WO2002014310A1

WO2002014310A1 - 2-[5-AMINO-6-OXO-2-PHENYL-1,6-DIHYDRO-1-PYRIMIDYL]-N-[1-(2-[5-t-BUTYL-1,3,4-OXADIAZOLYL]CARBONYL)-2-(R,S)-METHYLPROPYL]ACETAMIDE HYDROCHLORIDE

Info

Publication number: WO2002014310A1
Application number: PCT/JP2001/006859
Authority: WO
Inventors: Tsutomu Kojima; Takanori Okada; Kazuyuki Ohmoto
Original assignee: Ono Pharmaceutical Co., Ltd.
Priority date: 2000-08-10
Filing date: 2001-08-09
Publication date: 2002-02-21
Also published as: JPWO2002014310A1; AU2001277736A1

Abstract

2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidyl]-N-[1-(2-[5-t-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide hydrochloride (I). This compound is useful as drug (elastase inhibitor).

Description

2- [5-Amino-6-oxo-1-phenyl-1-, 6-dihydro-1-pyrimidyl] — N— [1-1 (2- [5-t-butyl-1,3,4-oxaziazolyl] potulponyl 1) 2- (R, S) -methylpropyl] acetamide 'hydrochloride compound

The present invention relates to a novel 2- [5-amino-6-oxo_2-phenyl-1,6-dihydro-1-pyrimidyl] -N- [1-1 (2- [5-t-butyl- 1,3 4-Oxadiazolyl] carbonyl) 1- (R, S) -methylpropyl] acetamide hydrochloride. For more information,

(1) Equation (I)

2- [5-Amino-6-oxo-1-2-phenyl-1,6-dihydroxy-1-pyrimidyl] -1-N- [1- (2- (5-t-butyl-1,3,4-oxaziazolyl) Carbonyl) —2— (R, S) monomethylpropyl] acetamide hydrochloride,

(2) its production method, and

(3) It relates to drugs containing them as an active ingredient. Background art 2 _ [. 5-Amino-6-oxo-1-2-phenyl-1,6-dihydric mouth-1-pyrimidyl] -1-N- [1- (2- [5-t-butyl-1,3,4) of the present invention -Oxaziazolyl] caprolponyl) -1- (R, S) -methylpropyl] acetamide 'hydrochloride is a novel compound and a compound useful as a pharmaceutical. Already, in Example 113 of WO98 / 24806, the compound of the present invention (formula

It is disclosed that a compound represented by the formula (II) (see below) which is a free form of (compound (I)) is useful as a serine protease (especially, elastase) inhibitor. The above specification also generally describes pharmaceutically acceptable salts.

The present inventors have prepared the formula according to the method described in Example 113 of WO98 / 24806.

When the compound represented by (II) was produced, it was found that the obtained compound did not have a single crystal form. In addition, it was very difficult for the compound thus obtained to completely remove impurities such as a solvent and to obtain a compound having exactly the same shape with good reproducibility.

In other words, it is extremely difficult to supply a compound obtained by the method described in the specification of TO98 / 24806 as a stable drug substance that always maintains the same quality, which is important for practical use as a drug. He had disabilities. Therefore, a crystal of the compound represented by the formula (II) which constantly maintains the same quality and is a stable drug substance has been desired. Summary of the Invention

The present inventors have achieved various acid addition salts of the compound represented by the formula (II), namely, hydrochloride, sulfate, methanesulfonate, and p-toluenesulfonate in order to achieve the above object. Upon close examination, only the hydrochloride gave crystals, and sulfate, methanesulfonate, and p-toluenesulfonate formed solids, but did not become crystals. Also, sulfate, methanesulfonate, p -Toluenesulfonate contains impurities and was found to be unsuitable for use as a drug substance.

In addition, 2- [5-amino-6-oxo-1-2-phenyl-1,6-dihydro-1-pyrimidyl] —N— [1— (2— [5—t_butyl—1,3,4-oxaziazolyl ] Capillonyl) 1-2-((R, S) monomethylpropyl] acetamide was dissolved in ethanol by heating, and the precipitated crystals were analyzed by adding an ethanol solution of maleic acid, lactic acid, malic acid, tartaric acid or phosphoric acid. Surprisingly, however, they are all free, and the desired acid adduct salts cannot be obtained, and no salts are formed for maleate, lactate, malate, tartrate, and phosphate. It has been found.

That is, 2- [5-amino-6-oxo-1_2_fueneru 1,6-dihydro-1_pyrimidyl] represented by the formula (I) — N— [1— (2— [5-t-butyl- The present invention has been completed by confirming that only 1,3,4-oxadazolyl] caprolponyl) -2-((R, S) -methylpropyl] acetamide gives stable crystals.

W098 / 24806 states that substituted oxaziazole, thiadiazol and triazole derivatives may generally form pharmaceutically acceptable salts, but the specific compound 2- [ 5-Amino-6-oxo-1 2 -phenyl-1,6-dihydro-1 -pyrimidyl] 1 N-[1-(2-[5-1 t -butyl-1,3,4-oxadiazolyl] porponyl) 1 2- The hydrochloride (compound of the formula (I)) of (R, S) -methylpropyl] acetoamide is not specifically described, and the hydrochloride compound of the formula (I) is a novel compound not described in the literature. It is.

The impurities contained in the novel hydrochloride compound can be completely removed, and the hydrochloride compound has good solubility in water, and has a very high blood concentration when administered orally to animals. Was. In other words, this novel hydrochloride compound always has the same quality, has a crystal form that can be supplied as a stable drug substance, has good solubility in water, is easy to handle, and has a high blood level when orally administered to animals. It has very high concentrations and is a very good pharmacological compound. Disclosure of the invention

The present invention

(1) Equation (I)

2- [5-amino-6-oxo-1 2-phenyl-1,6-dihydro-1-pyrimidyl] 1 Ν— [1-(2-[5-t-butyl-1,3,4- Oxadiazolyl] carbonyl) 1- (R, S) -methylpropyl] acetamide hydrochloride compound,

(2) their production method, and

(3) It relates to drugs containing them as an active ingredient. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows 2- [5-amino-6-oxo-12-phenyl-1,6-dihydro-1-pyrimidyl] —N— [1— (2— [5—t—butyl-1,3,4- 1 is a powder X-ray diffraction spectrum of (oxdiazazolyl) carbonyl) 12- (R, S) -methylpropyl] acetamide.hydrochloride (compound of the present invention).

Figure 2 shows the results of 2- [5-amino-6-oxo-1-2-phenyl-1,6-dihydride Rho 1-Pyrimidyl] — N— [1-1 (2- [5-tert-butyl-1,3,4-oxadizazolyl] caprolponyl) -1-2- (R, S) -methylpropyl] acetamide * Hydrochloride 3 is a thermogravimetric analysis chart of DSC of the invention compound). Detailed description of the invention

[Method for producing the compound of the present invention]

The compound of the present invention represented by the formula (I) can be produced by the following methods or the methods described in Examples.

That is, Equation (1)

The compound of the present invention represented by the formula (II)

2- [5-amino-1 6-oxo-1 2-phenyl-1,6-dihydro 1-pyrimidyl] represented by the following formula: Ν— [1— (2-[5-t-butyl-1,3,4-oxadiazolyl] [Ruponyl) -12- (R, S) -methylpropyl] acetamide in an organic solvent and a hydrochloric acid-containing organic solvent.

This reaction is known and includes, for example, organic solvents (ethanol, methanol, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, The reaction is carried out at a temperature of 0 to 50 ° C with an organic solvent containing hydrochloric acid (hydrochloric acid / ethyl acetate solution, nodioxane hydrochloride solution, noethanol hydrochloride solution, methanol solution of hydrochloric acid, etc.). BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail by reference examples and examples, but the present invention is not limited thereto.

The solvent in kakkou indicated by TLC at the point of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. The solvent in kakkoko shown at the NMR indicates the solvent used for the measurement. Example 1: 2- [5-amino-6-oxo-1-2-phenyl-1,6-dihydro-11-pyrimidyl] -1-N- [1-1 (2- [5-t-butyl-1,3,4 Process for the production of 1- (R, S) -methylpropyl] acetamide hydrochloride

2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-11-pyrimidyl] — N— [1— (2- [5-t-butyl-1,3,4-oxadiazolyl] caprolupnyl) To a suspension of 2-((R, S) monomethylpropyl] acetoamide (4.2 kg) in ethanol (i8.69 L) was added a 4 mol / L hydrochloric acid / ethyl acetate solution (2.32 L) under an argon atmosphere. Reaction mixture at 30 ° C 3 Stirred for 0 minutes. After confirming that all solids were dissolved, the reaction mixture was filtered and washed with ethanol (0.42 L). Cool the filtrate to 20 ° C and seed

(2.1 g) was added, followed by stirring for 4 hours. The precipitated crystals were filtered with a centrifuge while being dispersed in cold ethanol (1.0 L), and further washed twice with cold ethanol (3.0 L). The obtained crystals were vacuum-dried at room temperature for 16 hours, and further vacuum-dried at 60 ° C. for 15 hours to give the compound of the present invention (3.647 kg) having the following physical data.

TLC: R f 0.41 (cloth form: methanol: water = 100: 10: 1);

_{_{NMR (CDC1 3 + CD 3 0D}} ): 8.31 (d, J = 7.6 Hz, 1H), 7.76-7.50 On, 6H), 5.39-5.26 (m, 1H), 4.79 (brs, 2H), 2.60-2.34 ( m, 1H), 1.47 (s, 9H), 1.03 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H);

I R (KBr): v 3352, 3265, 2975, 2503, 1690, 1649, 1543, 1389, 1332, 1252, 1177, 1038, 897 cm.

When the compound of the present invention obtained as described above was analyzed by high performance liquid chromatography (HPL C), the purity was 97.7%. An analysis by gas chromatography revealed that 0.29% of ethanol remained.

Furthermore, analysis by ion chromatography revealed that chloride ion was contained at 6.97% by mass (96. lmo 1%).

The crystals of the compound of the present invention obtained as described above were subjected to measurement of powder X-ray diffraction spectrum under the following conditions and thermogravimetric analysis using a differential scanning calorimeter (DSC). The results are shown in FIGS. 1 and 2.

(1) Powder X-ray diffraction spectrum

Equipment: Powder X-ray diffractometer RAD-2C, manufactured by Rigaku Denki

Evening: Cu,

Phil Yuichi: Do not use, Voltage: 40KV,

Current: 20mA,

Scan speed: 2.0 ° / min

(2) Thermogravimetric analysis by DSC

Equipment: Shimadzu. DSC-50,

Sample size: .52mg,

Sample cell aluminum cell,

Nitrogen gas flow rate: ZOmLZmin,

Heating rate: 10 ° CZmin. Reference Example 1: Examination of various acid adduct salts (1)

2- [5-amino-1 6-oxo-1 2-phenyl-1,6-dihydro-11-pyrimidyl] -1-N- [1-1 (2- [5-t-butyl-1,3,4-oxadiazolyl] caproluponyl ) -2- (R, S) -Methylpropyl] acetoamide

The following various acids were added to a suspension of (2 g) in ethanol (9 ml). The suspension became a solution by the addition of the acid. Further, ethyl acetate (1 mL) was added to the solution, and the reaction mixture was stirred at room temperature for 2 to 3 hours. When crystals precipitated, they were filtered and dried. The solution that did not precipitate crystals was concentrated and dried. Table 1 shows the obtained results.

After drying in the reaction solution Hydrochloric acid z Ethyl acetate Crystal precipitation Sulfuric acid No crystal precipitation Solid methanesulfonic acid No crystal precipitation Solid Solid Toluenesulfonic acid No crystal precipitation Solid As shown in Table 1, sulfates other than hydrochloride, methanesulfonate No crystals were obtained for ρ-toluenesulfonate. The solids obtained after concentration of these were analyzed by —NMR, and found to form their respective salts, but contained large amounts of ethanol and ethyl acetate as impurities. Reference Example 2: Examination of various acid adduct salts (2)

2- [5-Amino-6-oxo-1-2-phenyl-1,6-dihydro-1-pyrimidyl] —N— [1-1 (2- [5-t-butyl-1,3,4-oxadiazolyl]] A suspension of (carbonyl) -12- (R, S) -methylpropyl] acetoamide (452 mg) in ethanol (8-9 ml) was heated to 70 ^ to dissolve it. To this solution, solutions of various organic acids in ethanol (1-2 mL) were added so that the total amount of ethanol became 1 OmL. After adding various organic acids, the reaction mixture was stirred at room temperature for 2 to 3 hours, and the precipitated solid was filtered and dried. Table 2 shows the results. Table 2

As is evident from Table 2, solids were obtained for maleate, lactate, malate, tartrate and phosphate, but — as a result of NMR analysis, they were all free. This indicates that maleate, lactate, malate, tartrate, and phosphate do not form salts. Experimental Example 1: Solubility of the compound of the present invention represented by the formula (I) in various solvents 10 Omg or more of the compound of the present invention was weighed out, and 1 mL of the various solvents was added. This mixture was stirred for 30 seconds using a Labo mixer and allowed to stand for 4 minutes and 30 seconds. This operation of stirring and standing was repeated seven times. During this operation, if the crystals were completely dissolved, the compound of the present invention was further added, and the mixture was stirred for 5 minutes. The supernatant was filtered with a 0.5 n filter using a centrifuge (3000 rpm, 2 minutes). 0.5 mL of the filtrate was taken, and the solvent was distilled off. However, when the solvent could not be distilled off, it was not distilled off. Acetonitrile was added to the obtained sample to dilute it in a concentration range of 0.2 mg / mL to 0.002 mg ZmL. The concentration of 10 L of this solution was determined by the absolute calibration curve method using high performance liquid chromatography (HPLC) under the following conditions, and the solubility was calculated. In this case, calibration curves were prepared for the compound of the present invention in acetonitrile at three concentrations of 0.2 mgZmL, 0.05 mg / mL, and 0.002 mgZmL. Measurement results See Table 3.

HP LC measurement conditions:

Column: CAPCELLPAK C8 UG120 (4.6mmi.d. X 150mm, No. ΒΟΑΒΙΟί 3), Temperature: 25 ° C,

Eluent: 20mmo 1 ZL aqueous solution of potassium dihydrogen phosphate (pH 8.0, sodium hydroxide) Zacetonitrile = 65Z35,

Flow rate: 1.0 mL / min,

UV: 235 nm.

Experimental Example 2: Stability of the compound of the present invention represented by the formula (I) (1)

Dissolve the compound of the present invention (20 mg) in ethanol (1 mL), and add 40 and 6 Stability at 0 ° C was measured using high performance liquid chromatography (HPL C) under the following conditions. Table 4 shows the results.

HP LC measurement conditions:

Column: CAPCELLPAK C8 UG120 (4.6jnmi. D. X 150mm, No. BOAB1013), Temperature: 25 ° C,

Eluent: 2 Ommo 1 ZL potassium dihydrogen phosphate aqueous solution (pH 8.0, sodium hydroxide) Noacetonitrile = 65/35,

Flow rate: 1.0mLZ min,

UV: 235 nm.

Table 4

Temperature

Time (hr)

0

1

Two

Four

6

Experimental Example 3: Blood concentration in oral administration

In a non-fasting Crj CD (SD) IGS male or female rat (6 weeks old), the compound of the present invention represented by the formula (I) was suspended in a 0.5% methylcellulose solution. Was administered by gavage in the stomach. From the rat jugular vein at 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after administration Bled, then centrifuged 20 min at 3000 r _P m, to obtain plasma. After deproteinizing the obtained plasma with acetonitrile, the compound concentration in the plasma was measured by high performance liquid chromatography (HPLC), and the area under the curve from 0 hours to 24 hours based on the obtained plasma concentration ( AUC, g · hrZmL) and maximum plasma concentration (C _max , M g / mL) were determined.

⁰ 〇!

Compound ¹ represented by formula (Π) was suspended in 0.5% carboxymethylcellular oral solution, and blood was collected from the jugular vein of rats at 30 minutes, 1, 2, 4, 6, 8, and 24 hours after administration Measured the blood concentration in oral administration in the same manner as described above. Table 5 shows the obtained results.

Table 5

Male female

300 mg / kg 1000 mg / kg 300 mg / kg 1000 mg / kg

(C _max xg / mL) 10.4 28.3 13.0 24.3 Formula (I)

(Compound of the present invention)

108 222 161 243

_{C ma x (μς / ηπί)} 3.96 4.39 5.13 6.23 Formula (II)

(Comparative example)

(Free body) AUvj ₀ -24hr

50.6 63.8 66.0 88.9

(μς · hr / mL) As is clear from Table 5, the compound of the present invention was found to have a higher blood concentration than the compound of the formula (II).

The compound of the present invention has an inhibitory effect on elastase. The inhibitory effect on elastase was confirmed, for example, by a screening system described below in a laboratory.

Experimental Example 4: Inhibitory effect on human neutrophil elastase

HEP S buffer (0.2M, PH8.0, 0.5ml), aqueous sodium chloride Liquid (2.5M, 0.2m1), polyethylene glycol 6000 (1%, 0.1m1), distilled water (0.04ml), test compound in dimethyl sulfoxide (DMSO)

(0.05m 1), and a mixed solution of MeO—Suc-A1aA1a—Pro—Va1—pNA (10, 20 and 40 mM, 0.01 ml each) at 37 ° C for 5 minutes. Pre-incubated. Human neutrophil elastase (HNE)

(2UZml, 0.1 ml) was added to the above mixed solution to start the reaction, and the absorbance at 405 nm was measured at 37 ° C for 10 minutes at intervals of 30 seconds. The elastase activity was defined as the production rate (V) of released p-nitroaline (pNA), and the change in absorbance per minute (AmO.D.Zmin) was calculated. The inhibition constant (K i value) was calculated from a Dixon plot of the obtained rate of change. Experimental Example 5: Elastase inhibitory activity in human neutrophil elastase-induced hamster lung hemorrhage model

Male Syrian hamsters were orally administered a test compound suspended in polyethylene glycol 400: ethanol: distilled water = 51:16:33. 60 minutes after the administration, HNE (10 UZ100 ^ lZLung) was administered to the detached trachea under anesthesia with pentoparubicil sodium (60 mg // kg, i.p.) to induce pulmonary hemorrhage. 60 minutes after induction, exsanguination and lethality, saline

(2.5 ml) was used to wash the bronchoalveolar vesicles, and the lavage fluid (BALF) was collected. Collected: BALF (0.2 ml) was diluted 10 times with distilled water (1.8 ml), and the hemolyzed solution was centrifuged at 3000 rpm and 4 ° C for 10 minutes. The absorbance at nm was measured, and the blood volume in BALF was calculated from the calibration curve. Experimental Example 6: Inhibitory effect on stimulation of elastinase activity in whole eight-muster blood by stimulating opsonized zymosan A test compound suspended or dissolved in polyethylene glycol 400: ethanol: distilled water = 51: 16: 33 or other suitable solvent was orally administered to male Syrian hamsters. 60 minutes after administration, blood was collected from the abdominal aorta of the animal under ether anesthesia. At the time of blood collection, 0.9 ml of blood was collected using a 3.8% sodium citrate solution (0.1 ml).

The obtained blood 540I was collected and incubated at 37 ° C. Five minutes after the start of the incubation, 601 was added as a stimulant, followed by incubation at 37 ° C for 30 minutes. The reaction was stopped by ice cooling. After stopping the reaction, the mixture was centrifuged at 3000 rpm at 4 ° C. for 10 minutes, and the obtained supernatant was collected and used for elastase activity measurement.

The elastase activity was measured using a Tris-HC1 buffer solution (ρΗ80, 0.2Μ, 100 1), aqueous sodium chloride solution (2.5Μ, 401), distilled water

(36 1) and Me O—Su e—Ala-A 1a—Pro—Va 1—ρ ΝΑ (5 OmM, 4 ^ 1) were mixed with the resulting solution, and the supernatant (20

1) was added and incubated at 37 ° C for 24 hours. The released p-nitroaline (pNA) was measured at an absorbance of 405 nm, and the inhibition rate was determined by the following equation. p and harm rate (%) = [1 {((test compound value-blank value) No (control value-blank value))]

X100

Experimental Example 7: Stability of the compound of the present invention represented by the formula (I) (2)

The compound of the present invention was allowed to stand at 5 ° C. and room temperature for 30 days, and the stability was measured using high performance liquid chromatography (HPLC) under the following measurement conditions. Table 6 shows the obtained results. HP LC measurement conditions:

Column: CAPCELLPAK C8 UG120 (4.6rami.d. X 150mm, No. BOAB1013), Temperature: 25 ° C,

Eluent: 20 mmol ZL dihydrogen phosphate aqueous solution (H 8.0, sodium hydroxide) nocetonitrile = 65Z35,

Flow rate UmLZ min,

UV: 235 nm. Table 6

[

The toxicity of the compound of the present invention was sufficiently low, and it was confirmed that the compound can be safely used as a pharmaceutical. Industrial applicability

[Application to pharmaceutical products]

The compound of the present invention represented by the formula (I) is a compound having an elastase inhibitory activity, and is an abnormal elastase-induced degradation of elastase, degradation of collagen fibers and abnormal degradation of z- or proteodarican in mammals, particularly humans. Diseases caused by, for example, arthritis, periodontal disease, nephritis, dermatitis, psoriasis, cystic fibrosis, chronic bronchitis, atherosclerosis, Alzheimer's disease, organ transplantation, cornea It is useful for treating and preventing or preventing ulcers and malignant tumors.

In order to use the compound represented by the formula (I), a non-toxic salt thereof, or a hydrate thereof for the above-mentioned purpose, it is generally used systemically or locally, in an oral or parenteral form. Is administered.

Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, per adult, once per day, in the range of lmg to 100mg, once to several times a day It may be administered orally or parenterally (preferably intravenously) once to several times daily, in the range of lmg to 100mg per adult per day, or It is administered intravenously over a period ranging from 24 hours to 24 hours.

Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or may be required outside the range.

When administering the compound represented by the formula (I), a solid composition, a liquid composition and other compositions for oral administration and an injection, an external preparation, a suppository and the like for parenteral administration are used. Used.

Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.

Capsules include hard capsules and soft capsules.

In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvierpyrrolidone, metasilicate. It is mixed with magnesium acid aluminate. The composition may contain, in a conventional manner, an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or Aspartic acid Such a solubilizing agent may be contained. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phosphate, or two or more layers, if necessary. You may. Also included are capsules of absorbable substances, such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such liquid compositions, the one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol). The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. This composition contains, in addition to the inert diluent, a buffering agent such as sodium bisulfite which provides isotonicity, for example, an isotonic agent such as sodium chloride, sodium citrate or citric acid. You may. Methods for producing sprays are described in detail, for example, in US Patents 2,868,691 and 3,095,355.

Injections for parenteral administration according to the present invention include sterile aqueous and Z or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). Further, sterile aqueous and non-aqueous solutions, suspensions and emulsions may be mixed and used. Such compositions may also contain preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solvents An adjuvant such as a dissolution aid (eg, glutamic acid, aspartic acid) may be included. These are sterilized by filtration through a Pacteria retention filter, combination of fungicides or irradiation. They can also be used to produce sterile solid compositions, for example, dissolved in sterile or sterile distilled water for injection or other solvents before use of the lyophilized product.

Other compositions for parenteral administration include external solutions, ointments, liniments, suppositories for rectal administration and intravaginal administration, which contain one or more active substances and are formulated in a conventional manner. Pessaries for administration, etc. are included.

[Formulation example]

Formulation Example 1:

The following components were mixed by a conventional method and then tableted to obtain 100 tablets each containing 5 Omg of the active ingredient.

2-[5-Amino-6-oxo-l-phenyl-l, 6-dihydro-l-pyrimidyl] —N— [1-(2- [5-t-butyl-1,3,4-oxadiazolyl] force Luponyl) 1-2-((R, S) monomethylpropyl] acetamide 'hydrochloride …… 5.0g carboxymethylcellulose calcium (disintegrant) …… 0.2g magnesium stearate (lubricant) …… 0.lg microcrystals Cellulose …… 4.7g Formulation example 2:

After mixing the following components in the usual manner, the solution is sterilized by the usual method, filled into ampoules in 5 ml portions, freeze-dried by the usual method, and 100 ampoules containing 2 Omg of the active ingredient in one ampule are added. Obtained.

2— [5-Amino-6-oxo-1-2-phenyl-1,6-dihydro-1-pi Limidyl] — N— [1— (2— [5_1: —butyl—1,3,4-oxaziazolyl] caprolponyl) —2- (R, S) —methylpropyl] acetamide-hydrochloride …… 2.0g Mannitol 20g distilled water '''5001111

Claims

The scope of the claims

Formula (I)

2- [5-Amino-6-oxo-1-2-phenyl-1,6-dihydric mouth—1-pyrimidyl] —N— [1— (2- [5_t-butyl-1,3,4-oxaziazolyl] Power-Ronil)-2- (R, S) monomethylpropyl] acetamide hydrochloride compound.

2. The compound according to claim 1, which is a crystal.

3. Equation (II)

2- [5-Amino-6-oxo-1-2-phenyl-1,6-dihydro-1,1-pyrimidyl] -N- [1- (2- (5-t-butyl-1,3,4-1) A process for producing the compound according to claim 1, wherein the compound is reacted with a hydrochloric acid-containing organic solvent in an organic solvent in the presence of (oxaziazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide.

4. It contains a compound represented by the formula (I) described in claim 1 as an active ingredient. Pharmaceutical compositions.

5. An elastase inhibitor comprising the compound represented by the formula (I) according to claim 1 as an active ingredient.