• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Compounds of formula I in which R, is a heterocyclic ring containing one or more heteroatoms selected from N, 0 and S; in which R2 is H, a straight or branched chain alkyl group containing 1 to 4 carbon atoms, an alkenyl group containing 3 to 6 carbon atoms, an alkynyl group containing 3 to 6 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms; in which R3, is H, a straight chain alkyl group containing 1 to 3 carbon atoms or a formyl group in which R4' R5 and R6 which may be the same or different, are H, halo, trifluoromethyl, hydroxy, an alkyl group containing 1 to 3 carbon atoms, an alkoxy group containing 1 to 3 carbon atoms, an alkylthio group containing 1 to 3 carbon atoms, phenyl or R4 and R5, together with the carbon atoms to which they are attached, form an optionally substituted second benzene ring; and their pharmaceutically acceptable salts have utility in the treatment of depression. Pharmaceutical compositions and processes for the preparation of compounds of formula I are disclosed.
    公开号:SU1274622A3
    申请号:SU833648006
    申请日:1983-09-29
    公开日:1986-11-30
    发明作者:Джон Армитейдж Бернард；Розиндейл Хауслей Джон；Эдвард Джеффри Джеймс；Норман Джонстон Дэвид
    申请人:Дзе Бутс Компани Плс (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of novel heterocyclic derivatives of cyclobutylaminomethane, which possess antidepressant activity and can be used in medicine.
    The aim of the invention is to obtain new heterocyclic cyclobutylaminomethane derivatives having new physiological properties in this series of derivatives.
    Example 1. A solution of 2-bromopyridine (12.3 g) in dry ether (80 ml) is added to a 1.55 M solution of butyl lithium in hexane (30 mm) at. The mixture was stirred at this temperature for 1 hour, then a solution of 1- (4-chlorophenyl) cyclobutanecarbonitrile (8 g) in ether (8 ml) was added and the temperature of the reaction mixture was allowed to rise to ambient. After 1 h, a solution of sodium borohydride (3 g) in cjrxoM diethylene glycol dimethyl ether (130 ml) was added and the mixture was heated to a temperature that was maintained for 2 hours. Water (100 ml) was added and the mixture was extracted with ether. The ether extract is extracted with 8N hydrochloric acid, and the acidic extract is washed with ether, basified with an aqueous solution of sodium hydroxide and extracted with ether. The ether extract is filtered through diatomaceous earth, dried, and the solvent is removed by evaporation. The residue is distilled in the range of 163-180 ° C under a vacuum of 0.2 mm Hg. As a result, an oil is obtained which is dissolved in ether. Hydrogen chloride gas is passed through the ether solution, and the resulting precipitate is heated with propan-2-ol, resulting in l- (4-chlorophenyl) -cyclobutyl (pyrid-2-yl) methylamine dihydrochloride, mp. 240-245 0 (decomposition).
    Similarly, the following compounds are prepared.
    1a, 1- (4-chlorophenyl) cyclobutyl (pyrid-3-yl) methylamine dihydrochloride, m.p. 275-280C.
    15, 1- (4-Chlorophenyl) cyclobutyl (pyrid-4-yl) methylamine dihydrochloride, m.p. 260-265 ° C.
    Example 2 A solution of 2-bromopyridine (4.8 g) in dry ether (30 ml) is added to a 1.7 M solution of butyl lithium in hexane ml) at -78 ° C with stirring. After 1 hour at this temperature, a solution of 1- (4-biphenylyl) cyclobutanecarbonitrile (4 g) in a mixture of dry ether (80 ml) and dry tetrahydrofuran (10 mp) was added to the reaction mixture and allowed to rise to 0 ° WITH. After cooling to -20 ° C, methanol (20 ml) was added dropwise and then water (30 ml). The aqueous mixture is extracted with ether, and the ether extract is washed, dried, and ground, and the result is 1- (4-bipheny-lyl) cyclobutyl (pyrid-2-yl) -methanimine as an orange oil. The oil was dissolved in propan-2-ole (200 ml) and heated to reflux with sodium borohydride (2.0 g), which was maintained for 5 hours. Water was added and propan-2-ol was removed by stirring. The aqueous residue is extracted with ether. A stream of gaseous hydrochloric acid is sent to the dried ether extract, resulting in a resin that is heated with propan-2-ol, resulting in a white solid, which after recrystallization from a mixture of methanol and propane-25 ol gives l- (4biphenylyl dichlorohydrate) hydrate ) 1C1klobutyl (pyrid-2-yl) methylamine. Mp. 240 ° C (decomposition).
    The corresponding compounds listed in Table 1 are prepared analogously.
    权利要求:
    Claims (1)
    [1]
    EXAMPLE 3 1-Methylpyrazole (4.8 g) was added to a mixture of dry ether (60 ml) and 1.7 M solution of butyl lithium in hexane (30 ml) under a nitrogen atmosphere at below 5 ° C. N, N, N, N-tetramethylethylenediamine (TMEDA) (8.3 g) was added and the mixture was stirred at 0-5 ° C for 1.75 h, and then 1- (4-chlorophenyl) cyclobutanecarbonitrile (6 , 0 g) and stirred for 90 min at 0-5 ° C. Water is added and the reaction mixture is extracted with ether. The extract is dried, dried and embedded in to give an oil, which is l- (4 chlorophenyl) cyclobutyl (1-methylpyrazol-5-yl) methanimine. The imine is stirred with a mixture of sodium borohydride (2 g) in diethylene glycol dimethyl ether (100 ml) under a nitrogen atmosphere at 95 ° C for 2 h. The mixture is drained - In water and the extract is extracted with ether. The extract is washed, dried and evaporated to give a residue, which is dissolved in dry ether. Hydrogen chloride gas is passed through a solution in ether to obtain the salt of 1- (4-chlorophenyl) cyclobuchyl (1-methylpyrazol-5-yl) methylamine hydrochloride (mp. 316– 318 ° C) containing 1.25 moles of hydrochloride and 0.25. The objective compounds listed in Table 2 were obtained in a similar manner, with the only difference being that the reaction between the heterocycle and -butyllithium is carried out at 40 ° C. EXAMPLE 4 A solution of 2 bromothiophene (32.9 g) in dry ether (50 ml) is added dropwise to a stirred mixture of magnesium shavings (4.85 g) and ether (50 ml) in an atmosphere nitrogen. When all of the magnesium is dissolved, a solution of 1- (3, 4-dichlorophenyl) cyclobutanecarbonitrile (30.6 g) in dry ether (200 ml) is added and the mixture is stirred for 1 hour and then heated to reflux temperature, which is maintained for 1 hour. The resulting solid, which is L1 (3,4-dichlorophenyl) cyclobutyl P (thien-2-yl) methaniminylmagnesium bromide, is collected by filtration. The solid is dissolved in ethanol (200 ml) and a solution of sodium borohydride (10 g) in ethanol (500 ml) is added. The mixture is heated to reflux temperature, which is maintained for 4 hours. The mixture is cooled, water is added (200 ml) and then 5 N solution of hydrochloric acid. The ethanol is removed by evaporation and the aqueous solution of the acidic mixture is made up with 5N sodium hydroxide solution. The aqueous layer is extracted with ether and the extract is dried. Hydrogen chloride is passed through a solution in ether, and chlorine hydrate of l- (3.4 dichlorophenyl) cyclobutyl 3 is obtained as a result. (thien-2-sh1) methylamine, m.p. 238-242 ° C. The target compounds listed in Table 3 are obtained analogously. Example 5. PdcTBop 4-methylthiazole (4.95 g) in ether (5 ml) was added to ethylmagnesium bromide obtained under nitrogen from magnesium shavings (1.2 g) and ethyl bromide (5.5 g) in ether (40 ml). A yellow precipitate forms, which dissolves when the ether is replaced by tetrahydrofuran (70 ml). 1 - (4-chlorophenyl) -cyclobutanecarbonitrile (6.0 g) is added and the solvent is replaced with toluene and the mixture is heated to 90 ° C, which is maintained for 2 hours. Water and a 2 N sodium hydrate solution are added. the reaction mixture is extracted with ether. The extract is dried and the solvents removed by evaporation. The residue is dissolved in ether and hydrogen chloride gas is passed through the solution, resulting in a gray-yellow solid, which is 1- (4-chlorophenyl) cyclobutyl (4-methylthiazol-2-yl) methanimine hydrochloride. This salt is heated to 95 ° C, which is maintained for 2 hours with a solution of sodium borohydride (2 g) in diethylene glycol dimethyl ether (100 mp). Water and a 2 N sodium hydroxide solution are added, then the reaction mixture is extracted with ether. The extract is dried and the solvents removed by evaporation. Residue Dissolve in ether and hydrogen chloride gas is passed through the solution to give a white solid. This solid is converted to the free base, which is purified by using a chromatographic column on florizil eluted with a mixture of ether and. cyclohexane, the result is l- (4-chlorophenyl) cyclobutylJ (4-methylthiazol-2-yl) methylamine, which is converted into the hydrochloride salt (mp. 230-232 C (decomposition)) containing 1.5 moles of hydrochloride, by dissolving the free base in ether and then passing gaseous hydrogen chloride through the solution. Example 6: The product from Example 4 in the form of a free base (2.0 g), a 98% solution of formic acid (8 ml) and a 37-40% aqueous solution of formaldehyde (16 ml) are displaced at 20 ° C for 1 h, and then heated to 55-60 ° C, which is maintained for 1 h and volatile materials evaporated at 95 ° C and atmospheric charging. The residue was basified with aqueous sodium hydroxide solution and extracted with ether. Hydrogen chloride gas is bubbled through the dried ether solution to precipitate the oil. The solvent is evaporated and the residue is triturated with dry ether and clarified by filtration. The filtrate is evaporated and the residue is triturated with dry acetone, the result is chlorine hydrate H, M-dimethyl- 1- (4 - chlorophene). cyclobutyl (thien-2-yl) methyl IOTHa, so pl. 185-190 ° C. Example 7. Acetic anhydride (5 ml) was added to the mixture of the product of example 4a in the form of a free base (3 g) and crushed ice (5 g), and the resulting mixture was stirred for 5 minutes. An aqueous solution of sodium hydroxide (5 N) is added to the mixture and the resulting alkaline, mixture is extracted with ether. The extract is washed with water, dried and the ether is removed when noMqtnji is quenched to form a residue, which is triturated with petroleum ether (so kp. 6080 s), a solid is obtained, which crystallizes from petroleum ether (kohl 80-100 ° C) N-acetyl-1- (4-chlorophenyl) cyclobutylthien-2-yl (methylamine), m.p. 105-108 ° C. The brran-dimethyl sulfide complex (2 ml) was added dropwise to a solution of the resulting N-acetyl compound (1.5 g) in dry tetrahydrofuran. The mixture is stirred for 30 minutes at 20 and at 40-45 ° C for 10 minutes. Water was added to the cooled reaction mixture, and then the mixture was extracted with ether. Hydrogen chloride gas is passed through the dried ether extract to give a solid, which is heated with boiling ether. The material that does not dissolve is Nethyl 1-C4-chlorophenyl) cyclobutyl-en-2-Sh1 (methylamine) hydrochloride, m.p. 204-207С Example8. A 1.7 m solution of butyl lithium in hexane (30 ml) is added under a nitrogen atmosphere to a stirred solution of diisopropylamine (5.2 g) in dry ether (20 ml) at 20 ° C. After 20 minutes, the mixture is cooled to 20 ml and added dropwise a solution of 1,3 dithiane (6 g) in dry ether (50 ml). A solution of 1 (4-chlorophenyl) cyclobutane carbonitrile (6 g) in dry ether (20 ml) is then added. The temperature is maintained at 0 ° C for 20 minutes. Sodium borohydride (2 g) in dry diethylene glycol dimethyl ether (150 ml) is added to the mixture, and then it is heated to a temperature of 90 ° C, which is maintained for 2 hours. Water is added and extraction is carried out with ether. The extract is washed, dried and evaporated, and a residue is obtained which is dissolved in ether. Hydrogen chloride gas is passed through the ether extract, as a result of which 1- (4-chlorophenyl) cyclobutyl 1,3-dithian-2-pcs) methylamine hydrochloride is precipitated, mp. 165-1b7 ° C (decomposition). Example 9: The product from Example 3 (1.49 g) was dissolved in absolute ethanol (45 ml) and Raney nickel (approximately 3 ml) was added. The mixture was stirred under a hydrogen atmosphere for 2.5 hours, and then the reaction mixture was filtered and the solvent was removed by evaporation. The residue was dissolved in dilute hydrochloric acid, and the solution was basified. A white solid is obtained which is extracted in ether. The extract is dried and as a result, 1- (4-chlorophenyl) cyclobutyl (tetrahydrofur-2-yl) methylamine is obtained as an oil (no physical constants were determined). Example 10, The product of Example 2 in the form of the free base is mixed with methyl formate and the mixture is held at ambient temperature for 4 days. A gum is formed, which is triturated with petroleum ether under heating, the result is N-formyl-1- (4-biphenyl-type) cyclobutylT (pyrid-2-yl) methylamine, m.p. 101 ° C. Example 11. The product from Example 24 in the form of a free base (3 g) and cyclopentanone (1.65 g) are mixed at room temperature, then heated with stirring to a temperature of 140 ° C, which is maintained for 18 hours. The mixture is then, in the form of a solution in a minimum amount of ethanol (200 ml), cooled to room temperature and treated with a suspension of sodium borohydride (2 g) in ethanol (20 ml). The mixture is heated to reflux temperature, which is maintained for 2 hours, then held at room temperature for 16 hours, and the solvent is removed. The residue is diluted with water, acidified with 2 N hydrochloric acid, alkalinized with a 2 N aqueous solution of sodium hydroxide and extracted with ether. The extracts are washed and dried, and the solvent is removed, leaving an oil, which is purified using chromatography, to give a grayish-brown gum, which is transferred to ether and is saturated with hydrogen chloride, resulting in sesquichlorohydrate Mr - ( 3,4-dichlorophenyl) cyclobutyl (2-pyridyl) -methyl) cyclopentaloxylate, so pl. 120-122 ° C. The therapeutic activity of the compounds of the formula I can be established by means of a study of the ability of the compounds of the invention to reverse the hypothermic effects of reserpine using the following procedure. The males of Charles Ryver of a CDI strain weighing 18 to 30 g are divided into groups of five and provide free access to feed and water. t After 5 hours, the temperature of each mouse is measured by a dental method and by an intraperitoneal method, reserpine (5 mg / kg) is administered to it in solution in deionized water containing ascorbic acid (50 mg / ml). The amount of fluid injected is 10 ml / kg body weight. After 9 hours from the start of the test, access to the feed is prevented, but water is still left free. 24 hours after the start of the test, the temperatures of the minus were measured, and then the test compound was suspended in 0.25% solution of hydroxyethylcellulose (manufactured by Union Carbide under the trade name Cellosize RR 15000) in deionized water at a dose of 10 mg / kg body weight. After 3 hours, the temperature of the whole is measured again. The percentage of the reduction in body temperature caused by reperio1 is then calculated by the formula Ii-Llli ± X 100, TS-T in which Tj. is the temperature in degrees Celsius after t hours. The average value for each group is calculated based on several different doses in order to calculate the value of the average dose that causes the 50% inversion (). All the compounds that are the final products of the examples, KOTopbje, are as follows, given the value of AU, B 30 mg / kg or less. This indicates the antidepressant activity of the compounds of the proposed method when applied to humans. The resulting compounds have low toxicity. The values of ED obtained in this way (d mg / kg) are given below: Example 1 3 Example Ze 3-10 3f 3-10 4 3-10 4a 3-10 4Ь 3-10 4c 3 4cL3-10 4e 10-30 4f 3- 10 4o 3-10 10-30 10-30 10-30 10-30 3-10 103-10 1110-30 Claims of the invention Method for preparing heterocyclic derivatives of cyclobutylaminomethane of the general formula J where R is 2-furyl, 5-methylfuryl-2, thienyl , 1-metsh1pyrrol-2-yl, 1-methylimidazol-2-yl, pyridyl, 4-methylthiazol-2yl, 1-methylpyrazol-5-yl, 1,3-dithian2-yl; g i 4 is hydrogen or halogen, trifluoromethyl methyl, methoxy, methylthio, phenyl; or, and R, taken together with the adjacent carbon atoms to which they are bonded, form a second benzene ring, optionally substituted by a chlorine atom, characterized in that the compound of general formula II
    where R |, R, Rj and R have the indicated meanings; .
    Y is lithium or MgBr or MgCl group
    subjected to reduction with sodium borohydride in an environment of an organic solvent, such as ethanol, propane-2ol, or diethylene glycol dimethyl ether at a temperature in the range between ambient temperature and boiling point of the reaction mixture for a time sufficient to complete the reduction.
    CHRiNHz-nHCl
    Table 1
    The imine was purified by distillation and isolated on vi (e-hydrochloride salts.
    Sodium borohydride is added in diethylene glycol dimethyl ether.
     Sodium borohydride is added in ethanol.
    Carbonitrile was added in ether solution.
    After the reduction, the solvent was removed by distillation, and the residue was pact-wc in ether, then the solution was washed with water.
    Salt contains 0.67 mol of water.
    Hemihydrate of ryokrystallieets; from propan-2-ol.
    Butyl lithium was added at -70 ° C, methanol at -40 ° C.
    The product was recrystallized from a mixture of ethanol and petroleum ether (so kip. BO-BO C).
    CHRiNH-nHCl
    Table 2
     4-Chlorophenyl 2-furyl1 225-230 4-biphenylyl 2-Tienyl1 165-170
    Ze 4-Chlorophenyl 1-Mvtilpyrrol-2-yl 1
     3,4-Dichlorophenyl 1-Methylimidazol-2-yl 2 259-261
    The imine was isolated as the hydrochloride salt.
    A solid containing an imine or an imine salt is precipitated by the addition of a solution of acetic acid in ether.
     The product was isolated as free base by high pressure liquid chromatography. The physical constants of the product are undecided.
    The imine intermediate had an ED of less than 30 mg / kg; this value was determined in accordance with the described test.
    TMEDA was not used.
    Sodium borohydride was added to propan-2-ol.
    Sodium borohydride was added in ethanol.
    The reaction between the heterocycle and butyl lithium was carried out at 0 ° C.
    CHRiNH2-nHCl
    Continued table 2,
    (decomposition)
    Table3
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    同族专利:
    公开号 | 公开日
    FI79529B|1989-09-29|
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    GB2128991A|1984-05-10|
    EG16546A|1990-10-30|
    BG38638A3|1986-01-15|
    ZW19483A1|1984-05-02|
    FI833453A|1984-03-31|
    KR900005256B1|1990-07-21|
    AU1922383A|1984-04-05|
    IN159442B|1987-05-23|
    FI79529C|1990-01-10|
    PT77364A|1983-10-01|
    GB8325826D0|1983-10-26|
    NZ205721A|1987-02-20|
    DD218094A5|1985-01-30|
    EP0108488A1|1984-05-16|
    HU200444B|1990-06-28|
    PT77364B|1986-03-20|
    YU196483A|1986-04-30|
    CA1239932A|1988-08-02|
    RO87259A|1985-08-31|
    FI833453A0|1983-09-26|
    HUT35254A|1985-06-28|
    GB2128991B|1985-11-13|
    NO833528L|1984-04-02|
    DK435583A|1984-03-31|
    ZA836849B|1984-05-30|
    IL69734A|1988-03-31|
    ES8504103A1|1985-04-01|
    NO158459C|1988-09-14|
    ES526089A0|1985-04-01|
    DE3362328D1|1986-04-03|
    KR840006225A|1984-11-22|
    IE56001B1|1991-03-13|
    PL243950A1|1984-12-17|
    IE832110L|1984-03-30|
    PH22424A|1988-09-12|
    CS241068B2|1986-03-13|
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    GR78725B|1984-10-02|
    AU561772B2|1987-05-14|
    DK435583D0|1983-09-23|
    JPS5989659A|1984-05-23|
    CS713183A2|1985-07-16|
    NO158459B|1988-06-06|
    AT18221T|1986-03-15|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8227901|1982-09-30|
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