JPH06157480A - New benzanilide derivative - Google Patents

Abstract

PURPOSE:To obtain a new derivative, having vasopressin antagonistic action and useful as a water diuretic agent, an anticardiac failure agent, an antihypertensive agent, etc. CONSTITUTION:The derivative of formula I [A is bond, lower alkylene or carbonyl; R<1> is carboxy, phenyl, amino, etc.; R<2> is lower alkyl) or its salt, e.g. 2-methyl-4'-[[5-(N-methylacarbamoylmethyl)-2,3,4,5-tetrahydro-1H1,5- benzodiazepin-1-yl[carbonyl]benzanilide. This compound of formula I is obtained by reacting, e.g. a compound of formula II with a compound of formula III in the presence of a condensing agent and a base such as trimethylamine in an inert organic solvent under cooling conditions, cooling to ambient temperature conditions or ambient temperature to heating conditions and further removing the protecting group when the resultant compound has the protecting group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzanilide derivative and a salt thereof which are useful as a medicine, particularly as an arginine vasopressin antagonist.

[0002]

2. Description of the Related Art Arginine vasopressin (AVP) is
It is a peptide consisting of 9 amino acids that is biosynthesized and secreted in the hypothalamus-pituitary system. Conventionally, as this arginine vasopressin antagonist, a peptide vasopressin antagonist (see, for example, JP-A-2-32098) and a non-peptide vasopressin antagonist (for example, JP-A-3-1738)
70, International Publication No. 91/05549 pamphlet (1991)), but the compounds of the present invention are novel compounds having different structures from these compounds.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have completed the present invention as a result of earnest research on a compound having an arginine vasopressin antagonistic action.

[0004]

That is, the present invention relates to a novel benzanilide derivative represented by the following general formula (I) (formula 2).

[0005]

[Chemical 2]

[Wherein A is a simple bond, a lower alkylene group or a carbonyl group (-CO-), and R ¹ is a carboxy group, a lower alkoxycarbonyl group, a phenyl group, an amino group, a mono- or di-lower alkyl group. A carbamoyl group or a pyridylmethylcarbamoyl group, and R ² represents a lower alkyl group. ]

The compound (I) of the present invention will be described in detail below.
Unless otherwise specified in the definition of the general formula in the present specification,
The term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. Therefore, as the "lower alkyl group", specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, se
c-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group, neopentyl group, tert-
Pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethyl Butyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2- Examples include ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, and the like. of, preferably, a methyl group, an ethyl group, an isopropyl group, a C ₁ -C ₄ alkyl group such as butyl group, more preferably, is a methyl group, an ethyl group

The "lower alkylene group" has 1 carbon atom.
To 6 linear or branched alkylene groups, specifically, methylene group, ethylene group, methylmethylene group, trimethylene group, propylene group, dimethylmethylene group, tetramethylene group, 1-methyltrimethylene group , 2
-Methyltrimethylene group, 3-methyltrimethylene group,
Examples thereof include ethylethylene group, pentamethylene group and hexamethylene group, and among them, C such as methylene group, ethylene group, methylmethylene group, trimethylene group and propylene group.
₁ -C ₃ alkylene group, especially a methylene group is preferable.

The "lower alkoxycarbonyl group" is a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group. , A pentyl (amyl) oxycarbonyl group, an isopentyloxycarbonyl group, a hexyloxycarbonyl group, an isohexyloxycarbonyl group and the like, and a carbonyl group substituted with a lower alkoxy group having 1 to 6 carbon atoms, among which methoxycarbonyl Group, ethoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group and the like, carbonyl group substituted by alkoxy having 1 to 4 carbon atoms, especially methoxycarbonyl group, ethoxycarbo group Le groups are preferred.

The "mono- or di-lower alkylcarbamoyl group" is a group in which the nitrogen atom of the carbamoyl group is mono- or di-substituted by the "lower alkyl group", and specifically, a methylcarbamoyl group, an ethyl group or an ethyl group. Carbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl group, sec-butylcarbamoyl group, tert-
Butylcarbamoyl group, pentylcarbamoyl group, isopentylcarbamoyl group, hexylcarbamoyl group, isohexylcarbamoyl group, dimethylcarbamoyl group,
Diethylcarbamoyl group, dipropylcarbamoyl group,
Linear or branched alkyl having 1 to 6 carbon atoms such as diisopropylcarbamoyl group, dibutylcarbamoyl group, diisobutylcarbamoyl group, dipentylcarbamoyl group, dihexylcarbamoyl group, ethylmethylcarbamoyl group, methylpropylcarbamoyl group, ethylpropylcarbamoyl group Carbamoyl group mono- or di-substituted with a group, preferably carbamoyl substituted with an alkyl group having 1 to 4 carbon atoms such as methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group and butylcarbamoyl group. A group, preferably a methylcarbamoyl group, an ethylcarbamoyl group can be mentioned.

The compound represented by the general formula (I) forms an acid addition salt. Also, depending on the type of substituent, it forms a salt with a base. The present invention also includes pharmaceutically acceptable salts of compound (I), such salts including mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, Butyric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, carbonic acid, glutamic acid, salts with organic acids such as aspartic acid, sodium, potassium, magnesium, calcium, aluminum Metal salts such as methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine, salts with bases such as organic bases such as ornithine, and ammonium salts. .

Further, the compound (I) of the present invention may contain an asymmetric carbon atom depending on the kind of the substituent, and such compound has optical isomers. The present invention includes isolated isomers and mixtures thereof. Furthermore, the present invention also includes hydrates of compound (I), various solvates, and polymorphic substances.

Among the compounds of the present invention, examples of particularly preferable compounds are as follows. 2-methyl-4 '-[[5
-(N-methylcarbamoylmethyl) -2,3,4,5
-Tetrahydro-1H-1,5-benzodiazepine-1
-Yl] carbonyl] benzanilide or a pharmaceutically acceptable salt thereof.

(Production Method) The compound of the present invention can be synthesized by various methods. The typical manufacturing method is illustrated below.

First method

[Chemical 3]

The compound (I) of the present invention (wherein A, R ¹ and R ² have the above-mentioned meanings) comprises a substituted benzoic acid represented by the general formula (II) or a reactive derivative thereof and a general formula (III ) Can be produced by amidating a substituted aniline represented by the formula (4) or a salt thereof with a conventional method and removing the protecting group when it has a protecting group. Examples of the reactive derivative of compound (II) include methyl ester, ethyl ester, isobutyl ester, t
Ordinary ester such as ert-butyl ester; acid halide such as acid chloride and acid bromide; acid azide; p
-Active esters obtained by reacting with phenol compounds such as nitrophenol and N-hydroxylamine compounds such as 1-hydroxysuccinimide and 1-hydroxybenzotriazole; symmetric acid anhydrides; halocarboxylic acids such as alkyl carbonate halides Mixed acid anhydrides such as organic acid mixed acid anhydrides obtained by reacting with alkyl ester or pivaloyl halide, and phosphoric acid mixed acid anhydrides obtained by reacting with diphenylphosphoryl chloride or N-methylmorpholine Thing; is mentioned.

When the compound (II) is reacted with a free acid or when the active ester is reacted without isolation, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphorylamide, diethylphosphorylcyanide or 1-ethyl- It is preferable to use a condensing agent such as 3- (3-dimethylaminopropyl) carbodiimide / hydrochloride. In particular, in the present invention, the acid chloride method, the method of reacting in the coexistence of an active esterifying agent and a condensing agent, and the method of treating an ordinary ester with an amine are advantageous because they can be easily and easily used as the compound of the present invention.
The reaction varies depending on the reactive derivative and condensing agent used, but is usually halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ether and tetrahydrofuran. , An ester such as ethyl acetate, an organic solvent inert to the reaction such as N, N-dimethylformamide, dimethylsulfoxide, etc., depending on the reactive derivative, under cooling, under cooling to room temperature, or under room temperature to heating .

In the reaction, the compound (III) is used in excess, N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline, The reaction in the presence of a base such as lutidine may be advantageous in that the reaction proceeds smoothly. Pyridine can also be the solvent. When R ^{1 of the} raw material compound (III) is an amino group or a carboxy group and the protection is required, after introducing a protecting group and subjecting this reaction to the reaction,
Remove the protecting group. The removal of the protecting group depends on the type of the protecting group, and for example, when a substituted or unsubstituted benzyloxycarbonyl group is used as the protecting group for the amino group, catalytic reduction, optionally by acid treatment, other tert-butoxycarbonyl groups such as A urethane type protecting group, an alkyl type protecting group such as a trityl group, or an acyl type protecting group such as a formyl group can be easily removed by acid treatment, and a phthaloyl group can be easily removed by heating with hydrazine. Further, when a methyl group or an ethyl group is used as a protecting group for a carboxy group, it is subjected to alkali saponification, and when a substituted or unsubstituted benzyl group is used, it is subjected to catalytic reduction or hydrofluoric acid treatment, and in some cases is subjected to alkali saponification. When the -butyl group is used, it can be easily removed by acid treatment, and when the trialkylsilyl group is used, it can be easily removed by contacting with water. Second manufacturing method

[0019]

[Chemical 4]

Where A and R ² have the meanings given above,
One of R ³ and R ⁴ is a lower alkyl group, the other is a hydrogen atom or a lower alkyl group, or one is a pyridylmethyl group and the other is a hydrogen atom.)
The mono- or di-substituted carbamoyl compound represented by b) comprises a corresponding carboxylic acid represented by the general formula (Ia) or a reactive derivative thereof, and a primary or secondary amine represented by the general formula (IV) or a salt thereof. Can be produced by reacting with and amidating. The reactive derivative, condensing agent, reaction conditions and the like are the same as those in the first production method. Third method

[0021]

[Chemical 5]

Where A and R ² have the meanings given above and R ⁵
Represents a lower alkyl group) The carboxy-substituted compound represented by the general formula (Id) can be produced by hydrolyzing the corresponding ester of the general formula (Ic). Although acid hydrolysis and the like can be applied to this method, it is preferable to apply a general alkaline saponification. Alkali saponification can be performed according to a conventional method, such as sodium hydroxide,
It is carried out by treating with an aqueous solvent of a base such as sodium carbonate or potassium tert-butoxide or a solution of an organic solvent such as methanol, ethanol, dimethylsulfoxide, toluene or xylene at room temperature to heating.

The compound (I) of the present invention can also be produced by amidating a 5-substituted benzodiazepine and a 4'-carboxybenzanilide derivative in the same manner as in the first production method, and removing the protecting group if necessary. . Also,
A benzodiazepine derivative having an unsubstituted 5-position, and a compound of the formula XA-
R ¹ (wherein X represents a halogen atom, an organic sulfonic acid residue, or a functional group such as a residue forming a hydroxyl group or a reactive derivative thereof when R ¹ -A- is an acyl group as a whole). It can also be produced by N-alkylation with the compound shown by a conventional method or amidation similar to the first production method. Furthermore, compounds refers to an amino group -A-R ^1, by hydrogenating the corresponding nitro compounds such as palladium carbon or Raney nickel in catalytic reduction using as a catalyst, also, R ¹ is a lower alkoxycarbonyl group In some cases, it can also be produced by esterifying the corresponding carboxylic acid by a conventional method. Further, the salt of the compound of the present invention can be easily produced by subjecting it to a usual salt-forming reaction.

The thus-produced compound of the present invention is isolated and purified by subjecting it to commonly used separation operations such as extraction, concentration, distillation, crystallization, recrystallization, filtration and various chromatographies. It

[0025]

INDUSTRIAL APPLICABILITY The vasopressin antagonist of the present invention has a water diuretic action, a urea excretion promoting action, a factor VIII secretion inhibiting action,
Vasodilatory effect, cardiac hyperactivity effect, mesangial cell contraction inhibitory effect, mesangial cell proliferation inhibitory effect, hepatic gluconeogenesis inhibitory effect, platelet aggregation inhibitory effect, aldosterone secretion inhibitory effect, endothelin production inhibitory effect, central blood pressure control effect, renin secretion It has regulatory action, memory control action, body temperature control action, prostaglandin production control action, etc., and is a water diuretic, urea excretion enhancer, vasodilator, antihypertensive agent, anti-heart failure agent, anti-renal failure agent, blood coagulation suppression Useful as an agent,
Heart failure, hyponatremia, pasopressin secretion abnormality syndrome (SIADH), hypertension, renal failure, edema, ascites, cirrhosis, hypokalemia, water metabolism disorder, diabetes, various ischemic diseases, circulatory insufficiency, renal dysfunction, etc. Effective for prevention and treatment. The usefulness of the compound of the present invention was confirmed below by the following test methods.

[0026] (1) V ₁ receptor binding assay (V ₁ receptor binding assay) Nakamura et al. Method (J.Biol.Chem., 258,9283 (1983) ) using a rat liver membrane preparation prepared in accordance with, [H] ³ −
Arg-vasopressin (2nM, specific
activity = 75.8Ci / mmol)), a membrane preparation (70 ng), and a test drug (10 ^-8 to 10 ^-4 M), 5 mM magnesium chloride, 1
mM ethylenediaminetetraacetic acid (EDTA) and 0.1%
3 in a total volume of 250 μl of 100 mM Tris-HCl buffer (pH = 8.0) containing bovine serum albumin (BSA)
Incubated for 0 minutes at 25 ° C. Then, the incubation solution was aspirated using a cell harvester and passed through a glass filter (GF / B) to remove free ligand and excess buffer solution, and the labeled ligand bound to the receptor was trapped on the glass filter.
The glass filter was taken out, sufficiently dried and then mixed with a liquid scintillation cocktail, and the amount of [H] ³ -vasopressin bound to the membrane was measured with a liquid scintillation counter, and the inhibition rate was calculated by the following formula.

[0027]

[Equation 1]

C ₁ : the amount of [H] ³ -vasopressin bound to the membrane in the coexistence of a known amount of the reagent and [H] ³ -vasopressin C ⁰ : [H] ³ when the reagent is removed - binding amount B ₁ with respect to vasopressin film: [H] ³ in the presence of an excess of vasopressin (10 ^-6 M) - the concentration of test agent which inhibited rate calculated by the amount of binding above with respect to the film of vasopressin is 50% The IC ₅₀ value was determined from the above, and the binding affinity of the non-radioactive ligand, that is, the dissociation constant (Ki), was calculated from the following formula.

[0029]

[Equation 2]

[L]; Concentration of radioligand KD; Dissociation constant obtained from Scatchard blot The negative logarithm of Ki calculated above was taken as pKi value. (2) V ₂ receptor binding assay (V ₂ r
eceptor bindingassay) Campbell's method (J. Biol. Chem., 247, 6167 (1972))
Was prepared according to. Using a rabbit kidney meningeal membrane specimen,
[H] ³ -Arg-vasopressin (2nM, specific activ
ity = 75.8Ci / mmol) and membrane preparation 100 ng and study medication (10 ^- the ⁸ to 10 ^-4 M), performs assays in a manner similar to V ₁ receptor binding assay described above,
Similarly, the pKi value was obtained.

A preparation containing one or more kinds of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is a carrier, an excipient or other additives usually used for preparation. It is prepared using the agent. The carrier or excipient for the preparation may be solid or liquid, and examples thereof include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil,
Examples include sesame oil, cocoa butter, ethylene glycol, and other commonly used ones.

For administration, tablets, pills, capsules, granules,
It may be in any form of oral administration such as powder and liquid preparation, or parenteral administration such as injection such as intravenous injection and intramuscular injection, suppository and transdermal preparation. The dose is appropriately determined according to each case in consideration of symptoms, age of the subject, sex, etc.
Usually, in the case of oral administration, 0.1 to 500 mg is administered once a day or in divided doses.

[0033]

EXAMPLES The compound of the present invention and the method for producing the same have been described above, but the present invention will be described in more detail below.
The invention is in no way limited by these examples. It should be noted that the raw material compounds of the present invention also include novel compounds, and production examples thereof are shown in Reference Examples. Reference example 1

[0034]

[Chemical 6]

Under ice cooling, 2,3,4,5-tetrahydro-
10 ml of a dichloroethane solution containing 2.5 g of p-nitrobenzoyl chloride was added to 40 ml of a dichloroethane solution containing 2 g of 1H-1,5-benzodiazepine and 1.36 g of triethylamine, and the mixture was stirred for 15 minutes under ice cooling. The reaction mixture was added to ice water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was crystallized from ethyl acetate to give 5- (4-nitrobenzoyl) -2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine 3.3
7 g was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.8-2.4 (2H, m), 2.7-3.3 (2
H, m), 3.5-3.8 (1H, m), 4.9-5.
2 (1H, m), 6.5-6.7 (1H, m), 6.8
-7.1 (2H, m), 7.42 (2H, d), 7.9
9 (2H, d) mass spectrum (FAB): m / z 298 (M ⁺⁺ )
1) Reference example 2

[0037]

[Chemical 7]

5- (4-nitrobenzoyl) -2,3
300 mg of 4,5-tetrahydro-1H-1,5-benzodiazepine, 150 mg of potassium carbonate and 2 ml of ethyl 2-bromoacetate were stirred in a sealed tube at 100 ° C. for 8 hours. After unreacted ethyl 2-bromoacetate was distilled off, the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue is filtered off, washed with diethyl ether and treated with 2- [5-
120 mg of ethyl (4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl] acetate was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.32 (3H, t), 1.96 (1H, m),
2.16 (1H, m), 3.16 (2H, m), 3.6
2 (1H, m), 3.98 (1H, d), 4.16 (1
H, d), 4.27 (2H, q), 4.72 (1H,
m), 6.57 (2H, m), 6.76 (1H, d),
7.06 (1H, m), 7.48 (2H, d), 8.0
0 (2H, d) mass spectrum (FAB): m / z 384 (M ⁺⁺ )
1) Reference example 3

[0040]

[Chemical 8]

2- [5- (4-nitrobenzoyl)-
Ethyl 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl] ethyl acetate (5.3 g) and 100% acetic acid solution of 10% palladium carbon (500 mg) were hydrogenated at room temperature. The reaction solution was filtered through Celite, and the solvent was evaporated. A 1N sodium hydroxide aqueous solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was filtered off, washed with diethyl ether and treated with 2- [5- (4-aminobenzoyl) -2,3,3.
4.7 g of ethyl 4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl] acetate was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.84 (1H, m), 2.06 (1H, m),
2.86 (1H, m), 3.15 (1H, m), 3.4
4 (1H, m), 4.27 (1H, d), 4.58 (1
H, d), 4.70 (1H, m), 6.6-6.7 (1
H, m), 7.0-7.5 (10H, m), 7.9-
8.0 (1H, m) mass spectrum (FAB): m / z 388 (M ⁺⁺ )
1) Reference example 4

[0043]

[Chemical 9]

5- (4-nitrobenzoyl) -2,3
600 mg of 4,5-tetrahydro-1H-1,5-benzodiazepine and 0.24 ml of benzyl bromide N, N
280 mg of potassium carbonate in the dimethylformamide solution
Was added and the mixture was stirred at 60 ° C. for 18 hours. The reaction mixture was added to ice water and extracted with ethyl acetate. Extract 1N hydrochloric acid, 1
Wash with N sodium hydroxide aqueous solution and saturated saline solution successively,
After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography.
From the fraction eluted with n-hexane / ethyl acetate = 5/1, 1-benzyl-5- (4-nitrobenzoyl)-
190 mg of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.84 (1H, m), 2.06 (1H, m),
2.86 (1H, m), 3.15 (1H, m), 3.4
4 (1H, m), 4.27 (1H, d), 4.58 (1
H, d), 4.70 (1H, m), 6.6-6.7 (1
H, m), 7.0-7.5 (10H, m), 7.9-
8.0 (1H, m) mass spectrum (FAB): m / z 388 (M ⁺⁺ )
1) Reference example 5

[0046]

[Chemical 10]

1-benzyl-5- (4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-1,5-
A solution of 300 mg of benzodiazepine and 1.05 g of tin (II) chloride dihydrate in 10 ml of ethyl acetate was heated under reflux for 1.5 hours. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added, the resulting precipitate was filtered off, and washed with ethyl acetate and water.
The ethyl acetate layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue is filtered off, washed with ether and 1- (4-aminobenzoyl) -5-benzyl-2,3,4,5-tetrahydro-
230 mg of 1H-1,5-benzodiazepine was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.78 (1H, b), 1.98 (1H, b),
2.81 (1H, b), 3.12 (1H, b), 3.4
1 (1H, b), 4.12 (1H, d), 4.56 (1
H, d), 4.66 (1H, b), 6.41 (2H,
d), 6.66 (2H, b), 7.02 (1H, d),
7.1-7.2 (3H, m), 7.3-7.5 (5H,
d) Mass spectrum (FAB): m / z 358 (M ⁺⁺ )
1) Reference example 6

[0049]

[Chemical 11]

In the same manner as in Reference Example 1, N-phenyl-o
From 2 g of phenylenediamine and 3 g of 4-nitrobenzoyl chloride, 4.4 g of 2'-anilino-4-nitrobenzanilide was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 6.8-7.0 (2H, m), 7.2-7.6 (5
H, m), 7.69 (2H, d), 8.1-8.5 (4
H, m) Mass spectrum (FAB): m / z 334 (M ⁺⁺ )
1) Reference example 7

[0052]

[Chemical 12]

Under ice cooling, a solution of 1.7 g of 2'-anilino-4-nitrobenzanilide in 40 ml of N, N-dimethylformamide was added to 840 mg of t-butoxy potassium, 1,2.
Add 1.14 ml of 3-dibromopropane and add 1 at 60 ° C.
Stir for 0 hours. The reaction mixture was added to ice water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography. n
-From the fraction eluted with hexane / ethyl acetate = 5/1, 1- (4-nitrobenzoyl) -5-phenyl-
300 mg of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.82 (1H, b), 2.45 (1H, b),
3.37 (1H, b), 3.50 (1H, b), 3.8
6 (1H, b), 4.51 (1H, b), 6.74 (1
H, d), 6.9-7.0 (4H, m), 7.1-7.
4 (4H, m), 7.43 (2H, d), 8.03 (2
H, d) Mass spectrum (FAB): m / z 374 (M ⁺⁺ )
1) Reference example 8

[0055]

[Chemical 13]

In the same manner as in Reference Example 3, from 290 mg of 1- (4-nitrobenzoyl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 1- (4-amino Benzoyl) -5-phenyl-
200 mg of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.7-2.5 (2H, b), 3.4-4.0 (4
H, b), 6.40 (2H, d), 6.7-7.3 (1
1H, m) Mass spectrum (FAB): m / z 343 (M ⁺⁺ )
1) Reference example 9

[0058]

[Chemical 14]

In the same manner as in Reference Example 1, 1- (4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-
1,5-benzodiazepine 450 mg, ethyl chlorooxalate 205 mg, 1-ethoxalyl-5-
560 mg of (4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.34 (3H, b), 1.94 (1H, b),
2.17 (1H, b), 3.09 (2H, b), 4.2
9 (2H, b), 4.70 (1H, b), 4.92 (1
H, b), 7.0-7.5 (4H, m), 7.75 (2
H, d), 8.08 (2H, d) mass spectrum (FAB): m / z 398 (M ⁺⁺ )
1) Reference example 10

[0061]

[Chemical 15]

In the same manner as in Reference Example 1, 1- (4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-
From 1,5-benzodiazepine 300 mg and benzoyl chloride 140 mg, 1-benzoyl-5- (4-nitrobenzoyl) -2,3,4,5-tetrahydro-1
420 mg of H-1,5-benzodiazepine was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.65 (1H, b), 1.75 (1H, b),
2.08 (1H, b), 3.05 (1H, b), 3.2
5 (1H, b), 4.91 (1H, b), 6.74 (1
H, m), 7.0-7.8 (10H, m), 8.0-
8.1 (2H, m) mass spectrum (FAB): m / z 402 (M ⁺⁺ )
1) Reference example 11

[0064]

[Chemical 16]

In the same manner as in Reference Example 1, 1-ethoxalyl-5- (4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 450 m
From g, 1- (4-aminobenzoyl) -5-ethoxalyl-2,3,4,5-tetrahydro-1H-1,5-
490 mg of benzodiazepine were obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.28 (3H, t), 1.8-2.2 (2H,
b), 3.08 (1H, b), 4.24 (2H, b),
4.42 (1H, b), 4.60 (1H, b), 4.8
0 (1H, b), 6.54 (2H, d), 6.80 (1
H, d), 7.0-7.3 (3H, m), 7.40 (2
H, d) Mass spectrum (FAB): m / z 368 (M ⁺⁺ )
1) Reference example 12

[0067]

[Chemical 17]

In the same manner as in Reference Example 1, 1-benzoyl-
5- (4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 400 mg
Thus, 300 mg of 1- (4-aminobenzoyl) -5-benzoyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.69 (2H, b), 3.20 (1H, b),
4.48 (1H, b), 5.50 (2H, b), 6.3
8 (2H, b), 6.8-7.8 (11H, m) Mass spectrum (FAB): m / z 372 (M ⁺⁺ )
1) Example 1

[0070]

[Chemical 18] Under ice cooling, 2- [5- (4-aminobenzoyl) -2,
2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl] ethyl acetate 900 mg, triethylamine 260 mg in dichloroethane solution 20 ml 2-
Toluoyl chloride (390 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was added to ice water and then extracted with dichloroethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was crystallized from ethyl acetate to give 1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-5-ethyl acetate 1.0 g Got

Physical and chemical properties Melting point 181-185 ° C. Elemental analysis value (as C ₂₈ H ₂₉ N ₃ O ₄ .1 / 2H ₂ O) C (%) H (%) N (%) Calculated value 69.98 6. 29 8.74 Experimental value 70.12 6.35 8.82 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.31 (3H, t), 1.96 (1H, m),
2.12 (1H, m), 2.47 (3H, s), 3.1
8 (2H, m), 3.67 (1H, m), 4.02 (1
H, d), 4.13 (1H, d), 4.25 (2H,
q), 4.71 (1H, m), 6.62 (2H, m),
6.77 (1H, m), 7.06 (1H, m), 7.2
-7.6 (8H, m) Example 2

[0072]

[Chemical 19]

1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1
H-1,5-benzodiazepine-5-ethyl acetate 200
mg, 40% methylamine / methanol solution (3 ml) was stirred in a sealed tube at 50 ° C. for 5 hours. After the solvent was distilled off, the residue was filtered and washed with ethyl acetate to give 2-methyl-4'-
[[5- (N-methylcarbamoylmethyl) -2,3
4,5-Tetrahydro-1H-1,5-benzodiazepin-1-yl] carbonyl] benzanilide 130 mg
Got

Physicochemical properties Melting point 199-204 ° C. Elemental analysis value (as C ₂₇ H ₂₈ N ₄ O ₃ .H ₂ O) C (%) H (%) N (%) Calculated value 68.48 6.17 11 .83 experimental value 69.08 6.17 11.66 nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.85 (1H, m), 2.12 (1H, m),
2.47 (3H, s), 2.83 (3H, s), 2.9
3 (1H, m), 3.17 (1H, m), 3.41 (1
H, d), 3.81 (1H, d), 4.06 (1H,
d), 4.74 (1H, m), 6.72 (1H, b),
6.82 (1H, b), 7.07 (1H, d), 7.2
-7.6 (9H, m) Example 2A

[0075]

[Chemical 20]

2-Methyl-4 '-[[5- (N-methylcarbamoylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl] carbonyl] benzanilide 240 mg of methanol Solution 5m
0.3 ml of 4N hydrochloric acid / ethyl acetate solution was added to 1.
After distilling off the solvent, recrystallization from methanol / ether gave 220 mg of hydrochloride.

Physicochemical properties Melting point 187-191 ° C. Elemental analysis value (as C ₂₇ H ₂₈ N ₄ O ₃ .HCl.1 / 3H ₂ O) C (%) H (%) N (%) Calculated value 65.12. 5.80 11.25 Experimental value 65.10 5.88 11.21 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.83 (1H, b), 2.13 (1H, b),
2.45 (3H, s), 2.82 (3H, s), 3.0
6 (1H, b), 3.26 (1H, b), 3.54 (1
H, b), 3.89 (1H, d), 4.65 (1H,
b), 6.71 (1H, b), 6.84 (1H, b),
7.2-7.6 (10H, m), 9.73 (1H, b) Example 3

[0078]

[Chemical 21]

1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1
H-1,5-benzodiazepine-5-ethyl acetate 200
0.4 ml of a 1N sodium hydroxide aqueous solution was added to 5 ml of a methanol solution of mg, and the mixture was stirred at room temperature for 18 hours. After distilling off the solvent, water and 0.4 ml of 1N hydrochloric acid were added to the residue. The precipitate is collected by filtration, washed with ethyl acetate and 1- [4- (2
-Methylbenzoylamino) benzoyl] -2,3,
150 mg of 4,5-tetrahydro-1H-1,5-benzodiazepine-5-acetic acid was obtained.

Physicochemical properties Melting point> 240 ° C. Elemental analysis value (as C ₂₆ H ₂₅ N ₃ O ₄ .1 / 5H ₂ O) C (%) H (%) N (%) calculated value 69.85 5.73 9.40 Experimental value 69.69 5.81 9.18 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.80 (1H, m), 1.98 (1H, m),
2.34 (3H, s), 3.06 (1H, m), 4.0
2 (1H, d), 4.16 (1H, d), 4.50 (1
H, m), 6.56 (1H, d), 6.80 (1H,
d), 7.0-7.1 (1H, m), 7.2-7.6.
(8H, m) Example 4

[0081]

[Chemical formula 22]

In the same manner as in Example 1, from 220 mg of 1- (4-aminobenzoyl) -5-benzyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 2-methyl-4 ' -[(5-benzyl-2,3,
4,5-Tetrahydro-1H-1,5-benzodiazepin-1-yl) carbonyl] benzanilide 190 mg
Got

Physicochemical properties Melting point 116-120 ° C. Elemental analysis value (as C ₃₁ H ₂₉ N ₃ O ₂ .1 / 2H ₂ O) C (%) H (%) N (%) Calculated value 76.84 6. 24 8.67 Experimental value 76.78 6.42 8.54 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.82 (1H, b), 2.04 (1H, b),
2.47 (3H, s), 2.85 (1H, b), 3.1
0 (1H, b), 3.43 (1H, b), 4.29 (1
H, d), 4.58 (1H, d), 4.70 (1H,
b), 6.67 (1H, b), 7.1-7.5 (16
H, m) Example 5

[0084]

[Chemical formula 23]

In the same manner as in Example 1, 2-methyl-4 ′ was obtained from 200 mg of 1- (4-aminobenzoyl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine. -[(5-phenyl-2,3,
4,5-Tetrahydro-1H-1,5-benzodiazepin-1-yl) carbonyl] benzanilide 170 mg
Got

Physicochemical properties Melting point 235-238 ° C. Elemental analysis value (as C ₃₀ H ₂₇ N ₃ O ₂ · 2 / 3H ₂ O) C (%) H (%) N (%) calculated value 76.09 6. 03 8.87 Experimental value 76.18 6.18 8.50 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.80 (1H, b), 2.19 (1H, b),
2.48 (3H, s), 3.39 (1H, b), 3.5
4 (1H, b), 3.80 (1H, b), 4.41 (1
H, b), 6.7-7.0 (5H, m), 7.1-7.
6 (12H, m) Example 6

[0087]

[Chemical formula 24]

In the same manner as in Example 1, 1- (4-aminobenzoyl) -5-ethoxalyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 480m
From g, 2-methyl-4 '-[(5-ethoxalyl-
2,3,4,5-Tetrahydro-1H-1,5-benzodiazepin-1-yl) carbonyl] benzanilide 2
90 mg was obtained.

Physicochemical properties Melting point 199-201 ° C. Elemental analysis value (as C ₂₈ H ₂₇ N ₃ O ₅ ) C (%) H (%) N (%) Calculated value 69.26 5.60 8.65 Experimental value 69.14 5.71 8.56 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.28 (3H, t), 1.89 (1H, b),
2.13 (1H, b), 2.46 (3H, s), 3.0
9 (2H, b), 4.26 (2H, b), 4.4-5.
2 (2H, m), 6.81 (1H, m), 7.0-7.
6 (11H, m) Example 7

[0090]

[Chemical 25]

In the same manner as in Example 1, 200 mg of 1- (4-aminobenzoyl) -5-benzoyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
Therefore, 2-methyl-4 ′-[(5-benzoyl-2,
3,4,5-Tetrahydro-1H-1,5-benzodiazepin-1-yl) carbonyl] benzanilide 130
mg was obtained.

Physicochemical properties Melting point 144-150 ° C. Elemental analysis value (as C ₃₁ H ₂₇ N ₃ O ₃ .H ₂ O) C (%) H (%) N (%) Calculated value 73.35 5.768 .28 experimental value 73.01 5.66 7.93 nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.75 (1H, b), 2.04 (1H, b),
2.48 (3H, s), 3.17 (2H, b), 6.8
-7.8 (17H, m) Example 8

[0093]

[Chemical formula 26]

In the same manner as in Example 2, 2-methyl-4 '
-[(5-Ethoxalyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl) carbonyl] benzanilide 180 mg, 2-methyl-
4 '-[(5-N-methyloxamoyl-2,3,4,
5-Tetrahydro-1H-1,5-benzodiazepine-
110 mg of 1-yl) carbonyl] benzanilide was obtained.

[0095] Physicochemical Properties mp> 240 ° C. Elemental analysis _{(C 27 H 26 N 4 O} 4 · 2 / as 5AcOEt) C (%) H ( %) N (%) Calculated 67.92 5.82 11. 08 Experimental value 67.87 5.67 11.25 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.60 (3H, s), 1.80 (1H, b),
2.07 (1H, b), 2.47 (3H, s), 3.0
9 (2H, m), 4.59 (1H, b), 4.7-5.
3 (1H, m), 6.80 (1H, m), 7.0-7.
6 (10H, m), 7.66 (1H, d) Example 9

[0096]

[Chemical 27]

1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1
H-1,5-benzodiazepine-5-acetic acid 200 mg,
1-Hydroxybenzotriazole 84 mg, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride 110 mg in tetrahydrofuran solution 20 m
60 mg of 2- (aminomethyl) pyridine was added to 1 and stirred at room temperature for 18 hours. The reaction mixture was added to ice water, made alkaline, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was crystallized from ether to give 2-methyl-4 '-[[5-N- (2-pyridinylmethyl) carbamoylmethyl-2,3,4,5-tetrahydro-1H
-1,5-benzodiazepin-1-yl] carbonyl]
250 mg of benzanilide was obtained. This compound 200m
g and 40 mg of oxalic acid were dissolved in methanol, the solvent was distilled off, and the residue was recrystallized from ethanol.
0 mg was obtained.

Physicochemical properties Melting point 176-179 ° C. Elemental analysis value (as C ₃₂ H ₃₁ N ₅ O ₃ .C ₂ H ₂ O ₄ .1 / 5H ₂ O) C (%) H (%) N (%) Calculated value 65.10 5.37 11.16 Experimental value 65.12 5.44 11.19 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.82 (1H, b), 2.03 (1H, b),
2.33 (3H, s), 3.03 (1H, b), 3.0
8 (1H, b), 3.58 (1H, b), 3.93 (1
H, d), 4.12 (1H, d), 4.4-4.6 (3
H, m), 6.60 (2H, s), 6.94 (1H,
d), 7.06 (1H, m), 7.2-7.8 (10
H, m), 8.48 (1H, m), 8.65 (1H,
b), 10.29 (1H, s)

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location A61K 31/55 ACV 9360-4C ACX 9360-4C C07D 401/12 243 8829-4C // (C07D 401/12 213 : 00 6701-4C 243: 00) 7167-4C (72) Inventor Kenichiro Sakamoto 2-5-9 Ninomiya, Tsukuba, Ibaraki Prefecture Rumi Tsukuba 232 (72) Inventor Yuno Yatsu 2-11, Hiradai, Ryugasaki, Ibaraki -7 (72) Inventor Isao Yanagisawa 2-22-8 Shakujidai, Nerima-ku, Tokyo

Claims (1)

[Claims] 1. A novel benzanilide derivative represented by the following general formula (Formula 1) or a salt thereof. [Chemical 1] [In the formula, A is a simple bond, a lower alkylene group or a carbonyl group (-CO-), and R ¹ is a carboxy group, a lower alkoxycarbonyl group, a phenyl group, an amino group, a mono-
Alternatively, it means a di-lower alkylcarbamoyl group or a pyridylmethylcarbamoyl group, and R ² means a lower alkyl group. ]