JPH0680056B2 - Phenylpyridazinone derivatives and cardiotonics - Google Patents

Description

TECHNICAL FIELD The present invention relates to a phenylpyridazinone derivative effective as a cardiotonic agent.

2. Description of the Related Art Cardiotonic drugs have a pharmacological action that acts on the heart to increase its contractile force, and various drugs including amrinone (US Pat. No. 4,004,012) are used for heart failure. However, its cardiotonic action is transient, and it is not always satisfactory because it is not suitable for oral administration.

DISCLOSURE OF THE INVENTION The invention has the general formula (In the formula, Is a single bond or a double bond, R ¹ and R ² are each hydrogen or phenyl, R ³ is hydrogen, alkyl or optionally substituted aralkyl, X is hydrogen, alkyl or halogen, Az is 1H-benzimidazole-1. -Yl, 1H-imidazol-1-yl, 1H-pyrazol-1-yl or 1H-
Represents 1,2,4-triazol-1-yl. And a salt thereof and a cardiotonic agent containing the same as an active ingredient.

The terms used in the definition of the compound (I) are explained below.

Alkyl is C ₁ -C ₅ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and benzyl, and aralkyl is benzyl, phenyl, phenylpropyl, phenyl-C ₁ -C ₅ alkyl such as phenylbutyl, and the like. Naphthylmethyl, naphthyl-C ₁ -C ₅ alkyl such as naphthylethyl, and the substituents which may be present on aralkyl are methyl, ethyl,
Examples of lower alkyl such as propyl, lower alkyl such as methoxy, ethoxy and propoxy and halogen, and halogen include fluorine, chlorine, bromine and iodine.

The target substance (I) is obtained by the process shown in the following reaction scheme.

(In the formula, R represents alkyl, and Az, R ¹ , R ² and R ³ have the same meanings as described above.) First step This step is a ring closure reaction of the starting ester (II), and II is hydrazine. -Reacting hydrates to lead to dihydropyridazinone (Ia). This reaction is carried out in a solvent such as hydrous alcohol such as hydrous methanol or hydrous ethanol, or acid-alcohol such as acetic acid-ethanol, preferably 15 to 100 ° C,
It is carried out at a temperature of 0-100 ° C.

Second Step The above dihydropyridazinone (Ia) is treated with a suitable oxidizing agent to give pyridazinone (Ib). Examples of the oxidizing agent include oxidizers that are usually used for dehydrogenation, such as zelenium dioxide, m-nitrobenzenesulfonic acid, and manganese dioxide. The reaction may be carried out by a conventional method for the oxidizing agent used. Generally, this reaction is carried out in a suitable solvent such as dioxane, tetrahydrofuran, diglyme, dimethylformamide, etc.
It is carried out at 80 ° C, preferably 10-50 ° C.

The raw material ester (II) is derived from, for example, 2-hydroxyacetophenones (III) in the process shown in the figure below.

Each step is carried out by a conventional method.

[In the formula, Az, R, R ¹ , R ² , R ³ and X have the same meanings as described above. The target substance (I) can be converted into a pharmaceutically acceptable acid addition salt. As an acid capable of forming such a salt, citric acid,
Examples thereof include organic acids such as malic acid, succinic acid, acetic acid and methanesulfonic acid, and inorganic acids such as hydrohalic acid, nitric acid, sulfuric acid and phosphoric acid.

The phenylpyridazinone derivative (I) of the present invention or a salt thereof can be orally or parenterally administered to humans or animals. For example, oral formulations include tablets, pills, granules,
Parenteral preparations such as capsules, emulsions and suspensions include suppositories and injections. These formulations are manufactured according to well-known methods using excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, suspending agents, dispersants, solubilizing agents, preservatives and the like. . Examples of the excipient include lactose, sucrose, starch, cellulose, sorbit and the like, examples of the binder include gum arabic, gelatin, polyvinylpyrrolidone and the like, and examples of the lubricant include magnesium stearate, talc and silica gel. The dose may be 10 to 250 mg per day for an adult by oral administration and 0.5 to 30 mg by intravenous injection in single or divided doses.

The embodiments of the present invention will be described below with reference to examples.

The abbreviations used in the examples of the present invention have the following meanings.

Me methyl, i-Pr isopropyl, Bz 1H-benzimidazol-1-yl, Im 1H-imidazol-1-yl, Py 1H-pyrazol-1-yl, Tri 1H-1,2,4-triazol-1-yl , Ph-phenyl Example 1 1-{(5- (3-hydroxy-4,5-dihydropyridazin-6-yl) -2-methoxyphenyl) vinyl}
-1H-imidazole 2- [1- (1H-imidazol-1-yl) vinyl]-
300 mg (0.95 mmol) of 4- (3-methoxycarbonylpropionyl) anisole is added to a mixed solution of 6 ml of ethanol and 3 ml of water, 1.45 mg (2.9 mmol) of hydrazine hydrate is added, and the mixture is heated under reflux for 18 hours. The reaction mixture is concentrated, ice water is added to the residue, and the mixture is extracted with dichloromethane. The organic layer is washed with water and dried with mirabilite. The solvent is distilled off, the residue is chromatographed on silica gel, eluting with 5% methanol / dichloromethane and the solvent is distilled off. The residue was collected by filtration with diisopropyl ether and recrystallized from a mixed solvent of ethyl acetate / diisopropyl ether, and the melting point was 194-195 ° C.
175 mg (62% yield) of the title compound are obtained as crystals of.

Elemental analysis: Calculated value as C ₁₆ H ₁₆ N ₄ O ₂ (%): C, 64.85; H, 5.44; N, 18.91 Measured value (%): C, 64.90; H, 5.33; N, 18.80 Example 2 7 The reaction is performed in the same manner as in Example 1 to obtain the target substance (Ia).

Example 8 1-{(5- (3-Hydroxy-pyridazin-6-yl) -2-methoxyphenyl) vinyl} -1H-imidazole 1-{(5- (3-hydroxy-4,5-dihydropyridazin-6-yl) -2-methoxyphenyl) vinyl}
-1H-Imidazole (500 mg, 1.69 mmol) was dissolved in dioxane (20 ml), selenium dioxide (2.3 g, 22.8 mmol) was added, and the mixture was heated with stirring at 50 ° C for 2 hours. Ice water is added to the reaction solution, which is made alkaline with sodium bicarbonate water, and then extracted with dichloromethane. After washing the organic layer with water, it is dried with sodium sulfate and the solvent is distilled off. The residue is subjected to silica gel chromatography, eluting with 7% methanol / dichloromethane, and then the solvent is distilled off. The residue is washed with ethyl acetate, collected by filtration, and recrystallized from a mixed solvent of methanol / ethyl acetate to obtain 200 mg (yield 40%) of the title compound as crystals having a melting point of 184-185 ° C.

Elemental analysis: Calculated as C ₁₆ H ₁₄ N ₄ O ₂ · H ₂ O (%): C, 61.53; H, 5.16; N, 17.94 Measured value (%): C, 61.26; H, 4.99; N, 17.80 hydrochloride: mp 230-245 ° C. elemental _{analysis: C 16 H 14 N 4 O} 2 · 2HCl · 1 / 3H 2 O calculated (%): C, 51.49; H, 4.50; Cl, 19.00; N, 15.01 Found Value (%): C, 51.81; H, 4.55; Cl, 18.93; N, 15.15 Examples 9 to 15 The reaction is performed in the same manner as in Example 8 to obtain the target substance (Ib).

Reference Example 1 2- [1- (1H-imidazol-1-yl) vinyl]-
4- (3-methoxycarbonylpropionyl) phenol V-1 8.2 g of 1H-imidazole (120.
To a solution of (6 mmol) dissolved therein, 3.6 g (30.3 mmol) of thionyl chloride was added dropwise under ice cooling. After stirring the mixture at the same temperature for 5 minutes, 5 g (20 mmol) of 2-hydroxy-5- (3-methoxycarbonylbropionyl) acetophenone was added. After stirring at the same temperature for 30 minutes, ice water was added, the mixture was made alkaline with an aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The extract is washed with water and dried over Glauber's salt, and then dichloromethane is distilled off. Ethyl acetate was added to the residue, the precipitated crystals were collected by filtration, and the crystals were recrystallized from a mixed solvent of methanol / ethyl acetate to give 3.6 g (yield: 60%) of the title compound V-1 as crystals having a melting point of 196-197 ° C. To get The filtrates were collected, the solvent was distilled off, the residue was subjected to silica gel chromatography, and eluted with 2% methanol / dichloromethane to give the title compound V-1 700m.
g (12% yield) are obtained. Further, elute with 5% methanol / dichloromethane and evaporate the solvent. The residue was crystallized from diisopropyl ether, collected by filtration and the by-product 2- [1- (1,1-di-1H-imidazolyl) ethyl] -4- (3-methoxycarbonylpropionyl) phenyl having a melting point of 137-138 ° C. V-2 1.7 g (yield: 23%) is obtained.

1-1: Elemental _{analysis: C 16 H 16 N 2 O} 4 · 1 / 10H 2 O Calculated (%): C, 63.61; H, 5.41; N, 9.27 Found (%): C, 63.42; H , 5.42; N, 9.24 1-2: Elemental analysis: Calculated as C ₉ H ₂₀ N ₄ O ₄ (%): C, 61.94; H, 5.47; N, 15.21 Measured value (%): C, 61.70; H , 5.41; N, 15.35 Reference Examples 2 to 6 The reaction is carried out in the same manner as in Reference Example 1 to obtain the compound (VI).

Reference Example 6 2- [1- (1H-imidazol-1-yl) vinyl]-
4- (3-methoxycarbonylpropionyl) anisole 2- [1- (1H-imidazol-1-yl) vinyl]-
4- (3-Methoxycarbonylpropionyl) phenol 1 g (3.3 mmol) was dried with dimethylformamide 20 ml.
After melting, 260 mg (4 mmol) of caustic potash (86% purity) was added under ice cooling. Then, 570 mg (4 mmol) of methyl iodide was added, and the mixture was stirred under ice cooling for 30 minutes. The reaction solution is poured into ice water, extracted with dichloromethane, washed with water, and dried with sodium sulfate. The solvent is distilled off, the residue is chromatographed on silica gel and eluted with 3% methanol / dichloromethane to distill off the solvent. The residue is crystallized with diisopropyl ether and collected by filtration. Recrystallization from a mixed solvent of ethyl acetate / diisopropyl ether gives 487 mg (yield 46%) of the title compound as crystals having a melting point of 94-96 ° C.

Elemental analysis: Calculated as C ₁₇ H ₁₈ N ₂ O ₄ (%): C, 64.95; H, 5.77; N, 8.91 Measured value (%): C, 65.02; H, 5.68; N, 9.04 Reference Example 7 ~ 9 The reaction is carried out in the same manner as in Reference Example 6 to obtain the target substance (II).

Activity data The compounds used in the following experimental examples are indicated by compound No., which is the same as the corresponding compound of Example No.

Experimental Example 1. Action of increasing contractile force in the isolated right atrium of the guinea pig: Test method After banging the heads of male and female guinea pigs weighing 400 to 600 g, the carotid artery was cut to exsanguinated and lethal, and then the right atrium was removed. did. Krebs-Ringer saturated with a mixed gas of 95% oxygen and 5% carbon dioxide and kept at 30 ℃
The isolated right atrium was suspended in a Magnus container filled with a dicarbonate solution, and its automatic movement was performed by the FD pick-up (Pi
ck up) (SB-1T, Nihon Kohden) and polygraph (Poygrap
h) (Nihon Kohden). The pulse rate was measured by a pulse counter (Pule Counter) from the automatic movement of the isolated right atrium.

The test compound was dissolved in methanol or dimethyl sulfoxide, and then 10 ⁻⁵ g / ml was administered in the Magnus container. Amrinone [5-amino- (3,4 '
-Bipyridine) -6 (1H) -one] ^10-5 g / ml was used.

result

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location // C07D 233/60 101

Claims (2)

[Claims] 1. A general formula (In the formula, Is a single or double bond, R ¹ and R ² are each hydrogen, alkyl or phenyl, R ³ is hydrogen, alkyl or optionally substituted aralkyl, X is hydrogen, alkyl or halogen, Az is 1H-benzimidazole -1-yl, 1H-imidazol-1-yl, 1H-pyrazol-1-yl or 1H-
Represents 1,2,4-triazol-1-yl. ) The compound or its salt shown by these. 2. General formula (In the formula, Is a single or double bond, R ¹ and R ² are each hydrogen, alkyl or phenyl, R ³ is hydrogen, alkyl or optionally substituted aralkyl, X is hydrogen, alkyl or halogen, Az is 1H-benzimidazole -1-yl, 1H-imidazol-1-yl, 1H-pyrazol-1-yl or 1H-
Represents 1,2,4-triazol-1-yl. ) A cardiotonic drug containing as an active ingredient a compound represented by