DE1643504C - Decapeptide L-Pyroglutamyl-Lglutaminyl-L-aspartyl-L-tyrosyl-L-threonylglycyl-L-tryptophanyl-L-methionyl-Laspartyl-L-phenylalanylamide, and its salts and processes for their preparation - Google Patents

Description

NH, OH OAc

2. H-Pyr-Glu-Asp-Tyr-Thr-Gly-Try-Met-Asp-Phe - NH ₂

NH ₂ OSO ₃ HOAc

3. H-Pyr-Glu-Asp-Tyr Thr-Gly-Try-Met-Asp-Phe-NH ₂

NH ₂ OSO ₃ H OH

4. H-Pyr-Glu-Asp-Tyr Thr-Gly-Try-Met-Asp-PheNFi ₂

5. Process for the production of the new decapeptide L - pyroglutamyl -L- glutaminyl -L- aspartyl - L - tyrosyl - L - threonyl -glycy 1 -L- tryptophanyl-L - methionyl - L - aspartyl -L- phenylalanylamid, with the phenol group of the tyrosyl radical free or blocked by a sulfuric acid residue and the alcohol group of the threonyl residue free or blocked by an aliphatic acyl radical with 1 to 4 carbon atoms and its pharmaceutical Usable salts, characterized in that the polypeptide of the above formula is known per se in polypeptide chemistry Process is established.

The invention relates to a new, therapeutically useful decapeptide l - pyroglutamyl-L - glutaminyl -L- aspartyl -L- tyrosyl - l - threonyl - glycyl - L - tryptophanyl - L - methionyl -L- aspartyi - L - phenylalanylamide. wherein the phenol group of the tyrosyl residue is free or blocked by a sulfuric acid residue and the alcohol group of the threonyl radical is free or through an aliphatic acyl radical having 1 to 4 carbon atoms blocked, and its pharmaceutically acceptable salts.

The decapeptide obtainable according to the invention and its derivatives show a high multiple biological

Affections can be used in both humans and animals.

There are numerous ways of synthesizing the decapeptide according to the invention, essentially consist in the fact that the protected amino acids are obtained by known methods of polypeptide chemistry or polypeptides condensed in a suitable order, this condensation being carried out in this way is that the decapeptide obtained has the desired sequence of ten amino acids.

The amino and carboxyl groups of the stepwise condensed amino acids and polypeptides that should not participate in the formation of the peptide chain, are blocked by a protective group, which can be removed again in a manner known per se by acidolysis or hydrolysis.

The following protective groups can be used to protect the amino group: TosyL, Carbo-

benzoxy, carbobutoxy, trityl, formyl, trifluoroacetyl and other groups commonly used in polypeptide chemistry.

For example, the following protective groups can be used to protect the carboxyl group

be: methyl, ethyl, t-butyl, benzyl, p-nitrophenyl and other groups commonly used in the field.

The condensation between the amino group of one molecule and the carboxyl group of another Molecules to form the peptide chain can be performed according to methods known in peptide chemistry for example by a suitable activated acyl derivative such as a mixed anhydride, an azide, a p-nitrophenyl ester and 2,4,5-trichloro

phenyl ester, or by direct condensation between the free amino group and the free carboxyl group in the presence of a suitable condensing agent such as a carbodiimide ζ. B. Dizyklohexyicarbodiimid or i-Zykionexy! -3-aiörphoiinylcarbodiimid and others known in the literature. The condensation can be carried out in a suitable solvent, e.g. B. Ν, Ν-dialkylformamides. lower aliphatic nitriles and pyridines such as dimethylformamide, acetonitrile and pyridine; the reaction starts at -20 ⁰ C to room temperature, and can at room temperature to 35 ° C during a period of 12 to 120 hours to be completed.
Tvpischs Sslzs dss? Riind ^l £ jn? G '? R' ¹ 3.beta. decapeptide available are the sodium salt, potassium salt, magnesium salt, calcium salt, gluconate, tartrate, malate, Athylendiaminsalz and other pharmaceutically veiwendbare salts.

As mentioned above, there are many possible syntheses for the decapeptide obtainable according to the invention.

In order to explain the invention in more detail, some examples of its production are given below.
The tetrapeptide L - pyroglutamyl - L - ghitaminyl-L - aspartyl - L - tyrosine - azide (I) is combined with the hexapcptide L-threonyl-glycyl-L-tryptophanyl-L-methionyl-L-aspartyl-L-phenylalanylamide (II) , whose hydroxyl group of the threonyl radical is replaced by an acyl radical

is blocked in a suitable solvent, such as Lastly is done by mild alkaline hydrolysis

Dimethylformannd, condensed, the decapeptide being the decapeptide (IV) being the decapeptide

peptidL-Pyroglutamyl-L-glutaminyl-L-aspartyl- ¹ ^ _ncnu

f. tyrosyl - L - threonyl - giycyl - l - trypiophanyl - UiU ₃ H

r - methionyl - l - aspartyl - l - phenylalanylamide (III) 5 '

is obtained, the hydroxy group of the threonyl-L-pyroglutamyl-L-glutanunyl-L-aspartyl-L-tyrosyl-

testes is blocked by an acyl residue. The deca- L-threonyl-glycyl-L-tryptophanyl-L-methionyl-

peptide (HD is marked with the J b »jj ',,, - _Λ

complex anhydrous pyridine-sulfuric anhy- L-aspartyl-L-phenylalanylamide (V)

dnd treated, with finally the decapeptide so

_L. pyroglutamyl - L- glutaminyl - l - aspartyl - l - ty- obtained, in which the hydroxy group of the threonyl residue

rosyl - L - threonyl - giycyl - L - tryptopharyl - L - methio-free.

_ny l - L - aspartyl - L - phenylalanylamide (IV) The above condensation can be obtained by the following

whose phenol group of the tyrosyl radical is represented by the equation, where the symbols

a sulfuric acid residue and the hydroxyl group of the 15 commonly used in polypeptide chemistry.

Threonylrestes is protected by an acyl residue. th symbols correspond to:

NH ₂ OAc

1

H-Pyr-GIu-Asp-Tyr-N ₃ + H-Thr-GIy-Try-Met-Asp-Phe-NHj I II

NH ₂ OAc

> H-Pyr-Glu-Asp-Tyr-Thr-Gly-Try-Met-Asp-PheNHj

III

NH ₂ OSO ₃ H OAc pyridine-SO, j II> H-Pyr-Glu-Asp-Tyr Thr-Gly-Try-Met-Asp-PheNH ₂

IV NH ₂ OSO ₃ H OH

oh- I I · I

^k H-Pyr-Glu-Asp-Tyr Thr-Gly-Try-Met ~ Asp-PheNH ₂

wherein Ac is an aliphatic acyl radical having 1 to 4 carbon atoms.

As stated above, there are various possibilities for the preparation of the decapeptide (III, IV, V) according to the methods known in polypeptide chemistry and used to form a polypeptide chain. A Example of this is the following:

NH ₂ OAc

H-Pyr-Glu-Asp-Tyr-Thr-N, + H-Gly-Try-Met-Asp-PheNH ₂ VI VII

NH ₂ OAc

“H-Pyr-Glu-Asp-Tyr-Thr-Gly-Try-Met-Asp-Phe-NHj

III

Ass the decapeptide (III). ^w 'e ohen described various secretions associated Over, the decapeptide (V) is obtained. sen.

Analogous results are achieved if the following examples are intended to enhance the present invention

explain other condensation by p-nitrophenyl ester or dung in more detail. 2,4,5-tricblophenyl ester in place of that by 60 the azide is applied. · 1

The decapeptide obtainable according to the invention with B e 1 s ρ 1 e 1

a sulfuric acid residue gives salts with organic

and inorganic bases; both this product and the manufacture of the first intermediate product

Its derivatives also have a strong, versatile 65 biological activity: in fact, they show NH ₂

hypotensive effectiveness and stimulate the movement |

ability of the gastrointestinal tract and the H-Pyr-Glu-Asp-Tyr-NH-NH ₂ (I)

7.5 g of carbobutoxy-L-tyrosine (J. Am. Chem. Soc, 75, 1953, p. 950) are converted by the mixed ethoxy-formic anhydride according to the method described by Greenst ei et al in Aminoacid Chemistry, 1961, p 978, process described with 4.150 g of carbobenzoxy- S hydrazine (Ben, 47, 1914, p. 2183) condensed. After standing overnight at room temperature, the mixture is evaporated to dryness in vacuo: the oily residue dissolved in ethyl acetate is washed in the cold with 0.5 hydrochloric acid, with an aqueous solution of sodium bicarbonate and with water until neutral.

The mixture was evaporated to dryness in vacuo and the return. i »'- d from ether-petroleum ether crystallized. You will then recrystallize Ätby! are »-t" etrolether becomes 7.700 g

CTB «> - NH-NH-CBO

, m.p. .18 to 120 ⁰ C. [a] f = -1.7 ° (c = 1 in dimethylformamide) 2.2 g of this product are left to stand at room temperature for 40 minutes in a solution of anhydrous hydrochloric acid in glacial acetic acid (1.33N). The mixture is evaporated to dryness in vacuo: the oily residue is collected and triturated with anhydrous ether. The solid product thus obtained is filtered, washed with anhydrous ether and dried. It will be 1.89 g

H-Tyr -NH-NH-CBOHCl

with a melting point of 125 to 128 ° C (dec.); Ia] I ' = 38.3 ° (c- 1 in 95% acetic acid), E _li2 = 0.75 GIu. A solution of this product in dimethylformamide in the presence of one equivalent of triethylamine becomes one equivalent of the mixed anhydride prepared in anhydrous tetrahydrofuran from 1.616 g in the cold

OBz

CTB-Asp-OH

(J. Am. Chem. Soc, 81, 1965, p. 620) and 0.542 g of ethyl chloroformate according to Greensteinetal (cited above), added. After standing overnight at room temperature the mixture is evaporated to dryness in vacuo, the oily residue with ethyl acetate added, with 0.5 η-hydrochloric acid, an aqueous solution of sodium bicarbonate and with water washed until neutral. After removing the solvent, the oily residue is made from chloroform Petroleum ether crystallizes, and 2, Sg

OBz

55

CBz

CTB-Asp-Tyr-NH-NH-CBO

H-Asp-Tyr-NH-NH-CBO HCI (VIII) |

(E ₁ = 0 65 GIu). One solution to this pro _,? ducts in dimethylformamide in the presence of an * equivalent of triethylamine are 0.624 g

NH,

CTB-GIu-ONP

added (this product with a m.p. of 150 to 153 ° C can be off

NH ₂

CTB-GIu- OH

and p-nitrophenyl in the presence of a condensing agent, such as dicyclohexylcarbodiimide). Ue mixture is under for 2 days Stirring kept at 35 ° C. It is evaporated to dryness in vacuo, and the oily residue becomes taken up with ethyl acetate. After acidic and alkaline washing, it is made from methanol-benzene and then from acetone-petroleum ether. crystallized.

NH ₂ OBz

! i

CTB-Glu-Äsp-Tyr-NH-NH-CBO

with a melting point of 173 to 175 ° C is obtained; ["] * * = -22.2 ^Cl (c = 1 in dimethylformamide). 2.55 g of this product are left to stand for 40 minutes at room temperature in a solution of hydrochloric acid in ice acetic acid (1.33N). The solvent is removed, the remaining foam collected and triturated with anhydrous ether. It is filtered, dried, and it becomes 2.08 g

NH ₂ OBz
H-Giu- / i.sp Tyr NH-NH-CBO-HC!

receive; E ₁₂ = 0.59 GIu.

The solution of this product in dimethylformamide in the presence of one equivalent of triethylamine 1.114 g of CBO-Pyr-ONP, manufactured according to Ann. 640, 1961, p. 145, added and kept at 35 ° C. for 2 days and then evaporated to dryness; the residue is taken up with ethyl acetate and water. The insoluble compound becomes the same Filici 'iiiii 1 normal \ vi * ßn »/ ^ hydrochloric acid in the Cold, washed with sodium bicarbonate solution and with water until neutral. The mix will dried and crystallized from methanol. It will

obtained, m.p. 138 to 140 ^° C; [a] l ° = - 20.7 ° (c = 1 in dimethylformamide). 1.100 g of this product are left to stand for 40 minutes at room temperature in a solution of anhydrous hydrochloric acid (1.33N) in glacial acetic acid. The solvent is removed in vacuo, the white foam that remains is triturated in anhydrous ether and the solid obtained in this way is filtered and dried. It becomes 1.03 g

60 NH ₂ OBz
CBO-Pyr-GIu-Asp-Tyr-NH-NH-CBO

obtained with a m.p. of 200 to 205 ° C; [u]? = -28.3 ° (c = 1 in dimethylformamide). 2 g of this product are dissolved in 30 ml of dimethylformamide and hydrogenated in the presence of 10% palladium-on-carbon. The catalyst is nitrided off, strongly mii

Washed dimethylformamide and the filtrate in aVacuum evaporated to dryness. The residue is taken up with anhydrous ether and filtered fund dried. It will be 1.00 g

NH ₂
H-Pyr-Glu-Asp-Tyr-NH-NH ;,

with a melting point of 198 to 200 C (dec. J obtained. E _1-2 = 0.54GIu.

Manufacture of the second intermediate product

9Ac
i
H-Thr-Gly-Try-Met-Asp PhC-NH ₂ HaΠΙ) from j Fp. IStrC, (ft] V = + As = 1 in dimethylformamide): 13.2 g of this salt are at 0 ' ^J C with a Solution of phosphorous acid acidified against Congo red: an oil separates out, which is extracted with ethyl acetate. After evaporation of the solvent, 7.3 g are obtained

OAc
to CTB-Thr -OH

obtained in the form of a foam. SB g of 2,4,5-trichloropheriol and 6.2 g of dicyclohexylcarbodimide are added to this product, dissolved in 6öml of ethyl acetate. After 2 days the mixture is filtered and evaporated to dryness. 13.2 g.

OAc

A solution of 1.04 g of H - Try - Met - Asp ic - Phe - NH ₂ (.. Prepared according to J. Chem Soc 1966, S. 555) in 7 ml of dimethylformamide 12:46 ml of triethylamine and 0.563 g of CTB - Gly - ONP ( prepared according to HcIv. Chim Ada. 45, J963. p. 16 * 7 "added and left to stand for 4 days at room temperature. The solvent is evaporated in vacuo, the residue is taken up with water and ethyl acetate, the organic layer with dilute hydrochloric acid and then with" a 5% aqueous solution of sodium bicarbonate, the mixture is evaporated to dryness and crystallized from methanol-ether, giving 0.95 g

CTB -CIy -Try-Mei -Α «* -Phe- N'H, (KU

receive. Melting point 190 ° C. In the meantime, the phenyl phenyl carbo-l.buio \ yO-acetyJ- i -ibreonine becomes the following formula

OAc

CTB Thr OCP
jui following kind hergestelii 8 g

OAc
H -Thr-OH

«Prepared according to J-Org. Chem. 29, 1964, p. 1629), dissolved in 100 ml of dimethylformamide, are treated with 11.9 g of p-nitrophenyl-butyl carbonate and with 14 ml of triethylamine. After 4 days, a further 2.4 g of nitrophenyl-1-butylcarbonai are added, and the solution is left to stand for a further 2 days. The lion is evaporated to dryness and taken up with a 5% aqueous solution of sodium bicarbonate and ether. The aqueous solution is acidified and extracted with ether. After removing the ether, 3.7 g of an oily residue are obtained, which is diluted with 30 ml of ethyl acetate, whereupon 3.14 g of dicyclohexylamine (DCEA) are added. After adding ether, 4.9 g separate

OAc

ί
CTB-Thr-OH-DCEA

JS

40

45 CTB -Thr -OCP

obtained in the form of an oil which is used as such.
0.9 g

H-Gly-Tr> -Mei-Asp-Phe-NH ₂

are dissolved in W with dimethylformamide and it becomes 0.95 s

OAc

CTB-Thr-OCP

and O2 , ml of triethylamine added. The mixture is kept at 32 ° C. for 5 days, the solvent is evaporated off in vacuo, the residue is taken up in water and crystallized from dimethylformamide ethyl acetate, a product having a melting point of 183 to 185 ° C. being obtained, [α]? = - 17 (c = 1 in dimethylformamide).
0.6 g of the thus obtained

OAc
!
CTB-Thr-Gly-Try-Met-Asp-Phe-NHj

are for 30 minutes at room temperature in a solution of anhydrous. Hydrochloric acid in glacial acetic acid (1.5 n) left to stand. After the addition of ether becomes

OAc

H-Thr-Gly-Try-Met-Asp-Phe-NH ₂ -HCl

precipitated E,., = 0.51 Leu: Mp. I55 "C (decomp.); [«] £ = -8 (c = i in 95% acetic acid).

Production of the decapeptides (III), (IV) and (V)

0.41 g of H-Pyr-Glu-Asp-Tyr-NH-NH ₂ , dissolved in 7 ml of dimethylformamide, are mixed at −20 ° C. with 0.75 ml of a solution of 2 normal hydrochloric acid in tetrahydrofuran and then with 0.09 m ¹ t . Butyinitrit-treated. After 6 minutes, verdeu 0.35 ml of triethylamine and cooled to -10 ⁰ C solution of 0.41 g

OAc -

H-thr-GIy-Try-Met-Asp-Phe-NHj-HCI

209 526/20?

I 643 504

added in 2.5 ml of dimethylformamide . After 5 minutes, 0.1 ml of triethylamine is added and the mixture is kept at -15 ° C. for 1 hour and at OX for 5 days. The solvent is removed in vacuo and the residue triturated in a solution of citric acid, after which it is evaporated to dryness and then washed with ether and then repeatedly with ethyl acetate. It will be 0.42 g

OAc

Citric acid, washed with a 5% solution of sodium bicarbonate and then with a 30% solution of sodium chloride. After drying over sodium sulfate, the solvent is evaporated off in vacuo and the residue is triturated with ether. The mixture is filtered and the solvent evaporated to ζ Trockr. It becomes 6.68 g

NH ₂
H-Pyr-Glu-Asp-Tyr-Thr

Gly-Try-Met-Asp-Phe-NH ₂ (III)

receive; Mp. 215 to 217 C (dec.): [«] ₀ = -21 (c = 1.1 in dimethylformamide); E ₅₈ = 0.33GIu.

0.42 g of this product in 6 ml of anhydrous pyridine are added at a temperature of -10 ⁰ C ζI 2 g of the complex pyridine - SO ₃ , suspended in 10 ml of anhydrous pyridine. The mixture is kept at room temperature for one night. It is poured into water and the residue is treated with a normal aqueous solution of sodium hydroxide until thymolphthalein changes continuously, whereupon it passes in countercurrent with the system butanol-ethanol-acetic acid-water (80: 16: 16: 128) (80 K = 4.3) is cleaned. It becomes 0.15 g

NH ₂

OSO ₃ H

H-Pyr-GIu-Asp-Tyr-Thr

Gly-Try-Met-Asp-Phe-NHj (V)

receive; E ₁₉ = 0.54 Cys (SO ₃ H); E ₅₈ = 0.41 GIu. The product thus obtained can easily be converted into the corresponding salts with an organic or inorganic base.

Example 2

The preparation of the decapeptide (V) is carried out as described in Example 1, but takes place on Place of the production of the intermediate product tetrapeptide (IX) from the dipeptide (VIII) the following: 2.465 g

NH ₂
CTB-GIu-OH

are condensed by the mixed ethoxyformic anhydride (quote above) with 5.71 g

OBz

H-Asp-Tyr-NH-NH-CBO-HCl

(produced as described in Example 1). The reaction mixture is left to stand at room temperature over Nachi. The solvent is evaporated off in vacuo and the residue is dissolved in water and ethyl acetate. The organic layer is separated and washed in the cold with a 3% solution of NH _{2 OBz}

I I

CTβ-Glu-Asp-Tyr-NH -NH-CBO

obtained, m.p. 173-175 ° C. After recrystallization from acetone petroleum ether, the melting point does not change: '5 C'] c = -22.5 U = 1 in dimethylformamide).
0.526 g

OH

CBO-Pyr

are by the mixed anhydride with 1.418 g of NH ₂ OBz

I. I.

H-Glu-Asp-Tyr-NH-NH-CBO-HCl
obtained by treating

NH ₂ OBz
CTB-Glu-Asp-Tyr-NH-NH-CBO

with a 1.33 normal solution of hydrochloric acid in glacial acetic acid, condensed.

The reaction mixture is left to stand at room temperature overnight. The solvent is evaporated off in vacuo and the solid residue is triturated in the cold with a 3% strength solution of citric acid, washed firmly with water and then again triturated with ethyl acetate and T.ther. The mixture is filtered and the solvent evaporated to dryness. After recrystallization from methanol, 135 g are obtained

4 ^ NH ₂ OBz

ί I

CBO-Pyr-Glu-Asp-Tyr-NH-NH-CBO

receive; Mp. 200 to 205 ^° C. An analytical sample has a melting point of 205 to 207 ^° C.; [aJS ⁷ = -28.3 * - (c = 1 in dimethylformamide).

Example 3

The preparation of the decapeptide (V) is carried out as described in Example 1, but takes place on

Place of the preparation of the intermediate pentapeptide (XI) from the tetrapeptide (X) the following: A

Solution of 8.47 g of CTB-GIy-ONP, 12.08 g,

H-Try-Met-Asp-Phe-NH ₂ -HQPQ

5.32 ml of triethylamine, 1.34 g of 1,2,4-triazo! and 0.2 ml of glacial acetic acid in 60 ml of dimethylformamide is left to stand at 28 ^° C. for 1 week.

The solution is filtered, concentrated in vacuo, Acidified in the cold with a saturated solution of citric acid and diluted with water. The resulting precipitate is washed and washed with

Ether rubbed; the mixture is filtered and alternated washed with ether and water. After 'recrystallization from methanol-ethyl acetate-ether will be 11.10 g

CTB - GIy - Try - Met - Asp - Phe - NH ₂ PCI)

obtained, m.p. 192 ° C (dec.). A recrystallized from dimethylformamide-ethyl acetate-ether analytical sample has a melting point of 196 ⁰ C. (Dec.); (Vj? = -27.3 ° (c = 1 in dimethylformamide). A suspension of 10.00 g

CTB - GIy - Try - Met - Asp - Phe - NH ₂

15th

in 120 ml of a 1.33 normal solution of hydrogen chloride in glacial acetic acid is stirred at 25 ° C. for 35 minutes. The solvent is evaporated in vacuo and the residue taken up with anhydrous ether, filtered and recrystallized from methanol-isopropanol. It will be 8.43 g

H - GIy - Try - Met - Asp - Phe - NH ₂ · HCl tion with the upper layer of the above-mentioned solvent system, 700 mg of the crude decapeptide (V) are obtained; Mp. 224-226 ⁰ C (dec.). The product thus obtained can be purified by chromatography.

pharmacology

The biological effectiveness of the products obtainable according to the invention and primarily the effectiveness on gastric secretion, gallbladder mobility, pancreatic secretions, and biliary secretion and the flow of arterial blood was determined. Those obtained in these attempts Results are given in the following tables, the effectiveness being one of the values according to the invention available products

Pyr-GIu (NH ₂ ) -Asp-Tyr (SO ₃ H) -Thr- * 31y- 1

■ - Try -

Try - Met - Asp - Phe - NH ₂ (V)

receive; M.p. 182-183 ° C (dec.); [α] "= -17 ° 25 set equal to 100 and weighted with the effective

(c = 1 in 95% acetic acid); E _{1 2} = 0.59 equality of the corresponding blocked decapeptide 0.55 Leu.

Example 4 Pyr-GIu (NH ₂ ) -Asp-Tyr (SO ₃ H) -Thr-

The preparation of the decapeptide V is carried out as described in Example 1, but the Replaced the step of making V from III with the following: 1 g

NH ₂ OAc

H-Pyr-Glu-Asp-Tyr-Thr

35 (OAc) -Gly-Tra-Met-Asp-Phe-NH ₂ (IV)

furthermore with the effectiveness of the human gastrin produced from the polypeptide

Pyr - GIy - Pro - Try - Leu - (GIu) ₅ - AIa

Gly-Try-Met-Asp-Phe-NH ₂ (III)

40

SO ₃ - - in 30 ml of anhydrous dimethylformamide, pyridine is g at -10 ⁰ C to 15.9 complex, suspended in 80 ml of anhydrous pyridine, is added. The mixture is left to stand overnight at room temperature and then evaporated to dryness in vacuo. The solid residue is dissolved in 150 ml of the lower layer of a mixture of n-butanol-ethanol-water (5: 1: 8) and the pH is adjusted to 3.2 with 1 n sodium hydroxide.

The mixture is extracted five times with 100 ml of the upper layer of the above mixture. the Extracts are evaporated in vacuo, the residue is taken up with chloroform. The mixture is filtered, the filtrate washed with chloroform and diethyl ether and then to dryness evaporated. It will be 900 mg

NH ₂ OSO ₃ HOAc

I Il

H-Pyr-Glu-Asp-Ty Thr

60

L-GIy-Try-Met-Asp-Phe-NH ₂ (IV)

receive. After weak alkaline hydrolysis of this product, followed by acidification and Extrak-L-Tyr - GIy - Try - Met - Asp - Phe - NH ₂

and with that of the gastrin-like synthetic pentapeptide (I.C.I. 50, 123)

CTB - β - Ala - Try - Met - Asp - Phe - NH ₂

is compared. This gastrin-like synthetic Pentapeptide is made by the britis'-h'-n company LCI. manufactured.

Its international name (English "generic name") is "Pentagastrin". I. C. I. has pentagastrin with brought the trademark Peptavlon® on the market (cf. "Merck Index" 8th edition, p. 793).

In particular, Table I shows the values corresponding to the following pharmacological activities.

Column I: Effectiveness on hydrochloric acid secretion:

It was assessed in vivo according to the increase in the volume of gastric juice and the strength of the acidity of the excreted juice is calculated. The products to be 'tested were in dogs and rats administered subcutaneously.

Spalteil: Effectiveness on gallbladder mobility:

It was made in situ on the gallbladder by sea piggy for intravenous administration of the products.

I 643

14th

Column III: Effectiveness on bile secretion:

It was determined by the increase in bile flow and the concentration of chelestones of bile in rats after intravenous administration of the Products.

Table I.

Column IV: Effectiveness on arterial blood flow:

It was determined by a flow meter placed in the pancreatic duodenal artery was after intravenous administration of the product to dogs.

links

Pyr - GIu (NH ₂ ) - Asp - Tyr (SO ₃ H) - Thr

GIy - Try - Mat - Asp - Phe - NH ₂ (V) ..
Pyr - GIu (NH ₂ ) - Asp - Tyr (SO ₃ H) - Thr

(OAc) - GIy - Try - Met - Asp

Phe - NH ₂ (IV)

Comparative substances:

human gastrin

CTB- / Ϊ-Ate-Try-Met-Asp-Phe-NH ₂

I hydrochloric acid secretion

dog

100

95

30th

RaUc

Il

Gallbladder

bcwcglichkcii

(Sea-

black)

100

III

Gallcnsckrcticm (Hall)

100

IV

Flow of

arterial blood

(Dog!

100

110

0.03
0.005

90

2
0.2

In Table II is the lowest active dose (MD) of the decapeptide

Pyr — GIu (NH ₂ ) -Asp — T; t (SO ₃ H) —Thr —Gly —Try — Met — Asp — Phe -N ⁵ H ₂ (V)
and that of the decopeptide

Pyr —GIu (NH ₂ ) -Asp —Tyr (SOjH) —Thr - (OAc) -GIy -Try - Met - Asp - Phe - Nh, (IV)
- determined in various tests - stated.

Table II

tries

Dekapeplid (VJ j Dckapcptid (IVj

ArI of the Vcrabreichuns

10Ong, lcg
ng / kg
0.0025 ng / ml

ng / kg

ng / kg

not determined!

Hydrochloric acid secretion from the stomach (dog)

Gastric hydrochloric acid secretion (rat)

Gastric secretion (frog)

External pancreatic secretion (dog)

External pancreatic secretion (cat)

Gallbladder mobility (guinea pigs)

Bile secretion (rat)

Vasodilation of the pancreatic duodenal part (dog) Decrease in arterial blood pressure (dog)

I ng = 0.001 ng.

_{The products obtainable according to the} invention can be used clinically in particular in the cholocystoraphy stimulation of the pancreatic and gastric secretion, in arterial hypertension and / or alkaline mixture of duodenal contents in the case of duodenal ulcers

The products can be administered orally or parenterally in the form of the compositions commonly used therapeutically administered.

3 ng / kg 2 ng, Tcg IO ng / kg 10 ng / kg 0.2 ng / kg 0.15 ng / kg 1000 ng / kg 870 ng / kg 4 ng / kg not determined 100 ng / kg Π0 ng, ks.

subcutaneous

intravenous

in vitro

intravenous

intravenous

intravenous

intravenous

intravenous

intravenous

Claims (1)

Patent claims: 1. Decapeptide L-pyroglutamyl-L-glutaminyl-L-aspartyl-L-tyrosyl-L-threonyl-glycyl-L-tryptophanyl -L -methionyl - L - aspartyl - L- phenylalanylamide, the phenolic group of the tyrosyl resle being free or blocked by a sulfuric acid residue and the alcohol group of the threonyl radical is free or blocked by an aliphatic acyl radical is, having 1 to 4 carbon atoms and its pharmaceutically acceptable salts.