• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Novel carbostyril derivatives and their pharmaceutically acceptable salts represented by the formula (1). <IMAGE> (1) wherein R1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group, R2 and R3 form, together with the adjacent nitrogen atom and further with an additional oxygen atom, a 5- or 6-membered saturated heterocyclic ring which may have a lower alkyl group or a phenyl-lower alkyl group as the substituent; the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton being a single or double bond. The derivatives are useful as the active ingredient in cardiotonic compositions.
    公开号:SU1331426A3
    申请号:SU823394100
    申请日:1982-02-15
    公开日:1987-08-15
    发明作者:Томинага Мисиаки；Янг Юнг-Сиунг；Огава Хиденори；Накагава Казуюки
    申请人:Оцука Фармасьютикал Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    one
    a carbonyl group, a lower alkoxycarbonyl lower alkyl group, a furoyl group, a lower alkyl sulfonoyl group, a substituted lower alkyl group having one substituent selected from the group containing a cyano group, a benzoyl sigroup group that may have from 1 to 3 lower alkoxy groups on the phenyl ring a group, a lower alkanoyl hydroxy group, a halogen atom and a carbomoyl group of a phenoxy-lower alkyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group containing an atomic halogen group, a lower a-alkoxy group, a lower a A pgroup or a phenoxy-lower alkyl group may have a lower alkylenedioxy group as a substituent on the phenyl ring, a phenyl lower alkyl group which may have 1 to 3 substituents on the phenyl ring selected from the group containing a lower alkyl group, a lower alkoxy group , a halogen atom, a nitro group, an amino group, a lower alkanoyl amino group, and a lower alkylthio group, or a phenyl lower alkyl group may have a lower alkyl dioxy group on the phenyl ring, a benzoyl group which may have and the phenyl ring by 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group.
    26
    a lower alkanoyl amino group and a lower alkyl thio group, or a phenyl lower alkyl group may have a lower alkylene-dioxy group as a substituent on the phenyl ring, a benzoyl group which may have 1 to 3 substituents on the phenyl ring selected from the group containing the lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group and a cyano group, or a benzoyl group may have a lower alkylenedioxy group on the phenyl ring as a substituent, a phenylsulfonoyl group which may have from 1 d 3 alkp groups as substituents, a benzoyl lower alkyl group which may have from 1 to 3 substituents on the phenyl ring selected from the group containing a halogen atom, an oxygroup, a lower alkyl group, a lower alkoxy group and a lower alkoylamino group a phenyl lower alkenylcarbonyl group that may have 1 to 3 substituents on the phenyl ring, selected from the group containing a halogen atom and a lower alkoxy group, or a phenyl lower alkanoyl group that may have 1 to 3 lower alkoxy groups on the phenyl ring group n as substituents, the carbon-carbon bond between the 3rd and 4th positions in the structure of the carbostyril being a single or double bond,
    characterized in that
    compound of general formula
    where A is a group of common CO
    I am about
    1 TH / 1S
    de F - carbon-carbon bond
    between the 3rd and 4th positions in the structure of carbostyril with the indicated values; R is an alkanoyl group, a lower alkoxycarbonyl group, a furoyl group, a benzoyl group which may have 1 to 3 substituents on the phenyl ring, selected from the group. | Containing a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group and a cyano group, or a benzoyl group can have a lower alkylenedioxy group as a substituent on the phenyl ring, a phenyl lower alkanoyl group which can have from 1 to 3 lower alkoxy groups as a substituent or phenyl group - lower alkenyl - carbonyl group, which ra may have 1 to 3 substituents on the phenyl ring. selected from the group containing a halogen atom and a lower apkoxy group,
    lead to interaction with the compound formula
    H - B, de B - a group of general formula
    -Y-ya
    R3
    (Or
    where r

     2
    R
    - carbon-carbon bond between the 3rd and 4th positions in the structure of carbostyril with the indicated values,
    with ycJlOvii, that when A is a group of the general formula
    0 Stage B is a group of general formula
    -N
    Cs

    where R, R and Rj have the indicated meanings,
    when A is P, -, then B is a group of general formula.-.
    where R and R have the indicated values Priority on the grounds. 17 .02.81, 15.04.81 with R and R are the same or different and represent a random lower alkyl group or a lower phenylalkyl group which may contain from 1 to 3 substituents belonging to the group consisting of a lower alkoxy group and a halogen atom in the phenyl ring, or a lower phenylalkyl group which may contain a lower alkylenedioxy group as a substituent on the phenyl ring, R and RJ may form together with the adjacent carbon atom with which they are bound, 5 or 6-member heterocycle through an oxygen atom with or without its participation or through a nitrogen atom or without its participation; moreover, said heterocycle may contain a lower alkyl group as a substituent.
    08/12/81 when R and Rj are the same or different and are each lower alkyl group which may contain hydroxy groups or halogen atoms as substituents, and Ri can form together with the nitrogen atom adjacent to them and to which they are bonded, A 5- or 6-membered saturated heterocycle with or without an oxygen atom or a nitrogen atom, and the heterocycle may contain a lower phenylalkyl group as a substituent; when
    when said heterocycle is a piperazinyl group, said piperazinyl group may contain a cycloalkyl group, a lower alkanoyl-lower alkyl group, a lower alkoxycarbonyl group, a lower alkyl group, a mixed lower alkyl group, containing carbon groups, a carbon group, a carbon group, a carbon group, a carbon group, a carbon group, and benzoyloxy groups which may contain from 1 to 3 lower alkoxy groups in the phenyl ring, hydroxyl group, lower alkanoyl oxy group and halogen atom, phenoxy-lower alumina yl group, zameshennuyu or unsubstituted phenyl-lower alkenyl carbonyl group, zameshennuyu or unsubstituted phenyl-nizschuyu alkanoilgrup ny,
    one
    The invention relates to methods for producing carbostyril derivatives of the general formula
    de

    R is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group; are the same or different, and each of them is a lower alkyl group which may have a hydroxy group or a halogen atom as a substituent, or a phenyl-niesh alkyl group which may have from 1 to substituents selected from the groups containing a lower alkoxy group and a halo atom - on the phenyl ring, or the phenyl-lower alkyl group may have a lower apkilendioxy group as a substituent on the phenyl ring, R and RJ may form together with the adjacent nitrogen atom and with or without an additional oxygen atom
    five
    0
    five
    0
    five
    0
    OR nitrogen, a 5 or 6 membered full heterocyclic ring which may have a lower alkyl group or a phenyl lower alkyl group as a substituent; when the heterocyclic ring is a piperazinyl group, the piperazinyl ring may have a lower alkyl group or a phenyl lower alkyl group as a substituent in the Dth position of the piperazinyl ring, the piperazinyl group may have lower alkenyl as a substituent in the 4th position - a group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a lower alconoyl group, a lower alkonoyl-lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkyl group, a furoyl group, a lower alkyl group l-sulfonoyl group, a substituted lower alkyl group having one substituent selected from the group containing a cyano group, a benzoyloxy group which may have from 1 to 3 lower
    313
    alkoxy groups on the phenyl ring, hydrogen group, lower alkanoyl-sigroup, halogen atom and carbonoyl group, phenoxy-lower alkyl group, which may have 1 to 3 substituents on the phenyl ring, selected from the group containing a halogen atom, lower alkoxygroup
    a pu and a lower alkyl group or a phenoxy-lower alkyl group may have a weak alkynylenedioxy group as a substituent on the phenyl ring, a phenyl lower alkyl group which may have 1 to 3 substituents on the Lenil ring selected from the group containing the lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group, a lower alkanoyl amino group and a lower alkyl thio group, or a phenyl lower alkyl group may have a lower alkylenedioxy group on the phenyl ring, a benzoyl group that may have on the phenyl ring 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group and a cyano group, or a benzoyl group may have a lower alkylenedioxy group as a substituent, a phenylsulfonyl group which may have on the phenyl ring 1 to 3 lower alkyl groups as substituents, a benzoyl lower alkyl group which may have on the phenyl ring
    0
    0
    2E
    15
    a ring of 1 to 3 substituents selected by an ich group containing a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, and a lower alkonoylamino group, a phenyl lower alkenylcarbonyl group which may have 1 to 3 substituents on the phenyl ring selected from the groups containing an atom halogen and a lower alkoxy group, or a phenyl-lower alkonoyl group which may have from 1 to 3 lower alkoxy groups on the phenyl ring as substituents, with a carbon-carbon bond between the 3rd and 4th positions in the carbostyryl frame e is a single or double bond, 30 with biological activity.
    The purpose of the invention is the synthesis of new compounds with valuable properties.
    Example 1. 50 g of 6- (o-pyridinium acetyl) -3,4-dihydrocarbostyryl chloride and 50 g of sodium hydroxide are suspended in 1 l of water. The suspension is stirred for 3 hours at 90 -. After completion of the reaction by introducing concentrated hydrochloric acid, the pH of the reaction mixture is adjusted to 2 to precipitate crystals. Then the crystals are collected by filtration.
    By recrystallization from dimethylformamide, 19.1 g of 6-carboxy-3,4-dihydrocarbostyril, light yellow crushed crystals, m.p. about 300 C.
    Example 2. The south of 6-carboxy-3,4-dihydrocarbostyril and 6.0 g of succinic acid N-hydroxyamide are suspended in 200 ml of dioxane. Then, a solution of 12.4 g of dichlorohexylcarbodiimide in 50 ml of dioxane is added dropwise to the suspension while cooling with ice and stirring. The reaction mixture is heated at 90 ° C for D h. After completion of the reaction, the reaction
    the mixture is cooled to room temperature. The precipitated crystals are removed by filtration. The mother liquor is concentrated by distillation. The residue is recrystallized from dimethylformamideethanol.
    10.8 g of 3,4-dihydrocarboxystyryl-6-carboxylate succinimide, colorless flaky crystals, m.p. 23A, 5-236 C.
    Example 3. 15.1 g of 6-acetyl-3,4-dihydrocarbostyril are dissolved in 100 ml of acetic acid. The solution was kept at ZZ-AO C. 10 ml of acetic acid containing 11.2 ml of bromine was added dropwise over 3.5 hours while stirring. The reaction mixture was incubated overnight and the precipitated crystals were collected by filtration and washed with a small amount of acetic acid. The crystals are treated with activated carbon using ethanol in a
    Example 7. 100 g of m-aminozoic acid are suspended in 1 l of ethyl ether and stirred at room temperature with D4.6 g of ethoxylated chloride added dropwise. Then the reaction mixture is heated at 40 ° C for 5 hours. Upon completion of the reaction, the precipitated material is collected by filtration, washed with water three times, dried. Perekr
    60 g of m-carboxy-N- / 5-ethoxyacryloyl
    aniline as colorless cotton
    solvent.
    19.5 g of 6-dibromoacetyl-3,4-dihydrocarbostyril are obtained in the form of light yellow needle-like crystals, so pl. 168-169 seconds
    Example 4 Into 250 ml of water, 26 g of sodium hydroxide are dissolved, then at 90-100 ° C, 35 g of 6-dibromoacetyl-3,4-dihydrocarbostyryl are added with stirring and the reaction is carried out for 3 hours. After the reaction has ended, the reaction mixture cool. Insoluble crystals. tpl 200,5-20
    Example 8. 8g m-carboxy 30 - | ethoxyacryloyl aniline was added with 80 ml of concentrated sulfuric acid and stirred at room temperature for 2 hours, and then at 50 ° C for 1 hour. The reaction was mixed with ice and the pH was adjusted to 3-4 with 10 N aqueous solution sodium hydroxide cross section. The precipitated crystals are collected by filtration, washed with water and recrystallized.
    35
    Example 8. 30 - | - ethoxyacryloyl 80 ml of concentrate and stirred in the course of 50 ° C for 1 h. poured into ice, pH р up to 3-4 by adding a hydroxide solution and collecting the crystals washed with water and over
    Filters are removed by filtration. The mother liquor is acidified with concentrated hydrochloric acid,
     . .in from dimethylformamide, the precipitated crystals collect the filter
    walkie-talkie and washed with water. The crystals are recrystallized from ethanol twice.
    10.5 g of 6-carboxy-3,4-dihydrocarbostyril are obtained as light yellow amorphous crystals, m.p. 324.5-45 327 C (decomp.).
    4.26 g of styryl are obtained in the form of bright crystals.
    Example 9. -3-phenylpropionate, chloride and 250 ml of di give up to about C. Then from 0 to 10 ° C, slowly stirring 122 g of stirring at the actual temperature of the subsequent exposure overnight. The reaction mixture was concentrated with the bottom lot and the layer was extracted with chloroform, dried and chlorofiltered. K residue
    Example 5 „60 g of 6- (o (chloro-acetyl) carbostyril is suspended in 0.5 kg of pyridine and stirred at 80-90 ° C for 2 hours. Then the suspension is stirred while cooling with ice for 1 hour. The precipitated crystals are collected ( Filtered and recrystallized from methanol.
    Obtain 70 g of 6- (o1-pyridinium acetyl) carbostyryl chloride 1/2-hydrate as colorless needle-shaped crystals, m.p. about 300 ° C.
    JO
    15
    20
    Example 6. 69.7 g of 6-β-pyridioucetyl) carbostyryl chloride and 65 g of sodium hydroxide are dissolved in 0.6 l of water and stirred at 60-10 ° C for 3 hours. While cooling with ice, the pH of the reaction mixture is concentrated hydrochloric the acid is adjusted to 2. The precipitated crystals are collected by filtration.
    By recrystallization from dimethylformamide, 41.4 g of 6-carboxy-carbostyryl are obtained; light brown, crushed crystals, m.p. about .
    Example 7. 100 g of m-aminobenzoic acid are suspended in 1 l of diethyl ether and stirred at room temperature with D4.6 g of α-ethoxyacrylate chloride, added dropwise. The reaction mixture is then heated at 40 ° C for 5 After completion of the reaction, the precipitated material is collected by filtration, washed with water three times, and dried. Perekri60 g m-carboxy-N- / 5-ethoxyacryloylaniline in the form of colorless hlopkooob,
    25 .. out
    different crystals. tpl 200,5-202 S.
    Example 8. 8g m-carboxy- 30 - | -ethoxyacryloyl aniline was added with 80 ml of concentrated sulfuric acid and stirred at room temperature for 2 hours and then at 50 ° C for 1 hour. The reaction mixture was poured into ice, the pH of the solution was adjusted to 3-4 with the addition of 10N aqueous hydroxide solution on three . The precipitated crystals are collected by filtration, washed with water and recrystallized.
    35
    from dimethylformamide
    4.26 g of 5-carboxycarbostyryl are obtained in the form of light yellow crushed crystals, m.p. about .
    five
    Example 9. A mixture of 50 g of methyl-3-phenylpropionate, 51.6 g of chloroacetyl chloride and 250 ml of dichloromethane is cooled to 0 ° C. Then, at a temperature from 0 to 10 ° C, 122 g of aluminum chloride is slowly added with stirring, at room temperature for 2 hours, followed by exposure overnight. The reaction mixture was poured into ice-cold concentrated hydrochloric acid and extracted with chloroform, then the chloroform layer was washed with water, dried and the chloroform was removed by distillation. Iso5 is added to the residue.
    propyl ether. The crystals are collected by filtration.
    By recrystallization from methanol, 53.4 g of methyl 3- (4-chloroacetylphenyl) propionate are obtained in the form of colorless needle-like crystals, mp,
    go-gz c.
    Example 10. 36.26 g of methyl 3- - (A-chloroacetylphenyl) propionate are dissolved in 300 ml of concentrated sulfuric acid. Then drop by drop while cooling with ice and stirring
    Bavly 20.9 g of fuming nitric acid (d 1.52). The reaction mixture was stirred at room temperature for 3 hours, then it was poured into ice water and extracted with chloroform. The chloroform layer is washed with water, dried and removed by distillation. The residue obtained is chromatographed on silica gel and crystallized by the addition of ether. The crystals are collected by filtration and recrystallized from methanol.
    26.7 g of methyl 3- (carboxy-2-nitrophenyl) propionate are obtained, light yellow crystals in the form of prisms, t „mp. 120-122 C.
    Example 11. 5 g of Mets 1-3- (4-carboxy-2-nitrophenyl) propionate, 8.87 ml of 2.226 sodium hydroxide dissolved in methanol, 100 ml of methanol and 1 g of 5% palladium-carbon containing 50% are mixed water. The mixture is catalytic; they are reduced at normal temperature and under normal pressure. The catalyst is removed by filtration. Concentrated hydrochloric acid is added to the mother liquor to adjust the pH to 1. The resulting crystals are collected by filtration and recrystallized from methanol.
    3.62 g of 7-carboxy-3,4-dihydrocarbostyril are obtained in the form of colorless needle-shaped crystals, m.p. above 320 S.
    NMR (DMSO), (f: 2.33-2.60 (m, 2H); 2.77-3.05 (m, 2H); 7.21 (d, J - 8.5 Hz, W); 7.38-7.53 (Im, 2H); 10.15 (s, IH).
    Example 12. To a solution containing 467 g of chloroacetyl chloride in 400 MP of dichloromethane, 735 g of aluminum chloride was added one third in three periods of time at a temperature below 30 ° C with stirring. Then at the same temperature at
    ten
    15
    31426
    200 g of carbostyril are added to the mixture by stirring. The reaction mixture is heated under reflux for 6 hours. After completion of the reaction, the reaction mixture is poured into ice-cold concentrated hydrochloric acid. The crystals formed are collected by filtration and flushed with hot methanol. 153 g of 6-chloroacetic acid are obtained. The mother liquor is concentrated by drying, the residue is purified with silica gel. On a chromatographic column “
    By recrystallization from methanol, 35.41 g of 8-chloroacetylcarbostyryl are obtained in the form of light yellow needle-like crystals, m.p. 177.5 0
    five

    0
    five
    0
    0
    five
    179 ° С „
    Example 13. 30 g of 8-chloroacetylcarbostyril are mixed with 300 ml of pyridine. The mixture was stirred at 80 ° C for 2.5 hours while heating. The reaction mixture is then cooled with ice. The resulting crystal is collected by filtration and washed with ether. By recrystallization from methanol, 40.85 g of 8 - (((- - pyridinium acetyl)) carboxylpid hemihydrate chloride is obtained in the form of colorless needle-shaped crystals, mp 261, 5-264, (decomp.).
    Example 14. 32 g of 8- (c-pyridinium acetyl / carbostyryl chloride, 300 MP of water and 32 g of sodium hydroxide are mixed. The mixture is stirred at 80-90 ° C for 5 hours. The reaction mixture is treated with activated charcoal. To my exact solution is added concentrated hydrochloric acid, bringing the pH of the solution to 3-4. The resulting crystals are collected by filtration and recrystallized from chloroform.
    20.17 g of 8-carboxycarboxystyryl are obtained in the form of colorless needle-like crystals, m.p. above ,
    NMR (DMSO): 6.57 (d, J - 9.5 Hz, 1H); 7.25 (t, J - 8.0 Hz, 1H); 7.94 dd, J 8.0 Hz, 1 He, 1H); 7.98 (d, J “9.1 Hz, W); 8.14 (dd, J 8.0 and 1.5 Hz, 1H).
    P r er. 15, 3.5 g of 6-carb ox-3,4-dihydrocarbostyril is dissolved in 30 ml of dimethylformamide, then 2.4 g of triethylamine are added to the solution. Under ice-cooling, 2.75 g of isobutyl chlorotic acid is added dropwise and stirring over 30 minutes. Then at room temperature9133U2610
    with stirring in the reaction with 2 ml of dimethylformamide and the mixture is added dropwise, 3.19 is heated at room temperature in teN-methyl-N- (4-methoxy) ben-elamina and 3 h. Then to the reaction mixture
    stirred for 5 hours. The reaction mixture was added with water. The mixture is extracted
    concentrated by drying and extracting with chloroform, washed with water and with neutron with chloroform and aqueous solution is crystallized with an aqueous solution of chloride
    sodium hydroxide. A layer of chloroformatry is in the same order. After drying
    washed with water and after drying to a residue of chloroform non-aqueous sulfate
    ether was added. The resulting crystals of chloroform are removed; distillates are collected by filtration. , under reduced pressure. Acetone is added to the semi-recrystallization from methanol to the residue, 1.84 g of 6-C-methyl-H- (4-marks-crystallization of the product. Sibenzyl) carbomoyl-J-3,4-dihydrocarbamoyl are obtained. 150 mg of 6-morpholinocarboxylate are obtained. styryl as colorless needle-shaped-15nyl-3,4-dihydrocarbostyril, colorless crystals, m.p. 144.5-146.5 s. Granular crystals, m.p.
    Example 16. Similarly, at -206-207 seconds (from ethanol), measure 15 is obtained as follows:
    6-N-Methyl-N- (3,4-methyl-di-dioxy- Example 20. 127 mg succinibenzyl) carbomoyl-3,4-dihydrocarbyl-5o 3,4-dihydrocarbostyryl-6.-carbocryl, colorless crystals in videsilate and 93 mg benzylpiperazine raspprism (ethanol), so pl. 170-171 ° C. Swelled in 2 ml of dimethylformamide. Mixture
    6-N-Methyl-N- (4-chlorobensyl) was prepared under stirring at room temperature -3 ° C, 4-dihydrocarbostyryl, colorless-Re for 24 hours. To the reaction mixture, prism crystals (water is added from ethano-25). The mixture is extracted
    la, so pl. 171, 5-172. With chloroform. Chloroform layer was washed. Example 17 127 ml of succinic water and neutralized with aqueous 3,4-dihydrocarbostyryl-6-carboxylic sodium chloride. After drying the silat and 39 ml of diethanolamine solution-chloroform layer with non-aqueous sulphate in 2 ml of dimethylformamide, the methacrylate chloroform is removed by distillation at room temperature under reduced pressure. To the preparation of 24 hours. Acetone is added to the reaction mixture to add water to the residue. The mixture is extracted from the chlorocrystallization of the product, roform. The chloroform layer is washed with recrystallization from ethanol in semi-aqueous solution and neutralized with an aqueous solution of 130 mg of 6- (4-benzyl-1-piperazine sodium) After drying the layer of chloronylcarbonyl) -3,4-dihydrocarbostiryl. roform non-aqueous sodium sulphate, chlo-colorless needle-like crystals, roform was removed by distillation with a pony-mp. 198-200 S.
    pressure. To the obtained residue. Analogously to example 20 receive
    acetone is added to crystallize - q the following compounds: product. (2-Phenoxyethyl) -1-piperazi 48 mg of 6- (diethanolamino-nilcarbonyl-3,4-dihydrocarbostyryl
    carbonyl) -3,4-dihydrocarbostyril, monohydrochloride, colorless needles. pl. 131-134 s. Different crystals, so pl. 271-274 ° C
    Example 18, 30 mg of thionyl-5 (decomp.).
    the read is added to 2.2 g of 6- (diethanolam- (2-cyanoethyl) -1-piperazincar
    nocarbonide) -3,4-dihydrocarbostyril. carbonyl-3,4-dihydrocarbostyryl monosulfide is stirred at room temperature — hydrochloride, colorless flakes over heat for 5 h, then the reaction crystals, so pl. 240-273 С:
    the concentration of the mixture is concentrated distilled g. (decomp.).
    under pressure. 50 ml of benzene is added to the os-6- (l-pipepazazinilcarbonyl) -3,4-taka. Opera - dihydrocarbostyril, colorless concentrations of concentration under reduced pressure-shuychatoobraznye crystals, so pl. The procedure is repeated three times. 21 1, 5-21.
    6- (di) -2-chloroethyl-ami- (3,4-dimethoxybenzyl) -1-pinocarbonyl-3, 4-dihydrocarbostyryl, perzinylcarbonyl-3,4-dihydrocarbo is obtained Example 19 1.0 g of succini-styryl monohydrochloride, colorless
    Foreign Ministry 3,4-dihydrocarbostyryl-6-carbo-granular crystals, so pl. 240 xylate and 0.37 g of morpholine dissolve 242 ° C (decomp.).
    II13
    (4-Methylbenzyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless crayfish, crystals, mp. 280-283 ° C (decomp.).
    (3,4-Dichlorobenzyl) -1-piperaz nilcarbonyl-3, 4-dihydrocarbostyryl monohydrochloride, colorless scaly-like crystals, mp. 284-287 C (decomp.).
    6-C4-4-Methoxybenzyl) -1-1 typer & zynylcarbonylJ-3,4-dihydrocarbostyryl monohydrochloride, colorless crystals in the form of granules, so pl. 262-264 ° C (decomp),
    (4-Chlorobenzyl) -1-piperazinyl-carbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless needle-like crystals, m.p. above 300 ° C.
    6- 4- (4-Nitrobenzyl) -1-piperazine-carbonyl-3,4-dihydrocarbostyryl monochloride 1/2 hydrate, light yellow crystals in the form of granules, so pl. 268- (decomp.).
    (3,4-Dimethoxybenzoyl) -1 - piperazinylcarbonyl-3,4-dihydrocarbostyryl, colorless crystals in the form of granules, mp. 238-239,
    6- 4- (4-11ianobenzoyl) -1-piperazinylcarbonyl} -3,4-dihydrocarbostyryl, colorless needle-like crystals, m.p. 294-297 p.
    6- 4- (4-Methoxy-benziol) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl, colorless powdery crystals, m.p. 247-249 C.
    (3-Chlorobenziol) -1-piperazinyl carbonyl-3,4-dihydrocarbostyryl, colorless powdery crystals, m.p. 258 5-260 ° C.
    6- 4-C4-Bromobenzoyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl, colorless powdery crystals m.p. 265.5-267 ,.
    6- 4- (3,4-Dichlorobenzoyl) -1-piperazinylcarbonylJ-3,4-dihydrocarbostyryl, colorless crystals in the form of granules, mp. 265-267 s (decomp.).
    (4-Nitrobenzoyl) -1-piperazinylcarbonl-J-3,4-dihydrocarbostyryl, light yellow crystals in the form of granules, mp. 287-289 ° C (decomp.).
    (4-Methylbenzoyl) -1-piperazinylcarbonyl 3,4-dihydrocarbostyryl, colorless flocible crystals, mp. 262-264 ,.
    6- (4-Carbamoylmethyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl,
    612
    colorless crystals in the form of granules so pl. 243.5-244 ° C.
    6- (4-Methyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl monohydroid, colorless powdery crystals, m.p. 258-259, (decomp.).
    (4-Chlorophenyl) (phenyl) methylZ-1- -piperazinylcarbonyl-3,4-dihydrobrostyryl 1/2-hydrate, colorless powdery crystals, m.p. 199-202 ° C (decomp.).
    (p-Toluenesulfonoyl) -1-pi-, perazinylcarbonyl-3,4-dihydrocarbostil, colorless crystals in the form of granules, so pl. 280-282 C.
    6- (4-Methanesulfonosht-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl, colorless needle-shaped crystals, so pl. 115-116.5 ° C.
    6- (4-Ethoxycarbonyl-1-piperazinyl-carbonyl) -3,4-dihydrocarbostyryl, colorless powdery crystals, m.p. 180-182 C.
    6- (4-p-Hexyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl monohydrochloride, colorless flaky crystals, m.p. 276-280 s.
    6- (4-Cyclohexinylmethyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl monohydrochloride, colorless flaky crystals, m.p. above
    6- (4-Isobutyl-1-piperazinylcarbo-NIL) -3,4-dihydrocarbostyryl monohydrochloride, colorless flaky crystals, m.p. 292-293.5 C (decomp.). 6- (4-Allyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl monohydrochloride, colorless flaky crystals, m.p. 235-238 ° C (decomp.).
    6- (4-1Topargil-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl myohydrochloride, colorless crystals in the form of granules, so pl. 249-251 ° C (decomp.).
    (4-Methylthiobenzyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless crystals in the form of granules, mp. 264 - 268 ° С (decomp.).
    6- 4- (3-phenoxypropyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless powdery crystals, m.p. 151- (decomp.).
    (6-phenoxyhexyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless to 1313
    powder crystals, so pl. 254-2574 (decomp.).
    6- 4- (2-Phenylethyl) -1-piperazinylcarbonyl-3, A-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless poro-like crystals, m.p. S2-272 ° C (decomp.).
    (J-Phenylpropyl) -1-piperazinecarbonyl-3,4-dihydrocarbostyryl monohydrochloride, 1/2 hydrate, colorless powdery crystals, m.p. 257-259 C (decomp.).
    (4-Aminobenzyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl, colorless crystals in the form of granules, mp. 213.5-214 ,.
    (4-Acetylaminobenzyl) -1-piperizincarbonyl J-3,4-dihydrcarbostyryl monohydrochloride 3/2 hydrate, colorless powdery crystals, mp. 229-231,
    (3,4,5-Trimethoxybenzoyl) -1-piperazinylcarbonyl-3,4-dihydroburostyryl, colorless powders, crystals, m.p. 174-176 C (decomp
    1-Methyl-6- (4-benzyl-1-piperazinyl-carbonyl) -1,4-dihydrocarbostyryl, colorless flociform crystals, m.p. 145-146 C.
    1-Allyl-b- 4- (2-phenoxyethyl) -1- piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless, threshold-like crystals, m.p. 239-241 ° C.
    1-Benzyl-6- 4- (2-phenoxyethyl) -1-, -piperazinylcarbonyl J-3,4-dihydrocarbostyryl monohydrochloride, colorless powdery crystals, m.p. 261-.
    1-Propargyl-6- 4- (3-fvnoxypropyl -1-piperazinylcarbonyl J-3,4-dihydrobrostyryl monohydrochloride, light yellow powdery crystals, mp 137-139 s (decomp.).
    (2-Furoyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl, colorless powdery crystals, m.p. 181-183.5 ° C.
    6- (4-Formyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl, colorless powdery crystals, m.p. 1-98-201 C (decomp.).
    6- 4- (3,4,5-Trimethoxybenzyl) -1- piperazinylcarbonyl-3,4-dihydrocarbostyryl. monohydrochloride, colorless needle-like crystals, so pl. 160-164 C.
    14
    6- 4- (3,4-Methylenedioxybentoyl) -1 -1 piperazinylcarbonyl-3, 4-dihydrocarbostyryl, colorless, porous crystals, m.p. 251-255 With (razl.)
    (2-Hydroxyethyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl dihydrate, colorless rhombic crystals, m.p. 277-279 ° C (decomp.). (Cyclohexyl-1-piperazyl-carbonyl) -3,4-dihydrocarbostyryl, colorless needle-like crystals, m.p. 170-172 ,.
    (3,4-Methylenedioxybenzyl) -1- 1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless flaky crystals, m.p. 277-279 ° C (decomp.).
    6- (1-Piperidylcarbonyl) -3,4-dihydrocarbostyryl, colorless powdery crystals, m.p. 173-174 0.
    6- (4-Methyl-1-piperidylcarbonyl) -3,4-dihydrocarbostyryl, colorless rhombic crystals, so pl. 212-213.5 ° C.
    6- (4-Benzyl-1-piperidylcarbonyl) -3,4-dihydrocarbostyryl 1/2-hydrate, colorless powdery crystals, m.p. 235-236.54.
    6- (1-Pyrrolidylcarbonyl) -3,4-dihydrocarbostyryl, colorless needle-shaped crista lla, so pl. 200-202 C.
    6-4 - () enoxibutyl) -1-piperazinylcarbonyl} -3,4-dihydrocarbostyryl monohydrochloride, colorless crystals in the form of granules, so pl. 250-252 C.
     3- (3-Chlorophenoxy) propyl} -1-piperazinylcarbonyl} -3,4-dihydroCarboustyl monohydrochloride., Colorless needle-like crystals.
    Melting point: 254-256.5 ° C (decomp.)
    6- {4- 3- (2-Chlorophenoxy) propyl -1-piperazinylcarbonyl V3,4-dihydrocarbostyryl monohydrochloride, colorless powdery crystals, m.p. 256-258 C.
    (4-Methylphenoxy) propyl -1- piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless flocible crystals, mp, 265-266.5 ° (decomp.).
     2- (4-methoxyphenoxy) piperazinylcarbonyl1-3,4-dihydrocarbostyryl monohydrochloride, colorless needle-like crystals, m.p. 270- (decomp.).
    6- 2- (3,4-Methylenedioxyphenoxy) ethyl -1-piperazinylcarbonyl UZ, 4-dihydrocarbostyryl monohydrochloride, colorless needle-like crystals, m.p. 164-1664 (decomp.).
    (2- (3-Chlorophenoxy) -piperazinylcarbonyl1-3,4-dihydrocarbostyryl monohydrochloride, colorless powder-like crystals, mp. 249-251,.
    6- 4- (Benzoylmethyl) -1-piperazinyl-carbonyl-3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless powdery crystals, m.p. 212-2154.
    6-G4- (4-Methoxybenzoyl) methylJ-1-piperaznylcarbonyl1-3,4-dihydrocarbostyryl monohydrochloride, colorless powdery crystals, m.p. 266.5-2694 (decomp.).
    6-C- (4-Chlorobenzoyl) methyl -1-piperazinylcarbonyl1-3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless flaky crystals, m.p. 242-245 C (decomp.).
    (3-Chlorobenzoyl) methyl -1-piperazinylcarbonyl J-3 4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless powdery crystals m.p. 143.5-146 ° C (decomp.).
    6- 4- (4-Methylbenzo-JJ) methyl -1-piperazinylcarbonyl1-3,4-dihydrocarbostyryl monohydrochloride, colorless powdery crystals, m.p. 270 (different).
     (4-hydroxybenzoyl) methyl -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride 1/2 - hydrate, colorless powdery crystals so pl. 162-164 seconds
    (2-Benzoylmethyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless flaky crystals, m.p. 205-207 C (decomp.).
    6- 4- (3 | -Benzoylpropyl) -1-piperaz nilcarbonyl-3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless needle-like crystals, m.p. 241-242,54.
    (5-Benzoylpentyl) -1-piperaz nilcarbonyl-3,4-dihydrocarbostyryl monohydrochloride monohydrate, colorless powdery crystals, m.p. 239-242 C.
    (4-Ethylbenzoyl) propyl -1 -1 -1 piperazinylcarbonyl V3,4-dihydrocarboxyrnp monohydrochloride 1/2-hydrate, colorless powdery crystals, m.p. 230-233 0 (decomp.).
    6 - ((4-Chlorobenzoyl) propyl -1-piperazinylcarbonyl1-3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless powdery crystals, mp 238-240 ° C.
    6-f (3,4-Dimethoxyben zoyl) propyl -1-piperazinylcarbonyl1-3,4-dihydrocarbostyryl monohydrochloride 1 / 2- hydrate, colorless powdery crystals, m.p. 225-228 c.
    (4-Methylbenzoyl) piperazinylcarbonyl-3,4-dihydrostiryl, colorless scaly-like crystals, m.p. 224.5-226 C (decomp.).
    (4-Methoxybenzoyl) piperazylcarbonyl1-3,4-dihydrocarbostyryl monohydrochloride monohydrate, colorless rhombic crystals of mp. 204-205 0.
    (4-Acetylaminobenzoyl) etkp -1-piperazinylcarbonyl 1-3,4-dihydrocarbostyryl, colorless powdery crystals, m.p. 207-209 ° С (decomp.
    (3-Ulorcinomoyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl 1/4-hydrate, colorless crystals in the form of granules, mp. 239.5-241 s.
    (3,4,5-Trimethoxycinmoyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl, m.p. 281-284 sec.
    6- (4-Acetylmethyl-1 -pipe {) azinylcarbonyl) -3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless powdery crystals, m.p. 225- (decomp.).
    (2-Hydroxypropyl) -1-piperazinyl carbonyl-3,4-dihydrocarbostyryl, colorless flaky crystals, m.p. 156-157,5 p.
    6- 4- (2-Acetyloxypropyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless powdery crystals, m.p. 239-2414.
    (3,4,5-Trimethoxybenzoyl-oxy) propyl -1-piperazinylcarbonylJ-3,4-dihydrocarbostyryl monohydrochloride, colorless powdery crystals, m.p. 220-222 ° C (decomp.).
    6-G (3,4-Dimethoxy-benzoyloxy) ethyl -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless rhombic crystals, m.p. 240-242 C (decomp.).
    6- (1-Piperazinylcarbonyl) carbostyryl monohydrochloride, colorless crystals
    granules in the form of granules, so pl. Vpepe 300 ° C.
    6- (4-Benzyl-1-piperazinylcarbonyl) carbostyryl monohydrochloride monohydrate, colorless crystals in the form of granules, mp, above 300 C.
    6-f4- (3-Chlorobenoyl) -1-piperazinylcarbonyl -carbostyryl, colorless powdery crystals, mp. above IQ 300 ° C ..
    (2-Phenoxyethyl) -1-piperazinyl carbonyl -carbostyryl monohydrochloride; colorless powdery crystals; mp. 28L-289 C (decomp.). 15
    (3- T) enylpropyl) -1-piperazinylcarbonyl -carbostyryl monohydrochloride, colorless powdery crystals, mp. 290-293 C (decomp.).
    (4-Methylbenzyl) -1-piperazi- 20 nilcarbonyl-carbostyryl monohydrochloride, colorless powdery crystals, mp above 300 ° C.
    6- (4-Isobutyl-1-piperazinylcarbo6- (2-Methyl-1-piperidylcarbonyl-3,4-dihydrocarbostyryl, powdery crystals are colorless, mp 164 C.
    7- (4-Benzyl-1-piperazinylcarbon-3,4-dihydrocarbostyryl monohydrohydride, colorless rhombic crystals, mp 260-262 0 (decomp.).
    7- (4-Isobutyl-2-piperazinylcarbyl nyl) -3,4-dihydrocarbostyryl monohychloride 1/2-hydrate, colorless powder crystals, m.p. 262 264 С (decomp.).
    (2-Benzoylethyl) -1-piperaz nilcarbonyl-3,4-dihydrocarbotiri monohydrochloride 1/2-hydrate, colorless rhombic crystals, so pl. 2 208 C (decomp.)
    (2-Phenoxyethyl) -1-piperazi nilcarbonyl-3,4-dihydrocarbotiri monohydrochloride, colorless flakes visible crystals, t, pl. 177-180 ° C
    8- (4-Isobutyl-1-piperazinylcarb
    Nile) -carbostyryl monohydrochloride 1 / 2- 25 Nile) -carbostyryl monohydrochloride.
    hydrate, colorless powdery crystals, so pl. above 300 C.
    6- 4- (3,4-Dichlorobenzyl) -1-piperazinylcarbonyl j-carbostyryl monohydrochloride 1/2-hydrate, colorless powdery crystals, m.p. above
    300 ° C.
    6- 4- (4-Chlorobenzyl) -1-piperazinylcarbonyl-carbostyryl monohydrochloride, colorless needle-shaped crystals, so pl. above
    5- (4-Isobutyl-1-piperazinylcarbonyl) -carbostyryl monohydrochloride 1/2-hydrate, colorless powdery crystals, m.p. 251-254 ° C (decomp.).
    5- 4- (2-Phenoxyethyl) -1-piperazinylcarbonyl -carbostyryl monohydrochloride, colorless powdery crystals, m.p. 227-229 C.
    (2-Benzoylstil) -1-piperazinylcarbonyl-carboxy-1 monohydrochloride 1/2-hydrate, colorless powdery crystals, m.p. 181.5.
    (3-Phenylpropyl) -1-piperazinylcarbonyl -carbostyryl MOHOIldrochloride, colorless powdery crystals, m.p. 226-228 ,,
    (3,4-Methylenedioxybenzyl) -1- piperazinylcarbonyl - carbostyryl monohydrochloride 1/2-hydrate, colorless powdery crystals, t, pl. 236-239 C (decomp.).
    6- (2-Methyl-1-Piperidylcarbonyl) -3,4-dihydrocarbostyryl, colorless powdery crystals, mp. 162-164 S.
    7- (4-Benzyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl monohydrochloride, colorless rhombic crystals, so pl. 260-262 0 (decomp.).
    7- (4-Isobutyl-2-piperazinylcarbonyl) -3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless powdery crystals, mp, 262- 264 C (decomp.).
    (2-Benzoyl ethyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless rhombic crystals, m.p. 205-208 C (decomp.)
    (2-Phenoxyethyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless flaky crystals, t, pl. 177-180 ° C
    8- (4-Isobutyl-1-piperazinylcarbo5
    colorless powdery crystals, so pl. 251-254 with (decomp.).
    (2-Benzoylethyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl,
    0 colorless powdery crystals, so pl. 182-184 ° C.
    (3-Enylpropyl) -1-piperazi-ylcarbonyl J-3,4-dihydrocarbostyryl, colorless powdery crystals, m.p. 195-196 ° C.
    Example 21. 1.0 g of 6- (I-piperazinylcarbonyl) -carbostyryl monohydrochloride, 0.72 g of m-chlorobenzoyl chloride and 1.4 Ntn of triethylamine are suspended in 15 ml of dichloromethane and the suspension is stirred at room temperature for 2 hours. The resulting crystals are collected by filtration.
    Recrystallization from dimethyl form5 amide yields 1.07 g of 6-4-C3-chlorobenzoyl) - -piperazinylcarbonyl -carbostyryl, colorless powdery crystals, m.p. above
    0
    50
    55
    Example 22. 3.0 g of 6- (1-piperazinylcarbonyl) -3,4-dihydrocarbosteryl and 4.0 MP of triztilamine are suspended in 20 ml of dichloromethane. To the suspension, drop by drop under ice cooling and stirring, 3 5 g of a solution of 3,4-dimethoxybenzoyl chloride and 20 ml of dichloromethane. The reaction is then continued for 1 hour at room temperature. Reaction mixture
    the aqueous solution is extracted
    poured into saturated sodium bicarbonate and chloroform. The chloroform layer is washed with water and neutralized with an aqueous solution of sodium chloride in a specific order and dried with non-aqueous sodium sulfate. The solvent was removed by distillation. The residue obtained is recrystallized from ethanol chloroform.
    4.1 g of (3,4-dimethoksibenzoyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyril are obtained, colorless crystals in the form of granules, mp. 238–239.
    Example 23. 1, 0 g of 6-carboxy-3,4-dihydrocarbostyril, 1.3 g of DCC and 1, 1 g of benzylpiperazine are suspended in 10 ml of dioxane. The suspension was stirred at 70 ° C for 5 hours. After completion of the reaction, the solvent was removed by distillation. Ether is added to the residue. The resulting crystals are removed by filtration. After this, the mother liquor is concentrated. The residue is dissolved in chloroform. The chloroform solution is washed with water and neutralized with an aqueous solution of sodium chloride, and then dried with anhydrous sodium sulfate. The solvent is distilled off. Recrystallization from ethanol gives 350 mg of 6- (4-benzyl--1-piperazinylcarbonyl) -3,4-dihydroburostyryl, colorless needle-like crystals, m.p. 198-200 ° C.
    Example 24. 1.0 g of 6-carbox-3,4-dihydrocarbostyril and 0.8 ml of triethylamine are suspended in 10 ml of tetrahydroauran. While stirring at room temperature, a solution of 1.0 g of diethyl chlorophosphate in 10 ml of tetrahydrofuran is added dropwise. Stirring is carried out at room temperature for 3 hours. To this reaction mixture is added dropwise a solution of 1.1 g of benzylpiperazine in 10 ml of tetrahydrofuran, then stirring is carried out at room temperature for 10 hours. After completion of the reaction, the reaction mixture the crystals are removed by filtration. The mother liquor is concentrated. The resulting residue is poured into a saturated aqueous sodium bicarbonate solution, and then extracted with chloroform. The organic layer is washed with water and neutralized with an aqueous solution of sodium chloride, then dried.
    flood sul1 fath sodium. The solvent is distilled off.
    Recrystallization from ethanol yields 1.07 g of 6- (4-benzyl-1-cyperazinylcarbonyl) -3,4-dihydrocarbostyril, colorless needle-shaped crystals, mp. 198-200 ° C.
    Example 25. 34.5 g of 6-carboxstyryl and 31 ml of triethylamine are spiked into 350 ml of dimethylformamide and stirred at room temperature. A solution of 28 ml of isobutyl chloroformate in 14 ml of dimethylformamide is then added dropwise. After stirring at room temperature for
    1 h to the mixture is added dropwise a solution of 37 g of benzylpiperazine in 21 ml of dimethylformamide and stirred at room temperature for 10 hours. The reaction mixture is poured into a saturated solution of sodium chloride, then extracted with chloroform. The chloroform layer is washed with water, neutralized with an aqueous solution of sodium chloride and dried with non-aqueous sodium sulfate. The solvent is removed by distillation under reduced pressure. The resulting residue is crystallized by adding ether. The crystals are collected by filtration. The crystals are dissolved in methanol. By adding concentrated hydrochloric acid, the pH of the solution was adjusted to pH 1. The resulting raw crystals are recrystallized from aqueous ethanol.
    Obtain 30.1 g of 6- (4-benzyl-1-piperazinylcarbonyl) -carbostyril mono-hydrochloride monohydrate, colorless crystals in the form of granules, so pl. vpepe
    300 C.
    Example 26. To a solution of 50 ml of dimethylformamide with 5.0 g of 6-carboxy-3,4-dihydrocarbostyril and 4 ml of triethylamine is added dropwise a solution of 3.87 g of isobutyl chloroformate in
    2 ml dimethyl Lormamide. After stirring at room temperature for 30 minutes, 5.5 g of benzylpiperazine is added dropwise to the solution.
    3 ml of dimethylformamide, and stirred at room temperature for 30 minutes, then stirring is continued at 50-60 ° C for 1 hour. The reaction mixture is poured into a large amount of saturated aqueous solution of sodium chloride and extracted with chloroform, the chloroform extract is washed with water and dried. After removing the solvent to the obtained residue
    2113
    diethyl ether is added to crystallize the residue.
    3.4 g of 6- (4-benzyl-1-piperazi-1-carbonyl) -3,4-dihydrocarbostyril, colorless needle-shaped crystals, mp 198-200 C, are obtained by recrystallization from ethanol.
    Example 27; To 100 ml of ethanol were added 2.0 g of ethoxycarbonyl-3,4-β-dihydrocarbostyril, 0.5 g of sodium ethoxide and 1.6 g of benzylpiperazine. The reaction was carried out in an autoclave at a pressure of 100 bar and KO-ISO C within 6 hours. After completion of the reaction, the reaction mixture is cooled and concentrated under reduced pressure. The resulting residue is dissolved in 200 ml of chloroform and the chloroform solution is washed with a 1% aqueous solution of potassium bicarbonate, diluted with hydrochloric acid and water, then dried with non-aqueous sodium sulfate. The solvent was removed by distillation and the residue was treated with silica gel on a chromatographic column (silica gel: Wako C-200, eluate: chloroform — methanol (v / v, 20: 1). The crystals were recrystallized from ethanol.
    300 mg of 6- (4-benzyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl are obtained, colorless needle-shaped crystals, mp, 198-200 ° C,
    Example 28, 1.9 g of 6-carboxy-3,4-dihydrocarbostyril is suspended in 200 ml of methylene chloride, then 2 ml of pyridine is added to the suspension and 1.4 g of thionyl chloride is added dropwise with stirring, maintaining the temperature 0 -20 ° C. After the addition of thionyl chloride, the reaction mixture is maintained at a certain temperature and stirred for 1 hour, then a solution of 1.74 g of benzylpiperazine in 10 ml of methylene chloride is added to the mixture. Next, the reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is washed thoroughly with an aqueous solution of potassium carbonate, then washed with water, diluted with hydrochloric acid, dried with anhydrous sulphate sodium atom. The residue is removed by distillation, treated with silica gel on a chromatographic column (silica gel: Wako C-200, zlyuat: chloroform - methanol (v / v,) 20: 1), Recrystallization from ethanol is obtained
    622
    325 mg of 6- (4-benzyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyril, colorless needle-shaped crystals, t, mp, 198-200 s,
    Example 29, BIO2 of dimethylLormanide was added 2.6 g of 3,4-dimethoxybenzoic acid and 1.65 g of 1,8-diazobicyclo (5.4.0) undecylen-7,
    then the outer part of the reaction volume is cooled with ice, and while stirring, 1.5 ml of isobutylchloromate are added dropwise with stirring. Then the reaction mixture is further stirred for 30 minutes. A solution of 2.6 g of 6- (1-piperazinyl) is added to the reaction mixture. a) -carbonyl-3,4-dihydrocarbostyril dissolved in 40 ml of dimethylformamide and stirred at room temperature.
    temperature for 5 hours. After completion of the reaction, the solvent is removed by distillation. The residue is extracted with about 300 ml of chloroform, then washed and diluted with an aqueous solution of sodium bicarbonate, water, hydrochloric acid and water in a specific order. After removal of chloroform by distillation, the residue is recrystallized from ethanol and chloroform,
    Obtain 1.8 g of (3,4-dimethoksibenzoyl) -I-piperazinylcarbonyl - -3,4-dihydrocarbostyril, colorless crystals in the form of granules, t, mp, 238 - 239.5 C,
    Example 30, 126 g of succinimide-3,4-dimethoxy benzoic acid and 137 ml of 6- (1-piperazinylcarbonyl) -3,4-dihydrocarbostyril are dissolved in 2 ml of dimethyl Lormamide and stirred for 24 hours. Then, to the reaction mixture water is added and extracted with chloroform, the chloroform extract is washed with water and neutralized with an aqueous solution of sodium chloride and dried out with non-aqueous sodium sulfate, the solvent is removed by distillation, and the residue is recrystallized from ethane-chloroform.
    Get 100 mg (3,4-dimethoksibenzoyl) -1-piperazinylcarbonyl - -3,4-dihydrostyryl, colorless crystals in the form of granules, t, mp, 238 - 239.5 C,
    55
    Example 31 To a solution of 4.8 g of 3,4-dimethoxy benzoic acid and 4 ml of triethylamine in 50 ml of dimethylformamide is added dropwise a solution of 3.87 g of isobutyl chloroformate in 2 ml
    dimethylformamide. After stirring at room temperature for 30 minutes, a solution of 8.1 g of 6- (1-piperzinylcaronyl) -3,4-β-dihydrocarbostyril in 3 ml of dimethyl- (ormamide) is added dropwise and stirred at room temperature for 30 minutes Further stirring is performed at 50-60 ° C for 1 hour. After completion of the reaction, the reaction mixture is poured into a sufficient amount of an aqueous solution of sodium chloride and then extracted with chloroform, the extra chloroform is washed with water and dried, and the solvent is removed by distillation. Recrystallized residue from this to obtain nolhloroforma - (3,4-dimethoxybenzoyl) -1-piperazinyl nilkarbonil -3,4-dihydrocarbostyril, colorless crystals in the form of granules, m.p. 238-239 ,.
    Example 32. To 100 ml of ethanol was added 1.8 g of ethyl 3,4-dimethoxy benzoic acid, 0.5 g of sodium ethylate and 2.4 g of 6- (1-piperazinylcarbonyl-3,4-dihydrocarbostyril. Reaction wire t in an autoclave at a pressure of 100 atm at 140-150 ° C for 6 hours After the completion of the reaction, the reaction mixture is cooled and concentrated under reduced pressure. The resulting residue is dissolved in 200 ml of chloroform. The chloroform solution is washed in 10% aqueous carbonate solution
    -
    potassium, diluted with hydrochloric acid and water in a certain order, then dried with non-aqueous sodium sulfate. The solvent is removed by distillation, and the residue is treated with silica gel on a chromatographic column (silica gel: Wako C-200, elution solvent: chloroform - methanol ( about./about.) 20: 1). The target crystals recrystallized from ethanol and chloroform.
    Obtain 250 mg (3,4-dimetok sibenzoyl) -1-piperazinylcarbonyl-3,4-dihydrostyryl, colorless crystals in the form of granules, so pl. 238 - 23Q
    jy, 3 (.
    Example 33 1.8 g of 3,4-dimethoxybenzoic acid and 2.75 g of 6- - (1-piperazinylcarbonyl) -3,4-dihydro-styrene are added to the solvent mixture 20 ml of dioxane with 20 ml of methylene chloride. While cooling the outside of the reaction vessel with ice and with stirring, a solution of 2.1 g of dihydrogen is added dropwise to the reaction mixture.

    5 o.
    B
    0 5
    Q
    five
    cyclohexylcarbodiimide dissolved in 5 ml of methylene, maintaining its temperature at 10–20 ° C and stirred at this temperature for
    3.5h The crystals formed in the reaction mixture are removed by filtration. The mother liquor is concentrated under reduced pressure. The resulting residue is dissolved in 100 ml of methylene chloride. The organic layer is washed with a 5% aqueous solution of hydrochloric acid and with water in a certain order. The organic layer is then dried with non-aqueous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained is recrystallized from chloroform ethanol.
    0.9 g are obtained (3, A-dimethoksibenzoyl-1-piperazinylcarbonyl-3,4-dihydrocarbostyril, colorless crystals in the form of granules, mp 238-239 ,.
    Example 34. 480 mg of 6-G4- (2- -phenoxyethyl) -1-piperazinylcarboyl-3,4-dihydrocarbostyril and 70 mg of 50% sodium hydride in oil are mixed with 5 mg of dimethylformamide and stirred at room temperature for 1 The solution of 0.17 MP of benzyl chloride in 3 ml of dimethylformamide is then slowly added dropwise to this mixture and stirred at room temperature for 4 hours. The reaction mixture is poured into a sufficient amount of water. Organic matter - extracted with chloroform. The chloroform layer is washed with water, dried and removed by distillation. The resulting residue is converted to the hydrochloride by addition of concentrated hydrochloric acid.
    Recrystallization from aqueous methanol gives 150 mg of 1-benzyl-6-4- - (2-phenoxyethyl) -1-piperazionylcarbo-, 4-dihydrocarbostyryl monohydrate, colorless powdery crystals, m.p. 261-264 S.
    Example 35. 26.4 g of 6- (4-benzyl-1-piperazinyl) carbonyl -carbostyryl are suspended in 800 ml of an ethanol-water solvent mixture, the pH is adjusted to 1 by addition of concentrated hydrochloric acid. are
    2.6g 5% palladium-carbon. The catalytic reduction is carried out at normal pressure and at 45-65 ° C. After completion of the reaction, the catalyst is removed by filtration. Solvent ud
    251
    distillate under reduced pressure. The residue obtained is crystallized by the addition of acetone. The resulting crystals are recrystallized from aqueous ethanol.
    Obtain 19.9 g of 6- (l-pipepazinil-carbonyl) -carbonyl my hydrochloride, colorless crystals in the form of granules, so pl. about 300 ° C.
    Example 36, Analogously to Examples 6, 24, 26-28, the following compounds were prepared:
    (3,4,5-Trimethoxyphenoxy) ethyl -1-piperazinylcarbonyl 1-3,4-dihydrocarboxystyryl monohydrochloride 1/2-hydrate, colorless powder, m.p. 238.5-240 ° C.
    (2-Chloropropyl) -1-piperazinyl-carbonyl} -3,4-dihydrocarbostyryl monohydrochloride, colorless powdery crystals, m.p. 238-239 C (decomp.).
    6- (4-Ethoxycarbonylmethyl-1-pipa
    razinylcarbonyl) -3,4-dihydrocarboxy-25 sodium bicarbonate and extracted
    reel monohydrochloride, colorless powdery crystals, so pl. 232-23 ° C (decomp.).
    (2-Ethoxycarbonylethyl) -1 piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride, colorless powdery crystals, m.p. 227-229.5 C (decomp.).
    6- (4-Propyl-1-piperazinylcarbonyl)
    -3,4-dihydrocarbostyryl monohydrochloride into hydrochloride by the addition of concentrated hydrochloric acid.
    Recrystallization from aqueous acetone yields 0.22 g of (2-acetoxypropyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate, colorless flaky crystals, m.p. 259-262 C.
    6- (4-Isopentyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl monohydrochloride, colorless flaky crystals, m.p. higher
    8- (4-Benzyl-1-piperazinylcarbonyl -carbostyryl monohydrochloride 3/2-hydrate, colorless powdery crystals, mp 177-180 ° C.
    5- (4-Benzyl-1-piperazinylcarbonyl -carbostyryl) monohydrochloride monohydrate, colorless granular crystals, m.p. 204-207 S.
    Example 37. 1.2 g of acetic anhydride 0.6 g of formic acid is stirred at 60 ° C for 2 hours, then 1.0 g of 6- (1-piperazinylcarbonyl) -carbostyryl is added. The mixture is stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture is poured into water and neutralized with 1 aqueous sodium hydroxide solution, 40%
    Reed, so pl. 239-241 C (decomp.).
    50
    Example 39 3.76 g of 6- (4-acetylmethyl) - -piperazinylcarbonyl) -3,4- 45 -dihydrocarbostyryl monohydrochloride. dissolved in 50 ml of methanol. Under ice cooling, 0.44 g of boron hydrogen boron (NaBH) was slowly added, stirred at room temperature for 1 hour. After completion of the reaction, concentrated hydrochloric acid is added to bring the pH of the reaction mixture to 1. Then most of the solvent is removed by distillation under reduced pressure. The residue is extracted with 1N. NaOH-chloroform. The organic layer is washed with water and dried with non-aqueous sodium sulfate. The residue is distilled off. Semi55
    42626
    It is extracted with chloroform. The organic layer is washed with water, neutralized with an aqueous solution of sodium chloride, dried with non-aqueous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The resulting residue is crystallized by adding ether and the desired crystals.
    Recrystallization from ethanol yields 0.15 g of 6- (4-FORMIL-1-piperazinylcarbonyl) -3,4-di hydrocarbostyryl, colorless powdery crystals, m.p. I98-20l c.
    Example 38: 0.5 g of 6-C4- (2-α-oxypropyl) -1-piperazinylcarbonyl-3,4-dihydrocarbosterine and 0.3 ml of triethylamine are dissolved in 10 ml of chloromethane, and the mixture is stirred at room temperature. 0.15 g of acetyl chloride is slowly added to the mixture and stirred at room temperature for 1 hour. The reaction mixture is poured into a saturated aqueous solution.
    chloroform. The organic layer is washed with water and neutralized with an aqueous solution of sodium chloride, then dried with non-aqueous sodium sulfate. The solvent is removed by distillation under reduced pressure. The resulting residue is treated with silica gel on a chromatographic column. The product is then dissolved in methanol, and 0.22 g of (2-a-acetylpropyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydride is obtained in a recrystallization from a water-tone by converting from water.
    40
    Reed, so pl. 239-241 C (decomp.).
    50
    Example 39 3.76 g of 6- (4-acetylmethyl) - -piperazinylcarbonyl) -3,4- 45 -dihydrocarbostyryl monohydrochloride. dissolved in 50 ml of methanol. Under ice cooling, 0.44 g of boron hydrogen boron (NaBH) was slowly added, stirred at room temperature for 1 hour. After completion of the reaction, concentrated hydrochloric acid is added to bring the pH of the reaction mixture to 1. Then most of the solvent is removed by distillation under reduced pressure. The residue is extracted with 1N. NaOH-chloroform. The organic layer is washed with water and dried with non-aqueous sodium sulfate. The residue is distilled off. Semi55
    271
    The residue is processed on a chromatographic column.
    Recrystallization from ethanol yields 2.26 g of (hydroxypropyl) -1-pipa razinylcarbonyl-3,4-dihydrocarbosty pkpa colorless flaky crystals, m.p. 156-157 ,.
    Example 40. Analogously to Examples 6, 22-24, 26-33, the following compounds were prepared:
    (A-Methoxyphenyl) acetyl-1-piperazinylcarbonyl-3,4-dihydrocarbostyryl, colorless powdery crystals, m.p. 158-160 ° C.
    Example 41. Analogously to Examples 23, 24, 26-28 and 35, the following compounds were prepared.
    5- (1-Piperazinylcarbonyl) -carbost (reel monochloride 1/2-hydrate, granuloid-colored crystals are colorless, mp above.
    7- (1-Piperazinylcarbonyl) -3,4-di-hydrocarbyl styryl monohydrochloride, colorless granular crystals, mp. 261.5-263 ° C.
    B- (I-Piperazinylcarbonyl) -carbostyryl, colorless granular cree; steel, m.p. above 300 ° C.
    The following compounds were used in the experiments:
    1.6- {1-Piperazinecarbenyl) -3,4- -dihydrocarbostyryl
    2. (2-phenoxyethyl) -1-piperazinylcarbonyl-3,4-dihydrocarboxyryl
    3.6- 4- (2-11 Dioethyl) -1-Piperazinylcarbonyl-3, 4-dihydrocarbostyryl monohydrochloride.
    4.6- (4-Methyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl.
    5. (3,4-Dimethoxybenzoyl) -1-piperazinylcarbonylJ-3,4-dihydrobrostyryl.
    6.6-4- (4-cyanobenzoyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl.
    7.6- 4- (4-Methoxybenoyl) -1-pipa razinylcarbonyl-3,4-dihydrocarbostyryl.
    8. (3-Chlorobenzoyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl.
    9. (3,4-Dichlorobenzoyl) -1-pipera Zinylcarbonyl-3, A-dihydrocarbo styryl
    10. (4-Nitrobenzoyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl
    628
    11. (4-Methylbenzoyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl.
    12.6- (4-Ethoxycarbonyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl.
    13.6- (4-Furoyl-1-piperazinylcarbonyl) -3,4-d-ihydrocarboxyryl.
    14. 6- (4-Benzyl-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl monohydrochloride.
    15. (4-Methylbenzyl) -1-Piperazinylcarbonyl-3, 4-dihydrocarbostyryl.
    16.6-4- (4-Methoxybenzyl) -1-Piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride.
    17.6-G4- (4-Chlorobenzyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride.
    18. (3,4-Dimethoxybenzyl) -1- piperazinylcarbonyl -3,4-dihydrocarbostyryl monohydrochloride.
    19. (4-Nitrobenzyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride.
    20. 6-N-Methyl-H- (4-methoxybenzyl carbamoyl-3,4-dihydrocarbostyryl.
    21. 6-N-Methyl-N- (3,4-methylenedi-. -Oxybenzyl) carbamoyl-3,4-dihydrocarbostyryl.
    22.6-N-Methyl-N- (4-chlorobensyl) carbamoyl} -3,4-dihydrocarbostyryl.
    23. Amrinone-3-amino-5- (4-pyridinyl- (2) -H) pyridinone.
    24.6- 4- (2-Lenoxyethyl) - -piperazinylcarNonyl-carbostyryl monohydrochloride.
    25. (3-Phenylpropyl) -1-piperazinylcarbonyl -carbostyryl monohydrochloride.
    26 (2-Beisoylethyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl
    27. Dobutamine-3,4-dioxy-N- 3- (4-hydroxyphenyl) -l-methyl propyl-α-phenyl-ethylamine.
    28. (4-Chlorobenzyl) -1-Piperazinylcarbonyl -carbostyryl monohydrochloride
    29. (3-Benzoylpropyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl Monohydrochloride 1/2-hydrate.
    30. (4-hydroxybenzoyl) methyl-1-β-piperazinylcarbonyl-3,4-dihydrocarbostyryl myhydrochloride 1/2-hydrate.
    31. 6-4-Propyl-1-piperazinylcarbonyl-3,4-dihydrocarbostyryl.
    291
    32. (3-Chlorobenzoyl) -methyl-1- -piperachinylcarbonyl-3,4-dihydrobrostyryl monohydrochloride 1/2-hydrate.
    33.6- (D-Isopentyl-f-piperazinylcarbonyl) -3, D-digdrocarbostyril.
    34.6-4- (4-Methylthiobenzyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride.
    35. (3,4,5-Trimethoxybenzyl) -1-piperizinylcarbonylJ-3,4-dihydroburostyryl monohydrochloride.
    36. (4-Aminobenzyl) -1-pipera zinylcarbonyl-3,4-dihydrocarboxyryl.
    37.6-4- (4-Aethylaminobenznl) -1- piperazinylcarbonyl1-3,4-dihydrocar bostyril monohydrochloride 3/2 hydrate.
    38.6- (4-Isobutyl-1-piperazinylcarbonyl) carbostyryl monohydrochloride
    1/2-hydrate.
    39.6-4- (4-Methylbenzoylmethyl) -1- piperazinylcarbonyl) -3,4-dihydrocar bostyril monohydrochloride.
    40. 6- (4-Cyclohexylmethyl-1-piperazinyl carbonyl) -3, 4-dihydrocarbyl ryl monohydrochloride.
    41. 6- (4-Isobutyl-1-piperazinyl-carbonyl) -3,4-dihydrocarbostyril monohydrochloride.
    42.6- (4-Propargyl-1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride.
    43. (4-Methoxybenzoyl) methyl -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride.
    44.6- (4-c-Hexyl-1-piperazinyl-carbonyl) -3,4-dihydrocarbostyryl monohydrochloride
    45.1-Methyl-6- (4-Benzyl-1-piperazinylcarbonyl) -3, 4-dihydrocarbostyryl.
    46.6- (4-Allyl-1-piperazinylcarbyl-nyl) -3,4-dihydrocarbostyryl monohydrochloride.
    47.1-Propargyl-6- 4- 2- 1) enoxy-ethyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride.
    48.1-Benzyl-6- 4- (2-Phenoxyethyl) -1-piperazinylcarbonylJ-3,4-dihydrocarbostyryl monohydrochloride.
    49.1-Allyl-6- 4- (2-phenoxyethyl) -1-piperazinylcarbonyl J-3,4-dihydrobrostyryl monohydrochloride.
    50. (2-Oksiztil) -1-piperazinylcarbonyl-3, 4-dihydrocarbostyryl dihydrate.
    630
    51.6- (1-Pileridylcarbonyl) -3,4- -dihydrocarbostyryl.
    52.6- (4-Methyl-1-piperidylcarbonyl) -3,4-dihydrocarbostyryl.
    53.6- (4-Benzyl-1-piperidylcarbonyl) -3,4-dihydrocarbostyryl 1/2 hydrate.
    54.6- (1-Pyprodylcabbonyl) -3,4-dihydrocarboxylic.
    55. (2-Chlorophenoxy) propyl -1-piperazinylcarbonyl-3, 4-dihydrobyroxyryl monohydrochloride.
    56.6-f4- {2- (4-MethoxyLenoxy) ethyl J-1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride.
    57. 6- 4- 2- (3,4-MethylenedioxyAenoxy) ethyl -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride monohydrate.
    58. 6-4 - () - Benzoylpentyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride monohydrate.
    59.6- 4- 3- (3,4-Dimethoxybenzoyl) propyl -1-piperazinylcarbonyl -3,4- -dihydrocarbostyryl monohydrochloride
    1/2-hydrate.
    60. (3-Chlorocinnamoyl) piperazinyl carbonyl-3, 4-dihydrocarbostyryl monohydrochloride monohydrate.
    61. (3,4,5-Trimethoxycin-mooyl) -1-piperazinylcarbonyl-3,4-dihydrocarbostyryl.
    62. (2-A-methyl-propyl) -l- -piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride 1/2-hydrate.
    63.5- (4-Isobutyl-1-piperaeinyl-carbonyl) -carbostyryl monohydrochloride 1/2-hydrate.
    64.7- (4-Benzyl-1-piperazinylcarbonyl) -3, 4-dicarbocarbostyryl monohydrochloride.
    65. (3-Phenylpropyl) -1-piperainylcarbonyl-3, 4-dihydrocarbenyl monohydrochloride.
    66.6- (4-Ethoxycarbonylethyl-1-piperazinylcarbonyl) -3, 4-dihydrocarbostyryl monohydrochloride.
    67. (2-Ethoxycarbonylethyl) -1-piperazinylcarbonyl-3,4-dihydrocarostil.
    68. (2-Chloropropyl-1-piperazinylcarbonyl) -3, 4-dihydrocarbostyryl onohydrochloride.
    69.6- (4-Methanesulfonyl-1-piperazinyl carbonyl) -3, 4-dihydrocarbosten.
    .311
    70 6- (4-F (-1rm11l-1-piperazinylcarbonyl) -3,4-dihydrocarbostyryl.
    71.6- {4-f2- (4-Lpetnlam 1iobenzoyl) ethyl -1-pi11era5INylcarbonyl 1-3, 4- -dihydrocarbos.
    72. (4-Methoxyfsnyl) -aietyl--1-piperazinylcarbonylJ-3,4-dihydroburostyryl.
    Pharmacological test 1, Adult mongrel dogs of either sex, weighing 8–13 kg, anesthetized with sodium pentobarbital by intravenous administration of 30 mg / kg. After another intravenous administration of sodium heparin in the amount of 1000 and / kg, the experimental dog was killed by bleeding. The dog's heart was cut off and immediately immersed in Locke's solution, then the right coronary artery was withdrawn with the help of cannulas into the arteries of the Kisa node (atrionector artery) and the right atrium was carefully separated. Then adult uncultured donors of both sexes weighing 18-27 were anesthetized with sodium. pentobarbital in the amount of 30 mg / kg by intravenous administration, and then treated with intravenous administration of sodium heparin in the amount of 1000 and / kg. The separated right atrium was supplied with blood due to blood withdrawn from the carotid (carotid) artery of the donor dog using a Peristaric pump. Blood pressure was continuously maintained at 100 mm Hg. The movement of the right atrium was measured using a force displacement transducer (transducer) at a static voltage of 2 g. The amount of blood flowing into the coronary arteries was measured using an electromagnetic flow meter. All data was recorded on an ink recorder. A solution containing the test compound was introduced into the artery through a rubber tube tightly connected to the cannula in an amount of 10-30 μl.
    The positive inotropic effect of the compound being tested is expressed as the percentage of voltage developed before and after the injection of the compound. The effect of the compound on the blood flow to the coronary artery is expressed in terms of the absolute value measured starting from the moment before the injection of the compound.
    The results are shown in Table. one.
    g 5 0 5 o Q
    g
    Q 5
    five
    2632
    Pharmacological test 2.
    Unbred dogs of both sexes, weight pshh 9-15 kg, were anesthetized with sodium pentobarbital, first at a dose of 30 mg / kg intravenously and then at a rate of 4 mg / kg h intravenously, using an infusion pump. The animals were allowed to breathe room air at a total volume of 20 ml / kg at a speed of 18 beats per minute using a respirator.
    The chest, opened, cut in the middle line, the heart was suspended in the pericardial bag.
    The force of myocardial contraction was measured using a strain gauge arch sewn to the left ventricle. Somatic blood pressure was measured on the left femoral artery using a pressure transducer (transducer). All records were made in a diagram using a linear recorder.
    The test compound was injected into the left femoral vein.
    The inotropic effects of the compounds are expressed as a percentage of the developed stress (tension) before the injection of soy / 1inu. The effect of a compound on blood pressure is expressed as the difference between the values before and after the injection of the compound.
    The results are shown in Table. 2
    Pharmacological test 3.
    Adult unbreeding dogs of both sexes weighing 18–13 kg were anesthetized with sodium pentobarbital in the amount of 30 mg / kg by intravenous administration. After another intravenous administration of sodium heparin at a dose of 1000 and / kg, the experimental dog was killed by bleeding. The dog's heart was cut off, a preparation was prepared consisting mainly of the anterior capillary muscle, cut off together with the ventricular septum, and placed in a cold Tyrode solution. The preparation was placed in a glass case with water and maintained at a temperature of about 38 ° C. Through the cannulated artery of the anterior septum, transverse blood circulation from the donor dog was performed at a constant pressure of 100 mm Hg. Donor dogs, pshh weight 18-27 kg, were anesthetized with sodium pentobarbital at a dose of 30 mg / kg intravenous
    3313
    administration, and then treated with intravenous administration of sodium heparin at a dose of 1000 and / kg. The papillary muscle was set in motion by rectangular pulses approximately 1.5 times with a voltage threshold of 0.5–3 V and a duration of 5 s with an atomic speed of 120 beats per minute using bipolar electrodes located at a pitch distance. The voltage developed by the papillary muscle was measured using a strain gauge. The muscle was loaded with a weight of about 1.5 g. The blood flow through the artery of the anterior septum was measured using an electromagnetic flow meter. The recording of the developed voltage and blood flow was recorded on a diagram with the help of a linear ink recorder.
    0
    1D

    five
    0
    26i
    The test compound was injected with p} | uterarially in the amount of 10-30 μl via s.
    The inotropic effects of a compound are expressed as the percentage of stress developed by the injection of a compound. The effect of the compound on the blood duct is expressed as the difference in magnitude before and after the injection of the compound.
    The results are shown in Table. 3
    Acute toxicity tests.
    Test compounds were orally administered to male rats to determine acute toxicity. Tests have shown that the LD of all compounds tested is above 3000 mg / kg.
    Thus, the compounds obtained by the inventive method increase the contractility of the heart, while they are slightly toxic.
    Table 1
    2A 25
    1 U mol. 1 U mol.
    table 2
    Table 3
    93.9 100
    6.5 5.5
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING PRODUCTION-
    CARBOSTERILES OF THE GENERAL FORMULA
    Hi where is hydrogen, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl lower alkyl group;
    Pj and Rj are the same or different and each is a lower alkyl group which may have an oxy group or a halogen atom as a substituent, or a phenyl lower alkyl group which may have 1 to 3 substituents selected from the 'group containing a lower alkoxy group or a halogen atom on the phenyl ring, or a phenyl lower alkyl group may have a lower alkylenedioxy group on the phenyl ring as a substituent; Rj and R 3 can form, together with the adjacent nitrogen atom and with or without additional oxygen or a nitrogen atom, a 5- or 6-membered saturated heterocyclic ring, which may have a lower alkyl group or a phenyl lower alkyl group as a substituent when the heterocyclic ring is a piperazinyl group, the piperazinyl ring may have a lower alkyl group or a phenyl lower alkyl group as a substituent in the 4th position of the piperazinyl ring, the piperazinyl group may have a lower substituent in the 4th position alkenyl group, lower alkynyl group, cycloalkyl group, cycloalkyl lower alkyl group, lower alkonoyl group, lower alkonoyl lower alkyl group, lower alkoxy-
    1331426 AZ carbonyl group, lower alkoxycarbonyl lower alkyl group, furoyl group, lower alkyl sulfonoyl group, substituted lower alkyl group having one substituent selected from the group consisting of cyano group, benzoyloxy group, which may have from 1 to 3 lower alkoxyalkano, alkoxy group and a carbomoyl group, a phenoxy lower alkyl group which may have from 1 to 3 substituents on the phenyl ring selected from the group consisting of a halogen atom, a lower α-alkoxy group, a lower an alkyl group or phenoxy lower alkyl group may have a lower alkylene dioxy group on the phenyl ring as a substituent, a phenyl lower alkyl group which may have from 1 to 3 substituents on the phenyl ring selected from the group consisting of lower alkyl group, lower alkoxy group, halogen atom, nitro , an amino group, a lower alkonoylamino group and a lower alkylthio group, or a phenyl lower alkyl group may have a lower alkylenedioxy group as a substituent on the phenyl ring, a benzoyl group which may have phenyl on the ring, from 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group, a lower alkonoylamino group and a lower alkylthio group, or a phenyl lower alkyl group may have lower alkylenedioxy on the phenyl ring a substituent, a benzoyl group which may have from 1 to 3 substituents on the phenyl ring selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group and a cyano group, or a benzoyl group have a lower alkylenedioxy group on the phenyl ring as a substituent, a phenylsulfonoyl group which may have 1 to 3 alkyl groups on the phenyl ring, a benzoyl lower alkyl group which may have 1 to 3 substituents on the phenyl ring selected from the group consisting of halogen atom, oxy group, lower alkyl group, lower alkoxy group and lower alkonoylamino group, phenyl lower alkenylcarbonyl group, which may have from 1 to 3 substituents on the phenyl ring selected from the group containing atom halogen, and a lower alkoxy group, or a phenyl lower alkonoyl group, which may have from 1 to 3 lower alkoxy groups on the phenyl ring as substituents, the carbon-carbon bond between the 3rd and 4th positions in the carbostyril structure being a single or double bond, arising from the fact that
    A is OH where A is a group of the general formula then B is a group of the general formula where R 1 is the carbon-carbon bond between the 3rd and 4th positions in the structure of carbostyril with the indicated values;
    R, is an alkonoyl group, a lower alkoxycarbonyl group, a furoyl group, a benzoyl group which may have from I to 3 substituents selected from the group containing a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group and a cyano group, or may have a benzoyl group an alkylenedioxy group as a substituent, a phenyl lower alkanoyl group which may have I to 3 lower alkoxy groups on the phenyl ring as substituents or a phenyl lower alkenylcarbonyl group which may have on the phenyl ring, from 1 to 3 substituents selected from the group consisting of a halogen atom and a lower alkoxy group are reacted with a compound of the general formula
    H - B, where B is a group of the general formula * 1 where Rp Rj, R, is the carbon-carbon bond between the 3rd and 4th positions in the carbostyril structure with the indicated values, provided that when A is a group of the general formula where is R ^, R and R 3 have the indicated meanings when the formulas
    A - then B is a group common where R ^ and R 4 have the indicated meanings. Priority by feature;
    02/17/81, 04/15/81 at R ^ and R 3 are the same or different and represent each lower alkyl group or lower phenylalkyl group, which may contain from 1 to 3 substituents belonging to the group consisting of a lower alkoxy group and a halogen atom in the phenyl ring, or a lower phenylalkyl group, which may contain a lower alkylenedioxy group as a substituent on the phenyl ring, Rj, and together with the adjacent carbon atom to which they are bonded, form a 5 or 6 membered saturated heterocycle through or without oxygen I or via a nitrogen atom, or without his participation, wherein said heterocycle may be substituted by a lower alkyl group.
    08/12/81 when Rj and R 3 are the same or different and represent each lower alkyl group, which may contain hydroxy groups as substituents or halogen atoms, U and Ro, can form together with the nitrogen atom adjacent to and to which they are attached, A 5- or 6-membered saturated heterocycle with or without an oxygen atom or a nitrogen atom, said heterocycle being optionally substituted with a lower phenylalkyl group; in the case where said heterocycle is a piperazinyl group, said piperazinyl group may contain a cycloalkyl group, a lower alkonoyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkyl group containing substituents belonging to the group ben1331426 of the zoyloxy group, which may contain from 1 to 3 lower alkoxy groups, a hydroxyl group, a lower alkonyloxy group and a halogen atom in the phenyl ring, a substituted phenoxine a higher alkyl group, a substituted or unsubstituted phenyl lower apkenylcarbonyl group, a substituted or unsubstituted phenyl lower alkanoyl group,
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1331426A3|1987-08-15|Method of production of carbostyryl derivatives
    US4531964A|1985-07-30|Heterocyclic compound and a herbicidal composition containing said compound
    EP0175363B1|1990-01-17|4,5-dihydro-3|-pyridazinones, process for their preparation and their use
    FI66372C|1984-10-10|FRAMEWORK FOR THE PHARMACOLOGICAL PROCESSING OF THE PHARMACOLOGICAL NETWORK I 5-ELLER 6-STATIONARY MEDIUM PYRIDAZINONRING SUBSTITUERADE BESIMIDAZOLER
    DE69532039T2|2004-07-08|isoxazoles
    US4760064A|1988-07-26|Carbostyril compounds, compositions containing same and processes for preparing same
    US4564619A|1986-01-14|Carbostyril derivative
    WO2006122800A1|2006-11-23|Substituted benzo|isoxazol-3-yl amine compounds as analgesics
    SU1584750A3|1990-08-07|Method of producing derivatives of 3|-pyridazinone
    HU190408B|1986-09-29|Process for producing pharmaceutical preparations comprising new benzimidazole-derivatives
    DE2825048A1|1978-12-14|NEW CARBOSTYRIL DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION
    EP0327800B1|1992-05-27|6-phenyldihydro-3|-pyridazinones, process for their preparation and medicines containing these compounds
    CH651300A5|1985-09-13|HETEROCYCLICALLY SUBSTITUTED AMINOPROPENNITRILE.
    DE102004021779A1|2005-11-24|New beta-agonists, process for their preparation and their use as medicines
    EP0089028B1|1988-05-25|Theophyllin derivatives, and process for their preparation
    DE3230209C2|1985-08-22|Carbostyril derivatives, processes for their preparation and cardiotonic agents containing them
    SU1241987A3|1986-06-30|Method of producing piperidinopropyl derivatives or their pharmaceutically compatible halides
    US4593035A|1986-06-03|Carbostyril derivatives
    RU2081872C1|1997-06-20|Dihydropyridine derivatives, mixture of their isomers, individual isomers or their physiologically tolerantable salts, methods of their synthesis, intermediate compounds and method of their synthesis
    US5340811A|1994-08-23|Isoquinoline-or quinoline-sulfonamide derivative and a pharmaceutical composition comprising the same
    DE3424586A1|1986-01-09|3-AMINOCARBONYLMETHOXY-5-PHENYL-PYRAZOLE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
    SE455701B|1988-08-01|SULFUROUS ISOQINOLINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
    DE3734083A1|1989-04-20|BENZIMIDAZOLES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
    AU644605B2|1993-12-16|Pyridone nitriles useful in treating cardiovascular disease
    US4806560A|1989-02-21|Imidazo[4,5-b]pyridin-2-one derivatives
    同族专利:
    公开号 | 公开日
    IT1157002B|1987-02-11|
    PH18085A|1985-03-20|
    FI77852B|1989-01-31|
    ES8305334A1|1983-04-01|
    SE445348B|1986-06-16|
    KR860001337B1|1986-09-15|
    NL8200593A|1982-09-16|
    FR2512818B1|1985-06-21|
    MX156153A|1988-07-19|
    DK152287B|1988-02-15|
    US4468402A|1984-08-28|
    PT74440A|1982-03-01|
    ATA59582A|1987-12-15|
    DK152287C|1988-07-11|
    NO159446B|1988-09-19|
    ES8401959A1|1984-01-01|
    ES518303A0|1984-01-01|
    DE3204892A1|1982-09-23|
    US4487772A|1984-12-11|
    CH651827A5|1985-10-15|
    BE892148A|1982-08-16|
    FI77852C|1989-05-10|
    CA1199915A|1986-01-28|
    SE8200916L|1982-08-18|
    NO820479L|1982-08-18|
    FI820338L|1982-08-18|
    PT74440B|1983-08-24|
    AT386198B|1988-07-11|
    AU8052882A|1982-11-11|
    KR830009036A|1983-12-17|
    ES509693A0|1983-04-01|
    NO159446C|1988-12-28|
    DE3204892C2|1988-03-24|
    IT8267177D0|1982-02-17|
    FR2512818A1|1983-03-18|
    DK66582A|1982-08-18|
    AU530264B2|1983-07-07|
    GB2094789B|1985-01-23|
    GB2094789A|1982-09-22|
    US4454130A|1984-06-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2997474A|1959-10-12|1961-08-22|Paul A J Janssen|1-aryl-omega- alkanols|
    US3555030A|1964-11-25|1971-01-12|Smith Kline French Lab|Muscle relaxant and analgesic compositions|
    US4115569A|1971-11-19|1978-09-19|Hoechst Aktiengesellschaft|Cyclic diamine derivatives|
    US4256890A|1972-09-14|1981-03-17|Otsukapharmaceutical Co., Ltd.|3,4-Dihydrocarbostyril derivatives and process for producing the same|
    IT998326B|1973-08-06|1976-01-20|Montedison Spa|DERIVATIVES OF QUINOLIN 8 CARBOXYL ACIDS WITH ANTI-PARAS SITARY ACTIVITY|
    US4022784A|1974-01-31|1977-05-10|Otsuka Pharmaceutical Company Limited|5-[1-Hydroxy-2-]alkyl-8-substituted-carbostyril and -3,4-dihydrocarbostyril derivatives|
    US4026897A|1974-01-31|1977-05-31|Otsuka Pharmaceutical Company|5-[1-Hydroxy-2-]alkyl-8-hydroxycarbostyril derivatives|
    US4145542A|1974-06-13|1979-03-20|Otsuka Pharmaceutical Co., Ltd.|5- 1-Hydroxy-2-!alkyl-8-hydroxy-3,4-dihydrocarbostyril derivatives|
    FI59246C|1974-06-24|1981-07-10|Otsuka Pharma Co Ltd|FOERFARANDE FOER FRAMSTAELLNING AV BENSCYKLOAMIDDERIVAT ANVAENDBARA VID TROMBOS- OCH EMBOLITERAPIN|
    JPS5328430B2|1975-04-09|1978-08-15|
    US3994900A|1976-01-23|1976-11-30|E. R. Squibb & Sons, Inc.|6--[[alkyl]oxy]-3,4-dihydro-4-phenyl-2-quinolinones|
    US4210753A|1976-03-17|1980-07-01|Otsuka Pharmaceutical Co., Ltd.|Carbostyril compounds|
    GB1589871A|1976-07-19|1981-05-20|Conder Group Serv Ltd|Tank construction|
    JPS609713B2|1976-10-08|1985-03-12|Otsuka Pharma Co Ltd|
    NZ187452A|1977-06-10|1980-05-27|Otsuka Pharma Co Ltd|N- substituted-aminocarbonylpropoxy-carbostyrils and their preparation|
    JPS5760337B2|1977-07-08|1982-12-18|Otsuka Pharma Co Ltd|
    DE2928583A1|1979-07-14|1981-01-29|Thomae Gmbh Dr K|Substd. alkoxy-carbostyril derivs prodn. - e.g. by cyclising 2-carboxyethyl-1-aminobenzene derivs., useful as antithrombotic and positive inotropic agents|
    PH17194A|1980-03-06|1984-06-19|Otsuka Pharma Co Ltd|Novel carbostyril derivatives,and pharmaceutical composition containing the same|
    FI77852C|1981-02-17|1989-05-10|Otsuka Pharma Co Ltd|Process for the preparation of novel, such as cardiac drugs, useful s unsubstituted amide and carbonyl carbostyril derivatives.|PH17194A|1980-03-06|1984-06-19|Otsuka Pharma Co Ltd|Novel carbostyril derivatives,and pharmaceutical composition containing the same|
    FI77852C|1981-02-17|1989-05-10|Otsuka Pharma Co Ltd|Process for the preparation of novel, such as cardiac drugs, useful s unsubstituted amide andcarbonyl carbostyril derivatives.|
    AU532361B2|1981-09-01|1983-09-29|Otsuka Pharmaceutical Co., Ltd.|Carbostyril derivatives|
    FI80022C|1982-07-05|1990-04-10|Otsuka Pharma Co Ltd|FOERFARANDE FOER FRAMSTAELLNING AV ETT NYTT, TERAPEUTISKT ANVAENDBART KARBOSTYRILDERIVAT.|
    US4845100A|1985-04-12|1989-07-04|Otsuka Pharmaceutical Co., Ltd.|Carbostyril derivatives and salts thereof, processes for preparing the same and cardiotonic composition containing the same|
    US4792561A|1986-05-29|1988-12-20|SyntexInc.|Carbostyril derivatives as combined thromboxane synthetase and cyclic-AMP phosphodiesterase inhibitors|
    US4921862A|1986-05-29|1990-05-01|SyntexInc.|Carbostyril derivatives as combined thromboxane synthetase and cyclic-amp phosphodiesterase inhibitors|
    DK397387A|1986-07-31|1988-02-01|Otsuka Pharma Co Ltd|CARBOSTYRIC DERIVATIVES AND SALTS THEREOF, AND PROCEDURE FOR THE PREPARATION OF SUCH COMPOUNDS|
    GB8709448D0|1987-04-21|1987-05-28|Pfizer Ltd|Heterobicyclic quinoline derivatives|
    US5227381A|1988-05-02|1993-07-13|Otsuka Pharmaceutical Co., Ltd.|Carbostyril derivative|
    DE3818830A1|1988-06-03|1989-12-14|Boehringer Mannheim Gmbh|BICYCLIC CARBOXAMIDS, METHOD FOR THE PRODUCTION THEREOF, AND THE MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    JP2686887B2|1992-08-11|1997-12-08|キッセイ薬品工業株式会社|Piperidino-3,4-dihydrocarbostyril derivative|
    JPH06239858A|1993-02-16|1994-08-30|Otsuka Pharmaceut Co Ltd|Peripheral vasodilator|
    CN1052224C|1993-04-07|2000-05-10|大塚制药株式会社|Peripheral Vasodilating agent containing N-acylated 4-amino piperidine derivatives as active ingredients|
    EP0709384B1|1994-10-31|1998-12-23|MERCK PATENT GmbH|Benzylpiperidine derivatives having high affinity for binding sites of aminoacid receptors|
    IL146309A|1999-05-21|2008-03-20|Scios Inc|INDOLE-TYPE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM AS INHIBITORS OF p38 KINASE|
    US6340685B1|1998-05-22|2002-01-22|Scios, Inc.|Compounds and methods to treat cardiac failure and other disorders|
    US6589954B1|1998-05-22|2003-07-08|Scios, Inc.|Compounds and methods to treat cardiac failure and other disorders|
    US6448257B1|1998-05-22|2002-09-10|Scios, Inc.|Compounds and methods to treat cardiac failure and other disorders|
    US6867209B1|1998-05-22|2005-03-15|Scios, Inc.|Indole-type derivatives as inhibitors of p38 kinase|
    WO2004014389A1|2002-08-13|2004-02-19|Warner-Lambert Company Llc|3,4-dihydroquinolin-2-one, 5,6-fused oxazin-3-one, and 5,6-fused thiazin-3-one derivatives as matrix metalloproteinase inhibitors|
    NZ547278A|2003-12-10|2010-01-29|Janssen Pharmaceutica Nv|Substituted 6-cyclohexylalkyl substituted 2-quinolinones and 2-quinoxalinones as PARP inhibitors for chemosensitization or radiosensitization|
    MY142362A|2004-01-29|2010-11-30|Otsuka Pharma Co Ltd|Pharmaceutical composition for promoting angiogenesis|
    EP2021340B1|2006-04-21|2014-07-23|The Government Of The United States, As Represented by The Secretary Of Health And Human Services|Beta-amyloid pet imaging agents|
    WO2010021681A2|2008-08-18|2010-02-25|CombinatorxPte. Ltd.|Compositions and methods for treatment of viral diseases|
    PT2445502T|2009-06-25|2017-09-22|Alkermes Pharma Ireland Ltd|Heterocyclic compounds for the treatment of neurological and psychological disorders|
    US8536328B2|2010-05-04|2013-09-17|Alkermes Pharma Ireland Limited|Process for synthesizing oxidized lactam compounds|
    AU2011270701B2|2010-06-24|2015-05-14|Alkermes Pharma Ireland Limited|Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives|
    CN109651285B|2019-01-30|2020-06-30|苏州大学|Synthetic method of polybrominated benzo [1,3] oxazine derivative|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP56022437A|JPS647968B2|1981-02-17|1981-02-17|
    JP56057732A|JPS649313B2|1981-04-15|1981-04-15|
    JP12714581A|JPS649315B2|1981-08-12|1981-08-12|
    [返回顶部]