• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention relates to heterocyclic substances, in particular the preparation of amino acid derivatives of the total C 6 H 5 -CH 2 -CH 2 -CHK-NHCHX-C (O) -Y, where K is C (O) OR 1 X - (CH 2 ) 4 -NH 2 Y is NAC (O) OH where R 1 is H or C 2 H 5 A - group: @ or their acid additive salts with hypotensive and cardioprotective effects, which can be used in medicine. The goal is to create new, more active substances of the specified class. The synthesis is carried out by reacting the compound YH, with the corresponding amino acid, and in the group Y, the carboxyl is protected by C 1 -C 4 alkyl, in the presence of a condensing agent, followed by deprotection of the protective groups by saponification. The desired product is isolated either in free form or in the form of the desired salt. For new compounds, a 50% inhibition of the activity of the enzyme converting angiotensin is achieved at a lower concentration of the substance than in the known case, i.e. (1.4 . 10 -8 -7.6 . 10 -8 ) - (2.9 . 10 -9 -3.5 . 10 -9 ) versus 7 . 10 -6 for enalapril. 1 tab.
    公开号:SU1544188A3
    申请号:SU864027899
    申请日:1986-08-04
    公开日:1990-02-15
    发明作者:Шнорренберг Герд；Роос Отто；Лезель Вальтер；Видеманн Ингрид；Гайда Вольфрам；Хефке Вольфганг；Арндтс Дитрих；Стреллер Ильзе
    申请人:Берингер Ингельгейм Кг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the preparation of new heterocyclic compounds, in particular amino acid derivatives, lysine, containing drotienopyridine in the molecule, which have hypotensive and cardioprotective effects.
    The aim of the invention is to obtain new compounds possessing
    valuable pharmacological properties.
    The method is carried out as follows.
    in a way.
    Example 1. (1- (3) -ethoxycarbonyl-3-phenylpropyl) -l-lysyl - -4,5,6,7-those trahydrothieno 3,2-e pyridine-4 (8) carboxylic acid.

    04
    drank) -tert-butyloxycarbonyl or a) N- (1-ethoxycarbonyl-3-phenylpro) -L-Ng-zin.
    In a solution of 247.5 g of 2-oxo-4-phenyl butyric acid ethyl ester and
    74.2 g of N -t-butyloxycarbonyl-L-γ-lysine in 1800 ml of 50% ethanol, 37.7 g of NaCNBH in 300 ml of ethanol are added dropwise over 31/2 h. The solution is then stirred at room temperature for 12 hours. The ethanol is evaporated in vacuo and the aqueous phase is adjusted to pH 9 with the addition of 1N. sodium liquor. Then extracted three times with ether. Using 1 n. The HC1 aqueous phase is adjusted to pH 4 and extracted three times with ethyl acetate (hereinafter referred to as ethyl acetate). The combined acetic ether extracts are dried over MgSO4. and in vacuum condensed. Get 116 g of a light yellow oil (88% of theoretical.).
    b) tert-Butyl ether (1 (8) - -ethoxycarbonyl-3-phenylpropyl) -l-M -tert-butyloxycarbonyl-lysyl -4,5,6, 7-tetrahydrothieno 3,2-e pyridine-4 (S ) - carboxylic acid.
    In cooled to О С solution of 4.3 g
    N- (1-ethoxycarbonyl-3-phenylpropyl) -., „-LN-butyloxycarbonyl-lysine, 3.3 g of tert-butyl ester 4,5,6,7-tetrahydrothieno 3,2-e-pyridine-4-carbono- acid, 2.1 g of 1-hydroxybenzotriazole and 2 ml of triethylamine in 40 ml of tetra
    rahydrofuran added 3.5 g dicyk35
    logexilcarbodiimide and stirred for one hour at 0 ° C and stirred for 12 hours at room temperature. After filtration, the solution is concentrated in vacuo, the residue is taken up in ethyl acetate, and washed successively. HC1 solution KHS03 and dried with water over MgSOq. and thicken. The oil is subjected to chromatography on silica gel (eluent: ethyl acetate / n-hexane 1: 1). Fractions with an RI value of 0.5-0.65 are purified by liquid chromatography with is4, 6 g of 4,5,6,7-tetrahydrothieno 3,2-methyl ester hydrochloride 3,2-c pyridine-4-carboxylic acid, 3.06 g of 1-hydroxy - benzotriazole and 5.6 ml of triethylamine in 75 ml of dimethylformamide / tetrahydrofuran (1: 1), 4.5 g of dicyclohexylcarbodiimide are added and the mixture is stirred at 0 ° C for 1 hour and at room temperature. After filtration, the solution in vacuum is concentrated, the residue is taken up in ethyl acetate, washed successively with 10 n. HC1, a solution of KNSOE and water, dried over MgSO4 and concentrated. The oil is subjected to chromatography on silica gel (solvent is acetic ether / n-hexane (1: 1). Fractions with an R / 0.4 value are purified by thin layer chromatography using an ethyl acetate mixture of n-hexane (1: 1). Fractions with a Rr value of 0.38 contain 2.3 g of methyl ester using a mixture of ethyl acetate and
    n-hexane (1: 1). Fractions with a value of 0pra (1 (5) -ethoxycarbonyl-3-phenyl R, 0.56 contain 1.8 g of tert-bu-propyl) -l-H-tert-butyloxycarbonyl ethyl ether (1 (8) -ethoxycar-- lysyl | -4,5,6,7-tetrahydrothienoJJ3,2bonyl-3-phenylpropyl) -H-NE tert-butyl - cj pyridin-4 (S) carboxylic acid. hydroxycarbonyl-lysyl 4,5,6,7-tetrahydride-b) (1 (8) -carboxy-3-phenylprothieno {W, 2nd pyridine-4 (S) carboxylic 55-nap) -b-lysyl | -4.5 , 6,7-tetrahydroxy acids., 2nd pyridine-4 (8) carboxylic acid) (1 (8) -ethoxycarbonyl-3-lots. -Phenylpropyl) -1.1-lysyl -4.5-6.7-tet- 2.3 g obtained according to a)
    ten
    41884
    Ragidrothieno 3,2-e-pyridine-4 (S) carboxylic acid.
    1.8 g of the compound obtained according to b) in 200 ml of 1N. HC1 in glacial acetic acid is stirred at room temperature for 30 minutes. The glacial acetic acid is distilled off in vacuo, the residue is treated with isopropanol / ether and the crystalline precipitate is filtered off, washed and dried. 1.1 g are obtained (80% of theor.)
    dihydrochloride of the above title compound. T. pl. 162 C (decomposition).
    Example 2. (1 (I) -carboxy-3-phenylpropyl) -b-lysyl -4,5,6,7-tetrahydrothieno 3,2-e pyridine-4 (S) -carboxylic acid.
    a) (1 (8) -ethoxycarbonyl-3-phenylpropyl) -L-N-tert-butyloxycarbonyl-lysyl-7, 5.6,7-tetrahydrothieno 3,2-cJ pyridine-4 (S) carboxylic acid methyl ester.
    In cooled to 0 ° C solution 8} 7 g of No.- (1-ethoxycarbonyl-3-phenylpropyl) - -L-N -t-butyloxycarbonyl-liine,
    „
    five
    4.6 g methyl ester hydrochloride 4,5.6,7-tetrahydrothieno 3,2-c pyridine-4-carboxylic acid, 3.06 g 1-hydroxy-benzotriazole and 5.6 ml triethylamine in 75 ml dimethylformamide / tetrahydrofuran (1: 1), 4.5 g of dicyclohexylcarbodiimide are added and stirred for an hour at 0 ° C and stirred for 12 hours at room temperature. After filtration, the solution in vacuum is concentrated, the residue is taken up in ethyl acetate, washed successively with 10 n. HC1, a solution of KNSOE and water, dried over MgSO4 and concentrated. The oil is subjected to chromatography on silica gel (solvent is acetic ether / n-hexane (1: 1). Fractions with an R / 0.4 value are purified by thin layer chromatography using an ethyl acetate mixture of n-hexane (1: 1). The fractions with a Rr value of 0.38 contain 2.3 g of methyl ester0
    0ra (1 (5) -ethoxycarbonyl-3-phenyl51
    СОР / ШНРННЯ and 12 mi 1 n. sodium hydroxide solution in 20 ml of acetonitrile was stirred at room temperature for 12 hours. Acetonitrile was distilled off in vacuo, the aqueous residue was extracted with ethyl acetate, using 1N. HC1 is neutralized and the precipitate is filtered off, washed and dried. The resulting crystals and 20 ml of 1N. HC1 in acetic acid in acetic acid is stirred at room temperature for 30 minutes. The glacial acetic acid is distilled off in vacuo, the residue is precipitated with isopropanol / ether, sucked off and dried.
    1.46 g (71% of theoretical.) Of the above product are obtained in the form of a colorless amorphous powder.
    T. pl. 175-178 ° C (decomposition).
    Example 3. (1 (5) -ethoxy-carbonyl-3-phenylpropyl) -b-lysyl} -4,5-6,7-tetrahydrothieno 2,3-cJ pyridine-7 (3) carboxylic acid.
    Described in example 1
    from 8.6 g of N- (1-ethoxycarbonyl-3-phenylpropyl) -T., - M-tert-butyloxycarbonyl-lysine and 6.6 g of tert-butyl ether 4,5.6,7-tetrahydrothieno 2, 3- -c pyridine-7-carboxylic acid, 2.3 g of the above compound are obtained as dihydrochloride, m.p. 186-188 ° C.
    Example 4. (1 (8) -carboxy-3-phenylpropyl) -b-lysyl -4,5,6,7-tetrahydrothieno 2,3-e pyridine-7 (8) carboxylic acid.
    Described in example 2 by a method of 4.4 g of H- (1-ethoxycarbonyl-3-phenylpropyl) -1, Me-t-butyloxycarbonyl-lysine and 2.3 g of methyl ester hydrochloride 4,5,6,7 -tetrahydrothieno-2, pyridine-7-carboxylic acid gives 0.9 g of the above compound as the dihydrochloride.
    T. it is 175 ° C (decomposition).
    Example 5. (1 (8) -carboxy-3-fenstropil) -G, -lysyl -4,5,6,7- -tetrahydrothieno. .Z-cj pyridine-5 (8) - carboxylic acid.
    As described in Example 2, a method of 11.2 g of N- (1-ethoxycarbonyl-3-phenylpropyl) -l-H-tert-butyloxycarbonyl-lysine and 6.0 g of methyl ester hydrochloride 4,5,6,7- tetrahydrothieno-2,3-e-pyridine-5 carboxylic acid gives 1.5 g of the above compound as the dihydrochloride. T pl. 170 ° C (decomposition).
    1886
    Example 6. (1 (8) -carboxy si-3-phenylpropyl) -1 / -lyshg | -4, 5,6,7-tetrahydrothieno 3,2-e pyridine-6 (S) -carboxylic acid.
    - Described in example 2, a method of 5.5 g of N- (1-ethoxycarbonyl-3-phenyl propyl) -tert-butyloxycarbonyl- -lysine and 3 g of hydrochloride methyl ester 4,5,6,7-tetrahydrothieno 3,2 -cj -pyridin-6 carboxylic acid gives 0.8 g of the above compound as the dihydrochloride.
    T. pl. 170 C (decomposition).
    Example 7. (1 (8) -ethoxycarbonyl-3-phenylpropyl) -l-lysyl - -4,5,6,7-tetrahydrothieno 2,3-e pyridine-5 (8) carboxylic acid.
    As described in example 1, a method of 8.6 g of N- (1-ethoxycarbonyl-3-phenylpropyl) -l-H-tert-butyloxycarbonyl-lysine and 6.6 g of tert-butyl ether, 4,5.6, 7-tetrahydrothieno 7., 3-cj-pyridine-5 carboxylic acid gives 2.0 g of the above compound as the dihydrochloride.
    T. pl. 106-109 ° C.
    Example 8. (1 (8) -carboxy-3-phenylpropyl) -b-lysyl -4,5,6,7-tetrahydrothieno L3,2-C1 pyridine-6 (8) carboxylic acid.
    Obtained according to Example 1 a) N- (1 (I, 8) -ethoxycarbonyl-3-phenylpropro-O-LN-tert-butyloxycarbonyl-lysine) is taken up in acetic ether and anhydrous simple diethyl ether is added. It is filtered and dried to give approximately 60% of the theoretical N- (1 (3) -ethoxycarbonyl-3-phenylpropyl) -2 (S) -N-tert-butyloxycarbonyl-lysine as colorless crystals.
    4.4 g of this compound is reacted by the method described in Example 2 with 2.2 g of 4,5,6,7-tetrahydrothieno 3,2-cJ pyridine-6 (S) carboxylic acid methyl ester hydrochloride. The purification was not carried out according to Example 2, but on silica gel using ethyl acetate / n-hexane (1: 1). Obtain 5.2 g (84% of theoretical.) Methyl ester of (1 (W) -ethoxycarbonyl-3-phenylpropyl) -b-lysyl -4,5,6, 7-tetrahydrothieno 3,2-e pyridine -6 (8) carboxylic acid as a colorless oil, which is further processed according to example 2 b) to obtain 3.0 g
    (75% of theory.) Of the above title compound.
    T. pl. 170 ° C (decomposition).
    Example 9. (1 (8) -carboxy-3 Fenschropyl) -1, -lysyl-4, 5.6,7-tetrahydrothieno 3,2-eJpyridin-6 (R) - carboxylic acid.
    As described in Example 8, from 2.2 g of (1 (8) -ethoxycarbonyl-3-phenylpropyl) -tert-butyloxy-carbonyl-lysine and 1.1 g of 4,5,6,7-tetra- methyl ester hydrochloride Hydrothieno 3, 2-pyridine-6 (R) carboxylic acid, 1.4 g of the above-mentioned compound are obtained as
    (colored crystals.
    Biological testing.
    The blood pressure lowering activity of the compound is primarily due to the ability to inhibit the enzyme's activity of angiotensin I conversion and, thus, to block the formation of the angiotensin II vasoconstrictor from angiotensin I. the concentration of the test compound at which the activity of the enzyme converting angiotensin I is inhibited by 50% /
    The results of the experiment are given in the table „
    concentrations than known, indicating a higher activity of new compounds compared with the known.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining the amino acid derivatives of the general formula
    ABOUT
    {about cn-gsn-sn-ins-sslsoon
    COOR, (CH Sv Ш1г
    where R is hydrogen or ethyl, A is a group of the formula
    OR
    or their acid addition salts, characterized in that the compound of the general formula
    O CH2 CH2-CH-NH-CH-C-OH
    COORt (CH2X
    NH-R-i
    where R has the indicated value; R is a t-butyloxycarbonyl protecting group,
    subjected to interaction with the compound of the formula
    45
    HN; -ЈOOR, -f
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    法律状态:
    优先权:
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