Water-soluble benzoazepine compound and its pharmaceutical composition

Abstract

The present invention provides a benzoazepine compound represented by following general formula (1): ##STR00001##
or a salt thereof,
wherein R represents a hydrogen atom, a hydroxy group optionally protected with a protecting group, etc., R.sup.1 represents a hydrogen atom or hydroxy-protecting group, and X represents an oxygen atom or a sulfur atom. The benzoazepine compound of the present invention and salts thereof have high solubility in water, and can be suitably used for injections.

Claims

1. A benzoazepine compound represented by formula (1) ##STR00041## or a salt thereof, wherein R represents a hydrogen atom, a hydroxy group optionally protected with a protecting group, a mercapto group optionally protected with a protecting group, or an amino group optionally protected with one or two protecting groups; R.sup.1 represents a hydrogen atom or a hydroxy-protecting group; and X represents an oxygen atom or a sulfur atom.

2. A benzoazepine compound according to claim 1 or a salt thereof, wherein X is an oxygen atom.

3. A benzoazepine compound according to claim 1 or 2, or a salt thereof, wherein R is a hydroxy group optionally protected with a protecting group.

4. A benzoazepine compound according to claim 1 or 2, or a salt thereof, wherein R is a hydrogen atom, a mercapto group optionally protected with a protecting group, or an amino group optionally protected with one or two protecting groups.

5. A benzoazepine compound according to any one of claims 1, 2, 3 and 4, or a salt thereof, wherein R.sup.1 is a hydroxy-protecting group.

6. A benzoazepine compound according to any one of claims 1, 2, 3 and 4, or a salt thereof, wherein R.sup.1 is a hydrogen atom.

7. A benzoazepine compound according to claim 1 or a salt thereof, wherein X is a sulfur atom.

8. A benzoazepine compound according to claim 1 or a salt thereof, wherein X is an oxygen atom, R is a hydroxy group, and R.sup.1 is a hydrogen atom.

9. A pharmaceutical composition comprising a benzoazepine compound of claim 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent and/or carrier.

10. A pharmaceutical composition according to claim 9, for use as a vasodilator, hypotensor, aquaretic agent, PKD, or platelet aggregation inhibitor.

11. An aqueous solution composition comprising a benzoazepine compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. An aqueous solution composition according to claim 11, comprising a benzoazepine compound of claim 1 or a pharmaceutically acceptable salt thereof, together with a buffer, isotonizing agent and injection solvent, and which is in the form of an injection.

13. An aqueous solution composition according to claim 12, further comprising a pH adjuster.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a graph showing the change in serum concentration of tolvaptan in female rats after rapid tail-vein administration of a solution of compound (1b) at a dose such that 1 mg of tolvaptan is produced per kg of body weight.

(2) FIG. 2 is a graph showing the change in serum concentration of tolvaptan in female rats after oral administration of a solution of compound (1b) at a dose such that 1 mg of tolvaptan is produced per kg of body weight.

BEST MODE FOR CARRYING OUT THE INVENTION

(3) Examples, test examples and preparation examples are given below to illustrate the present invention in further detail, but the scope of the invention is not limited to these examples.

Example 1

(4) ##STR00011##

(5) A 1.0 g quantity of tolvaptan (compound (2)) and 460 mg of 1H-tetrazole were dissolved in 30 ml of methylene chloride, and 1.2 g of dibenzyl diisopropylphosphoramidite was added dropwise to this solution at room temperature with stirring. The mixture was then stirred for 2 hours at the same temperature.

(6) The obtained reaction mixture was cooled to −40° C., and 6 ml of methylene chloride solution of 920 mg of metachloroperbenzoic acid was added dropwise thereto. The mixture was then stirred at the same temperature for 30 minutes, and at 0° C. for 30 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate, and then dried over anhydrous sodium sulfate. The obtained reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=1:1) to give 1.5 g of amorphous compound (1a-1) (yield 97.2%).

(7) NMR (DMSO-d.sub.6, 100° C.) δ ppm; 9.86 (1H, br s), 7.56 (1H, s), 7.50-7.10 (17H, m), 7.00-6.80 (2H, m), 5.60-5.50 (1H, m), 5.15-5.00 (4H, m), 5.00-2.75 (2H, m), 2.36 (3H, s), 2.34 (3H, s), 2.10-1.70 (4H, m)

Example 2

(8) ##STR00012##

(9) A 4.5 g quantity of tolvaptan (compound (2)) and 2.2 g of 1H-tetrazole were dissolved in 120 ml of methylene chloride, and a solution of 4.0 g of di t-butyl diisopropylphosphoramidite dissolved in 10 ml of methylene chloride was added dropwise to this solution with ice-cooling and stirring. The mixture was then stirred at room temperature for 2 hours.

(10) The obtained reaction mixture was cooled to −40° C., and 20 ml of methylene chloride solution of 4.0 g of metachloro perbenzoic acid was added dropwise thereto. The mixture was then stirred at the same temperature for 30 minutes, and at 0° C. for 40 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate, and then dried over anhydrous sodium sulfate. The obtained reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=1:1) to give 3.0 g of amorphous compound (1a-2) (yield 46.7%).

(11) NMR (DMSO-d.sub.6) δ ppm; 10.50-10.20 (1H, m), 8.00-6.50 (10H, m), 5.55-5.20 (1H, m), 4.90-4.50 (1H, m), 2.85-2.60 (1H, m), 2.40-2.20 (6H, m), 2.20-1.60 (4H, m), 1.60-1.30 (18H, m)

Example 3

(12) ##STR00013##

(13) A 5.3 g quantity of compound (1a-1) was dissolved in 100 ml of ethanol, and, using 2 g of 5% palladium-carbon as a catalyst, the solution was subjected to catalytic reduction at room temperature and atmospheric pressure for 10 minutes. The catalyst was removed from the solution by filtration, and the obtained filtrate was concentrated (4.2 g). The obtained residue was crystallized from methanol/water. The crystals were collected by filtration and then dried under reduced pressure (diphosphorus pentoxide) to give 3.5 g of white powdery compound (1b) (yield 88.5%).

(14) Melting point: 150 to 152° C.

(15) NMR (DMSO-d.sub.6-D.sub.2O, 100° C.) δ ppm; 7.50-6.70 (10H, m), 5.50-5.40 (1H, m), 5.00-2.50 (2H, m), 2.37 (6H, s), 2.40-1.50 (4H, m)

Example 4

(16) ##STR00014##

(17) A 3.0 g quantity of compound (1a-2) was dissolved in 100 ml of methylene chloride, and a solution of 10 ml of trifluoroacetic acid dissolved in 5 ml of methylene chloride was added dropwise to this solution with ice-cooling and stirring. The mixture was then stirred at the same temperature for 2 hours. The solvent was removed from the solution. The obtained residue was redissolved in methylene chloride, and then concentrated. The obtained residue was crystallized from methanol/water. The crystals were collected by filtration and then dried under reduced pressure (diphosphorus pentoxide) to give 1.9 g of white powdery compound (1b) (yield 76.8%).

Example 5

(18) ##STR00015##

(19) A 240 ml quantity of 1,2-dimethoxyethane (DME) and 84 ml of triethylamine (0.60 mol, 9 equivalents) were added to 30 g (66 mmol) of tolvaptan (compound (2)), and the mixture was cooled under a nitrogen stream to −15° C. A 19 ml quantity (0.20 mol, 3 equivalents) of phosphorus oxychloride (POCl.sub.3) was added dropwise to the obtained mixture at an internal temperature of no more than −12° C., and stirring was performed at −12° C. for 2 hours. A 200 ml quantity of 5 N sodium hydroxide aqueous solution was added to 1 kg of crashed ice, and the above reaction mixture were added in small portions thereto with stirring. To the obtained mixture was added 500 ml of toluene. The mixture was heated to 50° C. and then separated into an aqueous layer and a toluene layer. A 500 ml quantity of toluene was added again to the aqueous layer, stirring was performed at 50° C., and the mixture was then separated into an aqueous layer and a toluene layer. The aqueous layer was cooled to 10° C., 80 ml of 6 N hydrochloric acid was added thereto, and extraction was performed with 500 ml of ethyl acetate twice. The extract was dried over sodium sulfate and filtered, and the filtrate was concentrated. The concentrate was dried under reduced pressure at room temperature to give 34 g of amorphous compound (1b).

(20) Yield: 97%

Example 6

Production of Calcium Salt of Compound (1b)

(21) ##STR00016##

(22) (1) A 2.6 g quantity (5.0 mmol) of compound (1b) was dissolved in 25 ml of isopropyl alcohol, and 2.2 ml of 5 N sodium hydroxide aqueous solution was added thereto at room temperature. The obtained mixture was concentrated under reduced pressure. To the residue was added 30 ml of water to dissolve the solid content, and an aqueous solution of 0.61 g (5.5 mmol) of calcium chloride was then added thereto. The precipitated solids were collected by filtration, washed with water, and hot air-dried at 60° C. to give 2.2 g of white powdery calcium salt of compound (1b).

(23) Yield: 78%

(24) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.3-2.4 (10H, m), 2.8-4.5 (2H, m), 5.2-5.8 (1H, m), 6.4-8.1 (10H, m), 9.0-10.2 (1H, m)

(25) (2) A 280 mg quantity (0.53 mmol) of compound (1b) was dissolved in a mixed solution of 2 ml of methanol and 1 ml of water, and 43 mg (0.58 mmol) of calcium hydroxide was then added thereto. The mixture was stirred at room temperature for 1 hour. The precipitated solids were collected by filtration. The filtered material was suspended in methanol, stirred with heating, and then hot-filtered. The filtrate was concentrated, and the residue was recrystallized from methanol to give 75.4 mg of white powdery calcium salt of compound (1b).

(26) Yield: 25%

(27) Melting point: 263 to 265° C.

Example 7

Production of Magnesium Salt of Compound (1b)

(28) ##STR00017##

(29) (1) A 1.0 g quantity (1.9 mmol) of compound (1b) was dissolved in 15 ml of methanol, and 0.76 ml of 5 N sodium hydroxide aqueous solution was added thereto. The mixture was concentrated under reduced pressure. The residue was dissolved in 10 ml of methanol, and 3 ml of methanol solution of 0.18 g of magnesium chloride was added to the obtained solution at room temperature. Precipitated insoluble matter (NaCl) was removed by filtration, and the filtrate was concentrated. To the residue was added 10 ml of water, and stirring was performed with heating. The mixture after stirring was allowed to cool to room temperature. The insoluble matter was then collected by filtration, washed with water, and dried under reduced pressure at 60° C. to give 400 mg of white powdery magnesium salt of compound (1b)

(30) Yield: 38%

(31) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.4-2.4 (10H, m), 2.8-4.5 (2H, m), 5.3-5.5 (1H, m), 6.4-7.8 (10H, m), 9.7 (1H, br).

(32) (2) A 282 mg quantity (0.53 mmol) of compound (1b) was dissolved in 2 ml of methanol, and 41 mg (0.70 mmol) of magnesium ethoxide was added thereto with ice-cooling. To the obtained mixture were further added 2 ml of ethanol and an aqueous suspension (0.5 ml) of 36 mg (0.58 mmol) of magnesium hydroxide, and stirring was performed at room temperature for 1 hour. The insoluble matter was removed by filtration, and the filtrate was allowed to stand overnight. The precipitated solids were collected by filtration and then dried under reduced pressure to give 24.9 mg of white powdery magnesium salt of compound (1b).

(33) Yield: 11%

(34) Melting point: 250 to 252° C.

Example 8

Production of Monosodium Salt of Compound (1b)

(35) ##STR00018##

(36) A 0.5 ml quantity of 1 N sodium hydroxide aqueous solution and 1 ml of water were added to a methanol solution (2 ml) of 266 mg (0.5 mmol) of compound (1b) with ice-cooling, and the obtained solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol-water to give 45.2 mg of white powdery monosodium salt of compound (1b).

(37) Yield: 16%

(38) Melting point: 235 to 238° C.

Example 9

Production of Disodium Salt of a Compound (1b)

(39) ##STR00019##

(40) A 1.0 ml quantity of 1 N sodium hydroxide aqueous solution was added to a methanol solution (2 ml) of 276 mg (0.52 mmol) of compound (1b) with ice-cooling, and the obtained mixture was stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from acetone-water to give 221 mg of white powdery disodium salt of compound (1b).

(41) Yield: 73%

(42) Melting point: 250 to 252° C.

Example 10

Production of Diammonium Salt of Compound (1b)

(43) ##STR00020##

(44) A 1.0 ml quantity of 25% aqueous ammonia solution was added to a methanol solution (2 ml) of 271 mg (0.51 mmol) of compound (1b) with ice-cooling, and the obtained mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol-water to give 104 mg of white powdery diammonium salt of compound (1b).

(45) Yield: 36%.

(46) Melting point: 195 to 198° C.

Example 11

Production of Monopotassium Salt of Compound (1b)

(47) ##STR00021##

(48) A 0.5 ml quantity of 1 N potassium hydroxide aqueous solution was added to a methanol solution (2 ml) of 276 mg (0.52 mmol) of compound (1b) with ice-cooling, and the obtained mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from isopropyl alcohol to give 110.6 mg of white powdery monopotassium salt of compound (1b).

(49) Yield: 37%

(50) Melting point: 200 to 203° C.

Example 12

Production of Dipotassium Salt of Compound (1b)

(51) ##STR00022##

(52) A 1.0 ml quantity of 1 N potassium hydroxide aqueous solution was added to a methanol solution (2 ml) of 276 mg (0.52 mmol) of compound (1b) with ice-cooling, and the obtained mixture was stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. The insoluble matter was collected by filtration and then dried to give 273.9 mg of white powdery dipotassium salt of compound (1b).

(53) Yield: 86%

(54) Melting point: 255 to 265° C. (decomposition)

Example 13

Production of Zinc Salt of Compound (1b)

(55) ##STR00023##

(56) A 1.0 g quantity (1.9 mmol) of compound (1b) was dissolved in 15 ml of methanol, and 0.76 ml of 5 N sodium hydroxide aqueous solution was added to this solution. The mixture was concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of methanol, and 3 ml of methanol solution of 259 mg of zinc chloride was added thereto at room temperature. Precipitated insoluble matter (NaCl) was removed by filtration, and the filtrate was concentrated. To the obtained residue was added 10 ml of water, and stirring was performed with heating. The mixture was then allowed to cool to room temperature. The insoluble matter was collected by filtration, washed with water, and dried under reduced pressure at 60° C. to give 900 mg of white powdery zinc salt of compound (1b).

(57) Yield: 80%

(58) Melting point: 235 to 239° C. (decomposition)

(59) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.3-2.4 (10H, m), 2.8-4.5 (2H, m), 5.3-5.7 (1H, m), 6.6-7.7 (10H, m), 9.7 (1H, br)

Example 14

Production of Ethylenediamine Salt of Compound (1b)

(60) ##STR00024##

(61) A 0.074 ml quantity (1.1 mmol) of ethylenediamine was added to an ethanol solution (10 ml) of 600 mg (1.1 mmol) of compound (1b). The obtained reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from isoporpyl alcohol to give 250 mg of white powdery ethylenediamine salt of compound (1b).

(62) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.5-2.0 (3H, m), 2.1-2.4 (7H, m), 2.77 (4H, s), 2.8-4.3 (2H, m), 5.3-5.5 (1H, m), 6.6-6.9 (1H, m), 6.9-7.2 (2H, m), 7.2-7.5 (5H, m), 7.58 (2H, d, J=7.6 Hz), 9.80 (1H, br)

Example 15

Production of Diethanolamine Salt of Compound (1b)

(63) ##STR00025##

(64) A 0.14 ml quantity (2.3 mmol) of ethanolamine was added to an isopropyl alcohol solution (6 ml) of 600 mg (1.1 mmol) of compound (1b). A 6 ml quantity of isopropyl alcohol was added to the obtained mixture, dissolution was performed with heating, and recrystallization from isopropyl alcohol gave 280 mg of white powdery diethanolamine salt of compound (1b).

(65) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.4-2.0 (3H, R), 2.2-2.5 (7H, m), 2.75 (4H, t, J=5.5 Hz), 3.52 (4H, t, J=5.5 Hz), 2.8-4.3 (2H, m), 5.3-5.5 (1H, m), 6.7-6.9 (1H, m), 6.9-7.2 (2H, m), 7.2-7.4 (4H, m), 7.42 (1H, d, J=7.7 Hz), 7.57 (2H, d, J=6.5 Hz), 7.58 (2H, d, J=7.6 Hz), 9.80 (1H, br)

Example 16

(66) ##STR00026##

(67) A 1.3 ml quantity (6.6 mmol) of diphenyl phosphite was added to a pyridine solution (10 ml) of 1.0 g (2.2 mmol) of tolvaptan (compound (2)) with ice-cooling. The obtained mixture was stirred at 0° C. for 30 minutes, and then at room temperature for 30 minutes. To the reaction mixture was added 0.58 ml of ethanol, and stirring was performed at room temperature for 30 minutes. To this mixture was added 1 N hydrochloric acid, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=27:73.fwdarw.0:100). The purified product was concentrated under reduced pressure, and the residue was dissolved in a mixed solvent of 10 ml of acetonitrile and 10 ml of water and then freeze-dried to give 450 mg of white amorphous solid target compound.

(68) Yield: 38%

(69) .sup.1H-NMR (Toluene-d.sub.8, 100° C.) δ ppm: 1.0-1.1 (3H, m), 1.4-1.9 (4H, m), 2.31 (3H, s), 2.42 (3H, s), 2.0-4.0 (2H, m), 3.7-4.1 (2H, m), 5.5 (0.5H, d, J=4.8 Hz), 6.4-7.5 (10H, m), 7.8 (0.5H, d, J=8.6 Hz)

Example 17

(70) ##STR00027##

(71) A pyridine solution (50 ml) of 10.0 g (22 mmol) of tolvaptan (compound (2)) was ice-cooled, and 13 ml (66 mmol) of diphenyl phosphite was slowly added thereto under a nitrogen atmosphere. The obtained mixture was stirred at room temperature for 30 minutes. To this mixture was added 4.5 ml of methanol, and stirring was performed at room temperature for 30 minutes. The obtained reaction mixture was added with ice-cooling to 325 ml of 2 N hydrochloric acid, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0.fwdarw.93:7). The purified product was concentrated under reduced pressure to give 10.5 g of white amorphous solid target compound.

(72) Yield: 91%

(73) .sup.1H-NMR (Toluene-d.sub.8, 100° C.) δ ppm: 1.5-2.0 (4H, m), 2.41 (3H, s), 2.49 (3H, s), 3.0-4.2 (2H, m), 5.5 (0.5H, d, J=4.8 Hz), 5.5-5.8 (1H, m), 6.6 (1H, d, J=8.3 Hz), 6.7-6.9 (1H, m), 6.9-7.2 (6H, m), 7.3-7.5 (2H, m), 7.81, 7.84 (0.5H, d, J=8.1 Hz)

Example 18

(74) ##STR00028##

(75) A 0.1 ml quantity of water and 254 mg (1.0 mmol) of iodine were added to a pyridine solution (5 ml) of 500 mg (0.95 mmol) of the compound of Example 17, and the obtained mixture was stirred at room temperature for 30 minutes. To this mixture was added 2 ml of triethylamine, and concentration under reduced pressure was performed. A 20 ml quantity of toluene was added to the residue, and concentration under reduced pressure was performed. Water was added to the residue, and washing was performed with a mixed solvent of ethyl acetate and diethyl ether. To the aqueous layer was added 1 N hydrochloric acid, and extraction was performed with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=90:10.fwdarw.50:50). The purified product was concentrated under reduced pressure, and the residue was dissolved in 30 ml of water. The obtained solution was filtered through celite, and the filtrate was freeze-dried to give 140 mg of white amorphous solid target compound.

(76) .sup.1H-NMR (Toluene-d.sub.8, 100° C.) δ ppm: 1.4-2.0 (4H, m), 2.33 (3H, s), 2.34 (3H, s), 2.5-4.5 (5H, m), 5.4-5.7 (2H, m), 6.5 (2H, d, J=7.9 Hz), 6.7 (2H, d, J=7.9 Hz), 6.8-7.2 (5H, m), 7.2-7.4 (2H, m), 7.55 (1H, s)

Example 19

(77) ##STR00029##

(78) A 64 mg quantity (1.0 mmol) of sulfur was added to a pyridine solution (5 ml) of 500 mg (0.9 mmol) of the compound of Example 17, and the obtained mixture was stirred at room temperature for 2 hours. To this mixture was added 1 ml of triethylamine, and concentration under reduced pressure was performed. A 10 ml quantity of toluene was added to the obtained residue, and concentration under reduced pressure was performed. Water was added to the residue for dissolution, and filtration was performed using celite. To the filtrate was added 1 N hydrochloric acid, and extraction was performed with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. Water was added to the obtained residue, and the insoluble matter was collected by filtration and then dried to give 300 mg of white powdery target compound.

(79) .sup.1H-NMR (Toluene-d.sub.8, 100° C.) δ ppm: 1.1-2.0 (4H, m), 2.2-2.5 (6H, m), 3.5 (3H, dd, J=13.9, 14.9 Hz), 2.5-5.0 (2H, m), 3.5-5.7 (1H, m), 6.4-7.5 (10H, m)

Example 20

(80) ##STR00030##

(81) A 0.5 ml quantity of water, 0.5 ml of carbon tetrachloride, 0.5 ml of triethylamine, and 0.072 ml (1.2 mmol) of ethanolamine were added to an acetonitrile solution (5 ml) of 500 mg (0.95 mmol) of the compound of Example 17, and the obtained mixture was stirred at room temperature for 10 minutes. Water was added to this mixture, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0.fwdarw.80:20). The purified product was concentrated under reduced pressure to give 540 mg of white amorphous solid target compound.

(82) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.6-2.3 (4H, m), 2.36 (6H, s), 2.7-3.1 (2H, m), 2.5-4.5 (2H, m), 3.3-3.5 (2H, m), 3.65 (3H, dd, J=9.6, 11.2 Hz), 4.0-4.3 (1H, m), 4.4-4.8 (1H, m), 5.3-5.7 (1H, m), 6.7-7.1 (2H, m), 7.1-7.5 (5H, m), 7.57 (1H, s), 9.76 (1H, s)

Example 21

(83) ##STR00031##

(84) A 0.5 ml quantity of water, 0.5 ml of carbon tetrachloride, 0.5 ml of triethylamine, and 0.119 ml (1.2 mmol) of methylamine (40% methanol solution) were added to an acetonitrile solution (5 ml) of 500 mg (0.95 mmol) of the compound of Example 17, and the obtained mixture was stirred at room temperature for 10 minutes. Water was added to this mixture, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=94:6.fwdarw.85:15). The purified product was concentrated under reduced pressure to give 250 mg of white amorphous solid target compound.

(85) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.7-2.3 (4H, m), 2.37 (6H, s), 2.4-2.6 (3H, m), 2.8-4.3 (2H, m), 3.63 (3H, t, J=10.7 Hz), 4.4-4.8 (1H, m), 5.3-5.6 (1H, m), 6.6-7.1 (2H, m), 7.1-7.5 (5H, m), 7.58 (1H, s), 9.81 (1H, s)

Example 22

(86) ##STR00032##

(87) A 0.5 ml quantity of water, 0.5 ml of carbon tetrachloride, 0.5 ml of triethylamine, and 0.115 ml (1.2 mmol) of diethanolamine were added to an acetonitrile solution (5 ml) of 500 mg (0.95 mmol) of the compound of Example 17, and the obtained mixture was stirred at room temperature for 10 minutes. Water was added to this mixture, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=88:12.fwdarw.70:30). The purified product was concentrated under reduced pressure, and the residue was recrystallized from water-containing methanol to give 250 mg of white powdery target compound.

(88) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.6-2.2 (4H, m), 2.37 (6H, s), 3.0-3.2 (4H, m), 3.5-3.7 (7H, m), 2.8-4.3 (2H, m), 4.1-4.4 (1H, m), 5.3-5.7 (1H, m), 6.7-7.1 (2H, m), 7.1-7.5 (7H, m), 7.5-7.7 (1H, m), 9.80 (1H, br)

Example 23

(89) ##STR00033##

(90) A 3.8 mg (20 mmol) quantity of diphenyl phosphite was added to a pyridine solution (10 ml) of 3.0 g (6.7 mmol) of tolvaptan (compound (2)), and the obtained mixture was stirred at room temperature for 1 hour. To this mixture was added 2 ml of water, and stirring was performed at room temperature for 30 minutes. The obtained reaction mixture was concentrated under reduced pressure, 1 N hydrochloric acid was added to the residue, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated brine twice, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0.fwdarw.50:50). The purified product was concentrated under reduced pressure. The residue was dissolved in water, and the insoluble matter precipitated by adding 1 N hydrochloric acid was collected by filtration and then dried to give 0.83 g of white powdery target compound.

(91) Yield: 24%

(92) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.7-2.2 (4H, m), 2.35 (3H, s), 2.36 (3H, s), 2.8-4.3 (2H, m), 5.4-5.6 (1H, m), 5.8 (0.5H, br), 6.7-7.4 (8H, m), 7.47 (1H, d, J=2.3 Hz), 7.55 (1H, s), 9.79 (1H, br)

Example 24

(93) ##STR00034##

(94) A 2.9 ml quantity of phosphorus trichloride was added under a nitrogen stream to tetrahydrofuran (THF) (29 ml). The obtained mixture was ice-cooled, and 6.1 ml (44 mmol) of triethylamine was added thereto. This mixture was cooled in an ice-methanol bath. A THF solution (120 ml) of 10.0 g (22 mmol) of tolvaptan (compound (2)) was then added dropwise thereto at an internal temperature of not more than −10° C., and stirring was performed at the same temperature for 2 hours. A 130 ml quantity of 1 N sodium hydroxide aqueous solution was added dropwise to the obtained reaction mixture at an internal temperature of not more than 0° C., 200 ml quantity of water was further added thereto, and washing was performed with toluene twice. The obtained aqueous solution was cooled in an ice-methanol bath, 1 N HCl was added dropwise thereto at an internal temperature of not more than 0° C., and extraction was performed with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated to give 6.8 g of white amorphous solid target compound.

(95) Yield: 60%

Example 25

(96) ##STR00035##

(97) quantity of 3.8 ml (20 mmol) of diphenyl phosphite was added to a pyridine solution (10 ml) of 3.0 g (6.7 mmol) of tolvaptan (compound (2)), and the obtained mixture was stirred at room temperature for 1 hour. To this mixture was added 5.2 ml (66.6 mmol) of methyl glycolate, and stirring was performed at room temperature for 12 hours. To the reaction mixture was added 50 ml of water, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with 1 N hydrochloric acid twice, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:50.fwdarw.0:100). The purified product was concentrated under reduced pressure to give 0.79 g of white amorphous solid target compound.

(98) Yield: 20%

(99) .sup.1H-NMR (Toluene-d.sub.8, 100° C.) δ ppm: 1.6-2.2 (4H, m), 2.51 (3H, s), 2.60 (3H, s), 3.2-4.4 (2H, m), 3.53 (3H, s), 4.43 (1H, s), 4.47 (1H, s), 5.87 (0.5H, s), 5.9-6.1 (1H, m), 6.6-6.8 (1H, m), 6.8-7.0 (2H, m), 7.0-7.4 (5H, m), 7.48 (1H, s), 7.63 (1H, s), 8.27 (0.5H, s).

Example 26

(100) ##STR00036##

(101) A 0.8 ml quantity of water was added to a pyridine solution (7.9 ml) of 0.79 g (1.35 mmol) of the compound of Example 25. To the obtained mixture was added with ice-cooling 0.34 g (2.7 mmol) of iodine, and stirring was performed at room temperature for 1 hour. To the reaction mixture was added 1 N hydrochloric acid, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was dissolved in water and then freeze-dried to give 80 mg of white amorphous solid target compound.

(102) Yield: 9.9%

(103) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.7-2.3 (4H, m), 2.35 (3H, s), 2.36 (3H, s), 2.8-4.3 (2H, m), 4.49 (2H, dd, J=1.7, 10.1 Hz), 5.4-5.6 (1H, m), 6.7-7.1 (2H, m), 7.1-7.5 (7H, m), 7.54 (1H, s), 9.79 (1H, br)

Example 27

(104) ##STR00037##

(105) A 3.0 g quantity (6.7 mmol) of tolvaptan (compound (2)) were added in small portions to a pyridine solution (15 ml) of 3.8 ml (20 mmol) of diphenyl phosphite, and the obtained mixture was stirred at room temperature for 0.5 hours. To this mixture was added 2.8 ml (40 mmol) of 3-hydroxypropionitrile, and stirring was performed at room temperature for 0.5 hours. To the obtained reaction mixture was added 1 N hydrochloric acid, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0.fwdarw.10:1). The purified product was concentrated under reduced pressure to give 2.8 g of white amorphous solid target compound.

(106) Yield: 75%

(107) .sup.1H-NMR (Toluene-d.sub.8, 100° C.) δ ppm: 1.4-2.0 (6H, m), 2.33 (3H, s), 2.40 (3H, s), 3.1-3.8 (4H, m), 5.40 (0.5H, d, J=3.1 Hz), 5.3-5.4 (1H, m), 6.5-6.7 (1H, m), 6.7-6.9 (1H, m), 6.9-7.2 (6H, m), 7.2-7.5 (2H, m), 7.76 (0.5H, d, J=8.5 Hz)

Example 28

(108) ##STR00038##

(109) A 0.115 g quantity (3.6 mmol) of sulfur was added to a pyridine solution (10 ml) of 1.0 g (1.8 mmol) of the compound of Example 27, and the obtained mixture was stirred at room temperature for 2 hours. To this mixture was added 1 N hydrochloric acid, and extraction was performed with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0.fwdarw.85:15). The purified product was concentrated under reduced pressure to give 0.91 g of white amorphous solid target compound:

(110) Yield: 85%

(111) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.6-1.9 (3H, m), 2.0-2.3 (1H, m), 2.10 (3H, m), 2.36 (6H, s), 2.3-4.2 (2H, m), 2.7-2.8 (2H, m), 3.9-4.2 (2H, m), 5.5-5.8 (1H, m), 6.7-6.9 (1H, m), 7.0-7.4 (7H, m), 7.4-7.5 (1H, m), 7.56 (1H, s), 7.7-7.8 (0.3H, m), 8.5-8.6 (m, 0.7H), 9.76 (1H, br)

Example 29

(112) ##STR00039##

(113) A 300 mg quantity (0.5 mmol) of the compound of Example 28 was added to 5 ml of 28% aqueous ammonia, and the obtained mixture was stirred at room temperature for three days. To this mixture was added 1 N hydrochloric acid. The precipitated solids were collected by filtration and then dried to give 100 mg of white powdery target compound.

(114) Yield: 37%

(115) .sup.1H-NMR (Pyridine-d.sub.5-D.sub.2O, 90° C.) δ ppm: 1.6-2.4 (4H, m), 2.43 (3H, s), 2.53 (3H, s), 2.8-4.3 (2H, m), 5.1-5.4 (1H, m), 6.8-7.3 (6H, m), 7.4-7.7 (2H, m), 7.7-8.1 (2H, m)

Example 30

(116) ##STR00040##

(117) A 0.62 ml quantity (6.6 mmol) of phosphorus oxychloride and 0.92 ml (6.6 mmol) of triethylamine were added under a nitrogen stream to tetrahydrofuran (THF) (5 ml). The obtained mixture was cooled in an ice-methanol bath. A THF solution (10 ml) of 1.0 g (2.2 mmol) of tolvaptan (compound (2)) was then added dropwise thereto, and stirring was performed at the same temperature for 30 minutes. To this mixture were added 2.8 ml (20 mmol) of triethylamine and 1.1 ml (26.4 mmol) of methanol, and stirring was performed for 30 minutes. Water was added to the obtained reaction mixture, and extraction was performed with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0.fwdarw.80:20). The purified product was concentrated under reduced pressure, and the residue was recrystallized from water-containing methanol to give 400 mg of white powdery target compound.

(118) Yield: 33%

(119) .sup.1H-NMR (DMSO-d.sub.6, 100° C.) δ ppm: 1.7-2.2 (4H, m), 2.36 (6H, s), 2.8-4.3 (2H, m), 3.71 (6H, dd, J=10.2, 11.1 Hz), 5.5-5.6 (1H, m), 6.8-7.1 (2H, m), 7.1-7.5 (7H, m), 7.58 (1H, s), 9.80 (1H, br)

Test Example 1

Solubility of Compound (1b)

(120) Compound (1b) as obtained in Example 3 or 4 was added in excess to 0.1 N sodium phosphate buffer (pH 5, pH 6, pH 7, pH 8, pH 9, or pH 10), 0.1 N Tris/HCl buffer (pH 8 or pH 9), 0.1 N sodium hydrogencarbonate/HCl buffer (pH 8) or 0.1 N sodium citrate buffer (pH 8), and then shaken at room temperature for 16 days. If the test compound dissolved even after about 6 to about 8 w/v % had been added thereto, no further test compound was added.

(121) Each solution was filtered through a 0.45-μm filter, and then, under the following HPLC conditions, the solubility of compound (1b) was determined by absolute calibration.

(122) HPLC Conditions

(123) Detection: ultraviolet absorption photometer

(124) (measurement wavelength: 254 nm)
Column: YMC(ODS) AM-302 (4.6×150 mm)
Column temperature: constant temperature of approximately 2′5° C.
Eluate: acetonitrile/water/phosphoric acid=450/550/1
Flow rate: 1 ml/min
Injection volume: 10 μl

(125) TABLE-US-00001 TABLE 1 Solubility of compound (1b) in buffer solution (room temperature) Solubility of Solvent pH before pH after compound (1b) (100 mM buffer) dissolution dissolution (w/v %) Sodium phosphate buffer 5 3.0 0.58 6 3.0 1.31 7 3.1 0.76 8 3.3 at least 7.1* 9 3.3 at least 7.4* 10 3.4 at least 6.5* Tris buffer 8 2.9 0.74 9 3.4 at least 6.3* Citric acid buffer 8 4.2 at least 8.3* Sodium hydrogencarbonate 8 3.1 at least 7.1* buffer *Sample having a solubility so high that crystals could not be added in excess

Test Example 2

Solubility of Salt of Compound (1)

(126) A suitable amount of test compound is added to a test tube, and 2.5 ml of water is added thereto. After shaking at 37° C. for 30 minutes, the mixture is filtered through a 0.45-μm membrane filter, and 0.5 ml of the filtrate is accurately weighed. Mobile phase is added thereto to make exactly 50 ml, preparing a test solution (dilution ratio: 100-fold). Approximately 5 mg of free-form authentic sample is accurately weighed, and acetonitrile is added thereto to make exactly 50 ml. A 2 ml of this liquid is accurately weighed, and mobile phase is added thereto to make exactly 20 ml, preparing a standard solution (equivalent to 10 μg/ml). By liquid chromatography under the following conditions, 20 μl of both the test solution and standard solution are tested to obtain the peak areas At and As of the test solution and standard solution.
Concentration(μg/ml)=Ws/5×10×At/As×100=Ws×At/As×200
Ws: weighed amount of authentic sample (mg)
Test Conditions Detection: ultraviolet absorption photometer (measurement wavelength: 254 nm) Column: TOSOH TSKgel ODS-80Ts (0.46 cm×15 cm) Column temperature: constant temperature of approximately 40° C. Mobile phase: water/acetonitrile/trifluoroacetic acid=500/500/1 Flow rate: 1 ml/min

(127) TABLE-US-00002 TABLE 2 Test compound (Example No.) Solubility (w/v %) 5 >0.1 7 >0.1 8 >0.1 11 >0.1 16 >0.1 17 >0.1 20 >0.1 31 >0.1

Test Example 3

Solubility of Tolvaptan

(128) Tolvaptan was added in excess to Britton-Robinson buffer (pH 2, pH 7, or pH 12) or purified water, and then shaken at 25° C.±1° C. for 4 hours. Each solution was filtered through a filter, and then, using HPLC, the solubility of tolvaptan was quantified by absolute calibration.

(129) TABLE-US-00003 TABLE 3 Solubility of tolvaptan in Britton- Robinson buffer and purified water Solvent Solubility of tolvaptan (w/v %) Water 0.00002 pH 2 0.00002 pH 7 0.00003 pH 12 0.00002

Test Example 4

Serum Concentration of Tolvaptan in Female Rats after Tail-Vein Administration of a Compound (1b) Solution

(130) Experiment Method

(131) A solution of compound (1b) (equivalent to 1 mg of tolvaptan per ml of solution) was prepared.

(132) TABLE-US-00004 TABLE 4 Formulation (in 1 ml) Amount (mg) Compound (1b) 1.0* Sodium dihydrogen- 0.79 phosphate•dihydrate Mannitol 50 .sup.  Sodium hydroxide Suitable amount to adjust to pH 7.0 Water for Injection Suitable amount *Amount equivalent to 1.0 mg of tolvaptan per ml of solution
Preparation Method

(133) A 79 mg quantity of sodium dihydrogenphosphate•dihydrate and 5 g of mannitol were dissolved in about 90 ml of water for injection. A sodium hydroxide solution was added thereto, and a solution of pH 7 was prepared. Compound (1b) equivalent to 100 mg of tolvaptan was dissolved in this solution. A sodium hydroxide solution was added thereto, and the pH was adjusted to 7. Injection solvent was added to the obtained solution to make 100 ml, and sterile filtration was performed with a 0.2-μm filter to prepare a solution of compound (1b) (equivalent to 1 mg of tolvaptan per ml of solution).

(134) This solution was rapidly administered to female rats via the tail vein at a dose such that 1 mg of tolvaptan is produced per kg of body weight. From time to time, blood was collected from the jugular vein under light ethyl ether anesthesia, and serum concentration of tolvaptan was determined by high-speed liquid chromatography (HPLC).

(135) The results are shown in FIG. 1.

(136) Tolvaptan was initially detected five minutes after the intravenous administration of a solution of compound (1b) to female rats. This indicates that compound (1b) is rapidly hydrolyzed into tolvaptan in rats.

Test Example 5

Serum Concentration of Tolvaptan in Female Rats after Oral Administration of a Compound (1b) Solution

(137) Experiment Method

(138) A solution of compound (1b) (equivalent to 0.4 mg of tolvaptan per ml of solution) was prepared.

(139) TABLE-US-00005 TABLE 5 Formulation (in 1 ml) Amount (mg) Compound (1b) 0.4* Sodium hydrogencarbonate 2   Sodium hydroxide Suitable amount (pH 9.1) Water for Injection Suitable amount *Amount equivalent to 0.4 mg of tolvaptan per ml of solution
Preparation Method

(140) A 1 g quantity of sodium hydrogencarbonate was dissolved in about 400 ml of water for injection. A sodium hydroxide solution was added thereto to adjust the pH to 9.0, and water for injection was added thereto, preparing 500 ml of 0.2% sodium hydrogencarbonate solution. An 89 μl quantity of 1 N sodium hydroxide solution and compound (1b) equivalent to 20 mg of tolvaptan were added to about 40 ml of this 0.2% sodium hydrogencarbonate solution and dissolved. A 0.2% sodium hydrogencarbonate solution was further added thereto to make 50 ml, thereby preparing a solution of compound (1b) (equivalent to 0.4 mg of tolvaptan per ml of solution). The pH of this solution was 9.1. This solution is called “Solution A” hereinafter.

(141) A spray-dried tolvaptan powder equivalent to 60 mg of tolvaptan, which was prepared in a similar manner to Example 3 of JP1999-21241-A, was suspended in 50 ml of water for injection in a porcelain mortar. This suspension was diluted three-fold with water for injection, preparing a suspension of spray-dried powder equivalent to 0.4 mg of tolvaptan per ml of suspension. This suspension is called “Suspension B” hereinafter.

(142) The following tests were performed in order to examine the oral absorption characteristics of Solution A and Suspension B. Wistar female rats (body weight about 160 g) which had been fasted for about 18 hours were used as test animals. Solution A and Suspension B were each administered by forced oral administration using a sonde for oral administration at a dose of 2.5 ml/kg of body weight, producing 1 mg of tolvaptan per kg of body weight. The blood samples were collected from the jugular vein under light ethyl ether anesthesia periodically after dosing, and the serum concentrations of tolvaptan were determined by using HPLC-MS/MS (Waters).

(143) The obtained results are shown in FIG. 2 and Table 6. FIG. 2 shows the serum concentration-time profiles of tolvaptan after an oral administration of Solution A and suspension B (n=4). Table 6 shows the mean of the pharmacokinetic parameter values (n=4). The parameters in Table 6 have the following meanings. AUC.sub.8hr: area under the serum concentration-time curve for up to 8 hours after administration (ng.Math.hr/ml) AUC.sub.∞: area under the serum concentration-time curve for up to an infinite time after administration (ng.Math.hr/ml) C.sub.max: maximum serum concentration (ng/ml) T.sub.max: time to reach the maximum serum concentration (hr)

(144) As a result, it was confirmed that that the solution of compound (1b) (Solution A) takes a shorter time to reach the maximum serum concentration than the suspension of spray-dried tolvaptan (Suspension B), and also leads to greater maximum serum concentration (C.sub.max) and larger areas under the serum concentration-time curve (AUC.sub.8hr, AUC.sub.∞).

(145) TABLE-US-00006 TABLE 6 AUC.sub.8 hr C.sub.max T.sub.max AUC.sub.∞ (ng .Math. hr/mL) (ng/mL) (hr) (ng .Math. hr/mL) Solution A 217.5 61.0 1.3 230.1 Suspension B 73.2 26.4 1.5 76.1

(146) These results revealed that when administered in vivo, the compound of the present invention, compound (1b) in particular, increases absorption even more than conventional absorption improvement by amorphization, and consequently improves bioavailability of tolvaptan.

Preparation Example 1

(147) A 79 mg quantity of sodium dihydrogenphosphate•dihydrate and 5 g of mannitol were dissolved in about 90 ml of injection solvent. A sodium hydroxide solution was added thereto, preparing a solution of pH 7. Compound (1b) equivalent to 100 mg of tolvaptan was added to this solution. A sodium hydroxide solution was added thereto, adjusting the pH to 7. Injection solvent was added to the obtained solution to make 100 ml, and sterile filtration was performed using a 0.2-μm filter to give an injection of the present invention containing compound (1b) (equivalent to 1 mg of tolvaptan per ml of injection).

Preparation Example 2

(148) A 79 mg of sodium dihydrogenphosphate•dihydrate and 5 g mannitol were dissolved in about 90 ml of injection solvent. A sodium hydroxide solution was added thereto, preparing a solution pH of 7.5. Compound (1b) equivalent to 10 mg of tolvaptan was dissolved in the solution. Injection solvent was added to the obtained solution to make 100 ml, and sterile filtration was performed with a 0.2-μm filter to prepare an injection of the present invention containing compound (1b) (equivalent to 0.1 mg tolvaptan per ml of injection).

Preparation Example 3

(149) A 380 mg quantity of trisodium phosphate•dodecahydrate and g of mannitol were dissolved in about 90 ml of injection solvent. Compound (1b) equivalent to 100 mg, 300 mg or 1000 mg of tolvaptan was dissolved in the obtained solution. When dissolving compound (1b) equivalent to 1000 mg of tolvaptan, a sodium hydroxide solution was added to improve the solubility. The pH of each obtained solution was adjusted to 8 to 9 with sodium hydroxide or hydrochloric acid, and an injection solvent was added thereto to make 100 ml. The obtained solution was sterile-filtered through a 0.2-μm filter, preparing injections of the present invention containing compound (1b) (equivalent to 1 mg, 3 mg or 10 mg of tolvaptan per ml of injection).