FR2477148A1 - NEW 2 (1H) -PYRIDONES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS NEW 2 (1 H) -PYRIDONES OF FORMULA: (CF DRAWING IN BOPI) IN WHICH R AND R EACH REPRESENT A HYDROGEN ATOM OR AN ALKYL OR MONOCYCLIC ARYL GROUP CONDENSE POSSIBLY SUBSTITUTED. THESE COMPOUNDS CAN BE USED THERAPEUTICALLY AS ACTIVE SUBSTANCES OF MEDICINAL PRODUCTS.

Description

The subject of the present invention is new 2 (1H) -pyridones, their

  preparation and their application in therapy, as principles

drug assets.

  The invention relates more particularly to 2 (1H) -pyridones corresponding to formula I NH 2 (I)

  in which R 1 and R 2 each independently represent a hydrogen atom, an alkyl group or an optionally substituted monocyclic aryl residue, at least one of R 1 and R 2 being intended to mean an aryl residue, and

  when R2 signifies hydrogen, R1 must be different

  2-, 3- or 4-pyridyl, unsubstituted or substituted by one or two lower alkyl groups

  and the salts that form these compounds.

  The compounds of formula I may exist in another tautomeric form, for example in the iminol form. Of course, the invention is not limited to a particular form of the compounds of formula I and its preparation but includes all tautomeric forms and their preparation. For some

  reasons of simplicity, reference will be made in the description

  The term "monocyclic aryl residue" is understood to mean a moiety attached to the pyridone via a

  non-condensed aromatic cycle. This cycle can be carbon

  cyclic, for example phenyl, or heterocyclic

  click and hold up to 3 heteroatoms. As

  already indicated, this remainder may be substituted or unsubstituted.

  The invention relates in particular to compounds of formula Ia Ra (Ia) R wherein R1 and R are each independently of one another,

  i) a hydrogen atom or an alkyl group

holding 1 to 4 carbon atoms,

  ii) a phenyl group, a phenyl monosubstituted group

  killed by a dialkylamino group whose alkyl groups each contain from 1 to 4 carbon atoms, or a phenyl group carrying one or two substituents selected from alkyl and alkoxy groups each containing from 1 to 4 carbon atoms and halogens having a number atomic from 9 to 35, or

  iii) a pyrrolyl, furyl, thienyl, thiazolyl

  lyle, imidazolyl, pyrazolyl, pyridyl, pyrimidine

  dinyl, pyridazinyl or pyrazinyl, has been at least one of the symbols R and 2 to have one of the meanings given in (ii) or (iii) above, and when Ra is hydrogen, R1a in front of to be different

2 1

of a 2-, 3- or 4-pyridyl group.

  Preferred alkyl or alkoxy groups are

  methyl, ethyl, methoxy and ethoxy, in particular

  methyl and methoxy groups. Halogen is preferably chlorine or bromine, especially chlorine. In the rest dialkylamino,

  the two alkyl groups are preferably identical.

  Where R 1 or R 2, especially R 1 or R a signifies a heterocyclic residue, it is preferably 3-pyrrolyl, 3-furyl, 3-thienyl, 4-thiazolyl,

  4-imidazolyl, 3-pyrazolyl, 2- or 4-pyridyl, in particular

  4-pyridyl, 4-pyrimidinyl, 4-pyridazinyl or 2-pyrazinyl. Ra preferably means an alkyl group R1 or has one of the meanings given above

  under (ii) or (iii). R1 has in particular one of the

  cations given under (ii). Ra preferably has one

  the meanings given in (i) above, and

  especially a methyl group. Among the meanings

  indicated, i) is preferably an alkyl group. Among the meanings given, ii) is

  preferably a phenyl group which is optionally mono-

  substituted. When the phenyl group is monosubstituted, the substituent is preferably in the meta or para position, preferably in the para position. When the phenyl group is disubstituted, the substituents are preferably located at the meta and para positions. When the phenyl group is disubstituted, the substituents are preferably identical; the preferred substituents are alkoxy groups and halogens,

  in particular the alkoxy groups. Among the meanings

  cations, iii) is preferably a pyramid group

  rolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, in particular a

  furyl, pyridyl, pyrimidinyl or pyrazinyl, parti-

  especially the pyrimidinyl or pyridyl group, especially the pyrimidinyl group. Preferably Ra 1 has one of the symbols R 1 or R 2 has one of the meanings

data under i).

  In a group of compounds of formula Ia, the symbols Ra and Ra have a different meaning of the pyridyl group. In a subgroup, they have a

  meaning other than those indicated under (iii).

  Preferred compounds of the formula Ia are those having the formula Iaa aa

1I ",, ,,," ',, ,, N 2

  Wherein R 1 has one of the meanings given in ii) or iii) above. In a group of compounds of formula Iaa, aa

  R1 is different from the pyridyl group. In a sub

  aa group, R1 has one of the indicated meanings

under (ii) above.

  Another group of compounds of formula Ia of interest is represented by compounds of formula Ipa -a HH

2 days

  R2afA 0 (Ipa) in which RPa means i) a phenyl group, a phenyl group

  monosubstituted by a dialkyl group

  amino whose alkyl radicals each contain from 1 to 4 carbon atoms, or a phenyl group bearing one or two substituents selected from alkyl and alkoxy groups each containing from 1 to 4 carbon atoms and halogens having an atomic number of from 9 to 35, or ii) a pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group, and Rpa represents an alkyl group containing from 1 to 4 atoms

of carbon.

  Another group of compounds of formula Ia comprises the compounds of formula Ipb 2 (Ipb) in which RPb signifies a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and pob Rb has one of the meanings indicated As for another group of compounds of formula Ia which are of interest, mention may also be made of compounds corresponding to the formula Ipc RP c. (Ipc)

1

  H in which Rc has one of the meanings indicated above for pa RC can however not represent

a pyridyl group.

  According to the process of the invention, to prepare the compounds of formula I, a compound of formula II ERx is amine

(II)

  in which R1 and R2 have the meanings already given and R is a remainder capable of being transformed

in primary amin group.

into a primary amino group.

  The amination reaction can be carried out

  according to known methods, used for the preparation

  similar derivatives of 3-amino-2 (1H) -pyridone.

  R can mean a usual group susceptible -

  x to be converted into a primary amino group, for example the nitro group or, in particular, the carbamoyl group. Thus, when a compound of formula II is used where Rx is a carbamoyl group, it is possible to operate under the conditions of Hofmann degradation. 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 a solvent.

  The temperature of the reaction is advantageously between about 50 and 100; preferably she

is about 100.

  The compounds of formula I thus obtained can then be isolated from the reaction mixture

  and purified according to known methods.

  The compounds of the invention can be

  find in the free state or in the form of salts.

  If necessary, the free compounds can be converted into their salts; from the salts one can liberate

  Formile I compounds according to known methods.

  As acids suitable for the formation of salts

  of acid addition, mention may be made of hydrochloric acid

  that, malonic acid, p-toluenesulfonic acid and methanesulfonic acid. The appropriate bases for the formation of anionic salts are hydroxide

sodium or potassium.

  Starting materials can be obtained

  according to known methods, from known products.

  In particular, to prepare the compounds of formula II where Rx is a carbamoyl group, it is possible, for example, to partially hydrolyze a compound corresponding to formula III (III).

0

  H in which R 2 R 2 have the meanings already given, for example by means of sulfuric acid

or phosphoric acid.

  The compounds of formula III can be obtained for example by reaction of a compound of formula IV R1. wherein R 1 and R 2 have the meanings already given and Alk represents a lower alkyl group,

  preferably a methyl group, with cyanacetamide.

  For example, it is possible to operate in the presence of acetic acid, in which case it is possible to directly obtain a compound of

formula II.

  The compounds of formula IV may be prepared for example by reaction of a compound of formula V R

R2 0

  in which R1 and R2 have the meanings already given,

  with N, N-dialkyl (lower) -formamide-dialkyl (lower

  acetal, preferably N, N-dimethylformamide-

dimethyl or diethyl acetal.

  When the preparation of the starting materials is not described, they may be prepared according to methods known or analogous to those

described below.

  The following examples illustrate the present invention without in any way limiting its scope. Temperatures are all in degrees Celsius,

and are uncorrected data.

Example 1

  3-amino-6-methyl-5-phenyl-2 (1H) -pyridone 0.2 ml of bromine is added dropwise with stirring to a solution of 8.4 g of sodium hydroxide in 125 ml of bromine. ml of water. To this mixture, we add

  7.3 g of 1,2-dihydro-6-methyl-2-oxo-5-phenyl-nicotine

  and the mixture is heated with stirring at 100

  3 hours. After cooling to room temperature, the resulting solution is acidified with care by the addition of 6N hydrochloric acid and stirring is continued for 30 minutes. The precipitate formed is filtered under reduced pressure and recrystallized from methanol. This gives the title compound (F = 260-263). The mesylate of the compound

  the title melts at 220-222 (with decomposition).

  To prepare the starting material, the procedure is as follows: The mixture is heated at 80 for 5 hours,

  benzyl methyl ketone and N, N-dimethylformamidedimethyl

  acetal. The crude 4-dimethylamino-3-phenyl-3-butene-2-one thus obtained is reacted with cyanoacetamide at the boiling point in the presence of sodium ethanolate. It is then partially hydrolyzed at a temperature of 100 with sulfuric acid

  at 90% 1,2-dihydro-6-methyl-2-oxo-5-phenylpyridine-3-

  carbonitrile thus obtained (mp 290-294 after recrystallization).

  in methanol), which gives 1,2-dihydro-

  6-methyl-2-oxo-5-phenyl nicotinamide (melting at a temperature of

  greater than 300 after recrystallization from dimethylformamide). Proceeding as the compounds can be prepared in the table below, by the appropriate formula II carbamoyl carbamoyl. described in Example 1, of formula I indicated reaction with a compound means a group Ex. R1 - R2 m.p. 4-pyrimidinyl phenyl 2pyrazinyl phenyl 2-furyl 2-pyridyl m-methoxyphenyl 4-pyridyl omethoxyphenyl Me Me Me and Me phenyl HHH phenyl Me phenyl Me Me Me b 245-250 (dec) ms 231-234 b 256-260 b 218-220 b 192-194 b 231232 b 174-176 b 283-287 bv 240-243 b 262-264 b 296-299 b 189-191 b 239-242 b 244-2450 b 290-295 b 224-226 b in free form in the form of hydrochloride ms = in the form of mesylate Et = ethyl Me = methyl dec. = with decomposition The compounds of formula I and their salts

  have not been described so far in the literature.

  ture. In tests carried out on laboratory animals, they are distinguished by interesting pharmacological properties. In particular, they exercise cardiotonic activity, as evidenced by standard tests. For example, the normotonic dog numal anesthetized with an increase in left ventricular contraction force after intravenous administration of about 0.02 to about 2 mg / kg of a compound of formula I. This test was performed as follows. A dose of 65 mg / kg Numal is administered intravenously to a dog (or bitch) as an anesthetic. The animal is lying on his back

  and tied in this position on the operating table.

  After the usual preparations, a heparinized catheter is placed under radiological control in the right carotid artery to the left ventricle, and the transmission of pressure is recorded.

  by means of a donor membrane (Gould Statham P 23 Gb).

  The pressure increase is determined according to

  of time and recorded with a physiodifferentiation

  HSE. Increasing pressure in the ventricle

  left side gives the measure of the contraction force of the heart. The amplitude of the differential pressure

  is indicated in mm Hg / second. We keep the temperature

  body weight at an appropriate constant value (approximately 36 to 370). After a measurement period of approximately one minute, the substance to be tested is injected into the femoral vein and its effect on the recorded parameters is observed.

  The compounds of Examples 1 and 4, in particular

  compound of Example 1, demonstrate in

  this test, a significant cardiotonic effect.

  Thanks to these properties, the compounds of formula I can be used in therapy as cardiotonic agents, for example for the treatment of heart failure. They will be prescribed in daily doses of between approximately 10 and 500 mg of active substance, which will be administered at one time or in several unit doses, each containing approximately 2.5 to 250 mg of active substance, at the rate of 2 to 4 times a day, or in late form. An appropriate daily dose

  for example comprises from 10 to 100 mg of active substance.

  The compounds of the invention can be administered both in the free state and in the form

  of their pharmaceutically acceptable salts.

  preferably in the form of an acid addition salt. The activity of these salts is of the same order

  than that of the corresponding free compounds. The inventors

  The invention also comprises a pharmaceutical composition containing a compound of formula I in the free state or in the form of a pharmaceutically acceptable salt, in combination with pharmaceutical excipients or diluents. Such compositions may be, for example, in the form of a

solution or tablet.

Claims (13)

  1.- News 2 (1H) -pyridones, characterized in that they correspond to the formula I E2 I t '(I)  2 0   R20 wherein R1 and R2 each independently represent a hydrogen atom, an alkyl group or an optionally substituted monocyclic aryl group, at least one of R1 and R2 being an aryl residue; , and   when R2 signifies hydrogen, R1 must be different   2-, 3- or 4-pyridyl, unsubstituted or substituted by one or two lower alkyl groups,   and the salts that form these compounds.   2. Novel 2 (1H) -pyrrolidones, characterized in that they correspond to the formula Ia a 1 2P (Ia) 2 j H in which a- R and Ra represent, each independently, one R1 R2 the other,   i) a hydrogen atom or an alkyl group holding 1 to 4 carbon atoms,   ii) a phenyl group, a phenyl monosubstituted group   killed by a dialkylamino group whose alkyl groups each contain from 1 to 4 carbon atoms, or a phenyl group carrying one or two substituents selected from alkyl and alkoxy groups each containing from 1 to 4 carbon atoms and halogens having a number atomic from 9 to 35, or   iii) a pyrrolyl, furyl, thienyl, thiazolyl   lyle, imidazolyl, pyrazolyl, pyridyl, pyrimidine dinyl, pyridazinyl or pyrazinyl.   at least one of the symbols R1 and 2 must have one of the meanings given in (ii) or (iii) above, and when R2 signifies hydrogen, Ra must be different from a group 2 -, 3- or 4-pyridyl   and the salts that form these compounds.   3. The 2 (1H) -pyridones according to claim a a 2, characterized in that Ra and R2 each have a 1 2   different meaning of a pyridyl residue.   4. News 2 (1H) -pyridones, characterized in that they correspond to the formula Ipa (Ipa) pa e n O H   wherein RPa means i) a phenyl group, a phenyl group   monosubstituted by a dialkyl group   amino whose alkyl radicals contain from 1 to 4 atoes of carbon, or a phenyl group bearing one or two substituents selected from alkyl and alkoxy groups each containing from 1 to 4 carbon atoms and halogens having an atomic number of 9; at 35, or ii) pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, and R2a represents an alkyl group containing from 1 to 4 carbon atoms,   and the salts that form these compounds.   5.- novel 2 (1H) -pyridones, characterized in that they correspond to the formula Ipb Rpb i %% j1 H 2 (Ipb) R 2 in which R 1 signifies a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, and R * b represents i) a phenyl group, a phenyl group,   monosubstituted by a dialkyl group   amino whose alkyl radicals each contain from 1 to 4 carbon atoms, or a phenyl group bearing one or two substituents selected from alkyl and alkoxy groups each containing from 1 to 4 carbon atoms and halogens having an atomic number of from 9 to 35, or ii) pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl,   and the salts that these compounds form.   6. New 2 (1H) -pyridones, characterized in that they correspond to the formula Ipc (formula Ipc see next page)] 1 c (Ipc) in which Rpc means i) a phenyl group, a phenyl group,   monosubstituted by a dialkyl group   amino whose alkyl radicals contain caacun of 1 to 4 carbon atoms, or a phenyl group carrying one or two substituents selected from alkyl and alkoxy groups each containing 1 to 4 carbon atoms and halogens having an atomic number of 9 to 35, or i) pyrrolyl, furyl, thienyl, pyrimidinyl, pyridazinyl or pyrazinyl,   and the salts that form these compounds.   7.- News 2 (1H) -pyridones, characterized   in that they are selected from 3-amino-5-m-tolyl-   6-methyl-2 (1H) -pyridone, 3-amino-5-p-chlorophenyl-6-   methyl-2 (1H) -pyridone, 3-amino-3,4-dimethoxyphenyl-6-   methyl-2 (1H) -pyridone, 3-amino-5-phenyl-6-ethyl-   2 (1H) -pyridone, 3-amino-5-o-tolyl-6-methyl-2 (1H) -   pyridone, 3-amino-5-methyl-6-phenyl-2 (1H) -pyridone,   3-amino-5- (4-oyrimidinyl) -2 (1H) -pyridone, 3-amino   phenyl-2 (1H) -pyridone, 3-amino-5- (2-pyrazinyl) -2 (1H) -pyridone, 3-amino-5,6-diphenyl-2 (1H) -pyridone, 3 -am-no-5-S2-furyl) -6-methyl2 (1H) -pyridone, 3-amino-5- (2-pyridyl) -6-phenyl-2 (1H) -pyridone, 3-amino-5- m-Methoxyphenyl-6-methyl-2 (1H) -pyridone, 3-amino-5- (4-pyridyl) -6-methyl-2 (1H) -pyridone, and 3-amino-5-o-methoxyphenyl-6-methyl -2 (1H) -pyridone,   and the salts that form these compounds.   8. 3-Amino-6-methyl-5-phenyl-2 (1H) -pyri-   done and the salts that form this compound.   9. 3-Amino-5-p-methoxy-phenyl-6-methyl-   2 (1H) -pyridone and the salts that form this compound.   10. A process for preparing the 2 (1H) -pyridones of formula I NR21 1 <<N2 (I)   in which R 1 and R 2 each independently represent a hydrogen atom, an alkyl group or an optionally substituted monocyclic aryl residue, at least one of R 1 and R 2 being intended to mean an aryl residue, and   when R2 signifies hydrogen, R1 must be different   of a 2-, 3- or 4-pyridyl group unsubstituted or substituted by one or two lower alkyl groups, and their salts, characterized in that a compound of formula II R1 R x (II) is aminated - R 2   in which R 1 and R 2 have the meanings already given and R 1 is a residue which can be converted into a primary amino group, and, if appropriate, the compounds of formula I are converted into thus obtained in their salts.   11. The therapeutic application of the 2 (1H) -pyridones specified in any of the   claims 1 to 9, as active ingredients of drugs.   12. A medicament, characterized in that it contains, as active principle, at least one of the 2 (1H) -pyridones as specified in one of the   any of claims 1 to 9, in the free state   or in the form of a salt acceptable from the point of view pharmaceutical.   at.' 13.- A medicament, characterized in that   contains, as active substance, 3-amino-6-methyl-   -phenyl-2 (1H) -pyridone, in its free form or in the form   a pharmaceutically acceptable salt.   14.- A drug, characterized in that   contains, as active ingredient, 3-amino-5-p-   methoxyphenyl-6-methyl-2 (1H) -pyridone, in the free state or in the form of a pharmaceutically acceptable salt. 15. A pharmaceutical composition, characterized in that it contains, as active ingredient, at least one of the 2 (1H) -pyridones specified   to any one of claims 1 to 9, in   combination with acceptable excipients and vehicles from the pharmaceutical point of view.