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    • 专利摘要:
    Compounds represented by the following general formula (1) or (2): (FORMULA) (wherein R<s1>s represents H, a lower alkyl, lower alkenyl or phenyl-lower alkyl, R<s2>s represents H or a lower alkyl, A represents a lower alkylene, R<s3>s represents a lower alkyl optionally having a hydroxy group a lower alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl or benzoloxy-lower alkyl, R<s4>s represents a cycloalkyl optionally having a hydroxy group, cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl optionally having a lower alkoxy group on the phenyl ring, lower alkyl optionally having a hydroxy group, hetero ring group or hetero ring-substituted lower alkyl, and R<s3>s and R<s4>s may form, together with the adjacent N, a group represented by the formula of (FORMULA) (wherein R<s5>s represents phenyl, cycloalkyl or phenyl-lower alkyl, and B represents methine or N), provided that, when R<s3>s represents the lower alkyl, R4 represents the aforesaid group other than cycloalkyl, cycloalkylalkyl, and lower alkyl, and the bond between the 3- and 4-positions on the carbostyryl skeleton represents a single or double bond], the salts thereof, and process for preparing same. These compounds have the effects of preventing and curing thrombosis.
    公开号:SU1169535A3
    申请号:SU813280901
    申请日:1981-05-11
    公开日:1985-07-23
    发明作者:Ниси Такао；Танака Татсуеси；Накагава Казуюки
    申请人:Оцука Фармасьютикал Ко,Лтд (Фирма)；
    IPC主号:
    专利说明:

    - methine group or nitrogen atom, carbon - carbon bond between the 3rd and 4th positions in the carbostyryl. the skeleton is a single or double bond, the substituted position of the group
    / 3 Formula -0-A-CON Vl "4
    Any of the 5th, 6th, 7th, or 8th positions of the carbostyril skeleton, if the group of the formula
    -O-A-C ON „noditc
    "four
    in the 5th, 6th, 7th or 8th position of the carbostyril skeleton,
    R, is a hydrogen atom or a lower alknp; if R is a group
    Formulas -O-A-CON: 3,
    K4
    The 6th, 7th and 8th positions in the carbostyril derivative are occupied by hydrogen atoms and are not replaced by a group of form S
    ly -0-a -con
    if rj
    lower alkyl, R can be neither Cj - C d-cycloalkyl, C 3 - C j-cycloalkyl lower alkyl, nor lower alkyl,
    characterized in that the carboxyalkoxy carbostyril derivative of the general formula
    O-A-COOH Rt
    I RI
    the carbon - carbon bond by inter-, 4th positions in the carbostyryl 4ete has the indicated values: a hydrogen atom, a lower alkip or a group of the formula -0-A-COOH, where A has the indicated values, the group -O-A-COOH is in 5 , 6th, 7th or 8th position of the carbostyril skeleton ;: if the -OA-COOH group is in the 5th, 6th, 7th or 8th position of the carbostyril skeleton, a hydrogen atom or lower alkyl; if rj group
    The 5th, formulas -O-A -COOH, the 5th, 6th, 7th and 8th positions of the carbostyril skeleton are occupied by hydrogen atoms. and not substituted by groups of the formula -0-A-COOH
    interaction with the amine of the formula
    3
    -Hn;
    X
    where RJ and R have y: measured values, with the release of the desired product in free form.
    one
    This invention relates to a process for the preparation of new carbostyril derivatives of the general formula
    where R is a hydrogen atom, lower alkyl, lower alkenyl or phenyl lower alkyl,
    R is a hydrogen atom, lower alkyl or a group of the formula
    R,
    -O-A-CON

    R /
    where A is an enna or unsaturated lower alkylene group. R. is lower alkyl, hydroxy-n-alkyl, lower alkanoyloxy-lower alkyl or benzoyl. C-lower alkyl., R - Cj - C d-cycloalkyl, which may contain at least one hydroxyl group as a substituent (s) in the cycloalkyl ring, C - C gdikloalkyl-lower alkyl, phenyl phenyl-lower alkyl, which may contain at least one lower alkoxy g as a substituent (s) in the phenyl ring, a lower alkyl which. may contain at least one hydroxyl group, pyridyl or lower alkyl containing as a substituent, a heterocyclic residue selected from the group including pyridyl,. furyl, tetrahydrofuryl, 3,4-dihydro -2H-pyranyl, tetrahydropyranyl or thiens R, R and the nitrogen atom bound to it, as well as together or without another nitrogen atom, may form a group of the general formula -NQs-Rs where Rg is phenyl Cj - C, d-cycloalkyl,. or phenyl-lower alkyl, B - (methine group or an atom of an iota, carbon - carbon bond between 3 and 4 strands in the carbostyryl skeleton is a single or double bond in the j position, the groups of the formula -0- A-CON is any of the 5th, 6th, 7th or 8th positions of the carbostyril skeleton} if the group -0-A -CONC finds R f c in the 5th, 6th, 7th or. The 8th position of the carbostyril skeleton, R, - is a hydrogen atom or lower alkyl, if R is a group of the formula -o-A -CON G., the 5th, 6th, 7th and 8th positions in carbostyril derivative by hydrogen atoms and unsubstituted groups th formula / g -0-A-CON if RJ is lower alkyl, R can not be either Ca - C p-cycloalkyl, Cd - C-cycloalkyl-lower alkyl, nor lower alkyl ... The resulting new carbsteryl derivatives have an inhibitory effect on blood platelet aggregation, a property to inhibit the action of phosphodisterase, a property to enhance myocardial contractions (positive inotropic effect), an anti-ulcer action, an anti-inflammatory effect, a hypotensive effect, a property to strengthen cerebral red blood cells, to dissolve clots of thrombocytes, characterized by antagonism of thromboxane A and therefore suitable for the prevention and treatment of thrombosis and embolism, for example, cerebral apoplexy, cerebral infarction, myocardial infarction, as agents for improving cerebral blood flow, anti-inflammatory agents, anti-asthma agents, cardiac flow, anti-inflammatory agents, anti-asthma agents, cardiac flow, anti-inflammatory agents, anti-asthma agents, cardiac flow, anti-inflammatory agents, anti-asthma agents, cardiac flow In addition, the carbostyryl derivatives represented by the general formula I have low toxicity and especially minor side effects on the heart, such as, for example, an increase in heart rate, cardiovascular hypertrophy, myocardial disorders, or the like, although they are fast and well absorbed by the blood and can be stored in the blood. relatively high concentrations, and the previously mentioned pharmacological effects can be extended over a relatively longer period of time n-3J. The reaction of reacting amines with carboxylic acids is known. The conditions of the process depend on the nature of the starting reagents. 4.J The purpose of the invention is the synthesis of new compounds with beneficial pharmacological properties. The goal is achieved by the fact that according to the method of producing carbostyril derivatives of the formula 1, the carboxylalkoxycarbostyryl derivative is the general formula where R ,, and carbon is a carbon bond between the 3rd and 4th positions in the carbostyril skeleton has the indicated values: R is an atom hydrogen, lower alkyl or a group of the formula -O-A-COOH, where A has the indicated meanings) the group -O-A-COOH is in the 5th, 6th, 7th or 8th position of the carbostyril skeleton; the group-O-A-COOH is in the 5th, 6th, 7th or 8th position of the carbostyril skeleton, R, j is a hydrogen atom or lower alkyl if Rj is a group of the formula -O-A-COOH, The 5th, 6th, 7th and 8th positions of the carbostyril skeleton are occupied by hydrogen atoms and are not substituted by groups of the formula -O-A -COOH are reacted with an amine of the general formula -HN where Rj and R have the indicated values with the release of the target product in free form. Among the compounds represented by formula (I), compounds in which there is an acidic group can easily form salts with pharmaceutically acceptable basic compounds, including bases, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide ; with alkali metal alkoxides such as sodium methoxide, potassium ztilate. Of the compounds represented by the general formula (I), those compounds which contain a basic group can easily form salts with common pharmaceutically acceptable acids, which include such inorganic acids as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid and so forth. P. The compounds thus obtained can be easily isolated and purified using conventional isolation means, such as reprecipitation, extraction, recrystallization, column chromatography and preparative thin layer chromatography. The proposed compounds can be administered either as they are or together with conventional pharmaceutically acceptable carriers in both animals and humans. There are no particular limitations on unit dosage forms, and the proposed compounds can be taken in any desired unit dosage. Suitable forms: for single use include forms for oral administration: tablets, capsules, granules and solutions, and forms for parenteral administration, injections. The dosage of the active ingredient for administration is not limited to specific values; it allows selection over a wide range of values; However, to achieve the desired pharmacologic effect, it is recommended to select the indicated dose in the range of 0.06-10 mg per kg of live weight per day. It is also proposed that each single dose of administration of 1,500 mg of the active ingredient. Example 1 Into 100 ml of dimethylformamide 2.5 g of 6- (3-carboxypropoxy) carbostyril and 1.7 ml of triethylamine are added. The reactor containing the mixture is cooled outside. 1.4 ml of isobutyl chloroformate are added dropwise to this mixture with stirring with ice. After completion of the addition operation, stirring is continued for a further. 30 min, then to the reaction
    1.75 g of H- (2-hydroxyethyl) cyclohexylamine is added to the mixture, and stirring of the reaction mixture is continued for 3 hours.
    After completion of the reaction, the solvent was distilled off, and the resulting residue was extracted with about 300 ml of chloroform, washed with dilute aqueous NaHCO-, water, dilute hydrochloric acid, and water in this order. Chloroform is distilled off to obtain a residue, and the resulting residue is recrystallized from chloroform-petroleum ether to obtain 1.9 g of 6- {3- N- (2-oxo-ethyl) -N-cyclohexylaminocarbonyl propoxy carostyryl as colorless needle-like crystals. T. pl. 165-166 S.
    Example 2. To 100 ml of chloroform were added 2.5 g of 6- (3-carboxypropoxy) -3,4-dihydrocarbostyril 1, and 1.65 g of 1,8-diazabicyk0-5,4,0-undecene-7 (DBU). The reactor in which the mixture is located is cooled outside with ice, and 1.5 ml of isobutyl chloroformate is added dropwise to the reaction mixture with stirring. After the addition was complete, stirring was continued for another 30 minutes, 2.0 g of N- (2-hydroxyethyl) cyclohextamine was added to the reaction mixture, followed by stirring. continue at room temperature for another 2h,
    After completion of the reaction, the chloroform solution of the reaction product is washed with a dilute aqueous solution of NaHCO-, water, dilute hydrochloric acid, and water in this order. The chloroform solution was dried over anhydrous, then chloroform was distilled off, and the resulting residue was recrystallized from chloroform-petroleum ether to give 2.1 g of (2-hydroxyethyl 1) M-cyclohexylaminocarbonyl propoxy} -3, 4-dihydrocarboxyryl in the form of colorless, colorless, colorless, colorless, colorless propoxy) -3, 4-dihydrocarboxyryl in the form of colorless and colorless, in the form of uncolored protipoxy) 3-4 crystals. T. pl. 139-141, 5С.
    Similarly. to the described method E of example 2, the following compounds are obtained (examples 3-18).
    Example 3. 5- {3- N- (2-OK-Siethyl) -N-cyclohexyl-aminocaparbon-Propoxy-3, 4-dihydrocarbatirs
    Colorless needle-like crystals. T. pl. 130-131 ,.
    EXAMPLE 4 6-f3-N- (2 -OKsibutyl) -N-cyclohexyl-aminobacrylate Proproxy | -3, 4-dihydrocarbostyryl
    Colorless needle-like crystals. T. pl. 132-133 0.
    Example 5. 6- {3- N- (2-OKCHethyl) -Y-cyclooctylaminocarbonyl} propoxy-3, 4-dihydrocarbostyryl.
    Colorless crystalline vice. T. pl. 104-107 s.
    Example 6. 6- {3-L- (2-Hydroxypropyl) -N-Cyclohexyl-aminocarbonylJ PropoxyT-Carbostyryl. Colorless needle-like crystals, T. pl. 201-203 S.
    Example. 7. 6-C-CH- (4-Oxybutyl) -M-cyclohexylaminocarbonyl propoxy carbostyryl.
    Colorless crystalline powder of T. pl. 153-155 C.
    Example 8o 6- {4- m- (2-hydroxypropyl) -N-cyclohexylaminocarbonyl3-butoxy-3, 4-dihydrocarbylsil 1.
    Colorless needle-like crystals. T, pl 120.5-122 ,.
    Example 9 of 6 - ((2-Hydroxyethyl) -N-cyclohexyl IL-aminocarboxylic butoxy-3,4-dihydrocarbostyryl.
    Colorless crystalline powder. T. P 122-123 ,.
    Example 10. 6- {4- N- (2-Oxybutyl) -M-cyclohexylaminocarbo-butoxy} -3,4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. 91-93 ° C.
    Example 11. (2,3-Dioxypropyl) -N-cyclohexyl-aminocarbonyl Zbutoxy 3, 4-dihydrocarbostyryl.
    Colorless prism-like crystals. T. pl. 112.5-113.5С.
    Example 12. 6- {4- N- (2-Ocbybyl) -N-cyclopentylaminocarbo-NIL} butoxy1-3,4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. 102-103 S.
    EXAMPLE 13 (2-Oxybutyl) -N-cyclohexylaminocarbonyl butoxy carbostyryl.
    Colorless crystalline powder. T. pl. 127-128 ,.
    Example 14. N- (2,3-Dioxypropyl) -N-cyclohexylaminocarbonyl butoxy | carbostyryl.
    Colorless needle-like crystals. T. pl. ne-UO C.
    Example 13. 6-f4- N- (2-Oxybutyl) -Y-cyclooctylaminocarbonyl} butoxy} carbostyryl,
    Colorless crystalline powder, T. pl. 86-89 ° C.
    Example 16. 6- {5- N- (2-OK-vibyl) -N-cyclohexyl-aminocarbonyl} pentyloxy} 3, 4-dihydrocarbostyryl.
    Colorless crystalline powder. T. pl. 98-100С.
    Example 17. 7- 3-CH- (3-Oxy-propyl) -N-cyclohexylaminocarbonyl-Propoxy-3, 4-dihydrocarboxytes
    Colorless crystalline powder. T pl. 140-142C.
    Example 18. 6- {4-Sy- (2-Hydroxyethyl) -N-cyclohexylaminocarbonyl butoxy carbostyril.
    Colorless granule-shaped crystals. T. pl. 134-135C.
    Example 19 In 300 ml of chloroform were added 9.9 g of b- (3-carboxypropoxy) carbostyril and 6.5 ml of TLD. The reactor with this reaction mixture was cooled outside with ice outside, and 5.7 ml of isobutyl chloroformate was added dropwise with stirring. After the addition was complete, stirring was continued at room temperature for 1 hour, and 5.4 g of 2-ethylaminopyridine was added dropwise and then the reaction was continued for another 5 hours while stirring. Reaction mixture
    Pour with dilute aqueous NaHCO and water and concentrate. The residue thus obtained is worked up on a silica gel column chromatography (chloroform: methanol 20: 1 is used as a solvent), and the eluate thus obtained is concentrated and then recrystallized from methanol to obtain 4.5 g of 6-M-ethyl- N- (2-pyridyl) -aminocarbonyl propoxy carbostyril in the form of colorless needle-like crystals. T. pl. UB-UQ C.
    Analogously to the method described in Example 19, the following compounds were prepared (Examples 20-40).
    Example 20. 6- {3- N-Ethyl-L- (3 pyridyl) aminocarbonyl propoxy carbostyryl.
    Colorless needle-like crystals. T. pl. 148-149s.
    Example 21. 6-C3-N-Methyl-N- (3-pyridylmethyl) aminocarbonyl propoxy carbostyryl.
    Colorless needle-like crystals. T. pl. 169.5-171 0.
    Example 22. 6- 3-n-Etsh1-N- (3-pyridsh1methyl) aminocarbonyl propoxy carbostyryl.
    Colorless needle-like crystals. That pl. 145-147 s.
    Example 23. 6- 3-N-Metsh1-H- (2-furylmethyl) aminocarbonyl} propoxy carbostyryl.
    Colorless needle-shaped crystals T. pl. 125.5-127 ,.
    Example 24. b-3-CH-Methyl-K- (2-tetrahydrofurylmethyl) aminocarbonyl propoxy carbostyryl.
    Colorless needle-like crystals. T. pl. 123-125 s.
    Example 25. 6-C-C-Methyl-L- (2-thienylmethyl) aminocarbonyl propoxy carbostyryl.
    Colorless needle-shaped crystals T. pl. 133.5-135C.
    Example 26. 6- | 3-n-Metsh1-N-2 (3,4-dihydro-2H-pyranylmethyl) aminocarbonyl} propoxy carbostyryl.
    Colorless needle-shaped crystals That pl. 133.5-135C.
    Example 27. 6- | 3- M-Methyl-H- (2-tetrahydropyranylmethyl) aminocarbonyl Propoxy carbostyryl.
    Colorless granule-shaped crystals. T. pl. 150-151 ,.
    Example 28. 6- 3-n-Metsh1-H- (2-tetrahydropyranylmethyl) aminocarbonyl propoxy-3, 4-dihydrocarbostyryl.
    Colorless prism-like crystals. T. pl. 121.5-123.5 ° C.
    Example 29. 5- {3-L- (2-Oxy ethyl) -Y-cyclohexylaminocarbon propoxy) -3, 4-dihydrocarbostyryl. ,
    Colorless needle-like crystals. square 130-131 ,.
    ly.
    PRI me R 30. 6-tN-Etil-N- (3-pyridylmethyl) aminocarbonylmethoxyJ-3,4-dihydrocarbostyryl.
    Colorless needle-shaped crystals T. pl. 82-840.
    Example 31. 6- {5-N-Methyl-H- (2-tetrahydropyranylmethyl) aminocarbonyl pentyloxy-Carboutiryl.
    Colorless needle-like crystals. T. pl. 81-83 ° 0.
    Example 32 8-f3-N-MeTHn-K- (2-tetrahydropyranylmethyl) aminocarbonyl propoxy carbostyryl.
    Colorless needle-like crystals. T. pl. 115.5-117 C.
    EXAMPLE 33. 6- 4-N-ETHYL-L- (2-tetrahydropyranylmethyl) aminocarbonyl butoxy J-3,4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. 87-88.5С.
    Example 34. 6- 4-n-Propyl-L- (2-tetrahydropyranylmethyl) aminocarbonyl} butoxy-3, 4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. 77-79.5 ° C.
    Example 35 6- {4-CN-Butil-M- (2-tetrahydropyranylmethyl) amy-, nocarbonyl butoxy-3,4-dihydrocarbostirnl.
    Colorless needle-like crystals. T. pl. 93.5-95 ,.
    Example 26. 6- {3- N- (2-OXYethyl) -H - (2-tetrahydropyranyl) aminocarbonyl propoxy-1-carbostyril.
    Colorless needle-like crystals. T. pl. 175.5-177 0.
    Example 37. (2-Oxyethyl) -N- (3-pyridinemethyl) amine-carboxylic acid-3, 4-dihydrocarboxyryl.
    Colorless needle-like crystals. T. pl. 80-82 ,.
    EXAMPLE 38 6-4-Sy- (2-Oxyethi-I) -N- (2-tetrahydropyranylmethyl) aminoalkonyl // butoxy J-3,4-dihydrocarbostyryl.
    Colorless needle-shaped crystals. T. pl. 117-118 ,.
    EXAMPLE 39 6-4-CN- (3-Oxypropyl-N- (2-tetrahydropyranylmethyl) aminocarbonyl butoxy J-3, 4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. 98.5-100s.
    Example 40 6- {4- N- (4-Oxybutyl) -K- (2-tetrahydropyranylmethyl) aminocarbonyl butoxy) -3,4-dihydrocarbostyryl.
    Colorless needle-like crystals. T.pl. 114-11bS.
    Example 41. In 100 ml of dimethylformamide, 3.1 g of 1-benz1-6- (4-carboxybutoxy) -3,4-dihydrocarbostyril and 1.7 ml of triztilamine are added. Reactor with specified mixture
    cooled outside with ice, and 1.4 ml of isobutyl chloroformate was added dropwise to the mixture while stirring. After the addition was completed, stirring was continued for another 30 minutes, then 1.75 g of H-ethy1-H- (2-tetrahydropyranylmethyl) -amine was added to the reaction mixture and stirring was continued at room temperature B for 3 hours. After that. As the reaction was completed, the solvent was removed by distillation, and the residue thus obtained was extracted with approximately 300 ml of chloroform, washed with a dilute aqueous solution of NaHCOj, water, dilute hydrochloric acid, and water in the indicated order. The residue obtained is treated on a chromatographic column with silica gel (herewith, chloroform; methanol 20: 1 is used as a solvent) and the resulting
    5, the eluate is concentrated to obtain 2.3 g of 1-benzyl-6-M-s (2-tetrahydropyranylmethyl) -Y-ethylaminocarboxy1} butoxy} -3, 4-dihydrocarbostyril as a colorless syrupy substance.
    Infrared Absorption Spectrum), cm: 1620, 1690.
    Calculated,%: C 75, 29; H 8.28) N 6.06.
    5 Found: C 75.36, H 8.13; N 5.84.
    Example 42. In 400 ml of chloroform, 5 g of 6- (4-carboxybutoxy) -3,4-dihydrocarbostyril and
    0 3.2 g DBU. The reactor containing this mixture is cooled outside with ice, and 2.8 g of isobutyl chloroformate is added dropwise to this mixture with stirring. After finishing
    5 addition, stirring is continued for another 30 minutes, and then 3.9 g of N- (3-hydroxypropyl) -N-cyclohexylmethylamine is added to the reaction mixture and the reaction is continued for
    0 3h After completion of the reaction, the reaction mixture is washed with 1N. an aqueous solution of NaOH, 10% HC1 and water in this order and dried over anhydrous. Pulling agent
    5 is removed by filtration and the dry product thus obtained is concentrated to a residue. This residue is treated on a chromatographic column with silica gel (mixture of chloroform: methanol 40: 1 is used as a solvent). The resulting eluate is concentrated and recrystallized from a mixture of ethyl acetate - petroleum ether. 4.0 g of 6- 4-n-cyclohexylmeeth-N- (3-hydroxypropyl) aminocarbonyl butoxy J-3, 4-dihydrocarbostyryl are obtained in the whole colorless needle-like crystals. .. T. pl. 95-97 C.
    Analogously to the method described in Example 42, the following are obtained from / (ingi (examples 43-67) o
    Example 43. 6- {N (2-Oxy diethyl) -N-phenylaminocarbonylmethoxy carbostyryl.
    Colorless crystalline powder. T „pl„ 162-165 C.
    Example 44. 6- {3- N (2-Metoxyethyl) -K-cyclohexylaminocarbonyl propoxy carbostyryl
    Colorless granule-shaped crystals. T. pl. 142.5-143.5 p.
    Example 45. (2-0xy-1-methylpropyl) -N-cyclohexylmethylaminocarbonyl propoxy | carbostyrsch1.
    Colorless needle-like crystals. T. pl. 179.5-181 ,.
    Example 46. 6- {3-n (2 Oxyethyl-M-Butylaminokaryonyl propoxy} carbostyryl
    Colorless needle-like crystals. T. pl. 153-154 ° C.
    Example 47. 6- {Cs-di (2-Oxyethyl) aminocarbonyl JnponoKcnJ carbostyryl.
    Colorless needle-like crystals. T. pl. 122-123.5 p.
    Example 48. (2-Hydroxyethyl) -N-phenylaminocarbonyl butoxy-3,4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. PZ-Pb S.
    Example 49 6- {4-s (2-hydroxy-ethyl) -Y-benzylaminocarbonyl butoxy-3, 4-dihydrocarbostyryl.
    Colorless crystal creep. T. pl. 91.5-93s.
    Example 50 6- {4- N (2-OKCHethyl) -M-cyclohexylamino-aminocarbonyl Zbutoxy Y-3, 4-dihydrocarbostyryl
    Colorless lamellar crystals. T. pl. 123-125 C.
    Example 51. 6- {4- N (2-Oxybutyl) -Y-cyclohexylmethyl aminocarbonyl butoxy-3, 4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. 119-120 ,.
    Example 52. (2-Oxybutyl) -N-cyclohexane m.I-aminocaparbonyl butoxy-3 94-dihydrocarbostyryl.
    Colorless needle-shaped crystals T „pl. 123-125 s.
    Example 53 6-f4-N (2-MeT hydroxyethyl) -H-cyclohexylaminocarbonyl J-carboxyethyl „
    Colorless needle-like crystals. T. P 107109S.
    Example 54, (2-Hydroxyethyl) -N-benzyl-iinocarbonyl Jpants-Ioxy} -3, 4-dihydrocarbostyryl.
    Colorless crystalline powder. T. 93.5-95 ,.
    Example 55. (2-BeHzoyloxyethyl) -M-cyclohexylaminocarbonyl JnponoKCHJ carbostyryl.
    Colorless needle-like crystals. T. pl. 94-97 s.
    EXAMPLE 56. 6-f4-N (5-Oxypentyl) -N-cyclohexyl-methyl aminocarbonyl} butoxy-3, 4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. 113.5-115 ° C.
    Example 57 „(4-0 xybutyl) -Y-cyclohexylmethylaminocarbonyl7propoxy} -3, 4-dihydrocarbyti
    Colorless needle-like crystals. T. pl. 109-111 0.
    Example 58o (5-Propionyloxypentyl) -K-cyclohexyl methylaminocarbonylbutyl, oxy} -3,4-dihydroxyboustanyl.
    Colorless needle-shaped crystal T. pl. 60-62 C.
    Example 59. (2-Oxyethyl) -N- (p-3,4-dimethoxyphenet1) aminocarbonyl butoxy carbostyryolo
    Colorless needle-shaped crystal
    Example 60 6- {4-S (3-Acetoxypropyl) -N-2-tetrahydropyranylmethyl-aminocarbonyl butoxy-3, 4-dig hydrocarbyl carbon.
    Colorless needle-shaped crystal T. pl., 64,5-66,5Со
    Example 61 (2,3-Dioxypropyl) -M-cyclohexylmethylaminocarbonyl} butoxy-3 5 4-dihydrocarboxy-p.
    Colorless crystalline powder. T. pl. 112-1.
    Example 62 6- {4-CN (2,3-flHoxypropyl) -N-cyclohexylmethylamino-5 carbonyl butoxy carbostyryl.
    Colorless crystalline powder. T.Sch1 „125-128с.
    Example 63. (2-OKCH ethyl) -C- (3-hydroxyhexyl) aminocarbo-NIL propoxy carbostyrylo
    Colorless crystalline powder. T. plo 220-224 with
    Example 64. (2-Hydroxyethyl) -N-cyclohexylaminocarbonyl Jnpo-5 prxy} carbostyryl.
    Colorless needle-shaped crystals T. pcs. 176-178 s.
    Example 65. 4-Methyl-6-1 3- (N (2-hydroxyethyl) -K-cyclohexylamino-20 carbonyl propoxy} carbostyryl.
    Colorless needle-like crystals. T. pl. 171-173 S.
    Example 6 66o 1-Ethyl-6-4-n (4-hydroxybutch1) -H-cyclohexylmethylaminocarbonyl butoxy} -3, 4-dihydrocarbostyryl.
    Colorless syrupy substance.
    W-absorption spectrum -i, 1620, 1670o30
    Calculated,%: C, 73.26; H, 9.56; I, 6.33.
    Found: C 73.41 H 9.38, N 6.10.
    EXAMPLE 67: In 200 ml of chlorofor-35 Via, 5.9 g of 1-allyl-6- (3-carbrxypropoxy) carbostyril and 3.2 g are added.
    Dbu. The reactor with this mixture is cooled outside with ice, and 2.8 g of isobutyl chloroformate is added to the mixture with stirring over kanl. After the addition is complete, the reaction mixture is stirred for 1 hour, then 3.7 g of N-cyclohexylpiperazine is added dropwise to the reaction mixture and the reaction is then carried out for 5 hours. After completion of the reaction, the reaction mixture is washed with a 1% aqueous solution of NaOH i and water, then the organic layer is dried with anhydrous. The drying agent is removed by filtration and the mother liquor is concentrated. The residue thus obtained is treated on a chromatographic column with skli-55 gel (as a solvent: chloroform: methanol 30: 1 is used). From the resulting eluate, 4.2 g of 1-allyl-6-GZ-C4-cyclohexyl-1-piperisinylcarbonyl-propoxy carbostyril as a colorless oily substance were isolated.
    Infrared Absorption Spectrum V, 1645, 1680.
    Calculated,%: C 71.04; H 8.48 N 9.56.
    Found,%: C 70.95; H 8.61; N 9.72.
    Example 68. In 200 ml of chloroform, 5 g of 6- (3-carboxypropoxy) carbostyril and 3.2 g of DBU are added. The reactor with this mixture is cooled outside with ice, and 2.8 g of isobutyl chloroformate is added dropwise to the mixture with stirring. After the addition is complete, the reaction mixture is stirred for another 1 hour, then 3.7 g of N-cyclohexylpiperazine is added dropwise at room temperature, and the reaction is continued for 5 hours. After completion of the reaction, the reaction mixture is washed with a 1% aqueous solution of NaOH and water, then dried over anhydrous sodium sulfate. The drying agent is removed by filtration and the mother liquor is concentrated. The residue thus obtained is treated on a silica gel column chromatography (as solvent; 30: 1 chloroform: methanol is used) to obtain an eluate which is concentrated, the residue is recrystallized from water containing methanol to give 4 g of 6- {3- (4- cyclohexyl-1-piperazylcarbonyl) pripoxy Yacarbostyril in the form of colorless needle-like crystals. That pl. 184.5-185 00
    Analogously to the method described in Example 68, the following compounds were prepared (Examples 69-74).
    Example 69. 6- (3- (4-Fensh1-1-piperazinylcarbonyl) propoxy} carbostyryl.
    Colorless needle-like crystals. T. pl. 202.5-203,
    Example 70. (4-Phenyl-1-piperazinylcarbonyl) propoxy J-3, 4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. 182.5-183 ,.
    Example 71. (4-Phenyl-1-piperidylcarbonyl) propoxy carbostyril. Colorless needle-shaped crystals T. pl. igo-igi c. Example 72. (4-Benzyl-1-piperazinylcarbonyl) proproxy carbostyryl. Colorless prism-shaped crystals. T. pl. 174.5-175 ,. Example 73. (4-Cyclohex sil-1-piperazinylcarbonyl) propoxyJ-3, 4-dihydrocarbostyryl. Colorless needle-shaped crystals T. pl. 133-134C. Example 74. (4-Benzyl-1-Piperidylcarbonyl) propoxy carboxy reel. Colorless needle-shaped crystals T. pl. 145-14bs. Example 75. In a mixed solution of 20 ml of dioxane and 20 ml of methylene chloride, 2.5 g of b- (3-carboxy) propoxycarbostyril and 1.3 g of N- (2-hydroxyethyl) cyclohexylamine are added. The reactor containing this mixture is cooled outside with ice. Then a solution of 2.1 g of N, N-dicyclohexylcarbodiimide in 5 ml of methylene chloride is added dropwise to this mixture, keeping the temperature in the range of 10-20 seconds with stirring. After the addition was complete, the reaction mixture was stirred at the same temperature for 3.5 hours. The precipitated crystals were removed by filtration, and the resulting filtrate was concentrated under reduced pressure to dryness. The residue thus obtained is dissolved in 100 ml of methylene chloride and the organic layer is washed with a 5% aqueous solution of hydrochloric acid with a 5% aqueous solution of sodium bicarbonate and water in this order, and then dried over anhydrous (sodium sulfate, sodium. Solvent is removed by distillation and the resulting residue is recrystallized from chloroform-petroleum ether to obtain 1.1 g of 6- 3-LN- (2-oxyethyl) -N-cyclohexylaminocarboxylic prosthesis in the form of colorless needle-shaped crystals, mp. 166 C. Similar to the method described in Example 75, the following dinane compounds are obtained (Examples 76-98). Example 76. 6- {3-n-Ethyl-N- (2-pyridyl) aminocarbonyl Jnponoxy carbostyryl. Colorless needle-shaped crystals. mp 148-149 C. Example 77. 6- (3-CN-Methyl-N- (3-pyridylmethyl) aminocapronyl 7-propoxy} carbostyryl. Colorless needle-like crystals. M.P. 169.5-171.5 C. Example 78. 6- 3-N-Methyl-N - (2-furylmethyl) aminocarbonyl propoxy} carbostyryl. Colorless needle-like crystals. T. pl. 125.5-127 ,. Example 79. 6-GZ-N-Methyl-M- (2-tetrahydropyranylmethyl) aminocarbonyl Zpropoxy carbostyryl. Colorless granule-shaped crystals. T. pl. 150-151 ,. Example 80 6-f3-GN-Methyl-H- (2-thienylmethyl) aminocarbonyl propoxy carbostyryl. Colorless needle-like crystals. T. pl. 133.5-135 0. Example 81. (2-Hydroxyethyl) -H-cyclohexylaminocarbonyl 3 propoxy-3,4-dihydrocarbostyryl. Colorless needle-like crystals. T. pl. 130-131.5 ° C. Example 82 (2-tetrahydropyranylmethyl) aminocarbonyl j pentyloxy carbostyryl. Colorless needle-like crystals. T. pl. 81-83C. . Example 83. 6- {3-CM- (2-Oxybutyl) -K-cyclohexylaminocarbonyl ZPROPOXI} -3,4-dihydrocarboxystyrene1. Colorless needle-like crystals. M.p. 132-133 C. Example 84. 6 - ((2-Hydroxypropyl) -M-cyclohexylaminocarbonyl butoxy-3, 4-dihydrocarboxystyrene 1. Colorless needle-like crystals, mp pl, 120.5-122.5 C. Example 85. (2- Hydroxyethyl) -H-cyclohexylaminocarbonylJ6ytoxy-3, 4-dihydrocarboxyryl, Colorless crystalline powder, mp, 122-123. pl. 91-93 C, Example 87, (2,3-dioxipropyl) -N-cyclohexylaminocarbonyl Zbutoxy-3,4-dihydrocarbostyryl. Colorless prism-like crystals. Pl. 112.5-113., Example 88. (2 -O Ci-boyl) -N-cyclohexylaminocarbonyl J butoxy carbostyryl, colorless crystalline powder, mp 127-128.5 C. Example 89. 6 - (((2,3-Dioxypropyl) -H-cyclohexylaminocarboxylic acid)} carbotyryl. M.P. 138-140 0. Example 90. 6- {4- N- (2-Oxy, ethyl) -N-cycleQH-hexylaminocarboxylic 3 butoxy carbostyryl. Colorless crystalline powder of Pl.-134-135 C. Example 91. 6- - n- (2-Oxy (2-tetrahydropyranylmethyl and nocarbonyl propoxy carbostyryl. Colorless needle-like crystals. T. pl. 175.5-177 C. Example 92. 6- {4-Sy- (2-Oxy ethyl) -N- (2-tetrahydropyranylmethyl, aminocarbonyl} butoxy J-3,4-dihydrocarbostyryl, Colorless needle-like crystals. So pl. 117-188.5 ° C. EXAMPLE 93 (4-hydroxy-butyl) -N- (2-tetrahydropyransh1methyl) amynocarbonyl} butoxy-p-3,4-dihydrocarbylryl. Colorless needle-like crystals. So pl. IH-lie C., Example 94. 6- {3- N- (2-Me; toxiatsh1) -H-cyclohexylaminocarbonyl 1-propoxy car styryl. Colorless needle-like crystals. M.P. 142.5-143 ,. Example 95. 6- {4- N (2,3-DIoxypropyl) -N-cyclohexylmelamino icarbonyl butoxy-3,4-dihydrocarbostyryl. crystallized powder. T. S1 .112-114 C Example 96. (4-Phenyl-1-piperazinylcarbonyl) propoxySkar bostyril. Colorless needle-like crystals. T. mp. 202.5-203 ,. Example 97. 6- {3- y- (2-Oxy eth1) -H- (3-oxycyclohexyl) aminocarbonyl propoxy1carbostyr1. A colorless crystalline powder. T. 1SH.A.220-224s. "Example 98. 6- {4-y- (2-Oxy ethis1) - M-cyclohexylmethylaminocarboNSH1 butoxy-3,4-dihydrocarbostyril Beztsvetnge lamellar crystals. T. pl. 123-125C. Example 99. In 200 ml of methyl chloride, 2.4 g of 6- (3-carboxypropoxy) carbostyril is suspended and 2 ml of pyridine is added to this suspension. Then, with stirring, 1.4 g of thionyl chloride is added dropwise, and the temperature inside the reactor is kept in the range. After the addition is complete, the reaction is continued at the same temperature for an additional 1 hour while stirring. Then 2 ml of N- (2-hydroxyethyl) cyclohexylamine is added dropwise to the reaction mixture, after which the reaction is continued for another 4 hours at room temperature and with stirring. The reaction mixture is then thoroughly washed with an aqueous solution of K, COj, then again with water and dilute hydrochloric acid, and then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue obtained in this process is purified and separated on a chromatographic column (use silica gel of the brand Wako C 200, and chloroform-methanol 20: 1 is used as the solvent), and recrystallized from chloroform-petroleum ether. 1.2 g of (2-hydroxyethyl) -N-cyclohexylaminocarbonyl jnponoKcnj carbostyril are obtained in the form of colorless needles (R-different crystals. M.p. 165Tb C, The following compounds were obtained in analogy to the method described in Example 99, examples 100-119) Example 100. 6- 3-s-Ethyl-N- (2-pyridyl) aminocarbonyl proproxy carbostyryl. Colorless needle-like crystals, mp 148-149 0. Example 101 6- {3-CN-MeTi «iN- (3-pyridylmethyl) aminocarbonyl-yl propoxy carbostyryl. Colorless needle-like crystals, mp 169-171 pp. -Prme. P 102. 6- {3-N-MeTmiN- (2-tetrahydrofur1spmethyl) aminocarbonyl propoxy carbostyril Colorless needle-like crystals. M.P. 123-125 C. Example 103 6- {3-K-Yet yl-K- (2-thienylmethyl) aminocarbonyl} propoxy | carbostyryl.
    Colorless needle-like crystals. T. pl. 133.5-135C.
    Example 104 b-Cz-Ch-Mmethyl —N- (2-methylphenyl) aminocarbonyl Jpropoxy carbostyryl.
    Colorless needle-like crystals. T. pl. 126.5-127.5С.
    Example 105. 6-z-n-Methyl-M- (2-tetrahydropyranylmethyl) aminocarbonyl propoxy 1-3, 5-dihydrocarbostyryl.
    Colorless prism-like kris. T. pl. 121.5-123.5С.
    Example 106 .. (2-Oxybutyl) -H-cyclohexylaminocarbonyl propoxy-3, 4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. .
    Example 107. (2-Hydroxyethyl) -M-cyclohexylaminocarbonyl butoxy Y-3, 4-dihydrocarbostyryl
    Colorless crystalline powder. T. pl. 122-123,
    Example 108 6- {4-y- (2-Oxybutyl) -H-cyclohexylaminocarbonylJ butoxy | -3,4-dihydrocarbostyryl
    Colorless needle-like crystals. T. pl. 91-93 S.
    Example 109. 6-4 - CN- (2,3-Dioxypropsh1) -H-cyclohexylaminocarbonyl butoxy J-3,4-dihydrocarbostyryl.
    Colorless prismlike crystals. T. pieces 112.5-113 ,.
    Example 110. 6- {4- N- (2-Oxybutyl) -H-cyclohexylaminocarbonyl butoxyR; Carbostyryl. .
    Colorless crystalline powder. T. pl. 127-128 ,.
    Example 111. (2-OKciethyl) -N-cyclohexyl-aminobenzene butoxy carbostyril.
    Colorless granule-shaped crystals. T. pl. 134-135C.
    Example 112. 6-Cs-(2-Oxyztil) (2-tetrahydropyranyl) aminocarbonyl 2-propoxy-N-carbostyryl.
    Colorless needle-like crystals. T. pl. 175.5-177 0.
    Example 113. (2-Oxyetch1) -Y- (2-tetrahydropyranylmethyl) aminocarbonyl butoxy1-3,4-dihydrocarbostyryl.
    Colorless needle-like crystals. T. pl. 117-118 ,. ,
    Example 114. 6- {4- K- (4-Oxybutyl) -K- (2-tetrahydropyranylmethyl) aminocarbonylD butoxyJ-3,4-dioxy5 carbostyreneG.
    Colorless needle-like crystals. T. pl. 114-116 ° C.
    Example 115. (2-Methoxyethyl) -K-cyclohexyl-1-aminocarbonyl} propoxy} carbostyryl.
    Colorless granule-shaped crystals. T. pl. 142.5-143 ,.
    Example 116. (2,3-Dioxypropyl) -Y-cyclohexylmethylamide15 HOKap6oHKnj6yTOKCHJ-3,4-dihydrocarbostyryl.
    Colorless crystalline powder. T. pl. 112-114 s.
    Example 117. (4-Phenyl20 -1 -piperanylcarbonyl) propoxy 1carbostyryl.
    Colorless needle-like crystals. T. pl. 202.5-203,
    Example 118. 6- {3- N- (2-Oxyethyl) -M- (3-hydroxycyclohexyl) aminocarbonyl propoxy-1-carbostyryl.
    Colorless crystalline powder. T. pl. 220-224C.
    Example 119. (2-OKCH30 ethyl) -K-cyclohexylmethyl) aminocarbonylButoxy} -3,4-dihydrbcarbostyryl. Colorless lamellar crystals. T. pl. 123-125 0.
    Example 120. 3.8 g of (p5 -nitrophenoxycarbonyl) propoxy2car, bostyril is dissolved in 40 ml of dimethylformamide, then 1.6 htn of N- (2-oxyethyl) cyclohexanlamine is added to it, and the reaction mixture is stirred at 60-70 ° C for 12 hours. PRS (before completion of the reaction, the solvent is distilled off, and the resulting residue is purified on a chromatographic column with silica gel (5 silica gel w-aco C-200 is used, and chloroform: methanol 20 is used as a solvent : 1). The resulting crude crystals are recrystallized from chloroform - ke mixture to obtain 1.3 g of (2-oxystil) -H-cyclohexylaminocarbonylTpropoxyLcarbostyril as colorless needle-like crystals. mp. 5 165-166 p.
     Analogously to the method described in Example 120, the following compounds were prepared (Examples 121-134).
    Example 121, 6- 3-CN-3THn-N- (2-pyridyl) aminocarbonyl propoxy carboxyl,
    Colorless needle-like crystals. T. pl. 148-149 s.
    Example 122. 6- {3-N-Methyl-N- (2-tetra hydropyranylmethyl) aminocarbonyl propoxy} carbostyryl.
    Colorless granule-shaped crystals. T. pl. 150-151 ,.
    Example 123. 6-f4-N- (2,3-Dioxypropyl) -Y-cyclohexane 1 amino carbon 1 butoxy J-3,4-dihydrocarbostyryl ..
    Colorless prism-like crystals. T. pl. 112.5-113 ,.
    Example 124. 6- {4- N- (2-Oxybutt) -H-cyclohexylaminocarbonylJbytoxy | carboxyl.
    Colorless crystalline powder. T. pl. 127-128.5.
    Example 125. (2Oxyethyl) -K-cyclohexylaminocarboxy-nc13butoxy | carbostyryl. ,
    Colorless granule-shaped crystals. T. Sh1. 134-135®C.
    Example 126. 6- {3- N- (2-Oxyboobsh1) -M-cyclohexylamino-carboxy-1} propoxy-3,4-dihydrocarbotiri
    Colorless needle-like crystals. T. pl. 132-1J3fc.
    Example 127. 6- {4-CN- (2-Oxyethyl) -Y-cyclohexane-aminocarbonyl-1-3, 4-dihydrocarboxyryl
    Besvetsvetny crystalline powder. T. pl. 122-123.5 p.
    Example 128. 6- {4-CN- (2-Oxybutyl) -K-cyclohexylaminocarbonyl2butoxy-3, 4-digndrocarbostyryl
    Colorless needle-like crystals. T. pl. 91-93C.
    Example 129. (4-Phenyl-1-piperazinylcarbonyl) propoxy carbostyril.
    Colorless needle-like crystals. T. plo 202.5-203.,.
    Example 130. (2-Oxyethyl) -M-cyclohexylmethylaminocarbonyl butoxy5-3, 4-dihydrocarbosities (fil. Colorless lamellar crystal, mp pl. 128-3-125 C.
    Example 131. 6- {3- m- (2-Hydroxyethyl) -Y- (2-tetrahydropyranylmethyl 1 L aminocarbonyl propoxy carbostyryl.
    Colorless needle-shaped crystal T. pl. 175.5-177С „,
    Example 132. 6- {4-fN- (2-OKCHethyl) -M- (2-tetrahydropyranylmethyl) aminocarbonyl butoxy J-3,4-dihydro bostyril.
    Colorless needle-shaped crystals T. pl. 117-118.5С.
    Example 133. 6-f4-N- (4-Oxybutyl) -Y- (2-tetrahydropyranylmethyl) aminocarbonylHbutoxy} -3,4-dihydrocarboxyryl.
    Colorless needle-shaped crystals T. pl. 114-116 0.
    Example 134. 6- {3- N- (2-Metoxyethyl) -H-cyclohexyl-1-aminocarbonyl Jproproxy j carbostyryl
    Colorless granule-shaped crystals. T. plo 142.5 C - 143.5 С.
    Example 135. In 100 ml of ethanol, 2.7 g of 6- (3-ethoxycarbonylpropoxy) carbostyril, 0.5 g of sodium ethylate and 5 ml of K- (2-hydroxyethyl) cyclohexylamine are added and the reaction is conducted in an autoclave at a pressure of 110 atm at temperature 140-150 0 for 6 hours
    After completion of the reaction, the reaction mixture is cooled and concentrated under reduced pressure. The residue thus obtained is dissolved in 200 ml of chloroform and washed with 1% aqueous solution of ClSO, diluted with hydrochloric acid and water in the sequence indicated, and then dried over anhydrous sodium sulfate. Then the solvent is distilled off, and the resulting residue is purified on a chromatographic column filled with silica gel (W aco is used as silica gel, and chloroform: methanol 20: 1 is used as solvent.) The crude crystals thus obtained are recrystallized from chloroform-petroleum ether to obtain 0.9 g of 6- {3-rN- (2-hydroxy-I) -N-cyclohexylaminocarbonyl} propoxy carbostyril in the form of colorless needle-like crystals. M.p. 165-1bbs
    Analogously to the method described in Example 135-, the following compounds are obtained (Examples 136-143).
    Example 136. 6- {3- N-Methyl-N-C3-pyridylmethyl) aminocarbonyl propoxin carbostyryl.
    Colorless needle-like crystals. T. pl. 169.5-171 seconds Example 137. 6- 3-CN- (2-Oxybutyl) -N-cyclohexylaminocarbon-1 propoxy-3,4-dihydrocarbostyryl. . Colorless needle-shaped crystals T. pl. 132-133C. Example 138. (2-Oxy ethyl) -N-cyclohexyl-aminocarboxylic by-tox-3,4-dihydrocarboxyryl. Colorless crystalline powder. T. pl. 122-123 ,. Example 139. (2-Oxy butyl) -Y-cyclohexylaminocarbonyl butoxy-3,4-dihydrcarboxystyrene1. Colorless needle-like crystals. T. pl. 91-93C. Example 140. 6- {4-s- (2-Oxy butyl) -N-cyclohexylaminocarbonyl butoxyY-carbostyryl, Colorless crystalline powder. T. pl. 127-128 ,. Example 141. 6- {4-L- (2-Hydroxy) -N-cyclohexyl-aminobacrylate butoxy-1-carbostyryl. Colorless granule-shaped crystals. T. pl. 134-135 0. Pf mime 142. 6- {4- N- (2-Oxyethi1) -Y- (2-tetragi Dropyranylmethyl) aminocarbonyl butoxy 3,4-dihyd rocarbostiril. Colorless needle-like crystals. T. pl. 117-118.5С. Example 143. 6- {3- (4-Phenyl-1-piperazinsh1carbonyl) propoxy carbostyryl. Colorless needle-like crystals. T. pl. 202.5-203.5С. Example 144. In 100 ml of chloroform, 3.7 g of (2-hydroxyethyl) -N-cyclohexylaminocarbonyl propoxy carbostyril and 1.8 g of triethylamine are added. The reactor in which the mixture is located is cooled from the outside. Then 1.4 ml of benzoyl chloride are added dropwise to this mixture with stirring. After the addition is complete, the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is then washed with a 5% aqueous solution of NaHCOj, diluted with hydrochloric acid and water in this sequence, then dried over anhydrous sodium sulfate. The drying agent is removed by filtration and the mother liquor is concentrated. The residue thus obtained is treated on a chromatographic column with silica gel (30: 1 chloroform: methanol is used as the solvent), and the eluate is recrystallized from chloroform-petroleum ether to obtain 3.0 g of 6-t3-CN- (2-benzoyl) hydroxyethyl) -N-cyclohexyalamino carbonylproxy | carcinylide in the form of colorless needle-like crystals. T. plo 94-96 p. Analogously to the method described in Example 144, compounds were prepared (Examples 145-146). Example 145. 6-4-CN- (5-Propionyloxypentyl) -N-cyclohexylmethylaminocarbonyl butoxy | -3, 4-dihydrocarbostyryl. Colorless needle-like crystals. T. pl. 60-62 0 Example 146. (3-Acesh1Oxypropyl) -H- (2-tetracdro pyranylmethyl) aminocarbonylButoxy-3, 4-dihydrocarbylphenyl1. Colorless needle-like crystals. T. pl. 64.5-66.5 p. The following are the results of the pharmacological tests carried out for the proposed compounds. EXAMPLE 147. 1 g of 6- {3- (methyl-N- (3-pyridylmethyl) aminocarbonyl carbostyryl is dissolved in 20 ml of ethanol, then 10 ml of concentrated hydrochloric acid is added thereto and the mixture is stirred at room temperature temperature for 30 minutes, the Solvent is removed by distillation and the resulting residue is recrystallized from methanol to give 1.01 g of hydrochloride (methyl-N- (3-pyridylmethyl) aminocarbonyl J propoxyYarbostiryl, m.p. 280-283 ° C. Elemental data analysis are shown in Table 1.
    Table 1
    Continued table. one
    Continued table. one
    Continued table. one
    Continued table. one
    Continued table. f
    Continued table. one
    Continued table.
    Pharmacological test 1.
    The ability to inhibit platelet aggregation is determined using an AG-11 aggregometer (manufactured by Bryston Monufaturing Co.). The blood sample used for the test is a mixture of 1/9 (by volume) sodium citrate and a complete blood sample collected from the rabbit. The specimen is centrifuged for 10 minutes at a speed of ... 1000 rpm to obtain platelet-rich plasma (PRP). The PRP thus prepared was sampled, and the remaining blood sample was further processed in a centrifuge for 15 minutes at a speed of 3000 rpm to obtain platelet-poor plasma (PRP).
    The platelet count in PRP is determined by the method. Brecher Clohkite and PRP is diluted with PRJP to obtain. a PRP sample with a platelet concentration of AOR / nm for an adenosine diphosphate (ADP) aggregation test. A sample of PRP is also prepared with a platelet count of 450,000 / mm for the aggregation test induced by collagen. 0.6 ml of the indicated PRP sample is added to a 0.01 solution of the test compound of a predetermined concentration and the resulting mixture is placed in a repMoctar with a temperature of 37 ° C for 1 minute. Then 0.07 ml of ADRs or a collagen
    100 t
    100
    2 3
    100
    92.5
    four
    85, 7 5 6 7
    100
    100
    Lagen solution is added to the mixture. The transmission of the mixture is determined and the change in transmission is recorded using an aggregometer at an unbleaching speed of 1100 rpm. This test uses Auren Beronal buffer (pH 7.35 (to prepare an ADR solution or collagen. The ADR solution is adjusted to a concentration of 7, M, and a collagen solution is prepared, rubbed 100 mg of collagen with 5 ml of the specified buffer, and the supernatant is used as an inducer. Acetylsalicylic acid is used as a control for the aggregation test caused by ADR and the aggregation test caused by collagen, respectively. The inhibitory effect on platelet aggregation is determined in units of (percentage of inhibition in relation to . STI aggregation speed control aggregation (CA) is calculated by the formula:
    .§. 100,
    Ca
    where a is the transmission of PRP;
    b is the transmission of a PRP containing a test compound or aggregation inducer; C - PRP transmission. The inhibitory effect of carbostyryl derivatives on platelet aggregation of rabbits caused by collagen is presented in Table. 2, and a similar effect on aggregation caused by ADRs is presented in Table. 3
     T a -6 l and he. a, 2
    60.1
    100 7.2 14 4.0
    3.8 13.3
    15
    five
    five
    28 12 17 5 27 7
    12 65 Concentration,%, Compound Offered 1
    Continuation of table 2
    14
    2 2 O
    . I 15
    ABOUT
    eight
    ABOUT
    ABOUT
    ABOUT
    ABOUT
    ABOUT
    13
    ABOUT
    ABOUT
    ABOUT
    ABOUT
    9
    7 Soy of compound solution, mol. : E
    Continued table. 3 Test trials are subjected to compounds. Proposed compounds (1-23). 1.6- {3-СН- (2-Hydroxyethyl) -Y-cyclohexen aminocarboyl} propoxy} carbostyrsh1. 2.6- {3-n-Ethyl-H- (3-pyridylmeth1) aminocarbonyl amine-J-propoxy-carboxyethyl. 3.6 - 3- N-EtshI-N- (2-pyridyl) aminocarbonylTpropoxy-1-booster. 4.6- S-LN-Mermi-N- (2-furylmethyl) aminocarbonyl propoxy (carbostyryl. 5o 6- {3- n-Methyl-K- (2-thienylmethyl) aminocarbonyl} propoxy carbostyryl. 6. N-Methyl-K - (2-tetrahydropyra nylmethyl) aminocaparbQHSIJpropropoxy Jcap bostyryl 7.5- {4-N- (2-Oxybutyl) -N-cyclohexylmethylaminocarbonyl butoxy-3,4-dihydracarboxyryl. cyclohex silmethylaminocarbonyl butoxy-3,4-dihydrocarbostyryl. 9o) 2-Oxybutyl-K-cyclooxyl-1-aminocarbonyl) butoxy carbostyryl. 10. (2-Benzoyloxyethyl) -K cyclohexylaminocarbonyl; -Oxyethyl) -M-phenyls of nocarboni butoxy from 3,4-dihydrocarbyl.
    Continuation of table.3 12.6-f4-LN-Butyl-N- (2-tetrahydropiranylmethyl) aminocarbonyl butoxyl-3, 4-dihydrocarbostyryl. , 13.6-f4-iN- (2-Oxyethyl) -N- (2-tetrahydropyranylmethyl) aminocarbonyl 3 butoxy-3,4-dihydrocarbostyryl. 14. (4-Inch-I-l-pipiperzinylcabbenil) ProxylJ cassette. 15 .. (4-Benzip-1-piperazinylcarbonyl) propoxy-3,4-dihydrocarbostyryl. 16.6-tz- (4-phenyl-1-piperidi I carbonyl) propoxy carbostyryl. 17.6-z- (4-Phenyl-1-piperazinylcarbonyl) propoxy-3,4-dihydrocarbostyryl. 18.6- 3- (4-Cyclohexyl-1-piperazinylcarbonyl) propoxy-3,4-dihydrocarboxystyryl. 19.6- {3- N- (2-Hydroxyethyl) -N- (3-hydroxycyclohexyl) amine-carboxyl iproproxy carboxyryl. 20. (2-Hydroxyethyl) -H - (- 3,4t -dimethoxyphenet1) aminocarbonyl J butoxy carbostyril. 21.6- {4- M- (3-Acetyloxypropyl) -M- (2-tetrahydropyranylmethyl) amino-carbonyl butoxy 3,4-dihydrocarbostyryl. . 22.6- {4-n- (2-Hydroxyethyl) -H-benz 1-aminocarbonyl Zbutoxy J-3, 4-dihydrocarbostyryl.
    23.6- {4-.H- (2-Methoxyethyl) -H-cyclohexylaminocarbonyl butoxy carbostyryl.
    Known (24-69) compounds
    (comparative compounds).
    24.6- {g - G1-Methyl-K- (2-methylcyclohexyl) aminocarbonyl2proxyxy carbostyryl.
    25.6- {3-M-Methyl-M- (4-hydroxycyclohexl) aminocarboxylic propoxycarboxylate,
    26.6- 3- N-Methyl-H- (4-acetyloxycyclohexyl) aminocarbonyl propoxy carbostyryl.
    27.6- {3-N-MeTmi-N- (2,3,4-di- methoxyphenylethyl) aminocarbonyl propoxy carbostyryl.
    28. (N Cyclohexyl-T-benzshIaminocarbokil) propoxy | carbostyril.
    29.5-Chloro-6-jЗ- (N-methyl-N-cyclohexyl-1-aminocarbonyl) propoxy} carbostyryl.
    30.6- {3-N-Cyclohexyl-N- (2-chlorocyclohexyl) aminocarbonyl propoxy-3,4-dihydrocarbostyryl.
    31.6- {2-Oxy-3- (N-methyl-N-cyclohexylaminocarbonl) propoxy carbostyryl.
    32. (M-Metsh1-N-cyclohexylamino | carbonyl) -2-methylpropoxy 1 carbosyl reel.
    33.8-Oxy-5- (N-methyl-N-cyclohexylaminocarbon) propoxy-3,4-dihydrocarbostyryl.
    34., M-Benzyl-Y- (2t3, 4-dimethoxyphenylethyl) aminocarbonyl propoxy 3, 4 -dihydrocarbostyryl ..
    35.6,8-Dichloro-5- 3 (N-ethylanylcarbonyl) propoxy-3,4-dihydrocarbostyryl.
    36. (N-Cyclohexyl-aminocaparbonyl) propoxy carbostyrs1.
    37. (N-Allyl-N-cyclohexach I-aminocarbonyl) Pro-3,4-dihydrocarbostyryl.
    38.6-3- (N-Metsh1-Y-cyclohexylaminocarbonyl) propoxy-3,4-dihydrocarbostyryl.
    39. (N-Methyl-N-cyclohexane Iamino carbonyl). Propoxy-carbostyryl.
    40.6- {3- (K-Cyclohexylane-Inocarbonyl) propoxy carbostyryl.
    41.6- H- (N, N-Dicyclohexylaminocarbonyl) propoxy 3-3,4-dihydrocarbostyryl.
    42.6- | (3-Anilinocarboiyl) propoxy J-CH, 4-dihydrocarbostyryl.
    43.6-C3- (N-ethylanilinocarbonyl) propoxy carbostyryl,
    44.6- 3- (0,0-Dichloroanilinocarbonsh1) propoxy-3,4-dihydrocarboxystyrene®.
    45. (K-Butyl-M-cyclohexclaminocarbonyl) butoxy J-3,4-dihydrocarbostyryl.
    46. (M-Metsh1-Y-cyclohexyl-aminocarbonyl) propoxy 3-3,4-dihydrocarbostyryl.
    47.6-SZ- (H, L-Diphenylaminocarbonyl) propoxy-3,4-dihydrocarboxystyrene1,
    48.6- (1-Ethoxycarbonylethoxy) -3,4-dihydrocarbostyryl.
    49o 6- (1-Ethoxycarbonyltoxy) carbostyryl. ,
    50.1-Methyl-6- (1-Ethoxycarbonylethoxy) -3, 4-dihydrocarbostyryl.
    51.7- (1-Ethoxycarbonylethoxy) -3,4-dihydrocarbostyryl.
    52.6- (3-Ethoxycarbonylpropoxy) -3,4-dihydrocarbostyryl.
    53.6- (1-Amyloxycarboxy1Etoxy) -3, 4-dihydrocarbostyryl.
    54.6- (1-Isopropoxycarbonylethoxy) carbostyryl.
    55.5- (3-Ethoxycarbonylpropoxy) - -3, 4-dihydrocarbostyryl.
    56.b- (3-amyloxycarbonylpropoxy) -3,5-dihydrocarbostyryl.
    57.6- (3-Ethoxycarbonylpropoxy) car bostyril.
    58.6- (6-Ethoxycarbonylhexenx10xi) -3, 4-dihydrocarbostylIryl.
    59.b- (b-Carboxyhexyloxy) -3,4-dihydrocarbostyryl.
    60.8- (1-Ethoxycarbonylethoxy) -. -3,4-dihydrocarbostyrSH1.
    61.6- (1-Methyl-1-carboxyethyl) -3,4-dihydrocarbostyryl.
    62.b- (Z-Carboxypropoxy) carbostyril.
    63.6- (3-Cyclohexyloxycarbonylpropoxy) -3,4-dihydrocarbostyryl.
    64.6- (K-Isopropylaminocarboxyethoxy) -3,4-dihydrocarbostyryl.
    65.6- (Morpholinomethyl) - 3, 4-dihydrocarboxyryl.
    66.5- (H, L-Dimethylaminocarbonsh1methoxy) -3,4-dihydrocarbostyryl.
    67.1-ETSH1-5- z- (N-benzylaminocarbonyl) propoxyJ-3,4-dihydrocarbostyryl.
    68. (K-Propi-Laminocarbonyl) -2-methylpropoxy-3, 4-dihydrocarboxyryl.
    69. Aspirin,
    Pharmacological test 2.
    Counteraction against cyclic AMP phosphodiesterase. determined by the method of determining activity 2 and 3, i.e. To determine the counteraction against cyclic AMP phosphodiesterase, 10 mp solution prepared by adding 1 ml of MgCl to 50 mmol of tris-hydrochloric acid buffer pH 7.4 was added to platelets obtained by further centrifuging the rabbit PRP at 3000 rpm for 10 min, and the suspended platelets are ground in a teflon homogenizer. After that, twice, freeze the drug and thaw it twice, and then crushed 300 with an ultrasound power of 200 watts. After an additional 60 minutes of centrifugation at 100,000 G, the supernatant is collected for use as a crude enzyme solution. .
    10 ml of the crude buffer solution was injected into a 1.5–20 cm column filled with DEAE-cellulose, which was pre-buffered with 50 mm Tris-acetate buffer (pH 6.0), followed by washing and elution with 30 ml of 50 mm Tris-acetate buffer; then this buffer solution is treated with a linear gradient elution of 0 0.5 mol of acetate-tris-acetate buffer (the total amount eluted is 300 ml. The flow rate is 0.5 ml / min, and fractions of 50 mp are collected each. As a result operations get fractions with low acti less than 2 mol / ml min with a high (100 μm mol) con1 |); concentration of the Cyclic AIR of the substrate and still high activity above 100 p mol / ml min with a low (0.4 μm mol) concentration of the cyclic substrate. This fraction is used as cyclic AMP phosphodiesterase.
    About 1 ml of an aqueous solution of each test compound of a certain concentration is mixed with 40 mmol of buffer — Tris-hydrochloric acid, pH 8.0, containing 50 µg. serum albumin, and with 4 mmol MgClj containing pre-determined 1, O micron cyclic AMP
    (tritium AMP) and 0.2 MJJ of this mixed solution are used as the substrate solution.
    0.2 MP of the previously prepared cyclic AMP phosphodiesterase at a predetermined concentration is added to the indicated substrate solution and the resulting mixture is reacted for 20 minutes, highlighting tritium 5 AMP for tritium cyclic AMP.
    The reaction system was immersed in boiling water for 2 minutes to stop the reaction, and then the reaction solution was cooled in ice water, and 0.05 ml (1 mg / ml) was added to the solution to convert the resulting tritium 5-AMP into trithiute adenosine. snake and in the form of 5 -nucleotides and the reaction is carried out at for 10 min. The entire amount of the reaction solution was then introduced into a cation exchange resin column (AC 500 Wj 4,200-400 mesh, manufactured by BioRad Co, column size; 0, 5 cm) and the resulting tritium-anodesine alone was left to collect, washed with 6 ml of distilled water and eluted 1 , 5 ml 3 n. ammonia water. To the total amount of the eluate, 10 ml of a tritone-toluene type unification factor is added and the resulting tritiumadeno-ZIN is determined using a scintillation liquid counter to determine the activity of phosphydlesterase,
    Thus, the activation value (V) of phosphodiesterase of the test compound of a corresponding concentration is determined, and from this activation value of Vg and the control value V. obtained for water, which does not contain any test compound, the degree of resistance of phosphodiesterase (SPF,%) from following formula
    SPF .Y
    X 100.
    with
    Dp control using known 1-methyl-3-isobutyloxanthin.
    The results are shown in Table. four.
    ; T and l and c and 4
    Continuation of table 4
    1-Methyl-3-isoi7
     5.4 10 butyloxantine
    Pharmacological test 3.
    The positive inotropic effects of the new carbostyril derivatives of the invention are determined by method 4 J. as follows.
    Adult hybrid dogs of both sexes weighing 8–12 kg are anaesthetized with phentobarbital — Na at a dose of 1000 g / kg, intravenously. Following the next intravenous administration of heparin sodium (1000 µg / kg), test dogs are killed by bleeding them. The dog's heart is cut out and immediately placed in Lock's solution, then the arterial steam is cut out together with the interventional septum, the Septal artery is carefully removed, passed through a polyethylene cannula and stitched with thread, the Septal arteries (the rest are not attached to the arterial papillary ) stitched with thread. Then, donor hybrid dogs weighing 18-27 kg anesthetize phenabarbitaprm - Na (30 mg / kg), by intravenous administration, and sodium heparin (1000 µg / kg) is injected intravenously.
    The arterial papillary muscle cannulated through the septal artery is perfused with a polyethylene cannula with blood coming from the carotid artery of the donor dog with
    using a peristaric pump. Perfusion pressure is maintained constant at 100 mm Hg. The muscle is stimulated by electricity using an electronic stimulator through bipolar
    electrodes in contact with an interventional partition. The 2x stimulation force (the minimum value at which the effect occurred) at a frequency of 2 Hz, the duration of the pulsation
    2 ms
    The isometric contraction created by this is measured by force displacement, franducer. The amount of blood flowing through the coronary artery is determined by measuring the blood flow entering the septal artery using an electromagnetic flow meter. EC &amp; data is recorded on a recorder.
    The solution containing the test
    the compound is injected into the septal artery through a rubber tube connected to a polyethylene canoe in an amount of 10-30 µl „
    The results are shown in Table 5, where the increase (%) of contractions is expressed as the ratio of the number of contractions before and after the injection (injection) of the solution containing the test compound.
    Table 5
    62.5
    17 Pharmacological Test 4 The effect of increasing cerebral blood flow is determined by a known method. A hybrid dog (male weighing 12–20 kg) is fixed in a prone (position), 20 mg / kg of sodium phenobarbital is anesthetized and artificial respiration is performed at a frequency of 20 times / min. The cheekbone is then exposed and the bone is removed in order to open the venous sinus using a grinder, and venous blood is drawn from the cannulated vein. The blood flow velocity from the vein is determined using an electro-magnetic flow meter, and the number of drops of blood is measured by dawn.
    38.7
    89.4
    38.9
    94.3,
    2.7
    51.4 vi in 10 s using the drop counter. The effect of cerebral blood flow is determined by comparing the number of blood drops in 30 seconds at the maximum of the pressure that is observed before and after administration of the test compound. Each compound is dissolved in dimethylformamide, diluted with saline and injected through a cannula inserted into a profunda fomoris vein. As a comparative compound, papaverine is used. The crawled results are shown in Table. 6. Table 6
    Pharmacological test 5.
    The hypotensive effect of the compounds was measured by determining the maximum blood pressure of the test animals according to the Tail-Cuff method.
    Use two types of test animals.
    1. Cold beatt tire renoprival, hypertensive rats (R H R),
    Adult rats of the Wistar strain weighing 160-180 g are anesthetized with ether and the left-sided renal artery is clamped with a silver clip with an inner diameter of 0.2 mm, while the right-sided renal artery is left unoped. After 4 weeks after surgery, rats with a maximum blood pressure of more than 150 mm Hg are taken, and test animals are not given food during the night,
    2. Deoxicor Ticosterone Acetate (DOCA) saline, hypertensive rats (DNR).
    Male rats of Wistar strain weighing. 150-170 g are anesthetized with ether and husked off the left kidney. After a week.
    after the operation, once a week, 10 mg / kg of DOSA was given subcutaneously and 1% aqueous salt solution was given as drinking water, 5 weeks after the operation, rats with a maximum blood pressure higher than 150 mm Hg. Selected and used as test animals that are not given food during the night.
    Each of the test compounds was administered orally and blood pressure was measured before administration and after 1, 2, 4, 6 and 8 hours after administration. The results are shown in Table 7. "Blood pressure is measured using a Rectuhoriz type 8S recorder, Sanei Instrument, and a PE-300 Macro Bio System electro-diagnostic manometer.
    权利要求:
    Claims (6)
    [1]
    METHOD FOR PRODUCING CARBOSTERYRYL DERIVATIVES of the general formula where R * is a hydrogen atom, lower al “kil, lower alkenyl or phenyl lower alkyl ·,’
    R ^ is a hydrogen atom, lower alkyl or a group of the formula
    -0-A -CON X in which R 4
    A 'is a saturated or unsaturated lower alkylene group;
    Rj is lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl or benzoyloxy lower alkyl;
    R ^, ~ C 3 - C (0 ~ cycloalkyl, which may contain at least one hydroxyl group as a substituent (s) in the cycloalkyl ring, C e - C * 0 -cycloalkyl lower alkyl, phenyl, phenyl lower alkyl which may have at least one lower alkoxyl as substituent (s) on the phenyl ring, lower alkyl, which may have at least one hydroxyl group, pyridyl or lower alkyl having as substituent a heterocyclic radical selected from the group including pyridyl, furyl, tetrahydrofuryl, 3,4-dihydride -
    [2]
    2H-pyranyl, tetrahydropyranyl or thienyl Rj, R 4 and the nitrogen atom associated with them, as well as with or without another nitrogen atom, can form a group of the general formula - N B “Re where R ^. - phenyl, C $ - C * 0 -cycloalkyl or phenyl-lower alkyl, SU, t 1169535
    B is a methine group or a nitrogen atom; carbon - carbon bond between
    [3]
    3rd and
    [4]
    4 positions in carbostyril. the skeleton is a single or double bond, the substituted position of the group
    I of the formula —0 — A —CON is— X is any of
    [5]
    5th, 6th, 7th or 8th positions of the carbostyril skeleton; if the group of the formula
    -0-A 1 -C ON is located at 4 in the 5th, 6th, 7th or 8th position of the carbostyril skeleton,
    R z is a hydrogen atom or lower alkyl; if R 2 is a group of the formula -0-A f -C0N ^ 3, 5th, k 4
    [6]
    The 6th, 7th and 8th positions in the carbostyryl derivative are occupied by hydrogen atoms and are not substituted by a group of the formula -0-A 1 -CON C if R3 to 4 is lower alkyl, R + cannot be C 3 - C ) 0 - cycloalkyl, C 3 - C ^ -cycloalkyl lower alkyl, nor lower alkyl, characterized in that the carboxyalkoxy-carbostyryl derivative of the general formula
    O-A-COOH
    1 R1 where R ^ h carbon is the carbon bond between the 3rd, 4th and 4th positions in the carbostyryl skeleton have the indicated meanings: R 2 is a hydrogen atom, lower alkyl or a group of the formula -0-A '-COOH, where A 'has the indicated meanings, the group -0-A * -COOH · is in the 5th, 6th, 7th or 8th position of the carbostyril skeleton; if the group -0-A 1 -COOH is in the 5th, 6th, 7th or 8th position of the carbostyril skeleton, R 2 is a hydrogen atom or lower alkyl; if R 2 is a group of the formula -0-A '-COOH, 5th,
    The 6th, 7th and 8th positions of the carbostyril skeleton are occupied by hydrogen atoms. and are not substituted by groups of the formula —O — A | —COOH — react with an amine of the general formula
    R1;
    where R 3 and R 4 have the indicated meanings, with the isolation of the target product in free form.
    oneThe invention relates to a method of obtaining new carbostyril common formulas η|R 0-A -εΟΝζ1 gr 4 ABOUT N 0IRi
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    同族专利:
    公开号 | 公开日
    ZA803322B|1982-01-27|
    SE8102690L|1981-08-30|
    DK151956C|1988-08-15|
    ES8105290A1|1981-05-16|
    ES492230A0|1981-05-16|
    KR840004681A|1984-10-22|
    PH18532A|1985-08-09|
    FI76321C|1988-10-10|
    SU1395140A3|1988-05-07|
    AT381493B|1986-10-27|
    NL185146B|1989-09-01|
    NL8020199A|1981-12-01|
    NO813477L|1981-10-15|
    FR2477149B1|1983-06-24|
    GB2070588A|1981-09-09|
    NO160512B|1989-01-16|
    ATA909480A|1986-03-15|
    CA1159068A|1983-12-20|
    AU5985980A|1981-09-11|
    BE883713A|1980-12-09|
    DK151956B|1988-01-18|
    AU532319B2|1983-09-22|
    FR2477149A1|1981-09-04|
    GB2070588B|1983-10-19|
    PT71359B|1981-10-21|
    NO160512C|1989-04-26|
    WO1981002421A1|1981-09-03|
    PT71359A|1980-07-01|
    JPS6334845B2|1988-07-12|
    SE461147B|1990-01-15|
    IT8067888D0|1980-06-06|
    FI801843A|1981-08-30|
    KR860002099B1|1986-11-25|
    DK250381A|1981-09-03|
    FI76321B|1988-06-30|
    KR860002100B1|1986-11-25|
    DE3049959C2|1993-07-08|
    IT1129812B|1986-06-11|
    MX6752E|1986-06-25|
    CH647765A5|1985-02-15|
    DE3049959T1|1982-07-29|
    JPS56122356A|1981-09-25|
    NL185146C|1990-02-01|
    KR830002713A|1983-05-30|
    US4435404A|1984-03-06|
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    CA2771136A1|2009-08-21|2011-02-24|Otsuka Pharmaceutical Co., Ltd.|Process for producing benzo[b][1,4]diazepine-2,4-dione compound|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP55025658A|JPS6334845B2|1980-02-29|1980-02-29|
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