• 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:
    This invention relates to an aromatic oxo compound, in particular to the preparation of naphthalene derivatives. The goal is the discovery of new naphthalene derivatives with improved activity. The preparation is carried out by the reaction of the acitelen derivative f-ly R 1 -C @ C - R 2, where R 1 and R 2 are indicated above, with the benzaldehyde derivative or with its di (lower alkyl) acetal. 3 tab.
    公开号:SU1581217A3
    申请号:SU864013137
    申请日:1986-01-09
    公开日:1990-07-23
    发明作者:Ивасаки Тамео；Такасима Кохки
    申请人:Танабе Сейяку Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    of example 7
    example 8 ata
    (CDClj), (t., ZN, 3.91 (p. 4.15 (r.
    -O 0-) /
    CH2
    (d., 1H,
    1H, Ar), 7.70 (s.
    (CDC13), 1.38 (i.e., (q, 2H,
    P: 1.40 (t., ZN, 1.48 CH2CHNE), 3.50 (s., ZN, CH2CH3),, ZN, OMe), 4.10 (q, s., OCH2), s, OCHj), 6.00 (s., 2H, 6.72 (s., 1H, Ar), and 6.78
    Ar, I 9 Hz), 6.80 (see, 6.95 (d, IH, Ar, I 9 Hz),, 1H, Ar), 12.12 (s, 1H, OH)
    J: 1, 01 (t., ЗН,),, ЗН,), 1.45 (t., ЗН, 1.50 (t., ЗН,,), 4.02 ОНН2), 4.10 к. , 2H, OSSNg),
    The compound of example 9 from a mixture of ethyl acetate / / hexane
    A, 20 (q., 2H, OCH2), 4.40 (q., 2H, OCHg), 6.04 (s., 2H,), 6.79 (s., 1H, Ar, 1H), 6 , 82 (d., 1H, Ar Hz), 6.85 (s., HI, Ar), 6.97 (d, 1H, Ar), 7.72 (s, 1H, Ar), 12, 32 (s., 1H, OH).
    (CDCl3), eP: 0.93 (t, ZN, CH — CHj), 1.41 (t., ZN, CH2CH3), 1.50 (t., ZN, CH2CH3), 3.9-4, 4 (m, 6H, 3 OCH2), 6.00 (s, 2H, - OCH20-), 6.7-7.3 (m, 5H, Ar + OH), 7.38 (s., 1H, Ar), 7.6 (s., 1H, Ar).
    II re p 10. 2-BpoM 3s4,5- - rimethoxybenzaldehyde dimethyl acetal, 3,4-dimethoxybenzaldehyde and diethyl acetylenedicarboxylate are treated as in Example 1, as a result of which 1- (3,4-dimethoxyphenyl) is obtained as colorless crystals ) -2,3-bis- (ethoxycarboxy-O-oxy-b, 7,8-trimethoxynaphthalene. Melting point 138 140 ° C, NMR spectrogram (SBC1E),: 1.05 (t., ZN, CH2CH3), 1540 (t., ZN, SNgSNe), 3.21 (s., ZN, OMe), 3.80 (s., ZN, OMe), 3.85 (s., ZN, OMe), 3.95 (k ., 2H, OSSNg), 3.87 (s., 3N,
    OMe), 4.00 (s., ZN, OMe), 4.45 (q., 2H, OCH, j), 6.90 (s ,, ZN, Ar), 7.72 (s., 1H, Ar), 12.59 (s., HI, OH).
    W spectrogram (liquid paraffin), VMC (KC, 1735 (weak), 1720 (), 1655 (), 1590 (), 1510 (). Mace spectrogram (m / e 514 (M +).
    Example 11 „2-Bromo-3, 4,5-tr methoxybenzaldehyde methylmethyl acetal ,, 3,4-diethoxybenzaldehyde and dimethyl acetylenedienecarboxylate are treated as in Example 1, and as a result 1- (3,4-diethoxyphenyl) -2 is obtained as colorless crystals , 3- -bis- (methoxycarbonyl) -4 hydroxy-6,7,8-trimethoxy-naphthalene. I
    Melting point 138-140 ° C from ethyl acetate,
    NMR spectrogram (CDC13),: 1.05 (t., ZN, CH-iCHj), 1.40 (t., ZN CHaCH3), 3.31 (s., ZN, OMe), 3.90 (s ., ZN, OMe), 3.95 (s., ZN, OMe), 3.97 (s., ZN, OMe), 4.10 (s., ZN, OMe), 4.15 (q, 2H, CH7) 5 4.220 (q. 2H, CHg) 9 6.7-7.0 (m, ZN, Ar), 7.6 (s, 1H, Ar), 12.36 (s, 1H , HE).
    IR spectrogram (petroleum jelly °) m "ns 174 ° 1660" 1590 "1530.
    M / e J Mace spectrogram: 5.15 (M +).
    Example 120 2-Bromo-3, 5-methylenedioxybenzaldehyde dimethyl acetal, 4-methoxybenzaldehyde and dimethyl acetate-carboxylate are worked up as in Example 1, and as a result, 1- (4-methoxyphenyl) -2 is obtained as colorless crystals with reaching 63% yield. , 3-bis- (methoxy-carbonyl) -4-hydroxy-6,7-metstendioxy-naphthalene.
    Melting point 169-171 ° C from methanol.
    NMR spectrogram (CDC13), cP: 3.55 (s., ZN, OMe), 3.88 (s., ZN, OMe), 3.95 (s., ZN, OMe), 6.03 (s .
    2H, -0-CH; ), 6.72 (s., 1H, Ar), 6.9-7.4 (t, 4H, Ar), 7.75 (s., 1H, Ar), 12.20 (s, 1H, HE).
    IR spectrogram (liquid paraffin),, 7140 (), 1660 (), 1610 (), 1520 ().
    Mace spectrogram of St / eZ: Yu (M +).
    Example 13. A solution of 7 g of 3,4-β-dioxybenzaldehyde in 20 ml of dimethylformamnd is added dropwise over 15 minutes while cooling with ice to a mixture of 4.8 g of 60% sodium hydride in 70 ml of dimethylformamide. This mixture is stirred at the same temperature for 15 minutes. Then 50 g of n-propyl iodide is added to the mixture. After stirring for 12 hours, the mixture is evaporated to remove the solvent. The residue is subjected to extraction with diethyl ether and the extract is washed with water, dried,
    filtered to remove inorganic materials, and then evaporated to remove the solvent, resulting in 8.5 g of 3,4-dipropoxybenzaldehyde as a pale yellow oily product.
    Boiling point 130-136 ° C (under a residual pressure of 0.2 mm Hg).
    2-Bromo-3, 4,5-trimethoxybenzaldehyldimethylacetal, 3,4-dipropoxy-benzaldehyde and dimethylacetylenecarboxyl are treated as in Example 1, resulting in 1- (3, A-Dipropoxyphenyl) -2 as colorless needle-like crystals , 3- -bis- (methoxycarbochil) -4-hydroxy-6,7,8-trimethoxynaphthalene
    Melting point 132 ° C from ethyl acetate,
    NMR spectrogram (CDPlj), cG: 0.99 (t., ZN, CH2CHN), 1.05 (t., ZN,)., 1.6-2.1 (m, 4H, 2CH4), 3 , 21 (s., ZN, OMe), 3.42 (s., ZN, OMe), 3.73 (s., ZN, OMe), 3.77 (s., ZN, OMe), 3.89 (p., ZN, OMe), 3.8-4.2 (m, AH, 20SNg), 6.74 (p., 1H,
    Ar), b, 76 (c.t 2H, Ar), 7.59 (s., 1H, Ar), 12.25 (s ,, 1H, OH).
    Zh-spectrogram (vaseline
    oil) -O
    l) “ks.
     1740 ()
    1660 (), 1570 (), 1510 (). Example 14. A solution of 1, 55 M n-butyl lithium in 20 ml of hexane was added dropwise to a solution of 9.24 g of N- - (3,4-methylenedioxybenzylidene) -cyclohexylamine in 100 ml of tetrahydrofuran. The above addition operation is carried out at a temperature of from -70 to -60 ° C with stirring for 15 minutes. The mixture is then stirred at the same temperature for an additional 15 minutes, and a solution of 6.65 g of 3,4-dimethoxybenzaldehyde in 15 ml of tetrahydrofuran is added dropwise to this mixture at the same temperature for a 15-minute period of time. . Then the mixture is subjected to additional stirring at the same temperature for 15 minutes, after which it is poured into a mixture of 300 ml of water; with 300 ml of diethyl ether. The organic layer is separated from the mixture, washed with water, dried and evaporated under reduced pressure to remove the solvent. The yellow syrup thus obtained is subjected to chromatographic treatment in

    ten
    58121710
    silica gel column solvent; a 4: 1 mixture of benzene and diethyl ether, saturated with water, and the eluate is evaporated under reduced pressure to remove the solvent. The resulting colorless crystals are recrystallized from a mixture of ethyl acetate and hexane, and as a result, 8.7 g of 3,4-methyl nioles with and-2- (3,4-dimethyl and alpha) are obtained in the form of colorless needle-like crystals. oxibenzyl) benzaldehyde. Yield 69%.
    Melting point 129-130 °.
    NMR spectrogram (CBC1), cG: 3.55 (d „, O, 3N, I 9 Hz), 3.70 (d., O, 4H, I 9 Hz), 5.45 (d., O , ZN, I 10 Hz), 3.85 (s., ZN), 3.86 (s., ZN), 5.90 (narrow, M., 2H), 6.0-7.5 (m. , 6.7 N), 9.70 (s., O, 3N).
    IR spectrogram (petrolatum
    15
    20
    25
    thirty
    35
    40
    45
    50
    55
    oil), 0Wo (Kt, cm 1: 3410, 3300, 1610, 1600, 1520.
    Mace spectrogram (m / e): 31 6 (M).
    6.5 g of 3,4-methylenedioxy-2- (3,4-dimethoxy-alpha oxybenzyl) benzaldehyde is dissolved with heating in 10.5 ml of benzene. To this solution is added 3 mg of p-toluenesulfonic acid (monohydrate). The mixture was heated under reflux for 30 minutes. After cooling to room temperature, the mixture is allowed to stand overnight at -30 ° C. The precipitates are collected by filtration and then recrystallized from a mixture of rofuran tetrahydhene and methanol, resulting in 7.5 g of 1- (3,4-dimethoxyphenyl) -2 in the form of pale yellow prismatic crystals with reaching 83% yield. , 3- -bis- (methoxycarbon L) -4-hydroxy-7,8-methylenedioxynaphthalene.
    Melting point 228-229 ° C from T2F and MeOH.
    NMR spectrogram (DMSO-d), f: 3.50 (s., 3N, OMe), 3.74 (s, 3N, OMe), 3.82 (s, 3N, OMe), 3.91 (s., ZN, OMe), 5.92 (s., 2H,), 6.7-7.05 (m, ZN, Ar), 7.40 (d, 1H, Ar, Hz); 8.05 (d, 1H, Ar, I 9 Hz).
    IR spectrogram (liquid paraffin), VMti, Kc, media: 1730 (), 1659 (), 1630 (), 1590 (), 1510 (broad). (Wide strip).
    Mace spectrogram (m / e): 440 (MJ.
    Example 15.A “According to the procedure of Example 1, the interaction of 2-bromine
    eleven
    158
    3,4-dichlorobenzaldehyde and 3,4-dimethoxybenzaldehyde results in 2- (3,4-dimethoxy-hydroxybenzyl) -3,4-dichlorobenzaldehyde.
    IR (vaseline oil) - VwrtKC s 3350, 1605, 1600, 1520.
    B. According to the procedure of Example 1-6, the interaction of 2- (3, 4-dimethoxy-xs (-hydroxybenzyl) -3,4-dichlorobenzaldehyde and dimethyl acetylenedicarboxylate results in 1- (3,4-dimethociphenyl) 2,3 -bis- (methoxycarbonyl) -4-hydroxy-7,8 dichloronaphthalene in the form of colorless prisms.
    Melting point 209-210 ° C from ethyl acetate
    NMR spectrogram (DMCD-d), o 3.50 (s., LC, OMe), 3.75 (s., ZN9 OH), 3.85 (s, ZN, OMe), 3.95 (s ., ZN, OMe), 6.6-7.1 (m, ZN, Ar) e 7.8 (d, 1H, Ar, 1 9 Hz) h 8.4 (d, 1H Ar, Hz ), 11.98 (s., 1H, OH).
    W-spectrogram (liquid paraffin),) MWV (.e, 1730 (), 166 (), 1605 (), 1510 (OC).
    Example 16 According to the procedure of Example 1, the interaction of 2 bromo-4, tylenedioxybenzaldehyde dimethyl acetal, 3,4-diethoxybenzaldehyde and methylacetylene carboxylate leads to the formation of 1- (3,4-diethoxyphenyl) -2-methoxycarbonyl-4-hydroxy-6 , 7-methylenedioxynaphthalene in the form of colorless crystals.
    Melting point 189-190 ° C (after recrystallization from methanol).
    NMR spectrogram (CDC13), P: 1.38 (t., ZN, CH2CHNE), 1.44 (t., ZN), 3.53 (s., ZN, OMe), 4.05 (q. 2H, OCH4), 4.13 (q., 2HS OCH-j), .5.93 (s ,, 2H, OCHiO), 6.6-7 "O (m, 5H, Ar + OH), 7 , 2.1 (s., 1H, Ar), 7.50 (s., 1H, Ar).
    Example 17. 9.72 g of 1- (3,4-dimethoxyphenyl) -2,3-bis- (methoxy-carbonyl) -4-hydroxy 6,7,8-trimethoxy-naphthalene e prepared according to example 1, - from a solution of sodium ethoxyd prepared from 500 ml of ethanol and 2.76 g of metallic sodium. The mixture was heated under reflux for 3 hours. The reaction mixture was then cooled, after which 7.2 g of acetic acid was added. Next, the mixture is evaporated to dryness under reduced pressure. The residue is dissolved in 200 ml of chloroform.
    21712
    The chloroform solution is washed with water, dried, filtered to remove inorganic materials, and then evaporated to remove the solvent. The crystalline precipitates thus obtained were recrystallized from ethyl acetate, resulting in a colorless
    q prismatic crystals get
    7.2 g of 3- (3,4-dimethoxyphenyl) -2-methoxycarbonyl-3-ethoxycarbonyl-4-y-oxy-6,7,8-trimethoxy-naphthalene (from ethyl acetate).
    5 Melting point 151-152 ° C.
    NMR spectrogram (CDC13), f: 3.31 (t., ZN, SNgCH5), 3.22 (s., ZN, OMe), 3.41 (s., ZN, OMe), 3.80 (s ., ZN, OMe), 3.87 (s., ZN, OMe), 3.90
    0 (p., ZN, OMe), 4.00 (p., ZN, OMe), 4.35 (q., 2H, CH), 6.76 (p., ZN, Ar), 7.60 ( s, HI, Ar), 12.42 (s, 1H, OH).
    Example 18. 1- (3,4-Dimethoxy5 phenyl) -2,3-bis- (ethoxycarbonyl) -4- -oxy-6,7,8-trimethoxynaphthalene, prepared according to example 10, is treated with a solution of sodium methoxide as in example 17 as a result
    For which 1- (3,4-dimethoxyphenyl) -2-ethoxycarbonyl-3-methoxycarbonyl-4-hydroxy-6,7,8-trimethines of sinaphthalene (from ethyl acetate) are obtained as colorless prismatic crystals.
    “; Melting point 157-159 ° C. NMR spectrogram (CDClj):
    1.03 (t., ZN, CH2CH3), 3.22 (s., ZN, OMe), 3.8- (s., ZN, OMe), 3.75 (s.,
    9 ZN, OMe), 3.87 (s., ZN, OMe), 3.9 0 (q., 2H, CH2), 3.98 (s., ZN, OMe), 6.77 (s., ZN, Ar), 7.59 (s., 1H, Ar), 12.29 (s, 1H, OH).
    Example 19. 2-Bromo-4,5-methylenedioxybenzaldehyde-dimethyl-5-tal, 3-methoxybenzaldehyde and dimethyl acetylenedicarboxylate are treated as in Example 1, resulting in 1- (3-methoxyphenyl) -2,3-bis- ( methoxycarbonyl) -4 hydroxy-0 -6,7-methylenedioxinaftyline (from methanol),
    Melting point 152-154 ° C, JK-spectrogram (liquid paraffin), VMOtKC 9 cm 1: 1730 (), 1660 5 (00), 1610 (), 1660 (OS).
    Mace spectrogram (m / e}: 410 (Mf). NMR spectrogram (DMSO-d), o: 3.5 (s., 3N, OMe), 3.80 (s, 3N, OMe), 3 , 90 (s., ZN, OMe), 6.15 (s.,
    2H, -OCHjO), 6.60 (s., 1H, Ar), 6.7- 6.9 (m, 2H, Ar), 6.9-7.2 (m, 1H, Ar), 7.4 (d, 1H, Ar), 7.57 (s., 1H, Ar), 11-12 (broad 1H, OH).
    Example 20 2-Bromo-4,5-methylenedioxybenzaldehyde dimethyl acetal, 3 4-diisopropoxybenzaldehyde and di-ethylacetylene dicarboxylate are treated in the same manner as in Example 1, with the result that 1- (3,4-diisopropoxy- nyl) -2,3-bis (ethoxycarbonyl) -4-hydroxy- -6,7-methylenedioxynaphthalene from a mixture of ethyl acetate / hexaNo
    Melting point 123-124 ° C.
    Mace spectrogram (m / e): 123-124 ° C.
    NMR spectrogram (DMCO-d fe), o: 0.94 (t, ZN,), 1.35 (t, CH2CH, ZN), 1.30 (d, 6H, 2Me), 1.36 (d, 6H, 2Me), 3.96 (q., 2H, OCH2), 4.35 (q., 2H, OCH-i), 4.3–4.7 (m, 2H, 2CH) , 6.09 (s., 2H, OCH20), 6.6-7.1 (m, 4H, Ar), 7.55 (s., 1H, Ar), 12.19 (s., 1H, HE).
    Example 21. 2-Bromo-3,4,5-trimethoxybenzaldehyde-methylmethyl acetal, 3-methoxy-4-ethoxybenzaldehyde and dimethyl acetylenedienecarboxylate are treated as in Example 1, as a result of which, with a 67% yield in the form of colorless needle-like, crystals receive 1- (3-methoxy-4-ethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxy naphthalene.
    Melting point 159 ° C from ethyl acetate.
    NMR spectrogram (CDC1-), s / 1: 1.47 (t., ZN, 3.22 (s., ZN, OMe), 3.42 (s, ZN, OMe), 3.70 ( pp., ZN, OMe), 3.85 (p., ZN, OMe), 3.87 (p., ZN, OMe), 4.00 (p., ZK, OMe), 4.12 (r. , 2H, CH2), 6.75 (s., ZN, Ar), 7.56 (s., 1H, Ar), 12.21 (s., 1H, OH).
    Zh-spectrogram (liquid paraffin), 1730, 1710 (00), 1660 (OS), 1590 (OS), 1510 (OS).
    Example 22. 2-Bromo-3,4,5- -trimethoxybenzaldehyde dimethyl acetal, 3-ethoxy-4-methoxybenzaldehyde and dimethyl acetylenedicarboxylate are treated as in Example 1, resulting in the achievement of a 65% yield in the form of colorless needle-like crystals 1- (3-ethoxy-4-methoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxy-naphthalene is obtained.
    - Melting point 1 58 C of
    ethyl acetate.
    NMR spectrogram (CDC15), cf: 1.42 (s., 3HS-CHNSNe), 3.22 (s., 3N, OMe), 3.45 (s, 3N, OMe), 3.85 (s .
    ZN, OMe), 3.89 (s., ZN, OMe), 3.98 (s., ZN, OMe), 4.08 (q, 2H, CH), 6.76 (s., ZN, Ar), 7.56 (s., 1H, Ar), 12.21 (s, 1H, OH).
    Zh-spectrogram (vaseline
    5 oil), Ohm x, cm 1: 1740 (), 1655 (00), 1590 (OS), 1510 (OS).
    The naphthalene derivative (l) has a strong hypolipidemic effect and is characterized by the fact that
    0 it is able to reduce the total serum cholesterol level and at the same time increase the level of HDL cholesterol. Thus, the naphthalene derivative (l) can be used to treat or prevent hyperlipidemia (for example, hyperchlolestegenemia) or arteriosclerosis (atherosclerosis, Mencberg sclerosis, arteriolosclerosis) in warm-blooded animals, including humans.
    The daily dosage of the naphthalene derivative (l) may vary over a wide range depending on
    5, the severity of the disease, the age, weight and condition of the patient, etc., however, the daily dosage is preferred can usually be varied in the D range from 1.5 to 35 mg, in particular
    0 5 - 25 mg / kg live weight.
    The naphthalene derivative (l) can be introduced into the body of warm-blooded animals, including humans, either by oral or parenteral routes, although it is usually preferable to enter them through the mouth. The naphthalene derivative (l) can be used in the form of a pharmaceutical composition in a mixture with pharmaceutical acceptable additives and carriers for them. For example, a pharmaceutical composition for oral administration can be formulated in dosage form.
    5 pills, powders, capsules or granules, and may include pharmaceutically acceptable additives or carriers, in particular calcium carbonate, calcium phosphate, corn starch, potato starch, 5 sugar, lactose, talc, magnesium stearate, and the like. Mentioned pharmaceutical composition in solid form may additionally contain binding components, diluents, friability additives, wetting agents, and Top. Alternatively, a pharmaceutical composition for oral administration can be prepared in liquid dosage form
    1 IU, in particular in the form of aqueous or oily suspensions, solutions, syrups, elixirs, and m. Acceptable additives for such compositions in the form of metered liquids may include liquid carriers (bases), suspending agents 5 surfactants 5 soft bases and a similar tone. On the other hand, a pharmaceutical composition for parenteral administration may be added.
    prepared in the form of injectables or suppositories. Injectable preparations can be prepared in the form of either solutions or suspensions, which may include a pharmaceutically acceptable carrier (excipient), i in particular, an essential oil (for example, peanut butter, cucurinous oil ) or an aprotic solvent (for example, j, polyethylene glycol,
    glycol, lapoli and coconut).
    Practical and preferred options are presented in the following experiments and examples,
    An experiment on the effect on total serum cholesterol and on HDL cholesterol in serum /
    ten
    15
    23
    3S
    EY male rats (BUT body weight - 170 g, five individuals in each group) were kept under any conditions for 4 days. on a diet containing 2% by weight cholesterol and 0.5% sodium cholate. Then the rats were additionally kept in any conditions on the same diet, but including i 00 mg% or 20 mg% of the test compound. On the other hand, in this additional period, the living control group was kept on diets that did not include the test kinning. After 3 days, the rats were anesthetized with diotyl ether. After measuring the body weight, blood was collected from aortic abdominal rats. The blood was removed from standing at room temperature for 1 hour and subjected to its center by fugging. Then, in the thus obtained serum, the en was measured :; mathematically, total cholesterol levels. On the other hand, serum HDL cholesterol was separated from other types of cholesterol according to the method of lipoprotein sedimentation using dex rasulfate sulfate, after which its level was measured by the significant method in accordance with the described method. Based on the results obtained, in accordance with the above formulas, the effect of the test compound on the total serum cholesterol level and on the serum LBP-cholesterol level was calculated.
     The degree of sgloseni total Q level of cholesterol in serum
    G Average total cholesterol level in the serum of animals of the group that was treated.
    1 "- A.-h-ha-in - ™ .-; .-. ™ - -fc-h -..- in -.„ Li., "M". ". M., Leagues. u1.m,. „P 1 / Npl
      - ".. f K1 (JU„
    | The average total cholesterol level in serum of the blood of animals in the control group
    Percentage increase in HDL cholesterol level in the short
    G The average level of HDL cholesterol in the serum of N 1 animals of the group that was treated (
    The average level of HDL cholesterol in the serum of animals in the control group
    th - average total cholesterol level in the blood of animals in the control group was 152– 230 mg / dL |
    d - the average level of HDL - cholesterol in the serum of croz animals of the control group was 13.6 - 27.6 mg / dL
    five
    3
    S
    EY male rats (BOD body weight - 170 g, five individuals in each group) were kept under any conditions for 4 days. on a diet containing 2 wt.% cholesterol and 0.5 wt.% sodium cholate. Then the rats were additionally kept under any conditions on the same diet, but including i 00 mg% or 20 mg% of the test compound. On the other hand, in this additional period, the control animals were kept on a diet that did not include the test connection. After 3 days, the rats were anesthetized with diotyl ether. After measuring the body weight, blood was collected from the abdominal aorta rats. The blood was allowed to stand at room temperature for 1 hour and was subjected to its center by fugging. Then, in the serum thus obtained, the en: was measured by the total cholesterol level. On the other hand, serum HDL cholesterol was separated from other types of cholesterol according to the method of lipoprotein sedimentation using dextran sulfate, and then its level was measured according to the described method in a significant way. Based on the results obtained in accordance with the above formulas, the effect of the test compound on the total serum cholesterol level and on the LBP-serum cholesterol level was calculated.
    to 100
    Hyperlipemia is known to mean the symptom of an excess amount of lipids in the blood, and that hyptercholesterolemia is a symptom of the fact that one of the lipids cholesterol is contained in the blood in an excess amount, and this is closely associated with atherosclerosis. Cholesterol is usually found in the blood in a form where it is bound to lipoproteins, which is classified as very low density lipoprotein (VZDZ) cholesterol, low density lipoprotein (ZDZ) cholesterol, and high density lipoprotein (HDZ) cholesterol. Of these, VZDZ and ZDZ cause cholesterol deposition on the arterial walls and are the cause of atherosclerosis. In contrast, HDZ inhibits cholesterol deposition on the walls of the arteries, therefore, is effective in preventing and treating atherosclerosis. I
    Accordingly, for the treatment of hyperlimemia and atherosclerosis, it is important to lower blood cholesterol, especially for the treatment of atherosclerosis, it is very important to lower VZSZ cholesterol and ZDZ cholesterol and thereby reduce total cholesterol, but to increase HDZ cholesterol, which inhibits cholesterol deposition artery walls. In other words, it is important to increase serum HDZ cholesterol levels while simultaneously reducing total serum cholesterol levels (to reduce VZDZ ZDZ cholesterol levels).
    From this point of view, as shown in table. 3, the proposed compounds exhibit increased activity for lowering total serum cholesterol and increasing serum HDZ cholesterol compared to a known compound of similar structure.
    Thus, according to the proposed method, the activity is determined to reduce the total serum cholesterol level and increase the serum HDZ cholesterol level. As a result, the compounds demonstrate a decrease in total cholesterol level from about 27 to 71% and an increase in the level of HDZ cholesterol 24 to 178%. Thus, the compounds according to the invention have excellent hypolemic activity and are very useful for
    five
    and treatment of atherosclerosis. On the other hand, the known compound showed an increase in total cholesterol content by 18% and, therefore, is not effective for the prevention and treatment of hyperlipemia and atherosclerosis.
    权利要求:
    Claims (1)
    [1]
    As can be seen from the table. 3 of the claimed compounds have an improved activity compared with known compounds. Invention Formula
    Method for preparing naphthalene derivatives of general formula I IOH
    20
    five
    0
    0
    R, R4 RfR R, 5
    0
    five
    where R, is hydrogen or lower alkoxycarbonyl; R7 is lower alkoxycarbonyl;
    hydrogen or lower alkoxy; rpyf;
    lower alkoxy group; hydrogen or lower alkoxy;
    hydrogen, lower alkyl, lower alkoxy, benzyloxy or halogen; hydrogen, lower alkoxy or halogen or R Ј- and R together form methylenedioxy, a RT is hydrogen, or R and R together form methylenedioxy, and Eg- is hydrogen, provided that both of them and R are methylenedioxy, R is hydrogen Each of R 1 and Er is methoxycarbonyl and each EZ and R is lower alkoxy with at least C, and when Rr- and R are each methoxy, R 7 is hydrogen, R is hydrogen, and R g is ethoxycarbonyl and each from R and R is lower alkoxy and at least C, or R, hydrogen and P4 is lower alkoxy, characterized in that, is an acetylene derivative of the general formula
    55
    R 1 - С С R
    2
    where RJ and R have the indicated meanings, they are reacted with a benzaldehyde derivative of the general formula
    about 19
    153121720
    where Rj - R7 have the indicated meanings; or with his di (lower agasil) acetal.
    gr j Coi
    Example | Compound A 2
    sn3o
    ; CH30
     -h.
    "
    SNODO
    Table 1 Table 1 Physical properties
    Colorless crystals
    m.p. 182-184 ° C
    IR i) mo (cc vaseline oil,
     1740 (GS), 1660 (),
    1620 (OS), 1590 (OS), 1520
    (OS). +
    Mass spectrum (t / e): 396 (M)
    Colorless crystals m.p., 199-200 ° С Mass spectrum (t / e): 410 (M +)
    Colorless crystals
    t0 pl. 178-179 ° C
    IR 1) Vazel. butter,
    cm- ; 1725 (), 1660 (),
    1595 (OS), 1580 (), 1510
    () +
    Mass Spectrum (t / e): 426 (M)
    Yield 63%
    Colorless crystals
    t „pl„ 208-209 ° С
    IR VMO (Kt s Vaseline
    oil9 1730 (), 1660
    (), 1620 (), 1590 (OS).
    1SHO ()
    Mass spectrum (t / e): 456 (M)
    53% yield
    Colorless crystals t pl. IR l)
    / C 01 KS 9
    vaseline colorless crystals t pl. IR l)
    / C 01 KS 9
    vaseline oil ,, cm-1: 1730 (), 1660 (), 3620 (), 1590 (00), 1510 (OS)
    Mass spectrum (t / e): 532 (M4)
    Example Compound R
    G 1
    R. COOCH,
    13
    Eg SoSne
    R1 СООСгН5 R2 СООСаН5
    Rt h
    Ru COOC-jHj
    1- (3,4-Dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene71
    1- (3,4-Dimethoxyphenyl (-2,3-bis (methoxy-carbonyl) -4-hydroxy-7-methylnaphthalene 48
    1- (3,4-Dimethoxyphenyl) -2,3-bis (-ethoxycarbonyl) -4-hydroxy-6,7,8-trimethoxy-naphthalene57
    1- (3,4-Dimethoxyphenyl) -2-methoxycarbonyl-3-ethoxycarbonyl-4-hydroxy-6,7,8-trimethoxynaphthalene 71
    1- (3 4-Dimethoxyphenyl) -2-ethoxycarbonyl-3-methoxycarbonyl-4-hydroxy-6,7,8-trimethoxy-naphthalene 68
    1- (3,4-Diethoxyphenyl) -2-methoxycarbonyl-4-hydroxy-6, 7-methylenedioxynaphthalene49
    table 2
    Physical properties
    Yield 54%
    Colorless crystals
    m.p. 158-159 ° С
    IR (vaseline oil)
    (), 1660 (), 1620 (weak.), 1595 (). Mass spectrum (t / e): 468
    Yield 59%
    Colorless crystals
    m.p. 150-151 ° C
    W (vaseline oil),
    (), 1640 (), 1620 (OS), 1580 (weak.), 15 (weak.) Mass spectrum (t / e): 496
    Yield 59%
    m.p. 169-171 0
    KK (vaseline oil), /
    m. “cop
    cm-: 3400
    (OH), 1670 (), 1625 (), 1580 (weak.), 1540 (), 1515 () Mass Spectrum (t / e): 424 (Mf)
    Table 3
    J77 76
    93 178 144
    44
    1- (3,4-Dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6-methoxy-7-benzyloxy-naphthalene45
    1- (3,4-Diethoxyphenyl) 2, (methoxy-carbonyl) -4 ™ hydroxy, 6,7-metstendioxy-naphthalene60
    1- (4-Methoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-4,7-methylenedioxynaphthalene 27
    1- (3,4-Dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-HYDROXY-7 s8-methylenedioxy naphthalene 49
    1- (3,4 Dimethoxyphenyl) -2,3-bis (methoxy-carbonyl) -4-hydroxynaphthalene 61
    1- (3,4-Dimethoxyphenyl) -2,3-bis (methoxy-carbonyl) -4-hydroxy 6-methoxy-naphthalene 42
    1- (354-Dimethoxyphenyl) 253-bns (methoxycarbonyl) -4-hydroxy-6g, 7-dimethoxynaphthalene38
    1 - (3,4-Dimethoxyphenyl) -283-bis (methoxy-carbonyl) -4-gndroxy-758-dichloronaphthalene42
    probucol .15
    1- (3,455-Trimethoxyphenyl) -2, (methoxy-carbonyl) -4 hydroxy 6s7-methylenedioxy naphthalene (known) 18
    4, 4 - (1-Methylethylidene) bis (thio) (bis) 2E 6-bis (1,1-dimethylethyl) (phenol) or 4S4 - (isopropylidenedithio) bis (2,6-di-tert.-butylphenol ),
    Continued table. 3
    57 67 35
    34
    01
    82
    24
    94 30
    12
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    同族专利:
    公开号 | 公开日
    JPS61163264A|1986-07-23|
    DK9886A|1986-07-11|
    DD261786A5|1988-11-09|
    SU1577697A3|1990-07-07|
    DK9886D0|1986-01-09|
    DE3600575A1|1986-07-17|
    DE3600575C2|1987-03-19|
    引用文献:
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    KR0172772B1|1995-05-17|1999-03-30|김주용|Method of forming ruo2 film of semiconductor equipment|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP306085A|JPS61163264A|1985-01-11|1985-01-11|Formation of oxide film of platinum group metal|
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