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    • 专利摘要:
    Compounds of the formula: <IMAGE> or pharmaceutically acceptable acid addition or quaternary ammonium salts thereof wherein R2 is C1 to C6 alkyl: R3 is C1 to C6 alkyl; R4 is a single electron pair, hydrogen or lower alkyl; and the dotted lines indicate saturated or unsaturated bonds, are disclosed with analgesic properties.
    公开号:SU906378A3
    申请号:SU782652353
    申请日:1978-08-18
    公开日:1982-02-15
    发明作者:Кнолл Йожеф；Месарош Золтан；Хермец Иштван；Бернат Габор；Фюлеп Ференц；Вираг Шандор；Надь Габор；Сентмиклоши Петер
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    that R and K. denote hydrogen, and another denotes a 7- or 9-methyl group, and R denotes hydrogen, then R and R cannot simultaneously denote a methyl group, or if R2 denotes a methyl group, R 5 is an ethyl group, RA is hydrogen , and one of the substituents R and R, j is hydrogen, the other of the substituents R and K cannot denote a bromine atom, or R, R, R denote water, then R 1 cannot denote this group, or if R and R denote 6- or 8-methyl group, Ro can not denote a methyl group, or their salts, derived 2-aminopyridine form mul; or its acid salt with acid and 1 have the meanings indicated for these symbols) are introduced at 20–200 ° C, the boiling of the reaction mass with the compound CiOOBs, where R2 takes the meanings indicated for these symbols, R is a lower alkyl radical, with the proviso that, in the case of obtaining 2,3-dcmethyl-; 2-methyl-3-ethyl2, 3,7-trimethyl-; 2-methyl-3-ethyl-7-bromo- and 2,6,8-trimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine, the reaction is carried out in a mixture of phosphorus oxychloride and polyphosphoric acids and, if desired, a compound of the formula. ; W, where R, R, 2. Accept the values specified for these symbols are subjected to restoration. The desired products are isolated in free state or as salts. Preferably, 0.51.5 moles of the compound of formula III are used per mole of the compound of formula II. The interaction between the compounds corresponding to formulas II and III is carried out in the presence of an acidic condensing agent. As an acidic condensing agent, a mixture of polyphosphoric acid and phosphorus oxychloride is used. Preferably, 2-5 moles of phosphorus oxychloride and 1-150 g of polyphosphoric acid are used per 1 mole of the compound of formula II g. The process is carried out at 80-160 ° C. The reaction mixture is decomposed with lower alcohol, water or alkali. It is preferable to use polyphosphoric acid as the acid condensing agent. Polyphosphoric acid is used in an amount of 200-2000% per 1 mol of the compound of formula II and the process is carried out at 60-180 ° C. The reaction50 is also carried out using hydrochloric acid, acetic acid, or propionic acid as an acidic condensing agent. The reduction of compounds of formula IV is carried out preferably by catalytic hydrogenation, using Rene nickel, palladium, rhodium, platinum or platinum oxide as a catalyst, or by reduction with a complex metal hydride. Sodium borohydride, sodium cyanoborohydride or sodium bis (ethoxymethoxy) aluminum hydride is used as a complex hydride / metal. The reaction time depends on the temperature and reaction components. In most cases, the reaction time of the reaction mixture is 0.5-10 hours. The treatment of the reaction mixture is carried out by known methods. The treatment can be carried out in such a way that the reaction mixture is diluted with water, neutralized with alkali and the compound of formula IV is isolated in the form of the free base. Halogenated hydrocarbons (e.g., chloroform, x-benzene) are preferably used as the solvent. 5 If hapogenic hydrogen is used as an acidic condensing agent, then hydrohalides (compounds of the formula I) can be obtained first, which are then reacted with a compound of formula III in the presence of an aromatic tertiary nitrogen compound used as a solvent. The compounds of formula 1 obtained in this way may be subjected to reduction. During the catalytic hydrogenation of a compound of the Research Institute of Formula IV in the presence of Rene, Palladium or Rhodium nickel, a tetrahydropyrido (1,2-a) pyrimidine derivative is formed, corresponding to the formula ГRj and R take the values <R, R. If platinum or platinum oxide is used as a catalyst, then the octahydropyrido (1,2-a) pyrimidine derivative is obtained, which corresponds to the formula R and is taken as R, hc. , rh 2 and values for these characters. Derivatives of tetrahydroxy shrido (1,2-a) pyrimidine corresponding to formula V can be converted into derivatives octahydropide (1,2-a) pyrimidine as a result of catalytic hydrogenation in the presence of platinum or platinum oxide, corresponding to formula VI. Hydrogenation can be carried out at atmospheric or elevated pressure. As a solvent, water, alcohols (for example, methyl, ethyl alcohols, etc.), organic acids (for example acetic acid), ketones (for example, acetone, methylethyl) can be used. ketone), esters (for example, ethyl acetate, or mixtures of these substances. 78 Compounds of formula I can be converted to salts obtained using pharmaceutically acceptable organic or inorganic acids (e.g., hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, acetates, formates, maleates, citrates, lactates, and t, d.) The preparation of salts is carried out by known methods, for example, through the interaction of com; formula t with an appropriate acid (taken in approximately equimolar amount) in an organic solvent medium. The compounds of formula I can be converted into quaternary salts by reacting with quaternizing agents. For this purpose, all common quaternizing agents can be used, for example, alkyl halides (methyl bromide, ethyl bromide, ethyl iodide), dialkyl sulfates (dimethyl sulfate, diethyl sulfate), sulfonates (benzenesulfonic acid, para-toluenesulfonic acid,), and I also use the same code, I also use the same code, I also use the same code, I also use the same code, I also use the same code, I also use the same code, I also use the same code, I also use the same code I, I also use my cell programs, I, I will use Iaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa program Company, you can use any other Solvents commonly used in reactions of this type can be used as the reaction medium, for example, aromatic hydrocarbons (benzene, toluene), halogenated hydrocarbons (chloroform, chlorobenzene), ketones (acetone), alknpg nitriles (acetonitrile), nitro-napanes (for example, nitromethane), formamides (dimethylformamide), dimethyl sulfoxide, phosphoric acid hexametric triamide, etc. or mixtures of these solvents. Quaternary salts can be reduced. This interaction is carried out in known ways. Catalytic hydrogenation can be used or complex metal hydrides can be used, for example sodium borohydride, sodium cyanoborohydride, bis (ethoxymethoxy) sodium aluminum hydride. The reaction is carried out in such a way that the reduction is carried out using a complex metal hydride in a solvent depending on the reducing agent, for example, in water, aliphatic alcohol, an aromatic hydrocarbon, etc. These new compounds of formula I
    or their salts or their Quaternary suns have an analgesic effect on rats and dogs and are much superior to this non-probing action. In addition, no symptoms and disorders of the central nervous system are observed that occur in rats with large doses of probon and in dogs with low doses of lobone. It is a fact that the compounds of the form L1 I, in particular 2, b-dimethyl-3, ethyl 4-oxo-4H pyrido (l, 2-a) pyrimidine, its salts, and also quaternary} more cojm, strongly inhibit the action of the probe on the central The nervous system, t, e, has an affinity for the receptors, on which the probron exerts its action, but does not itself possess a specific activity, supports the hypothesis that receptors selectively sensitive to pyrido (l, 2-a) pyrimidines are loaded in the central nervous system. Another proof of this connection is the complete non-toxicity of the new compounds of formula I for Beagle dogs. Even at doses of 1 g / kg, the compound 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido {1,2-a) pyrimidine does not cause toxic changes and undesirable effects. However, this substance already in doses of less than 50 mg / kg inhibits the effect of a double lethal dose (600 mg / kg) of probon. The dogs treated in the ordered manner show complete painlessness without detecting the slightest signs of ataxia and incoordination. Animals do not die. All this means that the spectrum of action of the new compounds of formula 1 is significantly different from the spectrum of the action of the probe. From a therapeutic point of view, these compounds are more preferable than probon. They are a much more active anesthetic that does not affect the central nervous system. The preparations may contain conventional carriers (for example, talc, magnesium stearate, water, polyethylene glycol, etc.). Preparations may also contain conventional additives and auxiliary substances (for example, emulsifiers, destructive substances, buffering substances, etc.). Preparations are obtained by known methods, usually in a pharmaceutical program.
    The proposed pharmaceutical preparations, in addition to the compounds of the formula, may contain as biologically active substances other compounds with pharmaceutical activity. For this purpose, for example, other painkillers (for example, morphine) benzomorfan derivatives (for example, phenazocine, pentazocine), phenylpiperidine derivatives (for example, pethidine, nisentyl) can be used.
    The daily dose of the biologically active substance can vary within wide limits, with the dose in all cases depending on the existing conditions and needs and prescriptions of the physician. For oral administration, the daily dose of the biologically active substance is approximately 1-300 mg. Parenterally administered daily dosage of approximately 0.1 mg mg. However, the generic doses can be both above and below the indicated boundaries.
    The compounds of the formula D have valuable analgesic properties and the enhancing effect of morphine properties and can be used as analgesics acting according to a new type of mechanism. Table 1 shows the effect of the compounds of the formula I that increase the activity of morphism.
    In tab. 2 shows the pronounced properties of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine hydrochloride (hereinafter compound A, in comparison with the similar chemical structure of 2-methyl-3- ethy-1-4-oxo-4H-pyrido (I, 2-a) pyrimidine (hereinafter compound c) and hydrochloride 2,6,8-trimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a a) pyrimidine (hereinafter compound c). The experiments were carried out in accordance with a hot plate test and an algolytic test. The results obtained in the tests are presented in Table 2.
    In tab. 3 shows other comparative experiments between compounds A, B and C,
    The given numerical data clearly show the properties of compound A, This derivative significantly pre, rising compounds with similar chemical structure, as well as actively in the algolytic test. Comparative data of the analgesic properties of the compound of formula 1 and the known probe are given in table. 4. The starting materials used, corresponding to formulas II and III, are two known compounds. Example I. 10.8 g of 2-amino-6-methylpyridine and 14.4 g of ethyl 2-methyl acetate acetic acid are reacted with another in a mixture of 46 phosphorus oxychloride and 7.0 g of polyphosphoric acid, at 100 From 3 h. The intensive first release of chlorine of that hydrogen gradually weakens and then stops. The reaction mixture is decomposed with 100 ml of ethyl alcohol at a temperature in the range of 70-80 ° C, and then kept overnight in a refrigerator, in order to carry out crystallization. The crystallized product precipitated in the precipitate is washed with ethyl alcohol and dried. As a result, 20.2 g (90%) of 2,3,6-trimethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine hydrochloride are obtained. After recrystallization from a mixture of ethyl alcohol, GO alcohol and diethyl ether, a product with m.p. 215-220 C. Calculated,%: C 58.81; H 5.83, N 12.47, - C1 15.78. C, 2. Found,%: C 58.41; H 5.83, N 12.28; C1 15.62. If 2-H-propyl acetoacetic acid ethyl ester is used as the starting material instead of 2-methyl acetoacetic acid ethyl ester, then 2,6-dimethyl-3-H-propyl-4-oxo-4H-pyrido hydrochloride (I, 2-a) pyrimidine, which has so pl. 180-185 s. Calculated,%: C 61.78, H 6.78, N 11.08, C1 14.03. Q ,,. HCl Found,%: C 61.52, H 6.98, N 11.03, C1 13 95 If 2-M-butylacetoacetic acid ethyl ester is used as the starting material instead of ethyl 2-methyl acetoacetic acid, then hydrochloride 2,6-dimethyl-3-H-butyl-4-oxo-4H-pyrido (1,2- a) pyrimidine, with tl 216-217s. Calculated,%: C 63.03; H 7, N 10.50; C1 13.28,. HCI Found:%: 62.65; H 6.96; N 10.68; C1 13.46. If, instead of ethyl ester of 2-methylacetoacetic acid, ethylether of 2-decyl acetoacetic acid is used as the starting material, then 2,6-dimethyl-3-H-decyl-4-oxr 4H-pyrido hydrochloride (, 2-a) is obtained pyrimidine, so pl. 187 C. Calculated,%: C 68.45; H 8.90v N, 7.98; C1 10.10. Cr ,,, O.H.S. Found;%: C 68.35; H 8.72; N 7.92, C1 10.15. If 2-benzylacetoacetic acid ethyl ester is used as the starting material instead of 2-methyl acetoacetic acid ethyl ester, 2,6-dimethyl-3-benzyl-4-oxo-4H-pyrido (1,2-a) pyrimidine hydrochloride is obtained, m.p. 18619IC. Calculated,%: C 68, B9, H 5.70, 9.31, C1 11.79. 0.11, Found,%: C 68.25, H 6.13; N 9.48; C1 11.06. If 2-isobutyl acetoacetic acid ethyl ester is used as the starting material instead of 2-methylacetoacetic acid ethyl ester, 2,6-dimethyl-3-isobutyl-4-oxo-4H-pyrido (1,2-a) hydrochloride is obtained pyrimidine, so pl. 178-185 C, Calculated,%: C 63.03, H 7.17; N 10.50; C1 13.28. g, 4H j 20-nc Found,%: C 62.65- H, 6.80; N Yu, 68; C1 13.46. If instead of ethyl ester of 2-methylacetoacetic acid as the starting material | As 2-methyl-3-oxo-vale {janoic acid ethyl ester is used, 3,6-dimeish-2-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine hydrochloride is obtained, m.p. 202 0. Calculated,%: C 60.38; H 6.33; N il, 73i C1 14.85, C, Im.NS1 Found:% 60.11; H 6.70; N, 11.68; C1 14.56. P If 2-aminoshidine is used as the amino component and 2-ethyl acetoacetic acid ethyl ester is used as the oxo compound, then 2-methyl 3-ethyl-4-axo-4H-pyrido (1, 2-a) pyrimidine hydrochloride is obtained. with t, pl. 185 190С, Calculated,%: С 58.81; H 5.83; N 12.47; C1 15.78. C, .O.-HCl; Found: C 58.41, H 5.83, N 12.62; C1 15.65. If 2-aminopyridine is used as the amino component, and 2 INprrpidacetoacetic ester is used as the oxo compound; acid, then get the hydrochloride of 2-methyl-Z-And-propyl-4-oxo 4H-pyrido (1,2-a) pyrimidine, so pl. 210-215 C. Rassvdtano,%: C 60.38-, H 6.33, N 11.73; C1, 14.85; Found,%: C, 60.45; H 6.20; N 11.32; C1 14.80. If 2-aminopyridine is used as the amino component and 2-n-butylacetoacetic acid ethyl ester as the oxo compound, 2-methyl-3-H-butyl-4-oxo-4H-pyrido hydrochloride (1,2-pyrimidine, t 220-222C, Calculated,%: C, 61.78; H, 6.78; N, 11.08; C1, 14.08; C, Found,%: C, 61.89; And 6.80 / N J1, 00; C1 13.95. If 2-aminopyridine is used as the amino component, and 2-I-decylacetoacetic acid ethyl ester is used as the oxo compound, 2-methyl-3-H-d-cycl-4-oxo-hydrochloride is obtained. 4H pyrido (1,2-a) pyrim dyne, mp 200-202 0. Calculated,%: C 67.74; H 8.68; N 8.3i; C1 10.52, .HCl Found, %: C 67.81, H 8.75, N 8.19, - C1 10.40. If 2-amiiopyridine is used as the amino component, and 2-benzyl acetoacetate acid ethyl ester as the oxo compound, hydrochloride is obtained 2-methyl-3-benzyl-4-oxo-4H-pyrido (1,) pyrimidines, mp 180-190 C. Calculated.,%: C 67.02, And 5.27 / N 9.77 ; C1 12.36, C;, fcH, N O-HC1 8 Found,%: C 67.14, AND 5.32; 9.90; C1 11.98. If 2-aminopyridine is used as the amino component, and 2- (4-chlorophenyl (-methyl-acetoacetic acid ethyl ester) is used as the oxo-compound, then 2-methyl-3 -. (4-chlorophenyl (-methyl ) -4-OXO-4H-PIRIDO (l, 2-a) pyrimidine, mp 175-180 ° C. Calculated,%: C 67.25; H 4.94, 9.80; C1 22.08 , QgH iN OCI-HCl Found,%: C 67.01, H 5.03, 9.86; C1 22.25. Example 2. 10.8 2-amino-b-methylpyridine and 15.8 g of ethyl ester2- ethylacetate acetic acid is reacted with each other in a mixture consisting of 46 g of phosphorus oxychloride and 7 g of polyphosphoric acid and hydrochloric acid, for 3 hours and 120-130 ° C. The division of hydrogen chloride is carried out, which is initially intensive, slowly slowed down and then stopped. The reaction mixture is heated at 70-80 ° C by 100 ml of ethyl alcohol and kept in a refrigerator overnight for crystallization purposes.) The crystalline product which has precipitated out is filtered off, washed with ethyl alcohol and dried. The result is 22 g (92%) of hydrochloride. 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine. After recrystallization from a mixture of ethyl alcohol and diethyl ether, the product is calculated,%: C 60.38; H 6.83; 11.74; C1 14.85. Found,%: C 60.44 - ,. H 6.40; 11.90; C1 14.61. Example 3. 12.8 g of 2-amino-5-pyurdyridine and 15.8 g of ethyl 2-ethylacetoacetic acid are reacted with each other in a mixture consisting of 46 g of chloroxide and phosphorus and 7 g of polyphosphoric acid, Moreover, the reaction is carried out for 3 hours at 120-130 0. The release of hydrogen chloride, which was intense at first, gradually slows down and then stops. The reaction mixture is decomposed at 70-80 s by adding
    100 ml of water and after cooling are neutralized with sodium carbonate. The aqueous reaction mixture is extracted four times with chloroform, using 100 ml of the latter each time. The combined chloroform solutions are dried over sodium sulfate and then evaporated. Acetic acid ethyl ester was distilled off from the residue, and 20.2 g (91%) of 2-methyl-3-ethyl-7-chloro-4-OXO-4H-11IRIDO (1,2-a) pyrimidine were obtained. after recrystallization from a mixture of ethyl alcohol and diethyl ether has so pl. 1 i-PB S.
    Calculated,%: C 59.33; H 4.98; 12.58; C1 15.92.
    N
    H / t
    Found,%: C 59.20; H 5.02; 12.39; C1 16.07.
    N
    If 2-amino-3-methylpyridine is used as the aminocomponite, then 2,9-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine is obtained which has so pl. 90-92 S.
    Calculated,%: C 71.26, H 6.98, N 13.85.
    C 71.20, H 6.97,
    Found N, 13.70.
    If 2-aminopyridine is used as the amino component, and 2- (cyclohexylmethyl) -acetoacetic acid ethyl ester is used as the oxo-compound, then 2-methyl-3- (cyclohexylmethyl) -4-oxo-4H-pyrido (1,2- a) pyrimidine, which has so pl. 112-P4c.
    Calculated,%: C, 74.97; H 7.86;
    N 10.93,
    Found,%: C 75.10; H 7.86,
    M 10.95.
    If 2-amino-6-methylpyridine is used as the amino acid component and 2- (Cycloheximethyl) acetoacetic acid ethyl ester as the oxo compound, 2,6-dimethyl-3- (cyclohexylmethyl) -4-oxo-4H is obtained pyrido (1,2-a) pyrimidine, m.p. 124-126 ° C.
    Calculated,%: C 75.52; H 8.20; N 10.36,
    Found,%: C 75.40; H 8.22; N 10.29.
    Example 4. 4.77 g of 2,6-dimethyl-3-ethyl-4-oxo-4H-Pyrido (1,2-a) pyrimidine hydrochloride are dissolved in 50 ml of water and the pH of the resulting solution is adjusted to 7 by the addition of 10% solution of sodium carbonate. The reaction mixture is then extracted four times with chloroform, using 25 ml of the latter each time. The combined sodium sulfate and dried chloroform extracts are evaporated. Acetic acid ethyl ester was distilled off from the residue. AT
    the result is 4, O g (99%)
    2,6-dimethyl-3-ethyl-4-: pkso-4H-pyrido (1,2-a) pyrimidine. After recrystallization from a mixture of ethyl
    alcohol and diethyl ether product
    ff
    has 127-128 C.
    Calculated,%: C 71.26; H 6.98; N 13.85.
    Q H 4l20
    Found,%: C 71.09, H 6.98;
    N
    13.67.
    If 2-methyl-3-H-decyl-4-pxo-4H-pyrido (1,2-a) pyrimidine hydrochloride is used as the source material, then 2-methyl-3-H-decyl-4- oxo-4H-pyrido (1,2-a) pyrimidine, which has so pl. 66-67.5 p.
    Calculated,%: C 75.96; H 9.39;
    N 9.32.
    Q.-Wz
    Found,%: C 76.11, H 9.40,
    9.34.
    N
    Example 5. 4.45 g of 2-methyl-3-ethyl-7-chloro-4-oxo-4-pyrido (1,2-a) pyrimidine is dissolved by heating in ethyl alcohol. To the prepared solution was added 25 ml of ethiol solution of hydrogen chloride with a concentration of 28 wt.%. After cooling, the precipitated precipitated crystalline product is filtered and passed through ethyl alcohol. The result is 5.01 g (97%) of 2-methyl-3-ethyl-7-chloro-4-OXO-4H-Pyrido (1,2-a) pyrimidine hydrochloride (1,2-a) pyrimidine, which has so pl. 176-180 C.
    Calculated,%: C 50.98; H 4.57; N 10.81-, C1 13.68,
    (j H NgOCbHCl
     Found,%: C 50.82, H 4.74; 10.92; C1 13.44.
    Example 6  4.04 g of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) 15 pyrimidine is dissolved in 50 ml of ethanol and in the presence of 2 g of Rene nickel washed with ethyl alcohol before complete removal of water, hydrogenation is carried out at atmospheric pressure.  After absorbing the theoretically calculated amount of hydrogen (approximately 7 hours), the consumption of hydrogen ceases.  The catalyst is separated from the reaction mixture by filtration and the resulting ethanolic solution. evaporated.  The result is 4.10 g (99.5%) of 2,6-dimethyl-3-ethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine.  The product is a pale yellow colored non-crystallizable oily substance that can be distilled at a vacuum of 25 mm Hg. Art.  Calculated,%: C, 69.87; H 8.80, NP, 58.  Found,%: C 69.82, H 8.96, N 13.62.  If the reaction is carried out in the manner suggested, however, instead of Rene nickel, 10% palladium on activated carbon is used as a catalyst, then the theoretically calculated amount of hydrogen is absorbed within 10 hours.  The result is 2,6-dimethyl-3-ethyl-4-oxy-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine as a non-crystallizable oily substance.  Example 7  10.8 g of 2-amino-6-methylpyridine and 15.8 g of ethyl ester of 2-ethyl acetic acid are heated with stirring in 100 g of polyphosphoric acid for 90 minutes at 100 C.  The reaction mixture is then diluted with 75-100 ml of water, after which the pH of the mixture is adjusted to a value of 7 by the addition of 10% sodium hydroxide solution.  After precipitating the crystalline product, it is filtered off, washed with water and dried.  As a result, 17.2 g (85%) of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrcine are obtained. After recrystallization from a mixture of ethyl alcohol and diethyl ether, the product has t. square  127-128 C and does not give the temperature depression to melt, even when mixed with products, obtained in example 6, 8 PRI me R 8.  0.02 mol of 2-amino-3-hydroxypyridine and 0.02 mol of ethyl 2-ethyl acetic acid ester are reacted with each other according to Example 7.  As a result, with a yield of 73%, 2-methyl-3-ethyl-9-hydroxy-2-oxo-4H-pyrido (1,2-a) pyrimidine is obtained, which, after recrystallization from 70% ethanol, has m. square  128 ° C.  Calculated,%: C 64.6; H 5.92.   Found,%: C 64.90; H 6.15.  Example 9 0.02 mol of 2-amino-3-hydroxypyridine and 0.02 mol: 2-ztylacetoacetic acid ethyl ester are reacted according to Example 1.  As a result, 2-metsh-3-ethyl-9-hydroxy-4-4H-pyrido (1,2-a) pyrimidine hydrochloride is obtained with a yield of 59%, which, after recrystallization from a mixture of ethyl alcohol and diethyl ether, has m. square  175-178 C.  Calculated,%: C 55.12; H 5.47; C1 14.79.  C ,. , H ,, Found,%: C 55.22; H 5.51; C1 14.67.  Example 10  0.02 mol of 2-amino-3-hydroxypyridine and 0.02 mol of 2-benzylacetoacetic acid ethyl ester are reacted according to Example 7.  As a result, 2-methyl-3-benzyl-9-hydroxy-4-oxo-4H-pyrido (1,2-a) pyrimidine is obtained with a yield of 70%, which, after recrystallization from ethanol, has m. square  124-125 C.  Calculated,%: C, 72.16; H 5.30.  . i, Found,%: C 71.97; H 5.41.  Example 11  0.02 mol of 2-amino-5-nitropyridine and 0.02 mol of 2-ethyl acetic acid ethyl ester are reacted with each other according to Example 7. As a result, 2-megsh-3-ethyl-7- nitro-4-oxo-4H-pyrido (1,2-a) pyrimidine.  The product is slightly contaminated with 2-amino-5-nitropyridine, which is easily eliminated by recrystallization from ethyl alcohol.  . After double recrystallization from ethyl alcohol, a compound with Tcpl is obtained.  163-164 C.  Calculated, A- (Found,%: An example of no-3-nitropyridine and 0.02 mol of ethyl 2-ethyl acetoacetate is reacted with each other according to Example 3.  In a result of 51%, 2-methyl-3-ethyl-7-nitro-4-oxo-4H-pyrido (1,2-a) pyrimidine is obtained in the yield of 51%, which, after double recrystallization from ethanol, has m. square  164-165 ° C and does not give a depression in the melting temperature when mixed with the product obtained in Example 11.  Example 13  0.02 mol of 2-amino-4-methylpyridine hydrospichorid, 50 m of pyridine and 0.03 mol of 2-ethyl acetic acid ethyl ester are heated for 16 hours at reflux temperature of the reaction mixture. Then the solvent is distilled off from the reaction mixture under reduced pressure. and ketoester, which has not entered into the interaction.  The residue obtained is recrystallized from a mixture of ethyl alcohol and DIETI.  the ether.  As a result, with a yield of 39%, 2,6-dimethyl-3-ethyl-4-oxr-, 4K-pyrido (1,2-a) pyrimidine hydrochloride is obtained, which has m. square  192-198 After recrystallization from ethanol, t. square  The product rises to 195-199 seconds.  Calculated,%: C, 60.38; H, 6.33; Cl, 14.85.  C, 2. H (4; 20-HCl; Found: C, 60.41; H, 6.38; C1; 14.67 Example 14.  0.02 mol of 2-aminopyridine hydrobromide and 0.03 mol of 2-H-propyl acetoacetic acid ethyl ester are reacted with each other according to Example 13.  As a result, 2-methyl-3-H-pro-PIL-4-OXO-4H-PYRIDO (1,2-a) pyrimidine hydrobromide is obtained with a yield of 49%, which after recrystallization from ethyl alcohol sublimated at 210 C.  Calculated,%: C 50.90; H 5.34.  0 gNmM-H Found,%: C 50.81; H 5.20.  The base obtained in free form from hydrobromide in a known manner has m. square  57-58 C, 2-methyl-3-H-prop 1-4-oxo-4H-pyrido 90637818%: C 56.65; H 4.75.  (l, 2-a) pyrimidine crystallizes from C 56.50; H 4.60.  12.  0.02 mol 2-ami.  normal hexane.  When mixed with the base, isolated in the free state from hydrochloride, corresponding to example 1, the product does not depress the melting point. Calculated,%: C 71.26; H 6.98.  C, Found,%: C, 71.32; H, 6.86.  Example 15  0.02 mol of 2-aminopyridine hydroiodide and 0.03 mol of 2-n-propyl tetroacetic acid ethyl ester are reacted with each other according to Example 13.  As a result, with the yield of 53%, hydroiodide of 2-methyl-3-H-propyl-4-oxo-4H-pyrido (1,2-a) pyrimidine is obtained, which after recrystallization from ethyl alcohol has t. square  200-210С.  Calculated,%: C 43.66; H 4.58.  C, Found,%: C 43.41; H 4.67.  The base, isolated in a known manner in the free state of ns hydrobromide, has m. square  58-59®C and did not depress the melting point with the product corresponding to Example I4.  Example 16 About 02 mol of 2-aminonicotinic acid and 0.02 mol of ethyl ester of 2-ethyl acetoacetic acid are stirred for 1 h in 20 ml of polyphosphoric acid at 145 ° C.  The reaction mixture is then diluted with 10 ml of water. When cooled, it is neutralized by the addition of a 10% sodium hydroxide solution.  After separating the precipitate into an oily product, it is extracted three times with chloroform, each time using 25 ml of the latter.  The combined extracts are dried and evaporated.  As a result, 2-methyl-3-ethyl-9-carboxyl-4-OXO-4H-PYRIDO (1,2-a) pyrimidine is obtained with a yield of 42%, which, after recrystallization from ethyl alcohol, has m. square  177-} 79s.  Calculated,%: C 62.02; H 5.21.  c, 2.  Find%: C 62.10; H 5.13.  Example 17  From 0.02 mol of 2-amino-4-ethoxycarbonylpyridine; and 0.02 mol of ethyl ester 2-ethyl. Touksushi.  The acids according to example 7 are obtained in 64% yield of 2-methyl-3-eth-1 -3-ethoxycarbonyl-4-oxo-4H-, -pyrido (1,2-a) pyrimidine, which, after recrystallization from ethyl alcohol, has m. square  EA-Ub S.  Calculated,%: C 64.60, H 6.20.   Found,%: C 64.44; H 6.24.  Example 8  A mixture containing 0.02 mol of 2-amino-4-ethoxycarboyl nilpyridine, 0.02 mol of ethyl 2-ethyl acetoacetate, 10 ml of phosphorus oxychloride and 2 g of polyphosphoric acid is stirred for 2 hours at 120 C.  Then, the reaction mixture at 70-80 ° C is decomposed with 20 ml of ethylog alcohol and the solution is neutralized by cooling with ice by adding 10% sodium hydroxide solution. After this, the solvent is distilled off, the residue is extracted four times with chloroform, using 25 ml of each. last one.  The combined extracts are dried and evaporated.  The residue obtained after evaporation crystallizes upon trituration with diethyl ether.  As a result, with a yield of 42%, 2-methyl-3-ethyl-8-ethoxycarbonyl-4-oxo-4H-pyrido (1,2-a) pyrimidine is obtained, which, after recrystallization from ethyl. alcohol has t. square  95-96 C.  The resulting product gives a depression of the melting point with the product corresponding to example 17.  Example 19  0.01 mol of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine is dissolved in 20 m of acetone.  The prepared solution is mixed with 0.03 mol of methyl iodide and the reaction mixture is held for 24 hours in a refractory ampoule. at 150 C.  But the solution is evaporated to a volume of 10 ml and incubated.  24 h  As a result, with the release of 86% get.  1, 2,6-trimethyl-3-zhyl-4-oxo-4H-pyrido (1,2-a) hydrochloride iodide.  A yellow colored crystalline product, obtained after recrystallization from ethyl alcohol, has a t. square  .  203-206 ° C.  Calculated,%: C 45.37; H 4.98.  W7N; iO Found, / J: C 45.16 / H 4.81.  II p and mep 20.  0 , Q2 mol of 2-methyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine according to example 6, is subjected to reduction in the presence of René nizkel or palladium on activated carbon.  In the case of using Raney nickel with a yield of 96% (and in the case of using palladium on activated carbon with a yield of 97%), 2-methyl-3-ethyl-6,7,8,9-tetrahydro-4-oxo-4H-pyrido ( 1,2-a) pyrimidine in the form of a colorless viscous oily substance which can be distilled at 146-148 ° C.  (b mm Hg. Art. ).  After soaking for a short time, the product crystallized.  Calculated,%: C 68.72; H 8.39.  C ,, n ,, Found,%: C 68.67, H 8.40.  Example 21  0.01 mol of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine is dissolved in 20 ml of acetone.  The prepared solution is mixed with 0.03 mol of methyl iodide and the reaction mixture is kept in a refractory ampoule for 24 hours at.  Then the solution is evaporated to dryness, the residue is dissolved in 15 ml of methyl alcohol and the resulting solution is mixed with a solution containing 0.05 mol of sodium tetrahydroborate (ill) in 10 ml of water.  The reaction mixture is kept for 4 hours, after which methyl alcohol is distilled off and the aqueous fraction is extracted three times with chloroform, using 20 ml of the latter each time.  The extract is dried and evaporated.  To 10 ml of saturated ethyl chloride were added to the resulting oily product.  The product is crystallized by trituration with diethyl ether.  After recrystallization from a mixture of acetone and diethyl ether with a home 41%, 1,2,6-trimethyl-3-eth1-sh-, 2,3,6,7,8,9,9a-octahydro-4-oxo-4H are obtained pyrido (1,2-a) pyrimidine in the form of a white crystalline substance which begins to sublimate at 206 C.  Calculated,%; C, 60.81; H, 8.24; Ci, 13.8i.  (. —HCI Induced,%: C 60.64; H 8, 12; C1 13.96.  Example 22  10 g of 3-ethyl-2,6-dimethyl-4-oxo-4H-pyrvdo (1,2-a) pyrimidine is dissolved in 100 ml of ethyl alcohol.  A solution of 12 g of fumaric acid in 100 ml of ethyl alcohol is added to the prepared solution. The mixture is heated to temperature; boiling pans, and then. through cooling 21, the product is crystallized.  The crystalline material is filtered off, washed with a small amount of ethanol and then dried.  The result is 12. 5 g (78.5%) of di- (3-ethyl-2,6-dimethyl-A-oxo-4H-pyrido {1,2-a) pyrimidine) fumarate, which after recrystallization from ethyl alcohol has t. square  185-186 c.  Calculated,%: C 64.60; H 6.20; N 10.76.  .  Found,%: C 64.35 H, 6.24; N 10.40.  Example 23  10 g of 3-ethyl-2,6-dimethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine is dissolved by heating in 100 ml of ethyl methyl ketone.  A solution of 12 g of maleic acid in 100 ml of ethyl methyl ketone is added to the prepared solution.  The mixture is heated to boiling point and then the crystallized product is cooled.  The crystalline material is filtered off, washed with a small amount of methyl methyl ketone and then dried.  As a result, 14.0 g (87.9%) of 3-ethyl-2,6-dimethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine hydromaleateate, which, after recrystallization from ethyl alcohol, has m. square  one. 37-138C.  Calculated,%: C, 60.36; H, 5.70; N, 8.80.  BSEC 2 5 C 60.35; H 5.72; Nagyeno, Example 24.  The south of the 3-ethyl-2,6-dimethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine is dissolved by heating in 100 ml of acetone.  A solution of 7 salicylic acid in 100 ml of acetone is added to the prepared solution.  The mixture is heated to boiling point and then crystallization is carried out by cooling.  The crystalline product is filtered and washed with acetone and then dried. As a result, 11.5 g (67.6%) of 3-methyl-2,6-dimepsh-4-pkso-4H-pyrido (1,2-a) pyrimidine salicylate are obtained, which after recrystallization from ethyl alcohol has t. square  126-12 Calculated,%: C 67.04, H 5.92, N 8.22.  QjoH-jjJjO t1 found,%: C 67.50; H 5.94; N 8.25.  Example 25  South 3H-ethyl-2,6dn-methyl-4-oxo-4H-pyrido (I, 2-a) pyrimidine is dissolved by heating in 30 ml of ethyl alcohol. To the prepared solution was added 19.2 g of citric acid, dissolved in 100 ml ethyl alcohol.  The mixture is heated to boiling point and then crystallization is carried out by cooling.  The crystalline product is filtered off, washed with ethyl alcohol and then dried.  The result is 18.2 g (92.4%) of hydrochloride 3-ethyl-2,6-dimethyl-4-oxo 4H-pyrido (1,2-a) pyrimidine, which, after recrystallization from ethyl alcohol, has t. pl, 136-137 ° C.  Calculated,%: C 54.82; H 5.62,.  Navdano,%: C 55.08; H 5.70; N 7.01.  Example 26  10 g of 3-ethyl-2,6-dimethyl-4-oxo-4H-arido (1,2-a) pyrimidine is dissolved by heating in 100 ml of acetone.  To the prepared solution was added a solution of 13.4 g of malic acid in 100 ml of acetone.  The mixture is heated to boiling point and then the product is crystallized by cooling.  The crystalline product is filtered off, washed with acetone and then dried.  The result is P, 5 g (68.4%) of hydro-2-oxysuccinate Z-ethyl-2,6-dimethyl-4-oxo-4H-pyrido- (1,2-a) pyrimidine, which, after recrystallization from ethyl alcohol has t. square  141-142 C.  Calculated,%: C, 62.44; And 6.36, N Yu, 40.   Found,%: C 62.47; H 6.76, N 10.43.  Example 27  10.0 g of 3-ethyl2,6-dimethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine is dissolved by heating in 50 MP of ethanol.  To the prepared solution was added.  2.8 ml of sulfuric acid with a concentration of 96-97 weight,%.  The mixture is heated to boiling point and then crystallized by cooling.  The crystalline product is filtered off, washed with ethyl alcohol and then dried.  As a result, 5 g (33%) of 3-ethyl-2,6 dimethyl-4-Oxo-4H pirndo (i,) pyrimidine hydrogensulfate is obtained, which, after recrystallization from ethyl sgsh, will give t. square  199-200 0.  Calculated,%: C A7.99i H 5.40; N 9.33.   Na%,%: C 48.31; H 5.51; N 9.55, Example 28, the reaction was carried out according to Example 2, however, 2 amino-4-methylpyridine was used as the amino-compound, 3-ethyl 2.8 dimethyl-4-oxo hydrochloride was obtained in a yield of 64%. 4M pyrido (l, 2-a) pyrimidine, which, after recrystallization from r «gsh.   195 ethylovogche alcohol has 200 s.  Calculated,%: C 60.38 / H 6.33 / N 1.7A; C1 14.85.  . LAANN-11%,%: C 60.42; H 6.38 N P. , 82; Ci 14.67.  For example 29.  Reaction of the entities. according to example 2, however, 2 amino-4,6-dimethylpyridine is used as the Shchgino component.  As a result, with a yield of 71%, Z-ethyl-2,6,8-trimethyl-4-oxo-4H-pyrido (J, 2-a) pyrimidine hydrochloride is obtained, which after recrystallization from ethanol has m. pl 198-205c.  Calculated,%: C 61.78, - H 6.78; 11.08; C1 14.03.  fiN O-HCl Found,%: C 62.08; H 6.81; 1, 17; C1 13, -82.  Example 30  The reaction is carried out in the manner described in step 2, however, with the difference that the ethyl ester of 2-ethyl-3-oxo-peracid acid is used as the oxo compound.  As a result, with a yield of 75%, hydrochloride Z-ethyl-b-methyl-2-H prog-4-oxo-4H-pyrido (1, 2-a) pyrimidine is obtained, which, after pyrecrystallization from ethyl acetate, has m. Gsh, S.  Calculated,%; C 63, OZ; H 7.18, N 0.50, C1 13.29.  . "5NS1 Navdeno,%; C 63.28 / H 7.32; N 10. 58; C1 13.15.  Example 31  A mixture consisting of 2.16 g of 2-amino-5-mets1Niridine; 3.16, g of 2-hyglycetoacetic acid ethyl ester; 4.6 ml of phosphorus oxychloride and 1.4 g of polyphosphoric acid are not stirred for 45 minutes at 120-130 C.  The gas release, which was initially intense, weakens and then completely stops.  The reaction mixture is decomposed with 20 ml of ethanol and the crystallization is performed by cooling and scratching the vessel walls with a stick.  The crystalline product is filtered off.  The resulting 4.6 g of hydrochloride is dissolved in 20 ml of water.  The pH of the solution was adjusted to 7 by adding 20% sodium carbonate solution.  Precipitated crista. The product is filtered off, washed with water and dried.  As a result, 2 g (49%) of 3-ethyl-2,7-dimesh-1-4-oxo-4H-1 three (1,2-a) pyrimidine is obtained, which after recrystallization from methyl alcohol has t. square  154-15b S.  Calculated,%: C 71.26; H 6.98, N 13.85.  C, 2li ,, N. , 0 Found: C, 71.42; H 7.08 /, N 13.91.  Example 32  They work according to the procedure proposed in Example 7, but instead of 2-amino-6-methylshridine, 2-amino-5-bromopyr1-scnn is used as the starting material and 7-bromo-3-ethyl-2-methyl-4-oxo-4H is obtained pyrido (l, 2-a) pyrimidine with a yield of 69%, the product melts after recrystallization from ethanol at 139-140 C.  Calculated,%: C 49.46; H 4.15, 10.48; Br 29.91.   On. found%: C 49.62; H 4.20; 10.62; Br 29.67.  Example 33  They work according to the procedure proposed in Example 7, however, instead of 2-amino-6-methylpyridine, 2-amino-5-iodopyridine is used and 3-ethyl-7-iodo-2-methyl-4-oxo-pyrido (l, 2-a ) pyrimidine with a yield of 57%, the product melts after recrystallization from dimethylformamide at -150-152 °.  C 42.06: H 3.06 / Calculated,%; N 9.9; J 40.38.  C ,. H ,, NgJ 25 Found,%: C 42.28, N.  3.4i; N 8.72, J 40.44.  Example 34  They work according to the method proposed in Example 7, however, instead of 2-amino-6-methylpyridium, 2-amiko-3,5-dichloropyr dine is used and 3-ethyl-2-methyl-7,9-dichloro-4-oxo-4H is obtained pyrido (1,2-a) pyrimidine with a yield of 66%, which melts after recrystallization from ethanol at 179-180 C.  Calculated,%: C, 51.34; H 3.92; N 10.89; C1 27.58.  q, H, c, N2.  Found,%: C 5.42; H 3.86, N 10.54; C1 27.42.  Example 35  They work according to the procedure proposed in Example 7, one instead of 2-amino-6-methylpyridine, 2-amino-5-ethoxycarbonylpyridine is used and 3-ethyl-7-ethoxycarbonyl-2-methyl-4-oxo-4H-pyrido (l, 2-a) pyrimidine with a yield of 73%, which, after recrystallization from ethanol, melts at 94-96 C.  Calculated: C 64.90, H 6.20, N 10.76.  C, H Yaydeno,%: C 64.76; H 5.31; N 10.88.  Example 36  They work according to the method proposed in Example 7, but instead of 2-amino-6-methylpyridine, 2-aminopyridine-3-carboxylic acid is used and 3-ethyl-3-carboxy-2-methyl-4-oxo-4I-pyrido is obtained. (I, 2-a) pyrimidine with a yield that melts at 176-178 ° C after recrystallization from dimethylformamide.  Calculated,%: C, 62.06; H 5.21; N 12.06.  .  zHfiM Found,%: C 62.24; H 5.27, N 12.24.  Example 37  5 mol 3-ethyl-7-ethoxycarbonyl-2-methyl-4-oxo-4I-pyrido (1,2-a) pyrimidine in 15 ml of 15% weight. /about.  methanolic ammonia solution was allowed to stand for 3 days at room temperature.  The resulting crystals are filtered and recrystallized from dimetha formamide.  7-aminocarbonyl-3-etch-1-2-methyl-4-oxo-4H-pyrido (1,2-a) pyrimidine is obtained in a yield of 88% which melts at 289-292 C.  26 Calculated,%: C, 62.32; H 5.67; N 16.34.  gN},} Found,%: C 62.15 H 5.55, 16.78.  Example 38  They work according to the procedure given in example 37, however, they use 15 ml of 15% weight. /about.  methanol solution of methanol tire and get 3-ethyl-2-methyl-7- (| -methylaminocaron.  -4-oxo-4H-pyrido (1,2-a) pyrimidine, which, after recrystallization from ethanol, melts at 182-184 seconds.  Exit 87 ".  Calculated,%: C, 63.40; H 6.14; N 17.06.   Found,%: C 63, ZZ; H 6.20; N 17.22.  Example 39  Work according to the method outlined in example 37, but using 15 ml of 15% weight. /about.  a methanol solution of dimethylamine and get 3-ethyl-7- (S, N-dimethylaminocarbonyl-12-methyl- /; -oxo-4H-pyrido-O, 2-a) pyrimidine with a yield of 81%, which is outlined in.  Example 5 was transferred to the hydrochloride.  Hydrochloride after recrystallization from ethanol-dna :. m-ether melts at 183-185 C.  Calculated,%: C, 56.85; H 6.13; N 14.20; C1 11.99.  Found,%: C 56.74, And 6.06; N 14.43; C1 11.98.  Example 40  10 mol of 3-metsh1-7-aminocarbonyl-2-methyl-oxo-4H-Pyrido (I, 2-a) pyrimidine is boiled with 15 ml of phosphorus oxychloride for 1 hour.  The solution is concentrated and neutralized with 20% by weight. /about.  sodium carbonate solution.  The product is shaken 3 times with 20 ml of chloroform.  The chloroform solution, after drying with anhydrous sodium sulfate, is concentrated and the residue is recrystallized from ethanol.  3-methyl-7-cyano-2-metsh-1-4-oxo-4H-pyrido) pyrimidine is obtained in 70% yield which melts at 214-2 bs.  Calculated,%: C, 67.59; H 5.20; N 19. 71  LO Found,%: C, H, H, 5.38; M 19.66.  Example 41  10 mol of nopyridine and 13 mmol of ethyl 2-ethyl acetoacetate. . The boils are boiled for 3 hours in 10 ml of acetic acid and the reaction mixture is concentrated.  The residue, while heating, is dissolved in 2 ml of ethanol, and 1 ml of 30% by weight is added to the solution. /about.  chlorohydrate-ethanol solution.  Ose kpazhdeik vypadagavde crystals are filtered, washed with ethanol and dried.  3-ethyl-2-methyl-4-oxo-4H-pyrido (1,2-a) hydrochloride is obtained. pyrimidine with a yield of 22%, which after recrystallization from ethanol melts with decomposition at 246-247 ° C.  Calculated,%: from 58.80; H 5.83, N 12.47; C1.  15.78.  . . fgOCl Found:% from 58.63; H 5, 12.50; C1 15.80.  Example 42  10 mol of 2-aminopyridine and 15 mmol of 2-ethyl acetic acid ethyl ester are boiled for 3 hours in 10 ml of propionic acid and the reaction mixture is concentrated.  The residue is dissolved in 2 ml of ethanol with heating and 1 ml of 30% weight is added to the resulting solution. / about solution ethanol - hydrogen chloride.  . The precipitating crystals, after cooling, are washed with ethanol and dried.  3-ethyl-2-methyl-4-oxo-4H-pyrido {i, 2-a) pyrimidine hydrochloride is obtained in 35% yield, which after recrystallization from ethanol, melts at 246 ° C with decomposition.  The resulting product did not differ in melting point with that obtained in Example 41.  Example 43  ten . -mole of 2-aminopyridine and 15 mol of 2-ethyl acetoacetic acid ethyl ester in 15 ml of caproic acid is heated for 3 hours at 200 ° C and the reaction mixture is concentrated.  The residue is dissolved in 2 ml of ethanol when heated and 1 ml of 30% weight is added to the resulting solution. /about.  solution hydrogen chloride - ethanol.  After cooling, the crystals are filtered off, washed with ethanol and dried.  3-ethyl-2 methyl 4-oxo-4H-pyrido-{I, 2-a) pyrimidine hydrochloride is obtained in 46% yield.  After recrystallization from ethanol, the product melts at 246-247 ° C and does not differ in melting temperature with the product obtained according to Example 41 or 42.  Example 44  Manufacturing 75 g tablets.  375 g of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine hydrochloride, 525 g of crystalline cellulose and 70 g of amylopectin are hemogenised.  After granulating with 75 g of a lacquer solution (Eudragit), drying at 40 ° C, and grinding, the mixture is homogenized with 10 g of powdered talc and 10 g of magnesium stearate and tableted into tablets of 200 mg.  Example 45  Production of prolonged action dragee weighing 150 mg.  750 mg of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine hydrochloride, 750 g of crystalline cellulose and powdered polyvinylpyrrolidone are mixed in. homogenizer.  The mixture is granulated with a solution of 22.5 g of Eudragit in 175 cm of propanol.  The granulate is dried at 50 ° C, crushed, homogenized with 32.5 g of talc and 22.5 g of powdered magnesium stearate and tabletted into tablets, convex on both sides, weighing 345 mg.  Tablets made in this way (dradés) are provided in a known manner with film or sugar. coating.  Example 46, the manufacture of capsules weighing 50 mg.  A powder mixture of 250 mg of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine hydrochloride and 115 g of potato starch is moistened with a solution of 5 g of gelatin, 30 g of distilled water, - 3 g of 2n .  hydrochloric acid solution and 90% weight. / about, ethanol in a suitable mixer, granularit through a sieve with a hole size of 0.3 mm and dried at 40 C.  The granulate obtained is ground in a sieve with a clear opening size of 0.15 mm and mixed with a powdered mixture of 85 g of potato starch, 25 g of talc and 5 g of stearin.  Prepackaged in a suitable filling apparatus in hard gelatin capsules of 0.115 g.  Capsules pack in the usual way.
    29
    90637830
    Table 1
    2,3,6-Trimethyl-4-oxo-4H-pyrido {1,2-a) pyrimidine hydrochloride
    Hydrochloride 2,6-dimethyl-3-ETSH1-4-OXO-4H-pyrido (1,2-a) pyrimidine
    Hydrochloride 2-metSH1-3-ZTIL-4-OXO-4H-Pyrido (1,2-a) pyrimidine
    Hydrochloride 3 6-dimethyl-2-ethyl-4-oxo-4H-pyrido (-1,2-a) pyrimidium
    2-methyl-3-H-propyl-4-oxo-4H-pyrido (1,2-a) pyrimidine hydrochloride
    2,6-dimethyl-3-H-propyl-4-oxo-4H-tshrido (1,2-a) pyrimidine hydrochloride
    Breakdowns
    0.066
    0.780
    0.021
    0.796
    1,070
    0.012
    0,120
    0,0019
    0,0105
    0.502
    0.316 0.0025 0.607 0.069
    Table 2
    reached
    Also
    580
    2.6-Dimethyl-3-ethyl-4-ox CO 4H-pyrido (1,2-a) pyrimidine, hydrochloride
    2-MePSH.3 - ethyl 4-oxo-4I pyrcdo (15 2-a) pyrimidine, hydrochloride
    2, b, 8 Trimethyl 3-etyl-4-oxo-4H-pyrido (I, 2-a)
    pyrcnidine, hydrochloride
    g
    2,6--1 1methyl-3-M-propyl-4-oxo-4H-pyridoC1, 2-a) pirschdin, hydrochloride
    2,9-E and 3-ethyl4-oxo-4H-pyrvdo (, 2-a) pyrimidine, hydrochloride
    2,7DI mettI-3-ethyl-4-oco-4H pyrido (1,2 - a) pyrimidine, gndrochloride
    2-Methyl 7.3-these. -7-chloro 4-oxo-4H-dirido (1 ,, 2-a) pyrimidine, hydrochloride
    2,3,6-Trimethyl-4-oxo-4H-Pyrido {, 2-a) pyrimidine, hydrochloride
    Ta b l and c / a 3
    Table 4
    74
    520. 68
    620 300 100 180
    820 580 49 120
    48
    1200
    310
    800 500 75 150
    175
    98
    1100
    87
    175
    Test compound
    2-Cometil-3 - (- butyl-4-oxo-4H-pyrido (1,2-a) pyrimidine, hydrochloride
    2,6-Dimethyl-3-β-butyl-4-6 x co-4H-pyrido (1,2-a) pyrimidine, hydrochloride
    Metosulfate I, 6-dimethyl-3 - ethoxycarbonyl-4-oxo-4H-6, 7,8,9-tetrahydropyrido (1,2-a) pyrimidine (breakdown)
    Continued table. four
    Hot plate test, ED, mg / kg
    , {on rats) (on rats)
    RS i.v. S.C,
    RS I.V. S.C.
    251
    1100
    340
    NOSE
    50
    220
    1600 220
    权利要求:
    Claims (12)
    [1]
    Claim
    1. The method of obtaining derivatives of pyrido (1,2-a) pyrimidine of the formula where R is a hydrogen atom, a halogen atom, a lower alkyl radical, a nitro group, a hydroxyl group, a carboxyl group, methoxycarbonyl, ethoxycarbonyl
    - a hydrogen atom, a halogen atom or a lower alkyl radical, * / 1
    R 2 ~ alkyl radical containing 1-4 carbon atoms, '
    R 3 is an alkyl radical containing 1-12 carbon atoms, an arylalkyl residue with 7-9 carbon atoms, in which the phenyl group can be 'substituted in the ring with a halogen atom, or a cycloalkyl residue containing 6-8 carbon atomsJ
    Rif - free pair of electrons; a hydrogen atom or an alkyl radical with 1–2 carbon atoms, * dashed lines denote double bonds in some cases; provided that R ^ and R¾ are a methyl group, then R, 1C cannot simultaneously be hydrogen, or if one of the substituents R and R 4 is hydrogen, and the other is a 7-or 9-methyl group, and is hydrogen, then Rj cannot simultaneously denote a methyl group, or if 11 ^ denotes a methyl group, Rj is an ethyl group, R ^ is hydrogen, and one of the substituents R and R ^ is hydrogen, then the other of the substituents R and R ^ cannot denote an atom bromine, or if R, 'R ^, Rjj and R ^ are hydrogen, then R 3 cannot be an ethyl group, or and if R and R ^ are a 6- or 8-methyl group, Rj is a methyl group and R4. denotes hydrogen, then Rj cannot denote an ethyl group, characterized in that the derivative is 2-aminopyridine. on, formulas or its addition salt with acid (R and Rjf have the meanings indicated for these! symbols), are introduced into the reaction at 20-200 * 0 at boiling
    35 906378
    36 reaction mixture with the compound of the formula ¢ = 0
    СН-Ез Ш 5, 'ΰΟΟΒδ where R 2 and R 3 take the meanings indicated for these symbols;
    Rg. lower alkyl radical, 10 provided that, if 2,3-dimethyl-j 2-methyl-3-ethyl-, '2,3,7-trimethyl-; 2-methyl-3-ethyl-7-bromo- and 2,6,8-trimethyl-3-ethyl ~ 4-oxo-4H-pyrido (1,2-a) pyridine, 15 the reaction is carried out in a mixture of phosphorus oxychloride and polyphosphorus - ( acid, and, in the desired case, the obtained compound of the formula (where R, R ^, Rj HR 3 take the values indicated for these symbols, undergo reduction, followed by isolation of the target product in the free state or in the form of salts.
    [2]
    2. The method of pop. 1, characterized in that 0.5-1.5 moles of the compound of formula III are used per mole of the compound of formula 35 of Formula II.
    [3]
    3. The way popp. 1 “2, characterized in that the interaction between the compounds of formulas II and III is carried out in the presence of an acidic condensing agent.
    [4]
    4. The method of pop.Z, with the exception that in the capacity of an acidic condensing agent, a mixture of polyphosphoric acid and phosphorus oxychloride is used.
    [5]
    5. The method according to PP. 1-4, characterized in that for 1 mol of the compounds of formula II are used, 2-5 mol of phosphorus oxychloride and Ί-150 2 for polyphosphoric acid.
    [6]
    6. The way popp. 1-5, characterized in that the interaction of compounds corresponding to formulas II and III, is carried out at 80-160 ° C.
    [7]
    7. The method according to PP. 1-6, characterized in that the reaction mixture formed in the presence of phosphorus oxychloride and polyphosphoric acid is decomposed with lower alcohol, water or alkali.
    [8]
    8. The method according to PP. 1-9, characterized in that as the acidic condensing agent using polyphosphoric acid.
    [9]
    9. The method according to p. 8, characterized in that polyphosphoric acid is used in an amount of 200-2000 / (based on 1 mol of the compound of formula II and the reaction
    They are at 60-180 C.
    [10]
    10. The way to pop. 9, characterized in that hydrochloric acid, acetic acid or propionic acid are used as the acidic condensing agent.
    [11]
    11. The method according to π. 1, characterized in that the compound of formula IV is subjected to catalytic hydrogenation, and Raney nickel, palladium, radium, platinum or a mixture of platinum are used as a catalyst, or the compound of formula IV is reduced with a complex metal hydride.
    [12]
    12. The method according to π. II, characterized in that: that use sodium borohydride, sodium cyanoborohydride or sodium bis- (ethoxymethoxy) -aluminium hydride.
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    同族专利:
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    AU518364B2|1981-09-24|
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    CS238901B1|1985-12-16|
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    CS541778A1|1985-05-15|
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    引用文献:
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    AT286990B|1966-11-02|1971-01-11|Chinoin Gyogyszer Es Vegyeszet|Process for the preparation of new homopyrimidazole derivatives and their salts|
    HU169230B|1972-03-29|1976-10-28|
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    US3935197A|1975-05-16|1976-01-27|E. R. Squibb & Sons, Inc.|2-Styryl-4H-pyridopyrimidin-4-ones|HU180701B|1977-12-29|1983-04-29|Chinoin Gyogyszer Es Vegyeszet|Process for preparing pyrido-/1,2-a/pyrimidines containing a carboxylic or ester group on the pirimidimering|
    HU179143B|1977-12-29|1982-08-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing 9-hydroxy-groops-containing 6,7-dihydro-pyrido-square bracket-1,2-a-square bracket closed-pyrimidin derivatives and esters thereof|
    FR2449689B1|1979-02-20|1982-05-28|Logeais Labor Jacques|
    US4310526A|1979-05-08|1982-01-12|Farmitalia Carlo Erba S.P.A.|Substituted 6,7-methylene pyrido[1,2-a]pyrimidines useful as anti-allergic and anti-ulcer agents|
    PL129612B1|1980-07-24|1984-05-31|Rhone Poulenc Ind|Process for preparing novel derivatives of 2,3,6,7-tetrahydrothiazole/3,2-a/pirymidin-5-one|
    HU183408B|1981-04-28|1984-05-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing oral ratard pharmaceutical compositions|
    CA1211111A|1982-02-15|1986-09-09|Isao Yanagisawa|Process for preparing novel pyrimidone compounds|
    US5252572A|1988-02-03|1993-10-12|Chinoin Gyogyszer- Es Vegyeszeti Termekek Gyara Rt.|Pyridopyrimidine derivatives, pharmaceutical compositions containing them and process for preparing same|
    CA2081891C|1990-05-02|1999-03-16|Daniel T. Chu|Quinolizinone type compounds|
    DE10050662A1|2000-10-13|2002-04-18|Gruenenthal Gmbh|New substituted dihydropyrido-pyrimidine derivatives, useful for treating e.g. pain, urinary incontinence and tinnitus|
    DE10050661A1|2000-10-13|2002-04-18|Gruenenthal Gmbh|New substituted 3,4-dihydro-pyrimidopyrimidine and 3,4-dihydro-pyrazinopyrimidine derivatives useful for the treatment of pain, urinary incontinence, pruritis, tinnitus and diarrhea|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU77CI1765A|HU178910B|1977-08-19|1977-08-19|Process for preparing 2,3-disubstituted-4-oxo-4h-pyrido/1,2-a/-pyrimidines|
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