• 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:
    Compounds of the formula and pharmaceutically acceptable non-toxic acid addition salts thereof, in which R is hydrogen, methyl, ethyl, cyclopropylmethyl, or allyl; A is a residue of a D-amino acid selected from Ala, Abu, Nva. Val, Nle, Leu, lie, Gly(A1), Gly(Cp), Met, Cys(Me), Met(O), Cys(Me) (0), Ser, Thr, and Hse; R1 is C1-C3 primary alkyl, cyclopropylmethyl, allyl, ethylthiomethyl, 2-fluoroethyl, or propargyl; X is bromo, iodo, chloro, methyl, trifluoromethyl, or methoxy; and or in which R2 is hydrogen, acetyl, or acetoxymethyl and R3 is C1-C3 alkyl; which are useful analgesic agents, are described herein.
    公开号:SU1082319A3
    申请号:SU813345906
    申请日:1981-10-19
    公开日:1984-03-23
    发明作者:Дэвид Джеселлчен Пол；Теодор Шуман Роберт
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new biologically active compounds - tetrapeptides or their acid addition salts, which can be used in medicine. A known method for producing peptides by cleaving the Tert-butylox ka1) bonyl group from the corresponding blocked peptide by treating the latter with trifluoroacetic acid the presence of anisole at 1. The purpose of the invention is to obtain new compounds with interesting pharmacological properties. This goal is achieved by the method of obtaining tetrapeptides of the general formula R-Tyr-DAla-mtJ-NR-CH-CONH hydrogen, alkyl, alkyl, cyclopropyl X - bromine, chlorine, iodine and methyl, I.P., their acid addition salts, The fact is that the protected tetra peptide of the general formula fgOC K-Tyr DAlO-Gly-N-Cfl-CONH R, K and X have the indicated values, is released by processing with trifluoroacetic acid. The tetrapeptides of formula (T) are isolated in the form of acid additionally acceptable from a pharmaceutical point of view, non-toxic salts that include organic and inorganic kilotroses, such as salt, sulfur, sulfo, wine fumaric, hydrobromic, glycol, citric, mapeinova, phosphorus, nta on acetic nitrogen, benzoin, ascorbic, h-toluenesulfo-, ben zolsulfo-, naphthalene-sulfo-, propionic and others. The following abbreviations are used in the description: (-amino-oil on acid i, Ala - alanine, Cys - distein, Cys (Me) - (5-methyl) -cysteine, Cys (Me) (O) - (5-methyl) -cysteine sulfoxide , Gly - glidine, Gly (Al) - allylglycine, Gla (Cp) - cyclopropylmethylglycine, Hse - homoserine. Not - IZO-leucine, Leu leucine. Met - methionine, Met (O) methionine sulfoxide, Nle - norleucine, Nva - norvaline , Phe is phenylalanine, Ser is serine, Thr is threonine, Tyr is tyrosine, Val is valine, Ac is acetyl, AcOMe is acetoxymethyl, A is allyl, Cp is cyclopropylmethyl, Me is methyl, Et is ethyl, 1p iso-propyl, Pr -n-propyl, OMe - methoxy, Etm ethylthiomethyl, Fie - 2-fluoroethyl, Ppg - about Pargil, Vin, -butyl, i-Bu-iso-butyl, -t-butyl, s-Bu-second-util. Vo-ter-butyloxycarbonyl, Bzl-benzyl, CBZ benzoloxycarbonyl, DCC -NN-dicyclohexylcarbodimide, NVT - 1-hydroxybenzotriazole, DMF - NN-dimethylformamide, TFA - trifluoroacetic acid, THF - tetrahydrofuran, DEAE diethylaminoethyl, NMM - N-methylmorpholine, IBCF-iso-butyl chloroformate, 18-crown-6-1, 4,7,10,13 , 16 - hexaoxacyclo-octadecane. Each of the formuli compounds has a substituent in the phenalalanine meta position and, in addition, any or all of them can be in the form of a pharmaceutical-acceptable non-toxic acid-added salt. Example 1. Preparation of the salt of L- (K-methyl) tyrosyl-B-alanyl-glycyl-L- (K-cyclopropylmetesh1) -meta-bromo-phenylalanine amide acetate salt A. N-acetyl-1-b-cyano-B-b-metabromophenylalanine ethyl ester. To a suspension of 16.8 g (0.35 mol) of sodium hydride (50% solution in mineral oil) in 260 ml of dry THF, while stirring at room temperature, 59.56 g (0.35 mol) of ethylene hydrochloride are added in small portions amidocyanoacetate. A solution of 37.48 g (0.35 mol) of metabromobenzyl bromide in 50 ml (dry) of THF is added dropwise to the reaction mixture. The mixture is first cooled slightly, and then the stirring is continued at room temperature for 72 hours, after which it is decanted for 4 hours. The mixture is then cooled to room temperature and 80% ethyl alcohol is added. Stirring is continued for another 30 min, and then the reaction mass is poured into the HC1 W solution. The aqueous mixture is extracted with ethyl acetate, the ethyl acetate layer is separated and washed successively with water, IN with sodium bicarbonate solution and water. Ethyl acetate is dried over magnesium sulfate and concentrated in vacuo to an oil (107 g). NMR, 0 (acetyl), 3.4-3.5 (methylene) and 7.1-7.5 (meta-bromophenyl), B. V, L-Meta-bromophenylapanine. The product obtained in Step A U07 g, 0.32 mol) is suspended in a solution of 58.8 g (1.47 mol) of sodium hydroxide tablets and 220 ml of water. The resulting mixture is refluxed for 24 hours. The mixture is then cooled to room temperature and its pH is adjusted to 6.5 with 7N HCl solution. The resulting and precipitated product was collected, dried to give 41.01 g (53%) of the compound. B. N-triphosphate D, L-meta-bromophenylalanine. 46.53 g (O, 19 mol) B, b-meth ta-bromophenylalanine are added to 200 ml of trifluoroacetic acid. The mixture is cooled to 0 ° C and 29.3 ml (0.21 mol) of trifluoroacetic anhydride are added over 5 minutes. The resulting solution was stirred at 0 ° C for 1.5 h and 3 h at room temperature, after which the reaction mass was concentrated in vacuo. The residue is diluted with 400 ml of water and the product precipitated is collected and dried. A solid crystallized from ether-petroleum ether to give 28.4 g (44%) of the compound. Elemental analysis. Found,%: C 39.09; .I 2.46; N 4.32. C .., RgN03BrFi (340.1) Calculated,%: C 38.35; H 2.67; N 4.12. G. L-meta-bromophenylalanine. A mixture of 28 g (0.082 mol) of the product obtained in Step B is added to 500 ml of water, stirred and then a 2N solution of NaCR is added to it until a clear solution is obtained (pH 7.2. The carboxypeptidase A is added (25 m and the temperature is kept solution (37 C) at noMouui thermostatically, controlled water bath and pH 7.2 with the aid of a radiometer of the size of pN. The solution is vigorously stirred for 5 days, then the pH is adjusted to 5.0 and carbon is added and the mixture is filtered. the filtrate was adjusted to 3.0 using IN HCl and then the filtrate was extracted three times, with ethyl acetate, after the pH of the aqueous solution is adjusted to 7.0 with 2N NaOH solution and the solution is concentrated in vacuo until the L-isomer begins to crystallize. The mixture is cooled to room temperature, the precipitated product is collected, dried, 10.9 g are obtained (l09 %) Compound / D, tert-Butyloxycarbonyl-b-meta-bromophenylalanine. To a mixture of 25 ml of tert-butyl alcohol and 20 ml of water, 9.9 g (0.041 mol) of the product from step D, then 20.5 ml ( 0.041 mol) 2N NaOH solution and 8.9 g (0.041 nil di-tert-butyl carbonate. The mixture was stirred at room temperature for 5 hours, then 150 ml of water was added and the product was extracted with ether. The aqueous layer was separated, acidified to pH 2.5 with cold IN HC1 solution and extracted with ether. The ether layer is washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue is dissolved in petroleum ether and the solution held at overnight. The precipitated crystals were filtered, dried, yielded 11.3 g (80%) of the compound, melting point 124125 ° C, (ci) | , 7 ° (s, 0, EtOH). Elemental analysis. Found,%: C 49.25; H 5.59; N4.04. (344) Calculated,%: C, 48.85; H 5.27; N 4.07. E. bR-tert-butyloxycarbonyl-b-meta-bromophenylalanine amide. To a mixture of 50 ml of DMF 1 1.5 g (0.033 mol) # -t-butyloxycarbonyl-T gm e-bromo-, phenylalanine, cooled to 15 ° C, add 3.63 ml (0.033 mol) of NMM and 4, 33 ml (0.33 mol I I 50 -butyl chloroformate. The mixture is stirred at 5 minutes, after which anhydrous gaseous ammonia (gas) is bubbled through the reaction mass for 1 h. The reaction mass is stirred for 4 more hours at -15 ° Cs is poured into a mixture of crushed ice and IN sodium bicarbonate solution. The resulting aqueous solution is extracted with ethyl acetate. The organic layer is separated and washed sequentially in ode, 1.5N citric acid solution, and water. The organic phase is dried over magnesium sulphate and concentrated in vacuo to a solid. The solid is triturated with ether and the resulting precipitate is filtered and dried to give 11, (100% / compound t. R1.146-147 C, 9.8 (, 5 MeOH, elemental analysis. Found,%: C 48.85; H 5.33; N, (343.2) Calculated,%: C 48.99; H 5.58; S 8.16. J. Hydrochloride salt of b-meta-bro phenylalanine amide. In 60 ml of freshly prepared IN solution INS1 (gas) in glacial acetic acid containing 5 ml of anisole was added 11.1 g (0.032 mol | product of co. Stage E.). The mixture was stirred at room temperature for 30 minutes, then poured the precipitate obtained in ether p is collected and dried to obtain 8.75 g (98%) of the compound. (cL), 46 ° | (, 5 MeOHJ. Elemental analysis. Found S%; C 38.55; n4.41;: J 10, CgH N OClBr (279.6) 9 17 J LLL, I Calculated,%: C 38.67; H 4.33; 0j02 ,, 3 K-Cyc Opolpropylmethyl-b-meta-bromophenylalanine amide. 50 ML of anhydrous ethanol add lt g (0.015 mol) of the product co; tadii J, and then 5.04 g (0.06 mol solid) anhydrous sodium bicarbonate and 2.04 g (0.015 mol) of cyclopropylmethyl bromide. The mixture is refluxed for 7 hours and evaporated in vacuo to an oil. The oil is dissolved in 20 ml of chloroform and purified by column chromatography on a Grace-type and Diffison 62 column on silica gel in chloroform. The product is eluted by a post-step gradient up to 10% methanol. The product is isolated according to the profile determined by chromatography in a thin layer of the collected; fractions, 2.2 g (49%) are obtained. Compounds. NMR with; 1.6 (-NH-) and 7.0-7.4 (meta-bromophenyl). . And N-tert-Butyl, xycarbonyl-B-alanyl-glycyl-L- (N-cyclopropylmethyl) -meta-bromophenylalanine amide. B a mixture of 40 ml of DMF and 2.1 g (7.1 mol) of the product with a C-adium 3, cooled to OC, was added 1.87 g (7.1 mol) to tert-butyloxycarbonyl-D-alanyl-glidyl and then 0.96 g (, 7.1 mmol J of OBT and 1.46 g (7.1 mmol of DCC. The mixture is stirred at 4 h and then at room temperature for 72 h. The mixture is then cooled to O C, the resulting precipitate was removed by filtration, the filtrate was evaporated in vacuo, the residue was dissolved in ethyl acetate and the solution was extracted successively with IN solution of sodium bicarbonate, lj5N citric acid solution and water. the tooth is dried over magnesium sulfate and evaporated in vacuo to an oil to obtain 1.5 g (40%) of the compound. K. IF tper-Butyloxycarbonyl-IN-methyl-L-tyrosyl-D-alanyl-glycyl-L- (n-cyclopropylmethyl a) -meta-bromophenylalanine amide. A mixture of 50 ml of trifluoroacetic acid containing 5 ml of anisole and 1.5 g (2.9 mmol) of the product from step I was stirred at 0 ° C for 30 minutes and evaporated in vacuo without heating. The resulting oil is diluted with ether. The product formed from the top by settling is decanted, and the remaining oil is dried under vacuum. To 15 ml of dAF, 0.856 g (2.9 mmol) of N rpeT-butyloxycarboyl-K-methyl-L-tyrosine is added. The mixture is cooled to -15 ° C and 0.32 ml (2.9 mmol) of NMM and 0.38 ml (2.9 mmol) of u-butyl chloroformate are quickly added to the stirred solution. Stirring ri 15 C is continued for the next process. The resulting salt of TFA of the peptide is dissolved in 10 ml of DMF. The solution is cooled to and a bottom portion of 0.32 ml (2.9 mmol) of NMM is added. The solution is stirred until the end of the process and mixed anhydride is added to the previously obtained solution. The resulting mixture is stirred at -15 ° C for 4 hours, the loan is slowly heated to room temperature and stirring is continued overnight. The mixture is then poured into an IN solution of sodium bicarbonate, the aqueous solution is extracted with ethyl acetate. The organic phase is separated and extracted successively with water, 5 with a 1.5N citric acid solution, and water. The ethyl acetate is then dried over MgSO4 and concentrated in vacuo. The oily residue (1.6 g) is dissolved in acetone and applied to two preparative plates with a thin layer. The development is carried out in a mixture of chloroform and methanol at a ratio of 9: 1. The main component is separated from the plates of those and is eluted with silica-5-gel, 0.8 g (39% of the target compound is obtained). L. M-methyl-L-tyrosyl-B-alanyl-glycyl-L- acetate salt (L-cyclopropylmethyl a) -meta-bromophenylalanine amide. In 15 ml of TFA containing 3 ml of anisole, 0.8 g (1.2 mmol) of the product obtained in stage K is added. The mixture is stirred at 0 ° C for 30 minutes, then dried The resulting solid is dissolved in 9.0 ml of a 0.1 M ammonium acetate solution containing 31% acetonitrile. The resulting solution 30 is chromatographed on a column of sy gelgel (4x72 cmK. The column was treated with a pressure of 4.2 kg / cm and the eluate was analyzed at 280 nm. The appropriate fractions were collected and lyophilized. The resulting solid was dissolved in a 0.2 M solution of acetic acid (10 ml) and the solution was passed through a column with Sephadex (5x100 cm) pre-equilibrated with the same solvent.The eluate was analyzed at 280 nm and the corresponding fractions were collected, lyophilized, and 773 mg (97%) of the compound were obtained. (oC) J + 6.64 (, 5, 1NHC1) .45 Elemental analysis. Found,%: C 54.30; H 5.99; N 10.28. (662.2) Calculated,%: C 54.38; H 6.09; 50 N 10.57. Amino acid analysis,%: Ala 0.97 Gly 1.03; NHj 0.99. PREMIUME 2. Acetate salt, L- (K-methyl) tyrosyl-B-apanyl-glycyl-js-L- (N-ethyl) -mst-bromophenyl-llanine amide. (oC) J + 7.1 ° (, 5, IN HC1). 9 N N Gl rota N N Al L-L am N N Gl Lm N N Al L-L am N N Gl 8 Elemental analysis. Found,%: C 53.09; H 6.13; . 11.13. (636.5) Calculated,%: C, 52.83; H 6.02; 11.00. Amino acid analysis,%: Ala 0,99; y 1.01; NH 1.04. Example 3. Acetate salt of L-THzyl-B-alanyl-glycyl-L- (N-methyl) -me-bromophenylalanine amide. (ct) 25. (, 5, IN HC1). Elemental analysis. Found,%: C 52.13; H 6.09; 11.39. C2TH3bNy0 r (623) Calculated,%: C 52.09; H 5.83; 11.25. Amino acid analysis,%: Tug 1.01; a 0.99; Gly 0.99; NH 1.01. PRI and MER 4. Acetate salt of (N-methyl) tyrosyl-B-alanyl-glycyl (N-ethyl-meth-methyl phenyl al-a-shn ida. (9.2 (with 0.5, IN HC1) Elemental analysis. Found,%; C 60.68; H 7.00; 12.46. C29H4 NjO (517.7) Calculated,%: C 60.93; H 7.23; 12, 25. Amino acid analysis, %: Ala 0.98; y 1.02; NHj 0.96. P r and M e r 5. Tyrosyl-O-alanyl-glycyl-L- (N-ethyl) e-chlorophenylalanine amide acetate salt. (D} - 13.7 ° (, 5, IN HC1). Elemental analysis. Found,%: C 55.84; H 6.37; 12.35. CH j NjO-jCl (578.1) Calculated,%: C 56 , 10; H 6.28; 12.12. Amino acid analysis,%: Tyr 1.02; a 0.99; Gly 0.98; NHj 0.88. Example p 6. The (N-methyl) tyrosyl acetate salt B-alanyl-glycyl- (N-ztil) -meta-chlorophenylalany ida. (oi) if -9.2 (, 5, IN HC1) Elemental analysis Found:% C 57.11; H 6.45; 12.15. C28H38N50-, C1 (592.1) Calculated% : C 56.80; H 6.47; 11.83. Amino acid analysis,%: A1A 0.99; y 1.00; NHj 1.01. Example: Acetate salt b-tyrosyl 0-alanyl-glcyl-L- (N-ethyl meta-iodophenylallain amide,, o (, 5., lN HCl). Elemental analysis. Found,%: C 48.40; H 5.25; N 10.66. C2THasN 07J (669.5) Calculated,%:, 44; H 5.42; N 10.46. Amino acid analysis ,: Trit 1.0 Ala 0,99; Gly 0.99; NH 1.05. Example 8. Acetate salt of b-tyrosyl B-apanyl-glycyl-L- (H-cyclopropylmethyl-meth-iodophenylalanine amide. (O (,) 8 (, 5, IM J Elemental analysis. Found,% : C 50.00; H 5.22; N 1C, 23 C2gK gNg07J Calculated: C 50.08; H 5.51; N 10.07. Amino acid analysis,%: Tug 0.9 Ala 1.01; Gly 0.99; NH 0.95. Example 9 p. Acetate salt 11, - (K methyl) tyrosyl-B-alanyl-glycyl-L - {N-cyclopropylmethyl bmeta-iodophenylalanine anide, (tii + 0.787 ° (, 5, W SNODC Elemental analysis. Found,%: C 50.50; H 5.40; H 9.88. Calculated,%: C 50.78; H 5.68; N 9, 81. Biological tests of the described tetrapettids. Analgesic activity from compounds formulas (T} are set using a mouse test using a hot plate. This test uses a vertical acrylic cylinder containing as a base a hot flat surface, the temperature of which is maintained at 52 ° C. Your mice are given subcutaneously certain beforehand the amount of the test compound dissolved or suspended in a suitable carrier, 15 minutes after applying the test compound, the mouse is placed on a hot flat surface. The latent state is measured in seconds before jumping the mouse from a hot flat surface. The agent possesses an analgesic activity that causes an increase in this latent state as compared to the consensus mouse, which was introduced only to the carrier. This may occur in the dose range, which does not cause a loss of motor coordination or ability to move. Table 1 presents the ED values obtained from the tests. (- the dose that causes the analgesic effect in 50% of the tested mice. The analgesic effect is defined as the reaction of the latent state in the presence of the test compound, which is greater than or equal to the control reaction of the latent state plus two standard deviations. The effect of analgesia in percent considered as a statistical value and calculated by the methods of regression analysis of dose-effect data. Each dose-effect curve must have at least four points and each point is determined using data x obtained for at least ten treated mice and ten control mice. Table 1 In addition, the formulas (1 | oblasti1) have a low propensity for physical dependence. This fact was established by means of a test connected with the study of the motor ability of mice. A high correlation was established between the degree of propensity for physical dependence of the connection and its ability to induce locomotor activity in myrtles.Motor activity in mice was measured using POMOP1I cylindrical cells, manufactured GOVERNMENTAL wire, 5.08 cm tall and 28 cm in diameter. Six cells are placed in a soundproofed, ventilated chamber with uniform illumination. The beam of light passes through the center of the cell to the photo cell, located on the opposite side. Two mice are placed in each cage for 1 hour in order to acclimatize to the surrounding conditions. Then, a certain amount of the test compound is subcutaneously injected into a pair of mice, the remainder of the steam is treated with a saline carrier that does not contain the test compound.
    .r lc - i: ifllM:.
    Then myopia return for 3 hours in the corresponding cells. The number of meter readings for every 15 minutes is recorded, as well as the total for the three-hour period. Each interruption of a beam of light changes the meter reading by one.
    In tab. 2 shows the average of the total numbers for each group.
    out of ten mice using a specific compound and a specific dose.
    From Table 2 it can be seen that, in comparison with the known compounds, the compounds
    Formulas (I) have a significantly lower motor activity.
    权利要求:
    Claims (1)
    [1]
    The method of obtaining tetrapeptides of the general formula f BOC-K-Tu g R where R ~, R 1 and X have the indicated meanings,
    R-Tyr-ΓΑΙα- KR KR-CH-CONH 2 where R is hydrogen, alkyl C. ^ - C,;
    alkyl C ^ -C, cyclopropylmethyl;
    X is bromine, chlorine, iodine and methyl, or their acid addition salts, characterized in that the protected tetrapeptide of the general formula
    DAla-G-nj-K-CH “C0NH 2 is deprotected by trifluoroacetic acid treatment.
    6192801 ™ Πδ
    The invention relates to a method for producing new biologically active compounds - tetrapeptides or their acid addition salts, which can be used in medicine 5,
    A known method for producing peptides by cleaving the tert-butyloxycarbonyl group from the corresponding blocked peptide by treating the latter with trifluoroacetic acid in the presence of anisole at 0 ° C I 3.
    The purpose of the invention is the preparation of new compounds with interesting pharmacological properties.
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    同族专利:
    公开号 | 公开日
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    PL131155B1|1984-10-31|
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    US6258550B1|1993-04-23|2001-07-10|Virginia Commonwealth University|Polypeptides that include conformation-constraining groups which flank a protein-protein interaction site|
    US5928896A|1993-04-23|1999-07-27|Virginia Commonwealth University|Polypeptides that include conformation-constraining groups which flank a protein--protein interaction site|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/198,900|US4322340A|1980-10-20|1980-10-20|Pharmacologically active peptides|
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