• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    An azacycloalkane derivative useful for promoting the absorption of a medicine, an absorption promoting agent comprising at least one of the azacycloalkane derivatives as the effective ingredient for promoting the absorption and an external preparation containing the absorption promoting agent, the derivative being represented by the following formula <CHEM> wherein A is -CH2- or -S- for example, B is sulfur or oxygen, R is -SR'' in which R'' is an alkyl group or alkylthioalkyl group for example, or -OR'' in which R'' is as defined above, an alkyl group or substituted amino group, R' is a hydrogen atom, alkyl group or alkyloxy group for example, m is an integer of 0-5 and n is an integer of 1-15.
    公开号:SU1748644A3
    申请号:SU874203780
    申请日:1987-12-07
    公开日:1992-07-15
    发明作者:Тсудзи Масаеси；Иноуе Хисатака；Хатия Теруми；Накасима Микио；Саита Масару；Симозоно Юдзи；Накагава Акира；Сакаи Митинори
    申请人:Хисамицу Фармасьютикал, Ко, Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for producing new azacycloalkane derivatives of the general formula
    fr
    HCH2) n-S-R Ј H2) m
    where R is Ca-C12-alkyl,
    n 2-8 with m 1 or
    n 3-10 when m 3,
    which increase the permeability and permeability of drugs, has low toxicity, and can be used in medicine.
    The purpose of the invention is to develop, on the basis of a known method, a method for producing new azacycloapcane derivatives with valuable pharmacological properties.
    Example 1, 1.11 g of M-vinyl-2-pyrrolidone, 1.6 g of n-nonyl mercaptan, 8.0 mg of azo-bis-isobutyronitrile, and 20 ml of benzene are mixed together and stirred at boiling for 2-3 hours. The reaction mixture is washed with water, dried, the solvent is distilled off, and distilled in vacuo to give 2.01 g of colorless (n-nonylthio) ethyl azacyclo pentan-2-one.
    The final distillation was carried out using a rotary kiln with GTO-250R glass tubes. The temperature and pressure at which the distillation is carried out is the column temperature.
    The compound thus obtained has the following column temperature: 122-127 ° C / 0.2 mmHg.
    2
    00
    I

    with
    Calculated,%: C, 66.37; H 10.77; N 5.16
    C15H29NOS
    Found,%: C 66.43; H 10.62; N 5.20
    Example 2. 1.11 g of M-vinyl-2-pyrrolidone, 1.74 g of n-decylmercantan, 8.0 mg of azobisisobutyronitrile, and 20 ml of benzene are thoroughly mixed while heating to 80-90 ° C The resulting reaction mixture was washed with water, dried, freed from the solvent by distillation under reduced pressure, then finally distilled to give 2.39 g of colorless 1- (2-decylthio) ethyl azacyclopentan-2-one.
    The colorless compound thus obtained has the following characteristics:
    Appearance: colorless clear oil.
    The temperature of the column: 130-135 ° C / 0.2 mm Hg.
    Calculated,%: C 67.31; H 10.94; N 4.91
    Ci6H3iNOS
    Found,%: C 67.21; H 10.76; N 4.88
    EXAMPLE 3 1.25 g of 1- (2-propenyl) aza-cyclo-pentan-2-one, 1.46 g of n-octyl mercaptan, 8.0 mg of azobisisobutyronitrile and 20 ml of benzene are stirred at heating to 70 ° C for 10 hours. The reaction mixture was washed with water, dried, freed from solvent by distillation under reduced pressure, then finally distilled to obtain 1.47 g of colorless 1 - {(3-octylthio) propyl azacyclopentan-2-one.
    The colorless compound thus obtained has the following characteristics:
    Appearance: colorless clear oil.
    The temperature of the column: 122-128 ° C / 0.2 mm Hg.
    Calculated,%: C, 66.37; H 10.77; N 5.16
    C15H29NOS
    Found,%: C 66.46; H 10.81; N 5.02
    EXAMPLE 4.1- (3-Butenyl) -azacyclopentan-2-one, 1.32 g of n-heptylmercaptan, 8.0 mg of azo-bis-isobutyronitrile, and 20 ml of benzene are stirred while heating to 80-90 ° C for 3 hours. The resulting reaction mixture is washed with water, dried, freed from the solvent by distillation under reduced pressure, then finally distilled and obtain 2.30 g of colorless 1- (4-hetyl-thio) butyl azacyclopentan-2-one.
    The colorless compound obtained in this way has the following characteristics.
    Appearance: colorless clear oil.
    The temperature of the column is 125-131 ° C / 0.2 mm Hg.
    Calculated,%: C, 66.37; H 10.77; N 5.16
    C15H29NOS
    Found,%; C, 66.29; H 10.67; N 5.23 PRI mpe r 5.1.53 g 1- (4-pentenyl) azacyclopentan-2-one, 1.18 g n-hexyl mercaptan, 8.0 mg azo bis isobutyronitrile and 20 ml toluene stirred at 100 ° C for 5 hours. The reaction mixture was washed with water, dried, freed from solvent by distillation under reduced dosing, then finally distilled and 2.12 g of colorless 1- (5-hexylthio) pentyl azacyclopentane were obtained. 2-she.
    The colorless compound has the following characteristics.
    5 Appearance: colorless clear oil.
    The temperature of the column: 124-129 ° C / 0.2 mm Hg
    Calculated,%: C, 66.37; H 10.77; N 5.16 0 Ci5H2gNOS
    Found,%: C 66.35; H 10.89; N 5.00 PRI me R 6. 1.67 g of 1- (5-hexenyl) -aza-cyclopentan-2-one, 1.04 g1 of n-pentylmercaptan, 8.0 mg azo-bis- isobutyronitrile and 5 to 20 ml of xylene are mixed together while heating to 120 ° C. The resulting reaction mixture was washed with water, dried, freed from the solvent by distillation under reduced pressure, then 0 was finally distilled and 1.95 g of colorless 1 - {(6-pentylthio) hexyl azacyclopentan-2-one were obtained.
    The colorless compound has the following characteristics.
    5 Appearance: colorless clear oil.
    The temperature of the column: 126-131 ° C / 0.2 mm Hg
    Calculated,%: C, 66.37; H 10.77, N 5.16 0 C15H29NOS
    Found,%: C 66.41; H 10.72; N 5.28. EXAMPLE 7 1.53 g of 1- (2-propenyl) aza-cyclopentan-2-one, 1.74 g of n-decylm-ercaptan, 10.0 mg of benzoyl peroxide and 20 ml of 5 carbon tetrachloride are stirred under heating to 75-85 ° C for 8 hours. The resulting reaction mixture is washed with water, dried, freed from solvent by distillation under reduced pressure and then 0 is finally distilled and 3.16 g of colorless 1- (3- decylthio) propyl azacycloheptan-2-one.
    The colorless compound has the following characteristics.
    5 Appearance: colorless clear oil.
    The temperature of the column: 145-151 ° C / 0.2 mm Hg.
    Calculated% C, 69.67; H 11.38; N 4.28 Ci9H37NOS
    Found,%: C 69.84; H 11.32; N4,41
    EXAMPLE 8 1.67 g of 1- (3-butenyl) azacyclo-pentan-3-one, 1.60 g of n-nonyl mercaptan, 8.0 mg of azo-bis-isobutyronitrile and 20 ml of benzene are stirred at heating dB 80-90 ° C for 4 hours. The resulting reaction mixture is washed with water, dried, freed from solvent by distillation under reduced pressure. Then, final distillation is carried out and 2.32 g of colorless 1- (4-nonylthio) -butyl azacycloheptane are obtained. -2-she.
    The colorless compound obtained in this way has the following characteristics.
    Appearance: colorless clear oil.
    The temperature of the column: 148-152 ° C / 0.2 mm Hg
    Calculated,%; C, 69.67; H 11.38; N4.28
    C19H37NOS
    Found,%: C 69.55; H 11.36; N 4.41
    Example 9.1.81 g of 1- (4-pentenyl) azacyclopentan-2-one, 1.32 g of n-heptylmercaptan, 8.0 mg of azo-bis-isobutyronitrile and 20 ml of benzene are stirred while heating to 80-90 ° C 3 hours. The resulting reaction mixture is washed with water, dried, freed from solvent under reduced pressure, then finally distilled and 2.27 g of colorless H (5-heptylthio) pentyl azacycloheptan-2-one are obtained.
    The colorless compound obtained in this way has the following characteristics.
    Appearance: colorless clear oil.
    The temperature of the column: 144-149 ° C / 0.2 mm Hg
    Calculated,%: C 68.95; H 11, 25; N 4.47
    CieHasNOS
    Found %: C 68.81; H 11.13; N4.62
    Example 10. 1.95 g of 1- (5-hexenyl) aza-bicyclopentan-2-one, 1.18 g of n-hexyl mercaptan, 10.0 mg of benzoyl peroxide and 20 ml of carbon tetrachloride are stirred while heating to 75-85 ° C for 2 hours. The resulting reaction mixture is washed with water, dried, freed from the solvent by distillation under reduced pressure, then finally distilled to obtain 1.87 g of colorless 1- (6-hexylthio) hexyl azacycloheptai-2-one.
    The resulting colorless compound has the following characteristics.
    Appearance: colorless clear oil.
    The temperature of the column1 is 143-148 ° C / 0.2 mm Hg.
    Calculated,%: C 68.95; H 11.25; N 4.47
    CieHasNOS
    Found,%; C 69.12; H 11.30, N 4.23. PRI me R 11, 2.23 g of 1 (7-octenyl) ezaacyclopentan-2-one, 0.90 g of n-butylmercaptan, 5 8.0 mg azo- Bis isobutyronitrile and 20 ml of toluene are stirred under heating to 100 ° C for 5 hours. The resulting reaction mixture is washed with water, dried, freed from the solvent by distillation under reduced pressure, then finally distilled to obtain 1.95 g of colorless 1 - {(8 -butylthio) octyl azacycloheptan-2-one
    The resulting colorless compound has the following characteristics 15 Appearance: colorless transparent oil.
    The temperature of the column is 154-159 ° C / 0.2 mm Hg.
    Calculated,% C 68.95: H 11 25, N4.47 0 CieHasNOS
    Found,%: C 68.85, H 11.19; N4.55 The compounds of examples 12-19 were obtained analogously to example 1, the data on the column temperature of the compounds of examples 5 12-19 are presented in table. one
    The biological activity of compounds (I) was studied.
    PRI me R 20. Prepared test solution (liniment), having the following 0 composition, wt.%:
    Ketoprofen2.8
    Ethanol47.1
    Distilled water47.1
    5 Compound
    following example 23.0
    The effect of the compound of Example 2 on the subcutaneous penetration of ketoprofen was studied using hides from the back of a hairless mouse (female, 9 weeks old). using the cell diffusion method, which consists in injecting 0.5 ml of the indicated test solution to a donor, followed by determining the amount of ketoprofen that has penetrated the receptor layer (using liquid chromatography — high pressure liquid chromatography). For comparison, the described experiment was repeated, except for the fact that instead of the test solution containing the compound of Example 2, a control solution was introduced that did not contain this compound. The results are presented in table. 2
    5 As can be seen from the table. 2, the addition of the compound of Example 2 has a stimulating effect on ketoprofen penetration.
    PRI me R 21. Prepared aerosol solution of the following composition, may%
    Ketoprofen1,0
    Isopropyl myristate1, 0
    Ethanol20.0
    Fleon75,0
    Compound
    following example 23.0
    PRI me R 22. Prepared hydrophilic ointment of the following composition, wt.%: Indomethacin1,0
    White petrolatum25.0
    Stearic
    alcohol 20,0
    Propylene glycol 12,0
    НСО-604,0
    Methyl-p-hydroxybenzoate acid 0,1
    - Propyl-p-hydroxybenzoic acid
    Purified water34.8
    Compound
    following example 23.0.
    The activity of the compound of Example 2 is limited by the diffusion method of the sock pads in the same manner as in Example 20, except that the test compound is replaced by the indicated ointment being tested. The results are presented in tab, 3.
    As can be seen from table 3, the penetration of ndemethacin is facilitated by the addition of the synem of Example 2.
    PRI me R 23, Prepared gel ointment of the following composition, wt.%:
    Indomethacin1,0
    Diisopropyl acid1,1
    Ethanol 48,0
    Purified water46,9
    Compound according to Example 23.0 The activity of the compound was determined using the cell diffusion method in the same way as in Example 22, with the exception of K / G, that said ointment was taken instead of the test solution. The results are shown in Table. 4. As follows from the table. 4, the penetration of indomethacin is greatly enhanced by the addition of the compound of Example 2.
    PRI me R 24. Prepared a solution of the following composition, wt.%:
    Pindol ol4,0
    Propylene glycol46,5
    Ethanol46,5
    The compound (I),
    presented in table. 53.0
    Groups of four male Wlstar-Strain rats weighing 200-250 g each were formed, each with a skin on the back shaved with an electric razor
    Each of the tested solutions (pindolol-preparation content) was treated with a shaved skin on the back of rats of one of the group in the amount of 150 μl / 2.5 x 2.5 cm2 and then sealed this area. Three hours after treatment, experimental rats took blood to determine the concentration of pinodolol in serum using high-pressure liquid chromatography. The results are presented in table. five.
    For comparison, the experiment described was repeated, except that a control solution was used, which differed from the test solution only in that it did not contain 5 compounds (I). An experiment was also conducted using a comparative solution, which differed from the test one only in that the compound () was replaced by comparative compound 0. The results are presented in table. five.
    As can be seen from the table. 5, compound (I) in the test solution substantially contributes to the subcutaneous absorption of pindolol in comparison with the control group and also satisfactorily affects the absorption of pindolol compared to the comparative compound. In addition, there was no erythema or edema in the dorsal region of the skin treated with the test compound with 0 content of the compound of the invention.
    PRI me R 25. Prepared test solution of the following composition, May%.
    Pindolol0,4
    5Etanol 48.3
    Water48,3
    Compound
    following example 23.0
    The activity of the compound in Example 2 0 was determined using the cell diffusion method as in Example 20, except that the test solution 1 used was used instead of the solution tested in Example 20. The results are presented in Table. 6
    As can be seen from table b, the compound of example 2 has a significant effect on the penetration of pindolol compared with the control group 0 and also shows a satisfactory activity in comparison with the comparative compound,
    PRI me R 26, Prepared an acrylic tape of the following composition, g: 5 Pindolol1,2
    Nikasol TS-44437,68
    Citric acid0,6
    Compound
    following example 20.7
    1.0 mg / cm2
    The activity of this compound was determined using the cell diffusion method in the same manner as in Example 20, except that a tape of 0.785 cm2 (including 0.8 mg pindolol) was applied to the surface of the hide.
    The results are presented in table. 7.. As can be seen from the table. 7, penetration of pindolol from the test tape through the skin improved as a result of the addition of the compound of Example 2.
    PRI me R 27. Prepared control and test solutions of the appropriate composition (table. 8).
    In the experiments, several groups of rats were used, each of which contained four male Wistar-Strain rats weighing 200-250 g, which were not given food for 24 hours. Each of the control solutions A and B and the test solution were applied to shaved skin on the back of rats of one group in the amount of 175 μl / 2.5 x 2.5 cm, and then these areas were sealed. These rats were injected subcutaneously with 20% glucose. Two hours after glucose administration, the rats took blood and examined it for glucose content.
    For comparison, this experiment was repeated, except that azone was introduced into the test solution instead of the compound of Example 2.
    In addition, for comparison, the blood of the rats of the group, which was subjected only to fasting for 24 hours (normal group), was tested for blood glucose. The group of rats to which the control solution A was administered is the control group A, the control solution B is the control group B and the test solution is the test group. The results of the experiments are presented in Table. 9.
    As can be seen from the table. 9, the control group B (in which one glibenclamide was used) does not have any effect on the hypoglycemic activity compared to the control group B, while the test group (in which the compound of example 2 was used) has a significant effect on the amplification absorption of glibenclamide, as a result of which glibenclamide is absorbed subcutaneously and the level of glucose decreases. In addition, the compound of Example 2 has a strong effect on promoting absorption compared with azone used as a comparative compound,
    PRI me R 28. Prepared test emulsion of the following composition, wt.%:
    Glibenclamide1,0
    Monooleoylglycerolpylogulutamine ester47.0
    Purified water47.0
    Compound
    according to example 25.0
    PRI me R 29. Prepared a textural solution of the following composition, wt.% - 5-Fluorouracil (5-Fu) 1,8
    Ethanol47.6
    Water47,6
    Compound
    following example 23.0
    The activity of the compound was determined using the cell diffusion method in the same manner as in Example 20, except that the solution tested was replaced by the solution prepared in Example 20.
    The results are shown in Table. 10. As can be seen from the table. 10, the addition of the compound of Example 2 significantly increases the penetration of 5-Fu compared to the control, and the comparative compounds show no activity.
    PRI me R 30. Prepared a test solution of the following composition, wt.%: Phenol red0.07
    Purified water96.93
    Compound
    following example 23.0
    The effect of the compound of Example 2 on the subcutaneous penetration of phenol red, which is difficult to penetrate the skin using the skin (without hair) on the back of female mice (9 weeks old), was investigated using the cell diffusion method, which included the addition of 0.5 ml a solution of sodium chloride containing 2 mM phenol red to the donor, after which the amount of red phenol penetrated into the layer of receptors was determined using a fast-acting densitometer (559 nm). The results are presented in Table 11.
    As can be seen from the table. 11, the use of the compound of Example 2 in the test solution leads to a significant increase in the absorption of phenol red compared to the control and a satisfactory reinforcing effect is observed compared to the comparative compounds.
    For example, p31. Prepared a test solution of the following composition, wt.%: The drug from the table. 121.0
    Ethanol48.0
    Purified water 48,0
    Connection according to example 2. 3.0
    The activity of the preparation was determined according to the cell diffusion method in the same manner as in Example 20, except that instead of the test solution of Example 20, the indicated test solution was used and the amounts of various preparations penetrating the skin barrier were measured by standard methods. The results (mean values of 3-7 skin cells) are shown in Table 12.
    As can be seen from the table. 12, the use of compounds (I) leads to a significant increase in the penetration of various drugs.
    PRI me R 32. Candles were prepared and tested in the normal, control and test groups, each of which included 5 male rabbits weighing 2.5-3.5 kg,
    The composition of the candles is given in table. 13. These candles were introduced into rectum to rabbits in the amount of 0.3 g of candles / kg, respectively. Then, through the ear vein, blood was taken at certain intervals in rabbits to determine its glucose content by the glucose oxidase method. For comparison, this experiment was repeated, except that the compound of Example 2 was replaced with azone. The results are presented as changes in the level of glucose in the blood relative to the initial level prior to the administration of suppositories. 14,
    As can be seen from the table. 14,. in the control group (only insulin was administered) there was no visible effect on blood glucose levels compared to the normal group. On the other hand, in the test group (the compound of Example 2 was used), significant hypoglycemic activity in the blood was noticeable and, in addition, no wounding effect on the mucous membrane of the part of the rectum in which the candle was injected.
    PRI me R 33. Prepared candles with antibiotics and investigated their action in the control and test groups. Each group included 5 male rabbits weighing 2.5-3.5 kg each. Composition of AVRS-candles, May%: Ampicillin Na6.0
    Witepsol H-1591.0
    Compound
    following example 23.0
    The composition of the SET candles, wt.% Cefalotin Na6,0
    Witepsol N-15 91.0
    Compound
    for example 2,3,0
    Each of the rabbits was deprived of food for 124 hours before the experiment. These two kinds of candles were injected into the rectum in rabbits in the amount of 0.3 g of candles / kg, respectively. After that, blood was taken through the ear vein from the rabbits and high-pressure liquid chromatography was used to determine the serum antibiotic concentration. The results are presented in table. 15.
    As can be seen from the table. 15, the compound of Example 2 contributes significantly to the absorption of both antibiotics in the rectum.
    Example 34. Prepared candles of the following composition, wt.%: The drug presented
    in tab. 161.7
    Witepsol N-1596.0
    Compound
    following example 23.0
    The experiment of Example 33 was repeated, except that the indicated candles were used and there were 3-4 rabbits in each group. The results are presented in table. sixteen.
    As can be seen from the table. 16, the compound of Example 2 significantly increases the rectal absorption of indomethacin and 5-Fu.
    EXAMPLE 35. As one of the tests for compounds (I) for their local toxicity, a basic skin irritation test was performed using rabbit objects as objects. On the short-haired skin of the backs of Japanese rabbits weighing 2.5-3.0 kg each was put on a sticky patch intended for testing, on which 100 ml of a 3% test solution of the compound of example 2 was dropwise applied in 100 ml of polyethylene glycol 300 , then tightly attached it to the dorsal pelt for 24 hours. The irritation reaction of the dorsal pads of these rabbits was evaluated 3 times (24.48 and 72 hours after removing the patch) using the method corresponding to the Dreis method. For comparison, a similar procedure was performed, except that instead of the test solution (3%), a control solution was used (polyethylene glycol only); another 0 procedure was performed in which the compound of example 2 was replaced by a comparative compound aeon in the indicated 3% test solution.
    The results are shown in Table. 17, in which the overall assessment is represented by the following equation:
    Overall rating
     Score after 24 hours 4- score after 72 hours
    it is classified as mild irritation (0-2 points), moderate irritation (2-6 points), and severe irritation (6-8 points).
    As can be seen from Table 17, the compound from Example 2 has almost no irritating effect on the skin, just like a control solution, but the comparative compound Azone exhibits a moderate irritant effect for a time period of at least 72 hours.
    From the test described, it can be established that the compound of Example 2 has an extremely mild irritant effect on the skin.
    EXAMPLE 36. In order to determine the overall toxicity of compounds (I), rats were tested. Groups were created, each of which consisted of 4-5 male rats weighing 100-120 gm. Compounds (I) were administered to these groups, and one rat received 0.5 ml / 100 g. For 1 week after the administration of the preparation, the rats of the group were under observation to determine their common symptoms, changes in weight and mortality. For comparison, the procedure described was repeated using a comparative compound instead of compounds (I). The results in the form of LDB are given in Table 18.
    As follows from the table. 18, Compounds (I) do not cause unusual symptoms in rats and their death after oral or subcutaneous administration of these compounds.
    Thus, compounds I are completely safe. As can be seen from the results of the examples of compound (I)
    Constants of compounds I in examples 12-19
    权利要求:
    Claims (1)
    [1]
    in comparison with the known ones, they have a strong effect on the permeability and absorption of drugs through the membranes of a living organism, in particular the skin, as well as the membranes of the rectum, nose, mouth, vagina, etc. These effects are effective for a wide range of drugs or they enhance pharmacological effects. In addition, compounds (I) can be used together with a variety of bases and in various medical forms. Formula of the invention. A method for producing azacycloalkane derivatives of the general formula
    yMcH2)
    1СН2), p
    where R is C2 C12-alkyl;
    n 2-8 with m 1 or
    p 3-10 when m 3
    characterized in that the compound of the general formula
    O (HCH CH-CHj.
    (CH2} m
    where the type has the indicated meanings, it is reacted with a thiol of the general formula
    R-SH,
    where R has the indicated values, in the medium of an organic solvent at 70-120 ° C in the presence of azobisobutyronitrile or benzoyl peroxide.
    Table 1
    Note,
    And The number of ketoprofan penetrated in 48 hours in the test group
    The amount of ketoprofen penetrated in 48 h in the control group
    Note.
    d- The number of penetrated indomethacin in the study group for 48 h
    The number of penetrated indomethacin in the control group for 48 h
    Note.
    A- Number of indomethacin penetrated in 48 hours in the study group.
    The number penetrated for 48 h indomethacin in the control group
    table 2
    Table 3
    Table 4
    Note.
    Concentration of pindolol in serum in the tested group Concentration of pindolol in serum in the control group
    Note.
    Activity
    The number of pindolol penetrated in 48 hours in the test group The number of pindolol penetrated in 48 hours in the control group
    Table 5
    Table b
    Note
     The amount of pindolol penetrated in 48 hours in the test group The number of pindolol penetrated in 48 hours in the control group
    Note
    The level of glucose in the control group or tested
    . group glucose level in the normal group,
    The rate of reduction of 1-, t x 100%
    The glucose level in the control group And the glucose level in the normal group
    Table 7
    Table 8
    Table 9
    Note.
    And the amount of the penetrator in 48 h 5 - Fu in the tested group
    Amount penetrated in 48 hours 5-Fu in the control group
    Note
    d The amount of phenol red penetrated in 48 hours in the test group.
    The amount of phenol red penetrated in 48 hours in the control group
    Table 12
    The number of tested drugs, penetrated for 48 h in the control group
    Tab Face 10
    Table 11
    AIS antibiotics in the test group
    Note. Activity-ttt: g:
    AIS antibiotics in the control group
    Note.
    Actnviosti-AIS Reparata in the test group AIS drug in the control group
    Table 13
    Table 14
    Table 15
    Table 16
    Table 17
    Table 18
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    同族专利:
    公开号 | 公开日
    GR3006768T3|1993-06-30|
    CN1020605C|1993-05-12|
    DE3782182T2|1993-02-25|
    KR910000164B1|1991-01-21|
    DE3782182D1|1992-11-19|
    CA1336597C|1995-08-08|
    AU601402B2|1990-09-13|
    CN87100666A|1987-10-21|
    AT81505T|1992-10-15|
    EP0241050B1|1992-10-14|
    ES2046196T3|1994-02-01|
    JPH0643390B2|1994-06-08|
    AR245107A1|1993-12-30|
    KR880701227A|1988-07-26|
    JPS62238261A|1987-10-19|
    EP0241050A2|1987-10-14|
    SU1750422A3|1992-07-23|
    SU1750423A3|1992-07-23|
    WO1987006226A2|1987-10-22|
    CN1060287A|1992-04-15|
    CN1018452B|1992-09-30|
    EP0241050A3|1988-12-28|
    US4882359A|1989-11-21|
    WO1987006226A3|1988-04-07|
    AU7020787A|1987-11-09|
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    法律状态:
    2007-09-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20050211 |
    优先权:
    申请号 | 申请日 | 专利标题
    JP61079174A|JPH0643390B2|1986-04-08|1986-04-08|Azacycloalkane derivative|
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