• 专利附录
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    • 专利摘要:
    This invention provides a series of novel heterocyclic carboxamides of formula I in which the group -Y-Z< is selected from -C(ra)=C<, -N=C<, and -CH(Ra)-CH< and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
    公开号:SU1597098A3
    申请号:SU874202446
    申请日:1987-04-14
    公开日:1990-09-30
    发明作者:Джеффри Браун Фредерик；Квонг Йи Йинг
    申请人:Ай-Си-Ай Америказ Инк (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to novel heterocyclic carboxamide derivatives that can be used in the treatment of diseases involving leukotrienes, for example, allergic disorders such as asthma, inflammatory diseases, endotoxic or traumatic shock conditions.
    The purpose of the invention is the synthesis of new, more active compounds - leukotriene antagonists,
    Example 1, (K-cyclopentylmethylcarbamoyl) -3-C2- (N-methylcarbamoyl) -ethylZindol-1-ylmethyl 4-3-methoxybenzoic acid.
    A mixture of 4-Sat- (N-cyclopentylmethyl-carbamoyl) -3- (2-methoxycarbonylethyl)
    indole-1-ylmethyl-3-methoxybenzoic acid (0.3 g) and 4- (dimethylamino) pyridine (0.07 g) are combined in. pressure vessels with condensed methylamine (75 ml). The mixture is stirred for 24 hours. Then, the amine is allowed to evaporate. The residue is dissolved in water and acidified with 10% (v / v) hydrochloric acid. The sedimented precipitate is collected by filtration and washed with water.
    Obtain 0.26 g (89%) of the title compound as a white powder, t = 274-275 ° C.
    Num,%: C 66.13; H 7.15; K 8.15.
     But oh
    Found,%: C 67.83; H 6.75; N 8.46o
    The starting material is prepared in a manner that is easy to follow.
    a) o A solution of 4-methyl-3-nitrobenzoic acid methyl ester (4.46 g) in 23 ml of S, N-dimethylformamide is treated with N, N-dimethylformamide dimethyl acetal (8.18 g) and heated at 2 hours. The solvent Extraction and residue triturated with ether.
    E-4-C2- (dimethylamino) vinyl j-3-nitrobenzoic acid methyl ester (5.58 g, 98%) is obtained as a red powder.
    SR (80 MHz, deuterochloroform), h, per million: 2.98 (s, 6H, N (methyl)) 5.90 (to, W, CRN); 7.14 (dn, 1H, SNRNYu; 7.45 (ds, 1H,); 7.90 (double Do, 1H,); 8.47 (dn, 1H,).
    b). A solution of methyl eFira 2- (dimetschamino) vinyl J-3-nitrobenzoic acid (5.58 g) in 100 ml of tetrahydrofuran is hydrogenated at a pressure of 3.45 bar in the presence of J 0% (w / w) palladium on carbon (1, 1 g) for 35 min The catalyst is removed by filtration through diatomite, the filtrate is evaporated. The residue is dissolved in ethyl acetate. The resulting solution was successively washed with 10% (v / v) hydrochloric acid, water and brine, then dried with magnesium sulfate and evaporated.
    The methyl ester of indole-6-carbon is obtained. acids (3.32 g, 85%) as a white solid.
    NM (80 MHz, deuterochloroform); hours per million: 3.92 (p. ,, KN, OSI); 6.57 (m; 1H, ... H-nndol), 7.32 (t., W, H-indol); 7.10 (up to, 1H, H-indol); 7.87 (d.Do, 1H, N-indole); 8.16 (shir Co, 1H, N-indole).
    at). A solution of indole-6-carboxylic acid methyl ester (11.0 g) in a mixture of 150 ml of tetrahydrofuran, 150 ml of methanol and 63 ml of water is treated with 15.8 g of lithium hydroxide monohydrate. The mixture was stirred at 60 ° C for 6 hours and then concentrated to remove organic solvents :, The residue was dissolved in water, the solution was acidified with 50% hydrochloric acid (v / v). The resulting precipitate is collected by filtration and dried.
    Indole-6-carboxylic acid (9.6 g, 95%) is obtained as a brownish powder. That pl. 250-254 ° C.
    NMR (80 MHz, deuterochloroform), full name: 6.51 (m, 1H, H -indole); 8.04 (m, W, N-indole); 11.43 (broad s., 1H, H); 12.42 (broad, s, 1H, OH).
    d). A solution of 9.41 g of indole-6-carboxylic acid and 10.6 g of 1, 1-carbonyldiimidazole in 290 ml of methylene chloride is heated to reflux under nitrogen atmosphere for 30 minutes. The solution is cooled and treated with cyclopentstmethylamino (7.0 g). This mixture is heated to boiling for 30 minutes. The resulting solution is then diluted with methylene chloride, subsequently taken up with 10% (v / v) hydrochloric acid, 20% aqueous sodium hydroxide solution and brine, dried with magnesium sulfate and evaporated.
     6- (№-cyclopentylmethylcarbamoyl) indole (14.4 g, 91%) in the form of an ivory-colored powder, t „pLo 148150Сo
    5MP (80 MHz, dimethylsulfoxide-datero), h „per ppm: 3.19 (dd, 2H ,.CHjCH NH); 6.46 (bd, d, 1H, N -indole); 7.91 (d, 1H, H-indole); 8.29 (t „, 1H, CHjNH),
    d). K, N-dimethylformamide (20 ml) is cooled to 0 ° C for 15 minutes, warmed to room temperature and treated with a solution of 6- (L-cyclo pentylmethylcarbamoyl) indole (14.3 g) in 100 ml of dimethylformamide. The yellow mixture is stirred for 2 hours and then alkalinized to pH 14.
    by adding ice and 20% (w / v O aqueous solution of sodium hydroxide. The mixture is heated to boiling for 5 min. and left to cool. The precipitate formed is collected by filtration and triturated with ether. 6- (N-cycloplomethylcarbamoyl) - 3-formylindol (9.6 g, 60%) in the form of a brownish powder, mp 224-225 C. e), Mixture of 6- (N-cyclopentylmethylcarbamoyl) -3-formylindole (0.92 g), t-butyl 4-bromomethyl-3-methoxybenzoic acid ester (1.2 g) and potassium carbonate (0.7 g) in 17 ml of N, N-dimethylformamide are stirred for 48 hours at atmospheric Leray nitrogen. Water is added to precipitate out, which is collected by filtration and dried.
    The tert-butyl ether (N-cyclopentylmethylcarbamoyl) -3-formylindol-1-ylmethyl-3-methoxybenzoic acid (1.2 g, 71%) is obtained in the form of an ivory-colored powder, i.e. 134-135 C „
    . g) A solution of tert-butyl ester of 4.6- (N-cyclopentylmethylcarbamos1) -g-3-formylindol-1 -ylmethyl j-3-methoxybenzoic acid (1.2 g) and methyl ester (triphenylphosphoranylidene) acetic acid (1, 8 g) in 12 ml of dioxane are boiled under reflux for 48 hours. The solvent is evaporated. The residue obtained is purified by flash chromatography on silica gel (600 ml, eluting with ethyl acetate – hexane 3: 7.
    4-.b- - (N-cyclopentylcarbamoyl) -3- (2-methoxycarbonylvinyl) indole-1 -methyl-3-methoxybenoic acid t-butyl ester (1, Jg, 84%) is obtained as a yellow powder, m.p. 163-164 ° C.
    h) A solution of tert-butyl ester (N-cyclopentylcarbamoyl) -3- (2-methoxycarbonylvinyl) indol-1-ylmethyl) -3-methoxybenzoic acid (1.11 g) in methanol (10 ml) is treated with 10% (w / w ) palladium on carbon (0.28 g) and shaken under pressure (3.45 bar) of hydrogen for 24 hours. The catalyst is removed by filtration through diethomide, the filtrate is evaporated.
    A tert-butyl e (LiP 4-Sat- (L-cyclopentylmethylcarbamoyl) -3- (2-methoxycarbonylethyl) indole-1-ylmethyl-3-methoxybenzoic acid (1.04 g, 94%) is obtained as a gray foam, m. square 58-60 S.
    and). A solution of 4-t6- (N-cyclopentylmethylcarbamoyl) -3- (2-methoxycarbonyl1-ethyl) indole -1-ylmethylJ-3-methoxybenzoic acid tert-butyl ester (1.04 g) in 6 ml of dioxane is treated with 0.65 ml of triethylamine and 0 , 8 ml of trifluoromethanesulfonic acid trimethylsilyl ether. The solution is stirred for 24 hours and then diluted with water to give a viscous oil. The liquids are decanted. The oil is subsequently triturated with water and hexane. The resulting solid is recrystallized from a mixture of ethyl acetate in hexane.
    (N-cyclopentyl0 methylcarbamoyl) -3- (2-methoxycarbonyl ethyl) indol-1-methylmethyl-3-methoxybenzoic acid (0.3 g, 32%) is obtained in the form of an ivory powder, mp. 181-182С,
    five
    i) A solution of 3-methoxy-4-methylbenzoic acid (10.0 g), concentrated sulfuric acid (1 ml) and condensed isobutylene (200 ml) in 200 ml of methyl chloride 0 is placed in a container under pressure and stirred for 16 h Then the container is opened to see unreacted isobutylene. The remaining liquid is poured into 150 ml.
    5 of a 10% (w / v) solution of sodium hydroxide and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel (700 ml), eluting with a mixture of ethyl acetate and hexane 1: 9
    9.1 g (70%) of tert-butyl ester of 3-methoxy-4-methylbenzoic acid are obtained in the form of a colorless oil, o
    NMR (80 MHz, deuterochloroform), Cl, per million: 1.6 (s., 9H, C (CHR); 2.27 (s., 3N, methyl); 3.86 (s., 3N,
    With OSI,); 7.11 (d ,, 1H); 7.49 (M, 2H).
    to). Suspension of tert-butyl ester Z-methoxy-4-methylbenzoic acid (8.92 g), N-bromosuccinimide (8.57 g) and benzoyl peroxide (0.1 g)
    5 in carbon tetrachloride (150 ml) is heated to a boil and irradiated with an ultraviolet lamp for 1 hour. After cooling to room temperature, the suspension is filtered, the filtrate is evaporated. The residue was purified by flash chromatography on silica gel (700 ml), eluting with a mixture of ethyl acetate and hexane 5: 95p. 11.52 g (95%) of tert-butyl ether 4 bromomethyl-3-methoxybenzoic acid was obtained as a light yellow oil, NMR (80 KHz, detyrochloroform), h „per million: 1.5 (s. 9H, C ()) i 3.9 (s. 3N, OSI); 4.5 (co, 2H, CHjBr); 7.15 (dn, 1H); 7.4 (m, 2H) Example 2, N-14- 6- (N-cyclo-pentilmethylcarbamoyl) (N-methyl-carbamoyl) ethyl indole-methylmethyl-1-3-methoxybenzoyl | -2-methylbenzenesulfonamide. A solution of 4- {b- (L-cyclopentylmethyl carbamoyl) -3- | 2- (N-mr.thylcarbamoyl) ethyl Zindol-1-ylmethyl-3-methoxybenzoic acid (0.25 g) according to example 4- (dimethylamino) -pyridine (0.07 g), 1- (3-dimethylaminopropyl) -3 -ethylcarbamide dimide hydrochloride (0.12 g) and orthotoluenesulfonamide (0.09 g) in 3.0 m of methylene chloride are stirred under nitrogen atmosphere for 24 hours. The mixture is diluted with methylene chloride, followed in succession by 10% (v / v). v.) hydrochloric acid, water, and brine and extract. The resulting ivory-colored solid is purified by flash chromatography on silica gel (10 ml), which is eluted with a mixture of methanol and chloroform 1: The desired compound (0.06 g, 17%) is obtained in the form of ivory. That pl. . Calculated,%: C 65.02; H 6.27; S 8.66. -0.1 NgO Found;%: C 64.73; H 6.29; N 8.66. Example 3 “(2-Cyanovinyl) -6- (K-cyclo pentylmethylcarbamoyl) indol-1-ylmethyl} -3-methyxyxybenzoic acid tert-butyl ester. Analogously to Example 1, part (g), using cyanomethylenetriphenylphosphorus instead of methyl ester (triphenylphosphoranylidene) acetic acid, obtained the target compound as a yellow solid, (78%). NMR (partial 80 MHz, deuterochloroform), Cho per million: 3.41 (d.Do, 2H, 3.93 (s, 2, 1H, AXIS, E-isomer); 3.97 (C, O, 9H , OCH ,,, Z-isomer); 5.20 (d. O, 3N, CHCN, Z-isomer); 5.38 (s, 1, 4H, ArsN, Y-isomer); 5.44 (s. O, 6H, ArsN, Z-isomer); 5.74 (d, 0.7H, CHCN, E-isomer); 6.19 (shooting, s, 1H, NH). Example 4. (2-Cyanovinyl) -6- (K-cyclopentylmethylcarbamoyl) nndol-1-ylmethyl J-3-methoxybenzoic acid. Analogously to Example 1, part (s), starting from the compound from Example 3, the desired compound is obtained as a white powder (87 %), M.p., 277279 ° C. Calculated,%: C, 70.88; H, 5.95; N, 9.18 ° C, H, MsO. Found,%: C, 70.68; H 6.02; N 9.08. Example 5c N-t4- 3- (2-cyanovinyl) -6- (N-cyclopentylmethylcarbamoyl) indol-1-ylmethylJ-3-methyl-toxoxybenzoyl-2-methyl-benzenesulfonamide Analogously to Example 2, starting from the compound of Example 4, the desired compound is obtained in the form of a white solid (79%), mp 174176 C (c. Calculated,%: C, 65.89; H, 5.69; N, 9.04; Cz4L34 4 4-0.5; Found,%: C, 65.62; H, 5.63; N, 9.00. Example 6c N-) 4- | 6- (N-cyclopentylmethlcarbamoyl) -3-t2- (morphoIshnocarbonyl) ethyl indol-1 -ylmethyl} -3-methoxybenzoyl) benzenesulfonamide. Analogously to Example 2, starting from (L-cyclopentylmethylcarbamoyl) 7 3-E2- (morpholinocarbonyl) ethyl} indole-1-ylmethyl-3-methoxybenzoic acid and phenylsulfonamide, the title compound is obtained as white. solids (69%), t, pl. 244245 C. Calculated,%: C 64.70; H 6.16; N 8.16. N40, S Found,%: C 64.65; H 6.18; N 7.96. The original indole is obtained as follows. The solution (N-cyclopentylmethylcarbamoyl) -3- (2-methoxycarbonylethyl) indol-1-ylmethyl 3 3-methoxybenzoic acid (0.68 g) according to example 1, part (a) - (and), and 4- (dimethylamino) pyridine (0.17 g) in morpholine (4 ml) is heated under nitrogen for 48 hours. The reaction mixture is diluted with water and acidified with 10% (v / v) hydrochloric acid. The precipitate formed is collected by fnltion and washed with water. The product is purified by recrystallization from ethyl acetate. 0.31 g (41%) of 4- {6- (N-um of lopentylmethylcarbamoyl) (morpholinecarbonyl; ethyl} indol-1-ylmethylJ-3-methoxybenzoic acid is obtained in the form of a white powder. NMR (partial, 80 MHz, deuterochloroform), ppm: 1.2-1.8 (Mo, 9H, cyclopentyl); 2.7 (dd, 2H, CH 3.15 (t, 2H, COCHj); 3.2-3, 7 (m, 8H, morpholino); 3.92 (s., MN, OCHP 5.35 (s., 2H, ApCHj); 6.58 (t, 1H, NK); 7.17 (up, 1H ); 7.9 (s., LN, H-indol). EXAMPLE 7 N- | 4-t6- (N-cyclopentyl methylcarbamoyl) (morpholino carboyl) ethyl indol-1-Sh1methyl | -3-methoxybenzoyl | -2-methy l ben sol ulfonamid. Analogously to example 2, starting from 4- {b- (K-cyclopentylmethylcarbamoyl) (morpholinocarbonyl) ethyljind ol-1-ylmethyl g-3-methoxybenzoic acid according to example 6 gives the desired compound as a white powder (28%), t „pl 159-161c. Calculated,%: C 65.12, H 6.33; N 7 , 99. Cj., Found,%: C 64.75; H, 6.34; N, 7.88. Example 8 of N- | (N-cyclo pentylmethylcarbamoyl) (pyrrolidinocarbonyl) ethyl indol-1-ylmethyl-3-methoxybenzoyl 2) 2-methylbenzenesulfonamide Analogously to Example 2, starting from (L-cyclopentylmethylcarbamoyl) -3-f2- (pyrrolidinecarboiyl) ethyl} indole-1-ylmethyl-3-methoxybenzoic acid, the desired compound is obtained as a white powder (48%), Then square 190-191 ° C. Calculated,%: C, 66.64; H 6.48; N 8.18. Found,%: C 66.44; H 6.46; N 8.02. The starting indole is prepared as follows. A solution of (H-cyclopentylmethylcarbamoyl) -3- (2-methoxycarbonylethyl) indol-1-ylnethyl-3-methoxybenzoic acid (0.84 g), according to example 1, part (a) - (and), and 4- (dimethylamino) pyridine (0.21 g) in 5 ml of pyrrolidine is heated at 80 ° C for 48 hours in the atmosphere of nitrogen. The reaction mixture is diluted with water and acidified with 10% hydrochloric acid (v / v). The precipitate formed is collected by filtration and washed with water. 4-Ub (K-cyclopentsh1carbamoyl) (pyrrolidinocarbonyl) ethyl} indole-1-ylmethyl-3-methoxybenzoic acid is obtained in the form of a white powder (0.77 g, 85%). 5IMP (partial, 80 MHz, deuterodimethylsulfoxide), ppm: 1.12, 0 (m, 12H); 2.1 (m, 1H, NHCH, CH); 3.0 (s., ZN, the main.); 6.7 (d, 1H, Ar); 7.3 (s, JH, H-indole); 8.3 (1H, NH). Example 9. NI 4-1b- (K-cyclopentylmethylcarbamoyl) (H, N-dimethylcarbamoyl) propyl indol-1-ylmethyl-3-methoxybenzoyl 1-2-methylbenzene-sulfonamide in Analogously to Example 2, starting from (L-cyclopentylmethylcarbamoyl). dimethylcarbamoyl). propyl indol-1-ylmethylj-3-methoxybenzoic acid gives the title compound as a yellow powder (56%), so pl. 140-143 ° C. Calculated,%: C 65.18; H 6.65; N 8.21. C37H44N40tS - 0.5 Found:%: 65.15; H 6.65; N 8.11. The starting material was prepared as follows a). A solution of tert-butyl ether (N-cyclopentylmethylcarbamoyl) -3-formylindol-1-ylmethyl J-3-methoxybenzoic acid according to example 1, part (e), (2.8 g) and ( carbethoxyethylidene) triphenshphosphorane (4.6 g) in 29 ml of dioxane is refluxed for 18 hours, the solvent is evaporated. The resulting stack was purified by flash chromatography on silica gel (192 ml), eluted with ethyl acetate-hexane I: 4. Get tert-butyl ether (N-cycle opentylmethylcarbamoyl) -3- (2-ethoxycarbonylpropenyl-1-yl) indole-1-ylmethyl-3-methoxybenzoic acid (3.3 g, 100%) as a light yellow solid, t „ pl 18-120s NMR (80 MHz, deuterochloroform), ppm: 2.15 (to, 3N, CCH) j 3.40 (dd, 2H, NHCH); 5, A2 (p., 2H NCH); 6.22 (broad t., 1H, NH); 6.78 (d. 5H, Ap). b) A solution of tert-butyl ether (N-cyclopentylmethylcarbamoyl) -3- (2 Ethoxycarbonylpropylidene-1-yl) indole-1-ylmethyl J-3-methoxybenzoic acid (3.3 g) in methanol (30 ml is treated with 10% - palladium on coal (0.8 g) and shaken under a hydrogen pressure of 3.46 bar for 18 hours. The catalyst is removed by filtration through diatomite, the filtrate is charged in. The tert-butyl ether 4-Q6 is obtained (N-cyclopentyl methylcarbamoyl) (2-ethoxycarbonylpropyl) indol-1-ylmethyl J-3-methoxybenzoic acid (3.3 g, 100%) as a colorless oil. NMR (partial, 80 MHz, deuterochloride formalization), ppm: million; 3.40 (t, 2H, NHCH-J); 3.94 (s, OG, OCH); 4.10 (q, 2H, OCH); 5.33 (s , 2H, NCH / j) 6.14 (broad To, 1H, NH); 6.63 (d, 1H, Ap); 7.04 (s., W, n-indol); 7.85 (broad. s, 1H, H-indole.) c) Solution of tert-butyl ether (N-cyclopentylmethylcarbamoyl) -3- (2-ethoxycarbonylpropyl) indole-1-yl 1 methyl 3-3-methoxybenzoic acid (0.75 g) mixtures of 3.5 ml of tetrahydrofuran, 3.5 ml of methanol and 1.3 ml of water are treated with lithium hydroxide monohydrate (0.33 g). The mixture was stirred for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, the solution was acidified with 10% (v / v) hydrochloric acid. The resulting precipitate was collected by filtration and dried. The tert-butyl ether was obtained. (N-cyclopentylmethylcarbamoyl) -3- (2 carboxypropyl) -indole-1-ylmethyl J-3-methoxybenzoic acid (0.68 g, 95%) as a white powder, mp 195-197 ° C NMR (partial, 80 MHz , deuterochloroform) parts per million: 2.55-3.24 (mo, zn, diabetes, SNSNZ); 3.38 (t, 2H, NHCHj); 3,9Г (с., ЗН, OCHj); 5.24. (s, 2H, NCHi); 6.17 (broad t., 1H, 1,812 tftl) 6.61 (dn, 1H, Ap); 7.04 (s., 1H, N-indole); 7.85 (brs, 1H, N -indole) (d). A solution of tert-butyl ether (N-cyclopentylmethyl carbamoyl) - -3- (2-carbox typyl) indol-l-methylmethyl-3-methoxybenzoic acid (0.96 g) and 1,1-carbonyldiimidazole (0.42 g) in 9 ml of methylene chloride are refluxed under nitrogen for 1 hour. The solution is transferred under nitrogen to a pressure vessel containing 60 ml of condensed dimethylamine. After the vessel is sealed, the mixture is heated for 90 hours. The amine is then evaporated. The residue is diluted with water, acidified with 50% (v / v) hydrochloric acid and extracted with methylene chloride. The organic extract is washed with water and brine, dried over magnesium sulfate and evaporated. The residue is purified by flash chromatography on silica gel (160 ml), eluted with a mixture of methanol and chloroform 1: 9o. 4-Eb- (H-cyclopentylmethtcarbamoyl) -3-C2- (K, K-dimethylcarbamoyl) propyl indol-t-butyl ester is obtained 1-yl-type-3-methoxybenzoic acid (0.53 g, 53%) as a white crystalline foam, so pl. 7375С NMR (partial, 250 MHz, deuterochloroform), h per million: 1.18 (before, MN, CHSNZ); (s. 9H, C (CH3) h); 2, (mo, sh, chjch); 2.75 (s., SN, NCH ,,); 2.83 (s., NZ, NCH); 2.96-3.21 (Mo, 2H5 CH CHCH3); 3.40 (dd, 2H, NHCH); 6.17 (broad t, 1H, NH); 6.60 (up, W, Ar); 7.0.6 (s., 1H, H-indole); 7.86 (brs, 1H, N -indole). , e). A solution of tert-butyl ether 4- {6- (N-cyclopentylmethylcarbamoyl) -3- | 2- (M, K-dimethylcarbamosh1) propyl indol-1-methylmethyl-3-methoxybenzoic acid (0.53 g) in 3 ml of dioxane was analyzed with 0.31 ml of triethylamine and 0.38 ml of trifluoromethylsulfonic ester. The solution is heated under nitrogen to boiling for 30 minutes, allowed to cool, and then diluted with water and a precipitate is collected by filtration and dried under vacuum. This gives (N-cyclopentyl methylcarbamoyl) -3- {2- (N, N-dimethyl-apyl mil) ) propyl α-indol-1-ylmethyl) -3-methoxybenzoic acid (0.33 g, 66%) as a yellow powder, i.e. 120122С. NMR (partial, 250 MHz, deuterodimethylsulfoxide), h, per million: 1.04 (to, 3N, CHCHj); 2.07-2.24 (m, 1H, CHjCH); 2.7T (s., ZN, KSNz); 2.80 (s., SN, SNZ); 3.93 (s., ZN, OCH,); 5.42 (s, 2H, NCH,); 6.58 (d, III, Ar); 7.30 (s „, 1H, I -indole); 7.40 (up, 1H, H-indol); 7.90 (broad, s, 1H, I-indole); 8.33 (broad t, 1H, NH). Example 10. (N-cyclophenylcarbamoyl) -3- (dimethylcarbamoyl simethyl) indazol-1-ylmethyl 3-methoxy benzoic acid. By hydrolysis of the ester according to Example 9, part (c), starting from methyl (L-cyclopentylmethylcarbamoyl) -3- (dimethylcarbam iloxymethyl) indazol-1-ylmethyl-3-methoxybenzoic acid methyl ester, the target compound can be obtained in solid form. The original indazole was prepared as follows, a). A solution of 15.1 g of 3-amino-4-methylbenzoic acid in 150 ml of tetrahydrofuran is added to a solution of boron trifluoride ester (18 ml) in chloroform (450 ml, treated with alumina) at -15 over 15 minutes. The resulting mixture is further stirred for 5 minutes. To this mixture is added 14 ml of tert.-butylnitol. The reaction mixture is heated to 5 ° C. After stirring for 1 hour, 49 g of potassium acetate and 2.65 g of 18-crown ether-6 are added. The reaction mixture is allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was evaporated and 3: 7 acetone-ethyl acetate was added to it. (500 ml) and 150 ml of 1N hydrochloric acid. After stirring for 2 hours, 150 ml of brine is added to the mixture. The mixture is filtered. The aqueous filter is extracted twice with a mixture of acetone - ethyl acetate 3: 7 (100 ml). The combined organic extracts are dried over magnesium sulfate and evaporated. The residue obtained is dissolved in hot acetic acid (250 ml). 250 ml of a saturated ethereal HCl solution and 250 ml of ether are subsequently added thereto. After cooling to ambient temperature, the precipitate is filtered and treated with a mixture of acetone / ethyl acetate 3: 7 (500 ml) and brine (100 ml) for 1 hour. After separation of the phases, the aqueous layer is extracted with ethyl acetate (100 ml). The combined organic extracts are brine, dried with magnesium sulfate and evaporated. 6-1-arboxindazole (9.8 g, 57%) is obtained as a brown solid, m.p. above 250Co b) o To a solution of 4.0 g of 6-carboxyindazole in 14C ml of acetic acid, 1.53 ml of bromine is added. The mixture is stirred in the test for 24 hours. After 50 ml of saturated yy are added. fСГ -sodium bisulfite solution and 100 ml of brine mixture is arranged with ethyl acetate. “The organic layer is washed with brine, dried with magnesium sulfate and. evaporated. The resulting solid is ground to powder and dried under vacuum to obtain 5.88 g (99%) 3-bromo-6-arboxindazole as a light brown solid, t, taken to 250 ° C. at). To a mixture of 184 g of 3-bromo-6-karyuksindazol, 3.5 g of 1- (3-dimethylaminopropyl) -3-eylcarbodiimidehydroXJ opida, 3.48 ml of cyclopentylmethylamine, 120 ml of hls of methylene and 40 ml of dimethylfo; g 4-dimethylacnopyridine. After stirring for 48 hours, the reaction mixture is added to 450 ml of ethyl acetate: ha, washed with IH, hydrochloric acid, 0.5 M pai-BopoM sodium carbonate and brine,; tub with magnesium sulfate and evaporated; Ost | , ca. flash flash chromatography and jugdjda per 175 g of silica gel, successively elute xjiOpF ,,, with methylene (350 ml) and with an ethncetate – methylene chloride mixture 15:85. 3.6 g (72%) of 3-bromo-6- (N-cyclo.P-methylmethyl-carbamoyl) -indazole are obtained in a light red solid. That pl. 119-125 ° C. g) A mixture of 60%. The sodium hydrite dispersions (13 mg) are washed with petroleum ether and 0.75 ml of dimethylformamide is added. This mixture is cooled to 0 ° C. In RSe, a solution of 107 mg of 3-bromo-6- (N-cyclophenylmethylcarbamoyl) indazole in 0.75 ml of dimethylformamide is added. After stirring for 30 minutes, 4-bromomethyl 3-methoxybenzoic acid methyl ester (95 mg) was added. After 15 minutes of stirring, the mixture was allowed to warm to room temperature. The reaction mixture is stirred for 1.5 hours. 40 ml of ethyl acetate are added to it. The solution is washed with brine, water and brine, dried with magnesium sulfate and evaporated. The residue is subjected to flash chromatography on 1 g of silica gel, which is eluted with a mixture of ethyl acetate - methylene chloride 5:95. 4- (3-bromo-6 (N-cyclopentylmethylcarbamoyl) methyl ester is obtained - Dazol 1-ylmethyl) -3-methoxybenoic acid (136 mg, 82%) as a white solid, m.p., 161-162.5 Calculated,%: C 57.49; H 5.42; N 8.38. .j-, BrN304 Found,%: C 57.53; H 5.29; N 8.28, d) o To a solution of zinc bromide (6–75 g, dried at 180 ° C, pressure 67 Pa 2 h) in 90: ml of tetrahydrofurac, 25 ml of III solution of zinc magnesium bromide in ether are added. The mixture is stirred by 15 m at room temperature. temperature before adding 83 mg dichloro p, 1 -bis- (diphenylphosphino) ferrocene) palladium} (11), the reaction mixture; heated for 120 hours at 45 ° C. After the mixture was stirred for 48 and 84, additional portions of palladium reagent (183 mg each) were added to the mixture. The reaction mixture was added to and 50 ml of 1N hydrochloric acid N 250 ml of ethyl acetate was added. Stir 15 mixture min, after what go ea filter; through the diatomite together with a portion of ethyl acetate o. The organic layer is washed with water and brine, dried with magnesium sulfate and evaporated. The residue is flash chromatographed on 200 silica gel. It is distilled with methylene chloride (800 ml), a mixture of ethyl acetate and methylene chloride 2.5: 97.5 (500 ml) and a mixture of ethyl acetate: methylene chloride 5:95, to obtain a solid after recrystallization and methylene chloride and petroleum ether get 4-L6- (I-cyclopentylmethylcarbamoyl) -3-) methyl ester and niliHdazol-1-ylmethyl J-3-methoxybenzoic acid as a colorless solid (944 mg, 42%), t, mp . 138-140 ° C, re-hardening and re-melting at 168170, 0 ° C. Mass spectrum (chemical ionization) 48 (M + H), e), Solution of methyl ester (K-cyclopentylmethylcarbamoyl) -3-vinylindazol-1-ylmethyl-3-methoxybenzoic acid (700 mg) in a mixture of methylene chloride and methanol 1: 1 (30 ml) when ozonated for 25 minutes. Excess ozone is removed by passing oxygen through the reaction mixture for. Sodium borgndrid (100 mg) is added. The mixture is allowed to warm to room temperature. After stirring for 2 hours, the mixture was cooled to OC, terminate the reaction by adding 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (100 ml). The organic layer containing the insoluble precipitate is concentrated to approximately 50 ml and filtered. The solid is triturated under vacuum over potassium hydroxide for 18 hours. (N-cyclopentylmethylcarbamoyl) -3-hydroxymethylindazol-1-ylmethyl-3-3-methoxybenzoic acid methyl ester is obtained as a colorless solid (569 mg, 81%), t. mp, 187-187.5 ° C. Mass spectrum (chemical ionization): 452 (M + H), g). To a suspension of 60% sodium hydride dispersion (13 mg, washed with petroleum ether) in tetrahydrofuran (1 ml) was added a solution of (N-cyclopentylmethylcarbamoyl) -3-hydroxymethylindazol-1-ylmethyl-3-methoxybenzoic acid (151 mg) ) in a mixture of dimethylformamide - tetrahydrofuran 7: 1 (8 ml). After stirring for 45 minutes, 0.033 ml of dimethylcarbamoyl chloride was added. The reaction mixture was stirred for 15 minutes, allowed to warm to room temperature. After 3 hours, 1N hydrochloric acid is added. The mixture is extracted with ethyl acetate. The organic layer was brine and dried with magnesium sulfate. After shaking and purifying by flash chromatography on 15 g of silica gel eluted with ethyl acetate-methylene chloride 2: 8, methyl (N-cycloH1-methylmethylcarbamoyl) -3- (methimericarbamoyloxymethyl) indazol-1-ylmethyl-3-metho-hydroxy-hydroxymethylcarbamoylyloxymethyl) indazol-1-methylmethyl-3-metho-hydroxymethylcarbamoyloxyloxymethyl) indazol-1-methylmethyl-3-metho-hydroxymethylcarbamoylyloxymethyl) methyl ester indazol-1-methylmethymeroxymethyloxycarbamoyloxyloxymethyl) indazol-1-methyl-3-methyloxy-hydroxymethyl) 3-methyloxymethylcarbamoyloxyloxymethyl) methyl ether indazol-1-methyloxycarbamoyloxymethyl) indazol-1-methyl-methyl; solids (40 mg 23%).
    Mass spectrum (chemical ionization): 523 (M + H).
    The substances obtained may be useful in the treatment of diseases involving leukotrienes, such as allergic pulmonary disorders, such as asthma, senna fever and allergic rhinitis, and some inflammatory diseases, such as bronchitis, ectopic and atonic eczema, psoriasis, as well as vasospastic cardiovascular disease and endotoxic or traumatic shock.
    The proposed compounds are strong leukotriene aktogonists and can be used as pharmacological standards for the development and standardization of new models and analyzes of diseases, in the development of new therapeutic agents for the treatment of diseases involving leukotrienes. The compounds are used in combination with a pharmaceutically acceptable diluent or carrier, depending on the route of administration, for example, in the form of tablets, capsules, solutions or suspensions for oral administration: in the form of suppositories for rectal administration; in the form of sterile solutions or suspensions in dp administration by intravenous or intramuscular injection or infusion; in the form of aerosols or nebulized solutions or suspensions for inhalation; in the form of powders, together with a pharmaceutically acceptable inert solid diluent, such as lactose, for administration by injection.
    Tablets or capsules containing up to 250 mg (and usually from 5 to 100 mg) of the test compound are taken orally; For intravenous or intravenous injection or infusion, a sterile solution or suspension containing up to 10% by weight (0.05% to 5% by weight) of the compound is used.
    The dose of the substance varies depending on the method of administration and the complexity of the condition, as well as the weight and
    the age of the patient and may be, for example, given to warm-blooded animals (such as humans) from 0.05 to 25 mg / kg (0.5 to 10 mg / kg).
    The properties of the studied compounds of leukotriene antagonists can be demonstrated outside the body using a standard preparation of the tracheal band of the guinea pig. The tracheal tissue bands are in groups of eight, four of which are used as dimethyl sulfoxide as the control carrier, and
    5, four others: treat them with test compounds. All bands are exposed to leucrigen E (LTE at a concentration of 8-1 mol / L, followed by a period of equilibration for 50 minutes and recording the response-LTE. At a concentration of 8-10 mol / L can cause reductions of approximately 70-80 % of maximum agonist effect in this tissue.
    5 LCTs were washed for 40-45 minutes, the process was repeated twice to ensure reproducibility of the response. Instead of LTE, you can use leukotriene C (LTS) or D
    0 (LTD).
    After establishing the reproducibility of the tissue response, the test substances were added to the four solutions in the bath, followed by a 405 45 minute washout period. After 10 minutes of exposure to the test compound or carrier, add 8) M / L of LTE, LTD, or LTC and record the response. The percentage of inhibition of I by the test substance or the percentage of change compared to the control of the carrier is calculated for each tissue according to the following equation:
     . (X)
    five
    - (%),
    t ".
    权利要求:
    Claims (1)
    [1]
    where X is the increase in voltage of the previous response, mg; Y increase in voltage in the presence of a substance, mgo Average percent change for control of the carrier and test compound is calculated and evaluated for significance of differences using Student's test, t is a test for unpaired data. Tissues subjected to the action of the tested substances are re-tested to receive from 19 clicks on LTE LTD and LTC with the next AZ-minute prompting period. There is a tissue's ability to respond equal to that preceded by the test substance, then additional research is done. If the ability to respond cannot be stopped after the washing operation, the fabric is discarded. For all determinations, there is an inhibitor of cyclooxygenase - indomethacyc, at a concentration of 5-10 mol / l. The test substances demonstrate statistically significant activity as antagonists of LTS, LTD I / I.GSh LTE / (in the above tests at a concentration of about 0 mol / l or much less. The selectivity of the action of these substances as leukotrienes antagonists compared to non-specific depressor smooth muscle can be indicated by performing the described test outside the body using non-specific spasmogen - barium chloride at a concentration of 1.5 mmol / l, in the presence of indomethacin at a concentration of 5-1 0 mol / L. Activity as a leukotriene antagonist can also be demonstrated in laboratory animals, for example, in a standard guinea pig aerosol test, in which guinea pigs are pre-set the dose of the test substance (usually between 15 minutes and 1 hour) prior to aerosol infection. leukotriene LTD, (starting with 3 ml of solution) 30 mg / ml, and the action of the test substance, for the average time initiated by leukotriene, changes in breathing patterns (such as the onset of odds) is recorded and compared with breathing control guinea pigs that did not receive a dose of the substance. The test substances significantly increase the time until the onset of respiratory changes caused by leukotriene after their oral or intravenous administration, or by inhalation at a dose of about 100 mg / kg or much less, without any indication of unpleasant side effects with a slightly increased minimum effective dose. . For example, the compounds of Example 8 are effective 8 for oral administration at a dose of 2 mmol / kg, and there is no evidence of acute toxicity after oral administration of a dose of 30 mmol / kg. Known compound: R, - H, R cyclopentylmethyl, R j - H, R methoxy. Well - phenyl, provides inhibition of the 46% reduction caused by leukotriene E at a concentration of 100 nM. The proposed compounds have high activity at a lower concentration of 1-10 nM and are leukotriene antagonists, which is confirmed by the following data on the inhibition of activity against LTE4 (see table). The compounds obtained are of low toxicity. Claims of Invention A method for preparing heterocyclic carboxamides of the general formula OONHSOqiR hydrogen; - (Cz-c) cycloalkyl - C-C -alRJ - L-P; L-C - Cd-alkylene or vinyl P - () - alkylcarbamoyl, di (C | -C) -alkylcarbamoyl, cyano group, morpholinocarbonyl or. pyrrolidine; arbonyl; R (,) is alkoxy;
    R is unsubstituted phenyl or phenyl having a (C, -C4) -alkyl substituent; And - CH or N,
    characterized in that the compound of formula
    where R, -R4 have the indicated meanings;
    M - carboxy group,
    subjected to interaction with the sulfonamide of the formula
     t 2
    in the presence of a dehydrating agent.
    Priority featured:
    15.0A, 86 with R is hydrogen, Rj (Cz-C) -cycloalkh 1, is alkyl,
    RS L D C -C3-alkylene or vinylene; P - (C-C alkylcarbamoyl,. Di () alkylcarbamoyl, cyano, morpholinocarbonyl, R (C, -C4.) Alkoxy, unsubstituted phenyl or phenyl,
    having a (C-C4) -alkyl substituent, A — CH or N.
    10/15/86 with P - pyrrolidinocarbonyl.
    类似技术:
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    同族专利:
    公开号 | 公开日
    PL265151A1|1989-03-06|
    JPH0768211B2|1995-07-26|
    EP0242167A3|1988-10-12|
    ZW6387A1|1988-11-23|
    AU602515B2|1990-10-18|
    EP0242167A2|1987-10-21|
    IE870837L|1987-10-15|
    FI871632A0|1987-04-14|
    DE3774749D1|1992-01-09|
    NZ219978A|1990-08-28|
    IE60013B1|1994-05-18|
    AU7139387A|1987-10-22|
    HU199791B|1990-03-28|
    IL82126D0|1987-10-30|
    PT84681A|1987-05-01|
    ES2038172T3|1993-07-16|
    GB8707051D0|1987-04-29|
    PL153341B1|1991-04-30|
    NO871588L|1987-10-16|
    GR3003209T3|1993-02-17|
    JPS638369A|1988-01-14|
    DK190587D0|1987-04-13|
    CN87103504A|1987-12-09|
    DK190587A|1987-10-16|
    PT84681B|1989-12-29|
    FI871632A|1987-10-16|
    KR870010010A|1987-11-30|
    HUT43819A|1987-12-28|
    NO871588D0|1987-04-14|
    EP0242167B1|1991-11-27|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB868609175A|GB8609175D0|1986-04-15|1986-04-15|Heterocyclic carboxamides|
    GB868624698A|GB8624698D0|1986-10-15|1986-10-15|Heterocyclic carboxamides|
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