Method of producing derivatives of gonadoliberine

专利摘要:
The invention relates to gonadoliberin derivatives of the general formula (I) Glp-His-Trp-Ser-Tyr-X1-X2-X3-Pro-X4 wherein X1 is a glycyl group or a D-isomer of any natural or synthetic amino acid group, X2 represents an L-amino acid group having 1 to 4 carbon atoms in the side chain, L-phenyl-alanyl or L-tryptophyl group, X3 represents an L-amino acid group having a C1-4 alkyl or C2-4 alkanoyl-amide side chain, and X4 is a glycine amide or a C1-4 alkyl amide group, with the proviso that if X1 stands for a group other than glycyl and X2 is a tryptophyl group then X3 may not be leucyl, and the addition salts formed with therapeutically useable acids and complexes thereof. Furthermore the invention relates to a process for preparing these compounds. The new gonadoliberin derivatives can be effectively used for the reproduction process of fish, birds and mammals.
公开号:SU1396970A3
申请号:SU843827701
申请日:1984-12-21
公开日:1988-05-15
发明作者:Гулиаш Тамаш；Хорват Анико；Кери Дьердь；Николич Карой；Секе Балаж；Теплан Иштван
申请人:Кезпонти Валто-Еш Хительбанк Рт.Инновациош Алап (Инопредприятие)；
IPC主号:

专利说明:


cm
The invention relates to a method for the preparation of GnRH derivatives, new biologically active compounds that can be used in fish farming.
The purpose of the invention is a method for obtaining new derivatives of GnRH low-toxic and significantly increasing the ability to ovulate and sperm sterols.
GnRH derivatives are obtained using the solid phase peptide synthesis method,
The course of the reactions is followed with a ninhydrin test. When free amino groups are detected, the acylation is repeated. Depending on the nature of the amino acid, the duration of the binding process is 1 to 16 hours.
Cleavage of the protecting groups and separation of the peptide from the resin is carried out with liquid anhydrous hydrogen fluoride in one step. When N-dinitrophenyl is used, the protecting groups are removed even before the resin is cleaved by HF cleavage. The protected peptide resin is stirred in propyl amine containing dimethylformamide and, after removal of the solvent, is treated in the usual manner with HF. If the compound obtained is peptidyl-amyl amide, the peptide is separated from the resin by alkylammonolysis and then, depending on the nature of the protecting groups, is catalytically hydrogenated and / or hydrolyzed with acid.
The crude product is purified by gel filtration on Sephadex G 25, and elution is carried out with acetic acid solutions.
For further purification using HPhC columns, high pressure liquid chromatography and / or chromatography on silica gel. The purity of the peptides is examined by amino acid analysis and by thin layer chromatography. The R f - values of thin layer chromatography are determined on silica cartel (thin aluminum foil). Merk using the following solvent blends:
Ethyl acetate: pyridine: acetic acid: water 30: 20: 6: 11
Ethyl acetate: pyridine: acetic acid: water 60: 20: 6: 11
Ethyl acetate: pyridine: acetic acid: water 120: .20: 6: 11
Ethyl acetate: pyridine: acetic acid: water 2AO: 20: 6: 11
n-butanol: acetic acid: water:: ethyl acetate 1: 1: 1: 1
n-butanol: acetic acid: water
4: 1: 1
Isopropanol: 1 M acetic acid 2: 1
Ethyl acetate: pyridine: acetic acid: water 5: 5: 1: 3
nButanol: acetic acid: ammonia concentrated ammonia and water 1; }; water 6: 1: 1: 2
Methyl ethyl ketone: acetic acid:: water 125: 15: 20
Example 1. D- Phe, Gin - GnRH (M: 1243)
but). Synthesis.
1.25 g (1 mmol) of the benzhydrylamine hydrochloride resin (0.8 mmol / g Pierce) are allowed to swell in dichloromethane for 2 hours. When acylated with the help of amino acids, review as per the circumstances, repeat the following cycle: (see Table 1).
After the last stage, the weight of Glp-HislTos | -Trp-Ser | OBZlf-Tyr I OBZll-D-Phe-Leu-Gln-Pro-Gly - peptide resin is 2.28 g. DW: 1.05 g (66%) . M (gesch.) Obtained peptide: 1577.
b) Cleavage with HF.
3 ml of anisole and 100 mg of dithiothrit were added to the resin, then 30 ml of HF was condensed into a mixture. The mixture is stirred for 1 h at 0 ° C. Then, fluoride hydrogen is removed in a stream of nitrogen, the residue is suspended in absolute ether and then filtered. The solid residue is washed with 50% acetic acid. The filtrate is evaporated at. The residue is fed directly to gel chromatography.
at). Gel chromatography
The substance obtained according to the preceding paragraph is purified on a column of Sephadex G 25 (2.5 x 100 cm) with acetic acid as an eluting acid. Elution is carried out by absorption of UV light at a wavelength of 280 nm, as well as by thin layer chromatography. The elution rate is 15 Ml / h. Collect fractions between 300m and 350 ml and lyophilize. Weight 690 mg (55%).
d). High pressure preparative liquid chromatography
3
A preparative HPLC column (high pressure liquid chromatography column) of 2 cm in size (C, 5-silica gel. LRP-1, 13-24 mic. Whatman) is used. It is balanced by a mixture of 25% methanol with 75% 30% acetic acid. After equilibration, 230 mg of the substance purified by gel chromatography dissolved in that solvent mixture was applied to the column. A gradient of methanol (acetic acid whose composition varies linearly between 25% methanol 75% 30% acetic acid and 40% methanol) and 60% 30% acetic acid is eluted.
The elution rate was 2 ml / min, the pressure was 3.5-10 Pa. Fractions are detected using UV light with a wavelength of 280 nm, their content is monitored by thin layer chromatography. The weight of the pure target product D - Phe, Gin - GnRH after free-lashing is 133 mg. This corresponds to a total amount of 399 mg (32%) of the protected desired product. , 76; , 6bi, 33; , 93; , 83, T.PL. 175 -, - 68.0 (C
1,00;
0.1, 0.1 H CHjCOOH).
Amino acid analysis: Gly: 1.02; Pro: 0.95; Leu Phe: 1.02; Tyr: 1.01; Ser: 0.93; His :: 0.99; Glu: 1.96. T.PL. 175 - 178 ° C, c j -68 (c 0.1, 0.1 CHjCOOH).
P p and M e p 2. Trp, Gln - gona-doliberin. (M: 1226).
a). Synthesis.
Starting with 2.5 g (1 mmol) benzhydrylamine hydrochloride resin (O, L.mol equivalent / g) described in Example 1 in p. A), the peptide resin Glp-HisiDNPl-Trp-SerlO-BZI I Tyr-Gly- is obtained. Trp-Gln-Pro-Gly - resin. The weight of the peptide resin is 3.62 g; , 12 g (76%).
(M obtained peptide: 1468).
b). Removal of the protecting groups and separation of the peptide from the resin. Cleavage of dinitrophenyl protecting group (DNP) ..
The peptide resin is stirred at room temperature for 1 h in a mixture of 20 ml of dimethylformamide and 1 ml of propylamine. The resin is then filtered and washed with dichloromethane, then with ethanol.


Yu
3969704
Splitting with HF.
After removing the dinitrophenyl protecting group as described in Example 1, in paragraph b), the peptide is separated from the resin and the protecting groups from the peptide. At the end of both stages, 0.8 g (65%) of the substance remains
d). Gel chromatography
Work as specified in example 1 in p. C). The weight of the collected and lyophilized fractions is 520 mg (42%).
e) High pressure preparative liquid chromatography.
Work as indicated in example 1 in p. D) with the difference that the equilibration is carried out using a mixture of 18% methanol and 82% 20 30% acetic acid. The substance purified by gel chromatography is eluted from the column with a mixture of methenol / acetic acid, the composition of which varies linearly between 18% 25 methanol (82% 30% acetic acid and 35% methanol) and 65% 30% acetic acid acid. Fractionation, as well as other conditions, coincide with that of Example 1, p. D). The weight of the lyophilized desired product is 380 mg (31%), 66; , 57-,
thirty
go
. 12.0
35
, 78j tggs. 160 C (C 0.1; 0.1 N CHjCOOH).
Amino acid analysis: Glu: 1.93; Gly: 2.04; Pro: 1.00; , 98; Ser: 0.93; .Trp: 1.86; His 1.03.
P p and M e p 3. Trp, Leu, des Gly NH gonadodiberin-ztilamide (1198).
a). Synthesis.
As a first step in the synthesis, BOC-Pr is bound in a known manner to a chloromethylated polystyrene resin. 2 g of the BOC-Pr-o-resin obtained in this way (0.5 mol-equivalent / / g) are left to swell in dichloromethane for 2 hours and then in a manner described in item a) of Example 1 gradually. the corresponding protected amino acids are bound to the resin. After the last cycle, 3.02 g of Glp-HisIDNPf-Trp-Ser | OBZIf-TyrfOBZIf-Gly-Trp-Leu-Pro peptide resin is obtained. 5 1.02 g (83%). (M obtained peptide: 1486).
b). Removal of the protecting groups and separation of the peptide from the resin.
First, according to subparagraph b) of Example 2, the dinitrophenyl protecting group is separated from histidine. The peptide in the form of ethylamide is cleaved from the resin in order to remove it. For this purpose, 15 ml of ethylamine is condensed onto the protected peptide resin and the mixture is stirred at 0 ° C for 3 hours. The excess amine is removed with nitrogen. After that, washed with methanol, then dimethylformamide. The DMF solution is evaporated and the oil obtained as an evaporation residue is triturated with ether. The precipitate is filtered off.
The solid thus obtained, in order to remove the protective groups, is treated as described in b) of Example 1 with gaseous hydrogen fluoride. 71.0 ml (59%) of nonapeptide ethylamide are obtained.
d). Gel chromatography
They work as described in p. C) of Example 1 with a column from Sephadex
LRP-1 gel is equilibrated with a 10% methanol and 20% acetic acid aqueous solution. Elute by a linear gradient.
G 25 and as an eluting agent 25 contains in 20% acetic acid
I OBZI 1-TugIOBZI -Gly-Phe-Gln-Pro-Gly- resin (3W: 1.27 g (83%). M obtained peptide 1521.
b). Cleavage of protective groups.
The protected peptide described in example 1, p. B) is treated with anhydrous HF. 980 mg (82%) of the unprotected peptide are obtained.
at). Gel filtration.
The crude decapeptamide described in Example 1 p. C) is cleaned on a column filled with Sephadex G - 25 using 2M acetic acid.
Yield: 576 mg (49%).
d). Preparative FlPL chromatography (high pressure liquid chromatography).
Work as described in example 1 p. D)
way with the difference that
The LRP-1 gel is equilibrated with an aqueous solution containing 10% methanol and 20% acetic acid. Eluted by a linear gradient, which
WA use 30% acetic acid. The weight of the collected and lyophilized fractions is 490 mg (41%).
The crude peptide is purified further on a column of silica gel 60 (230-400 mesche Merck), see cm. Eluted with a mixture of ethyl acetate and pyridine, acetic acid and water in a ratio of 30: 20: 6: 11. The flow rate is 3 ml / h. 4 ml fractions were collected (trapped) and followed by elution by thin layer chromatography.
The corresponding gonadoliberine ethyl amide Trr LCU des Gly NH 5 fractions are determined on the basis of amino acids-i. lot analysis. Obtain 320 mg (26%) of lyophilized material. M.p. 167 - 174 ° С, o / JiJ - 5.9 (С 0.5i 0.1 N CHjCOGH), 6li K 0.42 -, 75.
Amino Acid Gly: 0.96; Gly Ley: 1.00; Ser Trp: 1, 88; His
P p. And M e p 4
analysis; . 0.97;
Pro
0.95-,
1.02;
0.89; Tug
1.03.
Phe, Gin Gonado


liberin ().
a). Synthesis. 1.25 g (1 mmol) of the benzhydrylamine hydrochloride resin (0.8 mol equivalent / g) is left to gag to swell for 2 hours in dichloromethane. From the swollen resin described in example 1 p. A), 2.9 g of the peptide resin Glp-His | Tos | -Trp-Ser are obtained.
0
0 his
1.03-,
1,00;
182 C.
Pro
Phe; T.PL, Leu Gonadog
acid, the amount of methanol from 10% with an increase up to 25% (2 150 ml). The elution is then continued using an increasing amount of 25 to 40% linear gradient (ml) containing metnol. The resulting fractions of pure peptide are collected and evaporated. Yield: 448 mg (38%), m.p. 182 С; 21.0 (C 5 0.1, 0, .1 H CHJCGOH).
,12; , 7; , 24; , 87,
Amino acid analysis: Ser; 0.85; Glu: 2.05; Gly: 2.13; Tyr: 0.92; 0.95; Trp: 0.81.
P p and M e p 5. Phe, liberin (M: 1172).
a). Synthesis.
0.62 g (0.5 mmol) of benzgi-Drilam-5 n-hydrochloride resin (0.8 mol equivalent / g) is allowed to swell in dichloromethane for 2 hours. Then, in a manner described in example 1 p. A), a peptide resin is obtained: Glp-HislTos | Trp-SerlOBZIL -Typ-IOBZI l-Gly Phe-Leu-Pro-Gly - resin.
Yield: 1.33 g aW: 695 mg (92%). M peptide obtained: 1506.
b). Processing with HF.
The protected peptide is treated with anhydrous HF as described in Example 1 b). 510 mg (87%) of crude decapeptide are obtained.
at). Gel filtration.
0
The crude decapeptamide prepared according to step b) described in Example 1 part b) is purified on a Sephadex G-25 column using 2M acetic acid. Yield: 363 mg (62%)
d). Chromatography on silica gel.
For further purification of the peptide, a column of 2x100 cm filled with silica gel 60, which is eluted in a 1: 1: 1: 1 ratio prepared with a mixture of n-butanol, acetic acid, water and ethyl acetate, serves. The content of the fractions is controlled by UV-spectral, as well as by thin-layer chromatography. .. Receive 299 mg (51%) of pure decapeptide. M.p. , “XS c-19.0 (, 1i 0.1 N CHjCOOH). , 55i, 39; , 62; , 73,
Amino acid analysis: Ser: 0.91; Gln: 0.97; Pro: 1.07; Gly:: 2.12; Leu: 1.00; Tyr: 1.03; Pye: 0.94; His: 1.05.
Under the conditions of the method described in Example 1, the compounds were prepared according to Tables 2 and 3 (Examples 6 to 9).
Biological tests of GnRH derivatives obtained under the conditions of the proposed method were carried out.
Gonadoliberin derivatives were administered to fish (the Acipenser Suthese harp) by intramuscular or subcutaneous injection in doses of 0.1 μg - 5 mg per 1 kg of weight (see Table 4).
Studies have shown that GnRH analogues in the indicated dose range favor fish ovulation (Acipenser Suthemis sterlet), while the known compound D-Ala des Clu SpK-ethylamide in the indicated dose range does not affect the ability of these fish to reproduce.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining GnRd derivatives of general formula I: Gep-His- Trp-Ser-Tyr-Xi-X j-Xj-Pro-Gly, where X is Gly, DPhe, DTrp, DAla, DLeu, t-butyl;
X, - Leu, Trp, Phe, GIN;
X 3 - Gin, Leu,
characterized in that the construction of the peptide chain is carried out by a solid phase method, starting from glycine and a benzhydrylamine hydrochloride resin, followed by
to the resulting glycylpolymer of the appropriately protected amino acids in the sequence due to the peptide of general formula I using an iodine or acid activated method, and from the resulting peptidyl polymer of formula II
Glp-His-Trp-Ser-Tyr-X, -X, j-X j-Pro-Gly-W,
Y Y Y where Y is dinitrophenyl or tosyl;
Y - OBZl;
W is benzhydrylamine; the protective groups and the polymeric substrate are cleaved off.
20
ten
Table 1
25
thirty
35
0
five
0
five
ethylamine and 90% CHClj, washing 2-fold 2
7CHClj, washing 2-fold 1
8 Ethanol washing 2 times 1
9CHjCl, 2 times multiple 1
103 mmol BOC-amino acids, dissolved in dichloromethane and 3 mm-
l DCC or DICK, growing-- 60 (disgraced in different ways
11CH Clj, flush 2-fold 1
12Ethanol wash 2 times 1
When bound by Gin, the active ester method is bound via BOC-GIn-CNP; in the case of pyroglutamic acid work without a protective group.
1396970
6 D-TrpS Phe, Leu -GnRH 168-170 7 D-Ala, Gln "- GnRH 182
8 D-Leu Gin -GnRH 183-185
9 0-t-butyl-B Seg - 178-179 -Gin -GnRH
ITABLE3
Amino acid analysis of the compounds corresponding to examples 9-12
60,871,011,121,04
70,911,900,951,10. 1.07
80,972,011,071,00
91,871,981,051,07
j.Table4
The number of ovulated fish,%, under the action of the compounds according to the invention per sterl (Acipenser Suthemis)
10 10 30 30
50 60 90
Table 2
0.1 0.1 H. 0.69 3.2 acetic acid
1.0 0.1 n. 0.55 43
vinegar
acid 1.0 0.1 n. 0.57 47
acetic acid 1.0 0.1 n. 0.63 37
vinegar
acid
1,000,920,951,021,87
1,001,02 -0,950,92
2,121.01 -0,930,91
1,000.96 -1.030.83
90
80
60
50.

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US6323179B1|1999-10-15|2001-11-27|Theresa Siler-Khodr|Chicken GNRH analogs and uses thereof in regulation of fertility and pregnancy|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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HU445883|1983-12-23|

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