• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Novel 3-(1-piperidinylalkyl)-4H-pyrido[1,2-a]pyrimidin-4- one derivatives, wherein the piperidine ring is substituted with an aroyl radical or a functional derivative thereof, said compounds being potent serotonin-antagonists.
    公开号:SU1068037A3
    申请号:SU813261927
    申请日:1981-03-24
    公开日:1984-01-15
    发明作者:Эдмон Жозефин Кеннис Людо；Каролюс Мертенс Жозефюс
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of novel pyrido (1,2-a) pyrimidin-4-one derivatives with valuable properties of serotonin antagonists that can be used in medicine.
    A known reaction is the alkylation of the adducts with 3-halo-4H-pyrido (1,2-a) pyrimidin-4-ones to form the corresponding 3-amino derivatives of flJ.
    The purpose of the invention is a method for producing novel pyrido (1,2-a) pyrimidine 4-one derivatives, which have valuable pharmacological properties,
    This goal is achieved by the fact that according to the method for producing 3- (1-piperidinylalkyl) -4H-pyrido (1,2-a) pyrimidin-4-one derivatives, the general formula
    where R is hydrogen, lower alkyl or hydroxy at the 2,3 or 4 position of the piperidine ring; R and independently of each other hydrogen, lower alkyl or halide}
     hydrogen or lower alkyl; ASk alkylene with 1-4 carbon atoms;
    Ar is an unsubstituted phenyl or substituted by one or two substituents from the number of halogen, hydroxy group, lower alkyl a or alkoxyl, thienyl, or their pharmaceutically acceptable acid-addition ;, salts derived 4H pyrid6 (1,2-a) pyrimidine 4-she of the general formula
    (Ii)
    TO
    where R is R and Alk. - indicated values;
    NoK — chlorine, bromine, or iodine — is reacted with a piperidine derivative of the general formula
    Mr.
    SU (III) about
    where R and Lg are the indicated values,
    in the presence of a base in an inert
    The organic solvent is preferably boiling followed by isolation of the desired product as a base or acid addition salt.
    It is preferable to obtain 3- {2- (4- / 4- f 4-fluorobenzoyl) -1-piperidinyl / ethyl -2-methyl-4H-pyrido (1,2-a) pyrimidin-4-one and its pharmaceutically acceptable acidic additive salts of 3- (2-chloroethyl) -2-methyl-4Npyrido (1,2-a) pyrimidine-4-one and hydrochloride (4-fluorophenyl; (4-piperidine-NIL) methanone.
    Used the term halogen includes fluorine, chlorine, bromine and iodine, lower alkyl - unbranched or branched alkyl with 1-6 carbon atoms.
    The 5th salts of the compounds are pharmaceutically acceptable (1 salts of such inorganic acids as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric; organic acids such as acetic, propionic, lactic, glycolic, - pyruvic, malonic, succinic, maleic, fumaric, block, vinna, citric, benzoic, brown, salicylic, methanesulfonic, h-toluenesulfonic, cyclohexanesulfaminic, 4-amino-2-oxybenzoic.
    A lower alkanol such as methanol, ethanol, propanol, butanol can be used as an inert organic solvent; an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene; a simple ether such as 1,4-dioxane, 1,1-oxybispropane; a ketone such as 4-methyl-2-pentanol; H, I-dimethylformamide, nitrobenzene and the like.
    In the interaction process, for example, an alkali metal carbonate or alkaline earth metal carbonate or an acidic carbonate can be used as a base. A small amount of the corresponding metal iodide, for example, sodium iodide or potassium iodide, may be added as the primary reaction.
    Some of the starting materials used are known compounds, others can be obtained, in accordance with known methods, for the preparation of analogous compounds.
    Intermediates of the formula (can be obtained by replacing the hydroxyl group of the corresponding 1U alcohols with a halogen, for example, by reacting alcohols (IX-) with thionyl chloride, sulfuryl chloride.
    phosphorus pentabromide, phosphoryl chloride
    Alcohols IV, used as starting materials, can be obtained by cyclization of the corresponding 2-aminopyridine Y with compound (U1) o
    3 hk-ssh .. alk-oK
    where R3, Alk and L have the indicated meanings, and R represents hydrogen or or L, which are poured together, form a bond.
    Compounds characterized by the formula 1 and pharmaceutically acceptable acid addition salts have valuable pharmacological properties. They are very effective serotonin antagonists and can be used in the treatment of various diseases caused by excessive secretion of serotonin. The activity of the compounds of formula (1) as antagonists serotonin is confirmed by the results obtained in the following tests.
    Test 1. Antagonistic activity towards serotonin in the caudal (caudal) artery in rats.
    In the experiment, caudal arteries taken from males weighing 210 235 g were used. Two spiral strips 5-6 cm long and 2 mm wide were obtained from each artery, fixed vertically in a 100 ml bath and filled with oxygenated Kreps-Henseleit solution (Krebc -Henseleit). Submaximal contractions of the arterial bands are induced by adding doses of serotonin (40 ng per ml) to the bath for 2 minutes and 10 minutes after each addition. The amplitude of the contractions is measured before and 5 minutes after the addition of the preparation. After washing off serotonin, the antagonist under investigation was added three times in order to check whether the contraction was preserved or normalized. The table shows the value of ED go in ng / ml for a number of compounds characterized by the formula (1I and intermediate compounds (UE) in the above experiment. The value of ED to denotes the minimum concentrations of drugs that reduce the amplitude of contractions by 50% compared to the normal value.
    Test 2. Efficacy in gastric diseases. Compound. 48/80, which is a mixture of oligomers obtained by condensation of 4-methoxy-α-methylbenzeneethanamine and formaldehyde, is a potential agent that provides the release of vasoactive amines such as, for example, histamine and serotonin from endogenous sources. In rats to which compound 48/80 is administered, significant changes in blood are observed in different vascular layers, cyanosis (cyanosis) of the ears and limbs is observed 5 minutes after the injection of the compound. Rats die of shock after 30 minutes. Fatal shock can be avoided if the rats are preformed. introduce classic Hi antagonist.
    0 However, the stimulating effect on gastric secretion is not suppressed. Thus, rats treated with 48/80 and protected from
    A shock by the Hi antagonist can have all the signs of intensive gastric gland activity: autopsy is noticeable, detectable by abdominal distension and a strong bright red nose on the entire mucous membrane corresponding to the areas of the destroyed glands. A number of known serotonin antagonists, such as, for example, methysergide, cyproheptadine; tsikarin, pipamperon,
    5 spiperone, pizotifen, metergolin Paul. cytosis (cyanosis) of the ears and limbs, as well as diseases associated with the glands of the abdomen and abnormal swelling of the stomach.
    Males of Wistar rats born from parents who are related to each other weighing 220-250 g are kept without food in
    5 for 16 h, water is obtained without limitation. Test compounds are administered in the form of a solution or suspension. A control rat and a pure rat receive the test compound. After an hour, 5- (4- (diphenylmethyl) piperazinylmethyl) -1-methyl-1H-benzimidaeol-2-methanol was administered subcutaneously to all of the Poros: 2.5 mg / kg. 2 hours after oral administration
    the test compound was administered compound 48/80 (immediately before administration dissolved in water at a concentration of 0.25 mg / ml) intravenously, to all rats (dose 1 mg / kg |, except for clean rats. After 4 h after intravenous injection of compound 48 (80 rats are decapitated, stomachs are removed. Next, the stomachs are examined for swelling and contents
    5 (blood, liquid, food) and carefully
    washed. Microscopic portions are assessed on a scale from O to ++ - I-, while O corresponds fully to the absence of visible lesions and the highest estimate corresponds to red strong spots covering more than half of the gland surface.
    The second half of the table refers to compounds characterized by the formula (II and intermediate compounds characterized by the formula. (UE) and doeg1M (in mg / kg J, for which the abdominal distention, like the diseases in the gastric gland, are completely absent in 50% of the rats studied.
    Compounds characterized by the formula (1j) completely prevent organ or tissue damage, which is caused by excessive secretion of serotonin; they also block the reduction of bronchial tissues and blood vessels caused by serotonin.
    vessels (arteries and veins) and, therefore, compounds can be used to treat gastrointestinal ulcers, bronchial spasm, hemorrhoids and similar diseases that are caused by hyperemia.
    A. Psshus intermediate products.
    Example 1. To a stirred mixture of 80 parts of sodium methoxide and 160 hours.
    methanol was added 50 parts of 2-thiopheneacetonitrile and then dropwise 66 hours, 1- (phenylmethyl-7-4-piperidinone. After the addition was complete, the mixture was boiled while stirring
    for 1 h, then the reaction mixture is cooled and evaporated. The residue is distilled, ot- / l- {phenylmethyl / -4-piperidinylidene / -2-thiophenacetonitrile is obtained 70 hours. Similarly
    4-methyl-c .- / 1- (phenyl 1. 1 methyl J-4-piperidinylidene / benzene-acetonitrile.
    Example 2. A mixture of 70 parts of d - "/ (phenylmethyl) -4-piperidinylidene / 2 thiopheneacetonitrile and 800 parts of methanol is hydrogenated under normal pressure at room temperature in the presence of 10 parts of 10% catalysato .palladium on activated coal After the calculated amount of hydrogen has been absorbed, the catalyst from the jFi is extracted and the filtrate is evaporated. as a result, 70 parts of 1- (pheny methyl) (2-thienyl) -4-piperidine acetonitrile are obtained. In an analogous way, (4-methylphenyl-4-piperidine acetonitrile is obtained. Example Z.K. A mixture of 74 h of di-N- (4-methylIlphenyl) -4-piperidine acetonyl), 95.4 parts of sodium carbonate, several crystals of potassium iodide and 1840 hours. 4-methyl-2-pentanone was added in portions of 39.21 parts (chloromethyl / benzene. After the addition was complete, the mixture was boiled under stirring for 24 hours. The reaction mixture was further cooled and 400 hours was added to it. water. The organic layer is separated, dried with potassium carbonate, filtered and evaporated. The oily residue is dissolved in ether and the This solution is saturated with gaseous water hydrogen chloride. The precipitated hydrochloride is filtered off and dried, yielding 68 h of di-ot- (4-methylphenyl -1- (phenylmethyl) -4-piperidine acetonitrile hydrochloride with mp 212-213 ° C. Example 4. To a stirred mixture of 29.6 hours, 1- (phenylmethyl -o (- (2-thienyl) -4-piperidineacetonitrile, and 100 parts of dimethyl sulfoxide) was added in portions of 4 4.60% sodium hydride. during the night. The reaction mixture is poured into water, the precipitated product is filtered off and extracted with chloroform. The extract is dried, filtered and evaporated. The residue is crystallized from isopropyl ether, 10 hours (35%) / 1- (phenylmethyl) -4-piperidinyl- / (2-thienyl | methanone, m.p. 100.5 ° C are obtained. 4,5-methylphenyl -1- (Phenylmethyl l-4-piperidinyl / methanones, m.p. C3.9 ° C. Example 5. To 5 parts of magnesium, 2.18 parts of 1,2-dibromoethane and several crystals of iodine are added. Further a solution of 28 parts of 4-chloro-1-methylpiperidine in 130 parts of tetrahydrofuran is added dropwise, while the reaction mixture is heated to 70 ° C. After cooling, a solution of 14 parts of 3-methylbenzonitrile is added dropwise in 90 hours tetrahydrofuran. After the tops the stirring is continued for another 1 hour at reflux. The reaction mixture is cooled and poured into a solution of 75 parts of ammonium chloride in water. The product is extracted with diisopropyl ether. The ex-tract is washed with water, dried, filtered and evaporated, 35 h are obtained. -3-methylphenyl) 1,1-methyl-4-piperidyl NIL) methanone in the form of an oily liquid. Example 6. A solution of 50 parts of 1-bromo-2-methylbenzene in 140 was added dropwise with magnesium. h, the ether and the resulting mixture is boiled with stirring for 15 minutes. The Grignard reagent is cooled before and added dropwise to a solution of 30 parts of 1- (phenylmethyl) -4-piperidinylcarbonitrile in 70 parts of ether. After the addition is complete, stirring is continued for another 4 hours at room temperature. The resulting reaction mixture was subjected to decomposition with a solution of 40 parts of ammonium chloride in 400 parts of water. The organic phase was separated, dried, filtered. and evaporated to give 31 parts (2-methylphenyl J / 1- (phenylmethyl j-4-piperidinyl / methanone as an oily liquid. In a similar way, (4-fluorophenyl / 4-methyl-1- (. phenylmethyl -4-piperidinyl / methanone as an oily liquid. Example 7. To the Grignard reagent stirred and cooled to 10-15 ° C, obtained from 13.5 parts of 4 ghlor-1-meTylpiperidine and 2.4 parts of magnesium in 68 parts of tetrahydrofuran, A solution of 10 parts of 4-bromobenzonitrile and 22 parts of tetrahydrofuran is dropped in drops. After the addition is complete, stirring is continued for a further 1 hour at a temperature refluxing The resulting reaction mixture was subjected to decomposition, pouring it into a solution for 50 hours, ammonium chloride in 250 parts of water. The resulting product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The resulting current was chromatographed on a column of silica gel, using eluent mixtures of trichloromethane and methanol (95/5 v / v /. The pure fractions are collected and the eluent is evaporated, yielded 10 hours, (4-5-methylphenyl / - (1-methyl-4-piperidinyl) methanone. Example 8. A mixture of 12 parts of ethylcarbochloride, 31 parts of (2-methylphenyl) - / 1- (phenylmethyl) -4-piperidinyl / methanone and 270 parts of dimethylbenzene with stirring, is boiled for 4 hours, the Ds1le mixture is evaporated, the residue is dissolved in chloroform. The resulting solution is washed with dilute hydrochloric acid. The organic phase is separated, dried, filtered and evaporated to give 20 parts of ethyl 4- (2-methylbenzene 1-1-piperidinecarboxylate as an oily liquid. Example 9: Using the method of example 8, using molar amounts of the appropriate starting materials ethyl 4- {4-methylbenzoyl) -1-piperidinecarboxylate} ethyl 4- (4-fluorobenoyl) -4-methyl-1-piperidinecarboxylate is obtained: ethyl 4- (2-thienylcarbonyl) -l-piperidinecarboxylate.
    Example 10: To a stirred mixture of 35 parts (3-methylphenyl M1-methyl-4-piperidinyl methanone, 1 hour sodium carbonate and 225 hours, dimethylbenzoyl is added dropwise 22 parts of ethylcarbochloride at a temperature of 20 ° C. After the addition of bales t under stirring for 6 hours. The reaction mixture is evaporated to give 12 parts of ethyl 4- (3-methylbenzoyl) -1-piprridinecarboxylate as an oily liquid.
    Similarly, receive; ethyl 4- {4-bromobenzoyl -1-piperidinecarboxyl ate.
    Example 11. A mixture of 103 parts of ethyl 4- (4-methylbenzoyl-1-piperidinecarboxylate and 900 hours. 48% solution of hydrobromic acid
    stir and boil for 3 hours. Then the reaction mixture is stirred while cooling in an ice bath. The precipitated product is filtered off, washed with water and acetone, 91 parts (86%) are obtained (4-methylphenyl (4-piperidinyl) methanone hydrobromide, m.p. 300 ° C).
    EXAMPLE 12 Analogously to Example 11, the following is obtained: (3-methylphenyl) U-piperidinyl / metashen hydrobromide; {4-bromophenyl) (4-piperidinyl) methanone hydrobromide; (2-Methylphenyl I (4-piperidinyl) methanone hydrobromide; (4-Piperidinyl) (2-thienyl methanone hydrobol MFA) (4-fluorophenyl) (4-methyl-4-piperidinyl methanone hydrobromide.
    Example 13. To a mixture of 155 parts of 1-fluoro-3-methoxybenzene, 75 parts of aluminum chloride and 650 parts of 1,2-dichloroethane with stirring are added in portions of 118 parts of 1-acetyl-4-piperidinecarbonyl chloride. After the addition is complete, stirring is continued for 1 hour at 40-50 ° C. The resulting reaction mixture is poured into a mixture of crushed ice and hydrochloric acid, then extracted with toluene. Extraction is dried, filtered and evaporated. The residue is purified by liquid chromatography at high pressure on silica gel using chloroform as eluant (Hexane and methanol (47.5: 47.5: 5 by volume. The resulting fraction (Aisomer) is collected and the eluent is evaporated; 1-acetyl is obtained 4- (2-fluoro-4-methoxybenzoyl / piperidine. The second fraction (B-isomer) is collected and the eluent is evaporated, 40 parts (25%) of 1-acetyl-2- (4-fluoro-2-hydroxybenzoyl) piperidine are obtained.
    A mixture of 40 parts of 1-acetyl 2- (4-fluoro-2-hydroxybenzoyl) piperidine and 150 hours. 6 N hydrochloric acid is stirred and boiled for 3 hours, then cooled. The precipitated product is filtered off, washed with acetone and dried, obtained 29 hours, .87%) (4-fluoro-2-hydroxyphenyl / (4-piperidinyl / methanone hydrochloride, so pl.
    EXAMPLE 14 To a stirred mixture of 4 parts of 60% sodium hydride and .180 parts of toluene was added dropwise 12 parts of ethyl 3-oxobutanoate at room temperature. Then 1 part of N, N-tridecylmethylammonium chloride is added and the mixture is heated to .40 ° C. At this temperature, 25 parts of (1- (3-chloropropyl) -4-piperidinyl) (4-chlorophenyl) methanone are slowly added to 45 parts of toluene. The mixture is heated to boiling and the mixture is kept at reflux. Overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated, yielding 24 parts of ethyl-o (acetyl-4 (4-fluorobenzoyl J-1-piperidine pentoanoate).
    B. Obtaining the target compounds (1
    Example 15. A mixture of 5 parts of 3- (2-chloroethyl} -2-methyl-4H-pyrido / 1,2-a / primidin-4-one, 4.9 parts (4-fluorophenyl / (4-piperidinyl | methanone hydrochloride, 5 parts of sodium carbonate and 160 parts of 4-methyl-2-pentanone are boiled under stirring for 24 hours. The resulting reaction mixture is cooled, inhaled with water and the layers are separated. The organic phase is dried, filtered and evaporated The residue is purified by chromatography on a column of silica gel using a mixture of chloroform and methanol as eluent (92: 8 vol. J, the pure fractions are collected and the eluent is evaporated; comfort from a mixture of ethanol and ether, get 3 parts of 3- 2- / 4-4-fluorobenzoyl -1-piperidinyl / ethyl.-2-methyl-4H-pyrido / 1, 2-a / pyrimidine, -4-sleep with m.p. 130
    Example 16. Analogously to example 20, using equivalent amounts of the corresponding starting materials, receive
    tch
    СНН4-4СНз
    n
    nn nn he
    n With N -400113
    SeN.SsRz. n n
    SH. 20H
    СНН4
    6-CH, Sat "4n Example 17. A mixture of 5 h, .3- (2-chloroethyl) -2-methyl-4H-pyrido / 1,2-a / pyrimidin-4-one, 6 h, phenyl (4- piperidinyl) methanone hydrobromide, 8 parts sodium carbonate, 0.1 parts potassium iodide and 240 hours, 4-methyl-2-pentanone with stirring, boil for 24 hours using a water separator. The resulting reaction is filtered. hot and the filtrate evaporated. The residue obtained is purified on a chromatographic column with silica gel using CH, -CHP-K.
    &
    Base
    Base
    1/2 C, .H2O by calling as eluent a mixture of chloroform and methanol (90:10 by volume /. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of ethanol and ether, get b h 3- / 2 - (. 4 -benzoyl-1-piperidinyl) ethyl / # 2-methyl-4H-pyrido / 1, 2-a / pyrimidin-4-one with mp, 122.2 ° C. Example 18. Using the method of example 16 and using equivalent the amounts of the corresponding starting materials are obtained
    Table continuation
    权利要求:
    Claims (2)
    [1]
    1. The method of obtaining derivatives of 3- (1-piperidinylalkyl) -4H-pyrido (1,2-a) pyrimidine ~ 4-one is general of the formula. ·.
    where R is hydrogen, lower alkyl or an oxy group at position 2,3 or 4 of the piperidine ring;
    R 1 and R 2 are independently hydrogen, lower alkyl or halogen;
    R 3 is hydrogen or lower alkyl;
    Aik - q - C, -alkylene;
    Ar is unsubstituted phenyl or substituted by one or two substituents from the number of halogen, oxy group, lower alkyl or alkoxide, thienyl or their pharmaceutically acceptable acid-adaptive salts, which is due to the fact that the derivative of 4H-pyrido (1,2-a ) pyrimidin-4-one of the General formula
    R 3 and about
    Aik - indicated values;
    Hal — chlorine, bromine, or iodine — is reacted with a piperidine derivative of the general formula wherein R and Ar are the indicated values, in the presence of a base in an inert organic solvent, preferably by boiling, followed by isolation of the target product in the form of a base or an acid addition salt.
    [2]
    2. The method of production according to π. 1 3- [2 / 4- (4-fluorobenzoyl) -1-piperidinyl / ethyl] -2-methyl-4H-pyrido (1,2-a) pyrimidin-4-one or its pharmaceutically acceptable acid addition salts, characterized in that 3- {2-chloroethyl) -2-methyl-4H-pyrido (1,2-a) pyrimidin-4-one-is reacted with 4-fluorophenyl (4-piperidinyl) methanol hydrochloride, followed by isolation target product in the form of a base or salt.
    Priority: according to en akam:
    03/28/80 with R, R 1 -R 3 , Aik - all values;
    Ar - unsubstituted phenyl or substituted by one or two substituents from the number of halogen, lower alkyl or alCoxyl, thienyl.
    09/29.80 at Ar - phenyl substituted with 1 or 2 hydroxy groups.
    SU, .1068037
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    同族专利:
    公开号 | 公开日
    FI71737B|1986-10-31|
    ES8300763A1|1982-11-01|
    CS256366B2|1988-04-15|
    US4342870A|1982-08-03|
    IL62494A|1984-08-31|
    ES500814A0|1982-11-01|
    YU43010B|1989-02-28|
    DK159390B|1990-10-08|
    IE51319B1|1986-12-10|
    IL62494D0|1981-05-20|
    IE810706L|1981-09-28|
    NZ196522A|1985-10-11|
    FI71737C|1987-02-09|
    RO82508A|1983-09-26|
    FI810956L|1981-09-29|
    CA1163994A|1984-03-20|
    HU187329B|1985-12-28|
    NO811058L|1981-09-29|
    MA19107A1|1981-10-01|
    DK159390C|1991-03-04|
    AU537700B2|1984-07-05|
    PT72740A|1981-04-01|
    GR72488B|1983-11-14|
    NO156752B|1987-08-10|
    PT72740B|1982-11-16|
    DE3168433D1|1985-03-07|
    NO156752C|1987-11-18|
    RO82508B|1983-08-30|
    EP0037265B1|1985-01-23|
    YU81081A|1983-12-31|
    EP0037265A1|1981-10-07|
    AU6842981A|1981-10-01|
    PH16530A|1983-11-10|
    BG36199A3|1984-09-14|
    DK138281A|1981-09-29|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US13484580A| true| 1980-03-28|1980-03-28|
    US06/191,632|US4342870A|1980-03-28|1980-09-29|Novel 3--4H-pyrido[1,2-a]pyrimidin-4-one derivatives|
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