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    公开号:SU904518A3
    申请号:SU772470259
    申请日:1977-04-08
    公开日:1982-02-07
    发明作者:Сваруп Дутта Ананд；Джозеф Гормли Джеймс；Фредерик Хэйвард Кристофер；Селвин Морли Джон；Джозеф Стэйси Джильберт
    申请人:Империал Кемикал Индастриз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    W Y: 3 i (OCaUL) CI I, OCOCJsHj ,;
    ooiCCHgaxc) ;; oaiiCHnOcoc -ii j, OBu Thr-Ш; ABOUT
    NHEt;
    OCQIJNHZ; OCCHjJaM.leZ; OCHiCH ak; OPh; YNSO NH (CH), iMfvie; ; v) H (CH2) 2.fJMe2 5 Me; 0 (CH2) 2.
    D-Thr-OH,. G and K together represent
    (9H2) (
    ED, - | НW-0Q (,
    IL o; t or k-tih jjj i
    It is concluded that the protecting groups in the compound of the formula i-T B-E-F-G-K NG are cleaved where R. is a hydrogen, methyl or acetyl radical; R is hydrogen; Z; Nth-A1a; Z-Asp; Z-Lys; Z-LysfZ); Z-LysfBoc) H-r.ly-Glyj Z-Asp (OBzl) Z-Lys (Z) -Z-Lys; Z-ArgCZ /) - Pro-Lys (Z); Z-Gly-Gly-Gly; Z-Leu-Leu-Leu; Z-Glu-Gly-OBzl ZLys; Z-Pro-Gln-Gln; Z-Asp (OBzl) -Gly-Gly-Gly; Z-Lys-Gly-Gly-Gly or Z-Gly-Gly-GlyJl43 s; Z-Arg (Z), -Pro-Lys (Z) -Pro-Gln-Gln; Boc; H-Glu (OBu); Boc-Lys (Boc); H-D-Lys (Boc); H-Lys (Boc); Boc-Phe H-Lyi; Boc-Gly-Gly-Gly or Boc-Gly-Gly-Gly-Gly-Gly-Gly; T - here; Tyr (Bzl); Tyr (Z) or Tyr (Bu); B - D-Ala; D-Asp; Azala; D-Leu; D-Ser; D-Thr; D-Trp; fb-ala; D-Ser (Bu); D-Lys; - D-Lys (Boc) or P-Met; E - Gly or Azgly; F - Phe; Azphe or Phe (6lO; G - Leu; Azleu; Me; Met; Pro; DL-Leu or Azpro; K - ate; NHi; 0 (. 0 (Gla) 2NI№; W; 0 (aii.) Iai; 0 (aia) Ora iOCOCJL ,; LHIGSh (OAc) O1gOAc;
    S12 (Qtocoq j y .i oai (ai2. Oai (a-ijOCOQ.fi,)
     Thr (Bzl); ShN I
    i MTR;
    0 (aii) eNHZ; 0 (.teZ; OCI-IiOi Ciij; OPhe; CI (au.SH; NHCCIia.) IMi.Ie; (aLWie ,,; NEto; No.; 0 (or DjThr-OBzl, G and K together represent by myself
    about xn
    , -NH The preparation of the starting compounds is carried out using various methods of peptide chemistry, for example, the carbodiimide or azide method for the preparation of mixed anhydrides, and the like. . In this case, the starting compounds blocked by various protecting groups are obtained. For example, benzyloxycarbonyl, tert, -butoxycarbonyl is used to block the imino groups. The hydroxyl group is protected with benzyl or t-butyl; the carboxyl group is protected to give ether methyl or ethyl alcohol. Known methods are used to remove these groups. Thus, benzyl or benzyloxycarbonyl is removed by hydrogenolysis; tert-butoxycarbonyl or tert-butyl - treating the starting compound with an acid, such as trifluoroacetic acid, or hydrogen chloride. Hydrated hydrogen in acetic acid is used to remove benzyloxycarbonyl or tert-butoxycarbonyl. Methyl or ethyl ester is cleaved by hydrogenolysis or alkaline treatment of the starting product. Upstream thin layer chromatography is carried out on silica gel coated plates (Kieselguhr G). Chromatography was carried out in the following solvent systems: butanol-1 - acetic acid - water 4: 1: 5 vol. h (RjA); butanol-1 - acetic acid - water - pyridine 15: 3: 12: 10 ob.h. (); butanol-2 (3 wt.%) - aqueous ammonia 3: 1 ob.h. (IvgC); acetonitrile - water 3: 1 ob.h. (RjD); acetone - chloroform 1: 1 ob.h. (R.fE); chloroform - ethanol 1: 4 ob.h. (Rrf); cyclohexane - ethyl acetate 1: 1 ob.h. (Rrg); cyclohexane ethyl acetate - methanol 1: 1: 1 ob.h. (RjH); chloroform - methanol - water 11: 8: 2 ob.h. (); chloroform - methanol 19: 1 ob.h. (RrP) and chloroform - methanol 9: 1 ob.h. (RtQ). Some of these solvent systems are also used for silica column chromatography (solutions G, K, Q, and P). In all cases, the plates are evaluated in ultraviolet light and treated with fluorescein, ninhydrin, and a reagent, chloroiodine starch. Unless otherwise indicated, R g means that a separate spot is detected by these methods. Acidic hydrolysates for all products are obtained by heating the peptide or the blocked peptide with 6N hydrochloric acid, with a content of 1 wt.about. phenol, in a sealed tube, from which air was pumped out, for 16 h at 110 ° C. The amino acid composition of each hydrolyzate was determined using the Locart card amino acid analyzer. In each case, compliance with the expected composition is observed. Examples 1-42. The blocked polypeptide is subjected to reductive cleavage. reductive cleavage is carried out in the following manner. HI. The starting material is dissolved in ethanol containing up to 25 water in an amount of 1 mmol, and 5 wt. 1 of a catalyst containing 5 wt.% Palladium carbon are added in an atmosphere of nitrogen and the reaction mixture is stirred at 20–25 ° C and carefully sparged. hydrogen. To complete the reaction, 5-6 hours are sufficient. Hydrogen is replaced with nitrogen, and the catalyst is filtered through a bed of diatomaceous earth. The product is isolated by evaporation of the filtrate in vacuo. Exit 90-95-. H2. This is carried out as in HI, but methanol is used instead of aqueous ethanol. NZ. This is carried out as in HI, but methanol is used as the reaction medium. H4. It is carried out as in N1, but aqueous ethanol is added with the addition of 1 equiv. hydrogen chloride. H5. It is carried out as in HI, but aqueous methanol is used with the addition of 1 eq. hydrogen chloride. The Nb. Is carried out as in HI, but dimethylformamide is used with the addition of 1 equiv. toluene-p-sulfonic acids. H7. It is carried out as in HI, but methanol is used with the addition of 1 eq. hydrogen chloride. H8. It is carried out as in HI, but a mixture of dimethylformamide with butanol is used as the reaction medium. H9. As in HI, it is carried out, but aqueous (90-95 VL) acetic acid is used as the reaction medium. . nude Carried out as in H9, but 1-2 eq.h is added. hydrogen chloride. H11. As in HI, aqueous dimethylformamide H12 is used as the reaction medium. It is carried out as in HI, but a mixture of aqueous ethanol and chloroform is used as the reaction medium. H13. It is carried out as in HI, but a mixture of methanol in dimethylformamide is used as the reaction medium. The result is a polypeptide derivative, are given in table. 1. Examples 43-b9- A blocked polypeptide is cleaved with hydrogen chloride according to the following procedures. 1. The starting compound is dissolved in ethyl acetate and a solution of hydrogen chloride in ethyl acetate is added in an amount sufficient to produce 2-6 N. Acids. The reaction is carried out at 20-25 ° C for 1-2 hours. Chlorine. The product is precipitated and filtered. The isolation was carried out by evaporation in vacuo. E2. This is carried out as in E1, but methanol is used instead of ethyl acetate as the reaction medium. EZ. This is carried out as in E1, but hydrogen chloride is used in a mixture of ethanol and ethyl acetate. E4. This is carried out as in E1, but acetic acid is used to grow the starting material with the subsequent addition of hydrogen chloride in ethyl acetate. E5. As in E2, it is carried out under a nitrogen atmosphere in the presence of an anti-infusion agent, for example 2-mercaptoethanol. Fuck As in E1, n is used diethyl ether instead of ethyl acetate as the reaction medium. A E7-Carried out, as in E1, dioxane is used as the reaction mixture with ethyl acetate. E8. As in E1, acetic acid is used as the reaction medium instead of ethyl acetate. E9. It is carried out, as in Et, under a nitrogen atmosphere in the presence of an anti-infusion agent, for example 2-mercaptoethanol. Her The blocked material is mixed with concentrated hydrochloric acid (about 10 ml / g) at O for 10 minutes. The excess acid is then distilled off in vacuo, possibly at a minimum temperature, and the product obtained is freeze dried. 8, the result is the polypeptide derivatives listed in Table. 2. Notes (footnotes) to the table. 2. 1. Salt HC1 2. Salt 2IIC1 3. Isolated by evaporation after filtration through diatomaceous earth i. The precipitate is isolated. 5. It is precipitated by the addition of ether. 6. It is precipitated by adding a mixture of methanol and ether. 7. It is crystallized from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C). 8. It is obtained in the form of a freeze-dried powder from water or a mixture of water with tert-butanol. 9. See ref. 8, in the presence of H. 10. Purify by chromatography on silica using solvent 0. 11. See ref. 10, using solvent K. 12. Clean on Sephadex G 15 v 0.01 M hydrochloric acid solution 13- Purified on Sephadex G 25 in 5 vol.% Acetic acid. 8 14.T.pl. 202-205С 15.1. 16.T.pl. 179-180С 17.Т.пл. 173-174 C 18.T.pl. 142rd) 19.p.pl. 118-120C 20.T.pl. 138-1 "0C 21.T.pl. ni-lU C 22.T.pl. 195-2004 (with different) 23.T.pl. 120-122C 2k. So pl. 174-17BS (with decomp.) 25. So. 120-12tC Examples 7088. The blocked polypeptide is cleaved with trifluoroacetic acid according to the following methods. F1. The starting compound was dissolved in trifluoroacetic acid (10 ml / g) and reacted at 2025 ° C for 1-2 hours. The product was isolated as trifluoroacetate by evaporation of the solution in vacuo. Using freeze drying in the presence of a large excess of hydrogen chloride, the corresponding hydrochloride is obtained. F2. It is carried out as in F1, but native (90 or 95 vol.) Trifluoroacetic acid is used. RH Carried out as in F1, but aqueous (90 or 95 vol.) Trifluoroacetic acid is used under a nitrogen atmosphere in the presence of an anti-sludge agent, for example 2-mercaptoethanol, notes (footnotes) to table. 3 1. Salt HC1 2. Salt of acetic acid 3. Salt of trifluoroacetic acid (TFA) i. Salt 2TPA 5.Separated by precipitation after filtration through diatomaceous earth. 6. Is precipitated by adding petroleum ether (so kip. 60-80 C). 7. Is isolated in the form of a freeze-dried powder from water or a mixture of water with tert-butanol. 8. See Footnote 7, in the presence of HC1. 9. Cleaned on Sephadex G 15 in 5 vol. aqueous acetic acid. 10.T.pl. 150-155С 11.Т.пл. 166-1684 Example 89. To a 235 mg (330 µmol) solution of an HT TD-Ser-Gly-Phe (6H) Ley-Qr.ie solution (starting compound 110) in methanol (5 ml) was added 1N sodium hydroxide solution (1.0 ml, 3 equiv. Parts), mixture re
    stir at ambient temperature for 3 hours. The solution is evaporated in vacuo, diluted with water and acidified with dilute hydrochloric acid solution. After clarification by filtration, the solution is subjected to freeze drying, the product is dissolved in an aqueous solution of acetic acid and passed through a column filled with Safadex G 15, the eluate is again lyophilized, and H-Tyr-D-Ser-Giy-Phe (6H) -Leu-ffl is obtained, R | C 0,38.
    Example 90. When treating H-Me-D-Ser-Gly-Phe (6H) -Leu-One (. Original compound 102) in an aqueous solution with sodium hydroxide (2 copies), followed by carrying out the process according to the method of example 89, H- Me-D-Ser-Gly-Phe (6 {|) -Leu-CH, R 0, “t.
    Example 91. 140 mg (22 µmol) Ac-Tug-D-Ala-niy-Phe-Leu-0t: i.e. (starting compound 123) is dissolved in 10 ml of warm dioxane and gradually the temperature of the solution is brought to ambient temperature, after which 12 ml of water and 1N aqueous sodium hydroxide solution (0.75 ml, 3.5 eq. parts) are added. The mixture was vigorously stirred at ambient temperature for 2.5 hours, then most of the dioxane was distilled off in vacuo. The residue is acidified by the addition of 1N hydrochloric acid. The resulting suspension is concentrated in vacuo. Aqueous ammonia is added to the residue along with an aqueous 0.05 M solution of ammonium acetate to obtain a clear solution. The excess ammonia was evaporated and the product was purified on a column filled with Sephadex G 25 in an aqueous 0.05 M solution of ammonium acetate. The eluate is lyophilized, giving Ac-Tyr-D-Ala-Gly-Phe-leu-CH, 0.56, 0, i (7.
    The methods indicated in the tables by the values H1-H13 inclusive, E1-E10 inclusive and Fi-F3 inclusive correspond to the values given, respectively, in Examples 1-42, 3-69 and 70-88. Other values are explained below.
    Active ester reactions
    A1. A solution of a suitable amino compound (1 mol) and the corresponding active ester (1.1 mmol) in dimethylformamide (mi 1810
    minimum volume) is maintained at 20–25 ° C until no positive reaction occurs with ninhydrin h. The reaction mixture is concentrated in vacuo and the crude product is isolated or precipitated by addition of a suitable organic solvent, or by treatment with water or a mixture of water and a suitable organic solvent. eg ether If necessary, additional purification is carried out.
    A2. Carried out as in A1, except that ethyl acetate is used as the reaction medium at C.
    A3. Carried out as in A1, but with the addition of 1-hydroxybenzotriazole (about 0.2 mmol).
    A4. Realizes; they are as in A1, but the reaction mixture is kept
    A5. It is carried out as in A1, but with the addition of 1-hydroxybenzotriazole (approximately 0.2 mmol), and the whole mixture is maintained at ° C.
    Mixed Anhydride Reactions
    81. A solution of a suitable C3-boxing component (1 mmol) in dimethylformamide (about 5 ml) is cooled to a temperature of -20 to and treated with N-methylmorpholine (1, 05 mmol) and then isobutyl chloroformate (1.05 mmol). The mixture is stirred at -20 to C for 5 minutes, and then the amino component solution is added.
    (1 mmol) in dimethylformamide. When using the salt of the amino component, N-methylmorpholine (1 mmol) is also added. The mixture is stirred at 20-25 ° C for 2 hours to complete the reaction, then it is evaporated in vacuo. The residue is partitioned between a dilute aqueous solution of citric acid and a suitable organic solvent which is not miscible with water and containing ethyl acetate.
    The product passes into the organic phase, which is separated and washed with an aqueous solution of citric acid and an aqueous solution of sodium bicarbonate, dried and evaporated in vacuo. If no suitable solvent is found, the dry matter is washed, which is then recovered by filtration after the final wash with water.
    82. As described in 81, but triethylamine is used as the t-retinal base. OT. It is carried out as in B1, but ethyl chloroformate is used to form a mixed anhydride. . It is carried out as in 81, but mixed anhydride is obtained with ethyl chloroformate and N-methylmorpholine in tetrahydrofuran. 85. Carried out as in 81, but mixed anhydride is obtained with ethyl chloroformate and triethylamine is used as the tertiary base. Azide Cl reaction. The hydrazide (1 mmol) of the carboxyl component is dissolved in dimethylformamide (about 5 ml), cooled to and converted to azide by treatment with a 6 M solution of hydrogen chloride (mmol) in dioxane, and then in tert-butyl nitrite (1.2 mmol). The disappearance of the hydrazide from the solution is revealed by applying the mixture on filter paper, followed by the addition of a mixture of ferric chloride and potassium ferricyanide. The mixture is stirred for 10 minutes at and neutralized by the addition of an equivalent amount of triethylamine (ie, mmol) and the required amino compound (1 mmol), dissolved in dimethylformamide (3 ml). When using the salt of the aninocomponent at this stage, the required amount of triethylamine (1 mmol) is also added. The reaction mixture was then stirred at OH — C for 18–24 h. The precipitate was filtered off, the filtrate was evaporated in vacuo, and the residue dissolved in a solvent not miscible with water, washed with aqueous citric acid, aqueous sodium bicarbonate and water, the product or evaporation of the solution or filtration if a precipitate appears. Reactions of N, N -dicyclohexylcarbodiimide D1. A suitable carboxyl-containing component (1 mmol) is dissolved in dimethylformamide (5 ml) and stirred at 4 ° C with the addition of N, N -dicyclohexylcarbodiimide (1.1 mmol) and the necessary ammonium component (1 mmol). The mixture is continued to stir at C (or in some cases at 20-25 ° C) until there is no positive reaction to ninhydrin (up to 18 hours). If the amino component is taken in the form of a salt, then triethylamine (1 mmol) is added to the reaction mixture at the beginning of the reaction. The precipitate is filtered off, the product is isolated by evaporation of the filtrate in vacuo, the residue is dissolved in a suitable organic solvent, for example ethyl acetate, and washed successively with an aqueous solution of citric acid, an aqueous solution of sodium bicarbonate and water, after which the dried extract is evaporated or the product is evaporated by adding an appropriate precipitator, for example petro | 1ethe ether (BP. 60-80 C). D 2. Carried out as in D1, but when added to the reaction mixture. 1-hydroxy benzotriazole (2 mmol). DZ. A suitable carboxyl-containing compound (1 mmol) is dissolved in dry tetrahydrofuran (2 ml) and N-oxysuccinimide (1 mmol) is added and then a solution of N | N-dicyclohexylcarbodiimide (1 mmol) in tetrahydrofuran (1 ml) is added. After an IS min, the amino component (1 mmol) is added and the mixture is stirred at 20-25 C for an hour, filtered, the filtrate is evaporated in vacuo, the product is redissolved in a suitable solvent, for example ethyl acetate, and the solution is washed successively with an aqueous solution of citric acid , an aqueous solution of sodium bicarbonate and water, dried and evaporated in vacuo. The reduction reaction of C1. To obtain hexahydrophenylalanine derivatives, a suitable intermediate compound containing phenylalanine (1 mmol) is dissolved in an 80% aqueous acetic acid solution, possibly containing some amount of hydrogen chloride, Adams catalyst from platinum oxide (50-150 mg) is added and restoration by passing a stream of hydrogen through the stirred mixture at 20-25 ° C until completion of the reaction. The catalyst was separated by filtering the solution through a bed of diatomaceous earth, and the filtrate was evaporated in vacuo. Hydrolysis of the ester 1. The ester (1 mmol) is dissolved in aqueous acetone (1015 ml) containing sodium hydroxide (1.1-1.2 mmol) and the solution is stirred at 20-25 ° C until the reaction stops, which is confirmed after 13 2-3 h thin layer chromatography. The mixture is concentrated under vacuum, the residual aqueous solution is washed with ethyl acetate. The mixture is acidified by addition of citric acid and the product is either extracted with a suitable solvent, for example ethyl acetate, or the product is isolated by evaporation, if feasible. The extract is washed with saturated saline, dried and evaporated under vacuum to obtain the necessary carboxyl-containing compound. U2. It is carried out as in E1, but a mixture of water, methanol and acetone is used. J3. It is carried out as in A1, but aqueous methanol is used as the reaction medium. 3, The hydrolysis is carried out with 1 eq. sodium hydroxide in water and the product is isolated in the form of its sodium salt by evaporation under vacuum. 35- Carried out as 31, but dioxane is used as the reaction medium. Acylation reactions K1. To an ice-cooled solution of the corresponding glycerol monoester (1 mmol) in chloroform (1 ml) containing pyridine (3 mmol) was added acetyl chloride (3 mmol) and the mixture was stirred at 20–25 ° C for 18 h. vacuum and the residue is redissolved in ethyl acetate, the solution is washed successively with water, a saturated aqueous solution of sodium bicarbonate and water. The dried extract is evaporated in vacuo, the residue is triturated with a small amount of methanol and filtered. The glycerol monoester required for such acylation is prepared as follows. An ester blocked with isopropylidene (50 mmol) in 2-methoxyethanol (300 ml) is heated on a steam bath for 6 hours with boric acid (500 mmol). The solvent is distilled off in vacuo and the residue is dissolved in ethyl acetate. After washing with water, the solution is dried and the solvent is distilled off in vacuo to give the ester as an oil, which is subjected to further purification by column chromatography using silica. K2. This is carried out as in K1, but palmitoyl chloride is used instead of acetyl chloride. KZ The benzoylidene-blocked glycerol monoester (1 mmol) and bonoic acid (k mmol) in trimethyl borate (5 ml) are heated on the steam bath for 20 minutes. Trimethylborate is distilled off, the residue is heated for an additional 20 minutes on a steam bath. The product was redissolved in ethyl acetate (30 ml), washed with water and recovered as the free glyoser monoester by evaporation. Acylation is then carried out with acetyl chloride, as in K1. To It is carried out as in K1, but hexanoyl chloride is used for the final acylation. Esterification reaction L1. The anhydrous blocked amino acid (10 mmol) is dissolved in dry pyridine (10 ml at and benzenesulfonyl chloride PO (mmol) is added). The mixture was stirred at 0 ° C for 15 minutes, then a suitable spiot (10 mmol) was added. The mixture was stirred at 18 ° C for 18 hours, then the pyridine was distilled off in vacuo. The residue was dissolved in ethyl acetate p (150 ml) and the solution was washed successively with water, 1N hydrochloric acid, water, 2N sodium bicarbonate and water. Dry and distill. Get the crude product. L2. To the stirred solution of a suitably blocked amino acid (5 mmol) in pyridine (5 ml), phenol (10 mmol) and N, M-dicyclohexylcarbodiimide (10 mmol) are added at 0 ° C and the whole mixture is stirred at 4 ° C for 18 h. After the mixture was mixed and the pyridine was evaporated in vacuo, the residue was dissolved in ethyl acetate (100 ml) and sorted in succession with water, an aqueous 2N sodium bicarbonate solution and water. The extract is dried and evaporated to give the crude ester. L3. An appropriately substituted amino acid (10 mmol) is dissolved in acetonitrile at and the required amount of alcohol (10 ml) is added along with pyridine (20 mmol) and (11 mol of 11-dicyclohexylcarbodiimide). The mixture was stirred at 18 ° C for 18 hours and then filtered and the solvent was distilled off in vacuo. The residue was treated with ethyl acetate and washed successively with an aqueous solution of citric acid and an aqueous solution of potassium bicarbonate. The extract is dried, evaporated in vacuo to give the crude ester. L. Is carried out as in L3, but acetone is used as the reaction medium instead of acetonitrile. Reaction with ammonia Ml. The determined methyl ester of the peptide is dissolved in a minimum amount of dimethylformamide and brought into contact with an excess of a concentrated solution of ammonia in ethanol for 3 days. at 20-25 ° C. The product is isolated by precipitation with water. The reaction with hydrazine 1. The peptide methyl ester (10 mmol) is dissolved in dimethylformamide (25 ml) and an aqueous solution of hydrazine hydrate (50 mmol) is added. The mixture is stirred at 20–25 ° C for 18 h, concentrated in vacuo to about half Boi 1 Tour (We) Rj D OD, nd M 0, 4 4, p P o D, U a 0.47
    Q1. To a solution of the compound of the formula Z-Tyr- (Bu) -aij isolated from 55.2 g (YuOmol) of its dicyclohexylamine salt in dry tetrahydrofuran (300 ml) is added 50 ml (800 mmol) of methyl iodide, 8.6 g of sodium hydri 1a (300 mmol) and the mixture is refluxed for 18 h in a bath at.
    An excess of sodium hydride is decomposed by adding ethyl acetate to the cooled suspension, and then water, to obtain an almost clear solution, which is concentrated in vacuo.
    The resulting aqueous solution is diluted with water (ISO ml) and washed twice. Adjust the pH of the aqueous solution to 3 by addition of citric acid and extract the product with ethyl acetate (ijOO ml, 2 × 200 ml). The extract is washed successively with water (OO ml), 10% w / v aqueous solution of sodium thiosulfate (100 ml) and then again with water until neutral.
    wash water reactions. The extract is dried over magnesium sulfate, evaporated, an oil is obtained, which is suspended in warm petroleum ether (200 ml, bp 60–80 ° C), then dissolved in ethyl acetate, and the product of the formula Z-Me- precipitates out of the solution cooled to C (Bu) - (H, m.p.
    eb-uh ° s.
    R1 to 5.33 g (17 mmol) of a solution of the compound Phe-Azley-NHiHCl and 2 ml (17 mmol) of triethylamine in 50 ml of chloroform were added 3.87 g (17 mmol) of a solution of the compound of formula ZNHNH-CO-C1. The mixture was kept at ambient temperature for 1 h, and then 400 ml of ethyl acetate was added. The solution is washed successively with water, 20 wt.ab. citric acid, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography using silica, chloroform, 2 vol%, and the product was precipitated by the addition of water. Other reactions P1. 729 g U mmol) Boc-Tyr (Bu) -D-Ala-Gly-Phe-Leu-OI (initial compound 1b1), 0.55 ml (7 mmol) of pure dry pyridine and 0.3 ml (6.7 mmol ) freshly distilled acetic anhydride is stirred at 2022 ° C for 10 minutes. The resulting solution is heated at EO-92C for 6 hours, then cooled and treated with water (15 ml). The stone-like substance is separated, decanted from the upper layer of the liquid, washed with water (5-15 ml) and dissolved in ethyl acetate (50 ml). The solution is washed successively with 10% w / v% aqueous citric acid solution (f10 ml), water (15 ml), 10% w / v% potassium bicarbonate iodine solution (3 l ID ml) and water (3 10 ml), dried ( anhydrous magnesium sulfate) and evaporated. The NMR spectrum of the obtained solid residue (530 mg) shows that it is a mixture of L, D, L, L L, B, B, B forms of the structural formula CHgCHHeg he-NH - CH - COCH methanol in chloroform and systems P and Q as eluents. Get the compound of the formula Z-Azgly-Phe-Azley-Sh2, so pl. 11b-120 ° C (with decomp.). S1. 17 i5 g (30 mmol) of a solution of Z-Tyr (Bzl) -OCp and 4.38 g (30 mmol) of Boc-NffIeNHi in 50 ml of dimethylformamide are incubated for 18 hours at ambient temperature. After diluting with 500 ml of ethyl acetate, the solution is washed successively with water of 20% w / w% citric acid aqueous solution and water. Evaporation of the dried extract in vacuo gives a solid which is directly treated with a solution of hydrogen chloride (100 mmol) in ethyl acetate for 2 hours at ambient temperature. The solvent is distilled off in vacuo to obtain the compound of the formula G Z-T) T (Bzl) -NHNHMe, HCl, m.p. 22322 C, RfD 0.82, R 0.6, 0.63 O, g (20 mmol) of the above hydrochloride are dissolved in 200 ml of chloroform and 2.8 ml (20 mmol of triethylamine and then 2.8 ml of (20 mmol) of isocyanatoacetic acid methyl ester. The mixture is stirred for 18 hours at ambient temperature, the solvent is evaporated in vacuo. The residue is dissolved in ethyl acetate, washed successively with water, 20% by weight of an aqueous solution of citric acid, saturated sodium bicarbonate and water. The dried extract is evaporated in vacuo to yield compounds of the formula Z-Tyr (Bzl) -Azala-Gly-C fe, cat After recrystallization from a mixture of methanol and ether, it has a melting point of 107-108 ° C. Notes (footnotes) to the table .. 1. Purify by precipitation 2.T.pl. 160-161C (with decomposition) 3. Recrystallize from petroleum ether t .kip. 60-80 C) t. Recrystallized from a mixture of isopropanol and ether (mp 18883). 5. Recrystallized from isopropanol (mp) 6.Colon chromatography on silica using chloroform and 2% methanol in chloroform. 7.Colon chromatography on silica using chloroform 8. Column chromatography on silica using chloroform and system P 9. Recrystallization from ethyl acetate (mp 128-130c) 10. Column chromatography on silica using 25% v / v ethyl acetate in cyclohexane 11. Colon chromatography on silica using System G 12. Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C, mp 9b-99 ° C) 13- Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C), t. pl. 202-2034). Recrystallization from ethyl acetate (mp. 122-123 ° C) 15. Column chromatography on silica using P and Q systems 16. Recrystallization from ethyl acetate (mp 177-17 ° C) 17-G1 recrystallization from ethyl acetate / petroleum ether (so pl. 60-80 ° C), so pl. 122-123C) 18. Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60-80C), so pl. 108.5-110 ° C) 19. Recrystallization of 2 methanol (m.p. 219-220 ° C) 20. Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C), m.p. 121-122 ° C) 21. Recrystallization from a mixture of toluene and benzene 22. Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C), so pl. TZZ-TZZ C) 23- Column chromatography on silica using system P 2. Column chromatography on silica using 3 vol. methanol in chloroform 25. Column chromatography on silica using the system Q 26. Recrystallization from a mixture of ethyl acetate and petroleum ether (m.p. 60-80 ° C), so pl. 122-12 C 27-Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C), m.p. 115-118C 28. Recrystallization from aqueous methanol, m.p. 1b2-1b3 C 29- Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C), so pl. 130-132 C 30. Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60-80 C), m.p. 15b-157 ° C 31. Lyophilic drying in the presence of HCl 32. Freeze drying 33- Column chromatography on silica using P, Q, and C systems. Recrystallization from a mixture of ethyl acetate and cyclohexane, m.p. 163-16 4 C 35. Recrystallization from methanol / ether, m.p. 130-131 C 36. Hydrolysis of ester during the operation (initial compound 137)
    Example
    Polypeptide
    -MeTut-D-Ala-Gly-Phe-Leu-Wfe,
    H-T) T-D-Ala-Azgly-Pl№-Azleu-h81j
    N-Tug-1) -A1a-S1u-P1yu-Bey-0 (CH2) M «2
    ll-Tyr-D-Ma-Cly-Phe-Leu-OCD ZgMGe
    H-Tyr-D-Ala-ay-Phe-Leu-aiJ
    H-Tyr-D-Ala-Gly-Pte-Nle-Ct.ie
    il-Tyr-D-Ala-Gly-.4ie (6H) -Uu-aj
    n-Tyr-D-Ala-Gly-Plie (6H) -Leu- (ie
    I l-Ty r-i-Asp-Gly-Plie-Lcu-Onc II-Tyr-Azala-Cly-Plie-Leu-ate
    U-Tyr-EKLeu-Gly-Plie-Leu-CMe
    li-Tyr-D-Ser-Cly-Aziihe-Leu-afe
    H-Tyr-U-Ser-Gly-Plje-Leu-0 (CHj) aOH
    H-Tyr-I} -Ser-Gly-Pl e-Leu-0 (
    H-iyr-I) -Ser-Gly-Pl -Leu-0 (Q)
    H- -Typ-D-Ser-Oly-Phe-Lett-OCHg
    CHOAe (OAC
    H-Tyr-D-Sep-Cl3f-l he-L "u-OCHj
    CmWOCuHjl
    H-Tyr-D-Ser-Gly-nie-Leu-OCHCaijQAc)
    19 H-Tyr-D-Ser-Gly-Phe-Leu-OCHCayXXX jy
    R .10
    Ajsll i
    5041 87 16
    I
    55 552060
    65
    69 77
    6510
    6130 83
    6022
    6148
    5790
    6652, 85
    6059 50 8ii 7
    79 77 6653 86
    67 50 6050 b 95
    71 65 67 50 87
    (
    68 62 59i9 i 89
      5654 81
    55 6v 9
    67 73 73 CH "OSOS |, H} 1
    67 71 is 58 6d 44 9c
    61 6 $ 4 S4 St) J 85 0 51820 37. Column chromatography on silica using K 38 system. Recrystallization from ethyl acetate / petroleum ether (b.p. 60-8 °), mp. 172-17 C 39. Recrystallization from a mixture of ethyl acetate and petroleum ether (mp. 60-80 ° C), mp. I O-lifl C 40. Column chromatography on silica using a mixture of ethyl acetate and methanol 1. Recrystallization from ethyl acetate / petroleum ether
    21
    (so kip. bo-c), so pl. 1b2-1b5 ° C (with decomp.)
    42. Recrystallization from a mixture of ethyl acetate and petroleum ether (bp. BO-BO C), mp.
    AZ Column chromatography on silica using 1 vol. methanol in chloroform
    4. Column chromatography on silica using Q and K systems.
    . M.p. 121-122С
    0i 5l822
    +6. Recrystallization from ethyl acetate, m.p. L8-250S
    7- Purification on Sephadex U1 20 in dimethylformamide
    5 48. Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C), m.p. 152-155 С
    49. Recrystallization from a mixture of ethyl acetate and petroleum ether (bp 60–80 ° C), m.p. 1b "-1b8S
    50. Column chromatography on silica using 5% v / v methanol in ethyl acetate
    / t a b l and c a)
    105 H7 1} 2 K5 (“7} H9 1, 7 OF 4J H9 1)) H9 I3 & H9 1J7 H2 127H2 128H5 YO H9 138 H5 PZ NI 1I Htl 115 H1I Yves NP 119 NP 114 Htl I. 117 Hit ItCl salt is heated by using chromatography on 25% of methanol and chloroform and solvent K The salt id is precipitated by the addition of methanol mixture with ether Salt with gnOAc is obtained as a freeze-dried powder from water or demolished water with tert.-butaiolon. Salt with 2NOAc is obtained as a lyophilized dried powder or si water with tert.-butanol in the presence of IIC1. It is purified by chromatography on silica using 25 about. mixtures of methanol and chloroform, in the presence of solvent K Salt with NO Ac Accepted as a freeze-dried drying agent from water or a mixture with tert-butanol Is recovered by evaporation after filtration through diatomaceous earth-Obtained as a freeze-dried powder in water or a mixture of water with tert-butanol; m.p. Salt IIC1 is isolated by evaporation after filtration through diatomaceous earth. Salt 1) C1 is obtained in the form of a dried ОО1. An excellent drying powder from water or a mixture of water with tert-butanol in the presence of id Salt IIC1 is precipitated by the addition of ether; m.p. Salt triperoxonane acid (TFA) precipitated by adding a mixture of ethyl acetate with ether; m.p. (razp.). The TPA salt is recovered by evaporation by filtering through diatomaceous earth. The TPA salt is recovered by evaporation after filtration through diatomaceous earth, mp. (decomp.). Salt T44 (recovered by evaporation after filtration through diatomaceous earth, mp. (diff.) Salt of TPA is recovered by evaporation after filtration through diatomaceous earth. The salt of TPA is isolated by evaporation after filtration through diatomaceous earth, i.e. iJtu -He C The id salt is obtained as a freeze-dried powder from water or mixed water; | with tert-butanol
    Polypeptide
    Example
    i-Tyr-D-Ser-Gly-Plic-Leu-aSu
    N-Tug-O-Thb-YuChCyu-Bei-ai
    h-Tyr-D-Tip-GiyPl "-Leu-CKe il-Tyr-B-Ala-Gly-Piic-Nlc-aie
    H-a-Ala-Tyr-U-Aia-Gly-Plic-Leu-aJe
    -Asp-Tyr4) -Ala-Gly-P} ie-Lei -CMa
    ll-Lys-NeTyr-D-SerGly-Wie-Uu-OMB
    H-Lyi-Tjr-l) -AlQ-Cly-pJie - DL - NHJllss (
    U-Lys (Boc) -Tyr-I) -Ala-Cly-Phc-leu-a.lc
    li-Tyr-U-Ala-Cly-Pl e-Lcu-Thr-a
    H-Gty-Gly-Tyr-D-Ala-Gly-ine-Leu-CMe 31 H-Aep H-Lyi-TyP-D-AlaJ2H-Ly8-H-Lye-r r-Alo-Cay-Phe-Leu- Ome
    33li-Arg-Pro-Lys-TyT-D-Aia-Giy-Plie-Leu-Cr-te
    H H-dy-y-Gly-TyT-D-Ala-Giy-Phe-Leu-ab
    35H-Gly-Giy-Giy-Tyr-D-Ser-Gly-Pije (6H) -Leu-QJo
    34li-Leu-Leu-Leu-Tyi: -D-Ala-Gly-Pl -Leu4 fe 37 38 39 i1
    tit ll-Aig-IVo-Lys-Pro-Cln-Gln-Tyr-D-Ala-niy-MjC-Lou-CMe
    R 1U
    fake
    59
    76
    59
    17 80 And
    62
    29 66
    1.9
    26 51 22
    73 76 77 68 57 5520
    5J
    20
    51 78 55 53
    to liS
    7 8 6 32
    58
    65 76 ko i9 2 13 88
    40 69 32 6065
    636030 Cty-Plie-; 11-С1и-0 у-ОЯ-Н-Ьу «-Туг-В-Д1а-О1у-рЬв-Ъ« м-СМе 36 60 27 H-Pro-Gin-Gili-Tyr-D-Ala-Gly-Plie- Leu-ateW H-Asp-Cily-Cly4Jly-: Tyr-D-Ala-Gly-Ph & Leu "CHe ll-Ly5-ay4Uy-G | .y-Tyr-D-Ala-Gly-Wie-LeU-Cl .fe32 72 "H-Gly-Gly-ClyJH-LT" -TyP-D-Ala-Hy-Wie-Le i-OMe 28 66 25 42 Lew-OTfe iO 6 "19 3
    25
    mixes 6ODY. with tert.butanopok in the presence of CA1
    The UC1 salt is recovered by evaporation after filtration of the "e-diatoneous earth"
    Is evaporated after filtering through diatomaceous earth.
    IKJl salt is purified with sephadex C-15 in 5% by volume aqueous acetic acid
    Salt 1IC1 is obtained in the form of a freeze-dried powder from water or a mixture of water with tert-butanol in the presence of IC1
    Salt 2IS1 purified by chromatography on silica using 25 OBD demolish
    methanol and chloroform using solvent K
    Is recovered by evaporation after filtragagin through diatomaceous earth.
    Salt llCi purified by chromatography on silica using 25% v / v mixture of methanol and chloroform
    Salt of TPA (: a1 is evaporated after filtration through diatomaceous earth; m.p.
    The ilCl salt is purified by chromatography on silica using 23 vol. Oyuchi of methanol and chloroform using solvent K NU Salt 2 (1C1 is obtained in the form of dried or mixture of water with tert-butanol 19 H5 199 9, 183 H9 203 H9 187 NP 19 I9 217 H9 180 H9 188 -N9 195 H9 198 H9
    26 Prodenmv t “VP. 1 Salt with CC.1 is obtained in the form of a freeze-dried powder from water or a mixture of water with tert-butanol. The salt with ZNOA is purified by chromatography on silica using 25% by volume. Dissolve methanol and chloroform using solvent K. Salt 1С1 is obtained as lyophilized dried powder from water or a mixture of water with tert.butanol, in the presence of tlCi Salt with HOAc is purified on Sephadex G-25 in 5% by volume acetic acid HC1 salt is purified by chromatography on silica using 25% by volume of a non-thiol-chloroform mixture and solvent K Sal with 2IS1 is purified on Sephadex G-25 in 5% by volume of acetic acid. The salt with HOAc is obtained in the form of a poroic powder-dried Iophilic water mixture from a scientific research institute of a mixture of water with tert-butanol, m.p. 218-219 ° C. The HQ salt is purified by chromatography on silica using 25 vol. mixtures of netdiol and chloroform, using a solvent, K Salt is purified in a similar manner and Sopy with 21IC1 is purified in the same way and obtained as a freeze-dried total amount of porous. It is cleaned with Sephad Xa G-25 in 5 vol. aqueous acid. Electrophoresis at pH 6.5. Sharpen to 0.78 relative to histidine as a standard label by freeze drying water powder.
    1 / h D
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    0 (ai2) CH .L1;
    Boc-Leu-Ш + {-Ю (СН2) ОН
    0 (CH,) ZgLi; Boc-Leu-Ш + HO (CH2), NHZ 73
    0 (C i meZLi; Boc-Leu-OH + SCHSUY e
    OCIijQI CHiLi;
    Boc-Leu-ai +: i; 3Qi2CH ai2
    opiiLz;
    Boc-Leu-CII + phenol Ql; Z-TyT (But) -a lH-Azphe-Lcu-OieiiCI El; Boc-AziAe-Le 3) LF 1lCh: 1l-C “BOS 3 2-S1n-S1pch1VI-Vs1C A4; Z-Gln-OCp 35H-Pbv-A11ei-I2 36H-Phe-Nlc-OMB.Tosai 37Z-Phe-Nlc-CMe B5; Z-Hic-P NX 38Boc-Phe-Azlcu-: D2, Boc-Phe-ai 3SU-Pro-Lys (Z) -CMc.liCl 40Boc-Pro-Lys (2) -CHc B1; Boc-l rq-ai 41H-ibAla-Cly-rhc-Oie 2Z-t -Ala-Gly-Wie-a4e LZ, ZDA a-OCp 43Z-Ajrg (Zi) -IYo-Lys (.Z) -ai w z -Ar6i: j) -i ro-Lys (Z) -a "AP: -An; {Zj) (Su 5H-Azgly-ilK-Azlcu-Nil.llCl 46Z-A2gly-Hie-A2lct Mi. |, Rl; Z-Azply-Cl 7h4; iy-Azi) lic-Leu- € He.llCl l eH4i} y-Phe-i4lc-Ofe.Tosai BS; Z- (Uy-ai + 36 fc9Z-Cly-Ilie-Mc-Ofc D2; Boc-Cly-ai 50Boc-Cly-AzpJie-Leu-afe 51Boc-Gly-Gly-Cly-ai 51AlX) c-Gl) -Gly -Gly-CKa B2; Boc-Cly-Ni SUBoc-Cly-Gly Cl) -CWe
    38
    Table 6
    7 70
    ten
    11 10
    Blitz 7 NO; 34 E7; 40 1: 1, 42 J3; 44 (IS; 46 D4; SO H6; 49 J4; 51B Atel / Nall / EMF-OMe 1 VIe-a-teJCl H-Azleu-Mi.llCl 6730 8 6077 ll-l.ys (Z) -CMe.JICl 3522 78 6264S8 II - {; iy-Phc-CWe.lX: i 642020 857880 39 332352 7273Э4 22 35 36 90 19 32 KCl-j) -Ofe.lJCl 60H-D-Aia.HCt 61Z-D-Afa A4; 62H-D-Asp 63Z-D-Asp (OBzt) A4-, 6 FT-D-IfiurTFA 65Boc-D-Leu B4; 66H-D-Lys (Boc) 67Z-D-Lys (Boc) B4-, 68H-D-Ivfet.HCl 69Boc-D-Ivfet A1, 70H-D-SerCBu) 71Z-D-SerCBu) B2, 72H-D -Thr 73Z-D-Tlir C1; 7 H-D-Trp.TFA A2}. 75Boc-D-Trp
    Lent 7
    Table 8 H10; 6188 1 Z-D-A a-OCp + 5373 62 kB 1 H2; 67 1 Z-D-Asp (CBzt) -OGp + 5322 F2, 651 Boc-D-Leu-III - 537 & 79 7 15 H2- 671 ZD-Lys (Boc:) - OH + 5376 76 65 E5i 69 Boc-D-Met-OCp + 53 H3, 7161 57 88 46 1 ZD-Ser (Bu) -ai-b5379 75 7 23 H2; 7358 36 71 20 1 Z-D-Thr-NHNH +5370 63 10 F3t 7561 55 27 1 Boc-D-Trp-OCp + 5379 70 9 60 2k
    tCO -
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    权利要求:
    Claims (2)
    [1]
    61 The claims of the method for producing polypeptides of formula 1 TrgB-B-F-G-R, where R is a hydrogen atom, a methyl or acetyl radical, Rj is a hydrogen atom, H-fJ-Ala; H-Asp; H-Lys-, H-lys (Boc); H-Gly-Gly; H-AspJlPtys, H-LysJTPLys, H-Arg-Pro-Lys; H-Gly-Gly-Gly; 11-Leu-Leu-Leu; H-Cru-Gly-ai H-Lys; H-Pro-Gln-Gln; li-Asp-Gly-Gly-Gly; H-Lys-Gly-Gly-Gly H-Gly-Gly-Gly-flbLys; II-Arg-Pro-Lys-Pro-Gln-Gln; Il-61u H-D-Lys; H-PheJlT-Sys or H-Gly-Gly-Gly-Gly-Gly-Gly; B - D-Ala; D-Asp; Azala; D-Leu; D-Ser; S-Thr; D-Trp; p-Ala; D-Ser (Bu); D-Lys or D-Met E - Gly or Azgly; F - Phe; Azphe or Phe (6H); G - Leu; Azleu; Nle; Met; Pro; DL-Leu or Azpro; K - ate; NHj; 0 (CH.i) aNH2; oCaijliNIfffe; OH; 0 (aij,) pH; OCCHiipAc; OSau OS-OSD; OCHtHrOAclGUQAcf oa {iCHCocoLi1f,) CH2oax:;. OCH (ai, 3, Yu1 (SNARCOS5H "Thr-OH; SP KI / 0 (0 (OCH-iai.CHi; OPh; NH (aic) aOH
    904518
    62
    t 5 and c in 19 (Sh2) M1 (Me; 0 (aI "l, P1; Chc; D-Tlir-W, and k together represent h-f No. 1-0 f II h II, or K-NH Based on the fact that ot protective groups in compound s and NVf (/ g T-B -E-F -G-K, / - hydrogen, methyl or acetyl radical, - hydrogen, Z; H-th-Ala; Z-Asp ; Z-Lys; Z-Lys (Z); Z-LysfBoc); H-Gly-Glyj Z-Asp (OBzl JZ4: ys; Z-Lys (Z) JZ (Lys); Z-ArgCZ} -Pro-Lys (Z); Z-Gly-Gly-Gly; Z-Lcu-Leu-Leu: Z-Glr-Gly-OBzl; Z-Cys; Z-Pro-Gln-Gln; Z-Asp (OBzl} -Gly-Gly- Gly; Z-Lys-Glyj-Glv-Gly; Z-Gly-Gly-Gly-Tz s; Z-ArgCZ) -Pro-Lys (Z) -Pro-Gln-Gln; Doc; H-Glu ((Bu) ; Boc-Lys (Boc); HD-Lys); H-Lys (Baugh); Boc-PheJH-Lys; Boc-Gly-Gly-Gly or Boc-Gly Gly-Gly-Gly-Gly-Gly; - Here; Tyr (Bzl), Tyr (Z) or TyrCBu); - D-Ala; D-Asp; Azala; D-Leu; D-Ser; .D-TIir; D-Trp; f-Ala; D-Ser (Bu- b); I; -Lys; D-Lys (Boc) or D-Met; -Giy or Azgly;-Ph e; Azphe or Fhef6Il); Leu; Ag1ei; Nle; Met; Pro; PL-Leu or Azpro; K-CMe; 0 (CHi) 2.NH2; 0 (.) aNIlMe; W; 0 (CH2: ipAc; 0 (CH2) jpCOCD; OaioCH (OAc) CFiamc;. OCI liCQiOCOC iy CK. Oai (aVCAc) 2; OCH (fflg) OCOC5-H. With OBut; n, r№l) .. w, -Q., - „О S 3. NHEt; Q (ai) zNHZ; A) OPhe; No. 1 (is NHCaiiVNIl.Ie; NEti; Me; 0 (CHL) Oh1e2 or D-Thr-OBzl, or G and K together represent ("-o or N-jra Priority by features; 08.O. 1976 with R, - H; H; H-Arg; II-Gly; il-Glu; H-Asp; H-Phe; H-fi-Ala; HD-Lys; il-Lys; H-Gjy-Gly-pl- I H-Lys; H-Peelmu; H-Gly-Gly-Gly-fTFTys; H-AspJH ys or H-Ly &4MVs; -. D-Ser; D-Ser (); D-Aia OR D-Thr -Giy; -Phe; -Leu; Met or Nle ;, -OH; NIIj; She; 0 (CH2) aCH (Me) g; OO QMHi; b (OCairOiNHi; 0 (ACHIII; OPhe; NHEt; -Ot N 21.05I976 with B - Azala; E - Azgly;: about 5 axes of the axis, in common, pr pr not FP. 6 F - Azphe; G - Azieu or Azpro; the real values of the radicals - 08, .766. 27.05 I976 with R - Me (when R. - hydrogen), the real values of the radicals - prioet 08-04.1976. - -ZUff R, - Me (when R2 - hydrogen), the values of the radicals are 08/08/1976 with the proviso that the molecule has at least a azaminoacid. 10/28/1976 with H-Gly-Gly; I-Leu-Leu-Leu; H-Arg-Pro-Lys; H- Pro-Gln-Gln; K-Gly-Gly-Giy; H-Lys4 ly-Gly-Gly; H-Asp-Giy-Gly-Gly; H-Arg-Pro-Lys-Pro-Glji-Gln or H-Gly-Gly-Gly-Gly-Gly-Gly; B - D-Lys; D-Trp or S-Met; E - Gly; F -.Phe; C - Pro K - oa4sh (sls) a-; 4, c; (x: n (a10Ac) ocHcaiiOCO-qj-Hja; osh aksooeJu ,;, o () JGAc or (:) (CH) 40ca: jf G and k (cis), - mcf (CHzV, and 10.28 The priority is 28i.l0.1976 provided that there is one azaaminoacid in the molecule at the Kramer.Sources of information that are considered in the examination 1. Schröder E., Lobke K. Peptides 1. M., Mir, 1967, p. ,
    [2]
    2. The same 5 s. 116.
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    同族专利:
    公开号 | 公开日
    DD130348A5|1978-03-22|
    DE2715803A1|1977-10-27|
    SE7704043L|1977-10-09|
    FR2347336B1|1980-07-18|
    NZ183712A|1979-10-25|
    CS202568B2|1981-01-30|
    PL197302A1|1978-02-13|
    PL106210B1|1979-12-31|
    AU2381977A|1978-10-05|
    JPS52139039A|1977-11-19|
    AU510760B2|1980-07-10|
    DK158077A|1977-10-09|
    HU176260B|1981-01-28|
    FR2347336A1|1977-11-04|
    FI771049A|1977-10-09|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2730851A1|1976-07-19|1978-01-26|Sandoz Ag|NEW POLYPEPTIDE DERIVATIVES, THEIR PRODUCTION AND USE|
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    US4259234A|1976-09-27|1981-03-31|Eli Lilly And Company|Analgesic compounds|
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    DE2933947A1|1979-08-22|1981-03-12|Hoechst Ag, 6000 Frankfurt|NEW PEPTIDAMIDES AND METHOD FOR THEIR PRODUCTION.|
    JPS6340199B2|1979-12-27|1988-08-10|Takeda Chemical Industries Ltd|
    FR2488253B1|1980-08-08|1984-01-27|Roques Bernard|
    US4495178A|1983-10-06|1985-01-22|G. D. Searle & Co.|Enkephalin analogs|
    JP2604268B2|1990-04-09|1997-04-30|富士写真フイルム株式会社|Liposomes and thin films using peptide derivative amphiphilic compounds, intermediates thereof, and peptide derivative amphiphilic compounds|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB14362/76A|GB1523812A|1976-04-08|1976-04-08|Polypeptide|
    GB2106376|1976-05-21|
    GB2205576|1976-05-27|
    GB2929876|1976-07-14|
    GB4483876|1976-10-28|
    GB4483776|1976-10-28|
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