BE896678A - NOVEL 2 (1H) -PYRIDINONE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS. - Google Patents

Description

       

  New 2 (1H) -pyridinone derivatives, their

  
Preparation and their use as medicaments The subject of the present invention is new derivatives of 2 (1H) -pyridinone, their preparation and their therapeutic use, as active principles of medicaments.

  
In particular, the invention relates to the derivatives of la (2H) -pyridinone of formula I

  

 <EMI ID = 1.1>


  
R signifies cyano, carbamoyl or amino and a) R signifies i) phenylemono-substituted or independently di-substituted by a group
- (CH2) mX or - (CH2) nY where m means 0 or an integer

  
from 1 to 4,

  
n means an integer from 1 to 4, X means cyano, carboxy, al coxycar-

  
bonyled whose remainder is C1-C4, carbamoyl or alkylsulfinyl

  
 <EMI ID = 2.1>

  
Y means a halogen having a number

  
atomic from 9 to 35, hydroxy, alkoxy

  
 <EMI ID = 3.1>

  
ii) phenyledi-substituted by a group
- (CH2) mX or - (CH2) nY where m, n, X and Y are as defined above, and <EMI ID = 4.1> has the meanings indicated under a) above for R. and

  
R2 has the meanings indicated under a) above

  
 <EMI ID = 5.1>

  
These compounds will hereinafter be designated compounds of the invention. For reasons of simplicity, the compounds of the invention have been defined in the present description with reference to the tautomeric form represented by formula I. However, the invention includes all the tautomeric forms of the compounds of the invention, such as for example the iminol form.

  
R preferably means cyano or amino, especially cyano. R, is preferably such that de-

  
 <EMI ID = 6.1>

  
under a) above, it preferably has the meaning i). When R. is as defined under b) above, it preferably means hydrogen or alkyl,

  
 <EMI ID = 7.1> a) above, it preferably means alkyl. When R2 is as defined under b) above, it preferably has the meaning i).

  
The phenyl rings are preferably monosubstituted. When a phenyl ring is mono-substituted, the substituent is preferably in the para position. When the phenyl ring is di-substituted, the substituents are preferably in the meta and para position.

  
When the phenyl ring is di-substituted and / or when

  
 <EMI ID = 8.1>

  
phenyl ring killers are preferably identical.

  
Meaning i) is preferred to meaning ii). The meaning i) is preferably phenylemono-substituted or independently di-substituted

  
 <EMI ID = 9.1>

  
preferably phenyl independently di-substituted by

  
a group - (CH2) mX and by alkyl, alkoxy or halogen.

  
m preferably means 0, 1 or 2, especially 0 or 1, especially 0. n preferably means 1 or 2, especially 1. X preferably means cyano or carboxy, especially cyano. Y preferably means hydroxy or amino, especially hydroxy.

  
 <EMI ID = 10.1>

  
of the alkoxycarbonyleet and / or the alkylsulfinyl residue preferably contain 1 or 2 carbon atoms, especially 1 carbon atom. Halogen preferably means chlorine or bromine, especially chlorine.

  
A preferred group of compounds of the invention comprises the compounds of formula la

  

 <EMI ID = 11.1>


  
in which R is as defined above and

  
 <EMI ID = 12.1>

  
phenyl ring killers are identical when they have a meaning other than hydrogen.

  
A preferred subgroup of the compounds of formula la comprises the compounds of formula Iaa
 <EMI ID = 13.1>
 in which R has the meaning given above,

  
 <EMI ID = 14.1>

  
In a subgroup of compounds of formula Iaa, R signifies cyano. In another subgroup,

  
R stands for amino. In another subgroup, all the substituents of the phenyl ring are identical when they have a meaning other than hydrogen.

  
A preferred subgroup of compounds of formula Iaa includes compounds of formula Iaaa

  

 <EMI ID = 15.1>


  
 <EMI ID = 16.1>

  
m 'means 0, 1 or 2

  
n 'means 1 or 2

  
 <EMI ID = 17.1>

  
above. In another subgroup, R stands for cyano. In another subgroup, R stands for amino. In another subgroup, m 'means 0 and n' means 1. In another subgroup, Xa means cyano. In another subgroup, Ya means hydroxy. In another subgroup, all the substituents of the phenyl ring are identical when they have a meaning other than hydrogen.

  
Another group of compounds of the invention includes the compounds of formula Ib

  

 <EMI ID = 18.1>


  
in which R has the meaning given above

  
 <EMI ID = 19.1>

  
phenyl ring substituents are the same when they have a meaning other than hydrogen.

  
Another preferred group of compounds of the invention comprises the compounds of formula le

  

 <EMI ID = 20.1>


  
 <EMI ID = 21.1>

  
given above for R, R. and R2, X having to signify cyano and Y hydroxy or alkoxy in Cl-C4 when

  
 <EMI ID = 22.1>

  
In a subgroup of compounds of formula le, Rc signifies cyano or carbamoyl.

  
Another group of compounds of the invention comprises the compounds of formula Ipa
 <EMI ID = 23.1>
 where Rpa stands for cyano or carbamoyl and <EMI ID = 24.1>

  
a halogen having an atomic number of 9 to 35, or

  
iii) phenylemono-substituted by cyano or

  
carboxy and

  
 <EMI ID = 25.1>

  
Another group of compounds of the invention includes the compounds of formula Ipb

  

 <EMI ID = 26.1>


  
 <EMI ID = 27.1>

  
Another group of compounds of the invention includes the compounds of formula Ipc

  

 <EMI ID = 28.1>


  
in which R has the meaning given previously and <EMI ID = 29.1> <EMI ID = 30.1> sedes the meaning given in a) above for Rpc and

  
 <EMI ID = 31.1>

  
being identical.

  
Another group of compounds of the invention comprises the compounds of formula Is

  

 <EMI ID = 32.1>


  
in which

  
R has the meaning given above,

  
R &#65533; means i) phenyl mono-substituted by a group <EMI ID = 33.1> ms means 0, 1 or 2 ns means 1 or 2 and

  
 <EMI ID = 34.1>

  
The invention also relates to a process for the preparation of a compound of the invention, which process comprises a) for the preparation of a compound of formula I '
 <EMI ID = 35.1>
 <EMI ID = 36.1>

  
born previously and R 'means cyano or carbamoyl, the reaction of a corresponding compound of formula II

  

 <EMI ID = 37.1>


  
 <EMI ID = 38.1>

  
with a corresponding compound of formula III

  

 <EMI ID = 39.1>


  
in which R 'has the meaning given above, or b) for the preparation of a compound of formula I "
 <EMI ID = 40.1>
 <EMI ID = 41.1>

  
born previously, the amination of a corresponding compound of formula IV

  

 <EMI ID = 42.1>


  
 <EMI ID = 43.1> tible to be transformed into primary amino group.

  
Process a) can be carried out according to the usual methods for the preparation of derivatives

  
 <EMI ID = 44.1>

  
di (lower alkyl) -amino, especially dimethylamino or diethylamino, used for cyclization with an acetamide. The reaction is preferably carried out in an inert solvent such as ethanol. Suitable reaction temperatures can range from room temperature to about the boiling temperature of the reaction mixture. It is preferably carried out under strongly alkaline conditions.

  
The reaction can however also be carried out in an acid medium, for example in the presence of acetic acid. In this case, one can directly obtain a compound of formula I 'in which R' signifies carbamoyleen starting from a corresponding compound of formula III in which R 'signifies cyano.

  
 <EMI ID = 45.1>

  
sation with a substituent of the phenyl ring, such as the cyano-methyl group, in the form of a precursor such as the bromo-methyl group, and of transforming the precursor substituent into the desired substituent when the cyclization is complete, for example transforming

  
 <EMI ID = 46.1>

  
Process b) can be carried out according to conventional methods for the preparation of ana-

  
 <EMI ID = 47.1>

  
usual radical used for the transformation into a primary amino group, such as nitro and especially

  
 <EMI ID = 48.1>

  
the reaction conditions for a Hofmann degradation can be used. The reaction is preferably carried out under strongly alkaline conditions,

  
for example in the presence of an alkali metal hydroxide and bromine. Preferably, water is used as the solvent. Suitable reaction temperatures can be between about 50 [deg.] And about
100 [deg.], Advantageously around 100 [deg.].

  
It may be indicated to carry out the amination with a substituent of the phenyl ring, such as the carbamoyl or cyano group, in the form of a precursor such as the cyano group or the bromine, respectively, and to convert the precursor substituent into substituent desired when the friend nation is finished, for example transforming the cyano group into a carbamoyl group or the bromine into a cyano group.

  
The compounds of the invention can be isolated from the reaction mixture and be purified in a manner analogous to known methods.

  
The compounds of the invention can be in free form or in the form of salts. The free forms can be transformed into salts according to known methods and vice versa. Acids suitable for the formation of acid addition salts include hydrochloric acid, malonic acid, p-toluenesulfonic acid and methanesulfonic acid. Suitable bases for the formation of anionic salts include sodium and potassium hydroxide. When in the form of anionic salts, the compounds generally have essentially the iminol form.

  
The starting materials can be obtained according to known methods, from known products.

  
 <EMI ID = 49.1> means di (lower alkyl) -amino can be obtained for example by reacting a compound cor-

  

 <EMI ID = 50.1>


  
 <EMI ID = 51.1>

  
previously, with an N, N-di (lower alkyl) -formamide-di (lower alkyl) -acetal, preferably dimethyl or diethyl acetal of N, N-dimethyl-formamide.

  
The compounds of formula V can be obtained according to known methods. Compounds of form

  
 <EMI ID = 52.1>

  
be obtained for example according to the following reaction scheme, the reaction steps which can be repeated for the preparation of compounds in which m and / or n signify a number up to 4 and the carbonyl group preferably being in protected form, for example under form of acetal.

  

 <EMI ID = 53.1>
 

  
Other compounds of formula V can be obtained in an analogous manner. An alkylsulfinyl substituent can be obtained by oxidation of an alkylthio substituent, for example with hydrogen peroxide

  
 <EMI ID = 54.1>

  
When the preparation of a particular starting product is not described in detail, it will be a known compound or which can be prepared in a known manner from a known product or in a similar manner to that described in the this request.

  
The following examples illustrate the present invention without in any way limiting its scope. All temperatures are given in degrees Celsius and are not corrected.

Example 1

  
 <EMI ID = 55.1>

  
pyridine-3-carbonitrile

  
6.2 g of cyanacetamide are added to a freshly prepared solution of 1.14 g of sodium in 200 ml of absolute ethanol. 10.6 g of 4-dimethylamino-3- (4-cyanophenyl) -3-butene-2-one are added and the solution is stirred for 5 hours at boiling temperature; the sodium salt of the title compound crystallizes quickly. The mixture is allowed to cool, the crystallized product is filtered and washed with ethanol and ether; the sodium salt melts above 300 [deg.] and the free form above 300 [deg.].

  
 <EMI ID = 56.1>

  
butene-2-one (E = 155-160 [deg.] / 0.005 mm Hg), used as starting material, is obtained by heating the

  
 <EMI ID = 57.1>

Example 2

  
4- (3-Cyano-1,2-dihydro-6-methyl-2-oxopyridine5-yl) -phenyl-acetic acid

  
11 g of 4-dimethylamino3- (4-methoxycarbonylmethylphenyl) -3-butene-2-one are reacted with cyanacetamide as described in Example 1. The title compound is thus obtained; it melts at 280-282 [deg.] after recrystallization from a mixture of dimethylformamide and ethanol.

  
The starting product is obtained as follows:
The 4- (2-oxopropyl) benzonitrile is heated for 5 hours to boiling in a concentrated aqueous solution of hydrochloric acid. We do

  
 <EMI ID = 58.1>

  
163-165 [deg.]) With gaseous hydrochloric acid in

  
methanol. The resulting methyl 4- (2-oxopropyl) benzoate carbonyled group (F = 48-50 [deg.]) Is transformed into acetal group by reaction with ethylene glycol

  
 <EMI ID = 59.1>

  
is reacted with lithium aluminum hydride in tetrahydrofuran. The protecting group

  
 <EMI ID = 60.1>

  
The resulting result (E = 130-135 [deg.] / 0.07 mm Hg) is eliminated using a 2N aqueous solution of hydrochloric acid and the unprotected compound thus obtained is subjected to bromination in ether with tribromide

  
 <EMI ID = 61.1>

  
obtained (not characterized) is reacted with an excess of sodium cyanide in ethanol and the

  
 <EMI ID = 62.1>

  
0.1 mm Hg) is hydrolyzed with a concentrated aqueous solution of hydrochloric acid. The 4- (2-oxopropyl) phenylacetic acid obtained (F = 92-94 [deg.]) Is esterified with methanol. The resulting methyl 4- (2-oxopropyl) phenylacetate (E = 120-130 [deg.] / 0.06 mm Hg) is reacted for 2 hours at 50 [deg.] With dimethyl acetal of N, N-dimethylformamide. The 4-dimethylamino-3- (4-methoxycarbonylmethylphenyl) -3-butene-2-one obtained is used for the following reaction in the raw state.

Example 3

  
3-amino-5- (2-methoxy-4-methylsulfinylphenyl) -6-methyl2 (1H) -pyridinone

  
To a solution of 15 g of sodium hydroxide in 230 ml of water is added dropwise, with stirring and at 0 [deg.], 3.7 ml of bromine. Then we add
17.6 g of 1,2-dihydro-5- (2-methoxy-4-methylthiophenyl) -

  
 <EMI ID = 63.1>

  
100 [deg.] For 3 hours. The mixture is allowed to cool to room temperature, it is carefully acidified with 6N hydrochloric acid, the mixture is stirred for a further 30 minutes and the brown precipitate which has formed is filtered off. The filtrate is extracted with ethyl acetate, the aqueous phase is concentrated and it is alkali or se with ammonium hydroxide. The precipitate is filtered off and the supernatant is concentrated. The title compound crystallizes (the hydrochloride melts at 224-226 [deg.] After crystallization from a mixture of methylene chloride and methanol).

  
1,2-dihydro-5- (2-methoxy-4-methylthio-

  
 <EMI ID = 64.1>

  
decomposition after crystallization from a mixture of methylene chloride and methanol), used as starting material, is obtained by heating with boiling

  
 <EMI ID = 65.1>

  
nitroethane in toluene in the presence of n-butylamine, transformation of the resulting nitrovinyl compound with iron powder and chlorhy-

  
 <EMI ID = 66.1>

  
(E = 140-150 [deg.] / 0.02 mm Hg), heating this compound with N, N-dimethylformamide dimethyl acetal for 3 hours at 80 [deg.] And reaction of 4-dimethylami -

  
 <EMI ID = 67.1>

  
resulting (F = 111-112 [deg.] after crystallization from a mixture of ether and petroleum ether) with cyanacetamide in glacial acetic acid at
100 [deg.].

  
The following compounds of the invention can be obtained in an analogous manner.

  

 <EMI ID = 68.1>
 

  
The compounds of the invention have interesting pharmacological properties and can therefore be used therapeutically as medicaments.

  
In particular, the compounds of the invention exert a cardiotonic activity, like this

  
has been demonstrated by conventional tests carried out on animals. Thus, for example, in the normotensive dog anesthetized with Numal, we observe an increase in the force of contraction

  
of the left ventricle after intravenous administration of the compounds of the invention. This test is carried out as follows:

  
It is administered intravenously to

  
dogs of both sexes weighing between 10 and 15 kg,

  
65 mg / kg of Numal as an anesthetic. The animal is lying on its back and tied in this position on the operating table. After having made the usual preparations, a heparinized catheter is introduced under radiological control into the right carotid to the left ventricle, and the pressure transmission is recorded by means of a donor membrane (Gould Statham P 23 Gb). The increase in pressure as a function of time is computerized and recorded with an HSE physiological differentiator. The increase in pressure in the left ventricle gives the measure of the force of contraction of the heart. The amplitude of the differential pressure is indicated in mm Hg / sec. We maintain

  
body temperature at an appropriate constant value (approximately 36 to 37 [deg.]). After a control period of approximately 40 minutes, the test substance is injected into the femoral vein and its effect on the recorded or computerized parameters is observed. In this test, the compounds of the invention exert a significant cardiotonic effect after administration by the intravenous route at doses of between approximately 0.02 and approximately 2 mg / kg.

  
Cardiotonic activity is accompanied by a reduction in afterload. Thus, in the test described above carried out on the anesthetized dog, a reduction in the arterial blood pressure and in the total peripheral resistance is observed after intravenous injection of the compounds of the invention at a dose of between approximately 0 , 2 and about 2 mg / kg.

  
For measurement of arterial blood pressure; a heparinized catheter is introduced under radiological control into the left femoral artery up to the base of the aorta. Blood pressure

  
is measured with a Statham pressure transmitter

  
P 23 AC, allowing precise assessment of systolic and diastolic pressure. Average blood pressure is calculated by adding a third of the ampli

  
 <EMI ID = 69.1>

  
diastolic vision.

  
Total peripheral resistance (PR) is

  
 <EMI ID = 70.1>

  
blood pressure _ diastolic pressure

  
mean left ventricle

  
 <EMI ID = 71.1>

  
cardiac flow

  
the determination of the cardiac output being carried out according to the thermodilution method using a catheter introduced under radiological control into the right jugular vein.

  
Furthermore, the compounds of the invention, as indicated by the compound of Example 1, unexpectedly have a long duration of action and good tolerance. For example, there is surprisingly little tachycardia.

  
Thanks to this property, the compounds of the invention can therefore be used in therapy as cardiotonic agents, for example for the treatment of heart failure. For this use, they will be prescribed at a daily dose of between approximately 10 mg and approximately 500 mg of active substance, which will advantageously be administered, for example by the oral route, in divided doses two to four times a day in the form of doses. unitary, or in a delayed release form. An example of a daily dose is 10 to 100 mg of active substance.

  
The compounds of the invention can be administered in free form or in the form of a pharmaceutically acceptable salt. These salts have the same order of activity as that of the corresponding free forms.

  
The invention therefore relates to the compounds of the invention, in free form or in the form of a pharmaceutically acceptable salt, for use as medicaments, in particular as cardiotonic agents.

  
The invention also relates to a medicament containing, as active principle, a compound of the invention in free form or in the form of a pharmaceutically acceptable salt.

  
As medicaments, the compounds of the invention can be used in the form of pharmaceutical compositions containing a compound of the invention in free form or in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutical diluent acceptable. Such pharmaceutical compositions, which also form part of the present invention, can be prepared according to the usual methods and can be presented, for example, in the form of solutions, capsules or tablets. Solubilizing or stabilizing agents such as cyclodextrins, such as

  
 <EMI ID = 72.1>

  
Please be used to prepare a solution.

  
The preferred compounds are the compounds

  
 <EMI ID = 73.1>

  
Example 1.


    

Claims (1)

1.- The 2 (1H) -pyridinones of formula I  <EMI ID = 74.1> in which R stands for cyano, carbamoyl or amino and <EMI ID = 75.1> di-substituted by a group - (CH2) mX or - (CH2) nY where m means 0 or an integer from 1 to 4, n means an integer from 1 to 4, X means cyano, carboxy, alkoxycar- bonyle in which the alkoxy residue is in Cl-C4, carbamoyl or alkylsulfinyl in Cl-C4, and Y means a halogen having a number atomic from 9 to 35, hydroxy, alkoxy <EMI ID = 76.1> - (CH2) mX or - (CH2) nY where m, n, X and Y are as defined above, and by C1-C4 alkyl, alkoxy in  <EMI ID = 77.1> atomic bre from 9 to 35, and R2 means hydrogen or alkyl in  <EMI ID = 78.1> has the meanings indicated under a) above  <EMI ID = 79.1> 2.- The 2 (1H) -pyridinones according to claim 1, characterized in that they respond to  <EMI ID = 80.1> in which R has the meaning given to the res-  <EMI ID = 81.1> 3. The 2 (1H) -pyridinones according to claim 1, characterized in that they respond to  <EMI ID = 82.1> in which R has the meaning given to the res-  <EMI ID = 83.1> under b) to claim 1 for R. and R2. 4. The 2 (1H) -pyridinones according to claim 1, characterized in that they respond to  <EMI ID = 84.1> in which R has the meaning given to claim 1,  <EMI ID = 85.1> ms means 0, 1 or 2 ns means 1 or 2 and  <EMI ID = 86.1> 5.- A 2 (1H) -pyridinone according to claim 1, characterized in that -R, R. and R2 in the  <EMI ID = 87.1> whether they are in free form or in the form of salts. 9.- A process for the preparation of the 2 (1H) pyridinones specified in claim 1, characterized in that it comprises <EMI ID = 88.1>  <EMI ID = 89.1> in which R, and R2 have the meanings given in claim 1 and R 'signifies cyano or carbamoyl, the reaction of a corresponding compound of formula II  <EMI ID = 90.1>  <EMI ID = 91.1> born in claim 1 and R is an eliminable group, with a corresponding compound of formula III  <EMI ID = 92.1> in which R 'has the meaning given above, or b) for the preparation of a compound of formula I "  <EMI ID = 93.1>  <EMI ID = 94.1> born in claim 1, the amination of a corresponding compound of formula IV  <EMI ID = 95.1>  <EMI ID = 96.1> tible to be transformed into primary amino group. 10.- The 2 (1H) -pyridinones specified in any one of claims 1 to 7, in free form or in the form of an acceptable salt from the point of pharmaceutical view, for use as medicines. 11. A medicament, characterized in that it contains, as active principle, a 2 (1H) -pyridinone as specified in any one of claims 1 to 7, in free form or in the form of an acceptable salt from the pharmaceutical point of view. 12.- A pharmaceutical composition, characterized in that it contains as active ingredient a  <EMI ID = 97.1> of claims .. to 7, in free form or in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable diluent or vehicle. 13.- A compound chosen from the compounds of formula II  <EMI ID = 98.1>  and the compounds of formula IV  <EMI ID = 99.1>  <EMI ID = 100.1> transformed into primary amino group. 14.- Products and processes in substance as described above with reference to the examples cited.