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    • 专利摘要:
    The invention provides a series of novel heterocyclic ketones of formula I (set out hereinafter) and pharmaceutically acceptable base-addition salts thereof, in which the values of R4, L, A, X and Q have the meanings defined in the following specification. The compounds of formula I are inhibitors of human leukocytic elastase. The invention also provides pharmaceutical compositions containing a compound of formula I, or a pharmaceutically acceptable base-addition salt thereof, and processes and intermediates for the manufacture of compounds of formula I.
    公开号:SU1678207A3
    申请号:SU884355719
    申请日:1988-05-06
    公开日:1991-09-15
    发明作者:Дьюк Эдвардс Филип；Джеймс Льюис Джозеф；Вилльям Перкинс Чарльз；Эми Трейнор Даяна；Алан Вилдонджер Ричард
    申请人:Ай-Си-Ай Америказ Инк (Фирма)；
    IPC主号:
    专利说明:

    where Ri is a group of the formula R2 - S02NHCO-, R2S02NHCONH- or CF3S02NH-, where R2 is chlorophenyl, X is oxygen or sulfur, Q is o-phenylene, unsubstituted or substituted by hydroxy group or (Ci-Cq) is alkoxycarbonyl, or Q - cis-vinylene, which are inhibitors of human leukocyte elastase (LEC). This property suggests the possibility of using these compounds in medicine.
    The purpose of the invention is to obtain new heterocyclic ketones, possessing a new type of biological activity for this purpose - the ability to inhibit human leukocyte elastase.
    The invention is illustrated by the following examples, in which, unless otherwise indicated:
    1) temperatures are given in degrees Celsius); operations are carried out at room
    temperature or at ambient temperature, i.e. at a temperature in the range of 18-25 ° C;
    2) solvent evaporation is carried out using a rotating evaporator under reduced pressure (600-4000 Pa 4.5-30 mm Hg) with a bath temperature of up to 60 ° C;
    3) instant chromatography was carried out on Merck Kieselgel (Art 9385) of the company E. Meok, Da.rmstadt, FRG; if acidic silica gel is indicated, a material produced by J.T. Baker Chemical Co., Phillipurg, NJ, USA and having a pH of about 6 when suspended in water, thin layer chromatography (TLC) was used on silica gel CHLF plates. Analtec 0.25 mm (Art 21521) supplied by Analtec, Newark, DE, USA:
    4) typically, the progress of the reaction is monitored by TLC, and the reaction time is given for illustration only;
    5) melting points are uncorrected and (dec) indicates decomposition; these melting points are temperatures obtained for substances prepared as described; polymorphism can result in the release
     substances with different melting points in some preparations;
    6) according to TLC, all final products were essentially pure and had satisfactory NMR spectra and microanalytical data;
    7) yields are given for illustration only and are not necessarily quantities that can be obtained by careful design of the process; if more material was required, some preparation procedures were repeated;
    8) if they are given, NMR data are presented as delta values for the main diagnostic protons, data in ppm (ppm) with respect to tetramethylsilane (TMS) as an internal standard, defined at 80 MHz or 250 MHz using CDCIa, DMSO-do or SOZOO as a solvent; Ar means an aromatic group or signal;
    9) reduced pressures are given as absolute pressures in Pascal x (Pa); other pressures are given in gauge pressure in bar;
    10) solvent ratios are given as volume / volume (v / v); solids ratios are given as May / May (m / m,);
    11) mass spectra (MS) were removed from an electron energy of 70 eV using a chemical ionization method using a direct exposure probe; when they
    5 is given, only peaks of ten percent of the main peak and larger are reported;
    12) when high pressure liquid chromatography (HPLC) data is reported, tR (retention time) is given FR (flow rate) is given in ml / min, Col A is the ODS Zorbax (trade mark) analytical column 4.6 mm x 25 cm and Col B - Phenomenex (trade mark) Zorbax S-8 analytical column 4.6
    5 mm x 35 cm.
    Nomenclature: For consistency and clarity, where possible, amino acid sequence type names are used. Typically, the stereochemical identification of the chiral center in the form of (S) indicates that the product is estimated to contain at least 95% of the (3) isomer at the specified center; lack of identification at the chiral center indicates a mixture
    5 isomers, which at the specified center does not necessarily constitute a 1: 1 mixture.
    Example. (4- (4-Chlorophenyl) sulfonyl-aminocarbonyl / benzoyl / -Lvalyl-M / 1 - / 5- / hydroxy-methyl) benzoxazol-2-yl / cad
    0 bonyl-2-methylpropyl / - -prolinamide (formula 1, a heterocycle containing X, N and Q - 5- (hydroxymethyl) -benzoxazol-2-yl, RI R2- (S02) - NHCO-, R2 4-CIC6H4
    but. Z-amino-4-hydroxybenzene
    5 alcohol.
    A mixture of 10% (v / v) palladium on carbon (5.25 g) and 4-hydroxy-3-nitrobenzyl alcohol (25.0 g) in ethanol (1.3 l (hydrogenated in a shaker at 3.4 bar within 23 hours after
    This mixture is filtered through diatomaceous earth and evaporated. The residue was subjected to flash chromatography, eluting with methanol: chloroform (0: 100 - 10:90), to give the product (11.92 g, 60%) as
    5 red solids, TLC, Rf 0.14, methanol: chloroform (5:95), MS, (M + 1), 139, 138, 123, 122, 110.
    B. (15) -Benzyloxycarbonyl-1-valyl-S- [/ 1- [hydroxy] - (5) / hydroxymethyl / benzo
    0 xazol-2-yl / methyl-2-methylpropyl / -L-n-linamide.
    (15) -Benzyloxycarbonyl-1.-validgM- [3-ethoxy-2-hydroxy-3-imino-1- [1-methyle] tylpropyl / -1-prolinamide hydrochloride (3.0
    5 g) and the alcohol obtained according to Example 1a (0.771 g) in absolute ethanol (20 ml) is heated at 65 ° C for 20 hours, the mixture is dissolved in ethyl acetate, washed (1N NaOH, brine), dried magnesium sulfate and evaporated. The crude product was flash chromatographed, eluting with acetohexanes (55:46) to give the product (858 mg) as a white solid, TLC, Rf 0.26, acetone: hexane (3: 2), MS, m / e 581 (M + 1), 563,501,473,455.
    Calculated,%: C, 61.73; H 7.10. N 9.29.
    C31H40N407 1.25H20
    Found,%: C 61.81; H 6.86, N 9.09.
    c. (15) -Benzyloxycarbonyl-1-valyl-M / 1- / 5 - // tertbutyldimethylsilyl-oxy / methyl / benzoxazol-2-yl / hydroxymethyl-2-methyl, propyl / -L-prolinamide.
    A solution of the product of example 1b (736 mg), tert-butyldimethylsilyl chloride (380 mg), 4-dimethylaminopyridine (7.8 mg) and triethylamine (0.37 ml) in dichloromethane (10 ml) is stirred at room temperature for 16 hours The solution is then dissolved in ethyl acetate. washed (1N HCl, saturated sodium bicarbonate, brine), dried over magnesium sulfate, and evaporated. The crude product was purified by flash chromatography, eluting with acetone: hexane (1: 3), to give the product (715 mg, 82%) in the form of a light yellow solid, TLC, Rf 0.46, acetone: hexane (2: 3), MS, m / e 695 (M + 1), 679, 587, 563, 455.
    Calculated,%: C 63.54, H 7.85, N 8.01
    C37H54N40 -1.025H20
    Found,%: C 63.44, H 7.75, N 7.54.
    d. (3) -Benzyloxycarbonyl-1-acyl-M- / 1- / 5 - // tert-butyl dimethylsilyloxy / methyl / benzoxazol-2-yl / carbonyl-2-methylpropyl / -L-prolinamide.
    Tert-butyl alcohol (0.068 ml) was added to a solution of the product of example 1c (500 mg) and Dess-Martin periodinane (1.22 g) in dichloromethane (5 ml) and the solution was stirred at room temperature for 16 hours. The resulting suspension partition between ethyl acetate and 1: 1 solution of saturated Na2S20s, saturated NaHCOa, the layers are separated and the ethyl acetate layer is washed (once with 1: 1 solution of saturated N328203, saturated with NHCO3, twice with saturated sodium bicarbonate, once with brine), dried over magnesium sulfate and evaporated.
    The crude product is purified by flash chromatography, eluting with acetone: hexane (1: 3), to give the product (448 mg, 90%) as a white solid, TLC, Rf 0.54, acetone: hexane (2: 3), HPLC, tR 6.18, Col A, FR 2, water: acetonitrile (1: 9), MS, m / e 603 (M + 1, base), 677, 635, 585, 460.,
    Calculated,%: C 63.72, H 7.59. N 8.03.
    C37H52N407SI 0.25H20
    Found,%: C 63.84, H 7.45, N 7.70. e. Benzyloxycarbonyl-bvalyl-y- / 1 / 5- (hydroxymethyl) -benzoxazol-2-yl / carbonyl-2-methyl propyl / -L-prolineam id.
    Tetrabutylammonium fluoride (1.2 ml of a 1 M solution in tetrahydrofuran) is added to a solution of the product of example 1d (418 mg) in tetrahydrofuran (5 ml). The resulting red solution is stirred at room temperature for 10 minutes and kept at 5 ° C for 16 hours.
    The red solution is partitioned between ethyl acetate and 1N. The HCI and ethyl acetate layers are washed (saturated sodium bicarbonate, brine), dried over magnesium sulfate and evaporated. Crude
    the product is purified by flash chromatography, eluting with acetone: hexanes (35:65), followed by another purification by flash chromatography, elution with methanol: chloroform (2.5: 97.5) to give the product (183 mg, 53% ) as a white solid, TLC, Rf 0.52, acetone: hexanes (3: 2), HPLC, tR 6.27, COI, A,, water: acetonitrile (40:60), MS, m / e 579 (M + 1), 561, 331,
    225, 197, 91 (base).
    Calculated,%: C 62.40, H 6.76, N 9.39.
    C31H3BN407 1.0H20
    Found,%: C 62.23, H 6.40, N 9.14. f. / 4 - / (4-Chlorophenyl) sulfonylamino-carbonyl / benzoyl / -1 -valyl-M- / 1- / 5- (hydroxymethyl) benzoxazol-2-yl / carbonyl-2-methylpropyl / - -prolinamide (formula I,
    a heterocycle containing X, N and 0-5- / hydroxymethyl / benzoxazol-2-yl; Ri R2 (S02) NH CO-; R2 4-C1SbN4).
    Trifluoromethanesulfonic acid (0.140 ml) is added to a solution of the substance obtained
    according to the procedure of example 1e, (182 mg) in dichloromethane (8 ml), stirred for 15 minutes and the mixture is evaporated. The residue is dissolved in tetrahydrofuran (10 ml), treated with 4-dimethylaminopyridine
    (293 mg), 4- (4-chlorophenyl) sulfonylaminocarbonyl / benzoic acid (113 mg) and 1- (3-dimethylaminopropyl) 3--ethylcarbodiimide hydrochloride (66.5 mg) and stirred at room temperature for 16
    h. The mixture was partitioned between 1 n. HCl and ethyl acetate, the ethyl acetate phase is washed (1N HCl, brine), dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography, eluting with methanol: chloroform: acetic acid (1.5: 97.5: 1.0) to give the product (77 mg, 32%) as a light yellow solid. TLC, Pf 0 , 28, methanol; chloroform: acetic acid (5: 9: 1), MS, m / e 766 (M + 1). 758,592,562,421,346,328.
    Calculated,%: C 55.48, H 5.49, N 8.29.
    ethyl acetate and washed (three portions of a 1: 1 mixture of saturated Ma25202: saturated NaHCOs, brine), dried over magnesium sulphate and evaporated.
    The crude product is purified by flash chromatography, eluting with acetone: hexane (25:75), to afford 2.20 g of solid, TLC, Rf 0.21, acetone: hexanes (30:70), MS. m / e 635
    (M + 29), 608 (M + 2), 607 (M + 1), 374, 331, 91. Calculated,%: C 62.43, H 6.38, N 9.10
    C32H38N408 0.50H20
    Sz7N4oS1 # OEZ 1.0N20 1, UNESC 15
    Found,%: C 55.42, H 5.33, N 8.77
    PRI mme R 2. / 5 / -4 - // 4-Chlorophenyl / sulfonylaminocarbonyl / benzoyl / -7-valyl-N- / 1- / 5- / methoxycarbonyl / benzoxazol-2 -yl / carbonyl 2-methylpropyl / -proline-amide (formula I, a heterocycle containing X, N and 0-5- (methoxycarbonyl) benzoxazol-2-yl, RI — Ra (SOa) NH —CO-, R2 4-CICeH4
    but. / 15 / -Benzyloxycarbonyl-bvalyl-M- / 1- (hydroxy) - / 5-methoxy-carbonyl / benzoxazol-2-yl / methyl-2-methylpropyl / -1 - prolinamide.
    Stirring solution / 1S / benzisloxycarbonyl-1-valyl-M- / 3-ethoxy-2-hydroxy-3-imino-1- / 1-methylethyl / propyl-1-1 -prolinamide-hydrochloride (5.47 d) and 4-carbomethoxy-2-aminophenol (5.10 g) in dry ethanol (50 ml) is heated for 3 hours at 60 ° C under nitrogen atmosphere. The mixture was dissolved in ethyl acetate, washed (1N HCl, 1N NaOH, three times, brine), dried over magnesium sulfate, and evaporated. The crude product was subjected to flash chromatography, eluting with acetone: hexanes (30:70), to give 2.210 g of product, TLC, Rf 0.18, acetone: hexanes (35:65), MS, 649 (M + 41), 637 (M + 29), 611 (M + 3), 6GO (M + 2), 609 (M + 1), 591.501.
    Calculated,%: C 62.73, H 6.74, N 8.76
    Sz2N4oM40v O.ZbsNzSOaSzNz
    Found,%: C 62.71, H 6.73, N 8.67. - about. (8) -Benzyloxycarbonyl-1 -8-alkyl-M- (1- (5-methoxycarbonyl) -benzoxazol-2-yl) (carbonyl-2-methylpropyl) - -prolinamide.
     Tert-butanol (0.340 ml) was added to a solution of the product of example 2a (2.70 g) and Dess-Martin periodinane (4.62 g) in dichloromethane (20 ml) and the solution was stirred at room temperature for 22 h. The resulting suspension was diluted
    Found: C, 62.43; H, 6.24; N, 8.90 s. / 5 / -1 -Valyl-1M- / 1 // 5- / methoxycarbonyl / benzoxazol-2-and / carbonyl-2-methyl propyl / -L-prolinamide,
    To the stirred solution of the product
    of Example 2b (500 mg) in dichloromethane (4 ml) under nitrogen atmosphere, trifluoromethanesulfonic acid (0.365 ml) is added dropwise. After 5 minutes, the reaction mixture was poured into distilled water (100 ml) and extracted three times with dichloromethane. The aqueous layer was adjusted to pH 8 with sodium bicarbonate and washed three times with dichloromethane, the aqueous phase was treated with 1N. sodium hydroxide (50 ml) and washed
    one more time with dichloromethane. The organic washings are combined, dried with sodium sulfate and evaporated to give
    185 mg (48%) white foam, TLC, Rf 0.22, methanol: chloroform (5:95).
    sec. / 5 / -4 - / (4-Chlorophenyl) sulfonyls of nocarbonyl / benzoyl / -1 -valyl-N-1 / - / 5-methoxycarbonyl / benzoxazol-2-yl / carbon yl-2-methylpropyl / - - prolinamide (formula I, heterocycle containing X, N and Q-5 / methoxycarbonyl / benzoxazol-2-yl, RI R2 (S02) NH CO-, R2 4-C1CeH4
    1- / 3-Dimethylaminopropyl / 3-ethylcarbodiimide hydrochloride (160 mg) is added to a solution of the product of example 2c (185 mg),
    1-hydroxybenzotriazole (110 mg) and 4- [(4-chlorophenyl) sulfonylaminocarbonyl] benzoic acid (280 mg) in tetrahydrofuran (3 ml) and the solution is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed (three times). times 1 N. HCl, saline), dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography with
    by elution with acetone: dichloromethane: acetic acid (20: 80: 1 drops / ml) to obtain 160 mg of solid, Rf 0.36, methanol: chloroform: acetic acid (5: 95: 1 drops / mg) HPLC, tp 15.84, Col A, water: acetonitrile: tetrahydrofuran: trift
    oroacetic acid (55: 35: 15: 0.1), FR 2, MS, m / e 684 (M29), 656 (M + 1). 375, 374, 356, 355, 354, 352, X 302, 283, 260, 259, 178, 163.
    Calculated,%: C 55.07, H 5.31, N 8.03
    CaaHUoCINsOioS 1, ОН20 -1, ОСНзС02Н
    Found,%: C 55.05, H 5.13, N 8.06.
    PRI me R 3. / 5 / - / 4 - / (4-Chlorophenyl) sulfonylaminocarbonyl / benzo-yl / -1 -valyl-M- / 1- / 6- (methoxycarbonyl) benzoxazol-2-yl / carbonyl-2-methylpropyl / L-proline-amide (formula I, a heterocycle containing X, N and Q 6- / methoxycarbonyl / benzoxazol-2-yl, Ri Ra (S02) NH CO-, R2
    but. (15) -Benzyloxycarbonyl-1 -valyl-M- (1- (hydroxy) - (6- (methoxy-carbonyl) b) benzoxazol-2-yl / -methyl-2-methyl propyl / - prolinamide.
    A stirred solution of / 15 / -benzyloxycarbonyl-1-valyl-1M- / 3-ethoxy-2-hydroxy-3-imino-1- (1-methylethyl) propyl / -1 - prolinamide hydrochloride (1.00 g ) and 5-carbomethoxy-2-aminophenol (930 mg) in dry ethanol (9 ml) is heated for 4 hours at 60 ° C under nitrogen atmosphere. The mixture was dissolved in ethyl acetate, washed (twice with 1N NaOH, brine), dried over magnesium sulfate, and evaporated. The crude product is subjected to chromatography, eluting with acetone: hexanes (35:65), to give 300 mg of product, TLC, Rf 0.50, acetone: hexanes (45:55), MS, m / e 610 (M + 2) , 609 (M + 1).
    L. (5) -benzyloxycarbonyl- -valyl-K1- (1- (6-) methoxycarbonyl) benzoxazol-2-yl / carbonyl-2-methyl propyl / -L-prolinam id.
    Tert-butanol (0.050 ml) was added to a solution of Example 3 (300 mg) and Dess-Martin periodinane (630 mg) in dichloromethane (3 ml) and the solution was stirred at room temperature for 17 hours. The resulting suspension is diluted with ethyl acetate and washed (three portions 1: 1 of a mixture of saturated Na25O3: NaOH3, brine), dried over magnesium sulfate and evaporated. The crude product is purified by chromatography, eluted with acetone: hexane (30:70), to give a solid, which is dissolved in acetonitrile (30 ml) and treated with 300 mg of activated carbon. The mixture is stirred for 10 minutes. filtered and evaporated to give 257 mg of product, TLC, Rf 0.49, acetone hexanes (40:60), MS, m / e 635 (M + 29), 608 (M + 2), 607 (M + 1).
    Calculated,%: C 62.43, H 6.38, N 9.10
    C32H38l U08 0.5 H20
    Found,%: C 62.62. H 6.28, N 8.94
    c./5/-1 -Valil-M- / 1- / 6- / methoxycarbonyl / benzoxazol-2-yl / carbonyl-2-methyl
    propyl-1-prolinamide trifluoromethanesulfonic acid salt.
    To a stirred solution of the product of Example 3b (210 mg) in dichloromethane (1.5 ml) under a nitrogen atmosphere is added dropwise.
    trifluoromethanesulfonic acid (0.15 ml). After 40 min, the reaction mixture is evaporated. The obtained solid is placed under vacuum for 1 h and used directly in example 3d below.
    TLC, Rf 0.00, acetone: hexanes (25:75), MS. m / e 244, 242, 235, 195, 189, 186, 181, 178, 121, 105.93.92.91, 79.
    d, / 5 / - / 4 - / (4-Chlorophenyl) sulfonyl-aminocarbonyl / benzoyl / -1-valyl-N- / 1- / 6 (methoxycarbonyl1) benzoxazol-2-yl / -cerbnyl-2-methylpropyl / -1 - prolinamide (formula f, heterocycle. Containing, X, N and Q 6- / methoxycarbonyl / benzoxazol-2-yl, RI R2 (S02). NH. CO-, R2
    1- / 3-Dimethylaminopropyl / -3-ethylcarbodiimide hydrochloride (75 mg) is added to a solution of the product of example Cc, 1-hydroxybenzotriazole (50 mg) and 4 - // 4-chlorophenyl / sulfonylaminocarbonyl / benzoic
    acid (130 mg) in methylene chloride (2 ml) and tetrahydrofuran (2 ml), followed by the addition of 4-methyl-morpholine (0.041 ml) and the solution is stirred at room temperature for 16 h. K reactionary
    4-methylmorpholine (0.041 ml) was added to the mixture and the reaction mixture
    mix another 7h. Reaction mixture
    diluted with ethyl acetate, washed (1N
    HCI three times, saline), dried
    over magnesium sulfate and evaporated. The crude product is purified by chromatography, eluting with acetone: methylene chloride: acetic acid (30: 70: 1), to give a solid (160 ml),
    which is further purified by flash chromatography using gradient elution with a mixture of acetone: methylene chloride: acetic acid (500 ml, 100: 1,900 ml 10: 90: 1, then 50: 50: 1) to obtain the target compound (71.6 mg ), TLC, Rf - 0.17, acetone: chloroform: acetic acid (10: 90: 1), HPLC, TR 15.84, Col A, FR 2, water: acetonitrile: tetrahydrofuran. Trift oroacetic acid (55:35 : 15: 0,1), MS, m / e
    794 (M + 1), 778, 777, 776, 423, 422, 421, 384, 374, 357, 356, 355, 354, 259.
    Calculated,%: C 54.57, H 5.3b, N 7.76 CseH / ioCINsOioS 1.0 H20 1.5 CH3 C02H Found; C 54.31, H 5.19, N 7.81
    PRI me R 4. / 4 - / (4-Chlorfenml) sulfonyl aminocarbonyl / benzoyl / - L-valyl-M- / 1- / 2-oxazolyl / carbonyl-2-methyl propyl / -L-proline imide ( Formula I, heterocycle containing X, N and Q 2-oxazolyl, Ri Ra (SCte) NH CO-, R2 4-CIC6H4
    a.2-trimethylsilyloxazole. n-Butyllithium (28.5 ml of a 2.54 M solution in
    hexa e) is added to a solution with a temperature of -78 ° C oxazole (5.0 g) in ether (150 ml). The resulting solution was stirred at -78 ° C for 30 minutes, followed by the addition of trimethylsilyl chloride (7.86 g) and the mixture was allowed to warm to room temperature. The reaction mixture is distilled; a fraction with a boiling point of about 130 ° C is collected, yielding 2-trimethylsilyloxazole (5.12 g), MS, m / e 142 (M + 1), 91, 73.
    b./15/-Benzyloxycarbohedl-1-valyl-
    N- / 1 - / 2-oxazolyl / -hydr-oxymethyl-2-yl propyl / -L-prolinamide.
    Solution of / 5 / -benzyloxycarbonyl-ва-valyl-M- / 1-formyl-2-methylpropyl / -C-prolineamide (7.4 g) and the product of example 4a (4.84 g) in toluene (10 ml) heated at 80 ° C for 24 hours and for 14 hours at 60 ° C. The solvents are evaporated, the residue is dissolved in tetrahydrofuran (50 ml), treated with 1N. HCl (5 ml) and stirred for 30 minutes. The mixture was dissolved in ethyl acetate, washed (1N HCl, saturated sodium bicarbonate, brine), dried over magnesium sulfate and evaporated. The crude material is purified by flash chromatography using a mixture of acetone: hexanes (30:70) to give the product (4.57 g), TLC, Rf 0.31, methanol: chloroform (5:95), m / m, m / e 501 (M + 1), 483, 393.
    Calculated,%: C 62.38, H 7.25, N 11.19
    S2bnzbmoe
    Found: C, 62.52; H, 7.22; N, 10.87.
    c./5/-Benzyloxycarbonyl-1.-valyl-M- (2-methyl-1 - / - / 2-oxazolyl) -carbonyl / propyl / -L-prolinamide.
    Tert-butanol (0.83 ml) was added to a solution of the product of example 4B (4.4 g) and Dess-Martin periodinine (15 g) in dichloromethane (150 ml) and the mixture was stirred for 16 h. The resulting suspension is partitioned between a mixture of saturated NaaSaOa: saturated NaHCOa (1: 1) and ethyl acetate. The ethyl acetate solution was washed (a mixture of saturated No. 25203: saturated MAHCO3 (1: 1), saturated sodium bicarbonate, brine), dried over magnesium sulfate and
    evaporated. The residue was purified by flash chromatography, eluting with acetone: hexanes (35:65), to give 4.8 g of a solid. This solid was dissolved in ethyl acetate, washed (saturated N328203: saturated NaHCO3 (1: 1), saturated with sodium bicarbonate, brine), dried over magnesium sulfate and evaporated to give the product as a white foam (3.74 g) , TLC, Rf 0.32, acetone: hexanes (40:60), MS, m / e 499 (M + 1), 266.
    Calculated,%: C 62.64, H 6.87, N 11.24
    C26H34N406
    Found,%: C 62.30, H 6.74, N 11.01.
    d. / 4 - / (4-Chlorophenyl) sulfonylamino-carbonyl / benzoyl-1-valyl-1CH- / 1- (2-oxazolyl) carbonyl-2-methylpropyl / -b-proline mid (formula I, heterocycle containing X , N and Q 2-oxazolyl, Ri R2 (SOa) NH CO-, R2 4gS1SbN4).
    Trifluoromethanesulfonic acid (0.89 ml) was added to a solution of the product of example 4c (1.0 g) in dichloromethane (15 ml) and stirred for 10 minutes, the solvent was evaporated and the residue was placed under high vacuum for 20 minutes. The residue is dissolved in tetrahydrofuran (40 ml) and treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chlorhydrate (429 mg), 4- / (4-chlorophenyl) sulfonylaminocarbonyl / benzoic acid (800 mg) and 4- dimethylaminopyridine (1.97 g). The mixture was stirred at room temperature for 16 hours, dissolved in ethyl acetate, washed (1N HCl, saturated sodium bicarbonate, brine), dried over magnesium sulfate, and evaporated. The crude material was purified by flash chromatography, eluting with acetone: hexanes: acetic acid (10: 90: 1-20: 80: 1), to give the product (930 mg), TLC, Rf 0.40, methanol: chloroform: acetic acid (5: 95: 1), HPLC, tR 7.35, Col A, FR 2, water: acetonitrile: tetrahydrofuran: trifluoroacetic acid (55: 35: 15: 0.1), MS, m / e 685 (M + 1), 668, 393, 377, 266, 248.
    Calculated,%: C 54.07, H 5.47, N 9.27
    C32H36CIN50eS 0.5 H20 1.0 CHFA
    Found,%: C 53.78, H 5.33, N 9.25. PRI me R 5. / 4 - / (4-Chlorfenml) sulfonyl-amino-aminocarbonyl / benzoyl /-valyl-L- / 1 / - (2-benzothiazolyl) carbonyl-3-methylpropyl / - -prolinamide (formula I, a heterocycle containing X, N, and Q 2-benzothiazolyl, RI R2 (S02) NH CO-, R2 4-CIC6H4
    a.M-a-Benzyloxycarbonyl-N-methoxy-N-methylvalinamide.
    A solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (19.07 g) in dichloromethane (500 ml) is cooled to -10 ° C. 1-hydroxybenzotriazole (13.44 g) and 4-methylmorpholine (11.5 ml) are added to this solution. A solution of M- (benzyloxycarbonyl) -L-valine (25.0 g) in dichloromethane (200 ml) is added dropwise to the reaction mixture. After the addition is complete, the mixture is warmed to ambient temperature and stirred for 0.5 h, and then cooled to 10 ° C. To the stirred reaction mixture is added dropwise a mixture of N-methyl-O-methylhydroxylamine hydrochloride (9.7 g) and 4-methylmorpholine (11.5 ml) in dichloromethane (150 ml). The reaction mixture is warmed to ambient temperature with stirring overnight. The mixture was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer is washed (10% HCI, saturated sodium bicarbonate, brine), dried over magnesium sulfate, evaporated and dried overnight under high vacuum to give the product as a resin (26.25 g), which solidifies in a freezer, TLC , Rf 0.57, chloroform: methanol (40: 1), MS, m / e 295 (M + 1). 234, 187, 162, 152, 119.
    b./5/-1-/2-Benzothiazolyl/2-benzyloxycarbonyl / amino-3-methyl-1-butanol.
    The dry ester (5 ml) is cooled to -78 ° C and n-butyl lithium (6.0 ml of a 2.54 M solution in hexane) is added. A solution of benzothiazole (1.83 g) in dry ether (15 ml) is quickly added dropwise. Stirring at -78 ° C is continued for Yumin. An ether solution (10 ml) of the amide obtained according to the procedure of Example 5a and used without further purification (2.00 g) was added through a thin tube (cannula) and the reaction mixture was allowed to warm to 30 ° C with stirring for 1 hour. The reaction mixture was cooled by pouring it into saturated NH / iCI and extracted with ethyl acetate. The extracts are dried with sodium sulfate and evaporated to give a yellow gloss. Purification by flash chromatography, eluted with hexane: ethyl acetate (10: 1), gave the product as a yellow glass (0.98 g) TLC, Rf 0.67, hexane: ethyl acetate (2: 1). MS, m / e 368 (M + 1), 206, 191. 162, 135, 91 (base),
    c.2-amino-1- / 2-benzothiazolyl / -3-methyl-1-butanone,
    The substance obtained according to the procedure of Example 5b (0.94 g) was dissolved in a mixture of dichloromethane (20 ml) and anisole (1 ml) under a nitrogen atmosphere. Trifyurmethanesulfonic acid (1 ml) was added and the reaction mixture was stirred for 10 minutes. The reaction mixture is diluted with dichloromethane and
    extracted with water. The aqueous extracts are washed with dichloromethane, brought to saturated sodium bicarbonate and extracted with dichloromethane. The organic solution was dried with sodium sulfate and evaporated to give a yellow oil (0.50 g). TLC, Rf 0.36, hexane: ethyl acetate (2: 1).
    d. Benzyloxycarbonyl-1 -valyl-M- / 1- (2-benzothiazole and l) -carbonyl-2-methi l propyl / -L-prolinamide
    5 Dichloromethane solution of the material obtained according to the procedure of sample 5c and used without further purification (0.5 g), 1-hydroxybenzotriazole (0.58 g) and benzyloxycarbonyl-b-valyl-b
    0 proline (0.74 g) is treated with 1- / 3-dimethylaminopropyl / -3-ethylcarbodiimide hydrochloride (0.47 g) and the reaction mixture is stirred under nitrogen for 15 hours. The reaction mixture is diluted with dichlorium lormethane, washed (saturated sodium bicarbonate. 10% HCI), dried with sodium sulfate and evaporated to give a yellow oil (1.48 g), TLC, Rf 0.39, chloroform: methanol (50: 1), MS , m / e 565 (MI,
    0 base), 332, 331.
    e.1 -Valyl-M- / 1- (2-benzothiazolml) carbonyl-2-methyl-propyl / -L-prolinamide.
    The amide prepared according to the procedure of Example 5d and used without
    5 additional purification (1.20 g) was subjected to the deprotection reaction using a procedure similar to that of Example 5c to give the product as an oil (0.34 g, 37%), TLC, Rf 0.34,
    0 chloroform: methanol (10: 1).
    f./4-/(4- Chlorophenyl) sulfonyl-carbonyl / benzoyl-1-valyl-M- / 1- (2-benzothiazolyl) carbonyl-2-methylpropyl / -1-proline amide (formula I, heterocycle, containing X, N, and Q 2-benzothiazolyl, RI R2 (303) NH CO-, R2).
    The amine obtained according to the procedure of Example 5e and used without further purification (0.34 g), 1-hydro 0 xybenzotriazole (0.21 g) and 4 - [(4-chlorophenyl) sulfonylaminocarbon yl / benzoic acid (0, 27 g) are combined in dichloromethane (12 ml), the suspension is treated with 1- / 3-dimethylaminopropyl / -3-ethyl5 carbodiimide chlorohydrate (0.17 g). Stirring is continued for 7.5 h. The reaction mixture is diluted with ethyl acetate and washed (saturated sodium bicarbonate, 10% HCl), dried with sodium sulfate and evaporated to give an oily foam. Purification by flash chromatography using elution with hexane: these acetate: acetic acid (50: 50: 1.5) gives the product as a white solid (0.32 g), TLC, Rf 0.29, hexanes: ethyl acetate: acetic acid (50: 50: 1.5) HPLC, tR 26, Col A, FR 2, water: acetoitrile: tetrahydrofuran: trifluoroacetic acid (55: 35: 15: 0.1), MS, m / e 752 (M + 1), 423.421, 393, 377, 342, 332.315, 314 (base), 313, 312, 136.
    Calculated,%: C 57.07, H 5.13, N 9.09
    SzbNz8S M 0732 OzCH3CUN
    Found: C, 57.32; H, 5.45; N, 8.76.
    Primerb / 5 / - / 4 - / (4-Chlorophenyl / sulphonylaminocarbonyl / benzoyl) -1-valyl-M- / 2-methyl-1- (2-thiazolyl) carbonyl propyl /-.- prolinamide (formula I heterocycle containing X, N and Q 2-thiazolyl, R1 R2 (S02) NH CO-, R2 4 -C1C6H4).
    a./5/-2-/Benzyloxycarbonyl/amino-3-methyl-1- [2-thiazolyl] -1-butanone. ,
    To a cooled (-35 ° C solution of thiazol (1.23 ml) in dry tetrahydrofuran (40 ml) was added n-butyl lithium (6.6 ml of a 2.18 M solution in hexane) over 3 minutes. Dark the brown reaction mixture is stirred in the temperature range from -30 to -25 ° C for 10 minutes. A solution of the substance obtained according to the procedure of example 5a and used without further purification (1.7 g) in a dry tetrahydrofuran (15 ml). Stirring at -30 ° C is continued for 15 minutes, the mixture is rapidly cooled by pouring it into saturated chloride the ammonium (100 ml) and the organics are extracted with ethyl acetate. The extracts are washed with saturated sodium bicarbonate, dried with sodium sulfate and evaporated to give a brown oil. Purification by flash chromatography using elution with a mixture of hexane: ethyl acetate (2: 1) gives the product as yellow oil (1.81 g, 98%) TLC, Rf 0.45, hexane: ethyl acetate (2: 1), MS, m / e 319 (M + 1), base), 275.
    b./5/-2-Amino-3-methyl-1- (2- thiazolyl) -1-butanone.
    The ketone obtained according to the procedure of Example Ba (1.8 g) is dissolved in dichloromethane (30 ml) and treated with trifluoromethanesulfonic acid (2.5 ml) in one portion, the reaction mixture is stirred at ambient temperature for 5 minutes. The mixture is diluted with dichloromethane and extracted with water. The aqueous phase is adjusted to basic pH.
    using saturated sodium bicarbonate and then extracted with dichloromethane. The extracts are dried with sodium sulfate and evaporated to give the product as a dark yellow.
    oils (0.78 g, 75%), TLC, Rf 0.7, chloroform: methanol (10: 1), MS, m / e 185 (M + 1, base) 167, 140,
    with. / 5 / -Benzyloxycarbonyl-Lvalyl-L- / 2-methyl-1-L72-thiazolyl / carbonylprop
    silt -prolinamide.
    The amino ketone prepared according to the procedure of Example 6b (0.73 g) was dissolved in dichloromethane (25 ml). Sequentially add to the solution
    benzyloxycarbonyl-1-valyl-1-proline (1.38 g), 1-hydroxybenzotriazole (1.07 g) and 1- / 3-dimethylaminopropyl / -3-ethylcarbodiimide hydrochloride (0.76 g). The mixture is stirred over night at a temperature of
    environment in a nitrogen atmosphere. The reaction mixture is diluted with dichloromethane, washed (saturated sodium bicarbonate, 10% HCI), dried with sodium sulfate and evaporated to give
    yellow oil (2.5 g). Purification by flash chromatography using elution with hexazhenyl acetate (1: 1) gives the product as a solid foam (1.6 g), TLC, Rf 0.3, hexane: ethyl acetate (1: 1),
    MS, m / e 515 (M + 1, base). 407, 331, 282.91.
    Calculated,%: C 59.64-, H 6.74, N 10.70
    35
    C26H34N405S -0.5N20
    Found,%: C 59.56, H 6.54, N 10.42.
    d./5/-1 -Valyl-M- / 2 methyl-1- / 2-thiazolyl / carbonylpropyl / -1-proline-amine trifluoromethanesulfonic acid salt.
    0 The ketone obtained according to Example 6c (0.51 g) is dissolved in dichloromethane (15 ml) and treated with trifluoromethanesulfonic acid (0.44 ml) in one portion. The reaction mixture is stirred at
    5 ambient temperature for 15 min. Evaporation and drying under high vacuum gave a white gum (1.17 g, more than 100%). The weight of the crude product, which is in excess of 100%
    0 output, trifluoromethanesulfonic acid is prescribed.
    e. / S / - / 4 - / (4-Chlorophenyl) sulphonylaminocarbonyl / benzoyl-Lvalyl-N- / 2-methyl-1- (2-thiazolyl) carbonylpropyl / -1-proline
    5 mid (formula I, heterocycle containing X, N and Q - 2-thiazolyl, Ri Ra (S02J NH CO-, Ra 4-CiCeH4
    A crude amino ketone prepared according to the procedure of Example 6d and used without further purification (0.13
    g), 4- / (4-chlorophenyl) sulfonamine-benzyl / benzoic acid (0.34 g) and 4-methylmorpholine (0.59 ml) is dissolved in tetrahydrofuran and the mixture is treated with 1- / 3-dimethylaminopropyl hydrochloride / - 3-ethylcarbodiimide. The mixture is stirred overnight under a nitrogen atmosphere. Evaporation gives a residue which is partitioned between water and ethyl acetate. The organic phase is washed (10% HCl, water, brine), dried over magnesium sulfate and evaporated. Instant chromatography, elution with chloroform: methanol: acetic acid (100: 2.5: 0.5) gives the product as a white foam (0.50 g). Another purification (the same solvent system used above) gives the desired product as a white foam (0.43 g), TLC, Rf 0.35, chloroform: methanol: acetic acid (100: 2.5: 0.5 , MS, m / e 702 (35CI-M + 1), 283, 282 (base), 120, HPLC-IR 8.54, Col A, FR 2, water: acetonitrile: tetrahydrofuran: trifluoroacetic acid (55 : 35: 15: 0,1). PRI me R 7. / (4-Chlorophenyl) sulfonyl / ureido / benzoyl / -1 -valyl-N- / 1- / 5- (methoxycarbonyl) benzoxazol-2-yl / carbonyl-2-methylpropyl - - proline imide (formula I, heterocycle containing X, N, Q 5- / methoxycarbonyl / -benzoxazol-2-yl, RI R2 (SOz) NH CO, NH, R2).
    a./3/-1 -Valyl-M- (1- / 5- (methoxycarbonyl) benzoxazol-2-yl / carbonyl-2-methyl p-propyl / -1-prolinamide.
    Trifluoromethanesulfonic acid (0.73 ml) is added dropwise to a stirred solution of the product of example 2b (1.00 mg) in methylene chloride (8 ml) under a nitrogen atmosphere. After 10 minutes, the reaction mixture was diluted with dichloromethane and washed three times with distilled water. The pH of the solution was adjusted to 8 by adding a solution of saturated sodium bicarbonate (25 ml). The basic solution is extracted vigorously with dichloromethane 6 times. Sodium chloride (10 g) is added to the resulting aqueous layer and the mixture is extracted twice with dichloromethane. All organic extracts were combined, dried with sodium sulfate and evaporated to give the product (620 mg), TLC, Rf 0.20, methanol: chloroform (5:95).
    b./5/-/4-/M1-/(4-Chlorophenyl / sulfononyl / ureido / benzoyl / - -valyl-M- / 1- / 5- (methoxycarbonyl) benzoxazol-2-yl / -carbonyl -2-methylpropyl / - L-prolinamide (formula I, a heterocycle containing X, N and Q 5- (methoxycarbonyl) benzoxazol-2-yl, RI R2 (S02) NH CO NH, R2
    1- / 3-Dimvtylaminopropyl / 3-ethylcarbodiimide hydrochloride (100 mg) is added to a solution of the product of example 7a (225 mg), 1-hydroxybenzotriazole (70 mg) and 4- (N - / (4-chlorophenyl) sulfonyl / in rhea to / -benzoic acid (190 mg) in dichloromethane (3
    ml) and the solution is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed (1N HCl three times), brine), dried over magnesium sulfate and evaporated.
    The crude product is purified by flash chromatography, eluting with acetone: methylene chloride: acetic acid (10: 90: 1) to give the title compound (271 mg) as a solid, TLC, Rf 0.14, acetone: dichloromethane: acetic acid (20: 80: 1), HPLC, IR 13.47, Co A, FR 2, water: acetonitrile: tetrahydrofuran: trifluoroacetic acid (55: 35: 15: 0.1), MS , m / e 699, 374, 245, 219,
    197, 178, 120.
    Calculated,%: C 51.55, H 5.62, N9.15.
    C38H44CIN6OioS -3.7H20 0.70 СНзС02Н
    Found,%: C 51.40, AND 4.97, N 9.8 P r i m e r 8. / 4 - / (Three fluoromethylsulfoyl / am benzoyl / -1 -valyl-N- / 1- / 5-methoxy-carbonyl / benzoxazol-2-yl / carbonyl-2-methylenepropyl / -1 - prolinamide (formula I, a heterocycle containing X, N and Q - 5- (methoxycarbonyl / benzoxazol-2-pl RI - CP3 (S02) NH-).
    a. Ethyl 4 - // trifluoromethylsulfonyl / amino / benzoate.
    Trifluoromethanesulfonic anhydride (4.1 ml) is added dropwise to a pre-cooled (0 ° C) solution of ethyl p-aminobenzoate (3.3 g) in dichloromethane (50 ml) under a nitrogen atmosphere. The reaction mixture was stirred for 1 hour at 0 ° C, then left to warm to room temperature and stirred for 1 hour. After the reaction mixture was evaporated, ethyl acetate (125 mg) was added to the residue.
    and the resulting organic solution was washed (1N HCl, then brine), dried with magnesium sulfate and evaporated. Purify the residue by flash chromatography, eluting.
    a mixture of chloroform: methanol (95: 5) to obtain the product as a white powder (1.27 g), TLC, Rf 0.37, chloroform: methanol (90:10),
    b.4 - // (Trifluoromethylsulfonyl) amino / benzoic acid.
    Solution 1 n. NaOH (8.4 ml) is added to
    a stirred solution of the product of example 8a (1.25 g) in methanol (25 ml). Water (2 ml) was added and the reaction mixture was stirred overnight. After distillation of methanol under vacuum water jet
    the pumped water residue is diluted with water (20 ml). The aqueous solution is washed with ethyl acetate, acidified to pH 2 with 1N. HCI and extracted with ethyl acetate (40 ml total). The organic phase is dried with magnesium sulfate and evaporated to give the product as a white powder (1.05 g), TLC, Rf 0.4, chloroform: methanol: acetic acid (96: 4: 0.2).
    c./5/-1 -Valil-M- (1- / 5- (methoxycarbonyl) benzoxazol-2-yl / carbonyl-2-methylpropyl / -1.-prolinamide.
    Trifluoromethanesulfonic acid (0.53 ml) is added dropwise to a stirred solution of the product of Example 2b (750 mg) in methylene chloride (5 ml) under a nitrogen atmosphere. After 20 minutes, the reaction mixture was diluted with dichloromethane and washed three times with distilled water. Sodium chloride (5 g) is added to the combined aqueous layers and the resulting solution is adjusted to pH 8 by adding a solution of saturated sodium bicarbonate (20 ml). The basic solution is extracted vigorously with dichloromethane eight times. The organic layers are combined, dried with sodium sulfate and evaporated to give the product (420 mg), TLC, Rf 0.28, methanol: chloroform (5:95).
    d./4- // Trifluoromethylsulfonyl / amino / benzoyl / -1 -valyl-M- / 1- / 5- (methoxycarbonyl) benzoxazol-2-yl / carbonyl-2-methyl propyl / h. prolinamide (formula I, heterocycle containing X, N and Q 5- / methoxycarbonyl / benzoxazol-2-yl, Ri CFa (S02) NH-).
    1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (240 mg) is added to a solution of the product of example 8c (420 mg), 4-dimethylaminopyridine (110 mg) and 4- (trifluoromethylsulfonyl) -amino-benzoic acid (340 mg) in tetrahydrofuran (3 ml) and the solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed (1N HCl three times, brine), dried with magnesium sulfate and evaporated. The crude product is purified by flash chromatography, eluting with methanol: chloroform: acetic acid (20: 800: 1), to give the desired compound (330 mg) as a solid, TLC, Rf 0.50, methanol: chloroform: acetic acid (5: 95: 1), HPLC, tp 15.61, CoL A, water: acetonitrile: tetrahydrofuran: vinegar acid (55: 35: 15: 0.1), FR 2, MS, m / e 752 (M + 29), 724 (M + 1), 706,374,356,351,323.
    Calculated,%: C 51.57, H 5.20, N 8.95.
    SzNzbRz OEZ 0.60 H20 0.80 CH3C02H Found. %: C 51.29, H 5.07, N 8.97
    The study of the biological activity of heterocyclic ketones.
    The potency of the compounds obtained according to the inventive method as inhibitors of elastase is primarily determined by the ability of the compounds to inhibit the action of human leukocyte elastase (LAC) on a peptide substrate of low molecular weight. The strength of the inhibitor or its activity is evaluated by kinetic determination of the dissociation constant (Ki) of the complex formed by the interaction of the inhibitor with the LEC. The substrate used was antioxide methoxysuccinyl-alanyl-prolylvaline-p-nitroanilide.
    The studies use the LEC enzyme from Elastitin Products, St. Louis, Mo., or purified according to the method of Vlscarello, B.R. and etc.
    Using purified LEC, the standard degree or rate of p-nitroanaline preparation was measured at 25 ° C spectrophotometrically in the visible spectrum at 410 nm using automatic data obtained from a Sagu 210 spectrophotometer (Varian Associates). Reactions were initiated by injecting 10 μl of the LEC solution into a 3-ml cuvette containing 2.89 ml of buffer (10-ml sodium phosphate, 500-ml NaCl, pH 7.6), 50 μl of the substrate solution in DMSO and 50 μl DMSO. The initial rates of the stable p-nitroaniline reaction are calculated by matching the experimental data with a linear dependence on time over the smallest linear squares. This rate, determined without adding an inhibitor, is used as a standard in calculating K | inhibitor.
    Typically, the heterocyclic ketones of the invention are not slow binding inhibitors of LEC; however, if heterocyclic ketones are found to be slow binding inhibitors of LECs, special assay methods are carried out to accurately determine the Kino values of their LBP input. In a typical experiment, 2.89 ml of buffer (10 ml sodium phosphate, 500 ml sodium chloride, pH 7.6), 50 µl of the inhibitor solution in DMSO and 50 µl of the substrate solution in DMSO were added to a 3-ml cuvette. The cuvette is sealed, inverted several times to mix its contents and kept in a spectrophotometer at 25 ° C. After 5 minutes (during this time, the reaction solution reaches thermal equilibrium) in a cuvette to initiate
    10 µl of the initial enzyme solution is added to the reaction. A two or three repetition of the experiments was carried out at a zero inhibitor concentration and at least at three non-zero inhibitor concentrations. Values K | calculated according to the Williams and Morrison method.
    Ki values for heterocyclic ketones of the formula I:
    The Ki value for known trifluoromethyl keto-amide derivatives of di-, tri-, and tetrapeptides that are LEC inhibitors is less than 10.
    Animal models.
    Animal models of emphysema include intratracheal (IT) administration of an elastolytic protease in order to cause slowly progressive destructive damage to the lungs. These lesions are usually assessed several weeks to several months after the initial stroke. However, these proteases also cause damage that becomes apparent in the first few hours. Early damage is initially bleeding, progresses to inflammatory damage by the end of the first 24 hours, and reaches fullness in the first week after a stroke. To take advantage of the results of this early damage, use the following model.
    Homchkov is first slightly anesthetized with brevital. Then phosphate buffered saline (PBS) pH 7.4 (in pure form or containing 400 µg LEC) is injected directly into the trachea. After 24 hours, the animals are sacrificed, the lungs are removed and carefully freed from extraneous tissue. After determining the wet weight of the lungs, the lungs are washed with PBS and the total number of isolated red and white blood cells is determined. After the introduction of the LEC, the values of wet weight of the lungs, the total number of red blood cells and the total number of white blood cells increase depending on the dose. Compounds that are effective inhibitors of elastase, can prevent or reduce to the limit the severity of damage caused by the enzyme, resulting in lower raw lung weight and lower values of the total number of blood cells (red and white) compared with the introduction of one LEC . Compounds may be evaluated by administration either at the same time or at various times prior to the administration of the LEC to determine their usefulness in preventing damage from the LEC. The compounds prepared by the proposed method give statistically significant reductions in the wet weight of the lungs and the total number of bodies relative to the administration of one LEC.
    As shown by the experiments, the compounds of the invention showed activity in at least one of the tests described above. However, there was not always a direct correlation between the activity of the compounds, whose Ki values were measured in inhibition inhibition tests, and reduced values of the total number of bodies and wet weight of the lungs in relation to the administration of one LEC obtained in the test with an animal model. In addition, in the experiment with the animal model, no clear signs of acute toxicity were observed.
    权利要求:
    Claims (1)
    [1]
    The invention The method of obtaining heterocyclic ketones of the formula I
     OU
     RrfVc-N-iv-N l
    n o
    where RI is a group of the formula R2 - S02NHCQ-, R2 S02NHCONH- or CF3S02NH-, where R2 is chlorophenyl; X is oxygen or sulfur; Q is o-phenylene, unsubstituted or substituted by a hydroxy group or {Ci-CO-alkoxycarbonyl, or Q-cis-vinylene, characterized in that the acid of formula II
    ABOUT
    M #
    And about
    : N /
    Q
    Rf Q-cooH
    gle RI has the indicated meanings, is reacted with an amino ketone of formula 111
    n 0 and O X
    : Q
    23167820724 ,,
    Priority is by signs of hydroxy or (C1-C alkoxycarbonyl. Or Q-cis-vinylene.
    11.05.87 at RI - a group of the formula R2 -11.02.88pri1-СРз502МН; X-oxygen
    S02NHCO- or R2; S02NHCONH-; R2 is chlorine or sulfur; Q - o-phenylene, unsubstituted or phenyl; X is oxygen or sulfur; Q is o-pheny-substituted by hydroxy or (C 1 -C 4 allen, unsubstituted or substituted by coxycarbonyl, or Q-cis-vinylene.
    类似技术:
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    同族专利:
    公开号 | 公开日
    FI91072B|1994-01-31|
    NO176519C|1995-04-19|
    FI882176A0|1988-05-10|
    EP0291234B1|1994-03-23|
    JPS6445395A|1989-02-17|
    IL86236D0|1988-11-15|
    ES2063034T3|1995-01-01|
    CN1037519A|1989-11-29|
    AU1539088A|1988-11-17|
    KR880013926A|1988-12-22|
    AU605284B2|1991-01-10|
    HU201963B|1991-01-28|
    FI882176A|1988-11-12|
    HUT46708A|1988-11-28|
    EP0291234A3|1990-08-22|
    US5164371A|1992-11-17|
    DK260588A|1988-11-12|
    EP0291234A2|1988-11-17|
    GB8809316D0|1988-05-25|
    NO882036L|1988-11-14|
    PT87454B|1992-08-31|
    ZA883006B|1988-11-11|
    PT87454A|1989-05-31|
    NZ224452A|1991-06-25|
    NO882036D0|1988-05-10|
    IL86236A|1994-12-29|
    CA1326107C|1994-01-11|
    DK260588D0|1988-05-11|
    DE3888568D1|1994-04-28|
    IE62524B1|1995-02-08|
    DE3888568T2|1994-07-21|
    FI91072C|1994-05-10|
    IE881416L|1988-11-11|
    NO176519B|1995-01-09|
    ZW4988A1|1989-12-06|
    AT103293T|1994-04-15|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB878711050A|GB8711050D0|1987-05-11|1987-05-11|Selected heterocyclic ketones|
    GB888803206A|GB8803206D0|1988-02-11|1988-02-11|Selected heterocyclic ketones|
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