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    • 专利摘要:
    Novel tetrazolylalkoxycarbostyril derivative of the formula (I): <IMAGE> (I) wherein R1 is a hydrogen atom, a lower alkyl group, a low alkenyl group, a lower alkanoyl group, a benzoyl group or phenylalkyl group; R2 is a hydrogen atom, a lower alkyl group or a group of the formula <IMAGE> R3 is a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a phenyl group or a phenylalkyl group; A is a lower alkylene group; the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is either single or double bond; and the substituted position of a group of the formula, <IMAGE> in the carbostyril skeleton is either 4-, 5-, 6-, 7- or 8-position provided that the only one such group of the formula can be substituted in the whole carbostyril skeleton, thus when R2 in 4-position is a group of the formula <IMAGE> then 5-, 6-, 7- or 8-position will have no such substituted group; furthermore, the phenyl group in the above-mentioned benzoyl group, phenylalkyl group or phenyl group may have substituted group(s). The above-mentioned novel tetrazolylalkoxycarbostyril derivatives have pharmacological activities such as platelet aggregation inhibitory action, antiinflammatory action, antiulcer action, vasodilatory action and phosphodiesterase inhibitory action and are useful as anti-thrombosis agent, cerebral blood flow improving agent, antiinflammatory agent, antiulcer agent, anti-hypertensive agent and anti-asthmatic agent.
    公开号:SU1064868A3
    申请号:SU792804457
    申请日:1979-08-30
    公开日:1983-12-30
    发明作者:Ниси Такао；Нахагава Казиуки
    申请人:Оцука Фармасьютикал Ко,Лтд (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of novel tetraolyl-alkoxycarbostyryls with valuable pharmacological properties that can be used in medicine. The known reaction of O-alkylation of phenols with alkyl halide compounds and their derivatives. The purpose of the invention is to obtain new tetrazolylalkoxycarbostyryls with valuable pharmacological properties. The goal is achieved according to the method of obtaining tetrazolylalkoxycarbostyril of the total formula where R is hydrogen, C ,, is C |,. Alkyl, Cg-C alkenyl, alkanoyl with 1-4 carbon atoms, phenylpkyl, where the alkyl has C; -Q benzoyl or trimethoxybenzoyl; hydrogen, C; -C-apkyl, or a group of the formula H - K / J II -0-A, K where C -C-alkyl, Cs-Cg-cycloyl kil (cycloalkyl) alkyl, where (cycloalkyl) alkyl, where cycloalkyl has Cj-Cg and C; fC J -alkyl, unsubstituted phenyl or substituted by one or two substituents from the number of halogen-, nit. Or C) - C-hyshyl; or phenylalkyl, where hyukyl has C, -Cz and phenyl can be replaced by one or two substituents from among C-C-alkyl, dialkylamine, where alkyl has Cyj-C / or alkylenedioxy groups; where alkylene has A - alkylene has Cj, the dotted line indicates a possible double bond in position 3 and 4; and the group KK. The -V can occupy only one of the positions 4, 5, 6, 7 or 8, and when R is such a group, the positions 5, 6, 7 or 8 cannot 1 of this group, in which it is hydroxycarbyl the general formula where R and the dotted lines have the indicated meanings; R is hydrogen, C, alkyl, or hydroxy and the latter can occupy only one position 4, 5, 6, 7, and if the hydroxy group occupies position 4, then positions 5, 6, 7 or 8 have substituents different from the hydroxy group with a tetrazole derivative of the general formula Y, where R and A are as defined above; X - halogen, followed by isolation of the target product. Compounds (t) obtained according to the proposed method inhibit blood platelet aggregation, have anti-inflammatory .-. Activity, anti-ulcer, vasodilator effect, inhibit phosphodiesterase and can be used as antithrombosis; average improves cerebral blood flow, anti-ulcer, anti-hypertensive and anti-asthma drugs. The compounds show high efficacy in the prevention or treatment of the above diseases with long-term use, have low toxicity and have a small side effect on the heart, do not cause tachycardia and myocardial insufficiency .. The method can be carried out in the presence of a hydrogen halide acceptor from inorganic bases such as sodium hydroxide or potassium, sodium or potassium carbonate, acid potassium carbonate or sodium, or silver carbonate; alkali metals like sodium or potassium; alcohols such as methylate or sodium ethylate; and organic bases such as triethylamine, pyridine, S, N-dimethylaniline, N-methylmorpholine, 4-dimethyl. 16.1 g of 1-cyclohexyl-5-chloromethyl-tetra-elol are obtained in the form of weights and needle crystals, .101103 C.
    Reference note e- R s 4-13. Using a method similar to that described in Example 3, the following compounds will be obtained;
    51-Phenyl-5-y-chloropropyl tetrazole
    61-Iopropyl-5-chloropropyl tetrazole
    1-Cyclopentyl-5-y-chloropropyl ash ev
    1-Cyclohexmethyl-5- | Chloropropyltetrazol.
    9 1-Cyclooctyl-5 - "- chloropropyl tetrazole
    10 1-cyclohexyl 1-5- (4-chloro 6-methyltetrazol
    11 .1-Beneyl-5-chloromethyltetrazole
    12 1- (2-Chloro-4-nitrophenyl) -5-chloromethyltetrazole
    13 . 1- (4-Ethylphenyl) -5-chloromethyltetrazole
    | one
    bp 205-210 R & D:: fCflC 3 (TMS)
    1.55 (d, 6b). 2.3 (m, 2fl) (t, 2H) 2.65 (d, 2H) 4.7 (m, Ifl)
    NMR "SDSvz (TMS)
    The color is 1.5-2.7 (m, YUN),
    3.1 (t, 2Ia,
    3.7 (t, 2I)
    4.6-5.0 (l, 1I) NMR: YCH: DSVZ (TMS)
    0.3-2.7 (t, 13I) 3.5 (t, 2I),
    3.75 (t, 2I), 4.15 (d, 2I)
       NMR: “GSDS, (TMS): 1.35-2.65 (t, 1bЯ), 3.0 (t, 2b)
    3.67 (t, 2H), 4.2-4.7 (t, 1H) NMR: (G-Dose (TMS)
    I 0.3-2.3 {t, 14Y) 2.6-3.1 (t, 2H) 3.35-3.77 (t, 2I)
    3.90-4.50 (t, 1I)
    NMR: C-SDS (TMS)
    4.67 (S, 2H) 5.37 (S, 2H),
    7.1-7.6 (t, 5H) NMR: (G-CDSe (TMS)
    slightly liquid
    4.8 (S, 2Я)
    7.76 (d, 1H),
    8.25-8.60 (t, 2I) NMR: (CDS TMS)
    colorless liquid
    1.3 (t, sd)
    2.75 4q, 2I)
    .4,8 (s, 2fl),
    7.43 (S. 4L). Example 1. In 200 ml of dimethyl formamide, 3.2 g of 6-hydroxycarbostyril, 3.5 g of potassium carbonate and 7.7 g of X-cyclohexyl-By-chloropropyl tetraeol are added and the mixture is stirred for 4 hours at 70–80 seconds. After completion of the reaction, dimethylformamide is distilled off under reduced pressure. The residue obtained is then extracted with 300 ml of chloroform and the chloroform layer is washed with a rape, with a sodium hydroxide solution and with water, and then dried with sodium sulfate. After removing the drying agent by filtration, the filtrate is concentrated and the residue is recrystallized from chloroform. Obtain 3.54 g of 6- / 3- (1-cyclohexyltetrazol-5-yl) propoxy / carbostyril in the form of colorless needles crystals, so pl. 211-212 ° C. Example 2. Using the method of example 1, get 6- / 3- (1-ethyltetrazol-5-yl) propoxy / carbostyril in the form of pale yellow crystals, so pl. 179-181.5 ° e. Example 3. To 100 ml of isopropanol were added 2.63 g of 6-hydroxy-1-methylcarbostyril and 2.64 ml of 1,5-diazobicyclo (5.4.0) undedecene-5 (DW the resulting mixture was boiled with reverse with stirring under stirring. After that, 100 ml of isopropanol containing 5–7 g of 1-cyclohexyl-5-1-iodopropyl tetrazole is added dropwise over 90 minutes. After the addition is complete, the reaction mixture is additionally heated under reflux with stirring 5. h and then concentrate. Received 4 4-chr- (1-qi "logexyl-tetrazol-5-yl) -propoxy / carbostyryl
    65- (3- (1-Benzyltetrazol-5-yl) PROPOXY) -3, 4-dihydrocarbyl styryl 75- / 1-Cyclohexyl tetrazol-5-yl / methoxy-3, 4-dihydrocarbostyryl.
    81-Venzyl-5- / 1-cyclohexyltetrazol-5-yl / methoxy-3, 4-dihydrbcarbostyryl
    95- / 3- (1-Cyclohexyltetrazl-5 yl) PROPOXI / -3,4-dihydrocarbostyryl
    0 5- / 3- (1-Cyclopentyltetrazol-5-yl) propoxy / -3,4-dihydrocarbo. Styryl
    247-249
    172-172,5
    219.5-221
    156-157
    220-221 5
    199.5-200% residue is extracted with 300 ml of chloroform, the chloroform layer is washed with dilute caustic soda solution and then with dilute hydrochloric acid. After drying with sodium sulfate, the chloroform is distilled off, and the resulting octate is recrystallized with kec acetone. Obtain 4.8 g of 1-methyl- / 3- (1-cyclohexyltetrazol-5-yl) propoxy / carbostyril in the form of colorless needle crystals, so pl. 150151, 5c. Example 4. 3.22 g of 6-hydroxycarbostyril and 3.51 ml of 1,5-diazobicyclo (5.4.4) undecene-5 (TLD) were added to 100 ml of ethanol and the resulting mixture was heated under reflux with stirring. . Then 100 ml of ethanol containing 7 g of 1-benzyl-5-y-iodopropyl tetrazole is added dropwise over 90 minutes. After the addition was complete, the reaction mixture was heated under reflux for 5 hours and then concentrated. The resulting residue was extracted with 300 ml of chloroform, the chloroform layer was washed with dilute aqueous sodium hydroxide solution, diluted with hydrochloric acid and water, and dried with sodium sulfate. After removing the solvent, the resulting residue is recrystallized from aqueous ethanol. Obtain 4 g of b- / 3- (1-benzIltetraeol-5-yl) propoxy / carbostyril in the form of colorless needle crystals, so pl. 152-154 ° C. Examples 5 to 41. The following compounds are prepared analogously:
    116 - / (1-Cyclohexyltetrazol-5-yl) methoxy / carbostyryl
    126- / 3- (1 Phenyltetraolg5-yl) propoxy / carbostyril
    4-Methyl-6- / 3- (1-cyclohexyltetraool-5-yl) propoxy / carbostyryl
    b- / 1-benzyltetrazol-5-yl / methoxy / carbostyril
    6- / 3- (1T Cyclohexylmethylte1: raEOL-5-IL) propoxy / carbostyryl
    b- / 3- (1-Cyclooctyltetrazol-5il:) propoxy / carbostyryl
    6- / 3- {1-Cyclopentyltetrazol-5yl) propoxy / carbostyryl
    6- / 4- (1-cyclohexyltetrazol-5yl) butoxy / carbostyril
    1-Benzyl-6- / 3- (1-cyclohexyltetrazol-5-yl) propoxy / carbostyryl
    1-Allyl-6- (3- (1-cyclohexyltetra sol-5-yl) propoxy / carbosti |) yl
    6- / 3- (l-Cyclohexyltetrazol-5il) PROPOXI / -3, 4-dihydrocarbostyryl
    1-Achechyl-b- / 3- (1-cyclohexyltetrazol-5-yl) propoxy / -3,4-dihydrocarbostyryl
    23 6- / 3- (1-Benzyl-tetrazol-5-yl) Colorless propoxy / -3,4-dihydrocarbosts - needle ryl crystals
    6- / 3- (1-Phenyltetrazol-5-yl) PROPOXI / -3, 4-dihydrocarbostyryl
    6- / 3- (1-Cyclohexylmethyltetrazol-5-yl) PROPOXI / -3,4-dihydrocarbostyryl
    6- / 4- (1-Cyclohexy tetrazol-5yl) butoxy / -3,4-dihydrocarbostyryl
    Table continuation
    278-281
    173-174
    226-228
    233.5-235
    175-175,5
    220-220.5
    196.5-197.5 177.5-178.5
    139-140 1 2-103,5
    154.5-155.5
    / 124-126,5
    136.5-138
     I.
    159-160,5
    “-
    137-138
    - -
    148-150,5
    1-Propyl-6- (1-benzyltetrazol27 -5-yl) methoxy-3,4-DIHYD
    1-ETHIL-6- / 3- (1-cyclohexyltetrazol-5-yl) PROPOXI / -3,4-dihydrocarbostyryl
    6- / 1- (2-Chloro-4-nitrophenyl) tetraerl-5-yl / methoxy-3, 4-dihydrocarbostyryl
    6- (1- (4-ethylphenyl) tetraeol-5yl / methoxy-3, 4-dihydrocarbostyryl)
    1- (3,4,5-Trimethoxybenzoyl) -6- / 3- (1-cyclohexyltetrazol-5-yl) Example 42. 3.2 g 6- / 3 - (. 1-cyclohexyltetrazol-5-yl) propoxy- five
    Table continuation
    NMR: CDCP, (TMS); awn 2,3
    3.25 (m, 6H) 5.2 (s, 2H) 5.65 (s, 2H) 6.6-6.9 (t, 2H) 7.0-7.5 {t, 6H)
    106.5-108.5
    214.5-216 (decomposition) is149-149, 5 sy / -3,4-dihydrocarbostyril and 3,4; 90% solution of DBM added 18t to
    100 ml of dioxane, the mixture is boiled at 9.5 and then cooled. After completion of the reaction, the solvent was distilled off, the resulting residue was dissolved in chloroform, the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, dried with sodium sulfate, and then treated with activated charcoal. After distilling off the solvent, the obtained residue is purified by chromatography on a column of silica gel (eluent: chloroform-methanol 10: 1 (volume-volume crystalline product is recrystallized from chloroform.
    1.1 g of 6 / - / 3- (1-cyclohexyltetrazol-5-yl) propoxy / carbostyril are obtained in the form of colorless needle-like crystals, m.p. 211-212 ° C.
    Example 43. In 500 ml of methanol, 2.5 g of 6- (3- (1-cyclohexyltetrazol-5-yl) propoxy / carbostyril) are added, 0.1 g of palladium catalyst and hydrogenated at 2.5 at 50 ° C are added. for 8 hours. After completion of the reaction, the catalyst is separated by filtration and the filtrate is concentrated to dryness. The residue is recrystallized from chloroform-petroleum ether.
    Obtain 1.5 g of 6- / 3- {1-cycloge | siltetrazol-5-yl) propoxy / -3,4-dihydrocarbostyril in the form of colorless
    1- / 3,4,5-Trimethoxybenzoyl-6- / 3- / (1-cyclohexyltetrazol-5-yl) propoxy / 3, 4-dihydrocarbostyryl
    1-Propionyl-6 - / (1-benzyltetrazol-5-yl) methoxy / -3,4-dihydrocarbostyryl
    Example .8. 1.8 g of 6- (3- (1.-Cyclohexyltetrazol-5-yl) propoxy / carbostyril) are dissolved in 50 ml of dimethylformamide and then with stirring and external cooling of the reaction vessel with ice, 0.15 g of sodium hydride is added over 30 minutes . AT
    needles, so pl. 154.5155,.
    Example 44. 1.8 g of 6- (3- (1-cyclohexyltetrazol-5-yl) propoxy / 3, 4-dihydrocarbostyryl) was dissolved in 30 ml of dimethylformamide and 0.14 g of sodium hydride was added. Under stirring and external cooling of the reaction mixture with ice over 1 hour, 0.41 ml of acetyl chloride was added dropwise. After the addition is complete, the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is then extracted with chloroform (three times, in 100 ml portions). The chloroform layer is washed with a saturated / sodium chloride solution and dried over sodium sulfate. After distilling off the chloroform, the obtained residue is purified by chromatography on a column of silica gel (solvent: ethyl acetate). The resulting fractions are collected and the residue is concentrated and recrystallized from chloroform-petroleum ether.
    Obtain 1.1 g of 1-acetyl-6- / 3- (1-cyclohexyltetrazol-5-yl) PROPOXI / -3, 4-dihydrocarbostyril in the form of colorless needle crystals, so pl. 124-126 ,. ... Examples 45-47. Using a method analogous to Example 44, the following compounds were obtained:
    57-59
    NMR: rfCDCBj (TMS): 1.2
    (t, 3N) 2.35, 3.25 (t, 6H) 5.2 (S, 2H) 5.65 (S, 2H) 6.6-6.9 (t, 2H) 7.0-7 , 5 (t, 6H)
    0.52 ml of allyl bromide is added dropwise with stirring at room temperature over 2 hours. The reaction mixture is concentrated, the residue is extracted with chloroform, washed with water and dried with sodium sulfate. After the drying agent was removed by filtration, the filtrate was concentrated and the residue was dissolved in chloroform. The chloroform solution is washed with water and then concentrated. The residue obtained is purified on a silica gel column (eluent: chloroform-methanol 50: 1). the fractions are collected and concentrated, the residue is recrystallized
    .one
    1-Benzyl-6- / 3- (1-cyclohexylamine-5-yl) propoxy / carbostyril
    1-Ethyl-6- / 3- (1-cyclohexyltetrazol-5-yl) propoxy / -3,4-dihydrocarbostyryl
    EXAMPLE 52 - 54. Using the method of Example 4, the following compounds are prepared:
    6- {3- / 1-Chr-3,4-Dimethoxy-. Colorless netil) tetrazol-5-yl / propoxy carotid bostyril
    ,,
    6- {3- / 1- (p-3,4-methylenedioxyphenol- Colorless netil) tetrazol-5-yl / propoxy) carbostil plates
    6- {s- / 1- {p-4-Dimethylamino phenethyl) tetrazol-5-yl / propoxy carbostyryl Inhibition of blood platelet aggregation. Inhibition of platelet aggregation by compounds obtained by the proposed method was studied using an A-11 aggregometer. A sample representing a mixture (1: 9 by volume) of CIT and rabbit blood was taken for the study. The sample was centrifuged for 10 minutes at a speed of 1000 rpm, and platelet rich plasma (PRP) was obtained, which was separated. The remaining blood was further centrifuged for 15 minutes at a speed of 3000 rpm and platelet-deficient plasma (PPP) was obtained. The platelet count in PRP was calculated using the Brecher-Clonkite method, and the PRP fraction was diluted with a PPP fraction.
    from chloroform-petroleum mixture
    ether.
     Obtain 1.2 g of 1-allyl-6- / 3- (1-cyclohexyltetrazol-5-yl) propoxy / carbostyril in the form of colorless needle crystals, so pl. 102g103 ,.
    Examples 49-51. Using a method similar to Example 48, the following compounds are obtained: I
    139-140
    106.5-108.5
    206-208
    195-197
    14G-143 to obtain a PRP sample with a platelet concentration of / v3000 in 1 ml for an adenosine diphosphate (ADP) induced aggregation test. A sample containing platelets in 1 ml was also obtained for the aggregation test induced by collagen. The specified PRP sample in the amount of 0.6 ml was added to 0.01 ml of the test compound solution and the resulting mixture was stirred in a thermostat with a temperature of 37 ° C for 1 min. Then, 0.07 ml of ADP or collagen solution was added to the mixture. The transmittance of the resulting mixture was determined; the change in transparency was recorded using an aggregometer at a stirring speed of 1100 rpm. AureiBeronal buffer with a pH of 7.35 was used to obtain ADP or collagen solutions. The ADP concentration in these solutions was 7.5–10 M, and the collagen solution was prepared by treating 100 mg of the gene call with 5 ml of the indicated buffer, and the supernatant was used as inducers of platelet aggregation. Adenosine and acetylsalicylic acid were used as control substances when tested for aggregation with ADP or collagen. The effect of inhibiting platelet aggregation was determined as a percentage, as the ratio of the rate of aggregation in the presence of the test compound with respect to the rate of aggregation of the same mixture in the absence of antiaggre- gant. The rate of aggregation is t 1 x 100, where a is the transparency of PRP, b is the transparency of PRP; containing the test compound and aggregation inducer; с - transparency of PPP. I tested the following substances. Suggested compounds: 1.6- / 3- (1-Cyclohexyltetraool-5-yl) propoxy / carbostyril 2.6- / 3- (1-Isopropyl tetrazol-5-yl) propoxy / carbostyril 3.6- / 3- (1-Cyclohexyltetrazol-5-yl ) PROPOXY / -Z, 4-dihydrbarbostyril 4.6- / 3- (1-Benzyltetrazol-5-yl) propoxy / carbostyryl 5.6- / 3- (1-Cyclohexylmethyltetrazol-5-yl) propoxy / carbostyril 6.6-uz- (1- Cyclooctyltetrazol-5-yl) propoxy / carbostyryl 7.6- / 4- (1-Cyclohexyltetrazol-5-yl propoxy / carbostyryl 8.1-Methyl-6- / 3- {1-cyclohexyltetrazol-5-yl) propoxy / carbostyryl 9.6- / 3 - {1-Phenyltetrazol-5-yl) prc coxy / carbostyril 10.4-Methyl-6- / 3- (1-cyclohexyltetrazo -5-yl) propoxy / carbostyryl 11.5- / 3- (l-Cyclohexyltetrazol-5-yl) propoxy / -3, 4-dihydrocarbostyryl 12.1-Benzyl-6- / 3- (1-cyclohexylhetrazol-5-yl) propoxy / Carbostyryl 13.1-Allyl-6- [3- (1-cyclohexyltetrazol-5-yl) propoxy] / Carbostyryl 14.1-Acetyl-b- / 2- (1-cyclohexyltetrazol-5-yl) propoxy] -3,4-dihydrocarboxyryl 15.6- (1- (4-Ethylphenyltetrazal-5-yl) methoxy) -3,4-dihydrocarbostyryl 16.1- (3, 4,5-Trimethoxybenzoyl) -g- 6- / 3- (1-cyclohexyltetrazol-5-yl) PROPOXI / -3, 4-dihydrocarbostyril Known compounds: 17. Ispirin (control compound) 18 .6- / 3- (5-Methylthiotetrazol-1) propoxy / -3,4-carbostyryl 19.6- / 3- (5-Methylthiotetrazol-2) propoxy / -3,4-dihydrocarboxy 20 .6- / 3- {Tetrazol-1-yl) propok-3, 4-dihydrocarbostyryl 21.5 / 2-Piperidine C1OTOxy / -3,4 hydrocarbostyryl 22.5 - / 2-Morpholinoethoxy / -3.4 hydrocarboucyl 23.5- / 3-Piperidinoprophoc-pane / 4-dihydrocarbostyryl 24.6- / 2-Morpholinoethoxy / -3.4 hydrrcarbostyryl 25.7- / 3-Piperidinopropoxy / dihydrocarboxyryl 6.8- / 3,4hydrrcarbostyryl 25.7- / 3-Piperidinopropoxy / dihydrocarbostyryl 6.8 tab. 1 shows the effect of inhibin carbostyril derivatives of collagen induced aggregate of rabbit blood. Table
    191064868
    - Continuation of the table. one
    In tab. Figure 2 shows the effect of inhibiting the carbostyril derivatives of ADP-induced rabbit blood platelet aggregation.
    table 2
    20
    Continued table. 2
    Inhibition of cyclic AMP phosphodiesterase activity. To determine the inhibitory activity, 10 ml of the solution obtained by adding 1.-mmol of magnesium chloride to 50 mmol of Tris buffer with P9 7.4 was added to the platelets obtained by additional centrifugation of the above described PPP fraction at a speed of 3000 rpm for 10 mKn and suspended platelets were ground in a teflon-ceramic homogenizer. After this, two-fold freezing and thawing and grinding with ultrasound from a 200 V generator for 300 s were carried out. After an additional 60-minute centrifugation under force. 100,000 g of the upper layer was taken as a crude enzyme solution. 10 ml of this buffer solution was passed through a 1 cm, column with DEAE-cellulose, which
    pretreated with 50 mmol
    tris-acetate buffer (pH 6.0), followed by washing and elution with 30 ml of 50 mmol trisacetate buffer and the resulting eluate was subjected to linear gradient elution with sodium acetate-acetate buffer in a concentration range of 0-1 mmol. The linear speed was 0.5 ml / m, and 5 ml of each fraction was taken. As a result of this operation, a fraction was obtained, which had an activity of less than 2 ppm / ml of ol high (100 mmol) concentration of cyclic AMP substrate, as well as a fraction with high activity at 100 p mol / ml at low (0 , 4 mmol) concentration of cyclic AMP substrate. This fraction was used as cyclic AMP phosphodiesterase.
    0.1 ml of an aqueous solution of each test compound was mixed with 40 mmol of tris buffer (pH 8.0 containing 50 mg of l-bumin serum and 4 mmol of magnesium chloride) containing 0.4 mmol of cyclic AMP (tritium cyclic AMP) and 0, 2 ml of this solution was used as a substrate.
    0.2 ml of the prepared concentration of cyclic AMP phosphodiesterase with the established concentration was added, and the substrate solution was reacted for 20 minutes, resulting in a tritium 5.-AMP from tritium cyclic AMP.
    Then the reaction system was immersed in boiling water for 2 minutes to stop the reaction, then the reaction solution was cooled in ice water to convert the resulting tritium into tritium-adenosine, 0.05 5 snake nucleotidase was added to the resulting solution and the reaction was carried out within 10 min. The reaction solutions were then passed through a cation-exchange resin (A650bW-4 200-400 mesh, manufactured by Bio-Pad, column size 0.5-1.5 cm), obtained by collecting tritium adenosine, washed with 6 ml of distilled water and eluted. 1, 5 ml of 3 N ammonia water. All the solvent was loaded into a 10 ml scintillator with a capacity of 10 ml and the amount of tritium-adenosine produced was determined using a liquid scintillation counter, which determined the anthosphosphodisterase activity.
    Thus, the sign- phosphodiesterase activation (Cd) of the test compound for each concentration, and phosphodiesterase inhibition rate (%) was determined from the specified activation value (Cp) and control value (C) obtained for water not containing the test compound using the following formula:
    Inhibition rate - - "100
    with phosphodisterase (%)
    Papaverine and 1-methyl-3-isobutylxanthine were used as control compounds.
    In tab. 3 shows the rate of inhibition of phosphodiesterase (%). T a b l and c a 3
    Stimulus qi blood supply to the cerebral hemispheres.
    The effect of stimulating the current through the brain was measured by the method described. The dog (male weighing 12–26 kg) was fixed in a supine position and anesthetized with sodium pentobarbital (20 ml / kg), forced respiration was maintained at a frequency of 20 times / min. Then, the skull was exposed and the superficial bone was removed before the appearance of the venous sinus and venous blood was drawn through the cannula. The amount of venous blood was measured using an electromagnetic blood flow meter and further measurement was performed using a drop counter by measuring the number of blood drops in 10 s.
    The effect of increasing blood flow through the brain was calculated by comparing the number of blood droplets in 30 seconds with the maximum magnification that occurred before and after applying the test compound. Each of the tested compositions was dissolved in dim &amp; tilformaidid, diluted with physiological saline, and a cannula was inserted into the basal vein of the femoral vein. Papaverine was not used as a control compound. The results obtained are presented in Table. four. , . . . IT a b l and c a Paparevin Hypotensive effect. The hypothetical effect of the compounds was determined by determining the maximum blood pressure of the subjects in the stomach according to the described procedure. For the experiments, two types of animals were used. For the first pa, male Male Gold Blatt rats weighing 160-180 g were anesthetized with ether, and the left renal artery was blocked with a silver clip having an inner diameter of 0.2 mm, while the right renal artery was left without any changes. Four weeks after the operation, rats with a maximum blood pressure above 150 mm Hg were taken, and they were used as test animals, these animals were not fed during the night. The second group of animals consisted of rats with increased blood pressure, caused by the introduction of deoxycorticosterone acetate (DOSA) in physiological solution (DNR). For this, male Wistar rats weighing 150-170 g were anesthetized with ether and the left kidney was isolated with a VE. One week after the operation, 10 mg / kg DOSA was administered subcutaneously once, and a 1% aqueous solution of sodium chloride was given as a drink. Five weeks after the operation, rats were taken, having maximum blood pressure above 150 mm Hg, and they were used as test animals, leaving n :: no food. I All tested compounds were administered orally, blood pressure was measured before use and after 1, 2, 4, 6 and 8 hours after use. Blood pressure was measured using a Recorder (Rectihoriz-type 85, San-ei Inst) and a PE-300 electro-stabilizer meter (Macro Bio-sy5tems, Houston, Tech.). The results are presented in Table 5. Acute toxicity distribution. The proposed compounds are used. orally in mice and determine the LD mg / kg of the compounds obtained by the proposed method. The results obtained are presented 5. us in tab. 6 Table 6 LDjp mg / kg Continued table. 6 Dyo mg / kg
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING TETRAZOLYL'ALCOXICARBOSTERILES of general formula I has C 4 -C 4 alkylenedioxy groups, where alkylene has C „-C 3 ;
    A - alkylene has C 1 * t ^;
    the dotted line indicates a possible double bond at positions 3 and 4;
    and the group “—and
    Λ V
    V w ’:
    only one of polo 7 or 8, and when R 2 troupe, then the position
    -0-A may occupy 4, 5, 6, such 6, 5, 7 or 8 may not have this group, characterized in that oxycarbostyr is in common with the formula where R 1 is hydrogen; C ^ -C-alkyl ', C 2 -C 4 alkenyl; C ^ -C ^ alkanoyl, phenylalkyl, wherein the alkyl has C ^ -C 4 , benzoyl or trimethoxybenzoyl;
    r2 is hydrogen, C ^ -C alkyl or. group of formula
    N — K
    J N
    -ο-α · λγ R 3 .
    wherein R ® - C n-C 4 -alkyl, C z ~ C 8 cycloalkyl, (cycloalkyl) alkyl wherein cycloalkyl has -Sts C E and C 4 -C 4 -alkyl, phenyl unsubstituted or substituted with one-/ him or two halogen, nitro or C 4 -C 4 alkyl substituents; or phenylalkyl, where the alkyl has C ^ -C 4 and phenyl may be substituted with one or two substituents from the number of Ci-C 4 -alkyl, where alkyl
    I where
    R 1 value;
    - hydrogen, C ^ -C 4 ~ alkyl or an oxy group and the latter can occupy only one of the positions 4, 5, 6, 7 or 8, the oxy group occupies the position 4, then the positions .5, 6, 7 or 8 have substituents that are excellent from an oxy group, are reacted with tetraeol derivatives of the general formula
    K — K '—X-dD Λ. _. R 3 .. I where R 3 and A have the above meanings;
    X is halogen, followed by isolation of the target product.
    R 2 and if that position .5
    IN
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    同族专利:
    公开号 | 公开日
    SE7907236L|1980-03-02|
    SE432252B|1984-03-26|
    IT1119929B|1986-03-19|
    ES483792A1|1980-09-01|
    CH641799A5|1984-03-15|
    DE2934747A1|1980-03-13|
    AR229342A1|1983-07-29|
    JPS5535019A|1980-03-11|
    JPS6155514B2|1986-11-28|
    NL183888C|1989-02-16|
    CA1139761A|1983-01-18|
    FR2434809B1|1982-09-17|
    AT364363B|1981-10-12|
    PT70136A|1979-09-01|
    US4277479A|1981-07-07|
    FI68398C|1985-09-10|
    ZA794627B|1980-08-27|
    FI68398B|1985-05-31|
    BE878548A|1979-12-17|
    GB2033893A|1980-05-29|
    DE2934747C2|1988-01-28|
    NO792829L|1980-03-04|
    MX6749E|1986-06-25|
    NO153177B|1985-10-21|
    NO153177C|1986-01-29|
    DK158788C|1990-12-10|
    AU5039779A|1980-03-06|
    AU538410B2|1984-08-16|
    GB2033893B|1982-12-01|
    FI792699A|1980-03-02|
    IT7968748D0|1979-08-31|
    DK158788B|1990-07-16|
    ATA584579A|1981-03-15|
    DK363179A|1980-03-02|
    FR2434809A1|1980-03-28|
    NL7906523A|1980-03-04|
    PH18452A|1985-07-18|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP53107869A|JPS6155514B2|1978-09-01|1978-09-01|
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