BENZAMIDE DERIVATIVES

Abstract: This invention relates to new benzamide derivatives having a vasopressin antagonistic activity, etc. and represented by general formula (I): wherein R<1> and R<2> are taken together to form benzene ring, etc., R<3> is hydrogen, etc, R<4> and R<5> are each hydrogen, etc., R<6> and <R7> are each hydrogen, etc., R<8> and R<9> are taken together to form benzene ring, etc., and A is lower alkylene, and pharmaceutically acceptable salts thereof, to processes for preparation thereof and to a pharmaceutical composition comprising the same.

Description: WO 01/00618 - PCT/JPOO/03463 DESCRIPTION BENZAMIDE DERIVATIVES TECHNICAL FIELD This invention relates to new benzamide derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament. BACKGROUND ART Some benzamide derivatives have been known as vasopressin antagonist, for example, in PCT International Publication Nos . WO 91/05549, WO 95/29152 and WO 96/41795, EP Application Publication No. 0620216, and Japanese Patent Application Publication No. H8-143565. DISCLOSURE OF INVENTION This invention relates to new benzamide derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to new benzamide derivatives and pharmaceutically acceptable salts thereof which possess activities as vasopressin antagonistic activity, vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in liver, activity for inhibiting growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity, oxytocin antagonistic activity and the like, to a pharmaceutical composition comprising the same and to a method for the treatment and/or prevention of hypertension, heart failure, renal insufficiency, edema, ascites, vasopressin parasecretion syndrome, hepatocirrhosis, hyponatremia, hypokalemia, diabetic, circulation disorder, cerebrovascular disease (e.g. cerebral edema, cerebral infarction, etc.), Meniere' s syndrome (e.g. Meniere' s disease, etc.), motion sickness and the like in human beings or animals. Additionally, the object compound is expected to be used in the prevention and/or treatment of vision disorders due to ocular circulatory disorders (such as intraocular hypertension, glaucoma, retinary pigmentary degeneration, macular degeneration, ischemic optic neuritis, iridocyclitis, retinal arterial obliteration, retinal phlebemphraxis, diabetic retinitis and choroid diseases) and vision disorders related to ciliary tension (such as shortsightedness) . One object of this invention is to provide new and useful benzamide derivatives which possess aforesaid activities . Another object of this invention is to provide processes for the preparation of said benzamide derivatives and salts thereof. A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said benzamide derivatives and pharmaceutically acceptable salts thereof. Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said benzamide derivatives and pharmaceutically acceptable salts thereof. The object benzamide derivatives of this invention are new and can be represented by the following general formula wherein R-*- and R 2 are taken together to form benzene, pyridine or thiophene ring, each of which may be substituted with one or more suitable substituent (s) , R 3 is hydrogen or lower alkoxy, R^ and R- 3 are each hydrogen or taken together to form a bond, R° and R are each hydrogen or taken together to form oxo, R° and R" are taken together to form benzene ring which may be substituted with one or more suitable substituent ( s) , and A is lower alkylene, and pharmaceutically acceptable salts thereof. The object compound (I) or its salt can be prepared by the processes as illustrated in the following reaction schemes . Process 1 (la) or its salt Process 2 (la) (lb) or its salt or its salt Wherein R , R , R , R , R" and A are each as defined above, and R10 i s lower alkyl. In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following. The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided. Suitable "lower alkyl" may be straight or branched C-i- Cg alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, ethylpropyl, hexyl or the like, in which preferable one is ethyl. Suitable "lower alkoxy" may be straight or branched C- j _- Cg alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, methylpropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which preferable one is methoxy. Suitable "lower alkylene" may be straight or branched C-^-Cg alkylene such as methylene, ethylene, propylene, trimethylene, ethylethylene, tetramethylene, pentamethylene, hexamethylene or the like, in which preferable one is tetramethylene . Suitable "halogen" may be fluorine, chlorine, bromine and iodine. The preferred examples of "suitable substituent (s) " in the term of "benzene, pyridine or thiophene ring, each of which may be substituted with one or more suitable substituent (s) for R^ and R^" and "benzene ring which may be o substituted with one or more suitable substituent (s) for R° and R 9 " may be lower alkyl, lower alkoxy, halogen, hydroxy and the like, in which preferable one is lower alkyl. Preferred compound (I) is one having benzene ring which is formed by taking together R^- and R , lower alkoxy for R , each hydrogen for R^ and R , each hydrogen for R° and R , benzene ring which is formed by taking together R° and R , and tetramethylene for A; or benzene ring which is formed by taking together R^ ~ and R 2 , lower alkoxy for R 3 , a bond which is formed by taking together R^ and R , oxo which is formed by taking together R° and R , benzene ring which is formed by taking together R° and R , and tetramethylene for A. More preferred compound (I) is one having benzene ring which is formed by taking together R-*- and R 2 , lower alkoxy for R , each hydrogen for R and R , each hydrogen for R° and R 7 , benzene ring which is formed by taking together RR° and R , and tetramethylene for A. WO 01/00618 , PCT/JPOO/03463 Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include an acid addition salt such as inorganic acid addition salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), or the like. The processes for preparing the object compound (I) are explained in detail in the following. Process 1 The object compound (la) or its salt can be prepared by reacting a compound (II) or its salt with a compound (III) or its salt. Suitable salts of the compounds (la), (II) and (III) may be the same as those exemplified for the compound (I). The reaction is usually carried out in a conventional solvent such as dioxane, tetrahydrofuran, toluene, xylene or any other organic solvent which does not adversely influence the reaction. The reaction temperature is not critical, and the reaction is usually carried out under warming to heating. Process 2 The object compound (lb) or its salt can be prepared by reacting a compound (la) or its salt with a reducing agent. Suitable salts of the compounds (la) and (lb) may be the same as those exemplified for the compound (I). Suitable reducing agent may be diborane, borane or its complex (e.g. borane-tetrahydrofuran complex, etc.), and the like . The reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran or any other organic solvent which does not adversely influence the reaction . The reaction temperature is not critical, and the reaction can be carried out under cooling to heating. The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like. It is to be noted that the compound (I) and the other compounds may include one or more stereoisomer (s) such as optical isomer(s) or geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixture thereof are included within the scope of this invention. Additionally, it is to be noted that any solvate [e.g. enclosure compound (e.g. hydrate, etc.)] of the compound (I) or a pharmaceutically acceptable salt thereof is also included within the scope of this invention. The object compound (I) and pharmaceutically acceptable salts thereof possess activities as vasopressin antagonistic activity, vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in liver, activity for inhibiting growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity, oxytocin antagonistic activity and the like, and are useful for the treatment and/or prevention of hypertension, heart failure, renal insufficiency, edema, ascites, vasopressin parasecretion syndrome, hepato- cirrhosis, hyponatremia, hypokalemia, diabetic, circulation disorder, cerebrovascular disease (e.g. cerebral edema, cerebral infarction, etc.), Meniere' s syndrome (e.g. Meniere' s disease, etc.), motion sickness and the like in human beings and animals. Additionally, the object compound is expected to be used in the prevention and/or treatment of vision disorders due to ocular circulatory disorders (such as intraocular hypertension, glaucoma, retinary pigmentary degeneration, macular degeneration, ischemic optic neuritis, iridocyclitis, retinal arterial obliteration, retinal phlebemphraxis, diabetic retinitis and choroid diseases) and vision disorders related to ciliary tension (such as shortsightedness) . In order to illustrate the usefulness of the object compound (I), the pharmacological data of the compound (I) are shown in the following. Test 1 Vasopressin 1 (VI) receptor binding (i) Test Method : Blood was obtained by venipuncture from normal subjects. Platelet-rich plasma (PRP) was prepared by centrifugation of whole blood at 200 xg for 10 minutes. PRP was centrifuged at 45,000 xg for 30 minutes. The remaining pellet was resuspended in 10 volume of ice cold 100 mM Tris-HCl (pH 7.4) buffer (containing 5 mM gC^r- 0.1% bovine serum albumin and 1 mM EDTA) , and centrifuged at 45,000 xg for 30 minutes again. The final pellet was resuspended in 100 mM Tris-HCl buffer. The resulting membrane preparation was used immediately for the binding assay. Competition assays were conducted at equilibrium (15 minutes at 30°C) by using 1.5 nM 3 H-vasopressin (40-87 Ci/mmol; New England Nuclear) in 100 mM Tris-HCl (pH 7.4) buffer. Nonspecific binding was determined by using 1 μM vasopressin. After incubation, reaction was terminated by adding 5 ml of ice-cold 100 mM Tris-HCl (pH 7.4) buffer, and then filtered rapidly through Whatman glass filter (GF/C) . The filter was washed twice with the same buffer. The glass filter was mixed with liquid scintillation cocktail, and radioactivity was counted in a liquid scintillation counter. Competition activity of the test compound was represented by IC5 Q values. (ii) Test Result: Test 2 Vasopressin 2 (V2) receptor binding (i) Test Method: For binding assays, the receptor cDNA was permanently expressed in Chinese hamster ovary (CHO) cells. CHO cells were transfected with a vector directing expression of the cDNA for the human V2 receptor and the clonal cell lines expressing human V2 receptor was established essentially as described previously (Nakajima, Y., et . al . J. Biol . Chem. , 1992, 267, 2437) . DNA-transfected cells were harvested and homogenized in ice cold 250 mM sucrose buffer containing 25 mM Tris-HCl (pH 7.4), 10 mM MgCl 2 , 1 mM EDTA and 5 μg/ml p-amidinophenylmethylsulfonyl fluoride (A-PMSF) . The homogenate was centrifuged at 500 xg for 10 minutes. The supernatant was centrifuged at 100,000 xg for 1 hour. The final pellet was suspended in 25 mM Tris-HCl (pH 7.4) buffer (containing 10 mM MgCl 2 , 1 m EDTA and 5 μg/ml A-PMSF), and stored in small aliquots at -80°C. Competition assays were conducted at equilibrium (2 hours at 22°C) by using 0.5 nM 3 H-vasopressin (40-87 Ci/mmol, New England Nuclear) in 100 mM Tris-HCl (pH 7.4) buffer (containing 5 M MgCl 2 , 5 μg/ml A-PMSF, 4 μg/ml leupeptin, 40 μg/ml bacitracin, 20 μg/ml chymostatin and 0.1% bovine serum albumin) . Nonspecific binding was determined by using 1 μM vasopressin. After incubation, reaction mixture was rapidly filtered through Whatman glass filter (GF/C) . The filter was washed twice with the same buffer. The radioactivity was counted in a liquid scintillation counter. Competition activity of the test compound was represented by IC^ Q values. (ii) Test Result: For therapeutic purpose, the compound (I) of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral, external (topical) or ophthalmic administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, eye drops or the like. If desires, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives . While the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day. The following Preparation and Examples are given for the purpose of illustrating this invention. Preparation 1 To a cooled solution of 2-methoxy-4- (2, 3, 4 , 5- tetrahydro-lH-1-benzazepin-l-yl) carbonylbenzoic acid (1.50 g) in dichloromethane (18 ml) were added thionyl chloride (0.584 ml), imidazole (803 mg) and triethyla ine (2.12 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. Then magnesium chloride (443 mg) , triethylamine (0.642 ml), potassium ethylmalonate (1.58 g) and N,N- dimethylformamide (1.8 ml) were added to the mixture. After 2 hours, lN-hydrochloric acid was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (chloroform to chloroform:methanol=10 : 1) to give 1- [3-methoxy-4- (ethoxycarbonylacetyl ) benzoyl ] -2, 3, 4 , 5-tetrahydro-lH-l- benzazepine (1.8 g) . NMR (CDC1 3 , δ) : 1.18 (3H, t, J=7.5Hz), 1.54 (1H, m) , 1.91-2.17 (3H, m) , 2.74-3.11 (3H, m) , 3.70 (3H, s), 3.88 (2H, s), 4.13 (2H, q, J=7.5Hz), 4.98 (1H, m) , 6.61 (1H, d, J=8Hz), 6.71 (1H, d, J=8Hz), 6.90 (1H, s), 6.92 (1H, t, J=8Hz), 7.10 (1H, t, J=8Hz), 7.23 (1H, d, J=8Hz), 7.59 (1H, d, J=8Hz) Example 1 A mixture of 1- [3-methoxy-4- (ethoxycarbonylacetyl ) - benzoyl] -2, 3, 4, 5-tetrahydro-lH-l-benzazepine (1.44 g) and o- phenylenediamine (413 mg) in xylene (20 ml) was refluxed for 50 minutes. The solvent was removed under reduced pressure and the residue was purified by column chromatography (chloroform:methanol=10 : 1) to give 4- [2-methoxy-4- (2 , 3, 4 , 5- tetrahydro-lH-1-benzazepin-l-ylcarbonyl) phenyl] -1, 3-dihydro- 2H-1, 5-benzodiazepin-2-one (1.32 g) . NMR (CDC1 3 , δ) : 1.53 (1H, m) , 1.89-2.17 (3H, m) , 2.71- 3.11 (3H, m) , 3.38-3.50 (2H, m) , 3.67 (3H, s), 5.03 (1H, m) , 6.69 (1H, d, J=8Hz) , 6.82 (1H, d, J=8Hz), 6.87 (1H, s) , 6.93 (1H, t, J=8Hz) , 7.02- 7.12 (2H, m) , 7.18-7.25 (3H, m) , 7.34-7.46 (2H, m) Example 2 To a solution of 4- [2-methoxy-4- (2 , 3, 4, 5-tetrahydro-lH- 1-benzazepin-l-ylcarbonyl ) phenyl] -1, 3-dihydro-2H-l , 5- benzodiazepin-2-one (2.27 g) in tetrahydrofuran (60 ml) was added borane-tetrahydrofuran complex ( 1.0M in tetrahydrofuran, 12.9 ml) at 0°C and the solution was stirred for 3 hours at the same temperature. Then the cooling bath was removed and the mixture was stirred overnight. lN-Hydrochloric acid was added to the reaction mixture and the mixture was stirred for 1 hour. The reaction mixture was basified with sodium hydrogen carbonate, extracted with ethyl acetate, and dried over sodium carbonate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (chloroform:methanol=100 : 1) to give the amorphous. The amorphous was triturated with isopropyl ether to give 2- [2- methoxy-4- (2,3,4, 5-tetrahydro-lH-l-benzazepin-l- ylcarbonyl) phenyl] -2,3,4, 5-tetrahydro-lH-l , 5-benzodiazepine (1.3 g) . NMR (CDCI3, δ) : 1.42-1.67 (2H, ) , 1.78-2.18 (4H, m) , 2.71-2.95 (3H, m) , 3.07 (1H, m) , 3.38 (1H, m) , 3.64 (3H, s), 4.13 (1H, m) , 5.04 (1H, m) , 6.65-6.79 (5H, m) , 6.86-7.17 (4H, m) , 7.21-7.39 (2H, ) Example 3 2- [2-Methoxy-4- (2, 3, 4, 5-tetrahydro-lH-l-benzazepin-l- ylcarbonyl) phenyl] -2,3,4, 5-tetrahydro-lH-l, 5-benzodiazepine (1.0 g) was dissolved in IN hydrochloric acid (5.0 ml) and the solution was lyophilized to give 2- [2-methoxy-4- (2,3,4, 5-tetrahydro-lH-l-benzazepin-l-ylcarbonyl) phenyl] - 2,3,4, 5-tetrahydro-lH-l, 5-benzodiazepine dihydrochloride (1.0 g) . NMR (DMSO-d 6 , δ) : 1.92 (1H, brs), 2.08 (1H, brt, J=8Hz), 2.73-3.16 (4H, m) , 3.58 (3Hx0.5, s) , 3.63 (3Hx0.5, s), 3.70 (1H, brs), 3.90 (1H, brs), 4.50 (1H, brs), 4.95 (1H, brd, J=10Hz) , 5.50-5.70 (2H, brs), 6.55-6.78 (3H, m) , 6.94 (1H, t, J=3Hz) , 7.10 (1H, dd, J=7, 3Hz), 7.16-7.38 (4H, m) , 7.47 (1H, brs), 8.08 (1H, brd, J=3Hz)

Claims: CLAIMS A compound of the formula: wherein R-*- and R are taken together to form benzene, pyridine or thiophene ring, each of which may be substituted with one or more suitable substituent (s) , R^ is hydrogen or lower alkoxy, R^ and R^ are each hydrogen or taken together to form a bond, R" and R are each hydrogen or taken together to form oxo, R° and R^ are taken together to form benzene ring which may be substituted with one or more suitable substituent (s) , and A is lower alkylene, and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R^- and R 2 are taken together to form benzene ring, R^ is lower alkoxy, and R and R^ are taken together to form benzene ring. A compound according to claim 2, wherein R 4 and R^ are each hydrogen, R° and R' are each hydrogen, and A is tetramethylene. A compound according to claim 3, which is 2- [2-methoxy-4- (2,3,4, 5-tetrahydro-lH-l-benzazepin-l- ylcarbonyl) phenyl] -2,3,4, 5-tetrahydro-lH-l, 5- benzodiazepine or its dihydrochloride. A process for preparing a compound of the formula: wherein R^ and R 2 are taken together to form benzene, pyridine or thiophene ring, each of which may be substituted with one or more suitable substituent (s) , R^ is hydrogen or lower alkoxy, R^ and R^ are each hydrogen or taken together to form a bond, R° and R' are each hydrogen or taken together to form oxo, R° and R" are taken together to form benzene ring which may be substituted with one or more suitable substituent (s) , and A is lower alkylene, or pharmaceutically acceptable salts thereof, which comprises, ) reacting a compound of the formula or its salt with a compound of the formula: or its salt to provide a compound of the formula: or its salt, in the above formulas, R 1 , R 2 , R 3 , R 8 , R 9 and A are each as defined above, and R-^ is lower alkyl, or 2) reacting a compound of the formula: or its salt with a reducing agent to provide a compound of the formula : or its salt, in the above formulas, R 1 , R 2 , R 3 , R 8 , R 9 and A are each as defined above. A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient. A compound of claim 1 for use as a medicament A method of therapeutic treatment and/or prevention of hypertension, heart failure, renal insufficiency, edema, WO 01/00618 η o PCT/JPOO/03463 ascites, vasopressin parasecretion syndrome, hepatocirrhosis, hyponatremia, hypokalemia, diabetic, circulation disorder, cerebrovascular disease, Meniere' s syndrome, motion sickness or vision disorders due to ocular circulatory disorders which comprises administering an effective amount of a compound of claim 1 to human beings or animals. 9. Use of a compound of claim 1 for the manufacture of a medicament for treating and/or preventing hypertension, heart failure, renal insufficiency, edema, ascites, vasopressin parasecretion syndrome, hepatocirrhosis, hyponatremia, hypokalemia, diabetic circulation disorder, cerebrovascular disease, Meniere' s syndrome, motion sickness or vision disorders due to ocular circulatory disorders in human beings or animals.

Inventors: OHKAWA TAKEHIKO, OSODA KAZUHIKO, SETOI HIROYUKI, OHKAWA, TAKEHIKO, OSODA, KAZUHIKO, SETOI, HIROYUKI
Applicants: FUJISAWA PHARMACEUTICAL CO, OHKAWA TAKEHIKO, OSODA KAZUHIKO, SETOI HIROYUKI, FUJISAWA PHARMACEUTICAL CO., LTD., OHKAWA, TAKEHIKO, OSODA, KAZUHIKO, SETOI, HIROYUKI
Application year: 2000
Main classification: C07D403
IPC codes: A61K31, A61P1, A61P3, A61P5, A61P7, A61P9, A61P13, A61P27, C07D403