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    • 专利摘要:
    This invention provides benzene derivatives which are leukotriene antagonists, formulations of those derivatives, intermediates for preparing the derivatives, and a method of using those derivatives for the treatment of conditions characterized by an excessive release of leukotrienes.
    公开号:SU1753946A3
    申请号:SU884355058
    申请日:1988-01-11
    公开日:1992-08-07
    发明作者:Марк Гапински Даррел
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new derivatives of benzophenone or diphenylcarbinol of the general formula
    A - ^ E (CH 2 ) p Z 'where A, D are the same or different and mean COORi, where Ri is H, CrC3-alkyl cyano, 5-tetrazolyl:
    E is oxygen:
    Y is CO-CHON;
    Z is hydrogen:
    p = 6-14;
    η = 0.1:
    m = 0-3, with anti-inflammatory activity, anti-leukotrienes, slow-reacting anaphylaxis (LTCn, LTD4), but also leukotriene LTB4.
    Derivatives of benzophenone are known, for example 5- [4- (4-benzoyl-3-hydroxy-2-propylphenoxy) butyl] tetrazole, which are similar in structure to the same purpose.
    However, these compounds have a relatively low anti-inflammatory activity.
    The aim of the invention is to develop a method for producing new derivatives of benzophenone or diphenylcarbinol, exhibiting higher anti-inflammatory activity.
    1753946 AZ
    The goal is achieved according to the method for producing derivatives of benzophenone or diphenylcarbinol of the general formula (I) consisting in the fact that the compound of the general formula (C); (II) is reacted with a compound of the formula
    1. (CHzImD ^ E (CH Z ) P Z. (|, |) Where AD-COOR1, CN;
    Rt-Ci-C3-alkyl;
    Li = COCI;
    L is H or L is COCI, Li-H;
    p, m - have the indicated meanings, in the presence of a Lewis acid catalyst, the product obtained is isolated and compound (I), where Ri-Ci-C3-alkyl, is subjected to alkaline hydrolysis, if necessary, to obtain a compound of formula (I), where Ri - And, or, if necessary, a compound of formula (I), where A and / or D is a cyano group, are reacted with tin azide to form a compound of formula (I), where A and / or D is 5-tetrazolyl, which, when if necessary, they undergo hydrolysis to obtain a compound of formula (I), where Ri is H, or a compound of formula (I), where Or a compound of formula (I), wherein YSO is subjected to borohydride reduction to obtain a compound of formula (I), wherein Y - CHOH.
    EXAMPLE 1.3- [3 ~ (Cyanomethyl) -4- (decyloxy) benzoyl] benzoic acid, ethyl ether.
    To a solution of 1.45 g of isophthalic acid, monoethyl ether monochloride in 25 ml of methylene chloride, cooled to 0 ° C in an ice bath, 2.73 g of aluminum chloride is added. After stirring for 1 h, 1.87 g of 2-decyloxybenzyl cyanide are added. The reaction was stirred at 0 ° C. for 4 hours and then poured into ice water containing hydrochloric acid. After stirring for 1 h, the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using 5-30% ethyl acetate in hexane as a solvent. The appropriate fractions' are combined and concentrated in vacuo. 1.1 g of the expected substance are obtained in the form of a colorless oil.
    Calculated,%: C 74.80; H 7.85: N 3.12 ^
    C28H35NO4 Found,%: C 75.84; H, 8.83; N, 3.82.
    Example! 3- [4- (Decyloxy) -3- (1 H-tetrazol-5-ylmethyl) benzoyl] benzoic acid, ethyl ether.
    A mixture of 1.0 g of the substance from example 1 and 2.2 gtri-n-butylstannylazide in 30 ml of tetrahydrofuran is heated under reflux for 10 days. The reaction mixture is cooled to ambient temperature. A mixture of hydrochloric acid and methanol was added and, after stirring for 30 minutes, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography using 30-75% ethyl acetate in hexane containing an additional 0.05% acetic acid as eluent. The appropriate fractions are cooled and concentrated. 592 mg of substance are obtained. Recrystallization from a mixture of hexane and ethyl acetate gives 580 mg of the desired substance.
    Calculated,%: C 68.27; H 7.37; N, 11.37. C28H36N4O4
    Found,%: C 68.56; H 7.50; N, 11.55.
    Example 3. 3- [4- (Decyloxy) -3- (1-tetrazol-5-ylmethyl) benzoyl] benzoic acid.
    A mixture of 580 mg of the substance from Example 2 and 280 mg of lithium hydroxide in 10 ml of acetone and 1 ml of water was stirred for 60 hours. The mixture was concentrated in vacuo and the resulting residue was partitioned between diethyl ether and water. The layers were separated and the aqueous layer was extracted with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and concentrated to dryness. The residue is crystallized from a mixture of hexane and ethyl acetate. Obtain 47 mg of the target substance, so pl., 147-150 ° C.
    Calculated,%: C 67.08; H, 7.14; N, 12.03.
    C26 H32N4O4
    Found,%: C 67.35; H 7.04; N, 11.76.
    The compounds of Examples 4-14 are prepared as in Example 1 from the corresponding acid chloride and the corresponding benzene derivative.
    PRI me R 4., 2- (Decyloxy) -5- [3- (ztoxycarbonyl) benzoyl] - benzeneacetic acid, ethyl ether, yield 45%, oil.
    Calculated,%: C 72.55; H, 8.12. S30N40O6
    Found,%: C 72.77; H, 8.13.
    PRI me R 5. 5- (Decyloxy) -2- [3- (ethyloxycarbonyl) benzoyl] - benzoacetic acid, ethyl ether, 4% yield, oil, NMR.
    PRI me R 6. 2- (Decyloxy) -5- [3- (ethoxycarbonyl) benzoyl] - without isol propanoic acid, ethyl ether, yield 83%, oil.
    Calculated,%: C 72.91; H, 8.29.
    S31N42O6
    Found. %: C 72.69; H 8.15.
    PRI me R 7. 2- (Decyloxy) -5- [3- (ethoxycarbonyl) benzoyl] - benzenebutanoic acid, ethyl ether, yield 34%. oil, NMR.
    Example 8. 2- (Decyloxy) -5- (3-cyanobenzoyl) -benzeneacetic acid, ethyl ether, 59% yield, oil, NMR, IR. MS.,
    PRI me R 9. 2 '- (Decyloxy) -5- (3-cyanomethylbenzoyl) - benzenepropionic acid, ethyl ether, yield 54%, oil, NMR.
    PRI me R 10. 2- (Tetradecyloxy) -5- [3 (ethoxycarbonyl) -benzoyl] benzeneacetic acid, ethyl ether, yield 81%, oil, NMR.
    PRI me R 11. 2- (Dodecyloxy) -5- [3 (ethoxycarbonyl) benzoyl] - benzeneacetic acid, ethyl ether, 5% yield, oil, NMR.
    PRI me R 12. 5- (3-Cyanobenzoyl) -2- (decyloxy) - benzeneacetonitrile, yield 61%, so pl. 83-85 ° C.
    Calculated,%: C 77.58; H 7.51; N, 6.96.
    C26H30N20O2
    Found,%: C 77.30; H 7.57; N, 6.72.
    Example 13. 2- (Decyloxy) -5- [3- (ethoxycarbonyl) benzoyl] benzene propionitrile, yield 92%, oil, NMR.
    PRI me R 14. 2- (Decyloxy) -5- (3-cyanobenzoyl) -benzenepropanoic acid, ethyl ether, 68% yield, oil, NMR, MS.
    The compounds of Examples 15-19 are prepared from the corresponding nitrile derivatives obtained in Example 2.
    PRI me R 15. 2- (Decyloxy) -5- [3- (1 Ntetrazol-5-yl) benzoyl] - benzeneacetic acid, ethyl ether, 16% yield, oil, IR. NMR, MS.
    PRI me R 16. 2- (Decyloxy) -5- [3- (1 Ntetrazol-5-yl-methyl) -benzoyl] benzenepropanoic acid, ethyl ether, 68% yield, oil, NMR.
    Example 17. [4- (Decyloxy) - [3- (1 H-tetrazol-5-ylmethyl) phenyl] [3- (1 H-tetrazol-5yl) phenyl] methanol. yield 54%, mp. 189-191 ° C.
    Calculated,%: C 63.02; H 6.60: N 22.93.
    C26H32N8O2
    Found,%: C 64.02; H 6.52: N, 22.84.
    Example 18. {4- (Decyloxy) -3- [2- (1 Ntetrazol-5-yl) ethyl] phenyl} - [3- (ethoxycarbonyl) phenyl] methanol, 58% yield, oil, NMR. IR, MS.
    PRI me R 19. 2- (Decyloxy) -5- [3- (1 Ntetrazol-5-yl) -benzoyl] - benzenepropanoic acid, ethyl ether, yield 31%, so pl. 80-81 ° C.
    Calculated,%: C 68.74: H 7.56; N, 11.06.
    C29H38N4O4
    Found,%: C 68.91; H 7.82; N, 11.13,
    The compounds of Examples 20-29 are prepared from the corresponding esters by the method described in Example 3, replacing Li hydroxide with potassium in aqueous methanol as a base; and solvent.
    PRI me R 20. 5- (2-Carboxybenzoyl) -2 (decyloxy) -benzeneacetic acid, yield 93%, mp 192 ° C with decomposition.
    Calculated,%: C 70.86; H, 7.35.
    S26N32O6
    Found,%: C 70.95; H, 7.30.
    PRI me R 21.2- (3-Carboxybenzoyl) -5 (decyloxy) -benzeneacetic acid, yield 60%, mp 92-94 ° C.
    Calculated. %: C 70.89; H, 7.32.
    SGBNzgOb
    Found,%: C 70.61: H 7.19.
    PRI me R 22. 5- (3-Carboxybenzoyl) -2 (decyloxy) -benzenepropanoic acid, yield 66%, mp 114-116 ° C.
    Calculated. %: C 71.34; H 7.54.
    С27Н34О6 • Found,%: С 71.56; H, 7.79.
    PRI me R 23. 5- (3-Carboxybenzoyl) -2 (decyloxy) -benzenebutanoic acid, yield 72%, mp 158-159 ° C.
    Calculated,%: C 71.77; H, 7.74.
    SgvNzbOb
    Found,%: C 71.48; H 7.48.
    PRI me R 24. 2- (Decyloxy) -5- [3- (1Tetrazol-5-yl) benzoyl] - benzeneacetic acid, yield 45%, so pl. 138-140 ° C.
    Calculated,%: C 67.22: H 6.94; N12.06. C26H32N4O6
    Found,%: C 67.32; H, 7.13; N, 11.91.
    PRI me R 25. 2- (Decyloxy) -5- [3- (1Netetrazol-5-ylmethyl) -benzoyl] -benzenepropanoic acid, yield 46%, mp. 137-139 ° C.
    Calculated,%: C 68.27; H 7.37; N, 11.37. C28H36N4O4
    Found. %: C 68.47; H, 7.40; N, 11.21.
    Example 26. 5- (3-Carboxybenzoyl) -2 (tetradecyloxy) -benzeneacetic acid, 4% yield, mp. 143-147 ° C.
    Calculated,%: C 72.55; H, 8.12 .. C30H40O6
    Found. %: C 72.27; H, 7.90.
    PRI me R 27. 5- (3-Carboxybenzoyl) -2 (dodecycloxy) -benzeneacetic acid, yield 27%, mp. 144-147 ° C.
    Calculated,%: C 71.77; H, 7.74.
    SgvNzbOb
    Found,%: C 69.86; H, 7.52.
    PRI me R 28. 3- {4- (Decyloxy) -3- [2- (1Netrazol-5-yl) ethyl] - benzoyl} benzoic acid, 63% yield, mp. 160-162 ° C.
    Calculated,%: C 67.90: H 6.97; N, 11.73. C27H34N4O6
    Found,%: C 67.83: H 7.20: N 11.54.
    PRI me R 29. 2- (Decyloxy) -5- [3- (1 Ntetrazol-5-yl) benzyl] - benzene propanoic acid, yield 95%. so pl. 139-140 ° C.
    Found,%: C 67.90; H 6.97; N, 11.73.
    C27H34N4O4
    Calculated,%: C 67.65; H 6.93; N, 11.72.
    EXAMPLES 30 and 31. 5- [2- (Carboxymethyl) benzoyl] -2- (decyloxy) benzenepropanoic acid, ethyl ether and 5 - [(2 carboxyphenyl) acetyl] -2- (decyloxy) benz olpropanoic acid, ethyl ether.
    5.0 g of ethyl 2-decyloxybenzene propanoate are added to a suspension of 3.98 g of aluminum chloride in 100 ml of methylene chloride. After stirring for 5 minutes, 2.4 g of polyphthalic anhydride is added and the reaction mixture is stirred for an additional 18 hours. The mixture is poured onto ice and 1Ν hydrochloric acid. After dissolving all solids, the mixture was extracted 3 times with ethyl acetate. The combined extracts were concentrated to dryness and the residue was purified by silica gel chromatography using 20-35% ethyl acetate in hexene as eluent to obtain the following substances:
    5- [2- (Carboxymethyl) benzoyl] -2- (decyloxy) benzenepropanoic acid, ethyl ether, 1.3 g, mp. 110-111 ° C.
    Calculated,%: C 72.55: H 8.12. SzoNioOb
    Found,%: C 72.10; H, 7.99.
    5 - [(2-Carboxyphenyl) acetyl] -2- (decyloxy) benzenepropanoic acid, ethyl ether, 0.9 g, oil, NMR.
    PRI me R 32. 5- (2-Carboxybenzoyl) -2 (decyloxy) -benzeneacetic acid, ethyl ether.
    Repeating the sequence of Examples 30 and 31 using phthalic anhydride and ethyl 2-decyloxybenzene acetate afforded the target material in 8% yield as an oil.
    Calculated,%: C 71.77; H, 7.74.
    SgoNzeOb
    Found. %: C 71.54; H, 7.84.
    The substances of examples 33-35 obtained by hydrolysis of the corresponding esters using the sequence of example 3 or examples 20-29.
    PRI me R 33. 5- [2- (Carboxymethyl) benzoyl] -2- (decicyclos) - benzene propanoic acid, yield 82%, mp 177-178 ° C. 5
    Calculated,%: C 71.77; Ή 7.74.
    SgvNzbOb
    Found,%: C 72.05; H, 7.52.
    PRI me R 34. 5 - [(2-Carboxyphenyl) acetyl] -2- (decyloxy) - benzenepropanoic acid, yield 75%, mp. 92-95 ° C.
    Calculated,%: C 71.77; H, 7.74. S28NzbOb
    Found,%: C 71.70; H, 8.00.
    PRI me R 35. 5- (2-Carboxybenzoyl) -2 (decyloxy) -benzeneacetic acid, yield 63%, mp. 154-155 ° C.
    Calculated,%: C 70.89; H, 7.32.
    SngNzgOb
    Found. %: C 70.98; H, 7.06.
    The following compounds are prepared from the corresponding acid chloride and benzene derivative by the method of Example 1.
    Example 36. 2- (Octyloxy) -5- [3- (ethoxycarbonyl) benzoyl] benzeneacetic acid, ethyl ether, 15% yield, oil, NMR.
    PRI me R 37. 2- (Decycloxy) -5- [4- (methoxycarbonyl) benzoyl] - benzeneacetic acid, ethyl ether, 46% yield, oil, NMR.
    PRI me R 38. 2- (Hexyloxy) -5- [3- (ethoxycarbonyl) benzoyl] - benzeneacetic acid, ethyl ether, yield 12%, oil. NMR
    PRI me R 39. 2- (Octyloxy) -5 - {[3- (ethoxycarbonyl) phenyl] hydroxymethyl} -benzene acetic acid, ethyl ether,
    To a solution of 220 mg of 2- (octyloxy) -5- [3 (ethoxycarbonyl) benzoyl] benzeneacetic acid, ethyl ether in 25 ml of ethanol, 20 mg of sodium borohydride was added. After 3 hours of stirring, 5 ml of water and 2 ml of hydrochloric acid are added. After stirring for 15 minutes, more water is added until the solution becomes cloudy. The mixture was poured into ethyl acetate and water. The layers were separated, the organic layer was washed with water three times and the combined aqueous extracts were extracted again with ethyl acetate. The ethyl acetate extracts are combined and dried over magnesium sulfate and concentrated to dryness. 190 mg of the expected compound are obtained in the form of a colorless oil.
    The following compounds of Examples 40-43 are prepared from the corresponding benzophenones by the method described in Example 39.
    Example 40.2- (Decyclosi) -5 - {[3- (ethoxycarbonyl) phenyl] hydroxymethyl} -benzene acetic acid, ethyl ether, 100% yield, oil.
    Calculated,%: C 72.26; H, 8.49,
    S30N42O6
    Found,%: C 72.49: H 8.78.
    Example 41.2- (Decyloxy) -5 - {[3- (ethoxycarbonyl) phenyl] hydroxymethyl} -benzo lpropanoic acid, ethyl ether, 79% yield, oil.
    PRI me R 42. 2- (Decyloxy) -5 - {[4- (methoxycarbonyl) phenyl] hydroxymethyl} -benacetic acid, ethyl ether, 51% yield, NMR.
    PRI me R 43. 2- (Hexyloxy) -5 - {[3- (ethoxycarbonyl) phenyl] hydroxymethyl} -benzene acetic acid, ethyl ether, 68% yield, oil, NMR.
    The following compounds of Examples 44-48 are prepared from the corresponding esters by the method of Example 3 or by the methods described for Examples 20-29.
    PRI me R 44. 5 - [(3-Carboxyphenyl) hydroxymethyl] -2- (octyloxy) - benzoacetic acid, yield 32%, mp. 136-138 ° C.
    Calculated,%: C 69.55; H, 7.30. S24N30O6
    Found. %: C 69.33; H 7.34.
    Example 43. 5 - [(3-Carboxyphenyl) hydroxymethyl] -2- (decyloxy) -benzeneacetic acid, yield 54%, mp. 123.5-125 ° C.
    Calculated,%; C 70.56; H, 7.74. SGBNZiOb
    Found. %: C 70.60; H, 7.74.
    PRI me R 46. 5 : [(3-Carboxyphenyl) hydroxymethyl] -2- (decyloxy) -benzenepropanoic acid, yield 80%. so pl. 147-149 ° C.
    Calculated,%: C 71.03; H, 7.95. S27N36O6.
    Found. %; C 74.24; H, 7.94.
    PRI me R 47. 5 - [(4-Carboxyphenyl) hydro-. roxymethyl] -2- (decyloxy) - benzoacetic acid, 58% yield, mp. 140-141 ° C.
    Calculated,%; C 70.56; H, 7.74. S26N34O6
    Found,%; C 71.48; H, 7.06.
    PRI me R 48. 5 - [(3-Carboxyphenyl) hydroxymethyl] -2- (hexyloxy) -benzeneacetic acid, yield 37%, mp. 132-135 ° C.
    Calculated,%>; C, 68.38; H, 6.78.
    SggNgbOb
    Found,%; C, 68.26; H, 6.73.
    PRI me R 49. 5 - [(3-Ethoxycarboxyphenyl) methyl] -2- (decyloxy) - benzene propanoic acid, ethyl ether.
    A solution of 820 mg of 2- (decyloxy) -5- [3- (ethoxycarbonyl) phenyl] hydroxymethyl] benzene propanoic acid, ethyl ether in 20 ml of acetic acid and 0.5 ml of sulfuric acid is subjected to catalytic hydrogenation in the presence of palladium on carbon for approximately 18 hours. The reaction mixture was filtered, ethyl acetate was added to the filtrate, and the organic mixture was washed with water. The organic layer was dried over magnesium sulfate and concentrated to dryness. The residue was purified by preparative thin layer chromatography using 15% ethyl acetate / hexane as eluent. 151 mg of the desired expected product is obtained in the form of a pale yellow oil, NMR.
    PRI me R 50. 5 - [(3-Carboxyphenyl) methyl] -2- (decyloxy) -benzenepropanoic acid.
    The target substance is obtained from the corresponding ethyl ester by hydrolysis described in examples 20-29. Yield 22%. so pl. 145-148 ° C.
    Calculated,%: C73.61; H, 8.24.
    S27N36O5
    Found. %: C 74.96; H, 9.03.
    PRI me R 51. 5 - [(3-Ethoxycarbonylphenyl) (hydroxyimine) methyl] - 2- (decyloxy) benzenepropanoic acid, ethyl ether.
    A mixture of 1.1 g of 2- (decyloxy) -5- [3- (ethylcarbonyl) benzoyl] - benzenepropanoic acid, ethyl ester and 220 mg of hydroxylamine hydrochloride in 25 ml of pyridine was dissolved g The heating at 70 ° C for approximately 18 hours react. the mixture was cooled to ambient temperature, ethyl acetate was added and the solution was washed several times with 1N hydrochloric acid and water. The organic layer was dried over sodium sulfate and concentrated in vacuo. Obtain 1.04 g of the desired target substance in the form of oil, NMR.
    PRI me R 52. 5 - [(3-Carboxyphenyl) (hydroxyimine) methyl] -2- (decyloxy) -benzenepropanoic acid.
    The target substance is obtained from the corresponding diester of example 51 by hydrolysis of example 3. The target product is restored with a yield of 81% and has a mp. 163-165 ° C.
    Calculated,%; C 69.06; H 7.51; N, 2.98. C27H35NO6
    Found,%; C 68.94; H 7.22; N 2.74.
    The target substance is obtained in 81% yield directly from 5- (3-carboxybenzoyl) -2- (decyloxy) benzenepropanoic acid by reaction with hydroxyamine hydrochloride, as described in Example 51. ...
    PRI me R53. 5- [1- (3-Ethoxycarboxyphenyl) ethenyl] -2- (decyloxy) benzenepropanoic acid, ethyl ether.
    A suspension of 840 mg methyltriphenylphosphine bromide in 20 ml of dry tetrahydrofuran is reacted with 1.2 ml of a 1.6 M solution of p-butyllithium in hexane. After stirring for approximately 3 hours at room temperature, a solution of 1.0 g of 5- {decyloxy) -2- [3- (ethoxycarbonyl) benzoyl] benzenepropanoic acid, ethyl ether in 10 ml of dry tetrahydrofuran is added. After stirring for approximately 18 hours, the reaction mixture was kept over silica gel using 0-15% ethyl acetate in hexane as eluent. The appropriate fractions were collected and concentrated to give 600 mg of the desired target substance; the NMR spectrum corresponded to the structure of the desired substance.
    PRI me R 54. 5- [1- (3-Carboxyphenyl) ethenyl] -2- (decyloxy) - benzene propanoic acid.
    The target substance is obtained from the diester of example 53 and example 3. The total yield of 14%. The final product has so pl. 74-78 ° C.
    Calculated,%: C 74.31: H 8.02. SgnezbOz
    Found,%: C 74.18; H, 7.73.
    PRI me R 55. 5- [3- (Ethoxycarbonyl) phenoxy] -2- (decyloxy) benzene propanoic acid.
    A. Preparation of 3- (4-methoxyphenoxy) benzoic acid
    To a suspension of 10.6 g of silver oxide in 75 ml of water, 7 g of sodium hydroxide is added. 10 g of 3- (4-methoxyphenoxy) benzaldehyde are added dropwise and the reaction mixture is heated to 60 ~ 70 ° C for 1 hour. The mixture is filtered, the filtrate is acidified to pH 2 with hydrochloric acid and the resulting precipitate is recovered by filtration. Crystallization from a mixture of ethanol and water gives 6.6 g of the desired intermediate, so pl. 141-143 ° C.
    Calculated,%: C 68.85: H 4.95.
    S14N12O4
    Found,%: C 68.75: H 4.83.
    B. Preparation of 3- (4-hydroxyphenoxy) benzoic acid.
    A mixture of 73 g of 3- (4-methoxyphenoxy) benzoic acid, 300 ml of 48% hydrobromic acid and 600 ml of acetic acid was heated under reflux for 48 hours. Then the reaction mixture was cooled to ambient temperature, poured into cold water and extracted with ethyl acetate . The organic extracts are dried and concentrated in vacuo. The residue is crystallized from a mixture of ethyl and hexane. Get 39.41 g of the desired intermediate substance, so pl. 172-174 ° C.
    Calculated,%: C 67.82: H 4.38.
    С13Н10О4
    Found,%: C 67.99; H 4.64.
    C. Preparation of 3- (4-hydroxyphenoxy) benzoic acid, ethyl ester.
    A solution of 4.9 g of 3- (4-hydroxyphenoxy) benzoic acid. 1 ml of sulfuric acid and 50 ml of ethanol are heated under reflux for 18 hours. The mixture is cooled to 25 ° C and concentrated in vacuo. The residue was dissolved in diethyl ether, washed with water and dried over sodium sulfate and concentrated in vacuo. Obtain 5.2 g of the desired intermediate. NMR spectrum corresponds to the structure of the desired product.
    A. Preparation of 3- (4-allyloxyphenoxy) benzoic acid, ethyl ester.
    To a solution of 5.17 g of the substance from Example 55C in 100 ml of dimethylformamide was added 0.79 g of a 60% dispersion of sodium hydride in the oil. After stirring for 1 h, 2.39 g of allyl bromide was added. The mixture was stirred overnight. Ethyl acetate was added, the mixture was washed several times with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. 4.79 g of the desired substance are obtained. The NMR spectrum corresponds to the structure of the desired substance.
    E. Preparation of 3- (3-allyl-4-hydroxyphenosi) benzoic acid, ethyl ester.
    A solution of 4.97 g of 3- (4-allyloxyphenoxy) benzoic acid, diethyl ether in 25 ml of Ν, Ν-diethylaniline is heated to 210 ° C. for about 2 hours. After cooling, ethyl acetate is added to the mixture and the organic solution is washed several times with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. Residue. Purify by silica gel chromatography using 10-30% ethyl acetate in hexane as eluent. The appropriate fractions are combined and concentrated in vacuo. Obtain 3.13 g of the desired intermediate. The NMR spectrum corresponds to the structure of the desired substance.
    F. Preparation of 3- (3-allyl-4-decyloxyphenoxy) benzoic acid, ethyl ester.
    To a solution of 3.13 g of the intermediate of Example 55 E in 150 ml of dimethylformamide was added 0.44 g of a 60% dispersion of sodium hydride in the oil. After stirring for 1 h, 2.9 g of decyl iodide are added. The reacting mixture was heated at 65 ° C. for 18 hours. After cooling to ambient temperature, ethyl acetate was added, and the organic layer was washed several times with saturated sodium chloride solution, dried and concentrated in vacuo. The residue was purified over silica gel eluting with 5-15% ethyl acetate in hexane. The appropriate fractions were combined and evaporated. 3.69 g of the desired intermediate are obtained. The NMR spectrum corresponds to the structure of the desired substance.
    G. Preparation of 3- [4-decyloxy-3- (3-hydroxypropyl) phenoxy] benzoic acid, ethyl ester.
    A solution of 1.85 g of the intermediate from Example 55F was dissolved in dry tetrahydrofuran and cooled to 0 ° C. Under a nitrogen atmosphere, 8.4 ml of a 0.5 M solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran was added and the reaction mixture was stirred for 18 hours while the solution was warmed to room temperature. Then the mixture was again cooled to 0 ° C and 10 ml of a 3N aqueous solution of sodium acetate were added, followed by the addition of 6.3 ml of 30% hydrogen peroxide. After stirring for 6 hours, the layers were separated. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 5-25% ethyl acetate in hexane. The concentration of the appropriate fractions gives 1.2 g of the desired intermediate.
    H. Preparation of 5- (3-ethoxycarbonylphenoxy) -2- (decyloxy) ben zol hydrochloric acid.
    200 mg of the intermediate from Example 55G are dissolved in diethyl ether. The solution was cooled to 0 ° C. and approximately 3 ml of Jones reagent was added. The reaction was stirred for 18 hours, allowing the mixture to warm to room temperature. Diethyl ether was added, the layers were separated, and the organic layer was washed with sodium bisulfate solution. The organic layer was dried and concentrated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with 30% ethyl acetate and hexane. Get 38 mg of the desired target substance.
    . . PRI me R 56. 5- (3-Carboxyphenoski) -2 (decyloxy) -benzenepropanoic acid.
    A solution of 510 mg of 5- (3-ethoxycarbonylphenoxy) -2- (decyloxy) benzene propanoic acid in 20 ml of ethanol reacts with an excess of potassium hydroxide in a small amount of water. After stirring for 18 hours, the solution was concentrated in vacuo. Diethyl ether was added, the layers were separated, and the aqueous layer was acidified with 1N hydrochloric acid. The aqueous layer was extracted with diethyl ether, and this extract was dried over sodium sulfate and concentrated in vacuo. Two crystallizations from ethyl acetate / hexane give 200 mg of the desired substance, mp. 102-104 ° C.
    Calculated,%: C 70.56: H 7.74. SgbNzdOb
    Found,%: C 71.28: H 7.32.
    PRI me R 57.5- [3- (Ethoxycarbonyl) benzoyl] -2-methoxybenzenepropanoic acid, ethyl ether.
    By the method of Example 1, 20.6 g of isophthalic acid monochloride and monoethyl ether and 30 g of ethyl 2-methoxybenzopropane are reacted with 57 g of aluminum chloride in dichloromethane. Obtain 53.6 g of the desired target substance in the form of oil.
    Calculated,%: C 68.74: H 6.29.
    S22N24O6
    Found,%: C 68.81: H 6.50.
    Example 58. 5- (3-Carboxybenzoyl) -2hydroxybenzenepropanoic acid.
    A mixture of 41.5 g of 5- [3- (ethoxycarbonyl) benzoyl] -2-methoxybenzenepropanoic acid, ethyl ether and 410 g of pyridine hydrochloride is heated at 180 ° C. for 4 hours. After cooling, hot water is added. Upon cooling, the target substance is precipitated from the solution, filtration of solids and crystallization from ethanol and water give 31.1 g of the target substance, mp, 197200 ° C,
    Calculated,%: C 64.97; H, 4.49.
    S17N14O6
    Found,%: C 65.24; H 4.73.
    PRI me R 59. 5- [3- (Ethoxycarbonyl) benzoyl] -2-hydroxybenzenepropanoic acid, ethyl ether.
    The substance from example 58 is heated for 4 days under reflux in ethanol, to which 1 ml of sulfuric acid is added. The mixture was cooled to ambient temperature and concentrated in vacuo. Ethyl acetate was added to the residue, and the organic solution was washed with water, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography using a mixture of ethyl acetate and hexane as eluent gives 21.52 g of the desired target substance, which crystallizes upon aging, mp. 68-70 ° C.
    Calculated,%: C 68.10; H, 5.99.
    C21H22OG
    Found,%: C 67.93: H 5.91.
    Example 60. 2- [6-Phenylhexyl) oxy] -5 (3- (ztoxycarbonyl) benzoyl] benzene propanoic acid, ethyl ether.
    To a solution of 2.89 g of 5- [3- (ethoxycarbonyl) benzoyl] -2-hydroxybenzene propanoic acid, ethyl ether in dimethylformamide, 370 mg of a 50% dispersion of sodium hydride in oil was added. After stirring for 1 h at room temperature, 2 g of 6-phenylhexanol mesyl ether was added. The reaction mixture is heated to 65 ° C and stirred overnight. After cooling, the mixture was added to ethyl acetate, washed several times with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Purification of the obtained solid over silica gel, eluting with 0-2% ethyl acetate in hexane, gives 1.88 g of the desired target substance in the form of an oil.
    Calculated. %; C 74.74: H 7.16.
    SZZNzeOb
    Found,%: C 74.26: H 7.27.
    The following compounds are prepared from suitable phenols and corresponding mesylates by the method described in Example 60.
    . Example 61.2- [6- (Phenylhex-5-enyl) oxy] -5- [3- (ethoxycarbonyl) benzoyl] benzene propanoic acid, ethyl ether, 64% yield. oil.
    Calculated. %: C 74.98; H, 6.86.
    SzzzzbOe
    Found. %: C 75.22; H, 7.09.
    Example 62.5- [3- (Ethoxycarbonyl) benzoyl] -2- [4- (phenylthio) butoxy] benzenepropanoic acid, ethyl ether, 42% yield, oil.
    Calculated. %: C 69.94; H, 6.41.
    C31H24O6S
    Found. %: C 68.39: H 6.14.
    PRI me R 63.5- [3- (Ethoxycarbonyl) benzoyl) -2- (4-phenoxybutoxy) -benzenepropanoic acid, ethyl ether, yield 59%, oil.
    Calculated,%: C 71.80: H 6.61.
    S31N34O7
    Found. %: C 71.81; H, 6.41.
    PRI me R 64. 5- [3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (4-methoxyphenyl) -5-hexenyl] oxy) ben zol propanoic acid, ethyl ether, yield 38.8 % oil.
    Calculated,%: C 73.10; H, 6.86.
    S34N38O7
    Found,%: C 70.47; H, 7.04.
    PRI me R 65. 5- [3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (4-methoxyphenyl) hexyl] oxy} -benzenepropanoic acid, ethyl ether, 66.5% yield, oil.
    . Calculated,%: C 72.83; H, 7.19.
    S34N40O7
    Found,%: C 72.21; H, 7.22.
    PRI me R 66. 2- [6- (4-Chlorophenyl) hexyl] hydroxy-5- [3- (ethoxycarbonyl) benzoyl) benzene propanoic acid, ethyl ether, yield 46.7%, oil.
    Calculated,%: C 70.14; H, 6.60.
    S33N34SYU6
    Found,%: C 73.04; H, 7.26.
    Example 67, · 5- [3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (4-fluorophenyl) hexyl] oxy} benzenepropanoic acid, ethyl ether, 56% yield, oil.
    Calculated,%: C 72.24; H, 6.80.
    Found,%: C 72.50; H, 7.28.
    PRI me R 68. 5- [3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (4-methylmercaptophenyl) -5hexenyl] oxy} -benzene propanoic acid, ethyl ether, 70% yield, oil,
    Calculated. %: C 71.05; H, 6.66. C34H38O6S
    Found,%: C 71.19; H, 6.85.
    PRI me R 69. 5- [3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (3-methoxyphenyl) -5-hexenyl] hydroxy} -benzenepropanoic acid, ethyl ether, yield 41%, oil, IR, MS, NMR.
    PRI me R 70. 5- (3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (2-methoxyphenyl) -5-hexenyl] hydroxy) benzene propanoic acid, ethyl ether, 18% yield, oil, MS, IR, NMR.
    Example 71.5- [3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (3-methoxyphenyl) hexyl] oxy} benzenepropanoic acid, ethyl ether, 94% yield, oil, MS, IR, NMR.
    Example 72.5- [3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (2-methoxyphenyl) hexyl] oxy} benzenepropanoic acid, ethyl ether, yield 98%, oil, NMR.
    PRI me R 73. 5- [3- (Ethoxycarbonyl) benzoyl] -2- [4- (phenylsulfinyl) butoxy] benzenepropanoic acid, ethyl ether.
    A solution of 317 mg of the compound of Example 62 in methylene chloride was cooled to -78 ° C. 127 mg of meta-chloroperbenzoic acid are added to the reaction solution with stirring. After stirring for 5 minutes, the external cooling bath is removed and stirring is continued for another 10 minutes. A few drops of dimethyl sulfide are added, followed by ethyl acetate. The solution was washed with sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography to give 143 mg of the target substance as an oil.
    Calculated. %: C 67.62; H, 6.22.
    C31H34O7S
    Found,%: C 67.39; H, 6.05.
    Example 74.5- [3- (Ethoxycarbonyl) benzoyl] -2- [4- (phenylsulfonyl) butoxy] benzenepropanoic acid, ethyl ether.
    Following the process of Example 73,, 326 mg of the sulfide from Example 62 was reacted with 262 mg of meta-chloroperbenzoic acid at room temperature for 2 hours to give 252 mg of the target substance as an oil.
    Calculated,%: C 65.75: H 6.00, C31H34O8S
    Found,%: C 64.71; H 5.95.
    The following compounds are obtained from the corresponding diesters by the method specified in examples 20-29.
    PRI me R 75. 5- (3-Carboxybenzoyl) -2 [b- (phenylhexyl) oxy) - benzene propanoic acid, yield 62%, mp. 99-101 ° C.
    Calculated,%: C 73.40; H, 8.37.
    SgenZoob
    Found. %: C 73.66; Η 6.41.
    Example 76. 5- (3-Carboxybenzoyl) -2 [6- (phenyl-5-hexenyl) oxy] benzenepropanoic acid, yield 70%, mp. 125-128 ° C. 5
    Calculated,%: C 73.71; H, 5.97.
    SggNgeOb ·,
    Found,%: C 73.92; H 5.71.
    PRI me R 77. 5- (3-Carboxybenzoyl) -2 [4- (phenylsulfonyl) butoxy] benzenepropanoic acid 10, yield 17%, mp. 135-137 ° C.
    Calculated. %: C 65.57; H, 5.30.
    C27H26O7S
    Found,%: C 66.60; H, 5.60.
    PRI me R 78. 5- (3-Carboxybenzoyl) -2-15 [4- (phenylsulfonyl) butoxy] -benzenepripanoic acid, yield 92.5%, mp. 197-199 ° C.
    Calculated,%: C 63.52; H, 5.13.
    C 2 7H 2 60aS 20
    Found,%: C 63.43: H 4.93.
    Example 79. 5- (3-Carboxybenzoyl) -2 {[6- (4-methoxyphenyl) -5-hexenyl] oxy} -benzenepropanoic acid, 64% yield, mp. 151-152 ° C. 25
    Calculated. %: C 71.70: H 6.02.
    S30N30O7
    Found. %: C 71.46; H 6.11.
    PRI me R 80. 5- (3-Carboxybenzoyl) -2 {[6- (4-methoxyphenyl) hexyl] oxy} -benzo-30 lpropanoic acid, yield 53.9%, so pl. 100-102 ° C.
    Calculated; %: C 71.41; H, 6.39.
    S30N32O7
    Found,%: C 71.57; H, 6.22. '35
    PRI me R 81. 2- [6- (4-Chlorophenyl) hexyl] hydroxy-5- (3-carboxybenzoyl) benzene propanoic acid, yield 75%, mp. 119-121 ° C.
    Calculated,%; C, 68.43; H 5.74. 40
    C29H29CIO6
    Found,%: C 68.55; H 5.42.
    PRI me R 82. 5- (3-Carboxybenzoyl) -2 {[6- (4-fluorophenyl) hexyl] oxy} -benzenepropanoic acid, 51% yield, mp. 45 118-120 ° C.
    Calculated,%; C 70.72; H 5.93.
    C29H29FO6
    Found,%: C 70.97; H 6.21.
    PRI me R 83. 5- (3-Carboxybenzoyl) -2- 50 {[6- (4-methylmercaptophenyl) -5-hexenyl] oxy} -benzenepropanoic acid, yield 74%, mp. 138-141 ° C.
    Calculated,%; C 69.48; H, 5.83.
    SzoZzoobb 55
    Found,%: C 69.70; H 5.92. ,
    Example 84.5- (3-Carboxybenzoyl) -2-.
    {[6- (3-methoxyphenyl) -5-hexenyl] oxy} -benzenepropanoic acid, yield 45%. so pl. 122-125 ° C.
    Calculated; %: C 71.70; H, 6.02.
    S30N30O7
    Found,%: C 71.94; H, 6.18.
    Example 85. 5- (3-Carboxybenzoyl) -2 {[6- (2-methoxyphenyl) -5-hexenyl] oxy} -benzenepropanoic acid, yield 33%, mp. 132–13b ° C.
    Calculated,%: C 71.70; H, 6.02;
    S30N30O7
    Found,%: C 71.98: H 6.07.
    PRI me R 86. 5- (3-Carboxybenzoyl) -2 {[6- (3-methoxyphenyl) hexyl] hydroxy} -benzenepropanoic acid, yield 76%, mp. 88-90 ° C.
    Calculated,%: C 71.41; H, 6.39.
    S3ON32O7
    Found. %: C 71.62; H, 6.61.
    PRI me R 87. 5- (3-Carboxybenzoyl) -2 {[6- (2-methoxyphenyl) hexyl] oxy} -benzenepropanoic acid, yield 74%, mp. 125-127 ° C.
    Calculated. %: C 72.41; H 6) 39.
    S30N32O7.
    Found,%: C 71.67; H, 6.56.
    The following compounds are prepared from the compound of Example 68 by the method described in Examples 73 and 74, respectively.
    Example 88. 5- [3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (4-methylsulfonylphenyl) -5hexenyl] hydroxy} benzenepropanoic acid, ethyl ether, 73%, oil.
    Calculated,%: C 69.19; H, 6.43.
    C34H38O7S. Found,%: C 69.00; H, 6.73.
    PRI me R 89. 5- [3- (Ethoxycarbonyl) benzoyl] -2 - {[6- (4-methylsulfonylphenyl) -5hexenyl] hydroxy} -benzenepropanoic acid, ethyl ether, 68% yield, oil.
    Calculated,%: C 67.31; H, 6.31.
    C 3 4H 3 aO8S 'Found,%: C 67.14; H, 6.54.
    The following compounds are obtained from the corresponding diesters by the method used in examples 20-29.
    Example 90. 5- (3-Carboxybenzoyl) -2 {[6- (4-methyl ether sulfon and l phen yl) -5-hexenyl ^ x and} -benzene propanoic acid, yield 71.8%, so pl. 119-122 ° C.
    Calculated,%: C 67.40; H, 5.66.
    C 3 qH 3 o07S
    Found,%: C 67.96; H 5.55.
    PRI me R 91. 5- (3-Carboxybenzoyl} -2 {[6- (4-methylsulphonylphenyl) -5-hexenyl] oxy} benzenepropanoic acid, 70% yield, mp 148-150 ° C .
    Calculated,%: C 65.44; H, 5.49.
    C 3 oH 3 oOsS
    Found,%: C 65.68; H 5.45.
    The compounds of formula (I) are useful in the treatment of any conditions, including clinically .20 clinical ones, which are characterized by excessive secretion of B4 or D4 leukotrienes. These conditions include instant hypertension such as asthma. Evidence obtained over the past few years has shown the presence of leukotrienes in the saliva of patients with chronic bronchitis and cyst fibrosis. The presence of leukotrienes is the cause of these diseases. Moreover, a material has been found in rheumatic synovial fluid that reacts antigenically with LTD4 antibodies. This confirms the existence of leukotriene permeability factor, which together with LTBa increases the inflammatory process. The compounds of the invention should reduce some symptoms of chronic bronchitis and fibrosis of the cyst and probably rheumatoid arthritis due to their ability to: ™ counteract leukotrins.
    The term overexposure of leukotrins refers to the amount of leukotrins sufficient to cause a certain condition associated with such an amount. The amount of leukotrienes that is considered excessive depends on various factors, including the specific leukotrin, the amount of leukotrin needed to cause a certain condition, and the type of mammal.
    The effectiveness of the compound in reducing the connection of leukotriene B4 with human peripheral neutrophils. For this purpose, freshly prepared films of leukocytes in centrifuned blood from two individuals were obtained from the local donor center. Cells are mixed and diluted to 484 ml with phosphoric acid buffer salt containing heparin (10 units / ml) and calf blood serum inactivated by heat (5%).
    This was divided into 20 ml portions and servings deposited on the surface of the FP (12 ml). The material is then centrifuged to 500 g for 40 minutes at room temperature. The obtained top layer of platelets and mononuclear cells was removed. The lower layer containing red blood cells and neutrophils is left. A buffer solution (1 ml per 4 ml of the lower layer) was added and the suspension was mixed. For each 1 ml of this mixture, 0.33 ml of 6% MacRODex was added. After stirring, the cells were precipitated for 1 h at'37 ° C. The obtained erythrocyte pill was removed, and the pop-up liquid rich in neutrophils was centrifuged to 500 g for 10 min at 4 ° C. The erythrocyte cells still present in this pill were dissolved by keeping 5-8 ml of ice-cold distilled water for 30-45 s. Then the volume was adjusted to 50 ml by adding ice-cold buffer solution and resuspending the cells. The suspension was then centrifuged to 300 g for 10 min at 4 ° C. Finally, the cells were resuspended at a density of 2 x 10 7 cells / ml in the sample buffer solution. This solution contained a balanced saline solution of HaNKS and 0.1% ovalbumin (pH 7.3). This separation process resulted in> 90% neutrophil cell preparations and> 90% viability.
    The binder radioligand sample was carried out by incubation of neutrophils (1 x 10 7 cells) with 0.1-0.2 pm 3 K - 1_TVL (150-220 curie / mol) and the experimental compound (1 x 10 ' 5 M and 1 x 10 6 M) in for 10 min at 4 ° C. Then the number of bound STs - LTB4 was measured and compared with the number of bound ones without an experimental compound. The analysis was carried out in microcentrifuge tubes with the addition of 10 ml of the experimental compound first. dissolved in DMSO, followed by the addition of 20 ml of H - LTB4. diluted in test buffer. and finally, 500 ml of cell suspension was added. After 10 min incubation, 300 ml of a mixture of dibutyl phthalate and dinonil (7: 2) were added to the tubes, centrifuged for 2 min in a microcentrifuge. We measured the radioactive bond to the cell pill by scintillation spectroscopy. Corresponding corrections for nonspecific 3 H - LTB4 bonds were separated. ''
    The results of the experiments are shown in the table.
    As can be seen from the table, the compounds of formula (I) are superior in inhibitory effect to the binding of tritium-labeled leukotrin B4 to human peripheral neutrophils.
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of obtaining derivatives of benzophenone or diphenylcarbinol of the General formula I
    W ^ E (CH2) p Z where A and D are the same or different. COORi, where Ri is hydrogen, Ci-C3 alkyl; CN, 5-tetrazolyl;
    E is oxygen:
    Y-CO, SNON:
    Z is hydrogen;
    p = 6-14; η = 0.1;
    m = 0-3, characterized in that the compound of the general formula (II) is reacted with the compound of the general formula (III) • E (CH 2 ) pZ where A and D are COORi. CN:
    Ri is Ci-C3 alkyl;
    Li - COCI:
    L-H or L-COCI, Li-H;
    p, m have the indicated meanings. in the presence of a Lewis catalyst, the resulting product is isolated and compound (I), where Ri is Ci-C3 alkyl, is optionally subjected to alkaline hydrolysis to obtain a compound of formula (I), where Ri is H, or, if necessary, a compound of formula I where A and / or D is CN, is reacted with tin azide to form a compound of formula (I), where A and / or D is 5-tetrazolyl, and which, if necessary, are hydrolyzed to obtain a compound of formula (I), where Ri H, or a compound of formula (I), where Y is CO, is reduced with borohydride to give Nia compound of formula (I), wherein Y-CHOH.
    Example IC50, μM (concentration at which 50% inhibition of the binding of tritium-labeled Leukotrin HF to human peripheral neutrophils is observed) 17 ' 3.1 20 3.2 21 3.4 22 0.81 23 1,1 24 2.2 25 0.27 26 5.7 28 0.75 29th 0.45 33 0.34 Known compounds example 43 8.11
    Compiled by G. Golev Editor N, Gunko Tehred M. Morgenthal Corrector. Dolinich
    Order 2777 Circulation Subscription
    VNIIIPI of the State Committee for Inventions and Discoveries at the State Committee for Science and Technology
    113035, Moscow, Zh-35, Raushskaya nab., 4/5
    Production and Publishing Plant Patent, Uzhhorod, st., Gagarina, 101
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US247987A| true| 1987-01-12|1987-01-12|
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