• 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:
    1467740 1,1-Dialkyl-n-butylamines LABAZ 15 May 1975 [20 May 1974] 28336/76 Divided out of 1467739 Heading C2C Novel 1,1-dialkyl-n-butylamines of the general formula wherein R 1 is an ethyl or n-propyl group and R 2 is (a) an ethyl, isopropyl, isobutyl or tert. butyl group when R 1 is a n-propyl group and (b) a n-butyl or isobutyl group when R 1 is an ethyl group, and pharmaceutically acceptable acid addition salts thereof are prepared by treating an isocyanate of formamide of the general formula wherein A is -N=C=O or -NHCHO, with a strong acid in an appropriate medium, optionally treating the resulting acid addition salt with a base and optionally reacting the resulting free base with an acid to form a pharmaceutically acceptable salt. Novel 1,1 - di - n - propyl - n - butylamine acid fumarate is prepared by reacting the corresponding amine (1 mole) with fumaric acid (1 mole), the amine being prepared analogously to the amines (I). Isooyanates (II) are prepared by reacting an amide of the general formula with chlorine or bromine in an alkaline medium. 1,1 - Di - n - propyl - n - butyl isocyanate is prepared analogously. Formamides (II) are prepared by heating an alcohol of the general formula with an alkali metal cyanide in the presence of an acid. Alcohols (IV) are prepared by reacting an alkyl lithium with an appropriate dialkyl ketone in an anhydrous ether medium. Acids of the general formula are prepared by treating an alcohol (IV) with formic acid in a sulphuric acid medium.
    公开号:SU1292666A3
    申请号:SU833567049
    申请日:1983-03-25
    公开日:1987-02-23
    发明作者:Пижероль Шарль；Эймар Пьер；Вернье Жан-Клод；Вебенек Жан-Пьер
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    eleven
    This invention relates to a process for the preparation of new chemical compounds of the hydrochloride or fumarate acid, 1-di (n-propyl) -n-butnlamine of formula
    (one)
    (CH, CH, jCH,), j with
    2)
    possessing antiparkinsonic action and inhibiting reperpinous and neuroleptic catatonia.
    The aim of the invention is to develop a method for producing new compounds in the range of aliphatic amines containing an amino group at a tertiary carbon atom, with improved pharmacological action.
    Example 1. Getting 1, -di- (n-propyl) -n butyl isocyanate.
    44 liters of sodium hydroxide in the form of tablets and 1200 ml of water are placed in a two-liter three-sided KOJtiSy equipped with a water cooler, a mechanical stirrer, a thermometer and a dropping funnel. The solution is cooled to 5 ° C and A8 ml of bromine is slowly added with stirring. The addition of bromine is carried out within 2 hours, and after the "" "m at O C, 111 g of 1,2-mon (p-propyl) -valeramide is added to the yellow-green solution. The mixture was stirred for 2 hours at 0 ° C. The oily phase was then extracted with three portions of diethyl ether (ZiO ml each) and the ether phase was washed twice with 100 ml of water, dried over magnesium sulfate and evaporated in vacuo. The yellow oil thus obtained is distilled off under reduced pressure of 5 mm Hg. C Thus, 103 g of betsvetnogo 1, 1-di (n-propyl) -n-buti, pisocyanate are obtained.
    Boiling point 78--79 ° C at a pressure of 3 mm Hg, Art., Yield 93%,
    Preparation of hydrochloride, 1-di (n-propyl) -n-butylamine,
    In a three-necked flask equipped with a mechanical stirrer, an addition funnel, a thermometer and a refrigerator, 200 ml of water and 90 F-W concentrated hydrochloric acid (d 1.19) are placed. The acid solution is heated to 90 ° C and then 105 g is added with strong stirring. di (n-propyl) n-butyl isocyanate, prepared as previously described. The addition operation is continued for 1 hour.
    26662
    after which the reaction medium is heated for 4 hours at a temperature of from 95 to 100 ° C. The mixture is then cooled to a temperature of approximately 5 ° C. The resulting crystals are filtered, BbicyiuHB in air, and then in a desiccator in the presence of g and hydroxide ka, pi. Thus, 99 g of hydrochloride 1, 1 di (; - -propid1) -n-butylamine is isolated in the form of a crystalline powder.
    Product 11; (with sublimation) at temperatures above 220 ° C, the yield of the target product is 90%,
    The resulting acid fumarate 1,1-d. And (n-propyl) -n-butylamine,
    To a solution of 1.16 g (0.01 mol) of fumic acid in 20 ml of acetone is slowly added 1 ,, 3 7 g {0.01 mol; 1, 1-di (n-propyl) -i-butylamine (p. 1, 4349), dissolved in 10 ml of acetone, the amine being prepared from the hydrochloride obtained earlier and a 30% aqueous solution of sodium hydroxide. Pere mix; eSHiBAT for
    2.5
     h, and then the crystals that form are filtered under reduced pressure with a foam, washed with acetone and dried in a vacuum.
    Thus, an acidic fumarate of 1, 1-di (g -: - propyl) -n-butyls is obtained in the form of a white powder. T, kip, 216 ° C (with sublimation), yield 100%,
    PRI mme R 2. Getting 1,1-di- (n-propyl) -n-butanol.
    In 230 ml. a three-necked flask equipped with a mechanical stirrer, nitrogen injection, a dropping funnel and a thermometer is placed in a nitrogen atmosphere 2.8 g (0.2 mol) in small doses of drink and S00 ml of anhydrous and purified tetrahydro (}: 1urana. Suspension of lithium in
    tetrahydrofuran is cooled to -20 ° C and then with stirring a mixture of 22.8 g (0.2 mol) of di (n-propyl;) ketone and 30 g (0.2 mol) plus 10% excess of propyl bromide is slowly added, the Add-on stage lasts about 3 hours, during which the temperature is kept at -20 ° C, the solution is allowed to stand for about 12 hours at room temperature, and
    then concentrate. The oil thus obtained is placed in water, extracted with diethyl ether, the latter is distilled off under reduced pressure.
    In this way, 2 g of 1,1-di (n-propyl) -n-butanol are obtained in the form of a liquid which has a slightly yellowish color. M.p. 78 - 80 C at 0.15 mm Hg, 60% yield.
    Preparation of 1,1-di (n-propyl) -n-butylamine hydrochloride.
    In a 250 ml three-necked flask equipped with a mechanical stirrer, a dropping funnel, a condenser, and an immersion thermometer, 6.5 g (0.1 mol) of dry potassium cyanide in the form of a powder, -14.4 g (0.083 mol) i, 1-di (n-propyl) -n-butanol and 12 ml of acetic acid. A mixture of 25 g of concentrated sulfuric acid (d 1.83) and 12 ml of acetic acid is slowly added with stirring. The addition is continued for about 2 hours, at which time the temperature is maintained at about 50 ° C. The reaction mixture is heated to 70 ° C for 2 hours and then slowly poured onto ice-cooled water. After that, it is neutralized with a 20% aqueous solution of sodium hydroxide and extracted with diethyl ether. The ether is evaporated to give an oil comprising N-formyl-1, 1-di (n-.propyl) -n-butyl-amine.
    The product thus obtained is refluxed for 2 hours in 20 ml of concentrated hydrochloric acid. During cooling, the amine hydrochloride crystallizes. It is filtered and washed with acetone.
    Thus, 11 g of 1, I-di (n-propyl) -n-butylamine hydrochloride are obtained in the form of a white powder. Yield 64%. Melting point - 220 s (with sublimation).
    The study of the pharmacological properties of the compounds obtained is carried out in the following manner.
    A standard test was used to investigate the antiparkinsonian effect of compounds associated with dolaminergic properties.
    Suppression of catatonia in mice caused by reserpine and neuroleptics.
    Suppression of catatonia caused by reserpine.
    After administering certain doses of reserpine to the rat, some symptoms are observed, in particular ptosis (prolapse of the upper eyelid),
    five
    0
    five
    Tatonia and a drop in overall temperature. These symptoms are caused by depletion of the intragranular reserve pool of biogenetic amines at synaptic terminals.
    The test compounds were administered orally as an aqueous solution to a group of rats of 10 males of the OFA line weighing approximately 1 to 50 to 200 g. Thirty minutes later, 5 mg / kg of reserpine was intraperitoneally administered. Three hours after the injection of reserpine, the animal is suspended by four legs to a horizontally stretched wire at a distance of I5 cm from the ground. Catatoni was among those animals that held their position at least for 30 seconds. Each animal that holds the position thus attached receives a mark of 1, and those that do not hold the position indicated receive a mark of 0. The maximum mark for the group is thus 10. Identical tests are undertaken with control animals that received only reserpine and none of the studied compounds.
    The table presents the results (100% suppression of catatonia caused by reserpine).
    35
    Compound
    Dose, mg / kg
    Hydrochloride
    1,1-di (n-propyl) -n-butylamine (l)
    Sour fumarate 1,1-di (n-propyl) - -n-butylamine
    Amantadine (structural analogue
    100
    These results show that
    Compounds T and IT are as active as amantadine, but at doses that are 20 and 33.3 times less than the dose of amantadine.
    Suppression of catatonia caused by neuroleptics.
    Blocking dopaminergic receptors with neuroleptics in the extra-pyramidal system interrupts catatonia
    rats. Catatonia is differentiated from edative properties by means of the test used above for recessinin catalysis. In the present case, the same markers are used. An oral dose of the compound to be studied in the aqueous solution was administered to groups of 10 male OFA trotters weighing 150 to 200 g. After thirty minutes, a dose of prochlorperazine 12.5 mg / kg was administered intraperitoneally. Three hours after the last compound was injected, catatonia was measured. Identical trials are conducted with control animals that receive prochlorperazine, but none of the compounds studied. The results obtained with the compounds listed above, in comparison with amantadine, fully comply with the data in the table.
    These results show that compounds G and II are 20 and 33.3 times more active than amantadine. Moreover, a compound with a dose as small as 1 mg / kg results in 70% inhibition of catatonia caused by neuroleptics.
    Additional tests carried out with the resulting i, 1-di- (n-propyl) -n-butylamine salts showed that such compounds are better than the corresponding free base.
    3flj.jj 1, l-di (n-propyl) -n-butyl fin in the hydrochloride and free base farm forms are 0.024 mol / kg and 0.030 mmol / kg, respectively. 1,1-di (n-propyl) -n-butylamine acid fumarate is more active than the free base or its hydrochloride (by 20-40%). Acute toxicity. In the acute toxicity test, LD oO was determined in mice by oral administration using the method of Lichfgland and Wilcoxon. The compound is administered in an aqueous solution and the observation period is 10 days after the administration of the test compound. Behind-
    Editor G. Volkova
    Compiled by Yu. Khropov Tehred L. Kravchuk
    Order 292/60
    Circulation 372Subscribe
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab, 4/5
    Production plant, polygraphic enterprise, Uzhgorod, ul. Project, 4
    LDjo (mg / kg)
    five
    the following results were recorded in comparison with amantadine; Compound
    G and I
    Amantadin1050
    The results show that the compounds according to the invention are generally more toxic than amantadine.
    Toxico-pharmacological however
    , , 50
    coefficient p: g. -- 100
    An effective dose that gives 100% inhibition of catatonia shows the following:
    Compound Indicator
    where ED represents 100
     .
    20
    T
    P
    Have mantadine
    20
    33.3
    ten
    25
    These figures show that compounds T and 11 have a general inhibitory effect on catatonia caused by reserpine and neuroleptic drugs, at a dose that is 2 and 3.3 times less than the toxic dose E in the case of amantgine, i.e. are more effective.
    30 F o r
    l 1
    the invention
    The method of producing hydrochloride or
    acid fumarate, butylamine formula
    di (n-propyl) -n
    ; cn, cn
    |
    1st
    c - nh.
    0
    five
    characterized in that, in order to develop a process for the preparation of new compounds in a series of aliphatic amines containing an amino group at a tertiary carbon atom, with improved pharmacological action, 1,1-di (n-propyl) -n-butyl isocyanate or I-formyl 1,1-di (n-propyl) -n-butylamine is treated with hydrochloric acid at 95-100 ° C and the resulting 1,1-di (n-propyl) -n-butylamine hydrochloride is extracted or sequentially treated with alkali metal hydroxide and fumaric acid.
    Proofreader L. Pilipenko
    权利要求:
    Claims (1)
    [1]
    30 claims
    A method of producing a hydrochloride or acid fumarate of 1,1-di (n-propyl) -butylamine of the formula 35 (CH, CH 2 CH 2 ) 3 C - NH 2 characterized in that, in order to develop a method for producing new compounds in the series of aliphatic amines, containing amino group 40 at the tertiary carbon atom, with improved pharmacological action, 1,1-di (n-propyl) -n-butylisocyanate or N-formyl - !, 1-di (n-propyl) -n-butylamine is treated with hydrochloric acid at 95-100 C and the resulting 1,1-di (n-propyl) -n-butylamine hydrochloride is isolated or sequentially treated with alkali metal hydroxide alla and fumaric acid.
    类似技术:
    公开号 | 公开日 | 专利标题
    US2789978A|1957-04-23|Dimethylaminopropyl-dipyridothiazane
    Gaudry1948|THE SYNTHESIS OF D, L-α-AMINO-ϵ-HYDROXYCAPROIC ACID AND A NEW SYNTHESIS OF D, L-LYSINE
    US2955111A|1960-10-04|Synthesis of n-alkyl-piperidine and n-alkyl-pyrrolidine-alpha-carboxylic acid amides
    SU1292666A3|1987-02-23|Method of producing hydrochloride or acid fumarate 1,1-di|-n-butylamine
    US2830082A|1958-04-08|N-| taurine compounds and method of preparation
    US3179665A|1965-04-20|9-|-thioxanthenes
    US3070628A|1962-12-25|4-allyloxybenzylamines
    US3139455A|1964-06-30|Phenoxyacetamidoximes
    US2503285A|1950-04-11|Beta-substituted alpha, beta-diphenylethylamines and the preparation thereof
    US2772280A|1956-11-27|Synthesis of 4-amino-3-isoxazolidone and its derivatives
    US2943092A|1960-06-28|Method of preparing 4-amino-3-isoxazolidinones
    SU440826A1|1974-08-25|METHOD OF OBTAINING AMINO KETONES
    US2864825A|1958-12-16|Pyrrolidines
    US3108099A|1963-10-22|Tertiaky ammo-methyl amides of
    US2725399A|1955-11-29|Tertiary dialkylamino propanols
    US3624217A|1971-11-30|2-|-5,6-dihydro-4h-1,3-thiazines for the control of rice blast
    US2650232A|1953-08-25|2-methyl-3-amino-4,5-di-hydroxymethylpyridine and its salts and the preparation thereof
    US2496363A|1950-02-07|Process for preparing certain pantothenic acid salts
    US7790926B2|2010-09-07|Alpha, omega-difunctional aldaramides
    US4062891A|1977-12-13|N-formyl-2,3,5,6-dibenzobicyclo[5.1.0]octan-4-methylamine
    US3450709A|1969-06-17|Process for the preparation of ring-substituted 2-aminoimidazoles
    US2705245A|1955-03-29|Trialkylamines and their salts
    US3790598A|1974-02-05|Process for preparing alpha-amino acids
    US3109022A|1963-10-29|Nu-aryl anthranilic acids
    US4022830A|1977-05-10|Process for preparing polychlorobenzamide derivatives
    同族专利:
    公开号 | 公开日
    ZA752863B|1976-04-28|
    GB1467740A|1977-03-23|
    CA1048549A|1979-02-13|
    OA05004A|1980-12-31|
    AU8102175A|1976-11-11|
    YU122675A|1982-02-28|
    DE2522218A1|1975-12-04|
    YU39318B|1984-10-31|
    ES437790A1|1977-05-16|
    HU173890B|1979-09-28|
    JPS569498B2|1981-03-02|
    FI61182C|1982-06-10|
    DK216575A|1975-11-21|
    DK145779B|1983-02-28|
    BE815273A|1974-11-20|
    NO139733C|1979-05-02|
    AR208548A1|1977-02-15|
    DK145779C|1983-08-22|
    SE7505606L|1975-11-21|
    NL172120C|1983-07-18|
    NL7505853A|1975-11-24|
    NO751771L|1975-11-21|
    DE2522218B2|1980-07-10|
    JPS514108A|1976-01-14|
    IT1049427B|1981-01-20|
    FI61182B|1982-02-26|
    NO139733B|1979-01-22|
    IE41032L|1975-10-20|
    FR2271811A1|1975-12-19|
    CH605606A5|1978-09-29|
    FI751468A|1975-11-21|
    FR2271811B1|1978-08-04|
    AT341488B|1978-02-10|
    DE2522218C3|1981-04-02|
    SE434262B|1984-07-16|
    GB1467739A|1977-03-23|
    ATA371575A|1977-06-15|
    IE41032B1|1979-10-10|
    NL172120B|1983-02-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4201725A|1974-05-20|1980-05-06|Labaz|Secondary amines|
    GR61148B|1976-06-03|1978-09-27|Labaz|Preparation process of active methylamine derivatives|
    JPS5427369A|1977-08-01|1979-03-01|Hitachi Ltd|Pattern formation method|
    FR2470758B1|1979-12-07|1982-07-02|Sanofi Sa|
    NZ516888A|1999-07-30|2004-02-27|Vertex Pharma|Acyclic and cyclic amine derivatives|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    BE144519A|BE815273A|1974-05-20|1974-05-20|METHYLAMINE ACTIVE DERIVATIVES|
    [返回顶部]