• 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:
    New pyridinyl aminoalkyl ethers, their N-oxides and their physiologically acceptable addition salts with acids, processes for their preparation and pharmaceutical formulations which contain these compounds and are useful in the treatment of cardiac arrhythmias.
    公开号:SU850002A3
    申请号:SU782699099
    申请日:1978-12-19
    公开日:1981-07-23
    发明作者:Фон Филипсборн Герда；Боэлль Вальтер；Ленке Дитер
    申请人:Басф Аг (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR SIMPLE PIRIDINILAMINOLLKILOVYH esters or their physiologically acceptable invention relates to a process for the preparation of novel pyridine derivatives namely to a process for preparing polyether esters piridinilaminoalkilovyh general formula R-A-K 0 ((T) K V; wherein R represents a hydrogen atom, -alkyl, benzyl; R — R is the same or different and denotes a hydrogen atom, methyl, substituted hydroxy, methoxy, dimethylamino groups, alkoxycarbonyl with 1-2 C atoms in alkyl, R and R together represent the residue —CHg-B- CH -, in which B is an oxygen atom, -N- or -O-CH-OCH „ , cH (CHj) 2 R is a hydrogen atom, phenyl is C-alkyl, the phenyl ring of which can be substituted by oxy, chlorine, trifluoro methyl, methyl, ioC-thienyl or ct-thienylmethyl; CO.PAY A is branched or unbranched C (-C-C1 -klyl6b) chain, unsaturated alkylene chain with 4 C atoms or L-thienyl residue; RS is a hydrogen atom, C-alkyl, optionally substituted with hydroxy, methoxy, phenyl or phenyl, optionally substituted with a methoxy group, -alkynyl, Cj ..- cycloalkyl, in the corresponding case substituted by methyl; R is a hydrogen atom or C-Alkyl) R and R together with an N atom means a 6-membered ring containing, as appropriate, an N atom, free or substituted by alkyl, benzyl or free or substituted methoxy group by phenyl, or their physiologically acceptable salts, which can find application in the chemical-pharmaceutical industry. Alkylation of 3-pyridinol by alkyl halides of fl} is known. The purpose of the invention is the development, on the basis of a known method, of a method for the preparation of new compounds possessing valuable pharmacological properties. The goal is achieved by the proposed method of producing simple pyridinylaminoalkyl ethers of the formula (I), which consists in the fact that the pyridinol of the general formula
    K R V-.
    H-B is abbreviated to P-OH, in which K, R, R and R have the above values are reacted with a compound of the general formula X-A-Y, in which X and Y are chlorine, bromine or iodine, and A has the above value, temperature from 0 to, in the presence of a base in an organic solvent medium, and the resulting compound of the general formula
    Р-О-Д-У
    is reacted with an amine of the formula R -NH-R, in which R and R are as defined above, at a temperature of 60-120 0, and the resulting desired product is isolated in free form or in the form of physiologically acceptable salts.
    The reaction of a compound of general formula (II) with a compound of general formula XA-Y is preferably carried out at a temperature of from 20 to.
    When reacting a compound of general formula (II) with X-A-Y, lower alcohols containing 1-4 C atoms, in particular methanol or ethanol, lower aliphatic ketones, benzene hydrocarbons, such as benzene as such or alkyl, are used as an organic solvent. or halobenzenes, such as, for example, chlorobenzene or toluene, simple aliphatic or cyclic ethers, for example distilled ether, tetrahydrofuran or dioxane, dimethylformamide or dimethyl sulfoxide. If ether is used as the solvent, hexamethylphosphoric acid triamide can be added to this ether as an additional solvent.
    In the case when there are no easily omnified functional groups in pyridinol, two-phase mixtures of solvents are used, in particular mixtures of water with a chlorinated hydrocarbon, for example, dichloromethane, or benzenehydrocarbon, for example benzene or toluene, a base mixture consisting of alkali metal hydroxide, e.g. sodium hydroxide, and quaternary ammonium base or phosphonium base, which are attached in a catalytic amount, IrlO mol%, based on compound (1I), in the form of a salt, For example triethylbenzylammonium chloride, tetrabutylammonium hydrogen sulfate, tributilgeksadedil-phosphonium bromide.
    The intermediate product of the formula (III is isolated and then reacted with the amine R -NH-R, or not isolated, directly subjected to the said reaction, it is advisable to remove the unreacted alkylating agent before.
    For the preparation of acid addition salts, in particular, such acids are used, which are suitable for the formation of therapeutically useful salts. These include, for example, hapogenic acids, sulfuric acid, phosphoric acid, nitric acid, fumaric acid, aliphatic, acyclic, aromatic or heterocyclic carboxylic or sulphonic acids, such as formic, acetic, propionic, sucroic, glycolic acid, glycolic acid, sypholic acid, acetic acid, propionic acid, succinic acid, glycolic acid, syphonic acid, fumaric acid, fumeric acid, acetic acid, propionic acid, hydrochloric acid. tartaric, citric, ascorbic, maleic or pyruvic acid, benzoic, anthranilic, p-hydroxybenzoic or salicylic acid, methanesulfonic, ethanesulfonic, hydroxyethane sulfonic, ethylene sulfonic ki slot, halobenzenesulfonic, toluenesulfonic, cyclohexylaminosulfonic acid or sulfanilic acid.
    The conversion to the acid additive salt can, if appropriate, serve to purify the obtained compounds and then transfer them to free bases.
    Compounds of the general formula () are also precipitated as optical antipodes or racemates, or as mixtures of diastere. The resulting mixture of diastereomers can be divided into diastereomers, for example, by chromatography and / or fractional crystallization.
    The racemates obtained can be separated by known methods into optical antipodes, for example, by reaction of interaction with an optically active acid and by separation into diastreomers, either by microorganisms or by recrystallization from an optically active solvent. Particularly suitable optically active acids are, for example, the D- or L-forms of tartaric acid, malic acid, mandelic acid, or camphorsulfonic acid.
    The starting compounds of formula (It) are prepared from oxazole of formula
    U y,
    where R and R have the meanings indicated for formula (II) and R stands for hydrogen, alkoxy with 1-5 C atoms or nitrile, are reacted with an olefin of formula Ii-ciH: where R and R are indicated for formula (I) and R means hydrogen, alkylsulfonyl with 1-5 C atoms or phenylsulfonyl, at temperatures from 20 to with the condition that at least one of the residues R and R0 means hydrogen, or if both residues R and R® mean hydrogen reaction carried out in the presence of a dehydrating agent, and in this case the resulting compound is connected in the usual way. m converted to acid addition salt. The compounds of the general formula (I) are distinguished by a strong antiarrhythmic and / or local anesthetic action. In particular, they can be used for the treatment of heart rhythm disorders. The preparation of the starting compounds of Formula (II) is illustrated by examples. Approximately 1. 4-benzyl-6-methyl -1,3-dihydro-furo (3,4-с) -pyridin-7-ol. . A mixture consisting of 296 g (2 mol of 3-methylsulfonyl-2,5-dihydrofuran and 692 g (4 mol) of 2-benzyl-4-methyloxazole) is heated to 20 ° C for 20 h. After cooling, the mixture is suspended in 1 l of methylene chloride The solution contains unreacted oxazole. The insoluble part is a mixture of 4-benzyl-6-methyl-1, 3-dihydro-furo (3,4-c) -pyridin-7-ol and 3,4-dimethylsulfonyl-tetrahydrophosphane which is separated with 1.35 L of nitromethane. 186 g of 4-benzyl-5-methyl-1,3-dihydro-furo (3,4-c) -pyridine-7-ol with mp 212 remain undissolved. -214s, after recrystallization from methano la, mp 2150c. Found,%: C, 74.4, H 6.2, N, 6.2 C. .. (Molecular weight 241) Calculated,%: C, 74.7, H 6.2, N 5.8 Hydrochloride, recrystallized from water, is melted at. The reaction is also carried out with 3-ethylsulfonyl-2,5-dihydrofuran or 3-phenylsulfonyl-2,5-dihydrofuran. Example 2. 4-benzyl-6-ethyl- 1, 3-dihydro-furo (3,4-c) pyridin-7-ol 2-benzyl-4-ethyloxazole. A) 128 g (0.5 mol) of phenylacetamide-cyclohexyl ether hydrochloride are added to a mixture of 23 g (0 , 25 mol) 2-ketobutanol and 100 g of N, N-dimethylamine. The reaction mass is heated for 2.5 hours before, after cooling, 250 ml of 10% sodium hydroxide solution are added and extracted with methylene chloride. After distilling off the solvent, the residue is subjected to fractional distillation. 9.5 g of 2-benzyl-4-ethyloxazole are obtained with a bp. 74 - 76 ° C / O, 2 mm. b) 9.4 g (50 mmol) of 2-benzyl-4-ethyloxazole and 29.6 g (200 mmol) of 3-methylsulfonyl-2,5-dihydrofuran are heated to 150 ° C for 15 hours. The unreacted sulfone is distilled off under high vacuum. The residue is taken up with methylene chloride, the undissolved part is sucked off and the filtrate is extracted with 150 ml of a 10% sodium hydroxide solution. The alkaline solution is neutralized and extracted with methylene chloride. When the methylene chloride solution was concentrated, 6.2 g of 4-benzyl-6-ethyl-1, 3-dihydro-furo (3,4-c) pyridin-7-ol with a mp. after recrystallization from nitromethane 148C. Found: C, 75.2; H, 6.7; N, 5.6. (Molecular weight: 255): C, 75.3; H, 6.7; N 5.5. Example 3. 4,6-dibenzyl-1,3-dihydro-furo (3,4-c) pyridin-7-ol. 44 g (150 mol) of 2,4-dibenzyl-5-ethoxyoxazole and 210 g (3 mol) of 2,5-dihydrofuran are heated to 180 ° C for 8 hours. excess 2,5-dihydrofuran is distilled off and the precipitate is taken up in ether. The undissolved portion is recrystallized from ethanol. This gives 17.6 g of 4,6-dibenzyl-1, 3-dihydro-furo (3,4-c) pyridin-7-ol, m.p. 204-205 C. Found,%: C 79.4, H.6.2, N 4.5. Cj-H-NOj. (Molecular weight 317) Calculated,%: C 79.5, H 6.0, N 4.4. The preparation of the compounds of general form (I) is illustrated by the following additions. Example 1. a) A mixture of 24.2 g (100 mol) of 4-benzyl-6-methyl-1,3-dihydro-furo (3,4-c) pyridine-7-ol, 113 g (1 mol) of 1, 3-dichloropropane, 2 g of benzyltriethylammonium loride, 100 ml of oluol and 100 g of 50% sodium hydroxide solution are heated to 90 s with stirring for 3 hours. The organic phase is separated and washed with 0 l of water. After distillation, dissolve and excess 1, 3-dichloropropane, 30.7 g of simple (4-benzyl-6-methyl-1, 3-dihydro-furo (3,4-c) pyidin-7-yl) -3-chloropropyl ether form a small portion 1,3-bis- (4-benzyl-6-methyl-1, 3-dihydro-furo (3,4-c) pyriin-7-hydroxy- / -propane, which does not react in the subsequent. B) A mixture of 24.2 g (100 mol) -benzyl-6-methyl-1,3-dihydro-furo (3,4-c) pyridin-7-ol, 226 g (2 mol), 3-dichloro-propane, 2 g bentiltriethylammonium chloride and 100 g of 50% sodium hydroxide solution are heated to 0c for 3 hours with stirring.
    The organic phase is separated and cleaved. 50 MP of water. After distillation of the excess of 1,3-dichloropropane, 30.7 g of growth (4-benzyl-6-methyl-1,3-dihydropyro (3,4-c) pyridine-7-yl) -3 chloropropyl ether with a small asthema 1 remain. , 3-bis- (4-benzyl-b-methyl1, 3-dihydro-furo (3,4-с) pyridine-7-hydroxy) -propane, which does not interfere with the subsequent interaction ..
    c) 24.2 g (100 mol) of 4-benzyl-6-methyl-1, 3-dihydro-furo (3,4-c) pyriin-7-ol are suspended in 80 ml of dry dimethyl sulfoxide 1a and by adding 3.5 g (120 mol) of sodium hydrochloride (85% in oil), while being converted to the sodium salt. Then it is added dropwise at a temperature from 0 to 10 OUc, FROM g (1 mol) of 1,3-dichloropropane and stirred for 15 hours at. Dimethyl sulfoxide and an excess of 1,3-dichloropropane are distilled off under high vacuum. The residue is dissolved in 250 ml of methylene chloride, extracted with 2 times 50 ml of 10% sodium hydroxide solution and washed with 10 l of water. After distilling off the solvent, 30.7 g of simple (4-benyl-b-methyl-1, 3-dihydro-furo (3,4-c) pyridyl-7-IL) -3-chloropropyl ether with a small portion of 1,3- bns- (4-benzyl-b-methyl-1, 3-dihydro-furo (3,4-с) -pyridin-7-oxo) propane.
    d) 8.0 g (25 mol) of the product obtained under a), b) or c) is heated to SWSS with 15 g (250 mol) of isopropylamine in an autoclave for 7 hours. Excessive 1 min is distilled off under reduced pressure. To purify the residue, it is chromatographed on silica gel (ethyl acetate, methanol). Formed (4-benzyl-6-methyl-1,3-dihydro-furo (3,4-c) pyridin-7-yl) -3-yzopropylamino-propyl ether is converted into bis-hydrochloride using dilute hydrochloric acid. which is recrystallized from isopropanol (7.8 g, so pl.).
    For product purification, extraction with dilute hydrochloric acid can also be used instead of chromatography, and adding 1N hydrochloric acid to the solution of the crude product so that the aqueous phase has a pH of 6.7. By separation and concentration
    the aqueous phase, simple (4-benzyl-b-methyl-1, 3-dihydro-furo (3,4-c) -pyridin-7-yl) -3-isopropylamino-propyl ether is obtained in the form of monochloride, while less contaminated remain in the toluene phase.
    In a similar way, the compounds listed in Table 2 are obtained. 1, and with high boiling point amines (above 100-120 ° C), the use of an autoclave is unnecessary.
    Examples 37-58. Analogously to Example 1 a), b) or c), the corresponding haloalkyl ether is obtained by reacting with 1,4-dichlorobutane, 1,4-dibromo-butene- (2), 1,5-dichloropentane or 1,5-dichloro-3. methylpentane instead of 1,3-dichloropropane. The ester obtained using an amine, analogously to Example 1 g), is converted to the compounds indicated in Table 3.
    Example 59. 4, b-Dibenzyl-1,3-dihydro-furo (3,4-c) pyridin-7-ol, is synthesized analogously to example 1a), by reacting with 1,4-dichlorobutane, translated into B-chlorobutyl ether. In this case, 4,6-dibenzyl-1, 3-dihydro-furo (3,4 g) pyridine-7-yl-5-isopropylamino-butyl eflr, hydrochloride bis-hydrochloride, is obtained, angshogically to Example 1g).
    Found,%: N 5.5
    Calculated; N 5,6
    (Yield 42%).
    Example 60 Analogously to Example 1, by reaction with l, 4-dichlorobutyric, 2-methyl-4,5-dicarbethoxy-6-benzyl-pyridin-3-ol is converted to the b-chlorobutyl ether. You get 2-methyl-4, 5-dicarbethoxy-6-benzyl-pyridin-3-yl-b-isopropylamino-butyl ester bis-hydrochloride (analogously to example 1) with mp.156166 ° C.
    Found,%: N 5.4
    Calculated,%: N 5.3 (OUTPUT 35%).
    Examples 61-65. Analogously to Example 1a), by reacting with 1/4-dichlorobutane instead of 1,3-dichloropropane, the corresponding 4-chlorobutyl ether is obtained, which, according to Example 1 g), is converted to the compounds listed in Table. four.
    Table 1
      (CH,) N (
    /
    , CH, iOCH5 CHjOCH
     f
    "
    76
    202-2047,07,1
    26
    1696,76,6
    95
    2006,86,7
    153-1557,47,4
    50
    Continued n ab ab.
    Continued table.
    invention formula
    1. A process for the preparation of pyridinylaminoalkyl ethers of the general formula
    -AND&
    i; j / -
    where R is a hydrogen atom, C-alkyl, benzyl
    R and the same or different and represent a hydrogen atom, methyl, substituted hydroxy, methoxy, dimethylamino55 groups; alkoxycarbonyl with 1-2 atomic C in alkyl,
    R and R together mean the residue -CHn-B-CH -, in which B is an oxygen atom,
    -O-CH-0-NILE
    I t
    f ČSN (CH5) CH,
      hydrogen atom, phenyl-C;,. -hryxyl, the phenyl ring of which may be substituted by hydroxy, by a chlorine atom. trifluoromethyl, methyl; or cai; -t yen and either a-thienylmethyl, A is branched or unbranched Stu-C (, is an alkylene chain, an unsaturated alkylene chain with 4 C atoms or a ct-thienyl residue; R5 is a hydrogen atom, C-alkyl, in the corresponding in the case of substituted hydroxy, methoxy, phenyl or phenyl, in a corresponding case substituted by a hydroxy group, Cl, -alkynyl, C, -cycloalkyl in the corresponding case substituted by methyl — hydrogen or C ,. -alkyl together with an N atom means a 6-membered ring containing in this case an N atom free or substituted by alkyl, benzyl or free or methoxy-substituted phenyl, or their physiologically acceptable salts, characterized in that pyridiol of the general formula / -Tu (7 //. abbreviated P-OH, in which R, R, (and R have the above values. subject to interaction with the compound of the general formula X-A-Y, in which X and Y mean chlorine , bromine or iodine, and A has the above value, at a temperature from O to, in the presence of a base in an organic solvent medium, and the resulting compound of the general formula P-O-A-U (III) is reacted with an amine of the formula R -NH-R, in which I and R have the above values, at a temperature eO-lZO C, and the resulting desired product is isolated in free form or in the form of physiologically acceptable salts. 2. The method according to claim 1 is different from the fact that the reaction of the compound of the general formula (II) with the compound of the general formula X-A-U are preferably at a temperature of from about 20 to about. Sources of information taken into account in the examination 1. R. Elderfield. Heterocyclic compounds. T. 1. M., 1953, p. 413.
    权利要求:
    Claims (2)
    [1]
    Claim
    R a and Rr are the same or different and mean a hydrogen atom, methyl, za1. A method for producing simple pyrimethoxy oxy, methoxy, dimethylaminodinylaminoalkyl ethers of general form 55 groups; alkoxycarbonyl with 1-2 atoms
    -sn a -b-cn lorod, *** si1KIL f where R 1 benzyl / mami C in alkyl,
    R 2 and R ^ together mean a residue in which B —atom kis — O — CH — OI f sn (sn 3 ) 3 hydrogen, phenyl-C ,. g -alR4 is a keel atom, the phenyl ring of which may be substituted by hydroxy, a chlorine atom, trifluoromethyl, methyl; or cL-thienyl or s-thienylmethyl,
    A is a branched or unbranched C ^ -C b alkylene chain, an unsaturated alkylene chain with 4 C atoms or an a-thienyl residue;
    R 5 is a hydrogen atom, -alkyl, $ substituted by hydroxy, methoxy, phenyl or phenyl, if appropriate, substituted by methoxy, -alkynyl, C, ^ -cycloalkyl, substituted by methyl, as appropriate,
    R b is a hydrogen atom or C ^ _ 6 -alkyl,
    R s and R b together with the atom N mean
    A 6-membered ring containing, as appropriate, an N atom, is free. 15 or substituted by alkyl, benzyl or free or methoxy substituted phenyl, or their physiologically acceptable salts, characterized in that, in order to obtain new compounds, pyridinol of the general formula abbreviated P-OH, in which R 5 , R 2 ·, rf 1 and R 1 * are as defined above, is reacted with a compound of general formula X-a-Y, wherein X and Y are chlorine, bromine or iodine, and a has the abovementioned meaning, at temperatures from 0 to 150 and C, in the presence of a base in an organic solvent medium, and the resulting compound rmula
    P-O-A-Y (III) is reacted with an amine of the formula R 6 —NH — R b , in which R 5 and R 6 are as defined above, at a temperature of 60-120 ° C, and the obtained target product is isolated in free in the form or in the form of physiologically acceptable salts.
    [2]
    2. The method of pop. 1 characterized in that the reaction of the compound of general formula (II) with the compound of general formula XA-A is preferably carried out at a temperature of from 20 to 100 ° C.
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    同族专利:
    公开号 | 公开日
    DK118578A|1978-09-18|
    CA1108148A|1981-09-01|
    AT364360B|1981-10-12|
    NO780931L|1978-09-19|
    SU799658A3|1981-01-23|
    NL189563B|1992-12-16|
    NO150605B|1984-08-06|
    CS202012B2|1980-12-31|
    SE446185B|1986-08-18|
    FR2383930A1|1978-10-13|
    HU177287B|1981-09-28|
    JPS53116382A|1978-10-11|
    GR64096B|1980-01-22|
    CH638186A5|1983-09-15|
    IT1093796B|1985-07-26|
    YU63678A|1983-01-21|
    ATA84080A|1981-03-15|
    IT7821099D0|1978-03-10|
    NO150605C|1984-11-14|
    ZA781552B|1979-04-25|
    NL7802719A|1978-09-19|
    DE2711655A1|1978-09-21|
    DE2711655C2|1987-07-16|
    AU525566B2|1982-11-11|
    AT364361B|1981-10-12|
    JPS6123790B2|1986-06-07|
    YU41016B|1986-10-31|
    IE46484B1|1983-06-29|
    FR2383930B1|1982-10-22|
    FI780842A|1978-09-18|
    IE780503L|1978-09-17|
    ES467931A1|1979-07-01|
    SE7802927L|1978-09-18|
    US4206117A|1980-06-03|
    FI74962B|1987-12-31|
    BE864917A|1978-09-15|
    LU79235A1|1978-06-28|
    CS202011B2|1980-12-31|
    NL189563C|1993-05-17|
    DD134090A5|1979-02-07|
    ATA187878A|1981-03-15|
    IL54265D0|1978-06-15|
    FI74962C|1988-04-11|
    AU3419578A|1979-09-20|
    YU225282A|1983-02-28|
    GB1599061A|1981-09-30|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE2711655A|DE2711655C2|1977-03-17|1977-03-17|
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