BENZAZEPINE COMPOUNDS, PREPARATION METHOD THEREFOR AND PHARMACEUTICAL USE THEREOF

Abstract

Benzazepine compounds, a preparation method therefor and pharmaceutical use thereof. Specifically, the present invention relates to a compound represented by formula II-1 or formula VIII-1, a pharmaceutical composition containing same, and pharmaceutical use thereof. The benzazepine compounds can be used for treating diseases associated with vasopressin receptors, in particular hypertension, heart disease, etc.

##STR00001##

Claims

1. A compound of formula II-1 or a pharmaceutically acceptable salt thereof, ##STR00041## wherein, Q is ##STR00042## wherein: L.sup.1 is (CH.sub.2).sub.m, and the (CH.sub.2) is optionally replaced by a heteroatom selected from the group consisting of O, S and N; L.sup.2 is (CH.sub.2).sub.n, and the (CH.sub.2) is optionally replaced by a heteroatom selected from the group consisting of O, S and N; m is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6; n is selected from the group consisting of 1, 2, 3, 4, 5 and 6; the (CH.sub.2) of L.sup.2 is optionally substituted with A; X is selected from the group consisting of O and S; R.sup.1 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl; the C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with group B; R.sup.2 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl; the C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with group B; R.sup.3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl; the C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with group B; or R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3, together with the N atom to which they are attached, form a 3-12 membered heterocyclyl group containing 1-3 heteroatoms; the 3-12 membered heterocyclyl group is optionally substituted with group B; A is selected from the group consisting of H, COOH, NH.sub.2, OH, halogen, cyano, nitro, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, 3-12 membered heterocyclyl, COR.sup.4, NHCOR.sup.4 and OCOR.sup.4; the NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with R.sup.4; R.sup.4 is selected from the group consisting of halogen, NH.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl; the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more groups selected from the group consisting of COOH, NH.sub.2, OH, halogen, cyano, nitro, oxo, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; group B is selected from the group consisting of H, COOH, NH.sub.2, OH, halogen, cyano, nitro and oxo.

2. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 1, wherein X is O.

3. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 2, wherein n is selected from the group consisting of 2, 3, 4 and 5.

4. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 2, wherein m is selected from the group consisting of 0, 1, 2, 3, 4 and 5.

5. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 2, wherein A is selected from the group consisting of H, COOH, NH.sub.2, OH, halogen, cyano, nitro, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl; the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with R.sup.4; R.sup.4 is selected from the group consisting of halogen, NH.sub.2, OH and C.sub.1-6 alkyl.

6. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 5, wherein L.sup.1 is CH.sub.2O, or L.sup.2 is (CH.sub.2).sub.m, and m is 0.

7. (canceled)

8. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 6, wherein L.sup.2 is (CH.sub.2).sub.2.

9. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 8, wherein R.sup.1 is C.sub.1-3 alkyl.

10. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 9, wherein R.sup.2 is C.sub.1-3 alkyl.

11. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 9, wherein R.sup.3 is C.sub.1-3 alkyl.

12. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 1, wherein, X is O; L.sup.1 is (CH.sub.2).sub.m, and m is 0; or L.sup.1 is CH.sub.2O; L.sup.2 is (CH.sub.2).sub.n, and n is selected from the group consisting of 2 and 3; R.sup.1 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl; R.sup.2 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl; and R.sup.3 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.

13. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 12, wherein the compound is selected from the group consisting of: ##STR00043##

14.-20. (canceled)

21. An isotopically substituted form of the compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the isotopic substitution is a substitution with a deuterium atom.

22. A pharmaceutical composition comprising at least one compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable excipient.

23. (canceled)

24. A method for preventing and/or treating hypertension, edema, abdominal dropsy, heart failure, renal dysfunction, syndrome of inappropriate vasopressin secretion, cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, polycystic kidney disease, cerebral infarction or myocardial infarction in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 22.

25. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 3, wherein n is selected from the group consisting of 2 and 3.

26. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 4, wherein m is selected from the group consisting of 0, 1, 2 and 3.

27. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 5, wherein A is selected from the group consisting of H, COOH, NH.sub.2, OH, halogen, cyano and nitro

28. The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 12, wherein, R.sup.1 is methyl, R.sup.2 is methyl, and R.sup.3 is methyl.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0249] FIG. 1 shows blood sodium curves of the compounds of the present invention in beagles.

[0250] FIG. 2 shows PK curves in beagle plasma after oral administration of compound 5 capsules and tolvaptan tablets.

[0251] FIG. 3 shows the urine volume of beagles during 0-6 h after oral administration of compound 5 capsules and tolvaptan tablets.

DETAILED DESCRIPTION

[0252] The present disclosure is further described below with reference to examples, which are not intended to limit the scope of the present disclosure.

[0253] Experimental procedures without conditions specified in the examples of the present disclosure were generally conducted according to conventional conditions, or according to conditions recommended by the manufacturers of the starting materials or commercial products. Reagents without origins specified are commercially available conventional reagents.

[0254] The structures of the compounds were determined by nuclear magnetic resonance (NMR) spectroscopy and/or mass spectrometry (MS).

[0255] NMR shifts (?) were given in 10.sup.?6 (ppm). NMR analysis was performed on a Bruker AVANCE-400 nuclear magnetic resonance instrument, with deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3) and deuterated methanol (CD.sub.3OD) as solvents and tetramethylsilane (TMS) as an internal standard.

[0256] MS analysis was performed on an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent; MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/Waters SQ Detector) and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0257] High performance liquid chromatography (HPLC) analysis was performed using the following HPLC instruments: Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0258] Chiral HPLC analysis was performed on an Agilent 1260 DAD high performance liquid chromatograph.

[0259] Preparative high performance liquid chromatography used Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0260] Preparative chiral chromatography used a Shimadzu LC-20AP preparative chromatograph.

[0261] The CombiFlash preparative flash chromatograph used was CombiFlash Rf200 (TELEDYNE ISCO).

[0262] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, 0.15-0.2 mm layer thickness, were adopted for thin-layer chromatography (TLC) analysis and 0.4-0.5 mm layer thickness for TLC separation and purification.

[0263] Silica gel column chromatography generally used 200- to 300-mesh silica gel (Huanghai, Yantai) as the carrier.

[0264] Known starting materials described herein may be synthesized using or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Chembee Chemicals, and other companies.

[0265] In the examples, the reactions could all be performed in an argon atmosphere or a nitrogen atmosphere unless otherwise specified.

[0266] The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon containing about 1 L of argon or nitrogen.

[0267] The hydrogen atmosphere means that the reaction flask is connected to a balloon containing about 1 L of hydrogen.

[0268] Pressurized hydrogenation reactions were performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogenator, or an HC2-SS hydrogenator.

[0269] Hydrogenation reactions generally involve 3 cycles of vacuumization and hydrogen purging.

[0270] Microwave reactions were performed on a CEM Discover-S 908860 microwave reactor.

[0271] In the examples, a solution refers to an aqueous solution unless otherwise specified.

[0272] In the examples, the reaction temperature refers to room temperature, preferably 20? C. to 30? C., unless otherwise specified.

Example 1

Preparation of Disodium (7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-benzo[b]azepine-5-oxycarbonyl)-L-glutamate (Compound 1)

[0273] ##STR00029## ##STR00030##

Step 1: Preparation of Compound 1-d

[0274] Commercially available tolvaptan 1-a (300 mg, 0.67 mmol), compound 1-b (204 mg, 0.67 mmol) and diisopropylethylamine (432 mg, 3.35 mmol) were dissolved in N,N-dimethylformamide (10 mL) in a nitrogen atmosphere, and the solution was stirred at room temperature for 3 h. Compound 1-c (297 mg, 1.005 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. After concentration, the residue was separated and purified by column chromatography to give compound 1-d (494 mg, yield: 93.92%).

[0275] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.45-10.15 (m, 1H), 7.86-7.65 (m, 1H), 7.60-7.51 (m, 1H), 7.46-7.33 (m, 3H), 7.33-7.24 (m, 3H), 7.18-7.08 (m, 1H), 7.01-6.58 (m, 2H), 5.96-5.60 (m, 1H), 5.00-4.52 (m, 1H), 4.08-3.92 (m, 1H), 2.84-2.72 (m, 1H), 2.43-2.31 (m, 6H), 2.30-2.21 (m, 3H), 2.21-2.11 (m, 1H), 2.07-1.92 (m, 1H), 1.89-1.67 (m, 2H), 1.59-1.47 (m, 1H), 1.41 (s, 9H), 1.40 (s, 9H).

Step 2: Preparation of Compound 1-e

[0276] Compound 1-d (394 mg, 0.88 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 24 h. A saturated solution of sodium carbonate was added to adjust the pH to 9-10. The mixture was washed with dichloromethane. The aqueous phase was adjusted to pH 1-2 with a 1 mol/L hydrochloric acid solution and extracted with ethyl acetate. After concentration, the residue was purified by preparative HPLC to give compound 1-e (163 mg, yield: 48.82%).

[0277] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 12.65 (br, 2H), 10.44-10.10 (m, 1H), 7.99-7.72 (m, 1H), 7.67-7.53 (m, 1H), 7.48-7.35 (m, 3H), 7.33-7.19 (m, 3H), 7.17-7.03 (m, 1H), 7.00-6.60 (m, 2H), 5.87-5.60 (m, 1H), 4.97-4.53 (m, 1H), 4.13-3.98 (m, 1H), 2.85-2.65 (m, 1H), 2.43-2.26 (m, 8H), 2.23-2.10 (m, 1H), 2.10-1.91 (m, 2H), 1.90-1.45 (m, 3H).

Step 3: Preparation of Compound 1

[0278] Sodium hydroxide (12.9 mg, 0.32 mmol) was dissolved in water (15 mL). The solution was cooled to 0? C., and a solution of compound 1-e (100 mg, 0.16 mmol) in acetonitrile (5 mL) was added dropwise with stirring. After the addition, the mixture was stirred for another 5 min. The mixture was lyophilized in vacuo to remove the solvent to give compound 1 (101 mg, yield: 94.39%).

[0279] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.45-10.12 (m, 1H), 7.85-7.60 (m, 1H), 7.59-7.15 (m, 7H), 7.15-7.02 (m, 1H), 7.01-6.57 (m, 2H), 5.96-5.57 (m, 1H), 5.00-4.55 (m, 1H), 3.90-3.75 (m, 1H), 2.83-2.70 (m, 1H), 2.43-2.31 (m, 6H), 2.27-2.03 (m, 3H), 2.03-1.83 (m, 2H), 1.83-1.47 (m, 3H).

[0280] MS: m/z [M+H].sup.+: 622.2.

Example 2

Preparation of 7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl methyl((S)-pyrrolidin-2-yl)methyl)carbamate (Compound 3) hydrochloride

[0281] ##STR00031##

Step 1: Preparation of Compound 3-b

[0282] Commercially available tolvaptan 1-a (225 mg, 0.500 mmol), di(p-nitrophenyl)carbonate (175 mg, 0.580 mmol) and diisopropylethylamine (323 mg, 2.50 mmol) were weighed into a reaction flask, and dry N,N-dimethylformamide (10 mL) was added. The mixture was stirred at room temperature for 3 h in a nitrogen atmosphere. Then, tert-butyl (S)-2-((methylamino)methyl)pyrrolidine-1-carboxylate (161 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate and water were added to dilute the reaction mixture. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and then with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography to give compound 3-b (280 mg, yield: 81%).

[0283] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.23 (s, 1H), 7.81-6.55 (m, 10H), 6.02-5.66 (m, 1H), 4.92-4.52 (m, 1H), 4.23-3.80 (m, 1H), 3.63-3.21 (m, 1H), 3.28-2.71 (m, 7H), 2.36 (s, 6H), 2.25-1.62 (m, 8H), 1.40 (s, 9H).

Step 2: Preparation of Compound 3

[0284] Compound 3-b (100 mg, 0.145 mmol) was weighed out. The system was purged with nitrogen three times, and a solution of hydrogen chloride in ethyl acetate (5.0 mL, 2.0 M) was added under an ice-water bath. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and triturated with ethyl acetate (4.0 mL) at room temperature for 1 h. The triturate was filtered, and the filter cake was washed with ethyl acetate (1 mL) and dried under reduced pressure to give the hydrochloride of compound 3 (75 mg, yield: 82%).

[0285] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.82-6.38 (m, 10H), 5.97-5.68 (m, 1H), 4.95-4.48 (m, 1H), 4.08-3.74 (m, 2H), 3.36-2.71 (m, 7H), 2.33 (s, 6H), 2.22-1.46 (m, 8H).

Example 3

Preparation of 7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-benzo[b]azepin-5-(2-(trimethylammonio)ethyl) phosphate (Compound 4)

[0286] ##STR00032## ##STR00033##

Step 1: Preparation of Compound 4-b

[0287] Commercially available tolvaptan 1-a (224 mg, 0.5 mmol) was dissolved in tetrahydrofuran (5 mL) in a nitrogen atmosphere, and the solution was cooled to ?60? C. Lithium bis(trimethylsilyl)amide (1.5 mL, 1.5 mmol, 1 M in THF) was slowly added dropwise. After the addition, the mixture was stirred at ?60? C. for 0.5 h. A solution of compound 4-a (538 mg, 1.0 mmol) in THE (2 mL) was then added dropwise. After the addition, the mixture was warmed to room temperature and allowed to react overnight. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was separated and purified by column chromatography to give compound 4-b (323 mg, yield: 91.11%).

[0288] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.44-10.14 (m, 1H), 7.81-7.45 (m, 3H), 7.45-7.21 (m, 15H), 7.20-7.00 (m, 1H), 6.87-6.62 (m, 1H), 5.72-5.45 (m, 1H), 5.17-4.96 (m, 3H), 4.94-4.46 (m, 1H), 3.52-3.37 (m, 1H), 2.85-2.69 (m, 1H), 2.45-2.25 (m, 6H), 2.25-2.08 (m, 1H), 1.95-1.45 (m, 3H).

Step 2: Preparation of Compound 4-c

[0289] Compound 4-b (323 mg, 0.46 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (6 mL). The solution was stirred at room temperature for 24 h. After concentration, the residue was diluted with ethyl acetate, and the pH was adjusted to 9-10 with a 1 mol/L solution of sodium hydroxide. The organic phase was extracted with water twice. The aqueous phases were combined, adjusted to pH 1-2 with a 1 mol/L HCl solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to give compound 4-c (190 mg, yield: 78.84%).

[0290] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.44-10.18 (m, 1H), 7.80-7.52 (m, 1H), 7.49-7.35 (m, 3H), 7.34-7.24 (m, 3H), 7.22-7.12 (m, 1H), 6.90-6.61 (m, 2H), 5.54-5.25 (m, 2H), 4.94-4.55 (m, 1H), 2.84-2.64 (m, 1H), 2.43-2.19 (m, 8H), 2.04-1.48 (m, 3H).

Step 3: Preparation of Compound 4

[0291] Compound 4-c (300 mg, 0.57 mmol), compound 4-d (700 mg, 2.84 mmol) and potassium carbonate (391 mg, 2.84 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the reaction was heated at 90? C. for 24 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 4 (154 mg, yield: 44.25%).

[0292] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.44-10.16 (m, 1H), 7.80-7.49 (m, 2H), 7.49-7.22 (m, 5H), 7.21-7.04 (m, 1H), 6.99-6.89 (m, 1H), 6.85-6.59 (m, 1H), 5.45-5.07 (m, 1H), 4.92-4.50 (m, 1H), 4.17-3.87 (m, 2H), 3.63-3.47 (m, 2H), 3.25-2.87 (m, 9H), 2.79-2.65 (m, 1H), 2.43-2.30 (m, 6H), 2.29-2.17 (m, 1H), 2.05-1.85 (m, 1H), 1.77-1.65 (m, 1H), 1.62-1.44 (m, 1H).

[0293] MS: m/z [M+H].sup.+: 614.2.

Example 4

Preparation of ((7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)oxy)methyl (2-(trimethylammonio)ethyl) phosphate (Compound 5)

[0294] ##STR00034##

[0295] Compound 5-a (prepared according to the method disclosed in WO2009/1968) (368 mg, 0.660 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (10 mL), potassium carbonate (910 mg, 6.60 mmol), and (2-bromoethyl)trimethylammonium bromide (1.63 g, 6.60 mmol) were added sequentially. The reaction was heated at 65? C. for 16 h. The reaction mixture was filtered. The filtrate was purified by preparative HPLC to give compound 5 (75 mg, yield: 17.68%).

[0296] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.41-10.24 (m, 1H), 7.54-6.74 (m, 10H), 5.22-4.94 (m, 2H), 4.86-4.58 (m, 1H), 4.06-3.99 (m, 2H), 3.51-3.44 (m, 2H), 3.13-3.08 (m, 9H), 2.78-2.67 (m, 1H), 2.40-2.34 (m, 6H), 2.23-1.47 (m, 5H).

Example 5

Preparation of ((7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)oxy)methyl L-valinate (Compound 11) hydrochloride

[0297] ##STR00035## ##STR00036##

Step 1: Preparation of Compound 11-b

[0298] Compound 11-a (200 mg, 0.393 mmol) (prepared according to the method disclosed in US2011/71084), N-Boc-L-valine (85 mg, 0.393 mmol), copper bromide (263 mg, 1.18 mmol), TBAB (380 mg, 1.18 mmol) and molecular sieve (560 mg) were weighed out. The system was purged with nitrogen three times, and DMF (7.5 mL) was added under an ice-water bath. The mixture was stirred at room temperature for 10 min. The ice-water bath was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite under reduced pressure, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was washed with water (25 mL?3) and then saturated brine (25 mL). The organic phase was dried, filtered and concentrated under reduced pressure to give a crude product (650 mg). The crude product was separated and purified by silica gel column chromatography to give compound 11-b (270 mg, yield: 100%).

[0299] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.07-6.45 (m, 10H), 5.68-5.31 (m, 2H), 5.20-4.65 (m, 3H), 4.32-4.12 (m, 1H), 2.60-2.35 (m, 6H), 2.28-2.11 (m, 1H), 1.86-1.60 (m, 4H), 1.52-1.19 (m, 9H), 1.05-0.77 (m, 6H).

Step 2: Preparation of Compound 11

[0300] Compound 11-b (270 mg, 0.398 mmol) was weighed out, and dichloromethane (24 mL) was added. The mixture was stirred to dissolve the compound completely. The solution was cooled to 5? C. in an ice-water bath in a nitrogen atmosphere, and TFA (3.0 mL) was added. After the addition, the mixture was stirred at that temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 11 (77 mg, yield: 29%).

[0301] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.44-10.17 (m, 1H), 8.38 (s, 3H), 7.82-7.19 (m, 8H), 7.19-6.91 (m, 1H), 6.87-6.61 (m, 1H), 5.83-5.43 (m, 2H), 5.38-5.06 (m, 1H), 5.01-4.80 (m, 1H), 4.58 (s, 1H), 4.02 (s, 1H), 2.44-2.28 (m, 6H), 2.26-2.07 (m, 2H), 2.07-1.87 (m, 1H), 1.85-1.66 (m, 1H), 1.65-1.43 (m, 1H), 1.10-0.70 (m, 6H).

Example 6

Preparation of ((((7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)oxy)formyloxy)methyl L-valinate (Compound 16) hydrochloride

[0302] ##STR00037## ##STR00038##

Step 1: Preparation of Compound 16-b

[0303] Compound 16-a (prepared according to the method disclosed in US2011/71084) (350 mg, 0.67 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (4 mL) was added. The mixture was stirred at room temperature to dissolve the compound completely. After the system was purged with argon three times, sodium iodide (150 mg, 1.00 mmol), N-Boc-L-valine (220 mg, 1.50 mmol) and diisopropylethylamine (432 mg, 3.30 mmol) were added sequentially. The reaction was heated at 50-55? C. for 16 h. 20 mL of purified water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL?2). The organic phase was collected, washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound 16-b (470 mg, yield: 97.01%).

[0304] MS: m/z [M+H].sup.+: 722.3.

Step 2: Preparation of (16)

[0305] Compound 16-b (470 mg, 0.650 mmol) was weighed into a reaction flask, and 1,4-dioxane (8 mL) was added. The mixture was cooled to 0-5? C., and a 4 mol/L solution of hydrogen chloride in dioxane (8 mL) was added. The mixture was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure. The crude product was purified by preparative HPLC to give the hydrochloride of compound 16 (175 mg, yield: 41.95%).

[0306] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.43-10.27 (m, 1H), 8.55 (s, 3H), 7.74-6.69 (m, 10H), 6.08-5.80 (m, 3H), 4.86-4.60 (m, 1H), 4.08-4.02 (m, 1H), 2.83-2.67 (m, 1H), 2.39-2.34 (m, 6H), 2.21-1.76 (m, 5H), 1.01-0.88 (m, 6H).

Example 7

Preparation of 2-(2-((7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)oxymethoxy)-2-oxoethoxy)acetic acid (Compound 14)

[0307] ##STR00039##

[0308] Compound 14-a (250 mg, 0.491 mmol) (prepared according to the method disclosed in US2011/71084), diglycolic acid (99 mg, 0.737 mmol), copper bromide (329 mg, 1.47 mmol), TBAB (475 mg, 1.47 mmol) and molecular sieve (700 mg) were weighed out. The system was purged with nitrogen three times. DMF (10 mL) was added under an ice-water bath, and the mixture was stirred at that temperature for 10 min. The ice-water bath was removed, and the mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through celite under reduced pressure, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was washed with water (40 mL?2) and then saturated brine (40 mL). The organic phase was dried, filtered and concentrated under reduced pressure to give a crude product (700 mg). The crude product was purified by preparative HPLC to give compound 14 (190 mg, yield: 65%). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ? 7.77-6.61 (m, 10H), 5.60-4.45 (m, 4H), 4.20-3.95 (m, 2H), 3.92-3.78 (m, 3H), 2.41-2.28 (m, 6H), 2.25-1.35 (m, 4H).

Example 8

Preparation of Compound M

[0309] ##STR00040##

Step 1: Preparation of Compound M-1

[0310] Commercially available tolvaptan 1-a (500 mg, 1.11 mmol) was weighed out and dissolved in dichloromethane, N-(tert-butoxycarbonyl)-L-valine (291 mg, 1.34 mmol) and DMAP (13 mg, 0.11 mmol) were added, and DCC (276 mg, 1.34 mmol) was added under an ice bath. The reaction was conducted at room temperature overnight. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a pale yellow gum (890 mg, compound M-1). The gum was directly used in the next step without purification.

[0311] MS: calculated 647.3, found 648.3[M+H].

Step 2: Preparation of Compound M

[0312] Compound M-1 (1.11 mmol) was weighed out. The system was purged with nitrogen three times, and a solution of hydrogen chloride in dioxane (5.0 mL, 4.0 M) was added under an ice-water bath. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give a pale yellow solid (700 mg, crude). The crude product was separated and purified by reversed-phase column chromatography and lyophilized to give compound M as a white solid (450 mg, yield: 69%).

[0313] MS: calculated 547.2, found 548.2[M+H].

[0314] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.99-8.41 (m, 3H), 8.11-5.87 (m, 11H), 4.88-0.396 (m, 1H), 2.81-0.87 (m, 20H).

Biological Assays

Test Example 1: Pharmacokinetic Study in Dogs

1. PK Study in Dogs

1.1. Study Protocol

1.1.1. Experimental Animals: Beagles, Non-Na?ve, Sourced from the Animal Repository of Medicilon: 999M-004.

1.1.2. Administration Regimen:

[0315]

TABLE-US-00001 Number of animals Route of Dose Concentration Dose volume Group Molecule (Male + female) administration (mg/kg) (mg/mL) (mL/kg) 1 Tolvaptan 2 + 1 PO* 1 0.5 2 2 Compound 5 2 + 1 PO* 4.3 2.15 2 *All animals were fasted overnight (10-18 h) before administration and feeding was resumed 4 h after administration.

1.1.3. Sample Preparation Method

[0316] A proper amount of tolvaptan and compound 5 was accurately weighed out and well mixed with a proper volume of 1% hydroxypropyl methylcellulose by vortexing or ultrasonication to give a 0.5 mg/mL solution of tolvaptan and a 2.15 mg/mL solution of compound 5 for intragastric administration.

1.1.4. Test Method

[0317] Tolvaptan and compound 5 were intragastrically administrated. Blood was collected before the administration and 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after the administration. EDTA-K2 was used as the anticoagulant, and the esterase inhibitor DDVP (manufacturer: Sigma) was added. Plasma samples were separated and cryopreserved at ?70? C., and the compound 5 and tolvaptan levels were determined by LC-MS/MS.

1.2. Experimental Results

[0318]

TABLE-US-00002 TABLE 1 Molecule C.sub.max AUC.sub.0-t AUC.sub.0-? adminis- Molecule T.sub.max (ng/ (h*ng/ (h*ng/ t.sub.1/2 trated detected (h) ml) ml) ml) (h) Tolvaptan Tolvaptan Mean 1.5 7.08 21.6 26.3 1.94 value SD 0.866 1.66 6.76 5.28 0.527 Com- Com- Mean 0.389 88.7 156 162 1.43 pound 5 pound 5 value SD 0.193 5.8 36.9 33.7 0.8 Tolvaptan Mean 2 45.9 347 372 4.22 value SD 1.73 5.6 151 135 0.639 Note: T.sub.max is the time to the peak concentration of the drug; C.sub.max is the peak concentration of the drug; AUC.sub.0-t and AUC.sub.0-? are areas under the drug concentration-time curve; t.sub.1/2 is the half-life of the drug in the body.

[0319] After being intragastrically administered to beagles, compound 5 achieved a higher exposure and a longer half-life than tolvaptan after converting into tolvaptan in vivo.

Test Example 2: Inhibitory Activity of the Compound of the Present Invention Against Arginine Vasopressin Receptor 2 (AVPR2)

1. Arginine Vasopressin Receptor 2 (AVPR2) Receptor cAMP Assay

1.1. Sample Preparation Method

[0320] The test compound was 5-fold diluted with assay buffer (Hank's balanced salt solution+20 mM HEPES+0.1% BSA+500 ?M IBMX (manufacturer: Sigma)). The highest initial concentration of the test compound in the assay was 10 ?M.

1.2. Cell Strain

[0321] Flpin-CHO-AVPR2 (the cell strain was constructed by Pharmaron Beijing Co., Ltd.; AVPR2 was derived from humans)

1.3. Test Method

[0322] 1) Cells were digested, resuspended in assay buffer and inoculated into a 384-well cell culture plate at a density of 8000 cells per well and a volume of 15 ?L per well. [0323] 2) The compound was diluted with assay buffer. [0324] 3) 2.5 ?L of the compound was added to each well, and the plate was incubated at 37? C. for 10 min. [0325] 4) Arginine vasopressin (manufacturer: MedChemExpress) was diluted with assay buffer to a concentration of 16 ?M. [0326] 5) 2.5 ?L of the 16 ?M solution of arginine vasopressin was added, and the plate was incubated at 37? C. for 30 min. [0327] 6) Eu-cAMP tracer and Ulight-anti-cAMP were thawed and diluted with lysis buffer (Eu-cAMP tracer, Ulight-anti-cAMP and lysis buffer were all taken from the cAMP assay kit (manufacturer: Perkin Elmer)). [0328] 7) 10 ?L of Eu-cAMP tracer was added to the experimental wells, and then 10 ?L of Ulight-anti-cAMP was added to the experimental wells. [0329] 8) The reaction plate was centrifuged at room temperature at 200 g for 30 s and left at 25? C. for 1 h, and data collection was performed using a microplate reader.
1.4. Experimental results

TABLE-US-00003 TABLE 2 Molecule IC.sub.50 (uM) CN101346390 compound 1b disodium salt* 0.047 Compound 5 0.008 *Hereinafter referred to as compound 1b disodium salt The results show that compound 5 has significantly higher inhibitory activity against the AVPR2 receptor than compound 1b disodium salt.

Test Example 3: Pharmacokinetic Study in Rats

1. PK Study in Rats

1.1. Study Protocol

1.1.1. Experimental Animals: SD Rats, Male and Female, Weighing about 220 g. Housing Environment: SPF. The Animals were Transferred from the Animal Repository (999M-017) of the Laboratory Animal Management Department, Shanghai Institute of Planned Parenthood Research.

1.1.2. Administration Regimen:

[0330]

TABLE-US-00004 Number of animals Route of Dose Concentration Dose volume Group Molecule (Male + female) administration (mg/kg) (mg/mL) (mL/kg) 1 Hydrochloride 3 + 3 i.v. 4.41 0.882 5 of compound 16 2 Compound M 3 + 3 i.v. 3.91 0.782 5

1.1.3. Sample Preparation Method

[0331] A proper amount of the compound was accurately weighed out and well mixed with a proper volume of 10% DMSO+35% PEG400+55% normal saline by vortexing or ultrasonication to give a clear solution for intravenous injection.

1.1.4. Test Method

[0332] Blood was collected at various time points after intravenous injection (before the administration and 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 h after the administration). EDTA-K2 was used as the anticoagulant, and the esterase inhibitor DDVP was added. Plasma samples were separated and cryopreserved at ?70? C., and the compound and tolvaptan levels were determined by LC-MS/MS.

1.2. Experimental Results

[0333]

TABLE-US-00005 TABLE 3 Molecule Molecule T.sub.max C.sub.max AUC.sub.0-t AUC.sub.0-? t.sub.1/2 Cl Vss administrated detected (h) (ng/ml) (h*ng/ml) (h*ng/ml) (h) (ml/min/kg) (l/kg) Hydrochloride Hydrochloride Undetectable of Compound of Compound 16 16 Tolvaptan Mean 0.083 1180 1830 1860 1.02 57 3.45 value SD 0 198 1110 1140 0.591 35.2 0.591 Compound M Compound M Mean 0.139 719 786 824 1.17 90.8 6.47 value SD 0.086 158 350 404 0.703 30 2.25 Tolvaptan Mean 1.42 76.2 452 492 2.1 value SD 0.665 41.3 514 516 0.941 Note: indicates it was not calculated. The hydrochloride of compound 16 achieved a higher exposure than compound M after converting into tolvaptan in vivo, and converted faster than compound M.

Test Example 4: Pharmacokinetic Study in Rats

1. PK Study in Rats

1.1. Study Protocol

1.1.1. Experimental Animals: SD Rats, Male and Female, Weighing about 180-220 g. Housing Environment: SPF. The Animals were Transferred from the Animal Repository (999M-017) of the Laboratory Animal Management Department, Shanghai Institute of Planned Parenthood Research.

1.1.2. Administration Regimen:

[0334]

TABLE-US-00006 Number of animals Route of Dose Concentration Dose volume Group Molecule (Male + female) administration (mg/kg) (mg/mL) (mL/kg) 1 Tolvaptan 3 + 3 PO* 9 0.9 10 2 Compound 5 3 + 3 PO* 12.9 1.29 10 *All animals were fasted overnight (10-18 h) before administration and feeding was resumed 4 h after administration.

1.1.3. Sample Preparation Method

[0335] A proper amount of tolvaptan and compound 5 was accurately weighed out and well mixed with a proper volume of 1% hydroxypropyl methylcellulose by vortexing or ultrasonication to give a 0.9 mg/mL solution of tolvaptan and a 1.29 mg/mL solution of compound 5 for intragastric administration.

1.1.4. Test Method

[0336] Tolvaptan and compound 5 were intragastrically administrated. Blood was collected before the administration and 10 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after the administration. EDTA-K2 was used as the anticoagulant, and the esterase inhibitor DDVP was added. Plasma samples were separated and cryopreserved at ?70? C., and the compound 5 and tolvaptan levels were determined by LC-MS/MS.

1.2. Experimental results

TABLE-US-00007 TABLE 4 Molecule C.sub.max AUC.sub.0-t adminis- Molecule T.sub.max (ng/ (h*ng/ t.sub.1/2 trated detected Sex (h) ml) ml) (h) Tolvaptan Tolvaptan Female Mean 2 412 1820 2.64 value SD 0 141 330 1.24 Male Mean 1.67 20.3 55.5 N.A. value SD 0.577 5.55 19.8 N.A. Com- Com- Female Mean 0.167 50.1 58.4 1.67 pound 5 pound 5 value SD 0 8.06 9.11 0.32 Male Mean 0.167 44.4 46.1 1.55 value SD 0 12.2 13.0 0.285 Tolvaptan Female Mean 5 319 2850 2.94 value SD 1 162 1120 0.356 Male Mean 3 32.3 165 3.44 value SD 1 9.99 22.7 1.74 The tolvaptan converted from compound 5 administered at an equivalent molar dose achieved a higher AUC.sub.0-t than tolvaptan.

Test Example 5: Pharmacokinetic Study in Beagles

1. PK Study in Beagles

1.1. Study Protocol

1.1.1. Experimental Animals: Beagles, Non-Na?ve, Sourced from the Animal Repository of Medicilon: 999M-004.

1.1.2. Administration Regimen:

[0337]

TABLE-US-00008 Number of Route Dose animals of Dose Concentration volume Group Molecule (Male) administration (mg/kg) (mg/mL) (mL/Kg) 1 Normal saline 3 i.v. 2 2 Compound 1b 3 i.v. 1 0.5 2 disodium salt 3 Compound 5 3 i.v. 0.5 0.25 2 4 Compound 5 3 i.v. 2.7 1.35 2 5 Tolvaptan 3 PO* 10 5 2 6 Compound 5 3 PO* 2.7 1.35 2 *All animals were fasted overnight (10-18 h) before administration and feeding was resumed 4 h after administration.

1.1.3. Sample Preparation Method

[0338] A proper amount of compound 1b disodium salt and compound 5 was accurately weighed out and well mixed with a proper volume of normal saline by vortexing or ultrasonication to give a 0.5 mg/mL clear solution of compound 1b disodium salt, a 0.25 mg/mL clear solution of compound 5 and a 1.35 mg/mL clear solution of compound 5 for intravenous drip administration.

[0339] A proper amount of tolvaptan and compound 5 was accurately weighed out and well mixed with a proper volume of 1% hydroxypropyl methylcellulose by vortexing or ultrasonication to give a 5 mg/mL solution of tolvaptan and a 1.35 mg/mL solution of compound 5 for intragastric administration.

1.1.4. Test Method

[0340] The compounds of the intravenous administration group were administered via an intravenous drip over 1 h. The compounds of the intragastric administration group were intragastrically administered. Time points of blood collection were: before the administration and 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 12 h and 24 h after the administration. About 1 mL of blood was collected via the jugular vein or in other suitable ways. EDTA-K2 was used as the anticoagulant, and the esterase inhibitor DDVP was added. Plasma samples were separated and cryopreserved at ?70? C., and the levels of related compounds in vivo were determined by LC-MS/MS. About 0.5 mL of blood was collected via the jugular vein or in other suitable ways, placed into separator gel blood collection tubes (without an anticoagulant) and centrifuged at room temperature at 3500 rpm for 10 min to separate the serum, and the concentration of Na.sup.+ in the serum was determined by using the ion-selective electrode method.

1.2. Experimental Results

[0341]

TABLE-US-00009 TABLE 5 Molecule C.sub.max AUC.sub.0-t adminis- Molecule T.sub.max (ng/ (h*ng/ t.sub.1/2 trated detected (h) ml) ml) (h) Compound Compound Mean 1 709 913 0.697 1b 1b value disodium salt disodium salt SD 0.5 244 584 1 mg/kg Tolvaptan Mean 1.33 102 212 1.29 i.v. value SD 0.577 17.8 52.4 0.392 Compound 5 Compound 5 Mean 1 889 1200 0.704 0.5 mg/kg value i.v. SD 0 76 86.6 0.0552 Tolvaptan Mean 1.17 17.3 46.4 1.76 value SD 0.289 2.07 5.42 0.232 Compound 5 Compound 5 Mean 1 5700 7850 0.647 2.7 mg/kg value i.v. SD 0 236 149 0.0352 Tolvaptan Mean 1 91.2 270 2.27 value SD 0 22.1 30.2 0.224 Tolvaptan Tolvaptan Mean 1.17 3.83 10.2 2.61 10 mg/kg value p.o. SD 0.289 1 2.3 1.28 Compound 5 Compound 5 Mean 0.5 61.5 122 1 2.7 mg/kg value p.o. SD 0 7.98 26.4 0.045 Tolvaptan Mean 2 47.1 201 3.13 value SD 0 11.7 40.7 1.21

[0342] FIG. 1 shows blood sodium curves of the compounds of the present invention in beagles. As shown in Table 5 and FIG. 1, the compound 5 administered via an intravenous drip at a lower dose than compound 1b disodium salt (0.5 mg/kg vs 1 mg/kg) can achieve a similar result in elevating the blood sodium level, which indicates that the compound 5 prototype molecule is active. The tolvaptan converted from the compound 5 administered intragastrically at a relatively low molar dose achieved a higher AUC.sub.0-t than the tolvaptan administered intragastrically, and has the effect of elevating the blood sodium level.

Test Example 6: Pharmacokinetic Study in Beagles

1. PK Study in Beagles

1.1. Study Protocol

1.1.1. Experimental Animals: Beagles (11?1.5 kg), Non-Na?ve, Sourced from the Animal Repository of Sichuan Greentech.

1.1.2. Sample Preparation

[0343] The tolvaptan tablets were commercially available (trade name: Ruibeitan (); manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd.). The enteric-coated capsules of compound 5 were obtained by directly encapsulating a proper amount of compound 5 in enteric-coated capsules (manufacturer of the enteric-coated capsules: Qingdao Yiqing Biotech Co., Ltd.).

1.1.3. Administration regimen:

TABLE-US-00010 Frequency Route of and period adminis- of adminis- Group Drug tration Dose tration 1 Tolvaptan tablets Oral 2 Single (containing 15 mg adminis- tablets/ adminis- tolvaptan/tablet) tration animal tration 2 Enteric-coated Oral 2 Single capsules of compound 5 adminis- capsules/ adminis- (containing 20 mg of tration animal tration compound 5/capsule)

1.1.4. Test Method

[0344] Each group included 3 male beagles. Intact tolvaptan tablets (2 tablets/animal) and enteric-coated capsules of compound 5 (2 capsules/animal) were intragastrically administered. Blood was collected before the administration and 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h after the administration. EDTA-K2 was used as the anticoagulant, and the esterase inhibitor DDVP was added. Plasma samples were separated and cryopreserved at ?70? C. The compound 5 and tolvaptan levels were determined by LC-MS/MS, and the urine volume during 0-6 h after the administration was recorded.

1.2. Experimental results

TABLE-US-00011 TABLE 6 Adminis- Molecule T.sub.max C.sub.max AUC.sub.0-t t.sub.1/2 tration detected (h) (ng/ml) (h*ng/ml) (h) Tolvaptan Tolvaptan Mean 1 98.5 359 3.6 tablets value SD 1.0-1.0 16.3 97.1 1.85 Enteric- Compound Mean 2 39.9 84.5 coated 5 value capsules of SD 0.5-4.0 2.86 21.1 compound 5 Tolvaptan Mean 2 132 511 2.96 value SD 2.0-4.0 50.5 98.6 1.26

[0345] FIG. 2 and FIG. 3 are the PK curves in beagle plasma and the urine volume during 0-6 h after oral administration of the enteric-coated capsules of compound 5 and tolvaptan tablets, respectively. As can be seen from Table 6 and FIG. 2, the tolvaptan converted in vivo from the enteric-coated capsules of compound 5 administered intragastrically to beagles at an equivalent molar dose achieved a higher AUC.sub.0-t than the tolvaptan tablets, and the effective concentration lasted about 2 more hours. As can be seen from FIG. 3, the intragastric administration of either the enteric-coated capsules of compound 5 or the tolvaptan tablets significantly increased the urine volume during 0-6 h after the administration to beagles.