Process for preparing 2/1h/-pyridinone derivatives and pharmaceutical compositions containing such sompounds

The present invention relates to a process for the preparation of 2 (1H) -pyridinone derivatives of the formula I and their salts

R is cyano, carbamoyl or amino; and

R 1 represents

(i) X or - (CH₂)_nPhenyl monosubstituted or disubstituted identically or differently, wherein n is 1, 2, 3 or 4;

X is cyano, carboxyl, alkoxycarbonyl having 2 to 5 carbon atoms or alkylsulfinyl having 1 to 4 carbon atoms; and

Y is hydroxy or carboxyl; or (ii) an X or - (CH₂)_nY, wherein n, X and Y are as defined above, and

Phenyl substituted with C 1-4 alkoxy; and

R₂ is C 1-4 alkyl.

These compounds are hereinafter briefly referred to as the compounds of the invention.

It should be noted that, for the sake of simplicity, the compounds of the invention are represented in the tautomeric form represented by formula (I). However, the invention also encompasses all other tautomeric forms of the compounds of formula (I).

The present invention also relates to the preparation of pharmaceutical compositions containing the compounds of formula (I) as active ingredients.

Compounds of similar structure but substantially different from those of the present invention are disclosed in U.S. Patent No. 2,070,606. U.S. Patent No. 3,044,568 to Sandoz; German Patent Publication No. Sterling Drug; European Patent Specification (Sterling Drug).

In the compounds of the formula I:

Preferably R is cyano or amino, especially cyano.

Preferred R 1 is as defined in i).

The phenyl group is preferably monosubstituted, in which case the substituent is preferably in the para position. When the phenyl group is disubstituted, the substituents are preferably meta and para. When the phenyl group is disubstituted, R 1 and R 6 are present₂ preferably they are the same.

The groups defined in (i) are more preferred than the groups defined in (ii). The preferred meaning of (i) may be phenyl monosubstituted or disubstituted, singly or differently. The preferred meaning of (ii) is phenyl disubstituted with X and alkyl, alkoxy or halogen.

n is preferably 1 or 2, in particular 1.

Preferably X is cyano or carboxyl, especially cyano.

Preferably Y is hydroxy.

The alkyl and alkoxy groups and the alkoxy unit of the alkoxycarbonyl groups and / or the alkylsulfinyl group preferably contain one or two, in particular one carbon.

Within the group of compounds of formula (Ia), those compounds of formula (Ia) in which

R [i] is as defined above for i) Rj; and

R₂ has the meaning given above.

In one subgroup of compounds of formula Ia, R is cyano, in another subgroup amino, and in a third subgroup all substituents on phenyl are the same unless they are hydrogen.

Within the group of compounds of formula (Ia), the compounds of formula (Iaa) in which

R and R₂ is as defined above; and

R 'is X^the or - (CH₂)_n, Phenyl monosubstituted or disubstituted singly or differently, wherein n 'is 1 or 2; X 'is cyano or carboxyl; and Y 'is a hydroxyl group.

Compounds of formula Iaa

- in one of its subgroups Rf is as defined above for X 'or - (CH₂)_nPhenyl substituted by monosubstituted Y;

in another subgroup, R is cyano;

- in a third subgroup R is amino;

- in a fourth subgroup, n 'is 1;

- in a fifth subgroup X^the is cyano; and

- in a sixth subgroup all substituents on the phenyl group are the same, unless they are hydrogen.

Another preferred group of compounds of the present invention is represented by the general formula (Ic) wherein

R^c, R 1 and R j are the same as R, R j and R above₂, with the proviso that if R^c X is cyano and Y is hydroxy.

In a subgroup of compounds of formula Ic, R^c cyano or carbamoyl.

A further class of compounds of the present invention are compounds of formula (Ipa) wherein

R^pa is cyano or carbamoyl; and

Rf is (i) phenyl monosubstituted or disubstituted or mono- or di-substituted with (C1-C4) alkylsulfinyl;

ii) phenyl substituted with one C 1-4 alkylsulfinyl group and a C 1-4 alkoxy group; or iii) phenyl substituted by cyano or carboxyl; and

R₂ has the meaning given above.

A further class of compounds of the present invention are compounds of formula (Ipb): wherein

Rf and R₂ Rf and R₂ has the same meaning as defined above.

A further class of compounds of the present invention are compounds of formula (Ipc) wherein

R is as defined above; and

Rf is an X^p or - (CH₂)_rY^p phenyl monosubstituted with

190 839 is n as defined above;

X^p is a carboxyl or alkoxycarbonyl group having 2 to 5 carbon atoms in total;

Y^p is hydroxy; and

R₂ has the meaning given above.

A further class of compounds of the present invention are compounds of formula (Is)

- where

R is as defined above;

The meaning of Rj

(i) an X⁸ or - (CH₂)_n5OH monosubstituted phenyl wherein ns is 1 or 2; and X 'is cyano or carboxyl; or ii) C 1 -C 2 alkylsulfinyl; and

Phenyl substituted with C 1-4 alkoxy; and

R₂ Represents a C 1-2 alkyl group.

The compounds of the present invention are prepared by preparing compounds of formula (Γ)

- where Rj and R₂ R 1 is as defined above and R 'is cyano or carbamoyl - a corresponding compound of formula II wherein R 1 and R₂ is as defined above, and R_x is a leaving group - reacting with a suitable compound of formula III, wherein R 'is as defined above, and optionally, for the preparation of compounds of formula I, wherein R 1 and R₂ is as defined above, a suitable compound of formula IV, wherein R 1 and R 6 are as defined above₂ is as defined above, and R_y carbamoyl is converted to an amino group and the resulting compound of formula I is isolated in free or salt form.

The first process is carried out in a manner known per se for the preparation of analogous 3-cyano or 3-carbamoyl-2 (1H) -pyridinone derivatives. R_xis, for example, a known group suitable for cyclization with an acetamide derivative, for example di (lower alkyl) amino, especially dimethylamino or diethylamino. This reaction is preferably carried out in an inert solvent such as ethanol. It is preferable to carry out this reaction at a temperature between room temperature and the boiling point of the reaction mixture under strongly alkaline conditions.

However, this reaction can also be carried out in an acidic medium such as acetic acid. In this case, the compounds of formula (Γ) in which R 'represents a carbamoyl group may be prepared directly from the corresponding compounds of formula (III) in which R' represents a cyano group.

Ring closure is carried out on a derivative of a phenyl group, such as a cyanomethyl substituent, for example substituted with a precursor, e.g. is converted to the desired substituent (e.g., cyanomethyl).

The second process is carried out in a manner known per se for the preparation of analogous 3-amino-2 (1H) -pyridinone derivatives. If R_y is a carbamoyl group, Hoffmann degradation can be used. This conversion is advantageously accomplished by employing strongly alkaline conditions such as alkali metal hydroxide and bromine. Water is preferably used as a solvent. Suitable reaction temperatures are about 50-100 ° C, preferably about 100 ° C.

For substituents on a phenyl group such as a cyano group, the carbamoyl group is converted to an amino group by a derivative containing the substituent, e.g.

The compounds of the present invention can be isolated and purified from the reaction mixture in known manner.

The compounds of the invention may be present in free or salt form. The free-form compounds can be converted into salts in known manner and vice versa. Suitable acids for the preparation of acid addition salts are hydrochloric acid, malonic acid, 4-toluenesulfonic acid and methanesulfonic acid. Bases suitable for the formation of anionic salts include, for example, sodium and potassium hydroxide. The anion-type salts are generally present in the tautomeric iminol form.

The starting materials may be prepared in a manner similar to known methods.

Compounds of formula II wherein R_xis di (lower alkyl) amino, for example, by preparing a corresponding compound of formula (V) wherein R, and R₂ is as defined above, with an N, N-di (lower alkyl) formamide di (lower alkyl) acetal, preferably Ν, Ν-dimethylformamide dimethylacetal or Ν, Ν-dimethylformamide diethyl -acetal interaction.

Compounds of formula (V) are prepared by methods known per se. Compounds of formula (V) wherein R_t or - (CH₂)_nPhenyl substituted with Y or monosubstituted with Y; and R₂ C 1-4 alkyl is prepared according to Scheme A. In this embodiment, the reaction steps may be repeated to produce compounds wherein n is an integer up to 4. The carbonyl group is preferably present in a protected form such as a ketal form.

Other compounds of formula V are prepared in a similar manner. For example, a compound containing an alkylsulinyl group is prepared by oxidizing the product containing the corresponding alkylthio group. Oxidation with, for example, hydrogen peroxide or

It can be carried out with 3-chloroperbenzoic acid.

If the preparation of the necessary starting materials is not described, these are known or may be prepared by methods known per se or analogous to those described herein or known per se.

The process of the invention is illustrated below

Examples are described in detail in Examples -3190839. In these examples, all temperatures are given in degrees Celsius without correction.

heating at room temperature gives 3- [4- (methoxycarbonyl) methylphenyl] -4- (dimethylamino) -3-buten-2-one, which is directly processed without characterization.

First example

Preparation of 3-Cyano-5- (4-cyanophenyl) -6-methyl) -2 (1H) -pyridinone

6.2 g of cyanoacetamide are added to a freshly prepared solution of 1.14 g of sodium in 200 ml of anhydrous ethanol, followed by addition of 10.6 g of 3- (4-cyanophenyl) -4- (dimethylamino) -3-buten-2 and the resulting solution was stirred at reflux for 5 hours. The precipitation of the sodium salt of the title compound soon begins. The mixture is cooled, the crystalline product is filtered off and washed first with ethanol and then with ether. The free base was obtained in 88% yield. Both the sodium salt and the free form melt above 300 ° C.

The starting material 3- (4-cyanophenyl) -4- (dimethylamino) -3-buten-2-one is prepared by treating 1- (4-cyanophenyl) -2-propanone with N, N-dimethyl- formamide dimethylacetal at 80 ° C for 1 hour. B.p. 155-160 ° C / 0.6665 Pa.

Second example

Preparation of 4- (1,2-Dihydro-2-oxo-3-cyano-6-methyl-5-pyridyl) phenylacetic acid g 3- [4- (methoxycarbonyl) methylphenyl] -4-dimethyl- Amino-3-buten-2-one was reacted with cyanoacetamide as in Example 1 to afford the title compound, m.p. 280-282 ° C (after recrystallization from dimethylformamide / ethanol). Yield: 29%.

The starting material was prepared as follows:

4- (2-Oxopropyl) benzonitrile was heated to reflux for 5 hours with concentrated aqueous hydrochloric acid to give 4- (2-oxopropyl) benzoic acid (m.p. 163-165 ° C), and the latter was introduced into methanolic solution by the addition of Convert to (2-oxo-propyl) -benzoic acid methyl ester (m.p. 48-50 ° C). The carbonyl group is protected in ketal form by reacting the latter ester with ethylene glycol in the presence of 4-toluenesulfonic acid. The methyl ester thus obtained is reduced to 2-methyl-2- [4- (hydroxymethyl) benzyl] -1,3-dioxolane in lithium tetrahydroaluminate in b.p. 130-135 ° C / 9.331 Pa. The protecting group is then deprotected with 2N aqueous hydrochloric acid, and the product thus obtained is converted into 1- [4- (bromomethyl) phenyl] -2-propanone in ether with phosphorus tribromide and then directly, without characterization, with excess sodium cyanide. in ethanolic solution to give 4- (2-oxopropyl) phenylacetonitrile (b.p. 140 ° C / 13.33 Pa). This nitrile is hydrolyzed with concentrated hydrochloric acid to give 4- (2-oxopropyl) phenylacetic acid (m.p. 92-94 ° C) and the acid is esterified in methanolic solution in the presence of hydrogen chloride gas. The resulting 4- (2-oxopropyl) phenylacetic acid methyl ester (b.p. 120-130 ° C / 7,998 Pa) was treated with N, N-dimethylformamide dimethylacetal for 2 hours at 50 ° C. example

Preparation of 3-Amino-5- (2-methoxy-4-methylsulfinylphenyl) -6-methyl-2 (1H) -pyridinone in a solution of sodium hydroxide g in water (230 ml) with stirring at 0 ° C, 3.7 ml of bromine 17.6 g of 2-oxo-1,2-dihydro-5- (2-methoxy-4-methyl-thiophenyl) -6-methyl-nicotinic acid amide are added dropwise followed by stirring at 100 ° C for 3 hours. on. After cooling to room temperature, carefully acidify with 6N hydrochloric acid, stir for 30 minutes, and filter the brown precipitate. The filtrate is extracted with ethyl acetate, the aqueous phase is concentrated and made basic with concentrated ammonium hydroxide solution. The precipitate is filtered off with suction. The mother liquor was concentrated and the title compound crystallized; yield: 15%. Hydrochloride, m.p. 224-226 ° C (after recrystallization from dichloromethane / methanol).

The starting material was prepared as follows:

2-Methoxy-4-methylthiobenzaldehyde was refluxed with nitroethane in the presence of n-butylamine on a toluene side. The corresponding nitrovinyl derivative thus obtained is directly converted, without characterization, into 1- (2-methoxy-4-methylthiophenyl) -2-propanone (b.p. 140-150 ° C / 2.666 Pa) using iron powder and hydrochloric acid.

This compound was heated with Ν, Ν-dimethylformamide dimethylacetal for 3 hours at 80 ° C to give 3- (2-methoxy-4-methylthiophenyl) -4-dimethylamino-3-buten-2-one (ether and petroleum ether). 111-112 ° C). Reaction of the latter product and cyanoacetamide in acetic acid solution at 100 ° C gives 2-oxo-1,2-dihydro-5- (2-methoxy-4-methylthiophenyl) -6-methylnicotinic acid amide, m.p. 278-281 ° C (with decomposition) (after recrystallization from dichloromethane / methanol).

In a similar manner, the following compounds of the invention are obtained:

number

a) Similar to the method described in Examples 1 and 2:

<td> 4.</td><td>amino carbonyl</td><td>4-cyanophenyl</td><td>methyl b&gt; 300</td><td> 63</td>

<td> 5.</td><td>cyano</td><td>2-methoxy-4-methyl- sulfinyl-phenyl</td><td>methyl-k&gt; 300</td><td> 47</td>

<td> 6.</td><td>cyano</td><td>4-carboxyphenyl</td><td>methyl b&gt; 300</td><td> 80</td>

<td> 7.</td><td>cyano</td><td>4- (hydroxymethyl) - phenyl</td><td>methylene&gt; 300</td><td> 29</td>

<td colspan="4">b) Similar to the method described in Example 3:</td><td></td>

<td> 8.</td><td>amino</td><td>4-carboxyphenyl</td><td>methyl 290-293</td><td> 32</td>

Notations: b = free form k = potassium salt na = sodium salt

190 839

The compounds of the invention, both in free form and in the form of their physiologically acceptable salts, exhibit interesting pharmacodynamic properties and are therefore useful as medicaments.

The compounds of the present invention have cardiotonic (cardiac contractile enhancement) activity as evidenced by standard assays. Thus, when administered intravenously at a dose of about 0.02 mg / kg to 2 mg / kg in a normal blood pressure anesthetized dog, "Numal" (allopropyl barbital) increases the contraction of the left ventricle of the heart.

The test method is as follows:

The experiments were performed on mongrel dogs of both sexes weighing 10-15 kg. Animals were anesthetized with 65 mg / kg intravenously administered Numal; the animal - with its spontaneous breathing fixed on an operating table, laid on its back. Following routine preparation, a heparinized catheter is inserted into the left ventricle under the right carotid artery under X-ray and the pressure is sensed by a transfer membrane (Gould Statham P 23 Gb). The changes in pressure increase over time are calculated and plotted using an HSE physio-differentiator. The increase in left ventricular pressure dp / dt is a measure of the ability of the heart to contract. The dimension of the differential pressure is given in mm Hg / sec. The measurement results are displayed on a Schwarzer multi-channel apparatus. Proper body temperature (about 36-37 ° C) is maintained. After completion of the control period of about 40 minutes, the test substance is injected intravenously into the femoral vein and observed for its effect on the recorded and calculated parameters.

The cardiotonic effect is accompanied by an afterload reduction effect. In the above-described anesthetized, normal blood pressure (normotonic) dog, the compound of the present invention is administered intravenously in an amount of about 0.2 mg / kg to about 2 mg / kg and the total peripheral resistance ("total peripheral resistance ").

To measure arterial blood pressure, a heparinized catheter is routed through the left femoral artery to the aorta, under X-ray. The pressure is measured with a Statham P 23 AC pressure transducer head, which allows accurate evaluation of systolic and diastolic blood pressure. The mean pressure is calculated by adding to the diastolic pressure the amplitude of the blood pressure (P_HÍKtolés- Pd_lactateJ '/ a-part.

All peripheral resistances (PR) are din sec cm ⁵units, it is calculated using the following formula:

_pR medium arterial blood pressure - diastolic left ventricular pressure _χthe cardiac output

The minute volume is measured by thermodilution using a catheter inserted into the right jugular vein under X-ray control.

Test results of the compound of Example 1 show that the compounds of the present invention exhibit unexpectedly long-lasting activity and unexpectedly favorable tolerance. For example, the compounds of the present invention have surprisingly low tachycardizing (heart rate-increasing) effects.

Accordingly, the compounds of the invention may be used as a cardiotonic drug, for example in the treatment of heart failure. For this purpose, the compounds described in Examples 1, 2 and 5, in particular Example 1, are advantageously used.

It will be understood that the dosage required to achieve this therapeutic target will vary with the material employed, the mode of administration and the desired therapeutic purpose. Generally, satisfactory results can be obtained with a daily dose of about 10 to 500 mg; if necessary, this dose may be administered in 2-4 divided doses or as a prolonged release formulation. For example, dosage forms suitable for oral administration generally contain from about 2.5 mg to about 250 mg of the active ingredient with solid or liquid carriers. A suitable daily dose is, for example, 10-100 mg.

The compounds of the invention may be administered alone or in the form of their physiologically acceptable salts, either alone or in a suitable dosage form. Pharmaceutical forms, such as solutions or tablets, may be prepared by methods analogous to known methods. The invention therefore also relates to the preparation of pharmaceutical compositions containing the compounds of the invention in free or physiologically acceptable salts. These pharmaceutical compositions can be prepared in a known manner using the excipients and excipients used in the pharmaceutical preparation.

Dissolution-promoting or stabilizing agents such as cyclodextrins such as β-cyclodextrin may be used to prepare solutions.