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    • 专利摘要:

    公开号:SU997606A3
    申请号:SU802864204
    申请日:1980-01-08
    公开日:1983-02-15
    发明作者:Гунар Фрибе Вальтер；Винтер Вернер；Тиль Макс；Роеш Андроники；Вильхельмс Отто-Хеннинг
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    solvent at boiling in the presence of a base, for example, tertiary amine j 2 J. The purpose of the invention is to obtain new simple aryl derivatives, esters (its variants) or their pharmaceutically acceptable salts, which have anti-allergic or anti-hypertensive activities, and to be intermediate products for the synthesis of biologically active compounds. The goal is achieved by the fact that according to the method of producing ether aryl ethers of general formula 1, one of the variants of which is that the compound of general formula I; 3 R where A, R, R ,,, R and R g are given values are reacted with a compound of the general formula Id x-cffj-eii-CHi-9, where X and Y represent a chlorine atom and bromine R .. is an atom hydrogen or together with Y can be an oxygen atom, and the resulting compound is treated with piperidine of the general formula lV: O HNvbra-Rg where R has the indicated value, and By necessity, if it means a hydrogen atom, the compound of general formula T is acylated and the target product is selected in free form or in pharmaceutically acceptable salt form. According to the second variant, the goal is achieved by the fact that the piperidine of general formula IV is reacted with a compound of general formula III and the resulting compound is reacted with a compound of general formula I and, if necessary, with R, the hydrogen atom / compound of general formula 1 is acylated and the target product isolated in free form or in the form of a pharmaceutically acceptable salt. The proposed two variants of the method differ from each other in the order of interaction of the reactants and are carried out in essentially the same way. The starting compounds of the general formulas I, III and IV are known substances or are prepared by known methods. Pharmacologically compatible salts are prepared in the usual way, for example by neutralizing the compounds of formula 1 with non-toxic inorganic or organic acids such as hydrochloric, sulfuric, phosphoric, hydrobromic, acetic, lactic citric, block, salicylic, malonic maleic, or succinic acid. For the preparation of drugs, the compounds of general formula 1 are mixed in a manner known per se with suitable pharmaceutical bases, aromatics and flavoring agents and dyes and, for example, molded in the form of tablets or dragees or, with the addition of appropriate auxiliaries, are suspended or diluted in water or oil, for example in olive. The compounds of the general formula T are administered orally or parenterally in a liquid or solid form. Preferably, water is used as an injection medium, which contains stabilizers, solvents and buffers that are common for injection solutions. Such additives are, for example, tartrate or brth buffer, ethanol, dimethylsulfox1 d, complexing agents (e.g., ethylene diamine tetraacetic acid J, high molecular weight polymers (e.g. liquid polyethylene oxide for viscosity adjustment or polyethylene derivatives of sorbitanhydrides). , lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high molecular weight polymers (such as polyethylene glycols). Suitable for oral administration. Compositions preferably contain sweet substances. For external use, the proposed substances of formula 1 are also used in the form of powders and ointments, for which they are mixed, for example, with powdered, physiologically compatible diluents or usual bases of ointments. the health and weight of the patient (the recipient), the extent of the disease, the type of simultaneously tested person under certain conditions of other treatments, the frequency of treatments (treatments) and the type of desired effect. The daily dose of the active compound is 0.150 mg / kg body weight. The most active is 0.5–40 mg / kg, preferably 1.020 mg / kg per day, in one or several administrations, in order to obtain the desired value. significant results. , Example 1. (4-Benzamido piperidine propoxy J-3,4-dimethylcoumarin. A mixture of 9.34 g (0.03 mol) of 7- {3-6throm-propoxy.) - 3,4-dimethylcoumarin, 6.13 g (0.03 mol) 4-benz4Mid piperidine, 12.43 g (0.09 mol) of triethylamine and 100 ml of tetrahydrofuran are refluxed for 6 hours and concentrated in vacuo, the residue is treated with water, extracted with methylene chloride and the extract is concentrated. After recrystallization from methanol, 6.5 g of (4-benzamido-piperidino) propoxy-3,4-dimethylcoumarin (50% of theory) are obtained. From TGO1. 201-203 ° C. Using 7-СЗ-bromopropoxy) -3,4-dimethylcoumarin as the starting product was prepared as follows. To a solution of 47.6 g (0.25 mol of 3,4-dimethyl-7-hydroxycoumarin in 250 (1 ml butanol, 77 ml of 1,3-dibrmpropane are added, the solution is heated to 3 h and 38.0 g of potassium carbonate is added. | After refluxing for 2 hours, the filtrate is concentrated and the filtrate is concentrated .-. After recrystallization from the cyclohexane, 51.9 g of the indicated starting material remains (67% of theory), mp 99-101 C. Example 2. Analogously to Example 1 The substances listed in Table 1 are obtained. Example 3: 7- (3-4-Benzamidopiperidino (propoxy / coumarin. To a solution of 0.58 g (0.025 mol) sodium in 100 ml of isopropanol is added 4, ; b5 g (0.025 mol) 7-oxy the marina is boiled under reflux for 10 minutes and 7.25 g (0.025 mol) of 3- (4-benzamidopiperidino propyl chloride in 25 ml of isopropanol is added. After boiling for 6 hours under reflux, the mixture is concentrated in vacuo, dissolved in chloride methylene, washed with 2N sodium hydroxide solution and then with water, concentrated and recrystallized from ethanol to obtain 8.9 g of 7- (3-4-benzyl dopiperidino-propoxy coumarin (88% of theory) with mp. 157-158 seconds. The 3- (4-benzamidopiperidi-o) propyl chloride used as the starting material is prepared as follows. A mixture of 80.0 g of 4-beisamidopiperidine, 38.6 ml of 1-bromo-3-chloropropane, 162 ml of tridtylamine and 700 ml of tetrhydrofuran is heated for 5 hours with reflux, filtered and the filtrate is concentrated. The residue is taken up in water and ethyl acetate, the organic phase and concentrate. 71.0 g of the indicated starting material remains (65% of theory) with a mp. 132133 C. PRI me R 4. Analogously to example 3, receive the substances listed in table. 2. Example 5. 1- / 4-Benzamidopiperidino (-3-9 3,4-dimethylcoumarin-7-yl6xy (-2-propanol. A mixture of 8.1 g (0.033 mol) of 3,4-dimethyl-7- (2,3-epoxypropoxy / coumarin, 6.73 g (0.033 mol) of 4-benzamidopiperidine and 75 ml of ethanol are refluxed for 6 hours, concentrated, the residue is treated with acetic ethyl ether, washed with water, concentrated and recrystallized from ethyl acetate 2.8 g of 1- (4-benzamidopiperidino-3- (3,4-dimethylcoumarin-7-yloxy-2 -2-propanol (26% of theory) are obtained, mp 178-180s. PRI me R 6. (4- (4-chlorobenzamido} piperidino (propoxy D-3,4-dimethylcoumarin. K with 6.6 g (0.02 mol) of 7-LZ- / - / 4-amino-piperidino (-propoxy (-3,4-dimethyl-coumarin, 100 ml of 2n sodium hydroxide solution and 75 ml of tetrahydrofuran) was added dropwise with a solution of 3.85 g (o, O22 mol) 4-chlorobenzoyl chloride in 25 ml of tetrahydrofuran, stirred for 5 hours at room temperature, filtered off and the precipitate was recrystallized from ethanol .. 5.5 g of 7- (3- / 4- / 4-xpor benzamido) are obtained (piperidino Mropoxy5 -3,4-dimethylcoumarin (59% of theory) with so pl. 212-214 ° C-. The 7- (3- (4-aminopiperidino-propoxy) -3, 4-dimethylcoumarin) used as the starting material is obtained as follows. The interaction of 7- / 3-bromopropoxC-3, 4-dimethylcoumarin H 4-oxyminopiperidine hydrochloride in a dioxane solution in the presence of a base of kronig gives 3,4-dimethyl-7- / 3- / 4-oxyminopiperidino / Zopoxy / coumarin with mp 198-20 € Pc, from which 7- / 3-4-amino-dipropy vidinopropoxy-3-4, 4-dimethylcoumarin with a mp of 4 is formed by catalytic hydrogenation on Rene Nickel in alkalized ammonia-methanol. 92-94 s. A similar compound is obtained, for example, by treating 7- (3- / 4-benzamidopiperidino / propoxy) -3,4-dimethylcoumarin with an alcoholic solution of potassium hydroxide. In addition, the compound can be obtained by introducing the interaction 4-. α-aminopiperidine with 7- (3-bromopropoxy) -3, 4-dimethylcoumarin at reflux in ethanol in the presence of triethylamine. The preparation is also possible by the interaction of 3- (4-amino-piperidino) pro-yl chloride with 7-hydroxy-3,4-dimethylcum :;
    Rin in isopropanol with the addition of sodium alcohol (6 hours reflux).
    P n measure 7. Analogously to example 6 receive. Substances listed in table. 3.,
    Example 6- / Z-M-Benzamidopiperidino (propoxy / -4-methyl-2-oxo-1, 2-dihydroquinolin.
    4.9 g (0.03 mol) of 6-hydroxy-4-methyl-2-OXO-1, 2-dihydroquinoline is dissolved in 60 ml of water and 30 ml of 1N sodium hydroxide solution. Then the solution is concentrated, the residue is dissolved in 75 ml of dimethylformamide and mixed with 9.8 g (0.035 mol) of 3- (4-benzamido-piperidine) -propyl chloride. After stirring for 4 hours, the solvent is distilled off in vacuo and the residue is dissolved in methylene chloride, dried and concentrated.
    After recrystallization from ethanol, 6.8 g of b- / 3- / 4-6-benzamido-piperidino are obtained (propoxy / -4-methyl-2-oxo-1, 2-dihydroquinoline (54% of.) With a melting point of 243-245 ° C ,
    Pr and measures 9. 7-1 3- / 4-Benzamidopiperidino / propoxy / -4-methyl-2-oxo-1, 2-dihydroquinolin.
    Analogously to example 8, by reacting 7-hydroxy-4-methyl-2-oxo-1,2-dihydro-quinoline with 3- / 4-be. Nitramido-piperidino / propyl chloride in methoxyethanol, the proposed compound is obtained. 275-27b With (46% of theory).
    PRI me R 10. 6- / 3- / 4-Benzamido piperidino / propoxy / -, 4-dimethyl-2-OXO-1, 2-dihydroquinoline.
    To a solution of 3, D g. (O, O 2 mol) 1,4-dimethyl-b-hydroxy-2-OKco-l, 2-dihydroquinoline, 7.0 g (0.025 mol) 3- / 4-ben 3 amidopy peridino / propyl chloride and 3.0 g (0.02 mol) of sodium iodide in 10 ml of water and 50 ml of methanol at a boiling point under reflux, add a solution of 0.8 g of sodium hydroxide in 10 MP of water, boil for another 3 h. , the residue is dissolved in methylene chloride, washed with dilute sodium hydroxide solution, concentrated and recrystallized from isopropanol. 4.0 g of the described compound are obtained (47% of theory) with mp 188 ° C.
    Example 11. 7- / 3- f4-Benzamidopiperidino propoxy D1,4-dimethyl-2-oxo-1, 2-dihydroquinoline.
    Analogously to Example 1G of the interaction of 1,4-dimethyl-7-hydroxy-2-oxo-1,2-dihydrohiioline with 3- / 4-benzamido-piperidino (propyl chloride in methoxy ethanol, we obtain the proposed compound with mp 193-195 C ( b7% of theory
    7- (3- / 4-Benzamidopiperidino) propoxy / -1-ethyl-4-meth14l-2-oxo-1,2-dihydrohins. Ling.
    As in Example 11, by reacting 1-ethyl-7-pxy-4-methyl-2-oxo-1,2-dihydroquinoline with 3- / 4-benzamidopipip Ridino / propyl chloride, the indicated compound is obtained with m.p. 164-165 C (from a mixture of dichloromethane with ether) (59% of theory).
    EXAMPLE 12 7- (3-У4 / -4 / -AMINOBENZAMIDO / Piperidino / propoxy / -3, 4-dimethylcoumarin.
    A solution of 4.2. g (0.009 mol) of 3.4 - dimethyl-7- (3- (4) -4-nitrobenzamido.peridino / propoxy / coumarin in 100 ml of methanol and 100 ml of tetrahydrofuran1 are hydrogenated at room temperature and a hydrogen pressure of 1 bar in the presence of 1 ml of nickel Rene. The filtrate was fired with methylene chloride and m & tanol, concentrated and the residue recrystallized from methanol. 2.8 g of the title compound are obtained (71% of theory), m.p. 242-245 0.
    Appro. 13. 7- / 3-y 4-Benzamidopipyridino (propoxy (-Z-n-butyl / 4-coumarin.
    4.65 g (0.02 mol) of 7-hydroxy-3-n-butyl-4-methylcoumarin are combined with 6.18 g (0.022 mol) of 3- / 4tbenzamide-piperidino-propyl chloride and 5.53 g of potassium carbonate (0, 04 mol) in 50 ml of dimethylformamide. After stirring for 4 hours at and after cooling, the proposed compound precipitates as a precipitate, which can be recrystallized from ethanol.
    5.4 g (58.6% of theory) of the title compound are obtained with a mp. 170171 s.
    From the concentrated filtrate by column chromatography (methylene chloride-methanol silica gel 9: 1 / another 2 g of pure compound is obtained /.
    PRI me R 14. Similarly to the top 13, the substances listed in Table 2 are obtained. four.
    EXAMPLE 15 Tablets are prepared, each of which contains 10 mg of 7- (3-f 4-benzamido-piperidino) propoxy / -3, 4-dimethylcoumarin, containing, g:
    1- / 3-I 4-Benzamidopiperidin but / -propoxy / -3, 4-dimethyl coumarin 10
    Lactose.80
    Starch29
    Magnesium Stearate 1
    This compound is finely ground and mixed with lactose and starch. The mixture is granulated in the usual manner. Magnesium stearate is added to the granulate and the mixture is pressed into 1000 tablets weighing 0.12 g each.
    The proposed method for the preparation of aryl ether derivatives allows. synthesize new compounds with anti-allergic activity.
    Compound
    3,4-Dimethyl-7- (3- (4-f4-fluoro-benzamido) -pchaperg1 dino-propoxycoumarin from .59
    7-f3-bromo-propoxch / -3,4-dnmethylcoumarin and 4- (4-fluoro-ben-amido / rchdin pipa
    3,4-Dimethyl-7- (4-methoxybeneacdado / piperidino / propoxycoumarin from 7- / 3-f poM-43-propoxy-3,4-dimethylcoumarin and 4- / 4-methoxybenzamido 7-piperidine
    3,4-Dimethyl-7- (3,4-M-methylbenzamido / piprridine) -propoxycoumarin from 7- (3–38-bromo-propoxy A3,4-dimethylkoumarin) h 4- / 4-methyl-benzamide / -piperidine
    7- (3- (4) tert.-Butylbenzamido / piperidine / propoxy) -3, 4-dimethyl l coumarin from 61 7- / brempropoxy / -3,4-dimethylcoumarin and 4- / 4-tert. butylbey 3 amide / piPeridine
    7- / 3- / 4-Acetamidepiperidine / -prepexy-3, 4-dimethylcoumarin from 7- / 3-brempreppeck-28 si / -3,4-dimethylcoumarin and 4-acetamidepiperidia
    3,4-Dimethyl-7- [3- (4-phenyl-Acetamidepiperidine) / prepexy / coumarin from 7- [3] Brempre-49 Pexie / -3,4-Dimethylcoumarin and 4-phenylacetate dipiperidine.
    3.4 Dimethyl-7- (3- / 2-methyl-. prepienamide D / piperidine / prepexycoumarin from 7- / 3-91
    -brepreppeksi / -3,4-dimethylcoumarin and 4- / 2-methylpreienamidopiperidine
    (4-Cyclohexancarylbases i.e., peri but j-prepoxyJ-. -3,4-dimethylcoumarx from 7- 36 - / J-brempropexy / -3,4-dimethylcoumarin and 4-cyclohexancarbe. Namidopiperidine -.
    7- / 3-f 4-Benzamidopiperidine / -propertexcumarip from 7- (3-87-brempeprepexy coumarin and 4-benzamidepiperidine
    Table 1
    I Exit, I
    M.p.
    (Ipact believeer)
    Hydrechleride
    268-270
    (izprepanel)
    Hydrochloride
    266-268
    (ioprep & nol)
    Hydrochloride
    272-274
    (izprepanel)
    Hydra chloride
    295-296
    (nsoprepanel)
    Hydrochloride 172-174 (isoprepanol)
    139-140 (ethyl acetate)
    176-178 (izopropanel)
    174-177
    (Izvesh opansl)
    156-157 (ethanol)
    Compound
    - / 3-f 4-Benzamidopiperidino-propoxy / -4-methylcoumain from 6t- (3-brompropoxy - 67
    4-methylcoumarin and 4-benzg
    midopiperidine
    7- / 3-f4-BenzamidopniperchDino / -propoxy-4-methylcoumarin-from 7- (3-brompropok-48 si 4-methylcoumarin from 7- (3-bromopropoxy / -4-methylcoumarin and 4-benamidopiperidine
    6- / 3- (4-Venzamidopiperidino-propoxy / 4-methyl-2-OXO-1, 2-dihydroquinoline from 6- (3-bromopropoxy - 53 -4-methyl-2-o-co-1,2-dihydroquinoline and 4-benzamidopiperidine
     (4-Benzamidopiperidino-propoxy / -4-methyl-2-OXO-1, 2-dihydroquinoline from 7- (3-bromopropoxy) -44-4-methyl-2-oxo-1,2-dihydroquinoline and 4-benzamidopiperidine
    6- / 3- {4-Benza (1idopiperidino-Propoxy) - -, 4-dimethyl-2 :: $) Xo-dihydroquinoline from 45 6- (bromopropoxy -1,4-dimetChL-2-OXO-1, 2-dihydroquinoline and 4-beisamidopiperidine
    7- / 3- (4-Benzamidopiperidino) -propoxy / -1,4-dimethyl-2-OXO-1, 2-dihydroninolin
    from 7- 3-bromopropoxy -1,4- 68-dimethyl-2-OKCo-l, 2-dihydroquinoline and 4-benzamidopiperidine
    7- / 3- (4-BenzamidopiperidinU-propoxy / -1-ethyl-4-methyl-2-OXO-1, 2-dihydroquinolin
    from 7- (z-brompropoxy -1-. -58
    -ethyl-4-methyl-2-oxo-1,2-dihydroxyioline and 4-benzamidopiperidine
    7 .- (3- (4-Benzamidopiperidino} -propoxyI-3-n-butyl-4-methylquiarin from 7- (3-bromo-56 propoxy-3-n-e-util-4-methyl-coumarin and 4-benzamidopy - peridina
    Continued table. one
    Exit, I T. pl., C
    % I (solvent);
    185-187 (methanol)
    164-166 (isopropanol)
    244-246 (ethanol)
    274-276
    (methoxyethacol)
    188-190 (isopropanol)
    192-194
    (methoxyethanol)
    164-166
    (dichloromethane-ether)
    170-172 (ethanol)
    13
    Compound
    7- / 3-M- (4-) Torbé 1-zamido-piperidm ./- propoxy-3-n-184-186
    -butyl-4-methylcoumarin and 7--54 (ethanol)
    -3-bromopropoxy / -3-n-butyl-4-methylcoumarin and 4- (4-fluorobenzamido piperidine 7- (3- / -Bonzamidopiperidite - but ji-nponoKCH / -4-methyl-8-n-177-178
    -propylcoumarin from 7- (3-bromo-50 (ethanol)
    jOponokcH-4-methyl-8-n-propylcoumarin and 4-6eH3aN onHnepH (Qing
    7- (4- (4-Fluoro-benzammdo) -piperidine ropoxt 1 / -4-methyl-8-n-propyl-coumarin 176 -177
    from 7- (3-bromopropoxy) -4-67 (ethanol)
    -methyl-8-n-propylcoumarin and 4- (4-fluorobenzamido) piperidine
    7- (3- (4-Benzamidopiperidino) -propoxy b3, 4-dimethyl-8-n-propylkomymarin from
    7- (3-brompropoxy) -3,4-190-192
    dime: il-8-n-propylkum-55 (ethanol)
    rina and .4-benzamidogtyperidina
    7- / 3- / 4- (4-Ltörbe zamido) -piperidino / -propoxy / -3, 4-dimethyl-8-n-propyl-205-207
    coumarin from 7- (3-brompro- 51 (ethanol)
    coxy) -3,4-dimethyl-6-n-propylcoumarin and 4- (4-fluorobenzamido) piperidine
    (4-Benzamidopiperidino) -propoxy / -3-n-butyl-116-118
    -4-methyl-8-n-propylcoumarin
    from 7- (3-bromopropoxy) -3. n- 61 CH, 2.
    -butyl-4-methyl-8-n-pro-methanol
    pilcoumarin and benzamidopiperidine
    7- / 3- (4- (4-Phterobenzamido) -piperidino-propoxy-3-n-butyl-4-methyl-8-n-pro-169-170
    Pilcoumarin from 7- (3-bromopro-50 (ethanol) coxy) -3-n-butyl-4-methyl-8-n-propyl coumarin and 4- / 4-fluorobenzamido / -piperidine.
    7- (3- (4-Benzamidopip: Yaridino) -proproxy / -4 .8-dimethyl-183g-184 coumarin from 7- (3-brompro-65 (ethanol) poxy) -4,8-dchmetilkumarina and 4-benzamidopiperidine
    7- (3- (4-Benzamidopiperidino) -product -3.4 8 trimethylcoumarin from 7- (3-bromopro-66 205-207 coxy) -3,4,8-trimethylcum-.rin and 4-benzamidopiperidine.
    99760614
    Continued table. one
    I So.
    (solvent) 66 48 56 43 40 62 27. 48 50
    Table 2
    t;
    Output,
    M.p.
    - ..: .. I (solvent)
    184-186 (methanol)
    164-166 (isopropanol)
    Hydrochloride
    268-269
    (isopropanol)
    1 hydrochloride 266-267 (isopropanol)
    Hydrochloride
    272-273
    (isopropanol)
    Hydrochloride
    295-296
    (isopropanol)
    Hydrochloride
    171-174
    (isopropanol)
    139-141
    ethyl acetate)
    176-179 (isopropane)
    17
    Compound
    7- (4-Cyclohexanecarbonamidopiperidino) propoxy U-3, 4-dimethylcoumarin from 7-hydroxy-3f4-dimethylcoumarin and 3- (4-cyclohexanecarbonamidopipyridino) propyl chloride
    7- / 3- (4-Benzamidopiperidino) propoxy U-3,4-dimethylcoumarin from 7-hydroxy-3,4-dimethylcoumarin and 3- (4-benzamidopiperidino) propyl chloride.
    1- (4-BenzAc1Idopiperidino) -3- (3,4-dimethylcoumarin-7-yloxy) -2-propanol from 7-hydroxy-3, 4-dimethylcoumarin and 3- (4-benzamidopiperidino) -2, 3-epoxypropylchloride.
    99760618.
    The continuation of the table. 2
    ..
    ,. | . M.p.
    I (solvent)
    175-177 (isopropane)
    202-204 (methanol)
    177-179 (ethyl acetate)
    T a b JJ and d a 3
    3,4-Dcmethyl-7- / 3- / 4- / 2-hydroxybenzamido / piperidcano / propoxy / coumarin from 7- / 3-У4-amino-piperidino / 67
    3,4-dimethylcoumarin and salicylic acid propoxy
    3,4-Dimethyl-7- / 3- / 4-thiophene-2-: car6onamilopiperidino / propoxch / coumarin from. 31
    7- / 3- / 4-aminopiperidino / propoxy / -3,4-dimethylkum. Rin and tiofvn-2-carboxylic acid chloride
    7- / 3- / 4-Benzenesulfonamidopyridine / propoxy / -3, 4-dimethylcoumarin iz29
    7- (3- (4-aminopiperidino-propoxy) -3, 4-dimethylcoumarin and benzene sulfonic acid chloride
    7- / 3- / 4- / 3,4-Dimethoxicinamoyl-amide / piperidino / propoxy / -3, 4-dimethylcoumarin from 7- / 3- / 4-amino-37
    piperidino / propoxy-3,4-. -dimethylcoumarin and chlorine, 3,4-dimethoxycinnamic acid hydride
    192-194 (ethyl acetate)
    197-200 (isopropanol)
    136-138 (isopropanol)
    195-196 (isopropanol)
    Compound
    7- / 3- / 4-Cyclopropanecarbonylamidopiperidino / propoxy A3,4-dimethylcoumarin from
    1-1 3-1 / 4-aminopiperidino / -propoxy / -3,4-dimethylcoumarin h cyclopropanecarboxylic acid chloride
    3,4-Dimethyl-7- / 3- / 4-furan-2 carbons1mido D1iperidino / propoxyUkumarin from 1- / 3- / 4-a№1Nopiperidino / propoxy / -3 | 4-dimethylcoumarin and furan-2-carboxylic acid chloride
    3,4-Dimethyl 7- / 3- 4-nitrobenzamido / piperidino / propoxy / coumarin from 7- / 3- / 4-, -aminopiperidino propoxy / -3, 4-dimethylcoumarin and 4-nitrobenzoyl chloride
    7- / 3- / 4- / 5-chlorop-2-methoxybenzamide / piperidino / propoxy / -3, 4-dimethylcoumarin from 7- / 3- / 4-aminopiperidino propoxy 3,4-dimethylcoumarin and 5-chloro-2- met6xybenzoyl chloride
    7- / 3- / 4- / 2, 3-dihydro-2-oxO-bei z azazol-3-yl-acetamido / piperidine propoxy-3,4-dimethylcoumarin from 7- / 3- / 4-aminopiperidino / propoxy / - 3, 4-Dimethylcoumarin and 2,3-dihydro-2-oxo-benzthiazole 3-yl-acetyl chloride
    7- / 3- / 4- 5-Chloro-2, 3-dihydro-2-oxo-bischiazol-3-yl-acetamchdo / piperidino / pro: poxy / - 3,4-Dimethylcoumarin from 7- / 3- / 4 -aminopperidino / propoxy / -3, 4-dimethylcoumarin and 5-chloro-2,3-dihydro-2-oxobenzthiazol-3-yl-acetyl chloride
    Continued table. 3
    I
    M.p.
    Output, (solvent)
    190-191 (isopropanol)
    182-183 (methanol)
    210-212
    (chloride
    methylene)
    151-152 (isopropanol.)
    221-222 (methanol)
    238-240 ()
    Compound
    7- / 3- / 4- / 4-Otor6eneam to / piperidino / propoxy / -3-n-butyl-4-methylcoumarin from 53 7-hydroxy-3-n-butyl-4-methylqumarin and 3- / 4- / 4-fluorobeneamido / piperchdino / -propyl chloride
    7- / 3- / 4-Benzamidopiperidino / propoxy / -4-methyl-8-n-propylcoumarin from 7-hydroxy-49
    - 4 - (ketil-8-n-propyl marina and 3- / 4-benzamidopiperidino-propyl chloride
    7- / 3- / 4- / 4-Fluorobenzamido /
    piperidino / -propoxy / -4-methyl-8 n-propyl coumar; 1H
    of .7-hydroxy-4-methyl-8-n-pro 68
    pillidine and 3- / 4- / 4-fluorobenzamido / piperidino / propyl chloride
    7- (3- / 4-benzamidog1ipkidino / propoxy) -3, 4-dimethyl 8-n-propyl cumari; 5 out of 7- 54-hydroxy-3,4-dimethyl-8-n-propyl coumarin and 3- / 4-benzamido piperidino / propyl chloride
    7- / 4- / 4-Fluorobenzam1; to /
    piperidine propoxy / -, 4-dimethyl-8-n-propylcoumarin
    from 7-hydroxy-3, 4-dimethyl-8-n- 51
    -propylcoumarin and 3- / 4- / 4-fluorobenzamido / piperidino /
    propyl chloride
    7- / 3- / 4-Benzamidopiperkidino / propoxy / -3-, n-butyl-4-methyl-V-n-propylcoumarin from 62
    7-hydroxy-3-n-butyl-4-methyl-8-n-propylcoumarin and 2- (4-benzamchdopiperidino) -propyl chloride
    7- / 3- / 4- / 4-Fluorobenzamido / piperidino / propoxy / -3-and-butyl-4g methyl-8-n-pro-1LCmarin from 7-hydroxy-3-n-butyl-4-50 -methyl-8 -n-g propyl coumarin and 3- / 4- / 4-fluorobenzamido / -piperidino / propyl chloride
    7- / 3- / 4-Benzamidopiperilino / propoxite 4,8-dimethylcoumarin from 7-ox-4,8-dime-68
    tilkujarina and 3- / 4-benzamidopiperidino / propyl chloride
    Table 4
    I So., "t
    Output,
    (solvent)%
    185-186 (ethanol)
    177-178 (ethanol)
    176-177 (ethanol)
    190-191 (ethanol)
    206-207 (ethanol)
    117-118 (column
    CH2.C-) methanol
    169-170 (ethanol)
    183-184
    Compound
    7- (3- (4-Benzamidopiperidino) / propoxy) - 3, 4, 8-trimethylcoumarin from 7-hydroxy-3,4g8-three methylcoumarin and 3- (4-benes) amides-piperidino / propyl chloride
    7- / 3- / 4-Beneamido-piperidino propoxy / 4-methyl-8-methylcoumarin from 7-hydroxy-4-methyl-8-acetylcoumarin and 3- / 4-benzamido-piperidino propyl chloride
    7- / 3-4-Benzamido-piperidino / propoxy / -3, 4-dimethyl-8-acetylkimarin from 7-hydroxy-3, 4-dimethyl-. 8-acetylcoumarin and 3- / 4-benzamidopiperidino / n opilchloride
    7- / 3- / 4-Benzamidopiperidino propoxy / -4-MeTHji-5-oxycoumarin from 5,7-dioxy-4-methylcoumarin and 3- / 4-benzamido-piperidino / propyl chloride
    7- [3- (4-Benzamidopiperidino / propoxy] -4-methyl-5-methoxycoumarin from the indicated compound 14. 1) methylio from 3-methoxy - 7-HPI-4-; methylcoumarin and 3-D-benzamide-piperidine propyl chloride
    7- / 3- / 4- / 4-Fluorobenzamido / piperidino / propoxy-4-me. Tyl-5-hydroxycoumarin from 4-methyl-5/7-dioxy-coumarin and 3- / 4- / 4-fluoro-azamido / -piperidino / propyl chloride
    7- / 3-4-Venzamidopiperidins / -propoxy / 4, 5-dimethyl coumarin from 4,5-dimethyl-7-hydroxycoumaria and 3- / 4-benzamidopiperidino / propyl chloride
    7- / 3-T / 4-Beneamido-piperidinHo / tiponOKCH / -3, 4, 5-trimethylcoumarin from 3,4,5-triglmethyl-7-oxycoumarin and 3-4-benzamidopiperidichno / propylchloride
    mules t
    Continued four
    M.p.
    (Yield, I. (Solvent)
    205
    208-209 (ethanol)
    207-208 (ethanol)
    Amorphous
    58
    Amorphous
    175-176
    51
    175-176
    88
    193-194
    61 ether where A is an oxygen atom or a N-ft group, and may be a hydrogen atom, a methyl or ethyl group) R and R; may be the same or different and denote a hydrogen atom or a lower alkyl group C (-C4. / R - a hydrogen atom; - aO1; hydrogen or an apkanoyl group with a maximum of 4 carbon atoms, an alkylcarbonyl group with 4-7 carbon atoms, phenyl acetyl, benzosulfonyl, fen-2-carbonyl, furan-2-carbonyl-2-oxobenzthiazol-3-yl, cinnamoyl, which can be substituted in the phenyl-nucleus by two methoxy groups, or benzoyl, which can be replaced by one-fold by hydroxyl, a fluorine atom, chlorine, methoxy, methyl tert.butyl, nitro, amine group, or twice a chlorine atom, or a methoxy group, a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or even a hydrogen atom, a methyl, methoxy or hydroxyl, or their pharmaceutically acceptable salts, which is different with the compound of formula L where A, R2 .7 and Rg have these values, interact with the compound of the general formula 1I x-CHj-CH-cH a where Xi Y means a chlorine or bromine atom R, is a hydrogen atom or, together with Y, can be an oxygen atom, and the compound obtained is treated with piperidine in the general form / w IV HW / VNH-R5 where Ri is indicated) e The shutter, and, where appropriate, if R oznachazt hydrogen atom, a compound of general formula T is acylated and the desired product is isolated in free form ilChe as a pharmaceutically acceptable salt thereof. compilation of derivatives of ryloshl ethers of general formO- represents an oxygen atom or an N-R group, and may be a hydrogen atom, a methyl or ethyl group; may be the same or different and denote a hydrogen atom or a lower alkyl group O, a hydrogen atom; a hydrogen atom, or an alkanoyl group with a maximum of 4 carbon atoms, a cycloalkylcarbonyl group with 4-7 carbon atoms, phenylacetyl, benzenesulfonyl, thiophene-2-carbonyl, furan-2-carbonyl-2-oxobenzthiazol-3-yl, cinnamoyl, which can be to be substituted in the phenyl radical by two methoxy groups, or benzoyl, which can be substituted once with hydroxyl, an atom. fluorine, chlorine, methoxy, methyl, tert-butyl, nitro-amino group or double-atoms of chlorine or methoxy groups, hydrogen atom and an alkyl group with 1 to 3 carbon atoms or geschetil; a hydrogen atom, methyl, methoxy or hydroxyl, pharmaceutically acceptable duplicates. piperidine of the general formula nn L-1Sh: -K5 has the above meaning of interaction with the compound of the formula M X-CHj-CH-CHj-S means a chlorine atom or a R / -hydrogen atom or so with Y may be an atom of ode, the th compound is subjected
    with compound
    the interaction of the formula AND
    A, R
    Where
    g
    values
    and if necessary
    hydrogen atom.
    Formula 1 is acylated, and the desired product is isolated in free form or as pharmaceutical. acceptable salt.
    Sources of information taken into account in the examination
    1. Weigand-Hilgetag. Experimental methods in organic chemistry. M. 1968, p. 335.
    2. The patent of Germany I 2550000,
    cl. C 07 O 473/34, published in 1977.
    权利要求:
    Claims (4)
    [1]
    1. The method of obtaining derivatives of simple aryl ethers of General formula I
    A
    A Vl J
    A
    -G 1 *
    Λ * 5 c'de A represents an oxygen atom or an NR ^ group, wherein R ^ may be a hydrogen atom, methyl or ethyl group ί th ^ and R ", may be the same or different and mean a hydrogen atom or a lower alkyl group C4-C4 .;
    R r 4
    [2]
    2. A method of obtaining derivatives of simple aryl ethers of the General formula I R 7 R i
    - a hydrogen atom;
    - a hydrogen atom or alkanoyl group with a maximum of 4 carbon atoms, a cycloalkylcarbonyl group with 4-7 carbon atoms, phenylacetyl, benzosulfonyl, thiophene-2-carbonyl ,,, furan-2-15-carbonyl-2-oxobenzothiazole.
    [3]
    -3-yl, cinnamoyl, which may be substituted in the phenyl core by two methoxy groups, or benzoyl, which 20 may be substituted once by hydroxyl, a fluorine, chlorine, methoxy, methyl, tert.-butyl, nitro, amino or double atom 25 chlorine, or methoxy groups, the '-atom of hydrogen, an alkyl group with 1-3 carbon atoms or acetyl;
    - a hydrogen atom, methyl, methoxy or hydroxyl, pharmaceutically acceptable where. or their salts, characterized in that the compound of the general formula £ <
    and. R g have a point of exposure, where A, given values,
    I action with a compound of the general formula IH
    A - represents an oxygen atom or an NR ^ group, wherein R ^ <may be a hydrogen atom, a methyl or ethyl group; may be the same or different and mean a hydrogen atom or a lower alkyl group C l - € | ;
    R 4 is a hydrogen atom; R is a hydrogen atom, or an alk’’noyl group with a maximum of 4 carbon atoms, cycloalkylcarbonyl group c.
    [4]
    4-7 atoms ш carbon, phenylacetyl, benzenesulfonyl, thiophene-2-carbonyl, furan- · '-2-carb'onyl-2-oxobenzthiaol-3-yl, cinnamoyl, which may be substituted in the phenyl core by two methoxy groups, or benzoyl, which can be substituted once with hydroxyl, atom *, fluorine, chlorine, methoxy, methyl, tert.-butyl, nitro7 amino group or twice with chlorine atom or methoxy groups;
    R is a hydrogen atom alkyl 'group with 1-3 carbon atoms or acetyl;
    - hydrogen atom, methyl, methoxy or hydroxyl, pharmaceutically acceptable wherein K th them or salts thereof, in that the piperidine of general formula wherein X and Y represent a chlorine or bromine atom, R / - a hydrogen atom or together with • Y can be an oxygen atom, and the resulting compound is treated with piperidine of the general formula IV 'NK l-Rj, where R' is as defined above · 5, reacted with a compound of the general formula (And where R, has the indicated meaning, and if necessary, if R ff starts a hydrogen atom, a compound of the general formula T acylates and targets minutes the product is isolated in free form or-in the form of pharmaceutically acceptable salts.
    JC-CHj-CH-CHj-y *; where X and Y are a chlorine or bromine atom and an Rj-hydrogen atom, or together with Y may be an oxygen atom, and the resulting compound is reacted with a compound of the general formula |!
    where A, R ^, Yl ,, R and Rg have the indicated meanings and, if necessary, with Rif denoting a hydrogen atom, the compound of general formula I is acylated and the target product is isolated in the free form or as a pharmaceutically acceptable salt.
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    同族专利:
    公开号 | 公开日
    US4330549A|1982-05-18|
    EP0013894B1|1982-02-03|
    ES487677A1|1980-06-16|
    JPS5598179A|1980-07-25|
    AU5435880A|1980-07-24|
    US4427680A|1984-01-24|
    YU6880A|1983-01-21|
    AU529663B2|1983-06-16|
    CA1141385A|1983-02-15|
    AT645T|1982-02-15|
    HU182084B|1983-12-28|
    DE3060160D1|1982-03-11|
    EP0013894A1|1980-08-06|
    DD148634A5|1981-06-03|
    CS226405B2|1984-03-19|
    DE2901336A1|1980-07-24|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3275658A|1963-05-23|1966-09-27|Upjohn Co|Tertiary-aminoalkoxy-substituted 3, 4-diphenylcoumarins|
    FR4161M|1963-07-30|
    DE1932384U|1965-11-30|1966-02-10|Wilhelm Klein & Soehne Spezial|MILLING DEVICE FOR KNIFE BLOCKS.|
    CH529746A|1968-08-01|1972-10-31|Spofa Vereinigte Pharma Werke|Process for the production of chroman derivatives|
    US4029801A|1970-09-03|1977-06-14|John Wyeth & Brother Limited|Pharmaceutical compositions and methods of treating hypertension|
    DE2162721A1|1970-12-19|1972-06-22|Dr L Zambeletti SpA, Mailand |Substituted coumarins and processes for their preparation|
    BE884459Q|1971-05-14|1981-01-26|Boehringer Mannheim Gmbh|4- -ALKYL) -PIPERAZINE DERIVATIVES AND PREPARATION METHOD|
    GB1410783A|1972-01-20|1975-10-22|Wyeth John & Brother Ltd|N-substituted 4-amidopyridines tetrahydropyridines and piperidines|
    US4148909A|1974-07-30|1979-04-10|Beecham Group Limited|Chromans to treat depression and reduce appetite|
    GB1493998A|1975-06-03|1977-12-07|Beecham Group Ltd|Propanolamine derivatives|
    US4210753A|1976-03-17|1980-07-01|Otsuka Pharmaceutical Co., Ltd.|Carbostyril compounds|
    CH619453A5|1976-03-17|1980-09-30|Otsuka Pharma Co Ltd|
    LU75688A1|1976-08-31|1978-04-13|
    GB1524260A|1976-11-23|1978-09-06|Beecham Group Ltd|Aminoalkyloneoxyd substituted 4-hydroxy-3 nitrocoumarins|
    FI782133A|1977-07-08|1979-01-09|Ciba Geigy Ag|PIPERIDINO-PROPANOLER AND FOER FARING FOR FRAMSTAELLNING|
    US4281132A|1977-10-29|1981-07-28|John Wyeth & Brother Limited|Piperidino ureas and thioureas|
    DE2901336A1|1979-01-15|1980-07-24|Boehringer Mannheim Gmbh|NEW ARYLETHERS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    DE2905876A1|1979-02-16|1980-08-28|Boehringer Mannheim Gmbh|NEW PIPERIDINOPROPYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    DE3034237C2|1979-09-18|1988-04-21|Otsuka Pharmaceutical Co., Ltd., Tokio/Tokyo, Jp|
    JP5718674B2|2011-02-25|2015-05-13|高砂香料工業株式会社|Macrocyclic triene lactones having non-conjugated triene structure, process for producing the same, and synthetic intermediates thereof|
    KR101343191B1|2011-11-29|2013-12-19|엘에스산전 주식회사|Photovoltaic system|
    JP5735588B2|2013-07-17|2015-06-17|三菱電機株式会社|Home controller, home device management system, notification message display method and program|DE2901336A1|1979-01-15|1980-07-24|Boehringer Mannheim Gmbh|NEW ARYLETHERS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    DE3034237C2|1979-09-18|1988-04-21|Otsuka Pharmaceutical Co., Ltd., Tokio/Tokyo, Jp|
    DE3025385A1|1980-07-04|1982-01-28|Boehringer Mannheim Gmbh, 6800 Mannheim|NEW TRICYCLIC ARYL ETHERS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    US4390541A|1980-12-19|1983-06-28|Lilly Industries Limited|Quinolone derivatives and their use in a method of controlling an immediate hypersensitivity disease|
    DE3117389A1|1981-05-02|1982-11-18|Boehringer Mannheim Gmbh, 6800 Mannheim|BENZOPYRANYLETHER, METHOD FOR PRODUCING THE SAME AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    DE3209271A1|1982-03-13|1983-09-15|Boehringer Mannheim Gmbh, 6800 Mannheim|BICYCLIC PHENOLETHERS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    JPS6013788A|1983-07-05|1985-01-24|Yamanouchi Pharmaceut Co Ltd|Novel coumarin derivative|
    US4808619A|1983-07-27|1989-02-28|Beecham Group P.L.C.|Di/tetra-hydroquinolines|
    DE3431004A1|1984-08-23|1986-03-06|Hoechst Ag, 6230 Frankfurt|NEW 3-PYRIDYL COMPOUNDS AND METHOD FOR THEIR PRODUCTION|
    US4701456A|1984-09-19|1987-10-20|Warner-Lambert Company|Aminoalkoxybenzopyranones as antipsychotic and anxiolytic agents|
    DE3520718A1|1985-06-10|1986-12-11|Herbert 7853 Steinen Hüttlin|FLUID BED APPARATUS|
    US4704390A|1986-02-13|1987-11-03|Warner-Lambert Company|Phenyl and heterocyclic tetrahydropyridyl alkoxy-benzheterocyclic compounds as antipsychotic agents|
    GB9018134D0|1989-09-29|1990-10-03|Ici Plc|Heterocyclic derivatives|
    US5082847A|1990-07-18|1992-01-21|SyntexInc.|Carbostyril compounds connected via an oxyalkyl group with a piperidine ring and having pharmaceutical utility|
    AT308535T|1997-07-31|2005-11-15|Hoffmann La Roche|O-SUBSTITUTED HYDROXYCUMARANONE DERIVATIVES WITH ANTITUMORAL AND ANTIMETASTIC EFFECT|
    CN100393716C|2006-05-18|2008-06-11|中国药科大学|Coumarin derivatives, and their preparing method and use as alpha, receptor agonist|
    EP2389376A1|2009-01-21|2011-11-30|Basilea Pharmaceutica AG|Novel bicyclic antibiotics|
    EP3233799B1|2014-12-19|2021-05-19|The Broad Institute, Inc.|Dopamine d2 receptor ligands|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19792901336|DE2901336A1|1979-01-15|1979-01-15|NEW ARYLETHERS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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