HU191299B - Process for producing 2/1h/-pyridinone derivatives increasing cardiac action - Google Patents

Abstract

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Description

FIELD OF THE INVENTION The present invention relates to a process for the preparation of compounds and pharmaceutical compositions for the treatment of heart failure.

More particularly, the present invention relates to a process for the preparation of certain novel 2 (1) -pyridinone derivatives and pharmaceutical compositions containing these compounds. Heart failure in mammals can be treated with these pharmaceutical compositions.

No. 2,070,606. I98l. British Patent Application Publication of September 9, 2002 discloses certain 2 (I) pyridinone derivatives and their use as cardiac enhancers.

A 4 313 95I. s. U.S. Pat. No. 4,198,125 discloses certain 3-substituted 6-lower alkyl-5-pyridinyl-2 (l) -pyridinones and their use as cardiac enhancers.

In its broadest aspect, the present invention relates to a process for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof. In the 2 (l) -pyridinone derivatives of general formula (I), the substituents have the following meanings:

X is hydrogen, halogen, cyanocarbamoyl or amino,

Y is C 1 -C 4 alkyl,

Z represents imidazol-1-yl, benzimidazol-1-yl, tetrahydro-benzimidazol-1-yl, 3- or 4-phenyl-piperidin-Ι-yl, 1,2-attached to the phenyl group; 4-triazol-1-yl or C 1 -C 4 alkanoylamino.

The present invention further relates to a process for the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of the present invention are useful for the enhancement of myocardial contraction and for the treatment of heart failure in mammals in need of such treatment. This treatment comprises administering to the body an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt of bile and a pharmaceutically acceptable carrier.

The compounds of the present invention may be prepared by a variety of processes which are considered equivalent to the invention.

In one such process, a compound of formula II, wherein X and Y are as defined above, is treated with a compound of formula Z-H wherein Z is as defined above.

This procedure may be carried out by treating a compound of formula II with a base, e.g. potassium carbonate - in the presence of ca. The reaction is carried out at 200-300 ° C with Z-H until the reaction is substantially complete. Usually a period of 24 to 36 hours is sufficient. Catalyst e.g. the presence of copper (I) iodide has a beneficial effect.

The compounds of formula (II) may be prepared by methods known to those skilled in the art. so e.g. a fluorophenyl-2-alkanone (or fluorophenylacetaldahyde) can be ion-condensed with N, N-dimethylformamide dimethylacetal to form the corresponding 1- (fluorophenyl) -2- (dimethylamino) -enylalkanone (alkanal).

Treatment of the thus formed alkanone (alkanal) with cyanoacetamide under basic conditions results in the formation of appropriately substituted compounds of formula II wherein X is - CN. This process is essentially carried out as described in British Patent Application 2,070,606, issued September 9, 1981, and in U.S. Patent No. 4,313,951. The -CN group of the compounds thus formed can, if desired, be converted to other -X groups as known to those skilled in the art.

Alternatively, a compound of formula (III) wherein Y and Z are as defined above may be converted to a compound of the present invention by a process substantially similar to that of the fluorophenyl-2-alkanone (fluorophenylacetaldahyde). ) for the conversion of a compound of formula (Π). In particular, a compound of formula (III) is reacted with an appropriate N - (fluorophenyl) -2 - (dimethylamino) ethenyl (N) -dimethylformamide-dimethyl-methylcyclate (IV). - during the formation of alkanone (or alkalone). The resulting alkanone or alkane is treated with ethanacetamide to give the corresponding substituted compound of general formula (I) in which X is -CN under basic conditions.

The -CN group of the compound prepared by this process can be converted to other X groups, where X is as defined above, as known to those skilled in the art.

The applicability of the compounds of the invention as cardiac agents can be demonstrated by demonstrating their efficacy by standard pharmacological test procedures. In one such procedure, e.g. a significant increase in myocardial contraction in pentobarbital anesthetized dogs, with little or minimal change in heart rate and blood pressure. This experimental procedure is described below.

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Investigation of the iuotropic effect on the myocardium in anesthetized dogs

This screening procedure consists of determining the effect of increasing the dose of intravenously administered compounds on myocardial contractility (dP / dt, maximal left ventricular pressure), heart rate, and aortic blood pressure in pentobarbital anesthetized dogs.

Method

Adult Mongrel Dogs of any Gender with Pentobarbital - 35 mg / kg i. v. - anesthetized and then anesthetized by continuous infusion of pentobarbital (3.5 mg / kg, hour). A tube is introduced into the trachea, but the animals are allowed to breathe freely. A cannula was inserted into the femoral vein to administer the test compounds. To measure arterial blood pressure, a Millar catheter tip pressure transducer or a fluid-filled catheter is introduced into the ascending aorta through the femoral artery. The Millar catheter tip pressure transducer is inserted into the left ventricle via the left carotid artery to measure left ventricular blood pressure. Needle electrodes are placed under the skin for the lead (II) electrocardiogram (ECG).

Left ventricular and arterial blood pressure are recorded with a tape recorder. The heart rate is also recorded using a biotachometer guided by the R wave of the ECG, and the first differential quotient (dP / dt) of left ventricular blood pressure obtained by a differentiating amplifier coupled to the appropriate pressure amplifier. At least 30 minutes before the test compound is administered, control data are obtained.

Depending on the solubility, the compounds are dissolved in 0.9% sodium chloride solution or dilute (0.1 or 1.0 N) HCl or NaOH and diluted with normal sodium chloride solution to the desired volume. Ethanol or dimethylacetamide may be used as the solvent, if appropriate dilution is available. If necessary, appropriate vehicle control is provided.

Each dose of test compound was administered in a volume of 0.1 mg / kg over a period of 1 minute.

When tested by the "anesthetized canine method" described above, the compounds of the invention are administered at ca. When administered intravenously at a rate of 0.01 to 0.31 mg / kg / min, these cause a dose-dependent significant increase in cardiac contraction, with little or no change in heart rate and blood pressure.

The following table shows representative results from these experiments for the compounds of the present invention, vo2q. The test compounds correspond to the formula I and the meaning of the substituents X, Y and Z are given in the table.

The compounds of the present invention form pharmaceutically acceptable salts with organic and inorganic acids. Suitable acids for the formation of salts are hydrochloric, sulfuric, phosphoric, boric, methanesulfonic and the like. Salts are prepared by reacting the free base with an appropriate amount of the desired acid in a known manner. The free base újraké ₃₀ pezhető if the salt with a base. For example, dilute water. base solutions may be used. For this purpose, dilute aqueous solutions of sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate are suitable. The free base forms differ slightly in their physical properties, such as solubility in polar solvents, from the corresponding salt forms, but for the purposes of the invention, the salts are otherwise equivalent to the corresponding free bases.

Spreadsheet

% change Example W X Y z Dczis, mg / kg body weight in myocardial contraction at heart rate blood pressure 1 H CN -ch ₃ 1-, R _e = 0.01 39 3 = r ₇ = h, 0.03 116 26 -1.5 A = Avg. binding 0, 00 136 38 7.00 0.30 139 54 -19.5 2 H H CH, A = Avg. binding 0.01 36 3 3 0.03 85 9 • 3 0.10 17 11 0.31 26 20 3 H —Nh ₂ -CHj A = Avg. binding 0.01 23 1 0.03 71 6 4 0.31 19 24 0, i0 14 12 1.00 84 16 30 4 H CN -CHj 2a., A = av. binding 0.01 6 5 - 4 0.3 8 10 4 0 10 8 11 5 O.il 1 11 5 1.00 12 9 10

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The compounds of the present invention are unsolvated or non-solvated. they may exist in solvated forms, including hydrated forms. Pharmaceutically acceptable solvents, e.g. water, ethanol, etc. the formed solvated forms are generally equivalent to the unsolvated forms for purposes of the invention.

The alkyl groups in the compounds of the present invention may be linear or branched C 1 -C 4. Typical examples of such groups are methyl, ethyl, isopropyl. Methyl and ethyl are preferred.

The compounds of the invention contain a Z group substituted phenyl group, which Z substituent may be located at the 3 or 4 position of the benzene ring. Most preferably, Z is attached to the 4-position of the benzene ring.

The compounds of the invention may be formulated and administered in a variety of oral and parenteral dosage forms. It will be appreciated by those skilled in the art that the following dosage forms may contain as active ingredient a compound of formula (I), a pharmaceutically acceptable salt of a compound of formula (I), or a mixture of such compounds and / or appropriate salts.

When preparing pharmaceutical compositions from the compounds of the invention, inert pharmaceutically acceptable carriers may be employed which may be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The solid carrier may consist of one or more substances which act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or disintegrating (tablet disintegrating) agents. The solid carrier may also be a capsule-forming material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active compound. In the tablet, the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and brought into the shape and size desired. The powders and tablets are preferably from about 1 to about 10 mg. They contain 5-70% of active ingredient. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term "composition" is used to include the preparation of the active compound with an encapsulating material which is used as a carrier for the preparation of the capsule; in the capsule, the active ingredient (with or without other carriers), carriers for magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, jelly, powders, wafers and capsules may be used as solid dosage forms for oral administration.

Liquid form preparations may include solutions, suspensions, and emulsions. As an example, aqueous or aqueous propylene glycol solutions for parenteral injection may be mentioned. Liquid formulations may also be prepared in aqueous polyethylene glycol solution. Aqueous solutions for oral use can be prepared by dissolving the active ingredient in water and optionally adding suitable colorants, flavors, stabilizers, and thickeners. Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active component in water with a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.

The pharmaceutical compositions may preferably be presented in unit dosage form. In this form, the composition is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing a fixed amount of preparation; such as packaged tablets, capsules, and powders in vials or ampoules. A unit dosage form may also be a capsule, a wafer, or the tablet itself, or an appropriate number of any such packaged forms.

The amount of active compound in a unit dose formulation may be varied or adjusted from 1 to 100 mg, depending on the particular application and the efficacy of the active ingredient.

When used as a therapeutic agent for cardiac function, the compounds used in the therapeutic process of the present invention will have a concentration in the range of ca. 0.001 mg <b. 1.0 mg / kg may be administered at a starting dose of one day. We prefer the approx. A dose range of 0.01 mg to about 0.5 mg / kg. However, the dosages may be varied according to the needs of the patient, the severity of the disease being treated, and the compound employed! Depending on. Determining the appropriate dosage for a given situation is within the skill of the art. It starts with lower doses, which are lower than the optimum dose of the compound. The doses are then increased in small amounts until the optimum effect under the circumstances is achieved. Conveniently, the total daily dose may be divided and administered in portions during the day, at appropriate intervals.

The following examples illustrate methods for preparing the compounds of the invention.

Example 1

1,2-dihydro-5- [4- (1H-imidazol-1-yl) phenyl]

Methyl 6 - 2 - oxo - 3 - pyridinecarbonyl.

5.0 grams of 1,2-dihydro-5- (4-fluorophenyl) -6

- a mixture of methyl 2-oxo-3-pyridine carbonitrile, 25 grams of imidazole, 5 grams of potassium carbonate, 0.5 grams of copper and 0.5 grams of copper (I) iodide for 24 hours at 200 ° C and for 8 hours. Keep at 260 ° C. After cooling, the reaction mixture was diluted with water and filtered. The filtrate was acidified with 6N hydrochloric acid and the precipitate was collected. This solid was boiled in methanol (3 L) and the hot mixture was filtered. The filtrate was concentrated to a volume of 200 ml and filtered; Thus 0.7 grams 1.2

dihydro - 5- [4- (1H-imidazol-1-yl) phenyl] - 6

methyl 2 - oxo - 3 - pyridine carbonyl is obtained. Mp 300-301 'C.

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Example 2

1,2-dihydro-3- (4- (1H-imidazol-1-yl) phenyl)

6 - methyl - 2 - oxo - 3 - pyridine carbonitrile (alternative method).

A mixture of 1.0 g of 1- [4- (1H-imidazol-1-yl) -2-propanone in 10 ml of Ν, Ν-dimethylformamide diethyl acetal in 20 ml of acetonitrile is stirred overnight. The mixture is concentrated in a rotary evaporator. It is dissolved in 20 ml of N, N-dimethylformamide and treated with 0.46 grams of cyanoacetamide and 0.6 grams of sodium acetate, refluxed for 5 minutes, cooled and concentrated in a rotary evaporator. and recrystallized from 2-propanol 0.2 grams

1,2-dihydro-5- [4- (1H-imidazol-1-yl) phenyl]

6-methyl-2-oxo-3-pyridine carbonitrile is obtained, m.p. 298-300 'C.

Example 3

1,2-dihydro-5- (4-fluorophenyl) -6-methyl-2-oxo-3-pyridine-carbonitrile.

A mixture of 4 grams of 4-fluorophenylacetone and 162.5 ml of N, N-dimethylformamide dimethylacetal in 75 ml of acetonitrile was stirred for 12 hours and the reaction mixture was concentrated on a rotary evaporator. The remaining solid was suspended in 100 mL of hexane and filtered. 59.6 grams of 4- (dimethylamino) -3- (4-fluorophenyl) -3-butene 2-one are obtained.

A mixture of 59.6 grams of 4- (dimethylamide) -3- (4-fluorophenyl) 3-buten-2-one, 26.7 grams of cyanoacetamide and 34.3 grams of sodium methylate in 830 ml of dimethylformamide is heated under reflux for 2 hours. and the reaction mixture was concentrated in a rotary evaporator. The remaining solid was suspended in 2 liters of water and stirred overnight. The aqueous mixture was acidified with 12N HCl, diluted with water to 1 liter and stirred for 2 hours. The solid product was collected, washed with water (500 mL) and washed with ethanol. 55.4 grams

1,2-Dihydro-5- (4-fluorophenyl) -6-methyl-2-oxo-3-pyridine carbonitrile is obtained.

Example 4 [4- (1H-imidazol-1-yl) phenyl] -2-propanone

34.5 grams of 4 - [4-1H-imidazol-1-yl] benzyldehyde (for the preparation of 1. LM Sitkina, AM Simonov, Him. Geterocyclo. Sed., Akad. Nauk Latv. SZR, 143, 1966; Chem. Abstr. 65, 13686 (1966), 150 ml of nitroethane and 8.3 g of ammonium beetate are refluxed for 60 hours. After cooling, the reaction mixture was concentrated in a rotary evaporator and finally dried under high vacuum. The residue containing 1- (4- (1H-imidazol-1-yl) phenyl) -2-nitropropene as a stereoisomeric mixture was used without purification.

I - [4- (1H-Imidazol-1-yl) phenyl] -2-nitropropene, 94.7 grams of iron powder and 1.2 grams of hydrated ferric chloride, prepared as described above, are prepared in 50 ml of methanol and 170 ml of water. The mixture was refluxed and treated dropwise with 85 ml of 12N hydrochloric acid for 4 hours. The reaction mixture was refluxed for an additional hour, then cooled and filtered. The filtrate was basified with 40% ammonium hydroxide solution and the whole was thoroughly extracted with ethyl acetate. The ethyl acetate solution was treated with activated carbon, dried over magnesium sulfate and concentrated in a rotary evaporator; a dark yellow oil is obtained. This material was chromatographed on Waters Prep 500 A using silica gel. Elution was carried out with chloroform containing 2% methanol. The major fraction contains I - [4- (1H-imidazol-1-yl) phenyl] -2-propanone.

Example 5

- [4- (2-Nitro-1-propenyl) phenyl] -1H-imidazole

292 grams (1.70 moles) of 4- (1H-imidazol-1-yl) benzaldehyde, 153.7 grams (1.97 moles) of 96% nitroethane and 15.4 grams (0.173 moles) of beta-alanine in 1000 ml The mixture prepared with n-butanol is refluxed for 9 hours. The reaction mixture is allowed to cool overnight, the solid is collected and washed successively with ether and water. 78.7 grams of dark yellow crystals are obtained, m.p. 119-120 'C. The filtrate was washed with ca. Concentrate to 500 ml and cool to 0 ° C. This gives a second fraction (87.2 grams) of product, m.p. 116-118 'C.

After evaporation of all the solvent, a red oil which crystallizes on standing for a few days is obtained. This was diluted with n-butanol (200 mL), cooled in a refrigerator and the solid collected and washed as above. 44.7 grams of dark yellow powder, op. 110-117 'C. (The preparation is carried out according to the general procedures described by L.M. Sitkina, A.M. Simonov, Him. Geterocyclo. Sed., Akad. Nauk Latv. SZRR, 143, 1966; Chem. Abstr. 65, 13686, 1966.)

6-8. example

The reaction of p-fluorobenzaldehyde with 4,5,6,7, -tetrahydro-1H-benzimidazole, 1H-benzimidazole and 4-phenylpiperidine provides the following products:

- (4,5,6,7-Tetrahydro-1H-benzodiazol-1-yl) benzaldehyde, m.p. 104-110 'C;

- (1H-benzimidazol-1-yl) benzaldehyde, m.p.

96.5-98 'C and

- (4-phenyl-1-piperidinyl) benzaldehyde, m.p. 117-119'C.

9-13. example

Following the procedure of Example 5, but using the appropriately substituted benzaldehyde, the following nitropropenes are obtained:

1- (4- (2-nitro-1-propenyl) phenyl] -1H-1,2,4-triazole, m.p.

1- (4- (2-Nitro-1-propenyl) -phenyl] 4,5,6,7-tetrahydro-1H-benzimidazole;

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1- (4- (2-nitro-1-propenyl) phenyl] benzimidazole, m.p. 147-149 'C;

(- (4- (2-nitro-1-propenyl) phenyl] acetamide; 1- (4- (2-nitro-1-propenyl) phenyl] -4-phenylpiperidine, m.p. 148-149 ° C). .

! 4th example

- (4- (1H-imidazol-1-yl) phenyl] -2-propanone

Into a 5 L three-necked flask fitted with a condenser, a separatory funnel and a mechanical stirrer was charged the following mixture: 218.4 grams (0.954 moles) of I - (4- (2-nitro-1-propenyl) phenyl) -1H-imidazole, 449 Iron powder (8.04 moles) (corresponding to 0.044 mm hole media), 6.4 grams FeCl ₂ · 6H _2, 0.350 ml methanol and 760 ml water. The mixture was heated to reflux with stirring and refluxed for 2.5 hours. The reaction mixture was cooled to room temperature, 1.9 L of CH ₂ CP was added and the mixture was stirred vigorously for 1 hour, the reaction mixture was filtered, and the inorganic solid was washed three times with 500 ml of hydrochloric acid. -500 ml of CH ₂ Cl ₂ and the layers were separated, the CH ₂ Cl ₂ layer was dried over MgSO ₄ and then filtered through a pad of silica gel (600 grams, 0.063-0.210 mm); wash with CH ₂ Cl ₂ and then with 13 L of 10% methanol in CH ₂ Cl ₂ . Evaporation of the solvent gives 126.7 grams of a brown oil which crystallizes on standing. The product is purified via the sodium bisulfate addition product; so

71.5-72.5 C is obtained.

-19. example

Following the procedure of Example 14 but using appropriately substituted nitropropenes, the following propanones are obtained:

- (4- (1H-1,2,4-triazol-1-yl) phenyl] -2-propanone, m.p. 97-98,5 'C;

- (4- (4,5,6,7-tetrahydro-1H-benzoimidazol-1-yl) phenyl] -2-propanone, m.p.

- [4- (1H-benzimidazol-1-yl) phenyl] -2-propanone;

- [4- (acetamido) phenyl] -2-propanone, m.p. 118-120'C;

1- (4- (4-phenyl-1-piperidinyl) phenyl] -2-propanone, m.p.

Example 20

1,2-dihydro-6-methyl-2-pxo-5- (4- (1H-imidazol-1-yl) phenyl] -3-pyridine-carbonitrile

125.3 grams (0.626 mol) of 1- [4- (1H-imidazol-1-yl) phenyl] -2-propanone cs 134.2 grams (1.13 mol / 1.8 equivalents) dimethylformamide dimethylacetal with 1 liter acetonitrile The resulting solution was stirred at room temperature for 18 hours and the resulting mixture was heated at reflux for 1.5 hours to complete the reaction. After evaporation, the residue was dissolved in 600 mL of CH ₂ Cl ₂ and the solution BCN pad of silica (300 grams, 0.025 to 0.053 mm ² mesh) filter and the bed was 3.0 liters of CH ₂ Cl ₂ and 3 using primed, Wash with 0 L of 5% methanol in methylene chloride. Evaporation of the solvent gave 132 g of a dark brown solid which was used directly without purification.

To a mixture of 132 g (0.514 mol) of the above 4- (dimethylamino) -3-buten-2-one derivative and 47.5 g (0.565 mol) of 2-cyanoacetamide in 800 ι, ΓΝ-dimethylformamide was added 62.0 g (1.15 mol) with stirring. sodium methylate and the resulting reaction mixture was heated to 120 ° C and maintained at this temperature for 3 hours. The reaction mixture was concentrated in vacuo on a rotary evaporator. The concentrate is ca. After treatment with 600 ml of methanol and 100 ml of acetic acid, the suspension is stirred for 15 to 30 minutes. After cooling in ice, the rusty solid was collected and washed with methanol and treated with ether.

65.8 g of product are obtained, m.p. 295-296.5 ° C (dec.).

grams of such material are recrystallized from 10 ml of dimethylformamide; 0.70 gram p.a., m.p. 306-307 ° C (dec.).

- Example 24

Following the procedure of Example 20 but using appropriately substituted propanones, the following pyridinones are obtained:

1,2-dihydro-6-methyl-2-oxo-5- (4- (2H-1,2,4)

triazol-1-yl) phenyl] -3-pyridine carbonitrile, m.p. 309-310 C (dec);

1,2-dihydro-6-methyl-2-oxo-5- (4- (4,5,6,7

- tetrahydro-1H-benzimidazol-1-yl) phenyl] -3-pyridine carbonitrile; Nuclear Magnetic Resonance Spectrum on hexadeutero dimethyl sulfoxide: shows 12.8 (bs, 1H); 8.15 (s, 1H); 7.8 (s, 1H): 7.5 (s, 4H); 25 (m, 4H);

3.3 (m, 4H) and 2.3 (s, 3H) ppm below the tetramethylsilyl signals;

1,2-dihydro-6-methyl-2-oxo-5- [4- (1H-benzimidazol-1-yl) phenyl] -3-pyridine carbonitrile, m.p. 350-353 'C (decomposed);

N - (4- (5-cyano-1,6-dihydro-2-methyl-6-oxo)

3-pyridinyl) phenyl] acetamide, m.p. 312-314 'C (dec.).

Example 25

1,2-Dihydro-6-methyl-2-oxo-5- (4 - (1H-imidazol-1-yl) phenyl] -3-pyridine-carbonitrile monohydrochloride

55.8 grams of 1,2-dihydro-6-methyl-2-oxo-5- [4- (1H-imidazol-1-yl) -phenyl] -3-pyridinecarbonyl are suspended in 500 ml of 10% aqueous methanol and slurry with stirring until pH 2 is reached cc. hydrochloric acid, After cooling overnight at 0 ° C, the solid is collected; washed with cold methanol then ether and dried in vacuo for 2 hours. 62.6 grams of monohydrochloride are obtained in the form of a light beige powder, m.p. 322-326 'C (beige).

-611

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Example 26

- (dimethylamino) -3- (4- (4-phenyl-1-piperidinyl)

- phenyl] - 3 - butene - 2 - one

4.0 grams of 1- (4- (4-phenyl-1-piperidinyl) phenyl)

A mixture of 2-propanone and 16 ml of dimethylformamide dimethylacetal was stirred at room temperature overnight and kept at 45-60 ° C for 6 hours. The solvent was distilled off and the residue was triturated with 2 x 100 mL hexane. The solid was filtered and dried; 3.5 g of orange powder are obtained, op. 93-100 'C. After standing overnight at 0 'C, an additional 0.7 gram of product precipitated out of the filtrate, m.p.

103.5 - 105 'C. This material is used directly for the next step without further purification.

Example 27

1,2-dihydro-6-methyl-2-oxo -5- (4- (4-phenyl-1-piperidinyl) phenyl] -3-pyridine carboxamide

A mixture of 2.6 g of 4- (dimethylamino) -3- (4- (4-phenyl-1-piperidinyl) phenyl] -3-buten-2-one, 0.75 g of cyanoacetamide and 0.8 ml of piperidine acetate in 25 ml of acetonitrile. After refluxing for 24 hours, the solid was collected, washed with CH 2 Cl 2 / ether and dried to give 0.80 g of a beige solid, mp 335-338 ° C (dec).

Example 28

- [4- (1H-imidazol-1-yl) -phenyl] -6-2 (1H) pyridinone

21.8 grams of 1-2-dihydro-5- [4- (1H-imidazole-1-if) phenyl] -6-methyl-2-oxo-3-pyridine carbonitrile were dissolved in 110 ml of 85% sulfuric acid and the solution was heated at 205 ° C for 19 hours. The reaction mixture was cooled to room temperature, poured into 600 ml of ice and the resulting solution was adjusted to pH cC. adjusted to 8 with ammonia. The precipitate was collected and recrystallized from dimethylformamide. 10.0 g of 5- (4- (1H-imidazol-1-yl) phenyl) -6-methyl-2 (1H) -pyridinone are obtained, m.p.

Example 29

- bromo-5- [4- (1H-imidazol-1-yl) phenyl] 6-methyl-2 (1H) -pyridinone

9.9 grams of 5- [4- (1H-imidazol-1-yl) phenyl] 6-methyl-2 (1H) -pyridinone are dissolved in 120 ml of acetic acid and treated dropwise with a solution of 2.15 grams of bromine in 16 ml of acetic acid. For 1.5 hours, maintaining the reaction temperature at 75-80 ° C. After a further 1 hour at 75-80 ° C, the reaction mixture was cooled to room temperature and cooled in an ice bath. The yellow precipitate was collected, washed with acetic acid, suspended in 100 ml of water and neutralized with 50% aqueous ammonia. The resulting off-white solid was collected, recrystallized from dimethylformamide and chromatographed on 300 g of silica gel; elution is carried out with dichloromethane containing 10% methanol to give 1.15 grams of 3-bromine

- 5- (4- (1H-imidazol-1-yl) phenyl) -6-methyl-2 (1H)

- pyridinone is obtained, op. 303.5-305 C (dec.).

Example 30

- amino-5- [4- (1H-imidazol-1-yl) phenyl] 6-methyl-2 (1H) -pyridinone

A solution of 5.0 grams of 1,2-dihydro-5- (4- (1H-imidazol-1-yl) phenyl) -6-methyl-2-oxo-3-pyridine carbonitrile in 25 ml of ca. The reaction mixture was heated, cooled to room temperature and poured into 150 ml of ice and the pH of the mixture was adjusted to 8 with cc ammonia. , 06 grams 1,2-dihydro-5 - [4 - (1H

- imidazol-1-yl) -phenyl] -6-methyl-2-oxo-3-pyridine

- Carboxamide, m.p. 311-313 'C (dec.).

1.48 grams of 1,2-dihydro prepared as above

- 5- (4- (1H-imidazol-1-yl) phenyl) -6-methyl-2

A mixture of oxo - 3 - pyridine carboxamide, 1.3 grams of sodium hydroxide and 50 ml of water was cooled in ice and treated dropwise with 0.385 ml of bromine over 10 minutes. The resulting solution was heated on a steam bath for 45 minutes, cooled to room temperature and neutralized with 6N hydrochloric acid. The solids were collected, treated with 20 mL of ON HCl, filtered and the filtrate was filtered. neutralize with ammonia. The solid was collected, dried and chromatographed on 35 g of silica gel eluting with 10% methanol in dichloromethane. 0.26 grams of 3-amino -5- (4- 1H -imidazol-1-yl)

- phenyl] -6-methyl-2 (1H-pyridinone, m.p. 302-304 'C (dec.).

Claims (10)

Patent yes A process for the preparation of a compound of formula (I) and pharmaceutically acceptable salts thereof X is hydrogen, halogen, cyano, carbamoyl or amino, Y is C 1 -C 4 alkyl and Z is benzimidazol-1-yl, tetrahydrobenzimidazol-1-yl, 3- or 4-phenylpiperidin-1-yl, imidazol-1 attached to the 3 or 4 position of the phenyl ring. -yl-1,2,4-triazol-1-yl or C 1 -C 4 alkanoylamino, characterized in that a) reacting a compound of formula II, wherein X and Y are as defined above, and A is fluorine, with a compound of formula ZH, wherein Z is as defined above, or b) reacting a compound of formula (III) wherein Z and Y are as defined above with N, N-dimethylformamide dimethylacetal of formula (IV) and treating the resulting compound with cyanoacetamide under basic conditions to form a compound of formula (I); wherein X is 7 -713 191,299, then the -CN group of this product is optionally hydrolyzed or reduced to a carbamoyl group, and the resulting carbamoyl group is optionally converted to an amino group, or, if desired, the resulting hydrogen atom is converted to a halogen atom and optionally converted to a salt. . The process according to claim 1, which is 1,2-dihydro-5 - (4- (1H-imidazol-1-yl) phenyl] -6> methyl-2-oxo 3-pyridine carbonitrile, wherein the appropriately substituted starting materials are used. The process according to claim 1, 1,2-dihydro-6 - methyl 2-oxo-5- [4- (1H-1,2,4-triazol-1-yl) - phenyl] -3-pyridine carbonitrile, characterized in that the appropriately substituted starting materials are used. A process according to claim 1, 1,2-dihydro-6 for the preparation of methyl 2-oxo-5- [4- (4,5,6,7-tetrahydro-1H-benzimidazol-1-yl) phenyl] -3-pyridine carbonitrile, characterized in that the appropriately substituted starting materials used. The process according to claim 1, 1,2-dihydro-6 - methyl 2-oxo-5- [4- (1H-benzimidazol-1-yl) - phenyl] -3-pyridine carbonitrile, characterized in that the appropriately substituted starting materials are used. The process of claim 1, N - [4- (5-cyano - 1,6 - dihydro - 2 - methyl - 6 - oxo - 3 - pyridinyl) - phenyl!] acetamide, wherein the appropriately substituted starting materials are used. The process according to claim 1, for the preparation of 5- (4- (1H-imidazol-1-yl) phenyl) -6-methyl-2 (1H) -pyridinone, wherein the appropriately substituted starting materials are used. The process according to claim I, 3-bromo-5- [4 - (1H-imidazol-1-yl) phenyl] -6-methyl-2 (1H) pyridinone, characterized in that the appropriately substituted starting materials are used. The process of claim 1, 3-amino-5- [5- (1H-imidazol-1-yl) phenyl] -6-methyl-2 (1H) - for the preparation of pyridinone, characterized in that the appropriately substituted starting materials are used. 10. A process for the manufacture of a medicament for the treatment of myocardial contraction and for the treatment of 2Q heart failure, characterized in that the compounds of I-11. A compound of formula (I) as claimed in any one of claims 1 to 4, wherein X, Y, and Z are as defined in that claim, or Thus, a pharmaceutically acceptable salt thereof is admixed with a pharmaceutically acceptable carrier.