Method of producing peptides

专利摘要:
Peptide compounds of formula 1, pharmaceutically acceptable base salts thereof, pharmaceutical compositions and their use as antiinfective agents <CHEM> where R1 is alkyl, cycloalkyl or cycloalkylmethyl; R2 is hydrogen or alkyl and R3 is hydroxy or an amino acid residue of the formula <CHEM> where X is hydrogen, alkyl or hydroxymethyl and n is an integer of 0 to 4 and R4 and R5 are alkyl, hydrogen, benzyl or cyclohexylmethyl.
公开号:SU1507212A3
申请号:SU864028527
申请日:1986-11-24
公开日:1989-09-07
发明作者:Патрик Риззи Джеймс
申请人:Пфайзер Инк (Фирма)；
IPC主号:

专利说明:

 This invention relates to a method for producing peptides — new biologically active compounds that can be used in medicine.
The purpose of the invention is to obtain new peptides - low-toxic compounds with a higher immunostimulating and anti-infective activity.
Example 1.-N-Heptanoyl-1-gamma-glutamyl-glycyl-P-alanine
(R, -CH, (CH) 5, Rt - H
D
. And Rj is -NHCH (CHj) COjH).
A. K-Heptanoyl-O-gamma-glutamyl (alpha-benzyl ether) -glycine.
To a solution of 897 mg (13.0 mmol) of glycine and 1.3 g (13.0 mmol) of triethyl amine in 10 ml of water was added 5.0 g (11.2 mmol) of H-heptanoyl-B-gamma-glu - Tamil (alpha-benzyl ether) -oxysuccinimide ester in 100 ml of dioxane. The resulting reaction mixture is allowed to stir at room temperature for 80 hours. This solution is then poured into 300 ml of ethyl acetate, and the separated organic phase is washed with 10% hydrochloric acid. native acid, water and solution
ate
o you
N9
 CM
3150
brine. The organic phase is separated, dried over magnesium sulphate and concentrated in vacuo to dryness. The residue was triturated with diethyl ether and filtered under a nitrogen layer of 3.43 g (74% yield).
B. M-heptanoyl-B-gamma-glutamyl-β-glycyl-O-alanine.
To a solution of 2.0 g (4.78 mmol) of N-heptanoyl-0-gamma-glutamyl (alpha-benzyl ether) -glycine. 1.75 g (5 mmol) of para-toluenesulfonic acid D-alanine benzyl ester salt, 506 g (5 mmol) of triethyl amine, and 675 mg (5 mmol) of 1-hydroxybenzotriazole in 100 ml of tetrahydrofuran added 3.03 g (7.17 mmol) of 1-cyclohexyl-3- (2-morpholinoethyl 1) carbodimide meta-p-toluenesulfonate. The reaction mixture is stirred at room temperature for 18 hours and poured into 300 ml of ethyl acetate, after which the organic phase is separated and washed with 10% hydrochloric acid, water, saturated sodium bicarbonate solution and brine solution. The organic phase is separated, dried over magnesium sulphate and concentrated in vacuo. The residue is triturated with diethyl ether and filtered under a nitrogen layer of 2.7 g. 2 g of solid in 75 ml of methanol with 400 mg of 10% palladium hydroxide on charcoal is agitated in a hydrogen atmosphere at an initial pressure of 50 pounds. per square inch for 4 hours. The catalyst is filtered and the filtrate is evaporated under reduced pressure, after which the residue is dissolved in water and lyophilized to form 1.23 g (yield 90%) of the desired product as a white solid. The resulting compound is characterized by NMR spectroscopy.
Example 2. N-Heptanoyl-B-gamma-glutamyl-glycyl-glycine
{R 1 - CH3 (CHg); Rj - H
and RJNHCH CO H),
A. Complex oxysuccinamide ester N-heptanoyl-B-gamma-glutamyl (alpha-benzyl ether) -glycine.
5 0 5 0 с о г
0
To the cold solution () of 13.0 g (31 mmol) of L-heptano L-O-gamma-glutamyl (alpha-benzyl ether) -glycine and 3.91 g (34 mmol) of N-oxysuccinamide in 400 ml tetrahydrofuran was added 7.0 g (34 mmol) of dicyclohexylcarbodiimide. The mixture is allowed to stir for 1 hour and at room temperature for 18 hours. The solids are filtered and the filtrate is concentrated under reduced pressure. The residue is triturated with diethyl ether and filtered under a layer of nitrogen to give 15.4 g (98%) of the desired intermediate.
B. Y-Heptanoyl-P-gamma-glutamyl-GLYCI-1-GLYCIN
To 2.0 g (3.07 mmol) of the N-heptanoyl-β-D-gamma-glutamyl (alpha-benzyl) -glycine oxysuccinimide ester ester, 446 mg (5.95 mmol) of glycine and 0.55 ml (3.9 mmol) of triethylamine in 10 ml of water. The resulting reaction mixture was allowed to stir at room temperature for 13 hours. This solution was poured into 100 ml of ethyl acetate, after which the organic layer was washed with 2.5% hydrochloric acid, water, and brine. The organic layer is separated, dried over magnesium sulfate and concentrated to dryness. The residue is triturated with diethyl ether and filtered under a layer of nitrogen to form 1.7 g of a white solid. 1.5 g of a solid in 75 ml of methanol containing 200 mg of 10% palladium hydroxide on charcoal is shaken in a hydrogen atmosphere at a pressure of 50 pounds per square inch for 3 hours. The catalyst is filtered, the filtrate is concentrated x vacuum. The residue is dissolved in water and lyophilized to form 1.12 g (yield 90%) of the desired product. The compound is characterized by NMR spectroscopy.
Example 3. N-Heptanol-P-gamma-glutamyl-glycyl-B-series
(RT - CH3 (CHg) j; Cg - H and Rj - -NHCH (CH, OH)).
five
Using 2.0 g (3.98 mmol) of N-heptenoyl-D-gamma-glutamyl (alpha-benzyl ether) glycine, alpha-benzyl ester) glycine, 780 mg (4.02 mmo O-benzyl) as ishojnh products O-serine and 0.556 ml (4.02 mmol) of triethylamine, following the procedure described in Example 3, receive 902 mg (yield 76%) of the desired product, mp 130-132 0 The compound was characterized by NMR spectroscopy.
Example 4. K-Heptanoyl-O-gamma-glutamyl-glycyl-B-alphaamine butyric acid (R, - CH. (CH) j;
VC - H and RJ --NHCH (CHjCH3) COjH).
The procedure described in Example 3 was repeated using 2.0 g (3.98 mmol) of N-heptanoyl-β-D-gamma-glutamyl (alpha-benzyl ester) -glycyloxysuccinamide ester, 400 mg (4.02 g) as starting materials. mmol). D-alpha-aminobutyric acid and 0.556 ml (4.02 mmol) of triethylamine, resulting in 632 mg (57% yield) of the desired product, so pl. 140- 141 C. The compound is characterized by NMR spectroscopy.
Example 5. N-Heptanoyl-O-gamma-glutamyl-glycyl-3-aminopropionic acid (R, - CH3 (CH2) j, R - H and R 3- —NH (CH,), CO, H) .
When performing the procedure described in the example of pollutants using 1.5 g (3.0 mmol) of the M-heptanoyl-B-ha m-glut-amyl (alphabenzyl ether) -glycine ester as starting products, 350 mg (3.9 mmol) of propionic acid 3-th and 0.55 ml (3.9 mmol) of triethylamine, 500 mg (yield 43%) of the desired product were obtained, mp. 135-138 ° C. The compound is characterized by NMR spectroscopy.
Example 6. N-Heptanone-P-gamma-glutamyl-glycyl-4-aminobutyric acid (R, - CH, (CH) 5i R, - H and R J - -NH (COj)).
The procedure described in Example 6 is repeated, replacing the β-3-aminopropionic acid with 410 mg (4.0 mmo of 4-aminobutyric acid, resulting in 600 mg (yield 50%) of the desired product, mp. 140 - Compound characterized by NMR spectroscopy.








0
EXAMPLE 7 K-Heptanoyl-O-γ-gamma glutamyl-glycyl-5-amine (pentaonic acid (R, - CH3 (CH,) j-, K, - H and RJ - -HH ( CH,) / SOGN).
Replacing 3-aminobutyric acid 470 mg (4.0 mmol) of 5-aminopentanoic acid and performing the procedure described in Example 6 yielded 520 mg (yield 42%) of the desired product, mp. 122-124 0. Compound. The study was characterized by NMR spectroscopy.
Example 8. N-Heptanoyl-O-5-gamgma-glutamyl-glycyl-6-amino hexane acid (R, - CH j (CH) fi Rj-H and R j - -NH (CH,)).
The procedure described in Example 6 was repeated again, replacing 3-amino-0 butyric acid with 530 mg (4.0 mmol). 6-aminohexanoic acid, resulting in 520 mg (yield 40%) of the desired product as a white foam. The compound is characterized by NMR spectroscopy.
Biological studies of the compounds obtained by the proposed method and the comparison compounds were performed on Balb C mice infected with Klebiella causing pneumonia. The results are shown in the table, where the method of administration of the tested compounds is indicated, the percentage of survival, i.e. the percentage of animals that survived the administration of the test compounds and placebo, i.e. The percentage of animals that survived when the properate was not administered.
five
0
five
Test compounds were administered for 24 hours in the indicated doses before infection and in the indicated doses during infection. The tests were carried out in comparison with the known compound FK-156. With regard to toxicity, in tested doses, the proposed compounds did not show such,
can be attributed to the category of low-toxic compounds.
Conducted tests have shown that the proposed compounds have low toxicity and have a higher immunostimulating and anti-infective activity, increasing the survival of the Balb C Klebsiella, which causes pneumonia.
55

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing peptides of the general formula
9
 D / COOH
 CH t
I
0
and
(CH7) 7CONHCHC-R3.
de R - C, -Cj-alkyl R - hydrogen;
R. - amino acid residue of the formula
. ABOUT
-I H-CH-CCH VCOOH I
X
where X is hydrogen, C, kil or hydroxymethyl, n 0 ... 4, integer,
differing in that
compound of general formula
R.CONH / SOOYAT O
5 (pH2) 2CONHCHC-OH
R,
where K and R have the indicated meanings;
R is benzyl
10 in the form of succinimide ester is subjected to a dehydrating interaction with a compound of the formula
15
D H2NCH- (CH) nCOOH
X
where X and p have the indicated meanings, followed, if necessary, by selective removal of protecting groups by hydrogenolysis over palladium oxide.
RjCONH D COjRij
 L (CHi) 2CONHCHCOR3 RI

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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DK156252C|1979-07-31|1989-12-18|Fujisawa Pharmaceutical Co|METHOD OF ANALOGUE FOR THE PREPARATION OF DI, TRIAL OR TETRAPEPTIDE DERIVATIVES OR SALTS THEREOF|WO1988001613A1|1986-08-27|1988-03-10|Pfizer Inc.|Crystalline n--d-gamma-glutamyl-glycyl-d-alanine, and processes and intermediates therefor|

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WO1988001612A1|1986-08-27|1988-03-10|Pfizer Inc.|Processes and intermediates for n--d-gamma-glutamyl-glycyl-d-alanine|

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JPH0621170U|1992-04-21|1994-03-18|多治見無線電機株式会社|Electrical connector|

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DE19712633A1|1997-03-26|1998-10-08|Laves Arzneimittel|Stimulation of interleukin, especially IL-6, production|

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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US8502351|1985-11-25|

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