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    • 专利摘要:
    A compound of the formula : <CHEM> wherein R<1> is hydrogen, lower alkyl, halo(lower)alkyl, halogen, aryl which may have suitable substituent(s), heterocyclic group, amino which may be substituted by suitable substituent(s) or N,N-di(lower)alkylamino(lower)alkyl, R<2> is hydrogen, lower alkyl or N-[nitrooxy(lower)alkyl]carbamoyl, X is -O- or -S-, Y is a single bond, lower alkylene or lower alkenylene, and Z is lower alkylene which may be substituted by suitable substituent(s) or lower alkyleneoxy(lower)alkylene, and pharmaceutically acceptable salts thereof, which have vasodilating activities, to process for the preparation thereof, and to a pharmaceutical composition comprising the same for therapeutical treatment of cardiovascular disorder in human being.
    公开号:SU1706388A3
    申请号:SU884356158
    申请日:1988-07-19
    公开日:1992-01-15
    发明作者:Сиокава Йоуити；Такимото Коити；Такенака Кохеи
    申请人:Фудзисава Фармасьютикал Ко., Лтд (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for the creation of new biologically active chemical compounds, namely, thiazolylcarbamoyl-substituted ether derivatives of nitric acid or their addition salts with hydrohalic acids, which have vasodilator activity and can be used in medicine for therapeutic treatment of cardiovascular disorders in humans.
    The purpose of the invention is to obtain a new heterocyclic class of carba-ioyl-substituted ether derivatives of nitric acid, which have an increased and longer-lasting efficacy of a vasodilating effect.
    Example. Preparation of M- (2-nitrooxyethyl) -.- methyl-β-thiazolecarboxamide and its hydrochloride.
    but. Phosphorus phosphorus (13.35 g) is added in small portions to a suspension of 2-methyl-thiazolecarboxylic acid (7.65 g) in dry, chloromethane for 10 minutes. The resulting mixture is stirred well for 1.5 hours at room temperature and then concentrated under reduced pressure. The residue is dissolved in dried benzene (0 ml and the mixture is concentrated under reduced pressure. A yellow powder of 2-methyl-α-zolcarbonium chloride is obtained.
    (9, 1 g).
    b. Triethylamine (91 ml) was added dropwise to a suspension of the. Amino-ethyl nitrate nitrate salt (8.18 g) in dried dichloromethane (95 ml) while cooling with ice and water. The resulting 2-methyl-4-thiaeolcarbonyl chloride is added in small portions to the slurry for 0 min. The resulting mixture was stirred for 30 minutes at the same temperature and concentrated under reduced pressure. The residue is dissolved in water and ethyl acetate, the organic layer is separated, washed with brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. An oily product of N- (2-nitrooxyethyl) -2-methyl-4-bis-1-d to ar-oxamide is obtained.
    IR (Nudnul),: 3280, 3135, 16147, 1618, 1278.
    at . K- (2-Nitrosni ethyl) -2-methyl- - thiazolecarboxamide is converted to the hydrochloride salt in the usual way then the salt is recrystallized
    five
    0
    five
    0
    five
    0
    five
    0
    five
    ethanol zotes. White crystals of K- (2-nitrooxyl) -2-methyl-β-thiazole carboxamide hydrochloride are obtained. Tg 133-13 ° C (decomp.). f
    IR spectrum (nudzhol), cm:, 1660, 167.0, 1286, 880.
    NMR (perdeutero-DMSO, o): 2.71 (AH, s) 3.61 (.H, quartet, L “Hz), 4.66 (2H, t, J 5 Hz) 8.12 (1H, s ) 8.60 (1H, bw, J - 5 Hz) 12.80 (1H, s). Mass spectrum, m / e: 231, 185, 163, 155, 126.
    PRI mme R 2. Preparation of M- (2-nitrooxyethyl) -2- (2-acetamido-thiazalyl) acetamide hydrochloride.
    but. According to the procedure described in Example 1a, 2-acetamido-thiazolyl acetyl chloride hydrochloride is obtained.
    IR Spectrum (Nujol), 266ff. (br.), 1777, 1683, 1377.
    b. According to the procedure described in Example 16 and B, N- (; -Nitroxyethyl) -2- (2-acetamido-thiazolyl) -acetamide hydrochloride is continuously obtained. M.p. 82-85 ° C (ethanol-diisopropyl ether). (
    IR spectrum (nudzhol), cm:,, 1699, 1650, 1612,, 1380, 1279,
    NMR (perdeutero-LMSOD): 2.12 (MN, s); 3.27-3.68 (, m); “4.55 (2H, t, J 5 Hz); 6.88 (1H, s); 8.00 - 9.33 (ЗН, m).
    Mass spectrum, m / e: 288,, -25, 183, 3.
    Example 3. The following substances are prepared according to the procedure described in Examples 1a and b, continuously.
    one). N- (2-Nitrooxyethyl) -2-acetame-mido-4-thiazole carboxamide.
    IR spectrum (nudzhol), cm: 3360, 3165, 3110, 1660,, 1620,, 1285, 1265, 1010, 865.
    NMR spectrum (perdeutero-DMSO,): 2.18 (3N, s); 3.5 OH, br.s.); 3.66 (2H, quartet, J 5 Hz); , 59 (2H, t, J 5 Hz); 7.81 (1H, s); 8.11 OH, t, J 5 Hz).
    Mass spectrum, m / e: 27k, 232, 211, 198, 169, 127, 43.
    2). M (2-Nitroxyethyl) -2- (N-methyl acetamido) -thiazole carboxamide. M.p. 13 + -135 1C (decomp., Ethanol). IR spectrum (nudzhol),, 1670, 1650, 1620 1280, 890, 870.
    NMR (DMSO-d6, d): 2.0 (3N, s); 3, -3.9 (2H. M); 3.75 (ЗН, s); , 68
    (2H, t, J - 5 Hz); 7.80 (1H, s); 8.51 (1H, broad t, j 5 Hz).
    Mass spectrum, m / e: 288, 2kb, 212, 183, Х1, «з.
    3). N- (2-Nitroxyethyl) -2-benzamido-thiazole carboxamide.
    M.p. 15 -155 ° C (decomp., Ethyl acetate-diisopropyl ether).
    IR Spectrum (Nujol), 3355,
    1650, 1630, 1535, 1285, 855, 705.
    NMR (L. MSO-d6, P: 3.71 (2H, quartet, J 5 Hz); 470 (2H, t, J - 5 Hz); 7, -8, (7H, m); 12.60 ( 1H c).
    Mass spectrum (m / e): 336, 283, 2bP 231, 105, 77.
    M. K- (2-Nitrooxyethyl) -2- (K, I-dimethylamino) -thiazolecarboxamide.
    Mp .: 9 -95 ° C (ethyl acetate-diiso propyl ether).
    IR spectrum (nujol), ЗЗбО,, 3090,, 162U, 1560, 1280, 985, 875 NMR (DMSO-d6, $): 3.08 (6H, s); 3.63 (2H, quartet J 6 Hz); 467 (2H, t, J 6 Hz); 7.38 (1H, s); 8.3D (1H, bw J 6 Hz).
    Mass spectrum, m / e: 260, 215, 197, 184 155, 12 /.
    five). M- (2-Nitrooxyethyl) -2-methyl-amino-thi.azogcarboxmide.
    M.p. 68-7: ° C.
    i
    IR spectrum (udzhol), cm: 3350,
    3220, ZPO,, 1630, 1585,, 1285, 860.
    NMR (CDC13, Ј): 3.00 (AH, s); 3.76 (2H, quartet, J 6 Hz); , 63 (2H, t, J 6 Hz); 5.5 (1H, broad s) 7.37 (1H, s); 7.56 (1H, brs).
    Mass spectrum, m / e:, 183, 170,
    1M, 113.
    6). N- (2-Nitpooxyethyl) -2, thyl-β-thiazole carboxamide.
    M.p. 1J-11b ° C (ethanol-diisopropyl ether).
    IR spectrum (nudzhol), cm: 1650, 1610, 1280, P.R.
    DMR (LMSO-l6, o) 2, (3N, s); 2.71 (ЗН, s); 3.63 (2H, quartet, J 6 Hz); 469 (2H, t, J 6 Hz); 8.9 OH, broad.t. , J 6 Hz).
    Mass spectrum, m / e: 199, 182, 169, 1140.
    7). , 1 -Bis (nitrooxymethyl) ethyl -2-methyl-β-thiazole carboxamide.
    M.p. 78-81 ° C (diisopropyl ether - n-hexane).
    IR spectrum (nudggl): ZZbZ, 313P, 166 ;;, 1675, 1530, 1285, 995, 87P, 7bi. 5 NMR (CDCl j, P: 1.57 (ZN, s);
    2.70 (ЗН, s); 483 (2H, d, J 7 Hz); 498 (2H, d, J 7 Hz); 7.0 (1H, broad s); 7.95 (1H, s).
    Mass spectrum, m / e: 2I, 126. 108). , 1-Bis (nitrooxymethyl) -2-nitrooxyethyl -2-methyl-thiazole, rboxamide.
    M.p. 102-10l} ° C (ethyl acetate-diisopropyl ether).
    15IK-spectrum (nujol), 3250, i650, 1630, 1270, 855. NMR (CDCl ,, J): 2.72 (3N, s); 5.00 (6H, s); 7.60 (1H, brs); 7.98 (1H, s). 20 Mass spectrum, m / e: 305,, 126.
    9). K- (2-Nitroxyethyl) -2-morpholino-thiazole carboxamide.
    M.p. 1.7-128 ° C.
    IR (Nujol), cm: 3200, 15, 1603, 1516, 1282, 1230, 1108, 893.
    NMR (DMSO-d6, (D): 3.2-4.0 (YUN, H); 466 (2H, t, J 5.5 Hz); 7.9 (1H, s); 8.32 (1H , t), J 6 Hz). 30 1 Mass spectrum, m / e:, 239, 226, 197.
    ten). K- (2-Nitrooxyethyl) -2-piperidino-h-thiazogasboxamide ..
    M.p. (decomp.), n-hexane-ethyl acetate).
    IR spectrum (nudzhol), cm: 3280,, 1620, 153 1282.
    NMR (CDClI,): 1, W-2.00 (bN, and), 3.22-3.93, (H, m); i, 63 (2H, t, J 5 Hz); 7.37 OH, s); 7.7 (1H, br.).
    five
    0
    five
    Mass spectrum, m / e:, 237, 224
    195.
    eleven). D) - (2-Nitrooxyethyl) -2-phenyl 4-thia zolka rboxamide.
    M.p. . (
    IR spectrum (nudzhol), cm: 3280, 1655, 1620, 12.82.
    NMR (AMCO-d6, f): 3, W-3.93 (2H, m); 473 (2H, t, J 5 Hz); 7.2-7.77 (ЗН, m); 7.93-8.28 (2H, m); 8.35 HE, s); 8.60-9.03 (1H, m).
    Mass spectrum, m / e: 293. 230, 217, 188.
    12). C- (2-Nitrooxyethyl) -2- (Ridyl 1 - -thiazolcarboxamide.
    M.p. 121-12b ° C (decomp., N-hexane-chloroform).
    and
    117 Of388 Р
    IR spectra (Nujol), cm 1: 3255, Mass spectrum, m / e: 289, 288, 226,
    1650, 160P, 1536, 128P.212, 183, b.
    NMR (LMSO-d, Ј): 3.52-3.95 (2H, T /). N- O, 3-Vis (nitrooxy) propyl
    with); 472 (2H, t, l 5 Hz); 7,605 2-methyl-thiazolcarboxamide.
    (F, dd, L 6.8 Hz); 8.28-8.57 (2H, NMR (DMSO-d6, Ј): 2.70 (ZN, s);
    m); - 8, bz-9, P5 (2H, m); 9.30 (1H, d, 3.6-405 (GN. M);, 2 (2H. M);
    J - 2 Hz) .5.3-5.8 (1H, i); 7.7 (1H, width s);
    Mass spectrum, m / e: 294, 231.7.97 (1H, s).
    218 | 89 10 Mass spectrum, m / e: 306, 243, 197,
    13). (2-Nitrooxyethyl) -2-laureyl- 155, 126, 98.
    amino-4-thiazolecarboxamide. example. The following substances
    M.p. 122-126 C (decomp. Diisopro-receive according to the method of examples 1a-b,
    lilac ether ethyl acetate). continuously.
    , , 15 1). N- (2-Nitrooxyethyl) -2-butyl-JK-spectrum (Nujol), cm: 3130, thiazolecarboxamide hydrochloride.
    1675, (shoulder), 1630, No., 1281.t.pl. 113-ПС (ethanol-dioproMNR (end ,,): 0.67-1.67 (21H, sawn Mp).
    ); 2.55 (2H, brt, L 7 Hz); IR spectrum (Nujol), OSU: 3l8D,
    3.67-400 (2H, i); 65 (2H, t, 20 3050, 2580 (shoulder), 1658, 1bZS, 1580,
    J 5 Hz); 7.3 (1H, brs); 7,771282.
    (1H, s); 9.33 (1H, brs). mr (LMSO-L,): 0.92 (3N, t,
    Mass spectrum, m / e: MC, 351, 183, j 6 Hz): 1.10-2.03 (H, m); Z.SZ
    155 I27, 0 c,, „(2H, brt, L 6 Hz); 3.3-3.83
    1M. K- (2-Nitrooxyethyl) -2-butyl-25 (m) & (2H, t, J - 5 Hz);
    AMITOpl T83-8bChCHY T 8 13 (1H) C); ° H Ch 853
    IR spectrum (nujol), 339, MDGG-GPRKTP m / e- 273 227 211
    e ";. with the PRC 1c / .l 1yppass spectrum, m / e. e- / y, ЈЈ /, ii,
    31ch5, 163P, 15chP, 1280.-7 1AR
     (special) ,, oz (J tzo 975K K: (2- „ITROOOXISTI„). 2 - (. Я2Н / T I - 3. “- 4.": .nino "t") .., (M " .rv.k ...
    m); H, 65 (2H, t, J - 5 G "); 7.43 ILTGTHKht- 0 ° C (oaz, egaiol)
    , -1-1-1 / iu about pl and y-1 / ID L decomp. "Ethanol /.
    H, br; 7.77 (1H, s); 9.37IR spectrum. (Nudzhol),
    (1NAHG-ktR, m / e: 302, 239, 232, 3J7 | J / 255J. 2j | 0, 1655. 1625, 15 “.0.
    22b c 97 09M 71 3, NMR JlcO-d): 2.88 (bN s);
    15). K- (2-Nitrooxyethyl) -2-labels - h / c 6 h -.
    Sicarbonylamino-tiazvlcarboxamid. 3,68 (2H quartet, J - 5 Hz); 472
    IR spectrum, (film),: 336040 Ј. 5 Hz); , 76 (2H s);
    (PGG), Sz17p, 1718.1622 (.uir). : i; HP: c7-T j
    NMR (CDClI,): 3,, 89 (2H, m); 3.91 (ЗН, s); 66 (2H, t, J - 5 Hz); Mass spectrum, b / e: 275. 274 231.
    7.0 (1H, brs); 7.77 (1H, s); 45 1}} 58,,
    8 29 (1Н width s) K- (2-Nitrooxyethyl) -h-methyl Nass-spectrum, and / e: 290, 227, 2145 "olcarboxamide hydrochloride.
    .or rn m.p. 76-7o C (decomp., Ethanol-di | b) .- (2-Nitroxyethyl) -2- (3-i-isopropyl ether).
    Tilureido) - -thiazoliboxamide.
    T pl. 128-Sh ° C (Rael. N-hexane-ei IR spectrum (Nujol), cm-: 3275,
    Ethanol) .3150, 2375, 1820, 1664 1638,
    IR spectrum (nudzhol), cm: 3360.1609, 1538, 1282 1274
    G / 00 1620, 1530 (width), 12RO.NMR (DMSO-d, P: 2.60 (ZN, s);
    NMR (LMSO-l ", 0): 2.73, (3N, d, 3.61 (2H, q. Hz); J.69 (2H,
    J - Hz), 3.5-3.87 (2H, m); 46855 t, L 5 Hz); 8.30 (2H, s); 8.67 (2H, m, L 5 Hz); 6.5P-6.83 (1H, m); (1H, bw, L 5 Hz), 9.23 (1H, s).
    7.65 (1H, s); B, OP-8.35 (1H, s); Mass spectrum, m / e: 231, 185. 168,
    10.8 (1H, s. C) .155. 26
    25
    PRI me R 5. The following substances are obtained according to the method of examples 1a and b, continuously,
    l) N- (2-Nitrooxyethyl) -4-thiazolecarboxamide.5
    IR spectrum (nudzhol), cm: 330, 3070, 1620, 1535, 1/77.
    2}. M- (2-Nitrooxyethyl) -2-amino 4-thiao-carboxamide.
    IR Spectrum (Nujol), 3350, 10 3280, 3175, 1635 (shoulder), 1620 (shoulder), 1605,, 1522, 1282..
    3). N- (2-Nitrooxyethyl) -.- chloro-4-thiazole carboxamide.
    IR spectrum (nudzhol), cm: 3315, 3080, (shoulder), 1615, 1535, 1280.
    M. M- (2-Nitrooxyethyl) -2-thiazolecarboxamide.
    IR (Nujol), 3280, 20 3085, 1650, 1520, 1275.
    five). N- (2-Nitrooxyethyl) -5 methyl-2-thiazole carboxamide.
    IR spectrum (nudzhol), cm: 3300, 1650 (tribe), 167.5,,,.
    6). N.N-Bis- (2-nitrooxyethyl) - 2,4-thiezoldicarboxamide.
    IR spectrum (nudzhol), cm:, 1671, 1625, 1610,,, 1.
    7). M- (2-Nitroxyethyl) -3 (2-methyl 4-thiazolyl) - (E) -propenamide.
    IR (Nujol),: 3200, 3105,, 1610, 1550, 1280.
    eight). C- (2-Nitrooxyethyl) -3- (4-35 azazolyl) - (E) -propenamide.
    IR (Nujol) 3250, 3080, 1650, 1620, 1558, 1277.
    9). N, N-Bis- (2-nitrooxyethyl) -. 2,5-thiazol-dicarboxamide.
    IR Spectrum (Nujol), 3300, 230, 1625, 1610, 1515, 1275, 865,.
    ten). N- (2-Nitrooxyethyl) -2-trifluoro-d, Etil-5-thiazole carboxamide.
    IR (Nujol), 3320, 1625, 1550, 1290, 1280, 1150, 860.
    eleven). K - (- Nitrooxyethyl) -2-trifluoromethyl-4-thiazole carboxamide.
    IR (Nujol), 3270, 1650, 162D, 1535, 1275.
    one .). N- Ј2- (2-Nitroxyethoxy) 2-methyl-5-thiao-carboxamide.
    IR (Nujol), 331 0, 55 1610, 156:, 1275, 1120, 870, 850.
    13). N- 2- (2-Nitroxyethoxy) ethyl - 5-thiazole carboxamide.
    five
    five
    0
    0
    five

    ,
    IR spectrum (ngdzhol.1,: 3280, 3070, 16M, 16/11, 12ftO, 111M.
    one ) . N- (2-Nitroxy yl) -2-fennl-5-thiazole carboxamide.
    IR (Nujel), 3300, 1622, 1550, 1278.
    15). M- (2-Nitrooxyethyl) -2- (3-nitrophenyl) -4-thiazolcarboxome.
    IR Spectrum (Nujol), 3395, 3110, 1650, 1620, 1-520, 1278..
    sixteen). K- (2-Nitrooxyethyl) -2- (2-nitrophenyl) - -thiazolecarboxamide.
    IR spectrum (film),, 3120 1655 (shoulder), 1625, 1525, 1357, 1280.
    17). (2-Nitrooxyethyl) -2-methyl 4-thiazolecarboximide.
    IR spectrum (nudzhol), cm: 3280, 3135,, 1618,, 1278.
    Example 6. The following substances are obtained according to the method of examples 1c, continuously.
    one). N- (2-Nitrooxyethyl) -2, 4-dimethyl-5 thiazolecarboxamide hydrochloride.
    IR spectrum (nudzhol), cm: 3175, 2270 (broad), 1890, 1660, 1620, 1525, 1278.
    2). K- (2-Nitrooxyethyl) -2-methyl-5-thiazolecarboxamide hydrochloride.
    IR spectrum (nudzhol), cm: 3230, 1655, 16YO, 1550, i; 85, 880, 86П.
    3). K - (.- Nitrooxyethyl) -5-thiazolecarboxamide hydrochloride.
    IR spectrum (nudzhol), cm: 3200, 3110 ,. , 2500, 1655, 1630,, 12RC, 995, 860,.
    four). M- (3-Nitrooxypropyl) -2-methyl 4-thiazolecarboxamide hydrochloride.
    IR spectrum (nudzhol), cm (: 380, 3060, 2650, 1660, 1620, 1550, 1280, 875.
    five). N-G2- (2-N-nitroxy) ethyl-2-methyl-4-thiazole carboxamide hydrochloride.
    IR spectrum (nudzhol), cm: 3190, 3060, 16507 1630, 1560, 1290, 900, 860.
    6). And- (A-Nitrooxybutyl) -2-methyl 4-thiazolecarboxamide hydrochloride.
    IR (Nujol), 3200, 3080, 1665, 1625, 1560, 1285.
    7). (2-Nitroxyethoxy) ethyl 4-thiazolecarboxamide hydrochloride.
    IR spectrum (nudzhol), cm: 3220, 3055, 1905, (br.), 1280.
    I
    The target compounds and their pharmaceutically acceptable addition salts with hydrohalic acids of the proposed method have vasodilating activity and prolonged exposure, and are suitable as a washable agent.
    The results of testing a representative compound of the method according to the invention are as follows.
    one). The effect on the isolated rat aorta.
    Test Method
    Aortas are removed from rats. Spiral strips of mm length are cut out of the aorta and suspended in an organic bath containing Tyrode solution at 37 ° C, purged with a gas mixture of 95% oxygen and 5 $ of carbon dioxide. Tonus gkrlos is recorded on a multichannel recorder with atel transducer force - displacement. After adjusting the initial stress to 0.5 g, add .3.2 -1T ° mol / L of norepinephrine to the organic bath to enhance the tone of the aorta bands to 0.9-1.1 g. Then add cumulus The active concentrations of the test substance and finally set 10 mol / l of papaverine to determine the maximum relaxation. The effective dose values (3fljo) are calculated by interpolating the curves: the average cumulative dose – activity (papaverine effect, 10 mol / l, is 100%).
    Subjects substances.
    And- (2-Nitrooxyethyl) -2-methyl-4-thiazolecarboxamide hydrochloride (compound 1) M- (2-nitrooxyethyl) - thiazolecarboxamide (compound 2), N- (2-nitroxyethyl) -5 ethyl; -thiazolcarboxalamide (compound 3) and K- (2-nitrooxyethyl) -3-pyridinecarboxaiide (comparative compound A).
    The results of the test.
    ten
    7P638812
    the use of blood 100-125 mm Hg and weighing 2 5-375 g. The animals introduced the small tubule into the left femoral artery and measured the mean blood pressure and heart rate using a pressure transducer. Medications were given orally. The animals were deprived of food for approximately 18 hours prior to the oral dose. Test drugs were dissolved in a salt solution or ethanol and administered orally at doses of 10 kg / kg. The duration of half the maximum effect reduction pressure was calculated as T 1/2.
    Test compounds: Compound 1, compound 2, compound 3 and compound A.
    Test results: Test T 1/2, min. Connection
    15
    20
    one
    2
    3
    BUT
    100
    200
    100
    50
    As can be seen from the above test results, the substances of the proposed method have not only increased vasodilating activity, but also a longer duration of this efficacy compared with the known compound. In addition, they are low toxic substances, i.e. are useful for treating cardiovascular disorders.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining thiazolylcarbamoyl-substituted ether derivatives of nitric acid of the general formula
    BUT
    IVt CONH-Z-ONO,
    s
    The value of ED50) g / ml
    9.1 9L
    1C 10
    -7
    2). Effect on rats with normal blood pressure.
    Test Method
    Used male SD rats, age / -9 weeks, with an average pressure
    where K is hydrogen or halogen, C4-C4. is alkyl, trifluoromethyl, phenyl, nitrophenyl, pyridyl, morpholino, piperidine, amino, C-C alkanoylamino, benzamido, C {-C-alkoxycarbonylamino, N- (C (-C-alkyl) amino, NjN-di- (CTC-alkyl) amino, N- (C-Svalkyl) -N- (C2-C.-alkanoyl) amino, 3 - (- C-Cd13
    an alkylureido group or N, F-di- (C (-C-alkyl, mino-C-Cf alkyl);
     hydrogen or C (-C4 alkyl; Z-C-C alkylene, optionally substituted by one or two nitroxy groups, or CfCt alkyleneoxy-C-C-alkylene, their addition salts with hydrohalic acids, characterized by the fact that the reaction of a compound of the general formula
    R
    NJ
    about
    7P638Я
    where r
    14
    and R each is as defined above, as its reactive derivative at the carboxy group, such as halohydride, with a compound of the formula
    HtN - Z - ON02,
    where z has the indicated values, in the form of a cope, in an anhydrous organic solvent medium in the presence of an organic base under cooling conditions, preferably at 0-5 ° C, with isolation of the desired product in free form or in the form of an addition salt with hydrohalic acid.
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    同族专利:
    公开号 | 公开日
    GB8717068D0|1987-08-26|
    KR890002067A|1989-04-07|
    AU1919988A|1989-01-27|
    NO883208L|1989-01-23|
    NO172049B|1993-02-22|
    US4923886A|1990-05-08|
    CN1021046C|1993-06-02|
    DK375988A|1989-01-21|
    DE3888415D1|1994-04-21|
    NO883208D0|1988-07-19|
    AU623858B2|1992-05-28|
    EP0300400B1|1994-03-16|
    PH24481A|1990-07-18|
    EP0300400A1|1989-01-25|
    IL86959A|1992-12-01|
    CN1031226A|1989-02-22|
    US5010093A|1991-04-23|
    PT88019A|1989-06-30|
    DE3888415T2|1994-07-14|
    HUT47551A|1989-03-28|
    FI883402A0|1988-07-18|
    SU1760984A3|1992-09-07|
    IL86959D0|1988-12-30|
    DK375988D0|1988-07-06|
    HU203227B|1991-06-28|
    AT102928T|1994-04-15|
    NO172049C|1993-06-02|
    MX12317A|1993-09-01|
    FI883402A|1989-01-21|
    PT88019B|1995-03-01|
    JPH0331709B2|1991-05-08|
    JPH0228167A|1990-01-30|
    ZA884987B|1989-05-30|
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    KR101045041B1|2009-10-27|2011-06-28|에스엠이엔지|A method for manufacturing of suture needle|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB878717068A|GB8717068D0|1987-07-20|1987-07-20|Nitric ester derivative|
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