• 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:

    公开号:SU831077A3
    申请号:SU792782353
    申请日:1979-06-22
    公开日:1981-05-15
    发明作者:Винтер Вернер；Фрибе Вальтер-Гунар；Кампе Вольфганг；Роеш Андроники；Вильхельмс Отто-Хеннинг
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new derivatives of dihydroquinolin-2-one of the general Formula of the known alkylation reaction, 1,2-dihydroquinolin-2-one of the general formula
    (n)! 0 where R ^, R a , Rj are the same or different and are hydrogen or alkyl with 1-4 carbon atoms; .
    r 4 is hydrogen, halogen, alkyl with
    1-4 carbon atoms or alkoxy group with 1-4 carbon atoms;
    η is the number 3;
    where R, R 2 and R 3 have the indicated meanings, are reacted with a piperazine derivative of the general Formula
    (W)
    A is a valency bond or, if appropriate, substituted with a phenyl * ® residue, a methylene group possessing biological activity.
    The reaction of Ν- and O-alkylation of G1J is known. _
    The purpose of the invention is the synthesis of new derivatives of dihydroquinolin-2-ones, with biological activity.
    The goal is achieved by where n, A and R ^ has the indicated values,
    X is a reactive residue, or 1,2-dihydroquinolin-2-one of the general formula
    that according to the method of obtaining compounds of the formula [1], based on from 30
    o (sn r ) -ss'
    (Έζ) where R ^, R £ , R 3 and n have the indicated meanings,
    X * is a reactive residue, is reacted with a piperazine derivative of the general formula
    where A have the indicated meanings, (Q, and if R ^ is hydrogen, the resulting compound is alkylated to give the desired product in free form or in the form of a salt.
    As the reactive residue X or X ^, all ordinary nucleophilic groups are used, chlorine and bromine are especially preferred, as well as mesyloxy and tosyloxy groups. The reaction is carried out by known methods. In a first embodiment of the process, the oxides of 1,2-dihydroquinolin-2-ones of general formula (II) in the presence of an alkali metal alcoholate in a suitable solvent such as ethanol, 25 isopropanol or preferably ethoxyethanol are condensed with piperazines of the formula (III) at elevated temperature. DimethylFormamide } dime ijQ ^ yl sulfoxide or hexamethanol is also used as a solvent. In a second variant of the process, the reaction of dihydroquinolin-2-one of formula (IV) with piperazines of formula (V) can be carried out in the above solvents, 35 preferably with the addition of the main agent.
    The starting compounds of the general formula (II), (III), (1U) and (V) are known or can be prepared by known methods. Pharmacologically compatible salts are prepared by conventional methods, for example, by neutralizing the compounds of formula (I) with non-toxic inorganic or organic acids such as hydrochloric, sulfuric, phosphoric, hydrobromic, acetic, lactic, citric, malic, salicylic, malonic, maleic or succinic acids. .
    For the preparation of medicaments, 50 compounds of the general formula (I) by known methods are mixed with suitable pharmaceutical carriers, flavoring, flavoring and coloring agents and formulated into 55 tablets or dragees or suspended and dissolved in water or oil, such as olive oil when adding appropriate excipients.
    The use of water, which contains a stabilizing agent used for injection solutions, or a buffer, is appropriate. Such additives are, for example, tartrate or, boate, as a buffer, ethanol, dimethyl sulfoxide, a complexing agent (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for controlling viscosity, or derivatives of polyethylene sorbitan anhydrides. Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, finely divided silicic acid, high molecular weight polymers (such as polyethylene glycols). Finished preparations for oral administration may contain, if desired, sweet substances and substances for flavoring. For external use, the compounds of formula (I) can be used in the form of powders and ointments, for which they are mixed, for example, with powdered Physiologically compatible diluents or conventional ointment bases.
    The structure of the compounds in the examples is confirmed by analysis of CHO, IR, UV, PMR and mass spectra.
    Example 1. 4-Methyl-7 (3-) 4 [4-chlorobenzide (piperazin-1-yl) propoxy-] -2 oxo-1,2-dihydroquinoline.
    2.3 g of sodium (0.1 mol) are dissolved in 320 ml of ethoxyethanol and immediately after that 17.5 g (0.1 mol) of 4-methyl-7-hydroxy-2-oxo-1,2-dihydroquinoline are mixed. The mixture was stirred for 15 minutes, then 31.6 g (0.11 mol) of 3- [4- (4-chlorobenzyl) piperazinzl-1] propyl chloride were added dropwise in 30 ml of ethoxyethanol and heated to 90 ° C for 10 hours. After that, the solvent was evaporated in vacuo, and the residue was mixed with water, extracted with methylene chloride and the organic phase was evaporated after drying. The evaporation residue is purified by stirring with ether. 22.9 g (53.8% of theory) of 4-methyl-7- (3-) 4 [4-chlorobenzyl (piperazin-) 1-yl) propoxy] 2-OKCO-1,2-dihydroquinoline remains, so pl. 170-171 ° C. The base is dissolved in methylene chloride and a small amount of methanol with the addition of an ethereal solution of hydrochloric acid, and immediately after dilution with ether the corresponding dihydrochloride precipitates, so pl. 271-272 ° C.
    Example 2. 3,4-Dimethyl-7 (3-) 4- (4-chlorobenzyl (-piperazin-1yl) -propoxy] -2-oxo ~ 1,2-dihydrochie. Compounds of the general formula (I) mOSUT are introduced in liquid or solid Form, orally and parenterally, as an injection medium, preferredinoline.
    From 9.46 g (0.05 mol) of 3,4-dimethyl7-hydro-2-oxo-1,2-dihydroquinoline 65 and 15.8 g (0.055 mol) of 3- [4- (4-chloro 5 benzyl) - piperazinyl-1] -propyl chloride is obtained analogously to the method described in the example of '1, 12, 8 g: · (58-2% of theory) of the target' 'compound, so pl.
    , 143-144 ° C. The corresponding hydrochloride melts, at 273-274 ° C, the water content is 4.2%.
    Example 3. 1-4-Cimethyl-7- (3-) 4- [4-chlorobenzyl (piperazin-1-yl) '- propoxy] -2-oxo-1,2 dihydroquinoline.
    From 9.46 g of 1,4-dimethyl-7-hydroxy-2-dioxo-1,2-dihydroquinoline and 15.8 g of 3 [4- (4-chlorobenzyl) piperazin-1-yl] propyl chloride are obtained analogously to example 1 15, 2 g (63.8% of theory) of the target compound in the form of monohydrochloride, so pl. 198 ° C. The corresponding dihydrochloride melts at 260,263 ° C. .
    P., p and mer 4. 4-Methyl-7- (3-) 4 [3-chlorophenyl (, piperazine -1-yl) -propoxy- '2-oxo-1,2-dihydroquinoline.
    Analogously to example 1 of 8.76 g (0.05 mol) of 4-methyl-7-hydroxy-2-’oxo
    11,2-dihydroquinoline and 15 g (0,055 mol) and 3- [4 (3-chlorophenyl) piperazin1-yl] propyl chloride with 1.55 (0.05 mol) sodium in 160 ml of ethoxyethanol after five hours at 90 ° C get the target compound, so pl. 212-214 ° C. Yield 10.5 g (51% of theory).
    Example 5. 4-Methyl-6- (3-) 4 [4-chlorobenzyl (-piperazin-1-yl) -propoxy] -2-oxo-1,2-dihydroquinoline.
    Dissolve 0.69 g (0.03 mol) of sodium in 75 ml of isiopyrol, mix with 4.89 g (0.03 mol) of 4-methyl / 6 oxy.-2-oxo-1,2-dihydroquinoline and mix in for 10 min at room temperature. After adding 9.5 g (0.033 mol) of 3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl chloride in 25 ml of isopropanol, it is heated for 16 hours to boiling, then evaporated in vacuo, the residue contribute to methyl chloride and shake with 1N sodium hydroxide solution. After that, the dried organic phase is evaporated and the residue is triturated with ether and the solid product is recrystallized from alcohol. The yield of 6.25 g (49% of theory) of the target compound, so pl. 195-197®C.
    Example 6. 4-Methyl-6- (3-) 4 [4-fluorobenzyl (-piperazin-1-yl) -propoxy] -2-oxo-1,2-dihydroquinoline.
    Analogously to example 5, the reaction of 4-methyl-6-hydroxy-2-oxo-1,2-dihydroquinoline with 3- [4- (4-fluorobenzyl) piperazin-1-yl] propyl chloride gives the title compound as a base, i.e. pl. 178-180 ° C (from alcohol).
    '_ For example, ρ_. 7.Metyl-6- (3-) 4 [4-tert-butylbenzyl (-piperazin-1-yl) -propoxy J-2-okco-I, 2-dihydrochind. ling.
    Analogously to example 5 as a result of the interaction of 4-methyl-6-hydroxy-2-oxo-
    1,2-dihydroquinoline with 3-G4- (4-tert- (butylbenzyl) piperazin-1-yl] _- Pro With pyleOuride, the title compound is obtained in the form of a base, mp 171172 ° С (from ethyl acetate).
    Example 8. 4-Methyl-6- (3-) 4- [4-methylbenzyl (-piperazin-1-yl) propoxy] -2-oxo-1,2-dihydroquinoline.
    Analogously to example 5 is subjected to interaction. 4-methyl-6-hydroxy-2-oxo-1,2-dihydroquinoline with 3- [4-methylbenzyl- (piperazin-1-yl)] propylchloride, the title compound is obtained in the form of a base, mp. 162-163 ° C (from ether).
    PRI me R 9. 6- (3-) 4- [4-Chloro-benzyl (-piperazin-1-yl) -propoxy.! - 2oxo-1,2-dihydroquinoline.
    4.8 g (0.03 mol) b-hydroxy-2-oxo-
    1,2-dihydroquinoline is dissolved in water (60 ml) and 30 ml of 1 N. caustic soda solution. Immediately after this, the solution was evaporated, the residue was taken up in 75 mp dimethylformamide and mixed with 14.3 g (0.05 mol) of 3- [4 (4-chlorobenzyl) piperazin-1-yl] propyl chloride. After stirring for 4 hours at 100 ° C, the solvent was removed in vacuo and the residue was taken up in methylene chloride. Shake everything with 1 n. sodium hydroxide solution and water, the organic phase is dried and evaporated in vacuo. The residue immediately after it is triturated with ethyl acetate and recrystallized from alcohol. The yield of the target compound 6.3 g (51% of theory ^ mp. Base 180-182 ° C.
    Example 10. 4-Methyl-6- (3-) 4- [2-propoxy-benzyl (-piperazin-1-yl) -proxy] -2-oxo-1,2-dihydroquinoline.
    Analogously to example 9, 4gmethyl-6-hydroxy-2-oxo-1,2-dihydroquinoline is reacted with 3- [4- (2-propoxybeneyl) piperazin-1-yl] propyl chloride_. The yield of the target compound 53% in the form of an oily base. From a solution in acetone with the addition of an ethereal solution of hydrochloric acid, the corresponding hydrochloride is obtained, which precipitates in an amorphous form, mp. 140-145 ° C. ' '' Example 11. 1,4-Dimethyl-6 (3-) 4- [4-chlorobenzyl (-piperazin-1-yl) -propoxy] -2-oxo-1,2-dihydroquinoline.
    Analogously to example 3, 1,4-dimethyl-6-oxidoxo-1,2-dihydroquinoline is reacted with 3- [4- (4chlorobenzyl) piperazin-1-yl] propyl chloride to obtain the target compound in the form of a hydrochloride, mp. 215-220®C (decomposes).
    Example 12. 4-Methyl-7- (3-) 4 [3-methoxybenzyl (-piperazin-1-yl) propoxy] g-2-oxo-1,2-dihydroquinoline.
    Analogously to example 1, 8.76 g (0.05 mol) are reacted
    4-methyl-7-hydroxy-2-oxo-1,2-dihydroquinoline with 15.5 g (0.055 mol) of 3- [4 (3-methoxybenzyl) piperazin-3-yl.] Propyl chloride in ethoxyethanol when heated to 90 ° C for 4 hours
    After processing, the crude product is triturated with ether. Yield 12.2 g (5.7.9% Oe from theory) of the target product, mp. 149-150 ° C. The corresponding hydrochloride melts at 265-268 in S.
    Example 13. 4-Methyl-7- (3-) 4-, [4-methoxybenzyl (-piperazin-1-yl) -propoxy] -2-oxo-1,2-dihydroquinoline.
    Analogously to example 12, using 3- [4- (4-methoxybenzyl) piperazin-1-yl] propyl chloride, the title compound is obtained in the form of a base. 15 Yield 11 g (52% of theory), mp 167-168 ° C. The corresponding dihydrochloride melts at 248-250 ° C.
    Example 14. 4-Methyl-7- (3-) 4-20 [2-methoxybenzyl (-piperazin-1-yl) -proxy -] - 2-oxo-1,2-dihydroquinoline ..
    Analogously to example 12, 8.76 g (0.05 mol) of 4-methyl-7-okoy ~ 2-oxo-1,2-dihydrrh-25 nolin are reacted and for 15.5 g (0.055 mol)
    3- £ 4- (2-methoxybenzyl) piperazin-1-yl} -propyl chloride and 4 hours at 90 ° C, the title compound is obtained in the form of a base. -JQ
    Yield 11.7 g (55.5% of the territory), mp 151-152 ° C. The corresponding hydrochloride melts at 265-266 ° C.
    Example 15. 4-Methyl-7- (3-)
    4- beneyl-piperazinyl-1 - (- propoxy) -,
    2-oxo-1,2-dihydroquinoline.
    Analogously to example 12, 8.76 g of 4-methyl-7-hydroxy-2-κι 1,2-dihydroquinoline is reacted with 3 [4-benzyl- (piperazin-1-yl)] propyl chloride for 4 hours at 90 ° C. . You isolate the target compound in the form of a base. Yield 11.4 g (58.3% of theory), mp. 185-186 ° C. The corresponding hydrochloride melts at 279,281 ° C. 45
    Example 16. 3-n-Butyl-4methyl-7- (3-) 4- [4-chlorobenzyl (-piperazin-1-yl) -propoxy] -2-oxo-1,2-dihydroquinoline.
    Analogously to example 1, jq is subjected to 3-n-butyl-4-methyl-7oxy-2-oxo-1,2-dihydroquinoline with 3 [4- (4-chlorobenzyl) piperazin-1-yl] -. propyl chloride in ethoxybutanol. The target compound is isolated in the form of a base. Yield 57.5%, mp. 148- ”
    149’s.
    The same compound is obtained if 7- (3-chloropropoxy-3-n-butyl-4-methyl) -2-oxo-)., 2-dihydroquinoline, so pl. 20 3 ° С; they are reacted with 6 (J) with 4- (4-chlorobeneyl) -piperazine in tetrahydrofuran in the presence of a tertiary base, such as Ethyl di-Ieopropylamine, for 8 hours, heating to a boil. 65
    Example 17. 4-Methyl-7- (3-) 4 [diphenylmethyl (-piperazin-1-yl) -propoxy -] - 2-oxo-1,2-dihydroquinoline. . Analogously to example 1, 8.76 g and 4-methyl-7-hydroxy-2-oxo-1,2-dihydroquinoline are reacted with 18.1 g of 3-4- (diphenylmethyl) piperazin-1-yl __-propyl chloride in ethoxyethanol .
    The target compound is obtained in the form of a base (15 g), so pl. 208210 ° C. Yield 64% of theory.
    权利要求:
    Claims (1)
    [1]
    1. Bühler, K., Pearson, D. Orga nnicheskie sintez h. 1, M. ed.Mir, 1973 p. 504,
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    优先权:
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