JPH03294291A - Tetragastrin derivative and gastric acid secretion promoter - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is fatty acid residue or lower alkoxycarbonyl; Trp is tryptophan; Met is methionine; Asp is aspartic acid; Phe is phenylalanine). EXAMPLE:Lauroyltetragastrin. USE:A gastric acid secretion promoter. PREPARATION:(A) A compound expressed by formula II is reacted with (B) a compound expressed by the formula R<1>OR<2> (R<2> is activated carboxyl) in an inert solvent, e.g. dimethylformamide at -20 to +40 deg.C for 30min to 24hr. Furthermore, e. g. pentachlorophenol is preferably used as the component (B) in a molar amount of equimolar to 5 times based on the component (A).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel tetragastrin derivative and a gastric acid secretion promoter containing the same as an active ingredient.

Prior art and its problems Gastrin was described by Edkins at 19
Discovered and named in 2005, Gregory
It is a gastrointestinal hormone whose structure was determined by et al. in 1964, and it is a polypeptide consisting of 17 amino acids,
Promote gastric acid secretion, increase gastric blood flow, increase gastric motility,
It is known to have various physiological effects such as promoting bile and pancreatic secretion. From the C-terminus of this gastrin, 4
A peptide consisting of Trp-Met-
Asp-Phe-NH2 possesses all the physiological effects of gastrin, and tetragastrin is a physiologically active peptide in which the N-terminal amino group of this peptide is protected with a benzyloxycarbonyl group.

Tetragastrin has the potential to be used as a therapeutic agent for various diseases due to its unique physiological effects, but it has the inherent instability of peptide compounds, that is, the risk of being degraded by various enzymes in the gastrointestinal tract. It has fatal drawbacks as a pharmaceutical, such as difficulty in absorption from the gastrointestinal tract.

The purpose of the present invention is to eliminate the above-mentioned disadvantages of tetragastrin, to have good enteral absorption and excellent mucosal absorption, and to have the same effects as tetragastrin in promoting gastric juice secretion, increasing gastric blood flow, and promoting gastric motility. The object of the present invention is to provide a new compound having excellent pharmacological actions such as bile and pancreatic secretion promoting action, and a gastric acid secretion promoter using the same.

Means for Solving the Problems According to the present invention, the general formula % Formula % (1) (1) The general formula R1 represents a fatty acid residue or a lower alkoxycarbonyl group. ] A tetragastrin derivative represented by the following and a gastric acid secretion promoter containing the derivative as an active ingredient are provided.

In this specification, when amino acids, peptides, active groups, etc. are expressed by abbreviations, rUPAc, IUB
The following are examples. In addition, when optical isomers are possible for amino acids, etc., the L-isomer is shown unless otherwise specified.

Asp...aspartic acid? '(et...Methionine Trp...Tryptophan Phe...Phenylalanine Boc...tert-butoxycarbonyl group O3u
...N-hydroxysuccinimide ester The compound of the present invention represented by the above general formula (1) of the basic invention is:
Unlike tetragastrin, it is broken down in the gastrointestinal tract and has excellent absorption through the intestine (small intestine, rectum) and mucous membranes such as the nasal mucosa and oral mucosa. Moreover, the compound of the present invention is
It exhibits excellent effects on promoting gastric juice secretion, increasing gastric blood flow, promoting gastric motility, and promoting bile and pancreatic juice secretion. Therefore, the compound can be clinically applied to the treatment of atrophic gastritis, achlorhydria, hypochlorhydria, achlorhydria associated with gastric cancer, etc. by oral administration, suppository administration, nasal spray administration, etc. It can exert remarkable effects as an appetite stimulant, a digestive stimulant, a bile and pancreatic juice secretion promoter, etc. The compound of the present invention is also useful as an auxiliary agent that can be administered together with an anticancer agent to allow the anticancer agent to reach the affected area efficiently and to reduce its side effects.

In addition, the compounds of the present invention have the characteristics that the various pharmacological actions described above last long and have low toxicity and side effects, and from this point of view as well, they are particularly preferred as the various pharmaceuticals described above.

In the present specification, the fatty acid residue represented by R1 in the above general formula (1) includes a linear or branched saturated or unsaturated (having a double bond) fatty acid having 2 to 20 carbon atoms. Residues are included. Specific examples include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, hexanoyl group, pivaloyl group, lauroyl group, myristoyl group, valmitoyl group, stearoyl group, arachitonoyl group, acryloyl group, methacryloyl group. Examples thereof include oleyl group, lyloyl group, lynoyl group, and the like. Among these, especially those with carbon number of 5~
Those having 20 carbon atoms are preferred, and those having 5 to 8 carbon atoms are most preferred.

In the opening formula (1), the lower alkoxycarbonyl group represented by R1 includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group.
Examples include alkoxycarbonyl groups having a straight or branched alkoxy group having 1 to 6 carbon atoms, such as a -butoxycarbonyl group, a pentyloxycarbonyl group, and a hexyloxycarbonyl group.

The compounds of the present invention can be produced by various methods. Specific examples thereof will be described in detail below with reference to reaction process formulas.

[Reaction process formula]

RI-NH-Trp-Met-Asp-Phe-NH2
(1) [In each formula, R+ is the same as above. R2 represents an activated carboxyl group. ] The compound (3) having an activated carboxyl group represented by R2 includes the corresponding carboxylic acid halide,
In addition to anhydrides, azides, etc., the carboxylic acids and, for example, pentachlorophenol, p-nitrophenol, N-hydroxysuccinimide, N-hydroxybenztriazole, N-hydroxy-5-norbornene-2,3-dicarboximide Active esters with etc. are included. However, when using an acid halide, the above reaction is preferably carried out in the presence of a deoxidizing agent, and the deoxidizing agent can be various basic compounds commonly used, such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, Carbonates such as sodium hydrogen carbonate, tertiary amines such as triethylamine, tripropylamine, pyridine, and quinoline, etc. can be used.

The reaction between compound (2) and compound (3) can generally be carried out in a suitable inert solvent. The inert solvents used here include various ones commonly used in this type of peptide bond forming reaction, such as dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).
, pyridine, dioxane, tetrahydrofuran (TH
F), ethyl acetate, N-methylpyrrolidone, hexamethylphosphoric acid triamide (HMPA), etc., and mixed solvents thereof can be exemplified.

Although there is no particular limitation on the proportion of each raw material compound used in the above reaction, it is generally preferred to use at least an equimolar amount of compound (3) to compound (2), preferably an equimolar amount to about 5 times the molar amount of compound (2). good.

The reaction temperature may be within the range commonly used for peptide bond-forming reactions, and is generally selected from the range of about -40°C to about 80°C, preferably about -20°C to about 40°C. The reaction time can generally be appropriately selected from the range of about 30 minutes to about 24 hours.

Thus, the tetragastrin derivative represented by the general formula (1) of the present invention can be produced by the method shown in the above reaction scheme.

After the completion of the above reaction, the derivative can be separated and purified from within the reaction system by conventional peptide separation methods such as extraction, partitioning, column chromatography, etc.

When the tetragastrin derivative of the present invention is used as a pharmaceutical, it is formulated into a general pharmaceutical composition using various commonly used carriers. Examples of the pharmaceutical carrier include commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants, depending on the form of use of the pharmaceutical preparation. These are appropriately selected and used depending on the dosage unit form of the resulting preparation.

As the dosage unit form of the above-mentioned pharmaceutical preparation of the drug of the present invention, various forms can be selected depending on the therapeutic purpose, and representative examples thereof include tablets, pre-divided tablets, powders, solutions, suspensions, emulsions, and granules. , capsules, skewers, oral mucosa-adhesive preparations (lozenges, buccal tablets, sublingual tablets, chewing agents, drop tablets, etc.), injections (solutions, suspensions, etc.), nasal sprays, ointments, etc. Can be mentioned. When forming into a tablet form, the above-mentioned pharmaceutical carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, potassium phosphate, water, and ethanol. , propatool, simple syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, dried starch, Disintegrants such as sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, white sugar, stearin, cocoa butter, hydrogenation Disintegration inhibitors such as oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, purified talc, Lubricants such as stearate, boric acid powder, polyethylene glycol, etc. can be used. Furthermore, tablets may be coated with conventional coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets,
They can be film-coated tablets, double tablets, or multilayer tablets. When forming into an emulsion, pharmaceutical carriers include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and laminaran. , agar, etc. can be used.

When forming into a half-split form, for example, polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride, etc. can be used as a pharmaceutical carrier. Capsules are usually prepared by mixing the active ingredient compound of the present invention with the various pharmaceutical carriers exemplified above and filling them into hard gelatin capsules, soft capsules, etc. according to a conventional method. When the drug of the present invention is prepared as an injection such as a solution, emulsion, or suspension, it is preferable that the drug is sterilized and isotonic with blood. For example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In this case, a sufficient amount of salt, glucose or glycerin to adjust the isotonic solution may be included in the drug of the present invention, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You may. Furthermore, the drug of the present invention may contain coloring agents, preservatives, fragrances,
Flavoring agents, sweeteners, etc. and other pharmaceuticals may also be included. When forming into an ointment such as a paste, cream, or gel, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. can be used as a diluent. Nasal drops and oral mucosa-adhesive preparations are prepared in powder form, aerosol form, liquid form, etc. suitable for atomization, jetting, spray administration, etc. using appropriate binders, diluents, propellants, etc. in accordance with conventional methods. prepared. For the preparation of the above powder form,
For example, it is appropriate to use water-absorbing base materials such as celluloses, starches, and polyacrylates; water, glycols, alcohols, nonionic surfactants, etc. are suitable for preparing aerosol formulations. Good to use. Formulations in the form of spray propellants can also be prepared using commonly used propellants (liquefied propellants) such as liquefied petroleum gas, carbon dioxide, fluorinated lower alkanes, and the like.

The amount of the tetragastrin derivative of the present invention represented by general formula (1) to be contained in a pharmaceutical formulation is not particularly limited and is appropriately selected from a wide range, but usually about 1μ
It is preferable that the content be about 20 g to 20 g.

The method of administering the above pharmaceutical preparation is not particularly limited and is determined depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, emulsions, solutions, suspensions, emulsions, granules, and capsules are administered orally; injections are administered intravenously alone or mixed with normal replenishing fluids such as glucose and amino acids, and as needed. Intramuscular, sarcastic, alone
It is administered subcutaneously or intraperitoneally, and the skewer is administered rectally.

Nasal drops are administered into the nasal cavity by inhalation or the like, and oral mucosa-adhesive preparations are administered to the oral mucosa.

The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, patient's age, sex and other conditions, degree of disease, etc.
Usually, the amount of the compound of the present invention, which is an active ingredient, is 1 body weight per day.
The amount per kg is preferably about 3 μg to 5 μg for injections, and about 50 μg to 1 μg for other routes, and the preparation can be administered in 1 to 4 divided doses per day.

EXAMPLES Hereinafter, in order to explain the present invention in more detail, production examples of raw material compounds for producing the tetragastrin derivatives of the present invention will be listed as reference examples, and then production examples of the derivatives of the present invention will be listed as examples. Furthermore, examples of pharmacological tests conducted on the derivatives of the present invention are listed below.

Reference example 1 Synthesis of lauroyl-03u 49.9 mmol of lauric acid was mixed with 150 yA' of ethyl acetate.
and perform thin layer chromatography (TLC). 54.9 mmol of N-hydroxysuccinimide ester was added, and 59.9 mmol of dicyclohexylcarbodiimide (DCC) was added while cooling with water, followed by stirring overnight.

Confirm the reaction with TLC and find that chloroform:methanol:water=
Using a developing solvent of 8:3:1, cerium sulfate]
After that, the precipitate was removed, and the solvent ethyl acetate was distilled off to concentrate. Thereafter, the concentrate was made into a powder using a small amount of ethanol, which was again dissolved in ethyl acetate and recrystallized from ethanol.

The above yielded 3.32 g of the target compound (yield 22.36%).
I got it.

Example 1 Lauroyl-HN-Trp-Met-Asp-Phe-
Synthesis of NH2[lauroyltetragastrinco Tp'A, Trp-Met-Asp-P
35 mmol of he-NH2Q, Q was dissolved in DMF, and 0.142 mmol of triethylamine was added to it.
mmol of lauroyl-03u was added, TLc was performed, and then 0.5 mmol of lauroyl-03u was added under water cooling. Add 142 mmol, 3~
Stirred for 4 hours. After stirring, the reaction was confirmed by TLC [confirmed by UV using a developing solvent of chloroform:methanol:water=8:3:1, and then DMF was distilled off and concentrated. The concentrated solution was made into a powder using a small amount of methanol, which was again dissolved in DMF, concentrated, and recrystallized from ethyl acetate.

As a result of the above, the target compound 6.20μ (yield 22.37%)
I got it.

Melting point = 242-243℃ (decomposition) Amino acid analysis value (N-terminal amino acid Phe is set as 1) T
rp O, 852 Met O, 848 Asp O, 99
45 The compound obtained above was subjected to HPL under the following conditions.
I did C.

[HPLC conditions] Column: AM-3023-5120A ODS (YM
(manufactured by Company C), 4.6mmX150m Eluent A:Q, 1%
TFA Eluent B Niacetonitrile Flow rate: 0.7zA'/min Concentration gradient 2 Time (min) A% 8%0.0 8
0 20 5.0 80 20 35.0 0100 40.0 01.00 45.0 80 20 As a result, the target compound had a retention time of 30.72
It was eluted in minutes.

Example 2 HexaJ, 1' LuHN-Trp-Met-Asp
-Phe-NH2[Synthesis of hexanoyltetragastrinco T)' A, Trp-Met-Asp-Phe-N
Dissolve 34 mmol of H2O, Q in DMF, add 0.034 mmol of N-methylmorpholine, and dissolve T
After performing LC, caproic anhydride 0.0 was added under water cooling.
41 mmol was added and stirred for 1.5 hours. After stirring, T
Confirm the reaction by LC [chloroform:methanol:water=
After confirmation by UV using a developing solvent of 8:3:1, DMF was distilled off and concentrated. Fe25 concentrate
It was powdered with Oa-containing ether.

As a result of the above, 20.28 cm of the target compound (yield 85.35%) was obtained.
) was obtained.

Melting point: 228-230℃ (decomposition) Amino acid analysis value (N-terminal amino acid Phe is set as 1) T
rp O,873Met O,909Asp 0.99
6. The compound obtained above was subjected to HPLC under the same conditions as in Example 1, and as a result, the target compound was eluted at a retention time of 1.21.16 minutes.

Example 3 13oc-HN-Trp-Met-Asp-Phe-N
Synthesis of H2[Boc-7 Tracastrinco TFA-Trp-Aet-Asp-Phe-N
u20. Q 9 3 Mi 17 moles in DMF
TLC was performed by adding 0.093 mmol of triethylamine under water cooling, and then (Boc
0.115 mmol of )20 was added and stirred overnight. After stirring, the reaction was confirmed by TLC [confirmed by UV using a developing solvent of chloroform: methanol: water = 8:3:1, and then concentrated by distilling off DMF, and the concentrated liquid was diluted with Fe2SO
It was made into a powder with 4-containing ether.

As a result of the above, the target compound 51.20μ (yield 79.10%)
) was obtained.

Melting point = 204-206°C (decomposition) Amino acid analysis value (N-terminal amino acid Phe is set as 1) T
rp O, 886 Met O, 904 Asp O, 97
7. The compound obtained above was subjected to HPLC under the same conditions as in Example 1, and as a result, the target compound was eluted at a retention time of 21.61 minutes.

Example 4 Acetyl-HN-Trp-Met-Asp-Phe-N
Synthesis of H2[7cetyltetragastrin] TFA, Trp-Met-Asp-Ph
e-NH2Q, Q34 mmol was dissolved in DMF, and 0.03 mmol of N-methylmorpholine was added to this.
4 mmol was added, and further 0.041 mmol of acetic anhydride was added under water cooling, and after stirring for 1.5 hours, the reaction was confirmed by TLC [chloroform: methanol: water = 8: 3:
After confirming by UV using the developing solvent of No. 1], DMF was distilled off and concentrated, and the concentrated solution was made into a powder with ether containing F and e2SO4.

This was applied to a reverse phase column [manufactured by YMC, AQS-50°180
The initial condition was 40% CH3 using the FPLC device.
Flow rate of CN flow3. Ozl! /min), 80% in 5 hours
It was purified to CH3CN.

The target compound was thus obtained.

Melting point: 220-222°C (decomposition) Amino acid analysis value (N-terminal amino acid Phe is set as 1) T
rp O, 886 Met O, 901 Asp O, 98
5. The compound obtained above was subjected to HPLC under the same conditions as in Example 1, and as a result, the target compound was eluted at a retention time of 16.38 minutes.

<Biological activity test> ■ Gastric acid secretion promoting effect test Wistar rats weighing 200 to 350 g were
After fasting for 4 hours, urethane 1. Anesthetize by intraperitoneal administration of 5 g/kg. Hair is removed from the abdomen, an incision is made along the midline to the area above the xiphoid bone, and a small hole is made in the forestomach and a cannula is inserted. Also, a small hole is made from the pylorus to the duodenal side and a cannula is inserted.

The cannula on the forestomach side is connected to a water pump, and saline is refluxed into the stomach for irrigation. After washing, use an automatic titrator.
, Hiranuma Comtite-7,) Titrate with 1/10N Na0[I, and leave until the amount of acid secretion becomes constant.

Thirty minutes after the amount of acid secretion stabilizes, the thigh is incised, and 1.284×7 10 mol/kg of the test drug solution is administered through the femoral vein, and the amount of acid secreted is measured.

The test drug solution was 1.284X10-6 test drug.
Mol/dimethylacetamide 53FA'+propylene glycol 5xl was used.

The results of the above test are shown in FIG.

The reading chart shows time (minutes) on the horizontal axis and acid secretion amount (μ equivalent 15) on the vertical axis.
The results are shown in a graph using the tetragastrin derivatives of the present invention obtained in each of the above examples and tetragastrin as a control as test drugs, respectively.
In the figure, (1) is hexanoyltetragastrin of the present invention, (2) is Boc-tetragastrin, (3) is lauroyl-tetragastrin, (4) is tetragastrin as a control, and (5) is indicates the control (no test drug added). The results for each test drug are shown in FIG. 1 above as the average values of 5 to 6 test animals in each group.

As shown in FIG. 1 above, when the tetragastrin derivatives of the present invention are used, a significant amount of gastric acid secretion is observed compared to the control, and from this, each of these derivatives has an excellent gastric acid secretion promoting effect. It is clear to show.

■ Small intestine absorption test For the tetragastrin derivative of the present invention and tetragastrin as a control, the absorption of each drug in the small intestine was determined.
The following tests were conducted using gastric juice secretion activity as an index.

1) Preparation of drug solution a Preparation of emulsion I Test drug 64% per kg of rat body weight. 2x7 10 mol was dissolved in 10 μl of dimethylacetamide, and 50 μl of glycerol-α-monooleate/(5
v/v%) and olive oil 50 μm (5v/v%) to prepare a drug solution. Separately, polyoxyethylene hydrogenated castor oil [HCO60, manufactured by Nikko Kamical Co., Ltd.] 20■ (2
w/v%) and (-) PBS 890μ! The drug solution prepared above was added to this solution, and the solution was sonicated [with an ultrasonic homogenizer (Sonicator) at 30 to 40 W for 1 hour.
5 minutes] to prepare emulsion I.

b. Preparation of emulsion
v/v%) and 50ttl of olive oil! (5v/v%)
Add to prepare a drug solution. Separately, polyoxyethylene hydrogenated castor oil [HCO60, manufactured by Nikko Riki Mikar Co., Ltd.] 1
0■ (1%4/v%) and his sugar ester LWA-1
570 [manufactured by Mitsubishi Kasei Co., Ltd. (-)] 10 μl was weighed, dissolved in 890 μl of PBS, the drug solution prepared above was added to this solution, and the solution was sonicated [using an ultrasonic homogenizer (Sonicator)].
1. : Prepare emulsion ① at 30 to 40 W for 15 minutes.

Preparation of 2% Sugar Ester Solution 64.2X = 7 10 mol of test drug per kg of rat body weight and 20 mol of sugar ester LWA1540
(1) is dissolved in dimethylacetamide 2-311, concentrated (using an evaporator) (-), and added to 1000 μl of PBS to prepare a 2% sugar ester solution.

2) Measurement of gastric juice secretion by small intestine administration fn 5 itu 1 loop method [J, Pharm, S
ci, 59.154 (1970)], each of the test drug solutions prepared above was prepared at a test drug concentration of 64.
．． The drug was administered to the small intestine of Wistar rats, 58 weeks old, male, weighing 200 to 300 g, at a concentration of 2×10 mol/kg (drug solution placement 1z/kg).

Before the above administration, the test animals were prevented from eating feces and fasted for 24 hours, and the animals were anesthetized, had their abdominal hair removed, had abdominal incisions, and had a cannula inserted in the same way as in the gastric acid secretion promoting effect test in ① above, and the animals were removed from the duodenum. Ligate the lower part of the cannula, and also
Surgery was performed to ligate approximately 3 ann (however, the bile duct was not ligated).

Said 1. Similar to the gastric acid secretion promoting effect test, the cannula on the forestomach side is connected to a water pump, the saline solution is refluxed into the stomach for irrigation, and then an automatic titrator is used.
The mixture was titrated with 1/ION NaOH and left for about 30 minutes until the amount of acid secreted became constant, and the amount of acid secreted was measured.

The obtained results are shown in FIGS. 2 to 4 in the same manner as in FIG. 1.

Figure 2 shows the results using Emulsion I, Figure 3 shows the results using Emulsion ■, and Figure 4 shows the results using 2% sugar ester solution. In each figure, (1) is the result of using Emulsion I. Hexanoyltetragastrin, (2) shows tetragastrin as a control, and (3) shows control (no drug added). In addition, the results in each figure are shown as mean+s, E, and M for 4 to 6 test animals in each test drug administration group (however, 2 animals in Figure 3), and each figure shows tetragastrin as a control. Significant differences are indicated by the marks below.

*: p<0.05 $ book + p<0. 01US
:p<0.001 From Figures 2 to 4 above, the tetragastrin derivative of the present invention (hexanoyltetragastrin), when administered to the small intestine, significantly inhibits gastric acid secretion in any drug solution form than the control tetragastrin. It is clear that the amount can be increased.

Also, 100% from the start of the test shown in each figure above.
minutes (however, in the case of the test shown in Figure 4, up to 90 minutes)
The results of determining the total gastric acid secretion amount (μ equivalent) are shown in Table 1 below.

No. table From Table 1 above, Tetragastrin of the present invention The derivative is Exhibits excellent gastric acid secretion promoting activity is clear.

Moreover, FIG. 5 is a graph comparing the administration results of the tetragastrin derivative of the present invention (hexanoyltetragastrin) in each test drug liquid form shown in FIGS. 2 to 4 above.

In the figure, (1) indicates administration in the form of an emulsion.
(2) is administered in the form of an emulsion, and (3) is 2%
Administration in sugar ester solution form is shown in each case.

From the figure, it can be seen that the tetragastrin derivative of the present invention exhibits the most excellent gastric acid secretion promoting activity when used in the form of emulsion I.

[Brief explanation of drawings]

FIG. 1 is a graph showing the results of a gastric acid secretion promoting effect test conducted on the tetragastrin derivative of the present invention. Figures 2 to 4 are graphs showing the results of small intestine absorption tests conducted on the tetragastrin derivatives of the present invention. FIG. 5 is a graph comparing the gastric acid secretion promoting activity of the tetragastrin derivative of the present invention in various administration forms. (that's all)

Claims (2)

[Claims] (1) General formula R^1-NH-Trp-Met-Asp-Phe-NH
_2 [In the formula, R^1 represents a fatty acid residue or a lower alkoxycarbonyl group. ] A tetragastrin derivative represented by (2) A gastric acid secretion promoter containing the tetragastrin derivative according to claim (1) as an active ingredient.