Method of producing peptides or salts thereof

专利摘要:
An animal growth promotant which comprises as an effective ingredient a peptide of the following formula I: wherein X is selected between hydrogen and t-butoxycarbonyl; A is selected from the group consisting of Leu, lie, Phe, Ahx, Met, MetO and Phe(CI), either of L- or D-configuration; B is selected from the group consisting of Pro, Ala, Gly, Val, Leu and Pip, either of L- or D-configuration; C is selected from the group consisting of Val, Leu, Met, MetO, lie, Phe, Phe(Cl) and Ahx, either of L- or D-configuration; or A, B and C independently represent a chemical bond provided that at least one of them is an amino acid residue; Y is selected from the group consisting of OH, OMe, OEt, OBzl, NH2, NH-Et, NEt2 and the veterinarily acceptable salts thereof. A feed or veterinary composition containing it, and a method for promoting the growth of animals are also provided. New compounds according to formula 1, wherein A is different from L-Leu or L-Phe or C is a chemical bond, as well as a method for preparing the same is disclosed.
公开号:SU1380615A3
申请号:SU853984706
申请日:1985-11-26
公开日:1988-03-07
发明作者:Хехт Барбара；Персео Джузеппе；де Кастильоне Роберто
申请人:Фармиталиа Карло Эрба С.П.А. (Фирма)；
IPC主号:

专利说明:

Estrate removal refers to a method for producing new biologically active compounds - peptides or their sodas, which have the ability to stimulate the growth of animals that can be used in veterinary medicine.
The purpose of the invention is new peptides with low toxicity and a higher ability to stimulate animal pt) CT.
The values of Rf are determined on the plates precoated with a silica gel layer 60 P / Merck), thickness
0.25 mm, 20 cm long with underframe
by the following developing systems:
System A. Benzene: gasoline (60:80) (ethyl acetate 70:10:40 by volume;
System B. Benzene: triacetate: acetic acid: water 100: 100: 20: 10 by volume (upper phase);
System C. Benzene: ethyl acetate: acetic acid: water 100: 100: 40: 15 by volume (upper phase);
System D. n-Butanol: acetic acid: water 4: 1: 1 by volume;
System E. Methylene chloride: methyl with a 98: 2 liter by volume;
System F. Methylene chloride: methyl alcohol 95: 5 by volume (E. Merk is a trade name).
Analysis by thin layer chromatography is carried out at a temperature and range from 18 to 25 ° C; therefore, the values of R vary by ± 5%. Melting points were determined in the openings of the capillaries using the Tottoli apparatus and they were not corrected. Most derivatives soften and decompose before melting. High-voltage electrophoresis on paper was carried out using an apparatus of the ferroforiginal-Frankfurt type 64 system on paper from the firm of Leichher and Schul No. 2317 at a pH of 1.2 (formic acid: acetic acid: water 123: 100: 777) and a voltage of 1600 at (40 V / cm) and at a pH of 5.8 (pyridine: acetic acid: water 450: 50: 4500) and a voltage of 1400 V (32.5 V / cm). These products are characterized by mobility relative to Glu at pH 1, (E, 2) h at pH 5, & (E)
The invention uses symbols and abbreviations commonly used in peptide chemistry. Other synols and abbreviations used are AcOEt - ethyl pstat; - dimethyl
0
five
0
five
ABOUT
0

five
formamide; EtjO is diethyl ether; MeOH - methyl alcohol; NMM-N-methyl morpholine; PE - petroleum ether; Phe (Cl) is para-chloro-b-phenylalanni; Pip-L - pipecolic acid; iPrjO - diisopropyl ether; iRGON-isopropyl alcohol; THF is tetrahydrofuran.
Example 1. Getting HC1 and H-Leu-Gly-Trp-OMe (IV).
Stage I. Boc-Leu-Gly-Obrl (I).
2.2 ml (20 mmol) of N-methyl morpholine and 1.98 ml (20 mmol) of ethyl chloroformate are sequentially added to a solution of 4.63 g (20 mmol) of Boc-Leu-OH in 60 ml of anhydrous tatrahydrofuran and at -12 ° C. .
After stirring at this temperature for 2 minutes, a cold solution (-30 ° C) of 6.75 g is added.
(20 mmol) tosylate H-Gly-OBrl and 2.2 ml of N-methylmorpholine (20 mmol) in 60 ml of dimethylformamide.
The reaction mixture is stirred for 45 minutes at -12 ° C and for 90 minutes at then filtered from the salts and evaporated under vacuum. The residue is dissolved in ethyl acetate and washed several times with saturated sodium chloride solutions containing a 1 M solution of citric acid, an acid solution, 1 M sodium bicarbonate solution, and water. The organic layer is dried over anhydrous sodium sulfate and the solvent is removed in vacuo.
6.81 g (yield 90%) of compound (I) were obtained as an oil. , 59.
Stage 2. Boc-Leu-Gly-OK (II).
6.6 g (17.44 mmol) of Boc-Leu-Gly- -OBrl (I), dissolved in 50 ml of methanol, are hydrogenated at room temperature and atmospheric pressure in the presence of 1.65 g of 10% palladium carbon. The catalyst was removed by filtration and the solution was concentrated in vacuo.
4.17 g (yield 83%) of compound (II) is obtained from a mixture of ethyl acetate and petroleum ether, melting point 115-121 ° C, / 29.0 ° (c 1, MeOH); Rtg 0.50; E 5.8 0.75.
Step 3. Boc-Leu-Gly-Trp-OMe (III).
Using 3.95 g (13.70 mmol) of Boc-Leu-Gly-OH (I) and 3.49 g (13.70 mmol) as starting materials
HCl-H-Trp-OMe and acting as described in Step 1, g (yield 90%) of partially purified compound (III) is obtained as a foam, using diethyl ether (Rf 0, Rfj 0.69) to prepare it. after. What this compound is used in the next stage.
Step 4. HCl-H-Leu-Gly-Trp-OMe Q (IV).
5.75 g (11.77 mmol) of Boc-Leu-Gly-Trg-OMe (III) is dissolved in 60 ml of a saturated solution of hydrogen chloride in glacial acetic acid, after which 6 ml of anisole and 3 ml are added to this solution 2-mercaptoethanol. After 30 minutes of this solution being placed at room temperature, the removal of the Baugh element is completed, and the solution-2 solvent is removed under vacuum conditions at 30 ° C. The crude product is purified by chromatography on a silica gel column (Merck) 0.040-0.063 mm, using a mixture of ethyl acetate 5 and methanol 9: 1 as the eluent.
From a mixture of ethyl acetate and diethyl ether, 3.05 g (yield 61%) of the compound was obtained. (Iv): melting point 180-185 ° C (foam); , t: l +16.9 (c 1, MeOH); Rf, 0.67; E 1 0.80.
Example 2. Getting HC1 "H-Ahx-Gly-Trp-OMe (VIII). Step 1. Boc-Ahx-Gly-OBrl (V).
Using as reference materials 4.63 g (20 mmol) of Boc-Ahx-OH. 6.75 g (20 mmol) of tosylate H-Gly-OBrl and acting as described in example 1 (step 1), from a mixture of ethyl acetate and petroleum ether, 6.66 g (yield 88%) of compound (V) ; melting point 84-86 ° C; (/ 1 -22.0 ° (c 1, MeOH); Rf 0.58.
Step 2. Boc-Ahx-Gly-OH (VI).
Using as a starting material 6.35 g (16.78 mmol) of Boc-Ahx-Gly-OBrl (VI) and acting as described in Example 1 (stage 2), 4.31 g are produced (yield 89% ) Compound (VI) as an oil: Rp 0.54; E y 50 0.74. .
Step 3. Boc-Ahx-Gly-Trp-OMe (VIII).
Using as a starting material 4.12 g (14.28 mmol) of Boc-Ahx55-Gly-OH (VI) and 3.64 g (14.28 mmol) of HC1 H-Trr-OMe act as described in the example 1 (stage 1), get
40
P



0
5.93 g (yield 85%) of compound (VII) as an oil: R f. 0.81.
Stage 4. HC1H-Ahx-Glu-Trr-OMe (VIII).
Using as the starting material 5.60 g (11.46 mmol) of Boc-Ahx-Gly-Trp-OMe (VII) and operates as described in Example 1 (step 4), but used in the methylene chloride stage containing an increasing amount of methyl alcohol. (up to 5%), as eluent, from a mixture of ethyl acetate (diethyl ether, 3.61 g (65% yield) of compound (VIII) are obtained: melting point 114-117 ° C (foam); J1 % +25.8 (c 1, MeOH); Rf JJ 0.64; E ,, 0.79.
Example 3. Getting HC1 (H-Ahx-Gly-Trp-Mec-OMe (X).
Step 1. Boc-Ahx-Gly-Trp-Met-OMe (X).
Using as a starting material 1.66 g (5.41 mmol) of Boc-Ahx-Gly-OH (VI, example 2) and 2.09 g (5.41 mmol) of HCl-H-Trp-Met-OMe and operating as described in example 1 (stage 1), but using methylene chloride at the purification stage, 2.85 g (yield 87%) of compound (IX) are obtained from a mixture of ethyl acetate and diethyl ether; Rf g 0.74.
Step 2. HCl-H-Ahx-Gly-Trp-Met- -OMe (X).
Using as the starting material 2.60 g (4.19 mmol) of compound (IX) and acting as described in example 1 (step 4), but used in the purification stage as eluent ethyl acetate containing an increasing amount of methyl alcohol (from 10 to 15%), from a mixture of isopropyl alcohol and diethyl ether, 1.40 g (yield 60%) of compound (X), melting point bb-1 (fc (foam), about / 7 d 5.9 (s 1 MeOH), Rfj, 0.70; E 5 0.60.
Example 4. Getting HC1 H-Ahx-Gly-Trp-Phe-OMa (XIV).
Step 1. Boc-Trp-Phe-OMe (XI).
Using as raw materials 6.09 g (20 mmol) of Boc-Trgr-OH and 4.31 g (20 mmol) of HCl-H-Phe-OMe and operating as described in example 1 (step 1), from a mixture ethyl acetate and diisopropyl ether give 7.73 (yield 83%) of compound (XI), melting point 117-120 ° C;
513
Jj / 20.2 ° (c 1, feOH); R 0.79; Rf, 0.56.
Stage 2, HCl H-Trp-Phe-OMe (XII)
Using as the starting material 7.47 g (16.05 mmol) of compound (XI) and acting as described in example 1 (step 2), from a mixture of ethyl acetate and diethyl ether, 5.55 g are obtained (yield 86 %) of compound (XII): R. 0.75; E 0.83.
Stated 3. Boc-Ahx-Gly-Trp-Phe-OMe (XIII).
Using as source materials 1.83 g (6.35 mmol) of Boc-Ahx-Gly-OH (VI) and 2.55 g (6.35 mmol) of HC1-H-TRp-Phe-OMe (XII) and operating as described in example 3 (step O, 3.19 g (yield 79%) of compound (XIII) is obtained as an oil: R g 0.76.
Stage A. HC1-H-Ahx-Gly-Trp-Phe- -OMe (XIV).
Using as a starting material 2.85 g (4.48 mmol) of Boc-Ahx-Gly-Trp-Phe-OMe (XIII) and acting as described in example 1 (step 4), but purifying the raw oily cleaved oxidized compound (XIV) by several washings with diethyl ether, and finally (XIV) was isolated from a mixture of isopropyl alcohol and diethyl ether (1.54 g, 60% yield). Rn 0.75 E ,, 0.68.
Example 5. Getting HC1 li-Leu-GI-y-Trp-Phe-OMe (XVI).
Step 1. Boc-Leu-Gly-Trp-Phe-OMe (XV).
Using as source materials 1.75 g (6.10 mmol) of Boc-Leu- -Gly-OH (II) and 2.45 g (6.10 mmol) of HC1-H-Trp-Phe-OMe (XII) and operating as described in example 3 (step 1), 3.10 g (yield 80%) of compound (XV) are obtained in the form of an oil: Rn 0.73
Stage 2. HC1-H-Leu-Gly-Trp -Phe- -OMe (XVI).
Using as a starting material 2.75 g (4.30 mmol) of Boc-Leu- -Gly-Trp-Phe-OMe (XV) and I act as described in Example 1 (from 7) from a mixture of isopropyl alcohol and simple diethyl ether, 2.09 g (yield 85%) of compound (XVI) are obtained: melting point 103-108 ° C (foam); , 9.4 (c 1, MeOH); Rj 0.73; E ,, 0.67.
0
five
0
06
with
5 g 5
five
iO
five
156
Example 6. Boc-Trp-Leu-NHJ.
Acting as described in the previous examples, the title peptide was obtained in 80% yield.
R 0.79, melting point 158 ° C (isopropyl alcohol-diisopropyl ether), at -18.4 ° (c 1, MeOH).
Example 7. HCI H-Trp-Leu-NHj ,.
Using the Boc-Trp-Leu-NHj obtained in the previous example as the starting material and acting as described in example 1 (step 4), the title compound is obtained in 94% yield, melting point 135 ° C ( ethyl acetate and diisopropyl ether), of d + 9.6 ° (s 1, MeOH), RJ 0.76; 84
Example 8. HC1-H-Trp-Val-OMe.
Step 1. Boc-Trp-Val-OMe.
To a solution of 12.17 g (40 mmol) of Boc-Trp-OH in 100 ml of anhydrous tetrahydrofuran, 4.5 ml (40 mmol) of N-methylmorpholine and 3.96 g (40 mmol) of ethyl chloroformate are sequentially added at a temperature of -12 ° s After stirring for 2 minutes, a cold solution of 6.70 g (40 mmol) of HCl-H-Val-OMe and 4.5 ml of N-methylmorpholine (40 mmol) in 50 ml of dimethylformamide is added to the reaction mixture. The reaction mixture is stirred for 1 hour at -12 ° C and 2 hours at a temperature of 0-15 ° C, filtered off the salt and evaporated under vacuum. The residue is dissolved in ethyl acetate and successively several times. washed with saturated sodium chloride solutions containing 1 M citric acid solution, 1 M sodium bicarbonate solution and water. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed in vacuo. 12.1 g (yield 84.4%) of the title compound are obtained from a mixture of isopropyl alcohol and diisopropyl ether. K. 0.81; Rj 0.87.
Step 2. HC1-H-Trp-Val-OMe.
12.52 g (30 mmol) of Boc-Trp-Val-OMe are dissolved in 15 ml of formic acid at room temperature.
After the removal of the Bose element is complete (monitored by thin layer chromatography), the solvent is evaporated in vacuo at 30 ° C. The residue is dissolved in methanol, cooled to 0 ° C, then to this
11 ml (33 mmol) of a ZM solution of hydrogen chloride in anhydrous tetrahydrofuran is added to the solution. The solvent is removed in vacuo, resulting in 9.55 g (90% yield) of the title compound, Rf 0.69, from a mixture of isopropyl alcohol and diisopropyl ether; E o 0.98 Glu.
Example 9.HC1. H-Pro-Trp-Met-NHo.
Step 1. Boc-Pro-Trp-Met-NH.
Using as the starting materials 1.722 g (8 mmol) of Boc-Pro O and 2.967 g (8 mmol) of HCl-H-Trp-Met-NHj and operating as described in Step 1 of Example 8, isopropyl alcohol is obtained 3.828 g (yield 90%) of the title compound: -70.2 (c 1, MeOH); R 0.38; R {0.73.
 Stage 2. HC1-K-Pro-Trp-Met-NH ,.
3.722 g (7 mmol) of Boc-Pro-Trp-Met-NHH is dissolved in 40 ml of formic acid at room temperature. After the removal of the Bore element (monitored by TLC) is complete, the solvent is evaporated under vacuum at. The residue is dissolved in methanol, cooled to 0 ° C, after which 3.6 ml (10.8 mmol) of a ZM solution of hydrogen chloride in anhydrous tetrahydrofuran are added to this solution. The solvents are removed in vacuo, resulting in the production of absolute ethyl alcohol 2.621 g (yield 80%) of the title compound; 0 -23.0 ° (s
1, MeOH); Rp 0.4l; ETj 0.76. Example Y. H-Leu-Gly-Trp
-Met-NH, -HCl.
By acting as described in the previous examples, the title compound is obtained in 79% yield: melting point 180- (isopropyl alcohol — simple
DIISOPROPYL ETHER, Ce / 7) - + 1.0 ° (s 1, MeOH), R 0,63; E 0.66 Glu.
Biological tests of peptides obtained under the conditions of the proposed method were carried out.
A test for protein synthesis in vivo and in laboratory conditions is carried out for 7 days using a group of six male rats (Wistar, Hageman, Extertal), 8

0
five
0
five
0
five
divided into subgroups of three animals that are contained in cages from macrolon, where wood chips are used as litter.
Water and food (standard diet Altromin 1321, containing 19% crude protein) are given to animals on demand.
The peptides are administered subcutaneously in the form of a solution, whose daily doses are from 0.1 to 100 ng / kg.
The preparation is measured in a liquid scintillation counter PL (1.0 ml of 5 ml scintillation fluid) of PRIAS.
B tab. 1 shows the results of measurements of the rate of synthesis of proteins by the liver tissue of male rats after treatment for 7 days (daily subcutaneous injections).
Measuring the rate of protein synthesis of the compounds listed in table. 1 is significantly different from the results obtained in the control group consisting of rats who were injected with physiological saline chloride solution daily by subcutaneous injection.
In determining the growth-promoting activity in a living organism in rats with an initial weight of approximately 79 g, the preparation is administered orally during feeding (standard diet Altromin 1320) in the dosages from. 4 to 250 mg / kg body weight. Weekly register weight gain and feed consumption. The results are shown in Table. 2 (doses of salt-converted peptides refer to free bases).
The tests carried out showed that the peptides obtained under the conditions of the proposed method are of low toxicity and significantly increase the rate of protein synthesis by the liver tissue.

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing peptides of formula (I)
X-A-B-trp-C-y - HCllp,
where X is hydrogen or a tert-butoxycarbonyl group; A - Leu or Ahx; B - Pro or Gly; C - Val, Leu, Met or Phe, or
independently of each other
represent a chemical bond with the proviso that at least one of them is an amino acid residue; methoxy or amino group; 1, when X is hydrogen, when X is a t-butoxycarbonyl group; Q
salts, differing by condensation of the compound
NIN formula (II)
XAA-OH
Q
five
with a compound of formula (III)
Н-Тгр-С-У, where А, В, С and У are indicated;
X - tert-butoxycarbonyl group
in the presence of dicyclohexylcarbodiimide, alone or together with the racemization prevention agent, or the mixed anhydride of the activated ester derivative, or azide of the compound of formula (III) and the target product is isolated after cleavage of the protective groups, if necessary.
Table 1
Boc-Trp-Leu-NKj 10
50 (example 6) 100
HCl-H-Trp-Leu-NH, 10 (Example 7) Q
HCl.H-Trp-Val (Example 8)
HC1-K-Pro-Tgr- -Met-NHj (example 9)
HCl-H-Leu-Gly--Trp-Met-NHj (Example 10)
HC1-H-Leu-Gly- -Trp-OMe (compound IV


-3.5 +31.7 -t-18.9
+ 31.4
+23,1
+ 1.6
+42.3
+44.1
+ 18.9 + 7.5 -0.3
+ 23.0 + 32.0 +29.6
-one
+ 11.9 + 21.6
100
Low toxicity
100
Low toxicity
100
Low toxicity
100
Low toxicity
100
Low toxicity
100
Low toxicity
eleven
159.5
+4.86
559.7
3, 50
+4, 37
Boc-Trp-Leu-NH ,,
79.0 + 8.7 79.0 + 4.7 238.5 + 10.5
236.5 + 11,
157.5
+ 3.55 530.2
3.37 + 7.92
1380615
12 Continuation of table 1
table 2
 79.0 + 4.7
78.7 + 7.0 236.5 + 11.6 237.3 ± 11.6

158.6
+ 4.27 574.6
3.62 + 1.09
HCl H-Trp-Leu-NH
78.0 + 4.6 78.8 + 3.1
238.0 + 9.9 238.5 + 8.8
159.4 159.7
+4,80 +5,00
568.4 536.2
3.56 3.56
+2, 73 +2.73
HC1 N
Initial weight Final weight Gain (absolute)
Gain,% relative to the control group
Feed intake, g
Feed payment, g (absolute value)
Payment of feed,% relative to the control group
-Rp-val-ome
79.8 + 5.6 78.5 + 6.179.8 + 4.7
246.8 + 15.4236.4 + 17.7236.2 + 12.8
167,0157,9156.3
+ 9.80 549.9
3.29 +10.11
+3,81 569.2
3.60 + 1.64
+2.76 554.2
3.54 +3.28
Table .a 3
79.2 + 6.1 239.9 + 13.5 160.7
+5.65 558.5
3.47 +5.19
Table 4

+2.76 554.2
3.54 +3.28
151380615
Table5
Indicators
HUD. Leu-Gly-Trp-Met-NH,
Baseline weight79.9 + 4.478.0 + 3.879.4 + 5.5
Final weight 243.8 + 21.1 255.7 + 6.5227.5 + 11.5
Gain (absolute) 163,9177,7148.1
Gain,% by ratio
to the control group +7.76 +16.83 -2.63
Feed intake, g 564.8 563.4 564.2
Payment of feed, g (absolute value) 3.45 3.17 3.69
Payment of feed,% in relation to the control group + 5.74 +13.39 -0.28
V
Table 6
Indicators
Initial weight 78.0 + 5.5 Final weight 230.0 + 14.3 Gain (absolute) 152.1 Feed consumption, g 556.9
Payment of feed, g (absolute value) 3,66
Doses, ng / kg body weight (mean + standard deviation)
31.6 63.3 126.6
Control group (mean otherwise + standard deviation)

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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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GB848430255A|GB8430255D0|1984-11-30|1984-11-30|Biologically active oligopeptides|

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