• 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:
    Quinazoline cardiac stimulants of the formula:- and their pharmaceutically acceptable salts, wherein X is a straight or branched chain alkylene group having a total of from 1 to 4 carbon atoms; and Y is a group of the formula:- where R1 is H or C1-C4 alkyl and R2 and R3 are each independently H or CH3; processes for their preparation; and pharmaceutical compositions containing them.
    公开号:SU1194257A3
    申请号:SU833597905
    申请日:1983-05-13
    公开日:1985-11-23
    发明作者:Фрейзер Кэмпбелл Симон；Энтони Робертс Давид；Кендрик Стаббс Джон
    申请人:Пфайзер Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    alkylate with an alkyl halide of general formula IV
    where RJ is C, -C-alkyl, to obtain a compound of general formula I, where R is C, -C-alkyl, or reduce the compound of general formula I, where Y is a group of the formula
    SO
    by the action of sodium borohydride to form a compound of general formula I,
    2. A method according to claim I, characterized in that the reaction of compounds of the general formulas (II) and (III) is carried out in the presence of triethylamine.
    i
    The invention relates to a method for producing new quinazoline derivatives of general formula
    SNSO - .0
    X-Y
    or its pharmaceutically acceptable salt,
    where X is an alkylene group with a straight or branched chain containing 1-4 carbon atoms, Y is a group of the formula
    , xSOr
    -N
    / 50d
    i-n NH
    R /
    3
    S02 №i
    or
    where R. is hydrogen or C -C-alkyl;
      each means hydrogen or methyl with cardiovascular activity and can be used in medicine.
    The purpose of the invention is to develop a method for producing new quinazoline derivatives having valuable pharmacological properties.
    Example 1. About, 71 g of 4-chloro-6, 7-dimethoxyquinazoline, 1.00 g (4-piperidyl) -prop-1-yl-iso-azolidine-1,1-dioxydihydrochloride (hemihydrate) and 2.2 ml triethylamine is mixed and maintained at reflux for 2.5 h in 10 ml of ethanol.
    The mixture is then precipitated and the volatile material is removed in vacuo. The residue is dissolved in 25 ml of water and
    extraction was carried out in three portions of 25 ml of chloroform. The extracts dried over magnesium sulfate are evaporated in vacuo, and the residue is subjected to chromatographic
    processed on silica grade Merck 60.9385), eluting with a mixture of methanol and ethyl acetate at a ratio of 1: 9, resulting in a butter-like residue. Last
    dissolved in a small amount of warm ethyl acetate, and cyclohexane is added to the solution until a slight haze appears. As a result of cooling in the refrigerator, 6, 7-dimethoxy-414- | 1 - (1,1-dioxoisothiazolindin-2-sh1) -prop-2-yl-piperidine-quinazoline with so pl. 129-131 ° C.
    Found,%: C 58.1; H 6.9;
    N 12,8
    C.
    C 58.0; H 7.0;
    Calculated, 12.9.
    N
    Examples 2-22. Analogously to Example 1, compounds were prepared without using 4-chloro-6,7-dimethoxy-
    nazoline, triethylamine and the corresponding piperidine, either in free base form or in hydrochloride or acetate salt form, depending on the form in which these piperidines were obtained; in cases where the piperidine salt is used, it is necessary to use an excess of triethylamine.
    The results of the preparation of the proposed compounds according to examples 2-22 are presented in table. one.
    These compounds were prepared by the reaction of 4-chloro-6,7-dimethoxy-quinazoline, triethylamine, and a mixture (in terms of hydrochlorides) (4-piperidyl) -ethyl-4-methyl-1,2,5-thiazolidine-1,1- (4-piperidyl) -ethyl-3-metsh1-1, 2,5-thiazolidine-, 1-dioxide dioxide in a ratio of 3: 1 and chromatographic processing on silica to decompose the product mixture into compounds according to examples 18 and nineteen, .
    Example 23. A stirred solution of 0.7 g of 1- (b, 7-dimethoxyquinazolin-4-yl-4- f (1,1-dioxotetrahydro-1, 2,6-thiadiazin-2-yl-methyl-piperidine- 2CHjCH20COCH5, obtained in analogy to Example 9, 4.0 ml of dimethylformamide is treated at room temperature with 100 mg of sodium hydride (50% dispersion in oil) and the mixture is stirred for 45 minutes, then 255 mg of isopropyl iodide is added to the mixture and the final mixture is stirred in for 6 hours. The solvent is removed in vacuo and the residue is dissolved in 50 ml of chloroform and 25 ml of water. After removing two portions of 20 MP of chloroform and dried over magnesium sulfate extracts, extract the oil-like product, which is chromatographed on two silica (Merck 60.9385), eluting with chloroform, resulting in a resin-like mass. After crystallization from ethyl acetate, 460 mg is obtained 1- (6,7-dimethoxyquinazolin-4-yl) -4- (1,1-dioxo-6-isopropyl tetrahydro-1,2,6-thiadiazin-2-yl) methyl 3-piperidine with t. square 158-161 С
    Found,%: C 56.7; H 7.2; N 15.3.
    C ,, H ,,
    calculated,%: C 57.0; H 7.2; N 15.1.
    Example 24. Analogously to example 23, using as starting materials sodium salt of 1- (6,7-dimethoxyquinazolin-4-yl); -4- (1,1-dioxotetrahydro-1,2,6-thiadisin-2-yl) -methyl | -piperidine-1 2CE CH20COSN, and methyl iodide give the compound
    N-.CH3
    Found,%: C 55.1; H 6.7; N 16,0
    . ° 4S
    Calculated,%: C 55.1; H 6.7;
    N 16.1.
    Example 25. At room temperature, 0.025 g of sodium borohydride is added to a stirred solution of 0.30 g of 1- (6,7-dimethoxyquinazolin-4-yl) -4-1 - - (1,1-diox-5-methyl-1, 2,6-thiadiazin-2-yl-prop-2-yl-piperidine in 5 mp absolutized ethanol.
    After stirring for 16 hours, the mixture is acidified to pH 1 by adding 2M hydrochloric acid solution and concentrated in vacuo. The residue is treated with an aqueous solution of carbonate
    sodium, adjusting the pH to 12, extracted with three portions of 10 ml of chloroform, and the combined extracts are dried over magnesium sulfate, evaporated with
    obtaining oil-like residue and subjected to chromatographic processing on silica (varieties Merck 60.9835 :) eluting with a mixture of methanol with etipadhet in the ratio
    1:20, thanks to what get a solid product. By recrystallization from a mixture of ethyl acetate and diethyl ether as white microcrystals, 0.15 g of 1- (6,7-dimethoxyquinazolin-4-yl) (1, -dioxo-5-methyltetrahydro-1, 2,6-thiadiazin-2- -yl | -prop-2-yl -piperidine with mp 172-1 ° C C. Found,%: C 57.2; H 7.3; N 14.6. C ,, Calculated,%: C 57, 0; H 7.2; N 15.1. Analogously to example 25, the compounds of the formula are obtained. The results of the preparation of the proposed compounds according to examples 26 and 27 are presented in Table 2. Example 28. Similarly, Example 1 using 4-chloro as starting materials -6,7-dime toxinhinazoline, (4-piperidyl) -ethyl isothiazo idin-1,1-dioxide and triethylamine receive the compound mp 204-206 ° С of the formula% СНгСН Ч Ш Found,%: С 56.8; H 6.7; N 13.2. CzoH, aN404S Calculated,% : C 57.1; H 6.7; N 13.3. Example 29. Preparation of certain acidic adducts (1, I -dioxo-2-isothiazolidinyl) -ethyl-peridin-b, 7 dimethoxyquinazoline (product of Example 4) Hydrochloride salt. 20.2 ml of concentrated hydrochloric acid is added to a suspension of 100 g of 4-G4-1 2- (1, 1-dioxy-2-isothia-lidinyl) -ethyl-piperidine-6 for 5 minutes. 7-dime toxyninazoline in 1 liter of technical ethyl alcohol, denatured with methyl alcohol. The mixture is heated to, and then cooled, with subsequent stirring at 0 ° C in 57 6 hours, 1 hour. The hydrochloride salt is filtered and dried in vacuo to give 103.5 g of salt, m.p. 227-229 C. Found,%: C 52.75; H 6.45; N 12.15. Ciott28 4 "4S-HCl Calculated,%: C 52.56; H 6.4; N 12.26. Tosylate salt. A solution of 4.5 g of p-toluenesulfonic acid in 20 ml of acetone is added to a suspension of 10 g of 4-G4-C2- (1, 1-DI.OXO-2-isothiazolidinyl) ethyl-pyperidine-6,7-dimethoxinhinazoline in 82 ml at room temperature. First, complete dissolution is achieved, after which the product is crystallized and the mixture is stirred at 0 ° C for 1 hour. The tosylate salt is filtered, washed with acetone and recrystallized from a mixture of acetone with technical ethyl alcohol denatured with methyl alcohol, resulting in 9.7 g salts with so pl. 156-157 C. Tartrate salt. A mixture of 1C g of 4- 2- (1,1-dioxo-2-isothiazolidinyl-ethyl-piperidine-6,7-dimethoxy-naphtha, 3.6 g (+) - tartaric acid, 70 ml of technical ethyl alcohol denatured by methyl alcohol , and 10 ml of water is maintained at reflux temperature until a clear solution is formed, then the prepared mixture is cooled to 0 ° C and granulated for 1 hour. The tartrate salt is filtered and washed with technical ethyl alcohol denatured by methyl alcohol. recrystallization from an aqueous solution of those 11.1 g of tartrate salt with a temperature of 116-118 ° C was tested on dogs in anesthetized state in order to evaluate the cardiac stimulating activity of the proposed compounds. Left ventricular pressure (AGE) in anesthesia administered by intravenous administration of 30 mg / kg of Nembutal, males and females of beagle dogs are measured by means of a Miller transducer injected into the left ventricle through the left carotid sinus artery. To fix the pressure in the left ventricle in the form of a graph, 4-channel devices are used, and a differential is used to obtain the maximum degree of pressure change in the left ventricle from the original LVL when the test compound is administered. The test compound, dissolved in an inert solvent, was injected into the femoral vein. The maximum degree of pressure change in the left ventricle (dp / dtjj j.) Is a measure of the maximum percentage increase in the force of contraction of the heart muscle (contractility forces of the heart) achieved by administering the test compound. Since for each dog it is possible to change the degree of its reaction to
    - ..
    CHf-D
    L
    g-)
    -CtifH
    SOo
    -CH, CH-NQ
     Og -CH-CHj-lQ
    SNS
    -CH-N
    55.5 6.513.6
    0.25 NO 138
    (55.5) (6.5) (13.6)
    155 57.4 7.0 12.7
    Free base
    (57.1) (6.7) (13.3)
    Free 192- 56,8. 6.8 13.0 base -193 y,) (6.7) (13.3)
    Free 159 57.8 7.0 12.6
    base
    (58.0) (7.0) (12.9)
    58.6 7.212.5
    Free 156 base
    (58.9) (7.2) (12.5)
    57,16,713,1
    Free 185 base -187
    (57.1) (6.7) (13.3) 78 cardiac pacemaker; each result obtained should be compared with the result obtained for the same dog using the known pacemaker, i.e. (Zn-butylureido) -piperidino-6, 7-dimethoxyquinazole 1a - bukineran. A known pacemaker in an acceptable solvent is also inserted into the femoral vein at least 30 minutes before the administration of the test compound. The test results are presented in Table. 3. Table 1
    SCL -sn, -y;) w
    S02
    ten
    S02
    -CH CH-N III
    eleven
    S02
     Nel
    P
    13 Nz
      so. Free-CH-b - NH base
    SNS
     / v
    -snn-to n
    Free
     - / base
    Continuation of table 1
    53 free, 26.2 17.1 base
    (53.1) (6.2) (17.2)
    Solvate with 131- 54,56,6 15,0
    aiLa. (.2) ".) (13.0)
    Monohydrate 179 54.66.5 16.6
    (54.1) (6.5) (16.6)
    Free 130 54.9 6.6 16.3
    base / ,. .h / h
    (55.0 (6.7) (16 J)
    Monohydrate 135 54.7 7.0 14.3, (54.9) (7.3) X14.5)
    Free 186- 54.3 6.6 16.8
    base -188 f g,, /, r /, (54.1) (6.5) (16.6.
    180 55.4 6.6. 15.9
    (55.2) (6.7) (16.1) 197- 55.1 6.8 15.8 -199,
    .6 EOA -CHCH -N W
    302
    CH1C., H5) -ZH
    17
    L
    -sn-sh- (
    18
    -CH CH -NUSHZ
    S02
    -CH-1S
    it
    SNS
    S02 -CHjCH N- hsch
    21
    M: from
     Lh 22 -CHCH N; t
    Shz
    Free 162- 55.9 6.9 15.9 base -163,
    Free 210 55.8 6.7 15.7 base 21 1. ,,
    Free 183- 55.0 6.8 -16.1
    base -185, v,. ,,
    155sU (6.7) (16.1)
    Free 169- 54.9 6.8 16.0
    base -172 / g-, t g -, / g,
    (5b, 1) (6.7) (i6, l)
    22054, 9 6.8 16.1 -221 (55.1) (6.7) (16.1)
    18255, 9 6.8 15.5 -184 (56.1-) (6.9) (15.6)
    90-93 56.0 7.0 15.1
    Free base
    (56.1) (7.0) (15.6)
    13
    SNS
    S02
    SNS SNM
    kA
    sh.
    27S SO,
    -sn.sn-to-sh.
    14
    1 194257 Table
    Monohydro-128- 51.9 6.8 13.1
    chloride MO- -131
    nogidrat (51,9) (7,2) (13,2)
    55.9 7.2 14.5
    Hemihydrate 206-207 (55.9) (7.2) (14.8)
    15 Connection for example
    70 to 0.25
    125 at 0.25
    96 at 0.25
    29 to 0.05
    18 to 0.05
    32 at 0.05 94 at 0.25 46 at 0.05 46 at 0.05
    37to 0.05
    67 when 0.25
    76to 0.05
    33 from 0.05
    19 at 0.05 25 at 0.05
    sixteen
    1194257 Continuation of table. 3
    27 39 33 33 29 39 38 31 25
    37
    29
    58
    28
    23
    25 Maximum increase in the force of contraction of the heart muscle,%, administered by the administration of the compound offered at the appropriate dosage, mg / kg known at dosage of 0.25 mg / kg
    权利要求:
    Claims (2)
    [1]
    1. The method of obtaining quinazoline derivatives of General formula I
    R 2 and R 3 ~ each means hydrogen or methyl g, characterized in that, quinazoline of the general formula II where 0 is C1 or W, is reacted with piperidine of the general formula III or their pharmaceutically acceptable salts, where X is a straight or branched alkylene group a chain containing 1-4 carbon atoms;
    Y is a group of the general formula>
    where X and Y have the indicated meanings, either with its acid addition salt, followed by isolation of the desired product in its free form or as a salt, or, if necessary, a compound of the general formula I, where R ( - hydrogen, is alkylated with an alkyl halide of the general formula IV m
    where R | - SuSualkyl, to obtain a compound of general formula I, where R <- C, - C is alkyl, | OR, a compound of general formula I is reduced, where Y is a group of the formula
    KjAAr, by the action of sodium borohydride to form a compound of general formula I
    [2]
    2. The method according to π, 1, characterized in that the reaction of compounds of General formulas (II) and (III) is carried out in the presence of triethylamine.
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    EP0094766A2|1983-11-23|
    DK210183D0|1983-05-11|
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    ES528481A0|1985-05-01|
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    DD216018A5|1984-11-28|
    IL68668D0|1983-09-30|
    PL247054A1|1985-03-26|
    PL241968A1|1984-08-13|
    YU105083A|1986-02-28|
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    引用文献:
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    RU2698194C2|2014-05-15|2019-08-23|Пфайзер Инк.|Crystalline form of 6-[-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile|US3971783A|1973-03-07|1976-07-27|Pfizer Inc.|4-Aminoquinazoline derivatives as cardiac stimulants|
    GB1460389A|1974-07-25|1977-01-06|Pfizer Ltd|4-substituted quinazoline cardiac stimulants|
    US4171363A|1977-02-22|1979-10-16|Bristol-Myers Company|1,2,3-Thiadiazole process|
    CA1086735A|1977-11-03|1980-09-30|John C. Danilewicz|Piperidino-quinazolines|GB8320958D0|1983-08-03|1983-09-07|Pfizer Ltd|Quinazoline cardiac stimulants|
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    法律状态:
    优先权:
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