A prophylactic/therapeutic composition containing WS7622A for preventing or treating disseminated intravascular coagulation, chronic respiratory tract infectious disease or chronic bronchitis

Abstract: A prophylactic/therapeutic composition for disseminated intravascular coagulation, chronic respiratory tract infectious disease or chronic bronchitis which comprises WS7622A mono- or disulfate ester or their pharmaceutically acceptable salt. WS7622A is known from European patent application 91110243.2 (EP-A-0 465 895).

Description: This invention relates to use of WS7622A mono- or disulfate ester or their pharmaceutically acceptable salt for the preparation of a medicament for preventing or treating disseminated intravascular coagulation (DIC) or chronic respiratory tract infectious disease. The some inventors of this invention previously invented a pharmaceutical composition comprising WS7622A mono- or disulfate ester having human leukocyte elastase inhibitory activity (European Patent Application No. 91110243.2). Now, the inventors of this invention have completed an invention directed to new medicinal uses for WS7622A mono- or disulfate ester or a pharmaceutically acceptable salt thereof which were not disclosed in the specification of the above application. This invention relates to the use defined above. WS7622A mono- and disulfate esters and pharmaceutically acceptable salts thereof, which are employed in this invention, and can be produced by converting WS7622A or a salt thereof (European publication No. 0387712 A1), which is known, to the corresponding sulfuric acid esters. Of these compounds, WS7622A disulfate ester disodium salt and WS7622A disulfate ester dipotassium salt have the following physicochemical properties. WS7622A disulfate ester disodium salt (disodium salt of WS7622A disulfate) : Appearance : Colorless crystals Solubility : Soluble; water, methanol Insoluble; chloroform, n-hexane Melting point : 257-263°C (decompn.) Specific rotation : [α] 23 / D + 37.5° (C=1.0, methanol) Molecular formula : C 47 H 61 N 9 O 19 S 2 Na 2 Elemental analysis : Calcd.: (for C 47 H 61 N 9 O 19 S 2 Na 2 ·6H 2 O) C 44.30, H 5.77, N 9.89, S 5.03, Na 3.61% Found : C 44.98, H 5.90, N 10.06, S 5.00, Na 3.98% Molecular weight : FAB-MS m/z 1188 (M+Na) + Thin-layer chromatography : Stationary phase Developing solvent Rf value Silica gel (Merck Art 5715) CHCl 3 -CH 3 OH-H 2 O (65:25:4) 0.11 n-Butanol-acetic acid-water (4:2:1) 0.29 Infrared absorption spectrum (attached Fig. 1) : ν KBr / max 3360, 2960, 1735, 1660, 1640, 1530, 1500, 1380, 1250, 1200, 1060, 1030, 940, 890 cm -1 1 H Nuclear magnetic resonance spectrum (attached Fig. 2) : (400 MHz, D 2 O)δ 7.50 (1H, s) 7.27 (1H, s) 7.33-7.24 (3H, m) 6.94 (1H, q, J=7Hz) 6.85 (2H, br d, J=8Hz) 5.53 (1H, m) 5.37 (1H, m) 4.80 (1H, br s) 4.63-4.57 (2H, m) 4.53 (1H, m) 4.06 (1H, m) 3.99 (1H, d, J=10Hz) 3.56 (1H, br d, J=14Hz) 3.46 (1H, m) 2.97 (3H, s) 2.97-2.88 (2H, m) 2.72 (1H, m) 2.59 (1H, m) 2.51-2.38 (2H, m) 2.09-1.91 (4H, m) 1.82-1.60 (3H, m) 1.77 (3H, d, J=7Hz) 1.50 (3H, d, J=6.5Hz) 1.40 (1H, m) 1.11 (6H, d, J=7Hz) 0.99 (3H, d, J=6.5Hz) 0.97 (3H, d, J=6.5Hz) 13 C Nuclear magnetic resonance spectrum (attached Fig. 3) : Amino acid analysis : WS7622A disulfate ester disodium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 ml) at 110°C for 20 hours and the hydrolyzate was concentrated to dryness and analyzed with a Hitachi 835 automatic amino acid analyzer. As the amino acid reference standards, Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used. As a result, threonine, valine, phenylalanine, ornithine, ammonia and several unknown ninhydrin-positive substances were detected. The following partial structural formula is proposed for WS7622A disulfate ester disodium salt. WS7622A disulfate ester dipotassium salt (dipotassium salt of WS7622A disulfate) : Appearance : Colorless amorphous powder Solubility : Soluble; water, methanol Insoluble; chloroform, n-hexane Melting point : 230-237°C (decompn.) Specific rotation : [α] 23 / D + 34° (C=1.0, methanol) Molecular formula : C 47 H 61 N 9 O 19 S 2 K 2 Elemental analysis : Calcd.: (for C 47 H 61 N 9 O 19 S 2 K 2 ·6H 2 O) C 43.21, H 5.63, N 9.65, S 4.91, K 5.99% Found C 43.96, H 5.44, N 9.97, S 5.09, K 4.49% Molecular weight : FAB-MS m/z 1236 (M+K) + Thin-layer chromatography : Stationary phase Developing solvent Rf value Silica gel (Merck Art 5715) CHCl 3 -CH 3 OH-H 2 O (65:25:4) 0.13 Infrared absorption spectrum (attached Fig. 4) : ν KBr / max 3360, 2960, 1735, 1660, 1640, 1530, 1500, 1405, 1380, 1250, 1200, 1050, 1030, 940, 890 cm -1 1 H Nuclear magnetic resonance spectrum (attached Fig. 5) : (400 MHz, D 2 O)δ 7.52 (1H, s) 7.28 (1H, s) 7.34-7.25 (3H, m) 6.96 (1H, q, J=7Hz) 6.87 (2H, br d, J=8Hz) 5.56 (1H, m) 5.40 (1H, m) 4.84 (1H, br s) 4.70-4.55 (3H, m) 4.10 (1H, m) 4.03 (1H, m) 3.60 (1H, br d, J=14Hz) 3.50 (1H, m) 3.00 (3H, s) 3.00-2.85 (2H, m) 2.76 (1H, m) 2.62 (1H, m) 2.55-2.40 (2H, m) 2.12-1.95 (4H, m) 1.90-1.65 (3H, m) 1.79 (3H, d, J=7Hz) 1.53 (3H, d, J=6.5Hz) 1.45 (1H, m) 1.14 (6H, d J=7Hz) 1.02 (3H, d J=6.5Hz) 1.00 (3H, d J=6.5Hz) Amino acid analysis : WS7622A disulfate ester dipotassium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 ml) at 110°C for 20 hours and the hydrolyzate was concentrated to dryness and analyzed with a Hitachi 835 automatic amino acid analyzer. As the amino acid reference standards, Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used. As a result, threonine, valine, phenylalanine, ornithine, ammonia and several unknown ninhydrin-positive substances were detected. The following partial structural formula is proposed for WS7622A disulfate ester dipotassium salt. The pharmaceutically acceptable salt of WS7622A mono- or disulfate ester includes mono- or disalts with inorganic or organic bases such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt etc.), ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt, pyridine salt and so on. WS7622A mono- and disulfate esters and pharmaceutically acceptable salts thereof are of use according to the invention as prophylactic-therapeutic agents for disseminated intravascular coagulation (DIC) and chronic respiratory tract infectious disease. As evidence of the usefulness of WS7622A mono- or disulfate ester or a pharmaceutically acceptable salt thereof, pharmacological test data on these compounds are presented below. Test 1 Protease inhibition assay (1) Method The buffer solution used throughout this assay was 0.5 M NaCl-containing 0.1 M HEPES [N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)], pH 7.5. Using a 96-well microtiter plate, 25 µl of 2mM methoxysuccinyl (Ala) 2 -Pro-Val-p-nitroanilide (a 100mM solution in dimethyl sulfoxide was diluted with the buffer solution) was mixed with 50 µl of the sample (10 µl of an organic solvent solution of the sample was diluted 5-fold with the buffer solution). The absorbance of the mixture at a wavelength of 415 nm was measured with a microplate reader (Corona Electric, Ibaragi Prefecture). Then, 6 µg/ml of human sputum elastase (HSE) was added and the mixture was allowed to stand at room temperature for 30 minutes. The absorbance at 415 nm was then measured. The percent inhibition (%) by the drug was calculated from the formula: 100 x (1 - r in the presence of an inhibitor/r in the absence of the inhibitor), wherein r represents the absorbance after 30 minutes' incubation minus the absorbance before addition of the enzyme. The inhibitor activities against other proteases were assayed using N-succinyl-(Ala) 3 -p-nitroanilide for swine pancreatic elastase (type IV, final concentration 5 µg/ml), N-alpha-benzoyl-Arg-p-nitroanilide for bovine pancreatic trypsin (type I, final conc. 16 µg/ml) and methoxysuccinyl-(Ala) 2 -Pro-Met-p-nitroanilide for bovine pancreatic chymotrypsin (type II, final conc. 1.5 µg/ml). HSE was obtained from Elastin Products Co., Inc., Missouri, U.S.A. All other substrates and proteases were purchased from Sigma Chemicals Company. Inhibitory activity of WS7622A disulfate ester disodium salt and WS7622A disulfate ester dipotassium salt against several kinds of serine proteases (2) Results IC 50 (M) Substance (M) Human sputum elastase Swine pancreatic elastase Trypsin (bovine) Chymotrypsin (bovine) WS7622A disulfate ester disodium salt 3.5x10 -8 4.9x10 -8 1.8x10 -4 2.0x10 -7 WS7622A disulfate ester dipotassium salt 5.9x10 -8 4.9x10 -8 2.0x10 -4 2.0x10 -7 Each inhibitory activity was expressed in 50% inhibitory concentration (IC 50 ). Test 2 Effects on the endotoxin-induced disseminated intravascular coagulation (DIC) model (1) Method The rat model of DIC was constructed by the method of Nishikawa et al. (Life Science 39 , 111, 1986). First, under pentobarbital anesthesia (50 mg/kg, i.p.), the right femoral vein of 7-week-old male Wistar rats was canulated with a PE-50 tube for infusion of endotoxin (LPS) and the drug. The normal group was infused with saline, while the control group was infused with 0.25 mg/kg/hr of endotoxin over a period of 4 hours. The drug treatment group was infused with a mixture of endotoxin and the drug, with the amount of the drug being set at 10 mg/kg/hr. All infusions were performed at the rate of 2.3 ml/hr. (2) Results Treatment n PLT count (x10 3 /mm 3 ) PT (sec) APTT (sec) Fig (mg/dl) FDP (µg/ml) Normal group 7 595±9.3 13.4±0.1 22.2±0.2 215±5.8 0.5±0.0 Control group 10 273±17.3 20.8±1.6 66.0±9.3 39±4.9 6.0±0.7 WS7622A disulfate ester disodium salt 7 318±16.0 (14.1%) 19.1±1.0 (23.4%) 52.8±8.3 (30.0%) 54±8.7 (8.2%) 5.0±0.0 (18.2%) The figure in parentheses denotes % inhibition. PLT : platelet PT : prothrombin time APTT : activated partial thromboplastin time Fig : fibrinogen FDP : fibrin and fibrinogen degradation products Test 3 Determination of the activity in elastase-induced pulmonary damage. (1) Method Hamsters under pentobarbital anesthesia were used. Saline or saline-containing human sputum elastase was instilled intratracheally via a small incision in the ventral neck region using 1 ml syringe with a 27-gauge needle. After 3 hours, animals were sacrificed by CO 2 asphyxiation, each animal's trachea was reexposed. The lungs were then lavaged using a 2.5-ml aliquot of saline and then withdrawing the saline, yielding a final volume of approximately 1.5 ml bronchoalveolar lavage (BAC) fluid from each animal. The cells of BAL fluid were collected by centrifugation and were then diluted with distilled water to disrupt, and the hemoglobin contents determined spectrophotometrically at 541 nm. Test drugs were dissolved in saline and instilled intratracheally in the same manner as used to instill elastase, at 5 minutes before instillation of elastase. (2) Results Inhibitory effect on elastase-induced lung hemorrhage Test compound 5 min predose (µg/site) Hemorrhage (OD 541 nm) % inhibition Normal - 0.31±0.12 - Control - 29.35±2.9 - WS7622A disulfate ester disodium salt 1 19.06±1.40 35.4 10 9.75±4.82 67.5 100 0.28±0.05 100.1 WS7622A disulfate ester dipotassium salt 1 19.71±1.20 33.2 10 10.73±1.20 64.1 100 0.35±0.16 99.9 The medicament prepared according to the invention can be in the conventional dosage forms such as powder, fine granule, granule, tablet, sugar-coated pill, microcapsule, capsule, suppository, solution, suspension, emulsion, syrup, injection, inhalant and so on. Where necessary, there may be incorporated in the composition a diluent or disintegrator (e.g. sucrose, lactose, starch, crystalline cellulose, low-substitution hydroxypropylcellulose, synthetic aluminum silicate, etc.), a binder (e.g. cellulose, methylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, etc.), a colorant, a sweetener, a lubricant (e.g. magnesium stearate etc.) and so on. Though dependent on the patient's age, body weight and clinical condition, among other factors, the medicament prepared according to the invention can be administered in a daily dose of 100 mg to 10 g and preferably 1 g to 5 g, as the claimed compound or pharmaceutically acceptable salt, which daily dose may be administered in 1-3 divided doses. Typical unit doses are 50 mg, 100 mg, 200 mg, 500 mg and 1 g.

Claims: Claim for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, PT, SE Use of WS7622A mono- or disulfate ester or their pharmaceutically acceptable salt, among which WS7622A disulfate ester disodium salt and WS7622A disulfate ester dipotassium salt have the following physico-chemical properties : WS7622A disulfate ester disodium salt : Appearance : Colorless crystals Solubility : Soluble; water, methanol Insoluble; chloroform, n-hexane Melting point : 257-263°C (dec.) Specific rotation : [α] 23 / D + 37.5° (C=1.0, methanol) Molecular formula : C 47 H 61 N 9 O 19 S 2 Na 2 Elemental analysis : Calcd.: (for C 47 H 61 N 9 O 19 S 2 Na 2 ·6H 2 O) C 44.30, H 5.77, N 9.89, S 5.03, Na 3.61% Found : C 44.98, H 5.90, N 10.06, S 5.00, Na 3.98% Molecular weight : FAB-MS m/z 1188 (M+Na) + Thin-layer chromatography : Stationary phase Developing solvent Rf value Silica gel (Merck Art 5715) CHCl 3 -CH 3 OH-H 2 O (65:25:4) 0.11 n-Butanol-acetic acid-water (4:2:1) 0.29 Infrared absorption spectrum (attached Fig. 1) : ν KBr / max 3360, 2960, 1735, 1660, 1640, 1530, 1500, 1380, 1250, 1200, 1060, 1030, 940, 890 cm -1 1 H Nuclear magnetic resonance spectrum (attached Fig. 2) : (400 MHz, D 2 O)δ 7.50 (1H, s) 7.27 (1H, s) 7.33-7.24 (3H, m) 6.94 (1H, q, J=7Hz) 6.85 (2H, br d, J=8Hz) 5.53 (1H, m) 5.37 (1H, m) 4.80 (1H, br s) 4.63-4.57 (2H, m) 4.53 (1H, m) 4.06 (1H, m 3.99 (1H, d, J=10Hz) 3.56 (1H, br d, J=14Hz) 3.46 (1H, m) 2.97 (3H, s) 2.97-2.88 (2H, m) 2.72 (1H, m) 2.59 (1H, m) 2.51-2.38 (2H, m) 2.09-1.91 (4H, m) 1.82-1.60 (3H, m) 1.77 (3H, d, J=7Hz) 1.50 (3H, d, J=6.5Hz) 1.40 (1H, m) 1.11 (6H, d, J=7Hz) 0.99 (3H, d, J=6.5Hz) 0.97 (3H, d, J=6.5Hz) 13 C Nuclear magnetic resonance spectrum (attached Fig. 3) : Amino acid analysis : WS7622A disulfate ester disodium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 ml) at 110°C for 20 hours and the hydrolyzate was concentrated to dryness and analyzed with a Hitachi 835 automatic amino acid analyzer. As the amino acid reference standards, Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used. As a result, threonine, valine, phenylalanine, ornithine, ammonia and several unknown ninhydrin-positive substances were detected. WS7622A disulfate ester dipotassium salt : Appearance : Colorless amorphous powder Solubility : Soluble; water, methanol Insoluble; chloroform, n-hexane Melting point : 230-237°C (dec.) Specific rotation : [α] 23 / D + 34° (C=1.0, methanol) Molecular formula : C 47 H 61 N 9 O 19 S 2 K 2 Elemental analysis : Calcd.: (for C 47 H 61 N 9 O 19 S 2 K 2 ·6H 2 O) C 43.21, H 5.63, N 9.65, S 4.91, K 5.99% Found : C 43.96, H 5.44, N 9.97, S 5.09, K 4.49% Molecular weight : FAB-MS m/z 1236 (M+K) + Thin-layer chromatography : Stationary phase Developing solvent Rf value Silica gel (Merck Art 5715) CHCl 3 -CH 3 OH-H 2 O (65:25:4) 0.13 Infrared absorption spectrum (attached Fig. 4) : ν KBr / max 3360, 2960, 1735, 1660, 1640, 1530, 1500, 1405, 1380, 1250, 1200, 1050, 1030, 940, 890 cm -1 1 H Nuclear magnetic resonance spectrum (attached Fig. 5): (400 MHz, D 2 O)δ 7.52 (1H, s) 7.28 (1H, s) 7.34-7.25 (3H, m) 6.96 (1H, q, J=7Hz) 6.87 (2H, br d, J=8Hz) 5.56 (1H, m) 5.40 (1H, m) 4.84 (1H, br s) 4.70-4.55 (3H, m) 4.10 (1H, m) 4.03 (1H, m) 3.60 (1H, br d, J=14Hz) 3.50 (1H, m) 3.00 (3H, s) 3.00-2.85 (2H, m) 2.76 (1H, m) 2.62 (1H, m) 2.55-2.40 (2H, m) 2.12-1.95 (4H, m) 1.90-1.65 (3H, m) 1.79 (3H, d, J=7Hz) 1.53 (3H, d, J=6.5Hz) 1.45 (1H, m) 1.14 (6H, d J=7Hz) 1.02 (3H, d J=6.5Hz) 1.00 (3H, d J=6.5Hz) Amino acid analysis : WS7622A disulfate ester dipotassium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 ml) at 110°C for 20 hours and the hydrolyzate was concentrated to dryness and analyzed with a Hitachi 835 automatic amino acid analyzer. As the amino acid reference standards, Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used. As a result, threonine, valine, phenylalanine, ornithine, ammonia and several unknown ninhydrin-positive substances were detected, for the preparation of a medicament for preventing or treating disseminated intravascular coagulation or chronic respiratory tract infectious disease. Claim for the following Contracting States : ES, GR Use of WS7622A mono- or disulfate ester or their pharmaceutically acceptable salt, among which WS7622A disulfate ester disodium salt and WS7622A disulfate ester dipotassium salt have the following physico-chemical properties : WS7622A disulfate ester disodium salt : Appearance : Colorless crystals Solubility : Soluble; water, methanol Insoluble; chloroform, n-hexane Melting point : 257-263°C (dec.) Specific rotation : [α] 23 / D + 37.5° (C=1.0, methanol) Molecular formula : C 47 H 61 N 9 O 19 S 2 Na 2 Elemental analysis : Calcd.: (for C 47 H 61 N 9 o 19 S 2 Na 2 ·6H 2 O) C 44.30, H 5.77, N 9.89, S 5.03, Na 3.61% Found : C 44.98, H 5.90, N 10.06, S 5.00, Na 3.98% Molecular weight : FAB-MS m/z 1188 (M+Na) + Thin-layer chromatography: Stationary phase Developing solvent Rf value Silica gel (Merck Art 5715) CHCl 3 -CH 3 OH-H 2 O (65:25:4) 0.11 n-Butanol-acetic acid-water (4:2:1) 0.29 Infrared absorption spectrum (attached Fig. 1) : ν KBr / max 3360, 2960, 1735, 1660, 1640, 1530, 1500, 1380, 1250, 1200, 1060, 1030, 940, 890 cm -1 1 H Nuclear magnetic resonance spectrum (attached Fig. 2) : (400 MHz, D 2 O)δ 7.50 (1H, s) 7.27 (1H, s) 7.33-7.24 (3H, m) 6.94 (1H, q, J=7Hz) 6.85 (2H, br d, J=8Hz) 5.53 (1H, m) 5.37 (1H, m) 4.80 (1H, br s) 4.63-4.57 (2H, m) 4.53 (1H, m) 4.06 (1H, m) 3.99 (1H, d, J=10Hz) 3.56 (1H, br d, J=14Hz) 3.46 (1H, m) 2.97 (3H, s) 2.97-2.88 (2H, m). 2.72 (1H, m) 2.59 (1H, m) 2.51-2.38 (2H, m) 2.09-1.91 (4H, m) 1.82-1.60 (3H, m) 1.77 (3H, d, J=7Hz) 1.50 (3H, d, J=6.5Hz) 1.40 (1H, m) 1.11 (6H, d, J=7Hz) 0.99 (3H, d, J=6.5Hz) 0.97 (3H, d, J=6.5Hz) 13 C Nuclear magnetic resonance spectrum (attached Fig. 3) : Amino acid analysis : WS7622A disulfate ester disodium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 ml) at 110°C for 20 hours and the hydrolyzate was concentrated to dryness and analyzed with a Hitachi 835 automatic amino acid analyzer. As the amino acid reference standards, Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used. As a result, threonine, valine, phenylalanine, ornithine, ammonia and several unknown ninhydrin-positive substances were detected. WS7622A disulfate ester dipotassium salt : Appearance : Colorless amorphous powder Solubility : Soluble; water, methanol Insoluble; chloroform, n-hexane Melting point : 230-237°C (dec.) Specific rotation : [α] 23 / D + 34° (C=1.0, methanol) Molecular formula : C 47 H 61 N 9 O 19 S 2 K 2 Elemental analysis : Calcd.: (for C 47 H 61 N 9 O 19 S 2 K 2 ·6H 2 O) C 43.21, H 5.63, N 9.65, S 4.91, K 5.99% Found : C 43.96, H 5.44, N 9.97, S 5.09, K 4.49% Molecular weight : FAB-MS m/z 1236 (M+K) + Thin-layer chromatography: Stationary phase Developing solvent Rf value Silica gel (Merck Art 5715) CHCl 3 -CH 3 OH-H 2 O (65:25:4) 0.13 Infrared absorption spectrum (attached Fig. 4) : ν KBr / max 3360, 2960, 1735, 1660, 1640, 1530, 1500, 1405, 1380, 1250, 1200, 1050, 1030, 940, 890 cm -1 1 H Nuclear magnetic resonance spectrum (attached Fig. 5) : (400 MHz, D 2 O)δ 7.52 (1H, s) 7.28 (1H, s) 7.34-7.25 (3H, m) 6.96 (1H, q, J=7Hz) 6.87 (2H, br d, J=8Hz) 5.56 (1H, m) 5.40 (1H, m) 4.84 (1H, br s) 4.70-4.55 (3H, m) 4.10 (1H, m) 4.03 (1H, m) 3.60 (1H, br d, J=14Hz) 3.50 (1H, m) 3.00 (3H, s) 3.00-2.85 (2H, m) 2.76 (1H, m) 2.62 (1H, m) 2.55-2.40 (2H, m) 2.12-1.95 (4H, m) 1.90-1.65 (3H, m) 1.79 (3H, d, J=7Hz) 1.53 (3H, d, J=6.5Hz) 1.45 (1H, m) 1.14 (6H, d J=7Hz) 1.02 (3H, d J=6.5Hz) 1.00 (3H, d J=6.5Hz) Amino acid analysis : WS7622A disulfate ester dipotassium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 ml) at 110°C for 20 hours and the hydrolyzate was concentrated to dryness and analyzed with a Hitachi 835 automatic amino acid analyzer. As the amino acid reference standards, Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used. As a result, threonine, valine, phenylalanine, ornithine, ammonia and several unknown ninhydrin-positive substances were detected, for the preparation of a medicament for preventing or treating disseminated intravascular coagulation or chronic respiratory tract infectious disease, wherein WS 7622A mono or disulfate ester or their pharmaceuticallly acceptable salts is admixed with a suitable pharmaceutically acceptable carrier or excipient and optionally suitable additives.

Inventors: EZAKI MASAMI, HATANAKA HIROSHI, INAMURA NORIAKI, NAKAHARA KUNIO, NOTSU YOSHITADA, OKAMOTO MASANORI, OKUHARA MASAKUNI, SHIGEMATSU NOBUHARU, SHINGU YASUHIKO, TAKASE SHIGEHIRO, TSUJII EISAKU, EZAKI, MASAMI, HATANAKA, HIROSHI, INAMURA, NORIAKI, NAKAHARA, KUNIO, NOTSU, YOSHITADA, OKAMOTO, MASANORI, OKUHARA, MASAKUNI, SHIGEMATSU, NOBUHARU, SHINGU, YASUHIKO, TAKASE, SHIGEHIRO, TSUJII, EISAKU
Applicants: FUJISAWA PHARMACEUTICAL CO, FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1992
Main classification: C07K2
IPC codes: A61K38, C07K4, A61K39, C07K14