly in the next step.
    Example 23. 2- (2,2-Dicarbat6 seethenylamino) -4-ethylthiazole.
    2-Amiyo-4-ethylthiazole (20.5 g 0.16 mol) and diethyl ethoxymethylene) malonate (.35 g, 0.17 mol) are pooled and heated on a steam bath for 2 hours 2- (2, 2-Dicarbethoxmetenylamine 4-ethylthiazole is obtained as an oil and after cooling it is used directly in the next stage, 0.75 on TON1SOIL chromatography on silica gel in chloroform / 1% ethanol).
    In a similar way, 2-amino-4-δ-propyl thiazole (58.6 g, 0.415 tmol) and diethyl ethoxymethylenemalonate (92 ml, 0.455 mol) Turn into 2- (2.2-dicar6
    ethoxyethenylamino) -4-isopropylthia-. 3OH (Rj.O., 7 for thin-layer chromatography in chloroform / 1% ethanol).
    Example 24. 2 {2,2-Dicarbethoxyethenylamino) -6-phenylcyclohexene-. angry .
    2.-Amino-B-phenylcyclohexentiazole (10.4 g, 42.2 N 1lb) and diethyl ethoxy-ethyl-malonate (10 ml, 49.5 mmol are combined and heated on a steam bath. After 15 minutes, a solution is obtained. After an additional 30 minutes of heating, the internal mass The solid product is recrystallized; from cyclohexane, purified 2-, (2,2-dicarbet6xyethenylamino) -phenylcyclohexentiazole is obtained (15, .3 g, mp 131-133C).
    Example 25. 2- (2,2-Dicarb ethoxyethenylamino) -6-methylcyclohexenthiazole. .
    2-Amino-b-methylcyclohexenthiazole (23.3, 139 mol) I heat T on the steam bath. After 10 minutes of heating, an orange oil is obtained. Heat another hour. The product is crystallized. Purified 2- / 2,2-dic-arbethoxyethenylamino 1-6-meter-2-hexentiene ash (40.2 g, mp. 106-109 s) is obtained by recrystallization from ethanol.
    Example 26. 2- (2,2-Dicarbethoxyethenylamino) -6 6 - dimeT1ShTsikLo hexentiazole.
    2-amino-b, 6-dimethylcyclohexentiazole (9.3 g, 53.8 mmol), diethylethoxymethylenemalonate (12 mp, 59.4 mmol) and ethanol (approximately 5 ml) are combined and heated on a steam bath for -1.5 The ethanol was evaporated during the initial heating period. The mixture is cooled, the product is crystallized. Purified 12- (2,2-dicarbethoxyethenylamino) -6,6-dimethyldichex-Ithiazole (14.3 mp 850 s) is obtained by recrystallization from hexane.
    Calculated: C 57.93; H, 8b; M 7.95.
    Cw Hj / i 04 N g S
    Found: C 57.22, HB, bb, 7.94.
    Example 27. 2- (2,2-Dicarbethok-seetenylamino) -4- (2-butyl) thiazole.
    A mixture of 2-amino-4- (2-butyl) thiazole (8.44 g, 54 mmol) and diethylethylamine (11.7 mmol) is heated on the steam bath for 1 h, cooled, 2- (2.2- dicarbethoxyethenzlamino) -4- (2-butyl) thiazole (17.6 r, R 0.75 on thin-layer chromatography on silica gel in the system with chloroform / 1% ethanol.
    Example28. Ethyl-g1-keto-1H6, 7-dimethylthiazol- 3, 2-a} pyrimidine2-carboxylate. . .
    2 - (2-Dick ar boci sie te nilamine - 4, 5i dimethylthiazole; {4.17 g, 14 shop) unite with 30 / u J) o Vihef; Au is heated at 1.5 hours. The reaction mixture is cooled and 125 ml of petroleum ether are added. The isolated solid is filtered off, combined with the mother liquor, and chromatographed on a 70x180 mm column with silica gel and chloroform in a silica gel.
    eluant. After the first fraction 5 in 125 ml, six fractions of 250 ml each are taken away, the solvent is distilled off to dryness / the resulting crude product, 42, pl.114-I5 ° C, is purified by re-V crystallization from cyclohex a: ethyl -1 -1 keto-1H -4,5-dimethlthiazol C pyrimidine-2-carbox; Gata 1764
    T.PL. 119-120 ° C ....:.;,
    Calculated: C 52.37; H 4.79 jN 11.10; g ion mass 252.. t5
    C H, 2 N. Ochb.,
    Found: C 52.21, H 4,, 23, ion mass 252.,
    . EXAMPLE 29 Ethyl-1-keto-1H-b methyl-7-ethylthiaeol TK, 2-aX pyrimy, 20 din-2-carboxylate. i.
    2-12-Dicarbethoxy ethenylamino) -4ethyl-5-methylthiazole (b, 25 g), combined with 30 ml of DowthenYw A and heated to heat for 2.5 h. The reaction 25 mixture is cooled, petroleum ether and Hadra product (1 , 95 g) is filtered. The crude product mg) is recrystallized from cyclohexane /. Get purified 1-keto-1H-6-metsh-7-ethyl thiaol {3,2-a; | pyrimidine-2-carboxinate (301-mg, TP. 122-124 S.).
    Calculated: C 54D2; H 5.30;
    N10,52. :: t
    C | 2H, 4 M,.
    Found: C 54.09 N H 5.26, N 10.63. | Example 30. Ethyl-1-keto-1H-ethyl-7-methylthiazole 3,2-a pyrimidine-2-carboxy: lat.
    The mixture of 2- (2,2-DicarbethoxyethenylaMO but) -4-metil-5-ethyl azole (12 g) and 60 ml is heated at a temperature of 3 hours. The reaction mixture is cooled and chromatographed on a 90x205 mm column with silica gel, 45 electrons chloroform containing 1% ethanol. Seven product-containing fractions of 250 ml each are collected, combined, the solvent is distilled off to an oily residue, and again JQ is chromatographed on a column of silica gel with the same silica gel with the same eluentrum. , Fractions; (1x5x8 ml) are combined, discarded. put the solvent to an oily /; the residue and the residue are crystallized at p-actiransh1 with diisopropyl ether ..; Recrystallization from cyclohexane i.-; results in ethyl 1-keto-: 1H-6-ethyl-7-methylthiazole Gz, 2-a1 Pyrimidine-2-carboxylate (2.45 g, T.PL.b5-6b c1 i60
    Calculated: C 54,12, H 5,30; N 10.52, mass of ion 266. C, gN, 4K2 OjS
    Found: C 54.26, H 5.23; N10,575 mass of ion 266. 5
    : Etc. And measure 31. Ethyl-KeTo-l-lH 6, 7-diethylthiazole-3, 2-a pyrite-2-carboxylate.
    A mixture of 2- (2,2-dicarboxyethenyl amino) 4,5-diethylthiazole (26.1 g) and 300 MnDoWlherm A is combined and heated at 225 ° C for 3.5 hours. The reaction mixture is cooled and chromatographed on a silica gel column ( 60x320 MMDowtheMrn A), PrмыmIvK) t hexane and the product is eluted with a mixture of hexane: chloroform 2: 1. Thirty-three fractions of 250 ml each. The eighth to thirty-third fractions are combined and the solvent is distilled off to obtain ethyl. 1-keto-1H-6,7-diethylthiazole; 2-a pyrimidine-2-carboxylate. (22 g, R-t 0.4-0.5 for thin-layer chromatography on silica gel chloroform / 1% ethanol.) As an oil.
    By this procedure, the following products of examples 12 and 14: 2- (2,2-dicarboxymethylenyl-amino) 4-ethyl-5-methylthiazol; 2- (2,2-dicarbopropoxy xtenyl amino) -4-ethyl-5-methylthiazole 2- (2,2diarboxyisoproproxy ethenylamino) -4 ethyl-5-methylthiazap; 2- (2,2-dicarbomethoxyethenylamino) -4,5-diethylthiazole {. (2,2-dicarbopropoxyethenylaminyl) and 4, 5-diethylthiazole; 2- (2,2-dicarboyzoprrpo "viethenylamino) -4,5-diethyl-. thiazole} 2- (2,2-dicarboethoxyethyl-amino) -4-pentyl thizol; 2- (2,2-dicarboethoxyethenylamino) -4- propyl-5 ethylthiazole J 2- (2,2-dicarboetrxyethenylamino -4.5 diisopropylthiazole; 2- (2,2-dicaroethoxyethienylamino) -5-propylthiazole) 22, 2-dicarotetoxyethylene ) -5-from propyl thiazole; 2 - (2,2-dicarbethoxyethenylamino) -5-pentshthiazole; 2- (2,2-dicarbethoxyethenylamino) -6-phenylcyclopenteniazoleJ 2- (2,2-dicarbethoxyethenylamine) -5,7-dimethylcyclohexenthiazoleJ 2- (2,2-dicarbethoxcetenylamino) 7-metschiclotoctiathiazole and 2-Meter and 2-(2,2-dicarbethoxcetenylamino) 7-metschicicooctenthiazole and 2-Meter and 2-(2,2-dicarbethoxcetenylamino) 7-metshicicooctenthiazole and 2-meccerocyntiazole and 2-Me and 2-(2,2-dicarbethoxcetenylamino) 7-metshicicooctenthiazole and 2-mets and 2-(2,2-dicarbethoxcetenylamino) 7-metshiclotoctiathiase and 2-Meter and 2-(2,2-dicarbetoxethenylamine) dicarbethoxy ethenylamino) -4,4-6-triethylcycpenthene methyl thiazole, respectively, are converted to methyl / l-Keto-1H-6-methyl-7-ethylthiazole 3,2-a) pyrimidine-2-carboxylate, respectively; propyl 1-keto-1H-6-methyl-7-e-thylthiazole 3,2-a} pyrimidine-2-carboxylate;
    isopropyl 1-keto-1H-6-methyl-7-ethylthiazl 3,2-aZ pyrimidine-2-carboxylate. methylM-keto-1H-b, 7-diethylthiazole | 3, 2-a3 pyrimid: n-2-carboxylate; propyl-keto-1H-6,7-diethylthiazole. 3,2-a pyrimndn-2-carboxylate, isopropyl 1-keto-1H-b, 7-diethylthiazole t3,2-a pyrimidine-2-carboxylate,.
    ethyl D-ketr-1H-7-pentylthiazole 3,2-aJ yrimidine-2-carboxylate; G Ethyl 1-keto-1Hgb-ethyl - / - propylthiazole 3,2-aJ pyr1YaMIDin-2-carboxylate, thyl 1-ketr-DN-6,7-diisoprprythiazole 3,2-a pyrimidine-2-carboxylate;
    ethyl 1-keto-1H-b-propylthiazole 3,2-a} pyrimidine-2-carboxylate; .ethyl-l-Kero14Hb-isopropyl thiazole {3,2-a pyrimidine-2-carboxylate7
    ethyl 1-keto-1H-6-pentylthiazole; 2-a pyrimidine-2-carboxylate; ethyl 1-keto-1H-b-fensh1cyclopentenazole 3,2-a pyrimidine-2-carboxylate ethyl 1-keto-1H-b, 8-dimethylcyclohexentiazole 3,2-a pi pi midin-2-carboxylate; ethyl 1-keto-1H-8-methylcyclooctentiazole 3,2-a-pyrimy in-2-carboxylate; ethyl 1-keto - 1H-b, 8,8-trimethylcyclo-15 pententhiazole 3,2-a3.pyrimidine-2-carboxylate.
    P r. And mёr 32. These L1-keto-1Ncyclopenteniazole Z., 2-aj. pyrimidine-2carboxylate .20
    2- (2, 2-Dicarbethoxyethenylamino) cyclopenteniazole (7.0 g) is combined with 40 ml 1) oy "1 Be1t A and heated at 225-230 ° C for one hour. The reaction mixture was cooled, and the chromatograph was chromatographed on a column of silica gel (70 x 80 ml). Dtherther A ps 1 hexane was used. The product was eluted with chloroform / 1% ethanol. Four fractions of 250 ml each were collected, combined. and the solvent is distilled off, the residue is oil. A part of the oil is crystallized by trituration with cyclohexane with a semi-crude product (1.91 g). By recrystallization of the crude product (.0.6 g), obtained-added purified ethyl 1-ke-35 to-1H-cyclopenteniazole 3,2-a pyrimidic-2-carboxylate (0.33 g, mp. 1021 RZS) ..
    Calculated: C 54.53, H 4.58 14 10.60.
    Cm H.Nj O-jS, H 40. Found: C 54.54; H 4.71J N 10.71.
    Example 33. ETHIL; 1-keto-1Ncyclohexentiazole, 2-a pyrimidine-. 2-Carbrxilat. ; :
    2- (2,2-Dicarbethoxyethenes1 45 but) cyclohexentiazole (12.6 g); -; combined with 125: ml1) o; 1ne) and is heated at 230C for: 25 minutes. The reaction mixture is cooled and. chromatographed on silica gel (80x i §0.X 320mm7. And washed with hexane and the product eluted with a mixture of chloro-forms / 1% ethanol in 14 fractions of 125 each. Crude ethyl 1-keto-1H-cyclohexentiazole 3,2-a} pyrimidine-2- its carboxylate (10.7 g, mp 92-94 s) is obtained by combining fractions and ot-; race solvent.,
    Alternative 2- (2,2-Dicarbethoxy ethylenylMino) cyclohexenthiazole (30 g, 0.25 stranded) in trifluoroacetic acid and hydride. (.101 g, b 8 MP, 0.4 V, mol); toluene (0.8 l) and ethanol (l l); blended and refluxed in Te4ejfnie 21 h. Reaction mixture 165
    cool and add 300 ml of water. The toluene layer is separated, washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, concentrated to 150 ml (suspension), diluted with 1 liter of ethanol (solution, concentrated to 280 ml, cooled to 5c, -Jella. It is poured and filtered to obtain relatively pure ethyl -1-keto-1H-cyclohexentiazole 1z, 2-a pyrimidine-2-carboxylate (47 Ruth. 105-106 с1.
    Pr 34: Ethyl; 1 - keto-1Ncycloheptentiazole 3,2-a pyrimidine2-carboxylate.
    2-Aminocycloheptentiazole (25.2 g, 0.15 mol) diethyl ethoxymethylenemallate (35.1 g: 0.165 mol) of HDowiherm A (400 ml) is combined and heated at 220-230 ° C for 2 hours. React the mixture is cooled and chromatographed on silica gel (90x235 mm). Dowtjierm A is eluted with hexane. The product was eluted with a mixture of 1: 1 hexane and chloroform in thirty fractions of 500 ml each., Fractions from the sixth to the thirtieth group. The solvent was distilled off to obtain the crude product in the form of a wet solid. Purified etchgg-1-keto-1H-cycloheptentiazole .. 1z, 2-a pyrimidium-2-carboxypate (27.1 - mp. 78-79 C) is obtained by recrystallization from diclohexane. . ,
    The same product is obtained by heating 2- (2,2-dicarbethoxy ethenylamine). Cycloheptiniazol BDowihernJ A, its isolation and purification in a similar way.
    Example 35. Ethyl 1-to-To-1-N-cycloooxteniazole 3,2-aJ pyrimidine 2-carboxylate ..
    A mixture of 2- (2,2-dicarbethoxyethenylamino) cyclooctentiazole (3.13 g) with 30 Dowtherm D was heated for 2.5 hours. The reaction mixture was cooled and chromatographed on a sl-gel (70x190 NO / i). Bowthertn A was eluted, g .tex number The product was eluted with chloroform / 1% ethanol in four fractions of 125 ml. The fractions are combined to be dissolved by distillation to an oily residue; and solid ethyl .I-keto-1H-cycloactenthia 13g2-ay pyrimidine-2-carboxylate (1.956.5 after the goneline chromatography on a silicon on silica, chloroform / 1 % ethanol) pssuchuyut rubbing with hexane.
    PRI me R 36. Ethyl 1-keto-1H7 - methylthiazole 3,2-a | pyrimiding 2carboxylate.
    Oles -2- (2,2-dikar.betrk eethenylamino) -4-methylthiazole (: 9.9. 50 MnDowthennA is heated for 2 hours. The reaction mixture is cooled and 50 ml of hexane is added, and the crude product is filtered. Recrystallization of cbjporo product 5 of ethanol is carried out to purified ethyl 1-keto-1H-7-methylthiazole 3.2 pyrimidine-2-carboxylate (4.6 g t, n 187-189 ° C). Alternatively, this ester is prepared by the condensation of 2-amino-4- methylthiazole directly with ethyl etuxymethylenemalonate by refluxing in trichlorobenzene Example 37. Ethyl 1-keto-1Nthiazole 3,2-a pyrimidine n 2-carboxy lat., 2- (2,2-Dicarbethoxy ethenylaminoethiazole (17.2 g) is combined with 200 m Dowtberm A and heated to 215 seconds for 30 minutes. The reaction mixture is cooled. To the resulting suspension 100 ml are added hexane and the crude product is filtered. Perekrist lizatsii, from ethanol leads to the production of purified ethyl 1-keto-1Ntiazol 3,2-a pyrimidine -2-carboxylate (B, O g so pl.184-185 ° C.). Alternatively, This ester was obtained by condensation of 2-aminothiazole directly with ethyl ethoxymethylenemalonate by refluxing in trichlorobenzyl. Example 38. Ethyl 1-keto1H-b-methylthiazole 3,2-aZ pyrimidine-carboxyl. 2- (2,2-Dicabethoxyethenyl amino) "5-methylthiazole (14.1 g) is combined with 150 ml DowlJJBMnA and the mixture is heated to 220 C. for 1.5 hours. The reaction mixture is cooled and 300 ml of hexane is added. The product is removed by filtration and. purified ethyl 1-keTO-lH-6-methylthiazole 3, pyrimidine - 2-k arboxyl at (6.4 g, mp 149-151 s) is obtained by recrystallization from the isopropyl ester. Alternatively, this ester is obtained by condensation of 2- amino-methylthiazole directly from ethyl ethoxymethylenemalonates in boiling trichlorobenzene. Example 39. Ethyl 1-keto1H-b-ethylthiazole, 2-a pyrimidine2-carboxylate. , 2- (2,2-Dicarbethoxistenylamino) -5-ethylthiaz6l (25.7 g, 86 mmol), trifluoroacetic anhydride (36.2 g, 172 mmol) and toluene (150 ml) are combined and heated under reflux to approximately 20 The solvent was distilled off to dryness, the precipitate was dissolved in chloroform with goiter. The chloroform solution was washed with saturated sodium bicarbonate solution and then saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was distilled off to dryness and triturated with diisopropyl ether. , get-ethyl 1-keto-1H-6-ethylthiazole 3,2-az 3 p irimidine-2-carboxylate (17.8 g, mp. 148–150 ° C). A portion of the product (5.2 g) is recrystallized from 75 ml of ethyl acetate to give a purified product (4.1 g mp. 149- 150 0). Calculated: C 52.37, H 4.79;. N11.10., C.4 N. Nn Oo &amp; ..,. Found: c52.30, H 4.51, N .11.19 Example 40. Ethyl 1-keto-1H7- (2-methyl-2-propyl thiazole Cz, 2-a1 pyrimidine-2-carboxylate. 2- (2,2-Dicarbethoxy ethylenylamino) - 4- (2-methyl-2- propyl) -thiazole (32.6 g) is combined with 400 mPowibe m A and heated to 230 ° C for 4 h. The reaction mixture is cooled and chromatographed on silica gel (60x600. mm) .Do Mthet mA elute hexane ml. The product is eluted with chloroform. Nine 500 ml fractions are collected. Combining fractions from the sixth to the ninth and the solvent is distilled off to dryness to give ethyl 1-keto1H-7- (2-methyl-2-propyl) thiazole Gz, 2-a pyrimidine-2-carboxylate (11.5 g. T mp 145-1470C). Additional product receive. (2.04 g) from a foil (1 fraction by distilling off the solvent to form a wet solid and triturating it with cyclohexane. 1 g from the larger batch is recrystallized from niclohexane to obtain the purified product (0.62 g, mp 148-149CJ. Calculated: C 55.70; H 7.55, N9.99. GI-J H | e, Found: C 55.14; H 5.58, N 9.95. Example 41. Ethyl-1-keto-1H -7ethylthiazole, 2-a pyrimidine-2-carboxylate. 2- (2,2-Dicarbztokxyethenylamino) 4-ethylthiazole (47.7, 1b tlol) is stirred in 500 ml of toluene and trifluoroacetic anhydride (45 tui, 0.32 mol.) When heated, it is heated. The reaction mixture is heated with reflux for 26 hours, cool and add 250 ml of ethyl acetate to it. It is carefully extracted with 250 ml of an aqueous solution of sodium bicarbonate (liberation of carbon dioxide) and then 250 ml of a saturated solution of sodium chloride, dried over anhydrous sodium sulphate and the solvent is distilled off. The residue is suspended in diisopropyl ether and the crude product is recovered by filtration. Recrystallization of the crude product from acetonitrile results in purified ethyl 1-keto-1H-7-ethylthiazole C3,2-a1 pyrimidine-2-carboxylate (10.33 g, mp. 175-177 ° C). Calculated: C62,37; H 2.79; N 11.10u M 12 Nj. O-js. Found: C, 52.34, H 4,, 85; N, 11.27.
    The second portion of the product (1.5-8 g, t, pl. PB-PV C) is obtained from the mother liquor with acetonitrile,
    PREMIER 42. Ethyl .l-KeTO -lH7-isopropylthiazyl 3,2-aZ pyrimidine 2-carboxylate.
     A mixture of 2- (2,2-dicarbethoxy) -4-iopropylthiazole (10 g) and 100 ml Dowiher
    A was heated at 220 ° C for 2 hours, cooled to room temperature overnight, and again heated to 220 ° C for an additional 5 hours. The mixture was cooled to room temperature, 200 ml was added. hexane, insoluble impurities are filtered off, hexane is distilled off, and the residue is chromatographed on 500 g of silica gel. PPAA / Lember A is eluted with hexane and the product is eluted with chloroform. The fractions containing the product are combined and the solvent is distilled off to dryness, the residue is suspended in diisopropyl ether and the product m.p. 143-144 ° C) are removed by filtration. The crude product is recrystallized from ethanol to obtain pure ethyl 1-keto-1H-7-isopropylthiazo H / 2-a pyrimidine-2-carboxylate (1.49 g, mp. 145-147 ° C).
    NMR; singlets S8,6 and 8 7,3, each corresponding to one proton and multiplets at 84.2. and about 1.2, corresponding to three protons and nine protons, respectively.
    Example 43. Ethyl 1-keto-1H7-phenylcyclic Hexentiazole 3,2-aZ pyrimidine-2-carboxylate.
    2- (2,2-Dicarbethoxyethenylamino) b-phenylcyclohexentiazole (15.3 g, 38.2 mmol) is suspended in 150 ml of toluene. Trifluoroacetic anhydride (lO, 8, 5 mmol) was added and the resulting clear solution was heated under reflux for 16 h. The reaction mixture was cooled to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 150 ml of 5% potassium carbonate and one 150 ml of saturated sodium chloride solution, dried over Na with anhydrous sodium sulfate, the solvent is distilled to dryness. The solid residue is recrystallized from acetonitrile to obtain purified ethyl 1-keto-1H-7-phenylcyclohexenthiazole, pyrimidine 2-carboxylate (9.89 g, m.p. . 160161, 5 ° C).
    PRI m a p 44. Ethyl .1-ketr-1H7-methylcyclohexentiazole 3,2-aZ pyrimidine-2-carboxylate.
    2- (2,2-Dicarbethoxyethenylamino) 6-methylcyclohex5 thiazole (40.2 rj 0.119 mol) is dissolved in 400 ml of toluene. Trifluoroacetic anhydride t, 32.5 ml, 0.237 mol) is added, and the mixture is ecothermic. The reaction mixture is refluxed overnight (16 hours), cooled, cooled to room temperature, diluted with 400 ml of ethyl acetate, extracted twice with 400 ml of 1N potassium carbonate and once with 400 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and the solvent is distilled off to dryness. Recrystallization from cyclohexane containing a small amount of acetate leads to the preparation of very valuable ethyl 1-keto-1H-7methylcyclohexentiazole 3, pyrimidine-2-carboxylate (29.3 g mp, 127-129 ° with).
    - Example 45. Ethyl 1-keto-1H7, 7-dimethylcyclohexentiazole, 2-aZ pyrimidine-2-carboxylate.
    2- (2, 2-Dicopethoxyethenyl dino) 6, 6-dimethylthiazole (13 g, 36.9 mmol) was dissolved in 130 ml of toluene. Trifluoroacetic anhydride (10.4 ml, 73.6 mmol) was added and the mixture boil under reflux for 16 h. The reaction mixture is cooled to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 130 ml of saturated sodium bicarbonate solution and once with 150 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and distilled off solvent. Recrystallization from hexane affords a purified ethanol. l 1-koto-1H-7,7-dimetshtsiklogeksentiazol s, 2-a pyrimidin-2karboksilata (9.40 g, m.p. 92-94s)
    Calculated: C 58.90; H 5.92JN 9.14
    Cl HieNi.
    Found: C 58.93, H 5.48 (N 9.01.
    Approx 46. Ethyl 1-keto-1H-7 (2-butyl) thiazole C, 2-a3 pyrimidine-2carboxylate.
    A mixture of 2- (2,2-dicarbethoxyethenylamine-4- (2-butyl) -thiazole (g
    175 MnDowthebm A is heated to 2.5 hours. The reaction mixture is cooled and chromatographed on silica gel (60x600 m). Dowthehtn A is eluted with hexane. The product was eluted with chloroform: hexane 2: 1. Fractions 4-8 (BOO ml each) are combined and the solvent is distilled to an oily residue, which is dissolved in 400 ml of hot hexane, treated with activated charcoal and cooled to give ethyl 1-KieTO-1H-7- (2- butyl) thiazole., 2-a1 pyrimidine-2-carboxylate 2.12 g. m. 105.5-10).
    Calcd .: C 55.70; H 5.75, C9.99.
      N, -. „, -.
    Found: C 55.82f H 5.40, N 10.22,
    Example 47. 1-keto-1H-b) 7 | Dimethylthiazole, pyrimidine-21carboxylic acid.
    Ethyl 1-to-eto-1H-6, 7-dimethylthiaeol, 2-aZ pyrimidine-2-carboxylate. i., 4i g) is heated on a steam bath with 20 ml of 48% hydrobromic acid for 1 hour. Dissolution takes several minutes, and the solid product begins to form. be called at the end of the reaction period. The reaction mixture is cooled and the product is recovered. By filtration. Recrystallization from ethanol yields purified 1-oxo-1n-b, 7-dimethylthiazole 3,2-a: 1 pyrimidine-2carboxylic acid (508 mg, mp.189g 190 ° C), i
    Calculated:, 21; H 3.60; N 12.4% 15
    The mass of the ion is 224.
    . ,
    -Found: From 48.21; H 3.68; N 12.44; ion mass 224.20
    Example 48. 1-ketr-1H-6-methyl-7-ethylthiazole, 2-a. Pyrimidine 12-carboxylic acid,
    I Ethyl 1-keto-1n-6-methyl-7-ethylbigazole 3,2-aZ pyrimidine 2-Kap6oKCij-25; Lat (971 mg) is heated on a steam bath with 15 ml of 48% bromide-disulfide. native acid dissolving occurred instantly. Heating is continued for. 2.5 h, after which the AOR, the reaction mixture is cooled, forming the WDI, the product is filtered off to obtain a solid. Recrystallization of the crude product from isopropline leads to the production of 1-keto-1-b-methyl-7.-Ethyl thiazole: C3., 2-a pyrimidine of 2-carboxylic acid: lots (354 mg, t. Square 201-202s). ;
    Calculated; : C 50.41; H 4.23; .11,75, V
    C (o .. 40
    Found: C 5-0.28 and 4.26; N 11.80, Example 49.1-Keto-1K-methyl-7-methylthiazole, 2-a pyrimidine-2-carbonoBa acid.
    Ethyl 1-keto-1H-6-ethyl-7-methyl-45. Thiazole 3,2-a pyrimidine-2 carbrone. the acid (1.33 p) is heated on a steam bath with 10 ml of 48% bromo-. hydrogen acid for 30 m. a solid precipitate is formed., en The mixture is cooled and the product is cooled. . removed by filtration. Recrystallization from isopropanol affords purified 1-keto-1H-b-ethyl-7-methylthiazole, 2-a pyrimidine-2-carboxylic acid (596 mg, mp. 174-176 0).
    Credited: C 50.41, H 4.23, fj 11.75.
     H, Oz Mg 5.:-:
    Found: C 50.44, H, 4.22, N 11.82; .
    Example 50. 1-Keto-1H-b, 7-vO
    p 50. Sz, 2-g
    diethylthiazole L3, 2-a pyridine-2-carboic acid ..
    EthylD-keto-1H-b, 7-distiltyazol Cz, 2-a pyrimidine 2-carboxylate "(19.2 g) is heated to 48% 65
    hydrobromic acid for 1 hour. Gas evolution was noted (probably the product of carboxylic acid.). The reaction mixture is cooled and alkalized. ammonium hydroxide is soluble and the unreacted substance and impurities are extracted with ethyl acetate. The aqueous phase is acidified with acetic acid
    and the solid is recovered by filtration. The crude product is recrystallized from isopropanol to obtain a partially purified product (5.4 g) in two experiments. The partially purified product (2.5 g) is recrystallized a second time: from isopropanol to obtain purified 1-keto1H-6, 7-diethylthiazole 3, 2-aJ pyrimidich-2-carboxylic acid (1.6 g. Mp. 104-10bC, decomposition) -.
    Calculated: C 52.37 H74; 49, H 11.10,
    С If Н „0-1 N7 &.
    Found: C 52.31, H 4.79; IV 11.16,
    PRI me R 51. 1-keto-1H-cyclopententhiazolr, 2-a pyrikshdin-2-carboxylic acid. - -.
    Ethyl 1-keto-1H-cyclopententium sol, 27a} pyrimidine-2-carboxyl
    (1.3 s heated with 15 ml of 48% hydrobromic acid - on a steam bath for 30 minutes. Dissolution takes place in 5 world, the solid precipitates at the end of the nage period. The reaction mixture is cooled and the crude product is removed Filtration. Recrystallization of isopropanol leads to the production of purified 1-keto-1H-., cyclopentengazol, 2-a pyrimidine-2-carboxylic acid (o, 51 g, mp 202-203.5 ° C) ,.
    Calculated: C 50.84; H 3, -41; N 11.86,
    S.E.
    Found: C 50.42, H 3.57, N 11.65.
    The sodium and potassium salts are obtained by dissolving the free acids in water with one equivalent of the corresponding hydroxide and the water is distilled off under vacuum or frozen; N-Methylmorpholine salts are obtained by dissolving the acid in - methipenchloride with a slight excess of N-methylmorpholine and the solvent is distilled off to dryness or the salt is precipitated by cooling and; The addition of the Texan-.
    EXAMPLE D 52. 1-Keto-1H-cyleslohexentiazole pyrimidine-2-cASrboxylic acid
    Ethyl 1-keto-1H-cyclohexentiazole, 2-a-pyrimidine-2-carboxylate (2.8 g) is heated on a steam bath with 30 ml of 48% hydrobromic acid. Dissolution occurs within a few minutes from the start of heating, at the end of the reaction period, the precipitation of the reaction product begins. The reaction mixture is cooled briefly in an ice bath and 1-keto-1H-cyclohexentiazole rSfZ-al pyrimidine-2-carboxy2 h-2-carboxylic acid (1.66 g, mp. 188-189 ° C ) detachment (1.66 g, mp. 188-189 ° C) are filtered. Recrystallization from ethanol yields 1.38 substances with the same melting temperature. Alternatively, this product is obtained by mixing 22.3 g of ethyl ester with 223 ml of 48% hydrobromic acid in a reduced pressure vessel. Dissolution occurs at 60-70 ° C. The reaction mixture is heated for 40 minutes to a maximum temperature of 85 ° C at a maximum pressure of 1.5 atm. The reaction mixture is cooled to 45 ° C, released, cooled, stirred for 1 hour, and the relatively pure product is filtered off (12.4 g, mp 192-194 ° C). The sodium salts are obtained by dissolving the acid in methanol with one equivalent of methoxide and distilling the solvent to dryness or by precipitating the salt by cooling and adding hexane. P and measures 53. 1-Kyoto-1H-cycloj heptantiazl t3,2-a pyrimidine-car: boyova: Kyslota. Ethyl 1-keto-1H-cyclopententhiazole 3,2-aZ pyrimidine-2-car-oxoxylate (5.8 is heated for 15 min on a steam bath with 50 ml of hydrobromic hydrobromide. The reaction mixture is poured into water with c6 lb, mixed, and the crude product is filtered off. Recrystallization from ethanol leads to a clear product of 1-keto-1H-cyclopententhiazole, 2-a pyrimidine ((2.63 g, mp 162-163. ° C. Calculated: C 54.53 / H 4, 10.60, mass of ion 264, C, 5 Oij. Found: P. 54.72 N. 4.73 N10.88, mass of ion 264. Amine salts are obtained by adding one equivalentas of amine to a warm ethanolic acid solution pic Example 54. 1-Keto-1H-cycloocteniazo p, 2-a pyrimidine-2-carboxylic acid, ethyl, 1-keto-1H-cyclooctentiazole H / 2-a pyrimidine-2- the carboxylate (1.23 g) is heated in an oil bath with 30 ml of 48% hydrobromic acid at 90 ° C for 4 hours, the reaction mixture is cooled, the pH is adjusted to 1.5 and the product is extracted with ethyl acetate. then a saturated solution of sodium chloride is dried over sodium sulfate and the solvent is distilled off to an oily residue. The oil was redissolved in ethyl acetate and the product was extracted into 1N. potassium hydroxide. The alkaline solution is acidified again. hydrochloric acid and the product is extracted with ethyl acetate. Ethyl acetate. The extract was washed with water and then with saturated sodium chloride solution, dried over anhydrous sodium sulphate to dryness to give 1-keto-1H-cycloheptentiazole 2f2-a pyrimidine-2-carboxylic acid (308 mg, Rf 0.6 by thin layer chromatograph .ii on silica gel chloroform / 1% ethanol). The procedure of examples 47-53 used. T to convert the corresponding alkyl 1-keto-1H-thiazole 3,2-a7 pyrimidine-2-carboxylates of example 31 to 1-keto-1H-6-methyl-7-ethylthiazole, 2-a1 pyrimidine-2-carboxylic acid, 1-keto-1H-6,7-diethylthiaool, 3,2-a pyrimidine-2-carboxylic acid,. . 1-keto-1H-7-pentylthiazole 3 ,. rimidin-2-carboxylic acid, 1-keto-1H-6-ethyl-7-propylthiazole 3,2-a pyrimidine-2-carboxylic acid} ..: -. . , 1-keto-6,7-diisopropyl thiazole t3,2-a pyrimidine-2-carboxylic acid. 1-keto-1H-b-propylthiazole, 2-a1. pyrimidine-2-carboxylic acid 1-keto-1H-6-isopropyl thiazole, 2-21 pyrimidine-2-carboxylic acid, 1-keto-1n-6-pentylthiazole | 3, 2-a pyrimidine-2-carboxylic acid / 1-keto-1H-6-phenylcyclopentenia 3,2-a pyrimidine-2-carboxylic acid; . 1-keto-1H-6,8-dimethyldichexenthiazole p, 2-a pyrimidine-2-carboxylic acid 1 1 keto-1H-8-methylcyclooctientazole {3,2-aj pyrimidine-2-carboxylic acid and 1-keto-1H-6 , 8,8-trimethylcyclopentene; thiazole, 2-a | pyrimidine-2-carboxylic acid. EXAMPLE 55 1-Keto-1H-7-methylthiazole 3,2-aJ pyrimidine-2-carboxylic acid. Ethyl 1-keto-1H-7-methylthiazole, 2-a pyrimidine-2-carboxis-1 (3.1 r) is heated on a steam bath with 50 ml of 48% hydrobromic acid. Dissolution occurs within 5 minutes. After 15 min of heating, the reaction-: mixture is cooled and the precipitated j3 precipitate the product is filtered off, -; Recrystallization from acetic acid. lots results in purified 1-keto-Z.N-7-metsh1Tiazol 3,2-aJ pyrimidine-2-carboxylic acid, 1.4 g, so pl. 265 ° С, decomposition), Calculated: С 45.71; H 2.88, N 13.33. Cfi "feo zs--: Found: C 45.57; H 3.04, N 13.40. Example 56. 1-Keto-1H-thiazole 3,2-aJ pyrimidine-2-carboxylic acid. Ethyl 1-keto-1H-thiazod 3,2-aa | rimidine-2-carboxylate 7.5 g) is heated on a steam bath for 20 minutes with 80 ml of 48% hydrogen bromide. acid. The dissolution takes place within 5 minutes and after a few minutes the solid precipitates out. The reaction mixture is cooled in an ice bath and the crude product is filtered off. A complete 1-keto-1H-Thiazole 3,2-a1 pyrimidine-2-carboxylic acid (4.66 g, mp. 276 ° C, decomposition) is obtained. Calculated: with 42.86 N 2.06; N 14, O N S Found: C 42,71; H 2.21; M 14.32 Alternatively, this acid can be obtained from the same. interme- diat boil with reflux in an excess of 2H. Sol Noi acid PRI me R 57. 1-keto-1H-b-methylthiazole, 2-a pch} indidin-2-carboxylic acid. -. Ethnl 1-Keto-1H-6-methyl thiazole 3,2-aJ pyrimidine-2-carboxylate (5.96 g) is heated on a steam bath for 1 h with 60 m of 48% hydrobromic acid. The reaction mixture is cooled in an ice bath and sausage PRODUCT; Start by pressing with isopropyl alcohol and ether. Crucifying the crude product from rame dimethylforma results in purified 1-keto-1H-6methylthiao 3,2-a7 pyrimidine-2-carbonic acid. (3.73 g, mp 2462 48 ° C. Decomposition). Calculated: C-iS, 71V H 2.38; N 13, Cg Nb O, N, 5. Found With 45/87; H 2., 94; N 13.47 Alternatively, this acid is obtained from the same intermediate by refluxing in 2N hydrochloric acid. Example 58. 1-Keto-1H-6ethylthiazral 3,2-a pyrimidine-2-carbonic acid. . Ethyl-1-keto-1H-6-ethylthiazole 13, Jr |, pyrimidine-2-carboxylate (12.6 rJ. Heated on a steam bath with 125 ml: 48% hydrobromic acid. Dissolution occurs within a few minutes. After 10 min. a solid is formed. The reaction mixture is cooled and the crude product (10.1 g) is filtered. Recrystallization 2.32 g of the crude product (from 6.8 g extracted by recrystallization from acetic acid) from isopropyl alcohol results in a purified 1-hydroxy 1H-6-ethylthiazole, 13.2-g11 pyrimidine-3-carboxylic acid (1.85 g, mp. 162-163 C). but: c48.21, H 3.60; N 12.4 C Hg O, NzS.; Found: C 48.177, H N. P p. and meas. 59 ... .1-Keto-1H-7 ( 2 1-methyl-2-propyl) thiazole 3,2-a pyrimidine-2-carboxylic acid: I am acid.: Ethyl-1-keto-1H-7- (2-methyl-2-prop. Dyl) thiazole, 2-a pyr. imidine-2-carboxylate (5.6 g) is heated in a steam bath for 6 hours with 60 ml of 48% hydrobromic acid. After 10 minutes of heating, the reaction mixture is fully heated. becomes very viscous. And the heated mixture the reaction mixture is cooled and the crude product is filtered off. Recrystallization from acetic acid and drying over dimethylformamvdbm leads to the commissioning of purified 1-cetho-1H-7- (2methyl-2-propyl.) Thiazole 3,2-aT pyri-midin-2-carboxylic acid / 3.33 g, t .pl. 241-2420C, -. Decomposition. ... .. - .. “. {Calculated: C 52.37; H 4.79; M11.10 i SmN ..; G Found: C 52.45 J H 4, 82; .11,26. Pr and measures 0. 1-Ketog1N-7-ethylthiazole 3,2-aZ pyrimidine-2-carvonic acid. , .. V Ethyl 1-keto-1H-7-ethylthiazole; 3, 2-a1 pyrimidine 2-car6oxylate (1.5 g) is heated on the Steam bath with 15 ml of 48% hydroomidate in: for 20 minutes. Dissolve for about 10 minutes and, after 10 minutes, precipitate to room temperature and dilute with approximately 25 ml of water and remove the crude product. by filtering. The crude product is partially purified by dissolving in 1N potassium carbonate and precipitated again by acidification with hydrochloric acid, recrystallisation, and acetic acid. Acids Lead to Preparing Eyes} dec. of 1-keto-1H-7 Etlltiazol p, 2-aj pyrimidine-2-carboxylic acid (594 mg, mp 206-. 209 РсУ.; .. ............ : .numbered about: C 48.21, H 3, 12.4 lll. .Hyde ND: C 48, Q1 | H 3.69) N 12.50. HP and measure 61. 1-Keto-1H-7-isopropyl thiazole | 3,2-a pyryutdin-2-carboxylic acid, Ethyl-1-keto-1n 7-isopropyl thiaole. , 2-aJ pyrimidine-2-carboxylate (909 mg) was heated on a steam bath with 10 MP of 48% hydrogen hydrobromide concentration for 2 min. within .inepBHX for five minutes, complete dissolution occurs, after 10 minutes the product begins to precipitate. After the period; The reaction mixture is cooled down to room temperature and sy-; the swarm is recovered by filtration.. Recrystallization from ethanol makes it necessary to obtain purified 1-keto-H7-isopropyl thiazole 3,2-a | pyrimidine 2-carboxylic acid (538 mg, so pl. | 216-217 ° C) ..
    Example 62 1-keto-1H-7phenylcyclohexentiazole, 2-a pyrimidine-2-carboxy acid.
    ethyl 1-keto-1H-7-phenylcyclohexentiazole 3,2-a pyrimidine-2-carboxylate 9.8 g) is heated under reflux with 200 ml of 48% hydrobromic acid for 20 minutes and dissolution takes approximately 10 minutes. The reaction mixture is cooled and the crude product is filtered off. Recrystallization from acetic acid Results in 1-ketoH-7-phenylcyclohexentiazap 3,2-aJ pyrimidine-2-carbrnic acid (2.25 g, T. L. 224-22 bC).
    Calculated: C, 62.56; H 4.32; N 8.58
    Ci7Ht4N,
    Found: C, 62.26; H 4.11; N8.52.
    An additional portion was obtained from the mother liquor (704 mg, mp 217-2200s).
    EXAMPLE 63. 1-Keto-1H-7-methyl Diclohexentiazole p, 2-a1 pyrimidine-2-carboxylic acid.
    Ethyl 1-keto-1H-7-methylcyclohexene thiazole [3,2-a pyrimidine-2-carboxy lat (27.5 g) is heated on a steam bath for 35 minutes with 275 ml 4Y% hydrobromic acid. After 10 min. Dissolution occurs, and the sequence 15 min. Precipitates the product. The reaction mixture is cooled to room temperature and the crude product (14.8 g, mp. 181.5 - 183.5 s) is filtered off and punched with water. Recrystallization from methyl formamide results in 1-keto-1H-7-methylcyclohexenthiazole, 2-a pyrmidine-2-carboxylic acid (10.1 g, so pl. 183.5-185,)
    Calculated: C 54,53; H 4.58, N 10.6
    Ci2 H (. ,,.
    Found: C 54.11, H 4.28; .
    the second portion of the product was obtained by adding water to the dimethylformamide mother liquor, (3.11 g, Mp 182-184 ° C).
    Approx 64. 1-Keto-1H-7,7-dimethylcyclohexentiazole 3,2-a pyrimidine -2-car (5-isoic acid.
    A mixture of ethyl 1-ketr-1H-7,7-dimethylcyclohexenthiazole, 2-a1 pyrimidine-2carbirxylate (7.9 g) with 80 ml of 48% hydrobromic acid is heated on a steam bath for 50 minutes. Before completion of the dissolution of the ester-ether ester, precipitation of the acid began. The reaction mixture is cooled, diluted with .100 ml of water and the crude product (6.7 g) is filtered off, washed with a small amount of water. Recrystallization of a RAW product from ethanol leads to the production of l-cep-lH-7,7-dimethylcyclic-pyrimidine-2-carbene pyrimidine-2-carbrnoric acid (4.7 g, so pl. 197-, 19C)).
    Calculated: C 56,10} H5., 07; W 10.06: C, H, 4 N, 0.5.
    Found: C 55, H 4.84; N10.14. Example 65. 1-Keto-1H-7- (2butyl) -thiazol 3,2-a pyrimidine-2carboxylic acid.
    Ethyl 1-keto-1H-7- (2-butyl | thiazole 3, 2-a pyrimidine-2-carboxylate (2, 0 bedine with 20 ml of 48% strength hydrobromic acid and heated on a steam bath within 25 minutes after 5 minutes dissolution takes place and after 10 minutes, precipitation of the product begins.ta.The reaction mixture is cooled to room temperature, diluted with 40 ml of water and the crude product is 1 g3, mp 191-194 ° C) is removed by filtration and washed with a small amount of water. Recrystallization of the raw material of the product from ethyl acetate, containing a small amount of ethanol, produces purified 1 st-1H-keto-7- (2-butyl) -thiazol 3 pyrimidine-2-carboxylic acid (606 mg, mp. 194-197 ° C).
    You are: C .52.37, H 4.79; W 11.10. C | H NjOv5,
    -Found: C 52.20, H 4; 38; M 11.11.
    An ethyl acetate uterine content is concentrated to form a small second batch of product.
    EXAMPLE 66.N - {5-Tetrazolyl 1-ket, o-1H-6,7-dimethylthiazole 3, pyrimidine-2-carboxamide. ;
    1-Keto. 1H-6,7-dimethylthiazol | 3, 2-a pyrimidine-2-.carboxylic acid (367 MG; 1, B ghol) is dissolved in 3 ml of dimethylformamide by heating on a steam bath. W, -N -carbonyldiimidazole (292 mg, 1.8 mmol) was added. At the end of the gas release, 5-aminotetrazole (153 mg, 1.8 mmol) is added, which dissolves first, and then the resulting pro-. The product precipitates. The reaction mixture is cooled and the crude product is removed by filtration. The crude product is recrystallized to obtain purified M-5-tetrazolyl) -1-keto1H-6, 7-dimethyltnazol {3,2-aJ pyrimidine-2-carboxamide (, mp. 317 °
    Calculated: C 41,23j .H 3.11, N 33.66
    CKI HQ about NjS ..
    Found: C 41.52, H 3.40; N 33.47.
    Pr and measures 67. H - -Tetrazolyl} 1-keto-1H-6-methyl-7-ethylthiazole | P 2 pyrimidine-2-carboxamide.
    1-keto-1H-6-metcp-7-ethylthiazole t3,2-al pyrmidine-2-carboic acid (238 mg, 1.0 mmol) is dissolved in 5 ml of dimethylformamide and heated on a steam bath. N, K -car bonildiimidazole (173 mg, 1.1 mmol) was added. After evolving the gas, 5-aminotetrazole (93.5 mg, 1.1 mmol) was added. The solid begins to precipitate after 15 minutes. The reaction mixture is rectified by filtration; ayut to give N - (5-tetrazol1; 1-keto-1H-6-methyl-7-ethylthiaole, 3,2-a pyrimidine-2-carboxamide (227 mg, m.p., 31p) Calculated: C 43.27; H 3.63 vN32, l C f / HnO NT S-. Found: C 43.20; H. 3, 72, .N 31.88. Example 68 N-fS-Tetrazolyl} 1 -keto-1H-6-ethyl-7-methylthiazole 3,2-a pyrimidine-2-carboxamide., 1-keto-1H-6-ethyl-7-me. methyl thiazole 3,2-a pyrimidine-2-carboxylic acid C37.6 mg, 2.0 mmol) was dissolved in dimethylformamide on a steam bath. N, M-dicarbonylimidazole. (357 mg, 2.2 mmol is added to a hot solution. After it has finished; no gas is added, 5-aminotetrazol is added to the gas. (187 mg, 2.2 mmol. A solid product starts to precipitate after a few minutes. The reaction mixture is cooled and the crude product is separated by filtration. Recrystallization from dimethylformamide gives N - (5-tetrazolyl) -1-keto1H-6-ethyl-7-methylthiazole Cz, 2-a pyrimidine-2-carboxamide (388 mg, T.PL ZOZ C, decomposition). Calculated: C 43.31 H 3.6VN 32.1., 02N75 Found: C 43.6; H 3.9, N 32.3. Example 1 69. N g ( 5-tetrazolyl 1-keto-1H-6,7-diethylthiazole t3,2-a pyrimidine-2-car boxamid. 1-keto-1H-6,7-diethylthiazole, 2-a1 pyrimidine-2-carboxylic acid (2.52 t, 10 mmol) and N, N - carbonyldiimide zol (1.7 3 g,. C mmol) is combined with 15 ml of dimethylformamide and heated on a steam bath. Dissolution and gas evolution occurs. At the end of the gas evolution 5-aminotetrazrl (1.13 g, -11) is added and the mixture is heated for 30 minutes. the precipitated product is recovered by filtration. Recrystallization of the crude product. A from acetic acid to produce purified N- (5-tetrazolyl) -1-keto. 1H-6,7-diethylthiazole pyrimidine-2-carboxamide (ifll g, T.PL., decomposition).:., Calculated: C 45.13, H 4.10; N 3Q, 7 ion mass 319.7 С | 1И | г о, N7 5 Found: from 45.18, H 4.24 "30.52, ion mass 319. im 70, N - (5-tetrazolyl). 1-keto-1H-cyclopenteniazole C3,2-a; Pyrimidine-2-carboxamide ,. 1 Keto-1H-cyclopentenyl 1iol L3,2-a7 pyrimidine-2-carboxylic acid (378 mg, 16 mmol) IR, N-car. Bonildiimidazole (2.85 mg, 17.6 mmol). combined with 3 ml of dimethylformamide and heated on a steam bath, dissolution and gas evolution takes place. After the evolution of gas, 5-aminotetrazole (150 mg, 17.6 mmol) is added. The mixture is cooled and the precipitated crude product is recovered by filtration. Recrystallization from dimethylformamide results in purified P- (5-tetrazolyl) -1-keto-1B-cyclopententhiazole, 2-a pyrimidine-2-carboxamide (313 mg, T.PL. 310 ° C). Calculated: C 43.6, H 3.0; N32.3, € (, H () .02 N75. Found: C 43.6, H 3.3; N32.0. I Example 71. M- (5 -tetrazolyl). -1-keto-1H-cyclohexentiazole 3,2-aJ pyrimidine-2-carboxamide. 1-keto-1H-cyclohexentiazole 3,2-aT pyrimidine-2-carboxylic acid (lot (0.5 g, 2 g-lmol of them, N -carbo-: nildiimidazole (0.36 g, 2.2 mmol) is dissolved in 3 ml of dimethylformamide at room temperature, and gas evolution takes place. gas, the reaction mixture is heated on a steam bath, and in the process of heating, additional evolution of gas occurs. To the hot solution, 5-amino acids are added trazol (o, 19 g, 2.2 mmol), after a few minutes the product precipitates. The reaction mixture is cooled and the crude product is recovered by filtration. Recrystallization of the crude product results in M (5-tetrazol) -1-keto-1H-cyclohexentia ash 3,2-a pyrimidine-2-carboxamide 319 mg, TPL 310 ° C, decomposition). Calculated: C 45.42, H 3.49; N 30.90. s, 2n ".S Found: C, 45.59, H 3; 62; N 30.44. Alternatively, the acid (2.07 g) is dissolved in 40 ml of methylene chloride and 1.74 ml of triethylamine at. Ethyl chloroformate (0.85 ml) in 8.1 ml of methylene chloride | was added over 20 minutes, maintaining the reaction temperature between O and. After a thermostati. {0-5 ° C for 45 minutes, 5- aminotetrazole (0.87 g) in 8.1 ml. dimethylacetamide and the reaction mixture are heated to 20 s / s S. temp. for 25 min and maintained at this temperature for 90 min. The product is recovered by filtration (2.0 g, T.PL. 308-310Cjl. The product obtained by this method (3.9 g) is recrystallized from dimethyl acetone of the preparation to obtain purified N - (5-tetrazolyl) -1-k1-1-1H-cyclohexene , thiazole 3,2-a pir, imidine-2-carboxamide (3.1 g, T.PL. 314-315 ° C) 1 The sodium salt of this amide is obtained by dissolving 5.5 g (17.3 mmol) of amide in 44 ml of water and 17.3 ml mmol) of 1N. sodium hydroxide with stirring for 30 minutes; pH 11.0). The solution is clarified and the salt is precipitated by the addition of 35 ml of acetone. The suspension is cooled to 5 ° C, crushed for 3 hours, the sodium salt is filtered off (4, .9 g) and washed with cold acetone. A solution of salt in water (10 mg in 1 MP of water) has a pH of 10.2. Perehris sodium salt is dissolved by dissolving 2.3 g in 23 ml of water at 60 ° C. The clarified solution is cooled for L h to 5 ° C and milled at this temperature for 1 h. The sodium salt is filtered (1.68 g), pH 100 mg of recrystallized sodium salt in 1 ml of water.8.8. Calculated: Noii GNP; H, 2O 13.7; weight reduction during drying 13,7; ec. neutralization 393. 42 H 0 0.2 N t S Found: 13., 43 weight loss when drying 13., 8, equivalent to neutralization 391, In the described method of mixed anhydride, equivalent amounts of methyl chloroformate propyl chloroformate, isopropyl chloroformate, butyl; chloroformate, tert-butyl chloroformate, pentylchloroformate, phenyl chloroformate or benzyl chloroformate are used instead of ethyl chloroformate with the same result. Similarly, the equivalent amounts of the other acids described in examples. 47-65 react with chloroformates and then with 5-aminotetrazole from the floor. by the corresponding N -, (5-tetrazolyl) amides. An example. 72, N- {5-Tetrazolyl) 1-keto-1H - cycloheptentiazole, 2-a pyrimidine-2-carboxagdide, 1-keto-1H-cycloheptentiazole 3,2-a pyrimidine-2-carboxylic acid (2.1 g , 8 pglol) and .N, N-carcass nildiimidazol (1.4 tons, 8.8 mmol) are combined with 15 gll of dimethyl formamide and the mixture is heated on a steam bath. After gas evolution, 5-aminotetrazole (0.86 g, 8.8 mmol) is added. After .5 min, a solid begins to precipitate. After an additional 30 minutes of heating, the reaction mixture is cooled, the product is filtered. Recrystallization of the crude product from dimethyl formaDa results in the purification of K- (5-tetrazolyl) -1-keto-1H cycloheptentiazole 3,2-aZ pyrimide 11H-2-car6o xamide (1, B1, pl. 295-29bs decomposition. Calculated : C 47.12; H 3.95; N29.5. Found: C 47.10-, H 4.11; N29.72 Example 73. M- (B-Tetrazolyl 1-keto-1H cyclooxe thiazole W, 2-a pyrimidine-2-carboxamide. A solution of 1-keto-1H-cyclooctyonthiazole, 2-a pyrimidine-2-carboxylic acid (308 mg, 1JJ mmol) in 10 ml of dimethylformamide at heating on a steam bath. Add N , N-carbonyl imimidazole. After the evolution of gas, 5-aminotetrazole is added (1 03 mg, 1.21 mmol.) The reaction mixture is heated for 10 minutes during which a solid begins to precipitate. The reaction mixture is cooled and the crude product is filtered off. Recrystallization from dimethylformamide gives N- (5-tetrazolyl-1- keto-1H-cyclooctentazole, 2-aj pyrimidine-2-carboxamide (183 mg, mp, decomposition). Calculated: C 48.69; H 4.38, N 28.3.9. NT. Found: C 49.01, H 4.63; N 27.35. EXAMPLE 74.N- (5-Tetrazolyl) "" 1-keto-1H-7-methylthiazole. 3, pyrimidine-2-carboxamide. 1T-keto-1H-7-methylthiazole L3,2-aj pyrimidine-2-carboxylic acid (o, 91 g, 4.3 mU4ol) HN, U-carbonididiimidazole (0.89 g, 5.5 mmol) was dissolved in 6 ml dimethylformamide and the mixture is heated on a steam bath. After the evolution of gas, 5-aminotetrazole (0.47 g, 5.5 mmol) is added, after completion of dissolution, the solid begins to give a solid. After a few minutes, the reaction mixture is cooled and the crude product is removed by filtration. Recrystallization from dimethylformamide yields a purified N - (5-tetrazolsh1) 1-keto-1H-7-methylthiazole | 3,2-a pyrimidine-2-carboxamide 1.0 g, so pl,). Calculated: C 38.99, H 2.54, N35.36. C 9 H-J. About MT5. Found: C 38., 97; N. 2.73; N 34.97, Example 75. (5-Tetrazolyl) 1-oxo-1H-thiazole 3,2-a pyrimidine 2-carboxamide .1-Keto-1H-thiazole Ij3,2-a pyrimidine-2-carboxylic acid (1, 96 g, 10 mmol) is dissolved in 20 ml of dimethylformamide on a steam bath. N, N -carbonyldiimidazo. G1 (1.78 g, 11.0 mmol) is added to the solution. After separation of the pelvis, 5-aminotetrazole monohydrate is added ( 1.13 g, 11 mmop). Less | than 1 min, a solid begins to precipitate. After heating for an additional 15 minutes, the reaction mixture is cooled and the product is filtered off. Recrystallization from dimethylformamide gives N- (5-tetrazolyl); 1-keto-1H-thiazole 3,2-a pyrimidine-2-carboxamide (1.8 g, so pl.). Calculated: C 36.50} H 1.91.73.37.25, Cg Hg O, N7 5. Found: C 36.62, H 2.76, H 37.72, Example 76.N - (5-Tetraerlyl; 1-keto-1H-6-methyl-iazole 1z, 2-aZ pyrimidine-2-carboxamide 1-keto-1H-6-methylthiazole 3,2-aZ, pyrimidine-2-carboxylic acid (2.1 g, 10 mmol) and M, N-Carbonyl imidazole (1.78 g, 11 mmol) are combined with 15 ml of dimethylformamide and heated on a steam bath. The dissolution is accompanied by evolution of gas. After the completion of gasification, 5-aminotetrazol monohydrate (1.13 g, 11 mmol) is added. A solid forms in less than a minute. After heating, the reaction mixture is cooled for 5 minutes. Filtration results in N- (5-tetrazolyl) 1-keto-1H-b-methylthiazole | 3,2-a pyrimidine, -2-carboxamide (2.33 g, so pl. 318 ° C). Calculated: C 38.99, H 2.54 - N 35.36 C o Nt Oo N76 Found: C 39, H 3.00; N35, Ex. Example 77. H- (5-Tetrazolyl) 1-keto -1H-6-ethylthiazole 3,2-a pyrimidine-2-carboxamide .. 1.:: Keto-1H-6; -ethylthiazole 3,2-aJ pyrimidine-2-carboxyic acid 0., 48 g 20 mmol) and N, N -carbonyldiimidazole (3.57 g, 22 ml) with 20 ml of dimethylformamide is heated on a steam bath. Dissolution is accompanied by gas evolution. After digestion of the pelvic, 5-aminotetrazap monohydrate (2.2.7 g, 22 mmol) is added. Less than . a solid is formed in a minute. The reaction mixture is heated additionally for 15 minutes, cooled and the crude product is separated; ilt ovaniem. Recrystallization from dimethylformamide leads to 14 - (5-tetrazolyl) -1-keto-1H-ethylthiazole t3f2-aj pyrimiline-2-carboxamide (4.7 g mp., Decomposition). Calculated: C, H 3.11; And 33.66. CiflHo Oh, NY 5 Found :; C 41.41; H 3.30} N 33.84. Example 78. N- (5-Tetrazolyl) l-keto-lH-7- (2- "util-2-propyl) -thiazOl {3,2-eCj dirimidine-2-carboxamide; 1-Keto-1H-7- (2-methyl-2-propyl) thiazole 3,2-a pyrimidine-2-carboxylic acid, (2/52 g, 10 mmol) and K, N carbonyl hiimidazole, 1.78 g, 11 mmol) is combined with 15 mm dimethylformamide; and the mixture is heated on a steam bath. The dissolution is accompanied by gas evolution and after a few minutes a solid is formed. Heating is continued for 10 minutes. The reaction mixture is cooled and the crude product is separated by filtration. Recrystallization from dimethyl yurmamide results in N - {5-tetrazolyl) -1-keto -1H-7- (2-methyl-2-propyl | thiazole, 2-a-pirsh1idin-2-carbokfamI) yes (1.6Z g, mp 280 ° C, decomposition Calculated: C 45.13 j H 4.10, 30.70 C | aI | 3 02 NT 5Found: C 45.22} H, 4.40 N 30.45 Example 79. H IZ-Tetrazolyl) 1-keto-1H 7-ethylthiazole 3,2-a pyrimidine-2-carboxamide. 1-Kyto-1H-7-ethylthiazol 3, 2-a pyrimidine-2-carboxylic acid (502.5 mg, 2.24 mmol) IR, N gcarbron nildiimidazole (399.7 mg, 2.46 mmol} is mixed with 3 ml of dimethylformamide and the mixture is heated on a steam bath. The dissolution is accompanied by the evolution of gas. After the evolution of gas, 5-amino-tetrazole monohydrate (253.0 mg, 2.45 mmol) is added.: From the resulting clear solution, a precipitate begins to form in 2 minutes The reaction mixture is heated for an additional 2 p min., Cooled to room temperature, and the crude product is filtered off. Recrystallization from dimethyl formamide results in N- (5-tetrazolyl) -1-keta.o-1H-7ethylthiazole., 2-a pyrimidine-2-carboxMida 48b mg, mp. 261-262 C, decomposition). Calculated: G 41.23; H 3.11,; M 3:, 66, ion mass 291. ClnHg. C., 02 5L - Found: - C, 41.35). H 3.31.M 33.55, Ion mass 291 ..: Example p 80.N (3-Tetrazolsh - D-keto-1H-7-isopropylthiazole C3, .2-a1 -,. Pyrimidine-2-carboxamide lVKeTo-lH-7-isopropyl thiazole 3,2-a1 pyrimidine-2-carboxylic acid (537 mg, 2.2 1 "aiol) and N, N - carbon ylmydaEOL (401 mg, 2.47 mmol) are combined with 30 ml dimethylformamide and the mixture is heated on a steam bath. The dissolution is accompanied by the release of gas.After assuring the inoculation of the reaction mixture, 6-aminotetrazole monohydrate (255 mg, mmol) is added. The product is immediately precipitated.The heating is continued for 20 min, after which the reaction cooled and the crude product filtered off. Shaking off dimethylformamide gives N - (5-tetrazolyl) -1-keto-1H-7-isopropylthiazol-3,2-a) pyrimidine-2-carbox # 1da (328 mg, mp) . Calculated: C 43.27; H Z.BV; K132D1. . . . . . Found: C 43.34, H 3.76, N 31.82. Example 81. M- (5-Tetrazolyl) 1-keto-1H-7-phenylcyclohexenthiazole 3,2-a pyrimidine-2-carboxamide. 1-Keto-1H-7-phenylcyclohexentiazole C3,2-a1 pyrimidine-2-carboxylic acid L980 mg, 3.0 mmol and N, N-carbonyl L-diimidazop (320 mg, 3.1 mmol) are combined with 12 ml of dimethylformamide and the mixture heated on a steam bath. After evolution of the gas, 5-aminotetraeolyl monohydrate (496 mg, 3.1 mmol) is added. After 10 minutes, the product starts to precipitate. The mixture is heated for 1 hour, then cooled to room temperature and the crude product (312 mg) is filtered off- Recrystallization from , dimethylformamide leads to purified N- (5-tetrazolyl -1-keto-1H-7-feiylcyclohexentiazole 3,2-a1 pyrimidine-2-carboxamide (131.5 mg, mp).
    Calculated; C 54.95} H, 3.84; 24.92. . .
    , H, 5.
    Found: C 54.38J, H 3.93} N 24.81.
    Example 82.N- (5-Tetrazalil) i; -keto-1H-7-methylcyclohexentiazole. 3 f2-a pyrimidine-2-carbrxamine.
    A mixture of 1-keto 1H-7-methylcyclohexentiazole 1z, 2-a3 pnrimidine-2-carboxylic acid (1.0 g, 3.78 mmol) and H, N -carbonyldiimidazole (675 mg, 4.16 mmol). With 6 ml dimethylformamide is heated on a steam bath. During the dissolution process, gas is released. After the evolution of gas is complete, 5-aminotetrazole (429 mg, 4.16 mmol) is added to the reaction mixture and heating is continued. After a few minutes, begins to form with sediment. After 30 minutes, the reaction mixture was cooled and the crude product (m.p.) was separated by filtration. Recrystallization from dimethylformamide results in C- (5-tetrazolyl -1-keto-1H 7 adetil "cyclohexentiazole 3, pyrimidine 2-carboxamide (980 mg, mp. 300 ° C
    Calculated: C 47.12) H 3.95; . N 29.59,
    CV, H ,,,
    Found: C 47.32, H 4.18, N 29.60,
    Example 83.N- (5-Tetrazolyl. 1-keto-1H-7,7-dimethylcyclohexenthiazole, 2-aZ pyrimidine-2 carboxamide.
    1-keto-1H-7,7-dimethylcyclohexentiazole 3,2-a pyrimidine-2-carboxylic acid (558 mg, 2, O mmol) and N, N-carbonyldiimidazole (357 mg, 2.2 mmol) are combined with 3 ml of dimethylformamide and the mixture is heated on a steam bath. Dissolution is accompanied by gas evolution. After completion of the gas evolution, 3-aminotetrazole monohydrate (227 mg, 2.2 mmol) is added and heating is continued for 20 minutes. The reaction mixture is cooled and the crude product (561 mg, mp. Filtered. Recrystallization from dimethylformamide leads to purified N- (5-tetrazolyl) -1-keto-1H g, 7-dimethylthiazole 3,2-a pyrimidine. 2-carboxamide (469 mg, mp. 300 ° C). Calculated: C 48.69, H 4.38 N28.39.
    C, 4H | 5 0, ..
    Found: C 48.80, H 4.18; N 28.42
    Example 84 .N - (5-Tetrazolyl) 1-keto-1H-7- (2-butyl) thiazole 3, 2-a pyrimidine-2-carboxamide.
    1-Keto-1H-7- (2-butyl) thiazole, 3,2-aZ pyrimidine-2-karOonum acid (379 mg, 1.5 mmol) and N, H-carbonyldiimidazole (270 mg, 1.66 mmol ) Combine with 3 ml of dimethylformamide and heat the mixture on the steam bath. Dissolution is accompanied by gas evolution. After gas evolution is complete, 5-aminotetrazole (170 mg, 1.65 mmol) is added and the mixture nocyie is heated, after a few minutes, the formation of a precipitate is heated for 20 minutes. The reaction mixture is cooled to room temperature.
    Perature and raw product are separated. 7
    by filtering. Recrystallization results in N- (5-tetrazolyl) 1-keto-1H-7- (2-butyl) thiazole 3, pyrimidine-2-carboxamide (247 mg, mp. 300 ° C).
    Calculated: C 45.13 JH 4.10VN3Q, 70 C | oH „0“ N75Found: -C 45.12; H 4.05; N 30.69.
    PRI me R 85. According to the method of examples 66-84. The following compounds are obtained from the corresponding 1-keto-1N-thiazole, 2-a pyrimidine-2-carboxylic acids:. . M - (5-tetrazolyl) -1-keto-1H-7-pentyl thiazole C3, 2-a pyrimidine-2-carboxamide /
    K - (5-tetrazrilyl) -1-keto-1H-6-ethyl7-propylthiazol 3, pyrimidine-2-carboxamide,
    N - (5-tetrazolyl) -l-KeTo-lH S, 7-diisopropyl thiazole, 2-a pyrimidine 2-carboxamide |
    H - (5-tetrazolyl) -1-keto-1H-6propylthiazole 3,2-a pyr imidine-2-carboxamide /.
    M - (5-tetrazolyl)., .- 1-keto-1I-6-isopropyl thiazole 3,2-a pyrimidine-2-g carboxamide I H - (5-tetrazolyl} -1-keto-1H-6-pentylthiazole 3 , 2-a pyrimidine-2-carboxamide -.
    vN - (5-tetrazole | -1-keto-1H-6-phen lg dicopententhiazole 3,2-pyrimidine 2-carboxamide;
    N- (5-tetrazolyl) -1-keto-1H-6.8 dimethylcyclohexentiol ol t3 / 2-atJ pyrimidine-2-carboxamide; N - (5-tyrazolyl) -1-keto-1H-8, methylcyclooctenthiazole DZ / Z-a, and pyrimidine-2 carboxamide and K- (5-; etraeo / lil) -1-keto-1H-6,8,8 . Trimethylcyclo pentenmethylthiazole 3,2-a pyrimidine 2-carboxamide.
    PRI me R 86. Capsules.
    I get the capsules by mixing the barely dududs of the ingredients, .h ::
    Calcium carbonate U & P 17.6
    Calcium Phosphate 18.8
    Magnesium Trisilicate UsP 5.2
    Lactose USP 5.2
    Potato
    starch. 5.2. Magnesium stearate A 0.8
    Magnesium Stearate. 0.35 and adding sodium V-α-tetrazolyl 1 -1-keto-1H-cyclohexentiazole t3,2-a pyrimidine-2-carboxamide trihydrate in an amount sufficient to provide capsules containing 10.25 and 50 mg of active ingredient per capsule (weights are equivalent to non-solvated, unsalted form). Compositions can be molded into standard 350 mg gelatin capsules.
    Capsules containing 2.0 and 6.0 mg of the active ingredient are prepared in a similar manner, with a total weight of 300 mg of the following mixtures per capsule, MG- :.
    Medicine 2.0 6.0
    N-Methyleluk. min 18,0 18,0
    Lactose,
    anhydrous 251.20. 237.20
    Wheat
    starch
    anhydrous 20.0 30.0
    . Talc. 8.80 8.80
    Example 87. BASIC tablets are prepared by mixing the following ingredients in a proportion by weight:
    Sucrose U5P 80.3
    Starch Tapioca 13.2
    Magnesium Stearate 6.5
    Sodium N- {5-tetrazolyl) -1-keto-1H-cyclohexenthiazole: 3,2-a pyrimidine-2-carboxamide trihydrate is added to this base / admixed to give tablets containing 20,100 and 250 mg of active ingredient per tablet. The compositions are pressed in standard ways. For tablets of small potency (e.g., 1.2.5 mg), a lower ratio of active and inert ingredient is used.
    Example 88. Solutions.
    Sodium N (5-tetrazolyl}. 1-keto-1H-cyclohexentiazole Pz, 2-a ririmidine-2-carboxesDa solutions are prepared as follows.
    Active Ingre-.
    dient6.04-g (7.49 sodium salt of trihydrate)
    Magnesium chloride
    hexahydrate 12.36 g
    Propylene gly-.
    Kohl376,00 g
    Distilled water 103 ml
    The resulting solution has an active ingredient concentration of 10 mg / ml and is suitable for parenteral and especially (benign intramuscular administration).
    Example 89. Aerosol suspensions, f
    For use as an antiallergic agent, a mixture of sodium N g (5-tetrazolyl) -1 keto-1H-cyclohexentiazole 3,2-a3 pyrimidine-2-carboxamide and other ingredients of composition a) is ground to a particle size of 1-5 microns in a roller mill . The resulting suspension is then placed in a container containing a valve, and the propellant (c) is injected under pressure through the valve valve pressure to 2.52, 9 atm at.
    Suspension A %: (a) Antiallergic agent (eq., unsolvated and not salt) 0.25 Isopropyl myristate 0.10. Ethanol 26.40
    (c) 60-40% mixture of 1,2 dichlorotetrafluoroethane-1 - chloropentafluoroethane 73, 25
    Suspension B, (a) | non-allergic agent (equivalent to unsolvated, not salt) 0.25 Ethanol 26.50
    (c) 60-40% mixture of 1,2 dichlorotetrafluoroan-1-chloropentafluoroethane 73.25 Suspension C (a) Antiallergic-. cue agent (equiv. unsolvated, not salt) 2.0 Ethanol 26.50
    (c) 60-40% of a mixture of 1,2 dichlorotetraf oretan-1-chloropenta--
    fluoroethane71.50
     Conducted .biological kssh-Gani data compounds.
    The antiallergic property of the compounds is assessed by passive skin anaphylaxin assay (PCA). The PCA test method used to evaluate compounds demonstrates excellent correlation between the activity of the compounds in the sjTOM test and their efficacy in the treatment of allergic asthma. The ability of agents to howl ps leuco X-ray PCA reactions is measured by the example of male Chile rat: 170-210 g. 170-210 g. In tests using reagent anti-serum enriched with 3gE antibodies and imimmune anti-serum that is found in antibodies of albumin of chicken egg, albumin in 48g Before antigenic infection, the reaginary antiserum is injected intradermally into the shaved skin of no1 rats: 5 h before infection, the hyperimmune antiserum is injected in the same way. In the urine, 60 µg of histamine dihydrochloride and 0.5 µg of serotonin criticaline sulfate are injected intradermally before antigenic infection, as a test for antihistamine, antiserotonin, and nonspecific types of blockade. Unity or saline is administered intravenously | and immediately thereafter, 5 mg of albumin of the egg and 2.5 mg of Eshb B2 B2 are injected into the saline. In the case of oral administration, the dye Evans .BEue and the albumin of the egg are given 5 minutes after the administration of the medicine. After 30 minutes, the animals are asphyxiated with chloroform, the skin is removed and visually examined. The effectiveness of each injection is evaluated by the diameter obtained at the injection site in mm and graduated with BO, 5, 3. or 4 is proportionally intense. te coloring dye. The multiple points for a given injection site are summarized for each group of five animals and compared with the control group treated with saline. The difference is expressed as a percentage of blockade due to the applied compounds. These compounds are tested for antiallergic activity in this way and the resulting activity is expressed as degree (%) of protection. Compounds of formula-1 (amides) and acido, R means hydrogen. Tested for antiallergic activity by PCA test, are shown in Table . and 2. The efficacy of the products as anti-ulcer agents is determined by testing the rats for limited cooling. In the 5-Test for feeding female rats (Charges RV # CD Siva in weighing 70-140 it, the drug or vehicle (control animals) was administered intraperitally (in a saline solution containing 1% carroxymethylcellulose and 0, 80) or oral (in water) for 3 hours before light anesthesia with ether, and in an inert position to separate plexiglas plates in an inert position. After the termination of the anesthesia, the fixed animals are placed in the refrigerator. at l0-12 ° C and after .3 h the animals are killed. The abdominal cavity of each rat is opened, they are set aside, and the stomach rat is pumped into the stomach with saline using an oral tube, the esophagus is laid aside and the stomach is cut out. The stomachs are placed in a 0.4% formaldehyde solution for 30 seconds to cure the outer layers and facilitate testing. Then each stomach is resolved along the greatest bend, part of the gland ((pancreas) is evaluated for damage. The number of gastritic erosions, their stiffness and stomachs are recorded. Total TecTMann-Whftnei) jv Peoxon is used to compare the average number of gastritic erosions in the control group with the average number gastritis erosions in each group treated with medication to determine the statistical difference. In this trial, .N - (5-tetrazolyl) thiazole 3,2-a pyrim idin-2-carbC) Xamide - (compound of formula T) showed extremely high activity. As shown below. Alternatively, the efficacy of the products as anti-ulcer agents is determined by testing ethanol-induced urine in rats. In this trial, male rats that fasted overnight were given medication (5 mg / kg) or water orally 50 minutes before oral dosing of absolute ethanol (1.0 ml). After the enchantment after ethanol contamination, the animals (group 3) are killed and their stomachs are analyzed by the presence of damage. All drugs are introduced into the solution in dilute sodium hydroxide. After opening the abdominal region, the clamped hemostat is placed on the pylorus, ё ml of a 4% formaldehyde solution is injected into the stomach with a gastritis tube, and the second clamped hemostat is used to close the esophagus. The stomach is removed, opened along the largest bend, and checked for disease by the ulcer. The numerical score used to quantify the damage caused by the introduction of ethanol is given below. ... Estimation of link scars Scars. Definition 1 - Normal stomach 2 Damage of small size 3 Damage, 2 or several, point damage may be present 4 Damage 2 / point damage may be present 5 Damage from hemorrhage For each group of animals, the infection index is calculated as follows. Index of stars; (the sum of the group's hems) x (the sum of the number of stars in the group) c (the share of the group, which has any degree of weight) .. -. .. The percent inhibition of infection is calculated as follows:% inhibition 100x (reference index of infection); (index of ulcers or drug treatment) + (index of ulcers control).
    The activity in these tests of various 5-tetrazolyl amides is represented by-in the table. Table 4 presents the activity of various acids .. c
    Most preferred is the compound formult 1, where R, IC-2 / taken together, means butylene M - (5-tetrazoyl) -1-oxo-1H-cyclohexoithiazole 3,2-aZ pyrimidine-2-carbox-fO MID, which alternatively may be referred to as 5,6,7,8 - tetrahydro-M-, (5-tetrazolyl}. - 4-oxo-4-H-pyrimyl (2,1-in) benzothiazole-3-carboxamide.
    .In addition to its oral anti-15 allergic activity, shown In; Table 1f the compound exhibits a grand va r Activity in the range of 0.03–1.0 mg / kg in the third of the XRD, and is 26 times more potent than Opt1aV in this application (as noted, jniaC exhibits activity in oral administration). The compound also blocks changes in skin permeability caused by the Tf K mediator in 25 passive cutaneous anaphylaxis (PCA), but does not interfere with the change in permeability caused by the intrdamal injection of histamine exogenus and serotonin. The absence of anti-histamine and anti-serotin activity shows that the anti-allergic mechanism is a mechanism to inhibit the release of a mediator, and not antagonism to the receptor of the media. ./. .,. ... .., .. 35
    . The compound inhibits dextran-induced release of histamine in
    brKHINU cavity of the rat. His EDdd
    0.33 mcc / kg, and the dose of 3n144 μg / kg, which indicates a high potency 40 of the first. An increase in histamine plasma., Caused by antigenic infection of rats, is passively sensitive to anti-serum, which is absorbed (on the active system} 1 static anaphylaxis. Protects d with the compound of formula 1). Its AU is 28 mcg / kg, i.e. it is 13 times more: effective. ,;
    PigsOp1 peo treated with a dose of 30 mg / kg of the compound. do not show protection against the bronchoconstrictive effects of the inhaled histaman. In the concentration area 10. before . the compound does not give an antagonism of the spasms (4 of the isolated intestine. |. of the guinean pig, induced by acetylcholine, histamine or slow response of the anaphylactic drug substance (5RSA), and the synthesis and secretion of SQ5 in the selected K1ZH1SY monocytes: stimulated with ionophore, not ing - v. .
    In addition to its potential activity in the ethanol-hydrated host in rats (see Table 3), the compound is potent in the quenched D5 method.
    limited cooling (indicated in detail), where it provides protection when administered orally in the region of 3-100 µg / kg. The compound also is de-active against aspirin-active actives, 100 mg / kg, where the effect is achieved in a dose area of 101000 µg / kg with an ED50 of SO of mKG / kg. Compound 3 is also active, but in the phenylbutazone gastritis ulcer model, where 200 µg / kg is oral.
    Although the compound is a highly potent anti-stranger agent, it does not affect the pentagastrin-stimulated acid release in dogs H Heijenha (5 mg / kg), therefore, differs from antisecretory prostaplandins and from cimetidine and atropine.
    In addition, the compound exhibits diuretic activity: when administered orally, the volume of urine increases with the use of doses in the region of 0.3-5 mg / kg. The maximum effect was a double increase in the volume of output, the concentration in sodium urine and K | 1 or amp 1L unchanged, but an increase in excretion was observed due to an increase in the volume of urine output. sodium and potassium. These characteristics indicate that the dose range for diuretic activity is significantly higher than the dose range for anti-ulcerative activity and lower than that for anti-allergic activity (l-lO mg / kg). .
    Some were treated for 2.4 hours and orally treated with this compound at doses of 10.30 or 100 mg / kg, and did not show any toxic effects. changes in blood glucose level. The effect of the compound on glucose Itolerance was evaluated in rats at doses of 10.30 schGy 100 mg / kg simultaneously with a GLUCOSE of 1 g / kg. Dose-dependent improvement in glucose was observed. tolerance. This effect may be due to a delay in glucose absorption due to the potential for effecting gastritis secretion. The compound has a slight antholergic effect. In aHe-treated dogs, cumulative doses of 5–15 mg / kg caused transient hypotension and various changes in cardiac activity. Blood pressure rise from epinephrine and bilateral carotid obstruction were weak. Transient cardio-muscular changes occurred only with cumulative intravenous doses up to 9, oh, 5–15 times the maximum effect. The main dose when used intravenously for antiallergic activity and much higher than the oral dose required for anti-ulcerative activity. In tolerant studies, the compound was given orally to dogs for seven days at doses of 50.150 and 300 mg / kg. At all doses, emesis was observed, which is usually inherent in dogs, but subsequent studies {showed that the emetic effect can be eliminated if the medication is administered with capsules after, and not before, the adoption of large pathological changes and microscopic evaluation no changes were noted in the liver, kidney, heart, and lung. In other studies, serum enzyme levels in dogs administered intravenous seeding for five days with consecutive daily doses of 1,310, 3, and 3 mg / kg remained normal. The rats were orally administered the compound at doses of 50.150 and 300 mg / kg per day for 10 days. No pathological changes were observed in the macro- and microscopic assessment of the liver, heart and lung kidneys. With the exception of eating serum glutamine. pyruvine transaminase observed at the highest doses, there were no changes in clinical chemistry. The compound was tested on mice with dosages of 100,300 and 1000 mg / kg (no lethal symptoms were observed under the skin and it was concluded that the drug was tolerant when given subcutaneously with id 5 mg / kg. At a dose of 32 mg / kg administered subcutaneously, no interactions were observed with a variety of active drugs. A single oral dose of the compound was administered (40 mg / kg) to a group of mice that were euthanized 6.12 and 24 h after ingestion. Microscopic oral activity%
    46
    43
    45
    25 94
    38 57 protection, amides of Formula I in the PCA test assessed the bone marrow and showed no chromosomal abnormalities. The same conclusions were made when mice were treated for five consecutive days with doses of 20 mg / kg. In vHro studies in which the compound was incubated on human lymphocytes at concentrations of 1000, 100, 10, or O µg / ml did not show any significant chromosomal damage induced by the compound. The compound in test 11U (1) did not produce mutations, therefore, it has no obvious mutagenic potencies. In the PCA test on rat, the ratio of the effectiveness of oral and intravenous doses of compound g is comparable due to good oral absorption. This is confirmed by observations of plasma concentrations 3- 7 µg / ml 1 hour after oral administration of the compound at doses of 50-300 mg / kg. In dogs, the drug is easily absorbed. After oral administration of the suspension or capsules, plasma concentrations of 9-26 µg / ml are taken after oral administration doses of 50-300 mg / kg. In both samples Consider the plasmids of the corresponding carboxylic acid metabolite (qo corresponding compound of the formula.} Comparable with the levels of the compound, this compound is identified as an important metabolite of the compound.. After the ninth daily dose, the levels of the initial drug and the metabolite are 2-4 times higher than after the initial dose, which confirms the possibility of maintaining the therapeutic level of the drug for an extended period. The compound in solid form or mixed with standard inert ingredients used in oral administration or in solution, shows good stability. facilitates the production of stable formations of this compound for clinical use. T a b l and c a
    Continued table. 1 ly
    PGP
     Inhibition,%
    CHj 96
    Ghj .59
    H 72
    CjHj 10
    N.§6
     45
    97.81 Oral activity (% inhibition (formula jl) in the ethanol-induced R assay;) I L
    . CHj27
    BUT
    , CgHs48
     CH2H548
    (CH ,, 421 45104262046 praline activity (% inhibition at a dose of 5 mg / kg) amide (form .G) in rats tested with ethanol-induced ulcers. Table 3 Table4 at a dose of 5 mg / kg) acids ulcers in rats. {Inhibition,% 11
    权利要求:
    Claims (2)
    [1]
    1. Schroeder E. and Lyubke K. M ", Mir, 1967, p. 116 ..
    Peptide ..
    equivalent to K, And ’. -carbonyldiimidazole as a dehydration-binding agent at 20-100 ° C in dimethylformamide, followed by isolation of the target product in free form or in the form of a salt.
    [2]
    , 2. A method of producing substituted Y- (5-tetrazolyl) -1-ket'o-1H-thiazole £ 3, 2-a] pyrimidine-2-carboxamides of the formula 1 o ^ c-nh- <II tf-N I n where each of Ry and R 2 is hydrogen or Su-Suily alkyl Ry and Iz taken together are alkylene C ^ - C ^ or phenylalkylene with 9 - C n , provided that the ring system thus formed is 5-8- the member, or their salts, are distinguished by the fact that the compound of the formula P, each of Ry and R 2 means a water or alkyl С-С $ or Ry and РБ 2> together, mean phenylalkylene Cg-Сc under the conditions, thus formed ring characterized in that Inonu -formulae R alkyl having - § where the RHODs are or that the target system is 5-8 membered or their salts c_я р> е-ак where the values Ry and β 2 are indicated above, they are reacted with the molar equivalent of the acid chloride of formula Ш '
    Ms / ® H o where is J - alkyl, benzyl, phenyl, in. in the absence of T equivalent of triethylamine at 0- + 5 ° C. in methyl chloride and the compounds obtained. Formulas IV '
    0 = C-0H ^ de values # y'th R 2 indicated above are introduced into interaction with one molar equivalent of 5-aminotetrazole in the presence of one molar where R, R | and Rj have the indicated values, are reacted with one equivalent of 5-aminotetrazole in dimethylacetamide at room temperature, followed by isolation of the desired product in free form! or in the form of salt.
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    EP0284017B1|1991-09-11|4-|-thiazole-derivatives with anti-allergic, anti-anaphylactic and anti-arthritic activity and compositions containing them
    EP0159707B1|1990-01-24|Triazolopyrimidine derivatives
    FI71158B|1986-08-14|PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC 1-XO-1H-THIAZOLO / 3,2-A / PYRIMIDINE-2-CARBOXYL SYROR
    同族专利:
    公开号 | 公开日
    AU520995B2|1982-03-11|
    IL61535D0|1980-12-31|
    SE8008189L|1981-05-24|
    FI67706B|1985-01-31|
    FR2470132A1|1981-05-29|
    JPS5687586A|1981-07-16|
    NL182565C|1988-04-05|
    PT72090B|1981-09-29|
    NL182565B|1987-11-02|
    DK151811C|1988-06-06|
    YU41953B|1988-02-29|
    ATA570780A|1985-12-15|
    DE3043979A1|1981-09-03|
    IE50404B1|1986-04-16|
    NO803521L|1981-05-25|
    CH649299A5|1985-05-15|
    CS782080A2|1985-06-13|
    AR231296A1|1984-10-31|
    GB2063862B|1983-06-22|
    ZA807293B|1981-12-30|
    HU179091B|1982-08-28|
    GB2063862A|1981-06-10|
    SE448732B|1987-03-16|
    DK413180A|1981-05-24|
    FI67706C|1985-05-10|
    IT8026176D0|1980-11-21|
    PT72090A|1980-12-01|
    DE3043979C2|1986-08-21|
    FR2470132B1|1983-07-29|
    FI803628L|1981-05-24|
    DK151811B|1988-01-04|
    ES8203363A1|1982-04-01|
    IN154926B|1984-12-22|
    CA1143731A|1983-03-29|
    GT198066458A|1982-05-15|
    KR830004322A|1983-07-09|
    IT1209373B|1989-07-16|
    IE802418L|1981-05-23|
    ES497066A0|1982-04-01|
    PH16666A|1983-12-13|
    AT380883B|1986-07-25|
    CS241476B2|1986-03-13|
    PL228008A1|1981-12-11|
    JPS617432B2|1986-03-06|
    DE3050491C2|1985-10-10|
    IL61535A|1984-06-29|
    LU82950A1|1981-06-04|
    AR228859A1|1983-04-29|
    EG14929A|1989-01-30|
    AU6459580A|1981-05-28|
    YU295080A|1983-06-30|
    NZ195596A|1984-05-31|
    NL8006362A|1981-06-16|
    GR72132B|1983-09-19|
    PL132354B1|1985-02-28|
    DD154608A5|1982-04-07|
    BE886319A|1981-05-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1331059A|1971-04-19|1973-09-19|Lilly Industries Ltd|Pyrimidotriazinone compounds|
    US4041163A|1976-03-29|1977-08-09|Pfizer Inc.|N--4-oxo-4H-pyrimidobenzothiazole-3-carboxamide antiallergy agents|
    DE2810863A1|1978-03-13|1979-09-27|Boehringer Mannheim Gmbh|1-OXO-1H-PYRIMIDO ANGLE CLAMP ON 6.1-B ANGLE CLAMP ON BENZTHIAZOLE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF|
    US4223031A|1978-05-05|1980-09-16|Mead Johnson & Company|Azolopyrimidinones|GB8300728D0|1983-01-12|1983-02-16|Erba Farmitalia|Substituted carboxy-thiazolo / 3 2 - a / pyrimidine derivatives|
    US4457932A|1983-07-22|1984-07-03|Bristol-Myers Company|Anti-ulcer agents|
    GB8422916D0|1984-09-11|1984-10-17|May & Baker Ltd|Compositions of matter|
    JP2690742B2|1987-03-30|1997-12-17|第一製薬株式会社|Heterocyclic amine derivative|
    EP0335442B1|1988-03-28|1996-05-15|Janssen Pharmaceutica N.V.|Agents for preserving or restoring the soundness of the skin|
    TWI500623B|2009-10-13|2015-09-21|Torrent Pharmaceuticals Ltd|Novel fused thiazolo and oxazolo pyrimidinones|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US9663179A| true| 1979-11-23|1979-11-23|
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