• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Nonapeptide and decapeptide analogs of LH-RH of the formula (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) and the pharmaceutically acceptable salts thereof wherein: V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl; W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl; X is a D-amino acid residue <IMAGE> wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or (b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl; Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl; Z is glycinamide or -NH-R1, wherein R1 is lower alkyl, cycloalkyl, fluoro lower alkyl or <IMAGE> wherein R2 is hydrogen or lower alkyl, are disclosed. These compounds exhibit potent LH-RH agonist properties.
    公开号:SU1681733A3
    申请号:SU802929801
    申请日:1980-06-10
    公开日:1991-09-30
    发明作者:Джозеф Нестор Джон；Генри Джонс Гордон；Генри Викери Брайан
    申请人:Синтекс /Ю.С.А./ Инк (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of non-peptide and decapeptide derivatives of the hormones LH-RH or their pharmaceutically acceptable salts, new biologically active compounds that can be used in medicine.
    The purpose of the invention is to obtain new peptide derivatives — low toxic compounds with a high ability to stimulate ovulation.
    Example 1. In a Beckman 990 peptide synthesizer reaction vessel, 0.8 g (0.8 mmol) of benzhydrylamino-polystyrene-divinylbenzene resin (manufactured by Lab Systems Inc.,) is placed. Amino acids are sequentially added to this resin.
    according to the synthesis program as follows. Stage 1.
    CH2CI2 washing 1 time 1.5 min 2.50% CFsCCteH / CteCk-deprotection 1 time 1.5 min
    3.50% СРзО32Н / СН2С12 - deprotection 1 time 30 min
    4. СНгС 2 washing 3 times 1.5 minutes
    5.10% triethylamine / CH2C 22 times 1.5 min
    6.CH2CI2 washing 3 times 1.5 min
    7. - amino acid solution 1 time addition
    8.M.M dicyclohexylcarbodiimir solution 1 time addition
    9.CH2CI2 rinsing and keeping the combination 1 time combination reaction 2 h
    10.CH2CI2 - Rinse adding
    1 time 1.5 min
    11.CH2CI2 Flushing Zraza 1.5 min
    12. Ethanol - Flushing Zraza 1.5 min.
    13.CH2CI2 Flushing Zraza 1.5 min. Stages 1-13 complete the combination cycle.
    for one amino acid, and the completion of the reaction is checked by the ninhydrin method.
    The resin is combined in series with a 2.5 molar excess of each protected amino acid and BCA. Thus, the resin is treated during successive coupling cycles with -0.433 g of Boc-Gly-OH, 0.432 g of Boc-Pro-OH, 0.857 g of Boc-Arg (that-, 0.462 g of Boc-Lei-OH, 0.504 g of Boc-Lei-OH (2 naphthyl) -0-alanine and 0.272 g of 1-hydroxybenzotriazole, 0.724 g of N-Boc, 0-2-bromobenzoyloxycarbonyl-sigrosine, 0.59 g of Boc-Ser (benzyl OH, 0.608 g of Boc-Trgr-OH, 0.654 g Boc-Hls (tosyl) -OH, and 0.524 g of pyra-glutamic acid.
    The resin is removed from the reaction vessel, washed with methylene chloride and dried in vacuo to give 2.0 g of a protected polypeptide resin.
    The polypeptide product is simultaneously removed from the resin and fully deblocked by treatment with anhydrous liquid hydrogen fluoride. A mixture of 2.0 g of the protected polypeptide resin and 2 ml of anisole (acceptor) in a Kel-F reaction vessel is treated with 20 ml of repeatedly distilled (from CoP3) anhydrous liquid HF at 0 ° C for 30 minutes. The H F is evaporated in vacuo, and the residue (nnpo) -Glu-Hls-Trp-Ser-Tyr-3- (2-naphthyl) -0-alanyl-c111-Agd-Pro-C1-NH2B as its HPal is washed with ether. The residue is then extracted with glacial acetic acid. The extract in acetic acid is lyophilized to obtain 0.8 g of a crude material.
    The crude polypeptide is placed on an Amberlite XAD-4 column 4x40 cm in size (polystyrene — 4% divinyl benzene copolymer) and eluted with a concave gradient from water (0.5 l) to ethanol
    2 (1 l). Test tubes containing fractions from a 690 ml effluent stream to
    1.470 ml, poured and stripped to dryness, to obtain 490 mg of the partially purified polypeptide.
    A sample of 150 mg of a partially purified product is subjected to partition chromatography on a 3x50 cm column of Sephadex — C-25 using a 1-butanol (toluene) acetic acid / water solvent system containing 1.5% pyridine in a 10:15 ratio: 12:18 Pure fractions are drained based on data.
    thin-layer chromatography (silica gel, BuOH (H20) HOAc (EtOAc, 1: 1: 1: 1) and HPLC / 5 micron, reverse phase, octadecylsilyl for packing, 40% 0.03 M NH4 OAc / 60% acetonitrile) . The desired product leaves the column in fractions of an effluent stream with a volume of 1000 ml to 1400 ml (Rf 0.1). Pure fractions are combined, stripped to dryness, taken into water and lyophilized, 57 mg of pure pyro-glutamyl-histidyl-tryptophyl-seryl-tyrosyl-3- (2-naphthyl) -D-alanyl-leucyl-argyniprolyl-glycyl cinamide in the form of its acetic acid additive salt D - 27.4 ° (c 0.9, HOAc), T. pl. 185-193 ° C (decomp.).
    Amino acid analysis data:
    D-Nal (2) 6J LHRH
    Ser0.82 (1)
    Glu0.97
    Pro0.93
    Gly0.97
    Leu0.99
    Tyr1,10
    His1.06
    NHa0.95
    Trp0.95
    Arg0,99
    Nal (2) 0.96
    Example 2. A synthesis program identical to that described in Example 1 was used to synthesize C-terminal Pgc-MH-CHaCH3 analogues. The Beckman 990 reaction vessel was charged with 2.13 g of BOc-Pro-0 resin prepared by an equimolar reaction ratios of dry cesium salt of Boc-Pro-OH-OH with chloromethyl-polystyrene / 1% divinylbenzene (Lab. Systems, Inc.,). The amount of Boc-Pro-0-resin taken contains 1.4 mmol of proline.
    The resin is combined sequentially with a 2.5 molar excess of each protected amino acid and BCA. The resin is reacted during consecutive cycles of blending with 1.61 g of Boc-Arg (tosyl) -OH, 0.93 g of Boc-Lei-OH H20. 0.94 g of Boc-3- {2-naphthyl} -0-alanine and 0.49 g of 1-hydroxybenzotriazole, 1.75 g of M-Boc-0-2-bromobenzyloxycarbonyl - titrosine and 1.11 g of Boc-Ser ( benzyl) -OH.
    At the moment of synthesis, the amount of protected polypeptide resin is divided in half, and one half is processed to complete the process using a sequential reaction with 0.57 g of Boc-Thr-OH, 0.77 g of Boc-Hls (OH, OH, 0.21 g of pyroglute - Minic acid.
    The resin is removed from the reaction vessel, washed with methylene chloride and dried in vacuo to yield 2.26 g of a protected polypeptide resin.
    Repeating the above procedure and replacing acetic acid with other acids during the equilibration of the resin, for example, the corresponding salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, benzoic acid and the like.
    Additive salts of acids of other compounds of formula 1 are prepared in the same way.
    B. If the salts have a low solubility in water, they are obtained by precipitation with water using the desired acid. For example: zinc salt of tannic acid - a solution of 10 mg of the acetic acid salt (pyro) glutamyl-histidyl-tryptophyl-seryl-tyrosyl-3- (2-naphthyl) -0-alanyl-leucyl-arginyl) prolyl-glycine-MH2 in 0.1 ml of water is treated with a solution of 8 mg of tannic acid in 0.08 ml of a 0.25 M sodium hydroxide solution. A solution of 5 mg of zinc sulphate as a heptahydrate in 0.1 ml of water is immediately added to the solution of the LN-RH analog.
    The resulting suspension is diluted with 1 ml of water and the precipitate is centrifuged. The surface layer is decanted and the residue is washed twice with 1 ml portions of water by centrifuging the precipitate and decanting the surface layer. The precipitate is dried under vacuum to obtain 15 mg of a mixed zinc salt of tannic acid and the above-mentioned LH-RH analog.
    Salt of pamoic acid - to a solution of 50 ml of acetic acid salt (pyro) glutamyl-histidyl-tryptophyl-seryl-tyrosyl-3- (2-naphthyl) -D-alanyl-leucyl-arginyl-prolyl-glycyl-NH2 in mixture 1, 6 ml of ethanol and 0.1 ml of 0.25 M sodium hydroxide add a solution of 11 mg of pamoic acid in 0.3 ml of 0.25 M sodium hydroxide. The solvents are removed under reduced pressure and the residue is suspended in 2 ml of water, centrifuged and the surface layer is decanted. The residue is washed with 1.5 mg of water, centrifuged and the surface layer is decanted. The precipitate was dried in vacuo to give 54 mg of the pamoic acid salt of the above LH-RH analog.
    Similarly, other salts are obtained with low solubility in water.
    C. Preparation of the acid addition salt from the free peptide.
    To a solution of 50 mg of (pyro) glutamyl-histidyl-tryptophyl-seryl-tyrosyl-3- (2-naphthyl) -D-alanyl-leucyl-arginyl-prolyl-glycylCHMH as a free base is added 30 ml of 1 N . acetic acid. The resulting solution was lyophilized to give 50 mg of the acetic acid salt of the above-mentioned LH-RH analogue.
    Similarly, replacing acetic acid with other acids (in stoichiometrically equivalent amounts with respect to the peptide), other additive ones are obtained.
    salts of acids of the compounds of formula (1), for example, salts with hydrochloric acid, hydrobromic, sulfuric, phosphoric, nitric acid.
    D. Preparation of salt with metal cation, for example, zinc salts.
    To a solution of 50 mg of (pyro) glutamyl-histidyl-tryptophyl-seryl-tyrosyl-3- (2-naphthyl) -b alanyl-leucyl-arginyl-propyl-glycyl NH2 acetic acid salt in a mixture of 0.4 ml
    5 0.25 M sodium hydroxide, 0.3 ml of water and 1 ml of ethanol were added a solution of 15 mg of zinc sulfate as heptahydrate in 0.2 ml of water. The precipitate is centrifuged and the surface layer is decanted. The precipitate is washed with 1 ml of water by centrifuging and decanting the surface layer. The precipitate was dried in vacuo to give 48 mg of the zinc salt of the above LH-RH analog.
    Similarly, get salt with
    5 other multivalent cations, for example, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, and the like.
    Example 5. A solution of 50 mg of acetic acid salt of (pyro) glutamyl-histidyl-tryptophyl-seryl-tyrosyl-3- (2-naphthyl) -6- alanyl-leucyl-arginyl-prolyl-glycyl-MH in 25 ml of water is passed through a 50 g column of Dowex 1 (a strongly basic, quaternary ammonium anion exchange resin), which was previously equilibrated with sodium hydroxide by its solution to obtain a hydroxide ion counter. Column eluted 15015 L
    0 water, the eluent is lyophilized to obtain 45 mg of the corresponding polypeptide as a free base.
    Similarly, other acid addition salts are converted to free bases.
    5 compounds of the formula (1), for example, the salts mentioned in Example 4.
    Example 6: Biological testing of the described compounds. Suppression of estrus in rats.
    0 Procedure: Female rats (Hilltop. Sprague Dawley) of approximately 200 g with open vagina are weighed up grouped by 5 per cage and 2 cages per group. Rats are injected subcutaneously, two
    5 times a day (except as indicated below) for 14 days. Vaginal swabs are taken daily to determine the stage of estrus cycle, and body weight is recorded at 0.1 and 2 weeks. Record the percentage of females showing partial suppression.
    The protected polypeptide is separated from the resin by aminolysis with 25 ml of ethylamine for 18 hours at 2 ° C. The ethylamine is allowed to evaporate and the resin is extracted with methanol. Methanol is evaporated to give 1.39 g of pyro-Clu-Hls tosyl - Trr-8r- (benzyl) -Unf (2-bromobenzyloxycarbonyl) -3-2-naphthyl-0-alanyl -1 e1-Agd- (to- ZIL) -RGO-MH-CH2CH3.
    The crude polypeptide is released by treatment with a mixture of 3 ml of anisole and 30 ml of re-distilled (from CoP3) anhydrous liquid HF at 0 ° C for 30 minutes in a Kel-F reaction vessel. The HF is evaporated under vacuum and the residue is washed with ether. The residue is dissolved in 2M acetic acid and lyophilized, yielding 0.82 g of crude (pyro) Glu-Hls-Trp-8g-Tug-3- (2-naphthyl) 0-alanine-1 El-Agd-Pgo MH-CH- CH3 in the form of its acetic acid additive salt. The final purification is achieved using preparative liquid chromatography with a high performance specimen of 20 mg on a column of 0.9x550 mm in size from 40-50 micron octadecyllylated creme extract (Merck, Licroprep Ssh). The eluent is a mixture of 64% 0.03 M NH40Ac / 36% acetonitrile. For four lyophilations, only 61 mg of the crude material is purified. After three lyophilisations from water, 15 mg of pure ethyl amide p and ro-gl utamyl-O-alanyl-leucyl-arginyl-proline are obtained in the form of its acetic acid addition salt, m.p. 180-190 ° C. apD-ST td.l.HoAc).
    Repeat the above procedure for cleaving and replacing ethylamine with a stoichiometric amount of n-butylamine, cyclo propyl amine, cyclohexylamine, trifluoromethylamine, pentafluoroethylamine. and 2,2,2-trifluoroethylamine, the corresponding n-butylamide, cyclopropylamide, cyclohexylamide, trifluoromethylamide, pentafluoroethylamide and 2,2,2-trifluoroethylamide of the above nonapeptide are obtained.
    Amino acid analysis data:
    Des Gly16 D-Nal (2) 6 ProNHEt9 LHRH
    Ser0.91 (1)
    Glu 1.01
    Pro0.99
    Leu1.02
    Tyr1,00
    His0.97
    YHL1.06
    Trp1.06
    Arg1,00
    Nal (2). 1.08
    Example (Pyro) C1-H18-Tgr-8er-Tug-3- (2-naphthyl) -O-A1O-1-ei-Agde-Pro-A2a Gly NHa.
    Compounds of formula I in which Z is -NH-C (0 NH-R2) are prepared by classical solution synthesis.
    For example, the following path may be used, where AzaGlyNH2 is NH-NH-C (0) -NH2.
    The combination of individual fragments can proceed according to the method of acylazide, according to
    by the combination of BCA / HBT or by other methods of racemization combination of free fragments. Compounds (1) and (2) are known. The compound (3) is prepared from (2) by removing the Cvz and nitro groups
    by hydrogenolysis followed by combination with L-Boc-3- (2-naphthyl) -0-alamino using DSS / HBT or another combination agent known in the art: af5D - -34.3 (C 0.34 SPLA). Amino acid analysis; Ser 0.74 (1); Glu 0.89 (1), Pro 0.94 (1), Lai 0.98 (1), Tir 1.00 (1), His-1.03 (1), MN3 1.13 (1), Trp 1.01 (1) ArgO, 99 (1), Mal (2), 1.08 (1).
    Tyr-Ome CdL-Leu-Arg-Pro-AlaGlyNH2 (1) JN02 (2)
    (pyro) G u-Hls-Trp-Boc-3- (2-naphthyl-D-Ser-Tyr-NaAla-Leu-Arg-Pro-AzaGly
    NH2H +
    35
    Mz- (2-naphthyl) -D-Ala-Leu-Arg-Pro-A2aGly-NH2
    (3)
     g} I 4- 5 (pyro) GlM-H s Trp-Ser-Tyr-3- (2-naphthyl) -D789 °
    Ala-Leu Arg-Pro-Ala-Gly-NH2
    Synthesis Scheme of Compound 1, where Z is NH (NHC (0) NH2.
    PRI me R 4. A. A solution of 0.1 g of hydrofluoric salt (nHpo} Glu-Hls-Trp-Ser-Tyr-3H (2-naphthyl) -0-A1a-Lel: Arg-prfr-Gly-NH2 (see example 1) is dissolved in 50 ml of water and passed through a column filled with
    50 g of Dowex 3 anion exchange resin, which was previously equilibrated with acetic acid and washed with deionized water. The column was eluted with deionized water and the effluent
    lyophilized to give the corresponding (pyro) glutamyl-histidyl-tryptophyl-seryl-tyrosyl-3- (2-naphthyl) -D-alanyl-lecyl-arginyl-propyl-glycyl-MH2 acetic acid salt. -27.5 ° (c 0.9, SPLA).
    estrus (i.e., only diestrus, but not estrus) from the 4th day and the percentage of females showing complete suppression of estrus (i.e., only diestrus) from the 4th day. The values of EDS are derived from the straight line of the dependence of the estrus suppression percentage data. LHRH analogues were administered as their acetate salts in physiological saline containing 0.1% bovine serum albumin. The volume of the injection was l, 0.2 ml, the analogue was present in a dose of 0.05, 0.1, 0.2 or 0.4 μg.
    The control group (physiological saline) showed no estrus suppression. The EDU values for the combined groups with partial and complete suppression of estrus are as follows:
    ConnectionEdzo (µg / injection)
    1. (Pyro) glutamyl-histidyltryptophyl-seryl-tyrosyl 3- {2-naphthyl) -0-alanyl leucyl-arginyl-glycyl-MH 0.08
    2. (Pyro) glutamyl-histidyltryptophyl-seryl-tyrosyl 3- {2-naphthyl) -0-alanyl leucyl-arginyl-prolyl-NHEt 0.11
    3. (Pyro) glutamyl-histidyl-tryptophyl-seryl-tyrosyl-3- (2-naphthyl) -0-ananyl-leucyl-arginyl-prolyl-azaglycyl-MHa0.04
    4. Compound for comparison:
    . D-Trp / 6-LHRH0.08
    The tests performed showed that the compounds obtained under the conditions of the described method are of low toxicity and have a high ability to stimulate ovulation.
    FORUMAWLAH AND ISLANDS
    The method of obtaining nonapeptide or decapeptide derivatives of the hormone LH-RH of the general formula
    (pyro) Sl-H18-Thr-5r-Tug-3- {2-naphthyl} - dAla-Leu-Arg-Pro-Z,
    where Z GlyNHz, NHNHC (0) NH2, or their pharmaceutically acceptable salts, characterized in that the compounds of general formula II:
    20
    (pyro) Cl-H18-Thr-8r-Tug-3- (2-naphthyl - RlR2 R3
    dAla-Leu-Arg-Pro-Z - (S) d.
    where RI is tosyl; R2 is benzyl;
    Рз - 0-bromobenzyloxycarbonyl; Z - Gly or absent, d 1 or 0;
    S - copolymer based substrate
    substituted styrene or styrene-divinylbenzene copolymer, treated with hydrogen fluoride and the target product is isolated in free form or in the form of a pharmaceutically acceptable salt.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining nonapeptide or decapeptide derivatives of the LHRH hormone of the general formula I (pyroX31u-H 1z-Tgr-5eg-Tug-3- (2-naphthyl) dAla-Leu-Arg-Pro-Z, where Z = GlyNH 2 , NHNHC (O) NH 2 , or their pharmaceutically acceptable salts, characterized in that the compounds of General formula II:
    (pyro) 61i-H1e-Tgr-5eg-Tug-3- (2-naphthyl) Ri Yag Yaz dAla-Leu-Arg-Pro-Z ’- (S) d, rii where Ri is tosyl;
    R 2 is benzyl;
    Yaz - 0-bromobenzyloxycarbonyl;
    Z 1 - Gly or absent;
    d is 1 or 0;
    S is a copolymer substrate based on substituted styrene or a copolymer of styrene with divinylbenzene. · Treated with hydrogen fluoride and the target product is isolated in free form or in the form of a pharmaceutically acceptable salt.
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    申请号 | 申请日 | 专利标题
    US06/047,661|US4234571A|1979-06-11|1979-06-11|Nonapeptide and decapeptide derivatives of luteinizing hormone releasing hormone|
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