FR2636329A2 - New pyridine derivatives, process for their preparation, their application as medicaments and the compositions containing them - Google Patents

Abstract

The present application for a first certificate of addition especially relates to the products corresponding to the general formula I of the main patent or related to this formula and corresponding to the formula I'A: R'A: C1-12 alkyl X: H or Cl to their application as medicaments and to the pharmaceutical compositions containing them.

Description

dans laquelle R représente un radical hétérocyclique renfermant 5 ou 6 chaînons, éventuellement substitué par un radical alcoyle renfermant de 1 à 5 atomes de carbone ou R représente un radical phényle éventuellement substitué par un ou plusieurs radicaux choisis dans le groupe formé par le radical hydroxy, les radicaux alcoyles ou alcoxy renfermant de 1 à 5 atomes de carbone, le radical trifluorométhyle, le radical nitro et les atomes d'halogène, R1 et R2, identiques ou différents, représentent un radical alcoyle renfermant de 1 à 5 atomes de carbone ou un radical hétérocyclique renfermant 5 ou 6 chaînons éventuellement substitué par un radical alcoyle renfermant de 1 à 5 atomes de carbone, ou un radical phényle ou naphtyle éventuellement substitués par un ou plusieurs radifidux choisis dans le groupe formé par le radical hydroxy, les radicaux alcoyles ou alcoxy renfermant de 1 à 5 atomes de carbone, le radical trifluorométhyle, le radical nitro et les atomes d'halogène, R3 représente un atome d'hydrogènew un radical alcoyle renfermant de 1 à 5 atomes de carbone ou un radical du type -(CF2)nCF3, n représentant un nombre entier entre 0 et 4, ainsi que les sels d'addition des produits de formule (I) avec les acides et les bases.In its main patent application filed on March 13, 1987 under No. 87-03465, the Applicant has described new pyridine derivatives of formula (I)

in which R represents a 5- or 6-membered heterocyclic radical, optionally substituted by an alkyl radical containing from 1 to 5 carbon atoms, or R represents a phenyl radical optionally substituted with one or more radicals chosen from the group formed by the hydroxyl radical, the alkyl or alkoxy radicals containing from 1 to 5 carbon atoms, the trifluoromethyl radical, the nitro radical and the halogen atoms, R1 and R2, identical or different, represent an alkyl radical containing from 1 to 5 carbon atoms or a a 5- or 6-membered heterocyclic radical optionally substituted by an alkyl radical containing from 1 to 5 carbon atoms, or a phenyl or naphthyl radical optionally substituted by one or more radicals chosen from the group formed by the hydroxy radical, the alkyl or alkoxy radicals; containing from 1 to 5 carbon atoms, the trifluoromethyl radical, the nitro radical and the at In the case of halogen atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a radical of the - (CF2) nCF3 type, n being an integer between 0 and 4, and the salts of addition of the products of formula (I) with acids and bases.

dans laquelle R1 et R2 ont les significations indiquées cidessus à l'action d'un acide ou d'un dérivé fonctionnel de cet acide de formule (IV) ::
R3COOH (IV) dans laquelle R3 a la signification indiquée ci-dessus, pour obtenir un composé de formule (V)

que l'on soumet à un agent de chloruration, pour obtenir un composé de formule (VI)

que l'on fait réagir avec un malonate d'alcoyle de formule

dans laquelle alcl représente un radical alcoyle renfermant de 1 à 5 atomes de carbone, en presence d'une base forte, pour obtenir un composé de formule (VII)

que l'on cyclise pour obtenir un composé de formule (VIII)

- soit l'on soumet un composé de formule (IX)

dans laquelle R1 et R2 ont les significations précédentes et alc2 représente un radical alcoyle renfermant de 1 à 5 atomes de carbone à l'action d'un acide ou d'un dérivé fonctionnel de cet acide de formule (IV) R3-COOH dans laquelle R3 a la signification précédente, pour obtenir un composé de formule (X)

que l'on hydrolyse en acide correspondant et que l'on cyclise cet acide en composé de formule (XI)

que l'on soumet ou bien à l'action d'un anion d'un acétate d'alcoyle CH3C02alc3, alc3 étant un radical alcoyle renfermant de 1 à 5 atomes de carbone pour obtenir un composé de formule (XII)

que l'on cyclise en un composé de formule (VIII) et que l'on soumet tous les composés de formule (VIII) à l'action d'une amine de formule NH2R, R ayant la signification indiquée cidessus, pour obtenir un composé de formule (I) ou bien l'on soumet le composé de formule (XI) à l'action d'un composé de formule (XIV) ::
CH3-CO-NH-R (XIV) dans laquelle R a la signification précedente pour obtenir un composé de formule (XV)

que l'on cyclise en un composé de formule (I), composé de formule (I) que l'on soumet, le cas échéant, à l'action d'un acide minéral ou organique pour en former un sel. The Applicant has also described a process for the preparation of the compounds of formula (I) characterized in that: - either a compound of formula (III) is subjected

in which R1 and R2 have the meanings indicated above for the action of an acid or a functional derivative of this acid of formula (IV) ::
R3COOH (IV) wherein R3 has the meaning indicated above, to obtain a compound of formula (V)

subjected to a chlorinating agent, to obtain a compound of formula (VI)

that is reacted with an alkyl malonate of formula

in which alcl represents an alkyl radical containing from 1 to 5 carbon atoms, in the presence of a strong base, to obtain a compound of formula (VII)

that is cyclized to obtain a compound of formula (VIII)

or a compound of formula (IX) is subjected

in which R 1 and R 2 have the above meanings and alc 2 represents an alkyl radical containing from 1 to 5 carbon atoms in the action of an acid or a functional derivative of this acid of formula (IV) R 3 -COOH in which R3 has the above meaning, to obtain a compound of formula (X)

that the corresponding acid is hydrolyzed and that this acid is cyclized to a compound of formula (XI)

an alkyl anion of CH 3 CO 2 alkal 3 is subjected to the action of an anion, alk 3 being an alkyl radical containing from 1 to 5 carbon atoms in order to obtain a compound of formula (XII)

that is cyclized to a compound of formula (VIII) and that all the compounds of formula (VIII) are subjected to the action of an amine of formula NH 2 R, R having the meaning indicated above, to obtain a compound of formula (I) or the compound of formula (XI) is subjected to the action of a compound of formula (XIV) ::
CH 3 -CO-NH-R (XIV) wherein R has the above meaning to obtain a compound of formula (XV)

cyclizing to a compound of formula (I), compound of formula (I) which is subjected, if appropriate, to the action of a mineral or organic acid to form a salt.

 In the main patent, the Applicant has also described the application of the products of formula (I) as medicaments and pharmaceutical compositions containing them.

dans laquelle R représente un radical hétérocyclique renfermant 5 ou 6 chaînons, éventuellement substitué par un radical alcoyle renfermant de 1 à 5 atomes de carbone ou R représente un radical phényle éventuellement substitué par un ou plusieurs radicaux choisis dans le groupe formé par le radical hydroxy, les radicaux alcoyles ou alcoxy renfermant de 1 à 5 atomes de carbone, le radical trifluorométhyle, le radical nitro et les atomes d'halogène, R1A et R2A identiques ou différents, représentent un radical alcoyle renfermant de 1 à 18 atomes de carbone ou un radical hétérocyclique renfermant 5 ou 6 chaînons éventuellement substitué par un radical alcoyle renfermant de 1 à 5 atomes de carbone, ou un radical phényle ou naphtyle éventuellement substitués par un ou plusieurs radicaux alcoyles ou alcoxy renfermant de 1 à 5 atomes de carbone, le radical trifluorométhyle, le radical nitro et les atomes d'halogène, étant entendu que l'un au moins des radicaux R1 ou R2 représente un radical alcoyle ayant de 6 à 18 atomes de carbone, R3 représente un atome d'hydrogène, un radical alcoyle renfermant de 1 à 5 atomes de carbone ou un radical du type -(CF2)nCF3, n représentant un nombre entier entre O et 4, ainsi que les sels d'addition des produits de formule (I) avec les acides et les bases.The present application for the first certificate of addition is intended primarily to describe the products related to the formula (I) of the main patent and corresponding to the general formula (IA)

in which R represents a 5- or 6-membered heterocyclic radical, optionally substituted by an alkyl radical containing from 1 to 5 carbon atoms, or R represents a phenyl radical optionally substituted with one or more radicals chosen from the group formed by the hydroxyl radical, the alkyl or alkoxy radicals containing from 1 to 5 carbon atoms, the trifluoromethyl radical, the nitro radical and the halogen atoms, R1A and R2A, which may be identical or different, represent an alkyl radical containing from 1 to 18 carbon atoms or a radical; heterocyclic ring containing 5 or 6 members optionally substituted with an alkyl radical containing from 1 to 5 carbon atoms, or a phenyl or naphthyl radical optionally substituted with one or more alkyl or alkoxy radicals containing from 1 to 5 carbon atoms, the trifluoromethyl radical, the nitro radical and the halogen atoms, it being understood that at least one of the radicals R1 or R2 represents an alkyl radical having 6 to 18 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a radical of the - (CF2) nCF3 type, n representing a whole number between 0 and 4, as well as the addition salts of the products of formula (I) with acids and bases.

 When R 3 represents an alkyl radical, it is preferably a methyl or ethyl radical, but it may also represent an n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl radical.

 When R 1A or R 2A represent an alkyl radical they may also represent the alkyl radicals indicated above, it being understood however that at least one of the radicals R 1A or R 2A represents an alkyl radical having from 6 to 18 carbon atoms, these radicals being hexyl, heptyl, octyl, nonyl, decyl, indecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, linear or branched radicals.

 When R represents a heterocyclic radical containing 5 or 6 members, it is preferably thiazolyl, 4,5-dihydro thiazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidyl and tetrazolyl radicals.

 When these heterocyclic radicals are substituted by an alkyl radical, it is preferably methyl or ethyl radicals.

 When R represents a substituted phenyl radical and when R 1 and R 2 represent a substituted phenyl or naphthyl radical, it is preferably a substituent chosen from the group consisting of the methyl, ethyl, methoxy, ethoxy and trifluoromethyl radicals, an atom halogen which is an atom of chlorine, fluorine, bromine, iodine and preferably a chlorine atom.

 When R3 represents a radical - (CF2) nCF3, n is preferably equal to 0, 1 or 2.

 When R 1 and R 2 represent a heterocyclic radical, it is preferably a pyridinyl or thienyl radical.

When this radical is substituted by an alkyl radical, it is preferably methyl or ethyl radicals.

 The addition salts with inorganic or organic acids may be, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, propionic, formic, benzoic, maleic, fumaric, succinic, tartaric and citric acids. oxalic, glyoxylic, aspartic, alkanesulfonic such as methanesulfonic acid and arylsulfonic, such as benzene sulfonic acid.

dans laquelle R'A représente un radical alkyle ayant de 1 à 12 et préférentiellement de 1 à 6 atomes de carbone et X représente un atome d'hydrogène ou un atome de chlore.The present application for the first certificate of addition also relates to products conforming to general formula (I) of the main patent or related to this formula (I) and corresponding to the general formula (I'A)

in which R'A represents an alkyl radical having from 1 to 12 and preferably from 1 to 6 carbon atoms and X represents a hydrogen atom or a chlorine atom.

 The alkyl radicals represented by the radical R'A can be chosen from the radicals mentioned above. Methyl, ethyl, isopropyl, n-propyl or hexyl radicals are preferred.

 X preferably represents a hydrogen atom or a 4-chloro radical.

 Among the products which are the subject of the present application for the first certificate of addition, the products described below in the examples are preferred, namely - 6- (4-chlorophenyl) 4-hydroxy-5-methyl N- (2-thiazolyl) 2 (trifluoromethyl) 3-pyridinecarboxamide.

5-ethyl-4-hydroxy-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

4-hydroxy-6-phenyl-5-propyl N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

5-hexyl-4-hydroxy-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

4-hydroxy-5-isopropyl-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

 More particularly, the following product is preferred: 5-ethyl-4-hydroxy-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

dans laquelle R1A et R2A ont la signification précédente.The products of formula (IA) can be prepared according to the process described in the main patent application and recalled above, with the appropriate starting materials. Thus it is possible to use the process starting from the products of formula (IIIA)

wherein R1A and R2A have the above meaning.

dans laquelle R1A et R2A ont la signification précédente.from products of formula (IXA)

wherein R1A and R2A have the above meaning.

 In a preferred embodiment of the process for preparing the products of formula (IA) - the acid of formula (IV) is in the form of acid chloride or anhydride.

the reaction between the amine of formula (IIIA) and the acid of formula (IV) takes place in the presence of a base such as triethylamine.

- Chlorination agent used to obtain the compound of formula (VI) from the compound of formula (V) is phosphorus pentachloride or triphenyl phosphinetetrachloride carbon mixture.

the alkyl malonate used is ethyl malonate, and the reaction with the compound of formula (VI) is carried out in the presence of sodium hydride.

the cyclization of the compound of formula (VII) is carried out by heating, for example at a temperature of between 150 ° C. and 250 ° C.

the hydrolysis of the compound of formula (X) is carried out by the action of hydrochloric acid or sodium hydroxide, the cyclization of the acid corresponding to the compound of formula (X) to the compound of formula (XI) is carried out in the presence of acetic anhydride or trifluoroacetic anhydride.

the compound of formula (XII) is obtained by the action of zinc of ethyl bromoacetate on the compound of formula (XI) in the presence of methylal.

the condensation between the compound of formula (VIII) and the amine of formula NH 2 R is carried out in the presence of a base such as sodium hydride or a trialkyl aluminum which is preferably a trimethyl or a triisobutylaluminum.

the reaction between the compound of formula (XI) and the compound of formula (XIV) takes place in the presence of an organolithium or a lithium amide, for example in the presence of n-butyllithium or of lithium diisopropylamide. This reaction is preferably carried out at a low temperature of about -70 ° C.

the cyclization of the compound of formula (XV) into a compound of formula (I) is carried out in the presence of an alkaline agent, such as a hydride, for example sodium hydride, or an alkaline carbonate such as sodium carbonate or potassium carbonate.

 It is also possible to use potassium tert-butoxide or an amine such as 4-dimethylaminopyridine, piperidine or triethylamine.

 The products of formula (I'A) in which R'A represents an alkyl having from 1 to 5 carbon atoms and which all fall within the general formula (I) of the main patent, can be prepared, of course, by the process of this invention. main application, recalled above, the products of formula (I'A) in which R'A represents an alkyl having from 6 to 12 carbon atoms, products which fall within the formula (IA) can be prepared by the same process as above mentioned at the beginning of the products (IIIA) or (IXA).

 Like the products of the main patent application, the products of the present application for the first certificate of addition and their addition salts with acids have interesting pharmacological properties. They are compounds with anti-inflammatory and antirheumatic properties.

 They have been found active in models of chronic inflammation and in some models of autoimmune diseases.

These products have a peripheral analgesic component.

 These properties justify the application of the compounds of formula (IA) in therapy and the subject of the invention is also, as medicaments, the products of formula (IA) in their racemic or optically active forms, as well as their salts. addition with pharmaceutically acceptable acids.

 The invention also relates, as compositions, to the products of formula (IA) in their racemic or optically active forms, as well as their addition salts with pharmaceutically acceptable acids.

 The invention more particularly relates, as medicaments, the following products - 6- (4-chlorophenyl) 4-hydroxy-5-methyl N- (2-thiazolyl) 2 (trifluoromethyl) 3-pyridinecarboxamide.

5-ethyl-4-hydroxy-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

4-hydroxy-6-phenyl-5-propyl N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

5-hexyl-4-hydroxy-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

4-hydroxy-5-isopropyl-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

and most particularly 5-ethyl-4-hydroxy-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide, and their addition salts with pharmaceutically acceptable acids.

 The medicaments, object of the present invention, can be advocated in the treatment of inflammatory degenerative diseases such as osteoarthritis, various collagenosis (tendinitis, etc.), rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis) and in the treatment of other autoimmune diseases such as systemic lupus erythematosus, glomerulonephritis, multiple sclerosis and the treatment of psoriasis.

 The drugs, object of the invention, can also be used in the treatment of muscle, joint or nerve pains, dental pain, migraines, shingles.

 The invention extends to pharmaceutical compositions containing as active ingredient, the drugs defined above.

 These pharmaceutical compositions can be administered orally, rectally, parenterally or locally by topical application to the skin and mucous membranes.

 These compositions can be solid or liquid and be in the pharmaceutical forms commonly used in human medicine, for example, simple or coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels and aerosol preparations; they are prepared according to the usual methods. The active ingredient can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, the fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives.

 The dosage varies in particular according to the route of administration, the condition treated and the subject in question.

 For example, in adults, it can vary between 20 mg and 2 g of active ingredient per day, orally.

(Tétrahedron Letters 1971 (51) p. 4 897).The starting products of formula (IIIA) are prepared by the action of ammonia in the presence of a titanium salt, for example titanium tetrachloride on the compounds of formula (IIA):

(Tetrahedron Letters 1971 (51) p.4 897).

 The starting materials of formula (XA) corresponding to the products of formula (X) in which R1 represents R1A and R2 represents R2A of the process of the invention, are prepared as indicated in European Patent No. 102,318.

 The following examples illustrate the invention without limiting it.

 EXAMPLE 1 6- (4-Chlorophenyl) -4-hydroxy-5-methyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

Step A: 3- (4-Chlorophenyl) -2-methyl-3 - [(trifluoromethyl) amino] 2-propenoic acid.

 To a stirred mixture under an argon atmosphere of: 21.57 g of electrolytic zinc and 500 cm3 of tetrahydrofuran, 2 cm3 of ethyl 2-bromopropionate and an iodine crystal are added under reflux. When the zinc is initiated, 34.4 g of 4-chlorobenzonitrile is added and then refluxing 36.96 cm3 of ethyl 2-bromopropionate. The reflux is maintained for another 30 minutes and then cooled and poured over a solution of 100 g of ammonium chloride in 1 liter of water. It is extracted with ether and concentrated under reduced pressure to give 76 g of the intermediate ene amine to which 150 cm 3 of pyridine is added and then at 20 ° C.-22 ° C., slowly, 52.5 cm 3 of trifluoroacetic anhydride is added. hour at room temperature and poured on a mixture of 1 liter of water and ice and 150 cm3 of concentrated hydrochloric acid. Extracted with ether and evaporated to dryness under reduced pressure. The residue (100 g) is taken up in 300 cm3 of ether, extracted with 200 cm3 of N sodium hydroxide and the alkaline phase is modified with hydrochloric acid concentrated to dryness under reduced pressure. The oil obtained (40 g) is crystallized in 100 cm 3 of hexane and 8.4 g of desired product are obtained, mp = 165 ° C.

Stage B: 4- (4-chlorophenyl) 5-methyl 2- (trifluoromethyl) 6H1,3-oxazine.

 A mixture of 12.7 g of 3- (4-chlorophenyl) -2-methyl-3 - [(trifluoroacetyl) amine 2-propenoic acid, prepared as in Step A and 30 cm 3 of acetic anhydride. It is evaporated to dryness under reduced pressure, the residue is taken up in ice water, evaporated and drained. The residue is dissolved in ether, dried, filtered and concentrated under reduced pressure. 11.53 g of the desired product are obtained, mp 98-100 ° C.

Analysis for: C12H7NO2F3cl
C t H% N% w% F%% calculated 49.76 2.44 4.84 12.24 19.68% found 50.1 2.4 4.7 12.0 19.6
Stage C: 6- (4-chlorophenyl) -4-hydroxy-5-methyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridine carboxamide.

 To a mixture of 9.8 g of 2- (acetylamino) thiazole and 290 cm3 of anhydrous tetrahydrofuran is added, with stirring and argon, to 0iC to cm3 of n-butyl lithium 1,4 M in hexane, cooled then -70-C / -75iC and a solution of 10 g of (4-chlorophenyl) 5-methyl 2- (trifluoromethyl) 6H-1,3-oxazine obtained in stage B in 100 cm3 of tetrahydrofuran. The solution obtained is poured into 700 cm 3 of water and 150 cm 3 of 2N hydrochloric acid (pH 1), extracted with ether and concentrated under reduced pressure. The residue is taken up with 100 cm3 of tetrahydrofuran and 4.2 g of 4-dimethylaminopyridine, stirred for 1 hour at room temperature and then poured into 500 cm3 of water and 25 cm3 of 2N hydrochloric acid (pH 1). ethyl acetate and concentrated under reduced pressure. The residue (17.6 g) is taken up in ether and the insoluble is filtered off and concentrated to dryness under reduced pressure. The residue is chromatographed on silica, eluting with ethyl acetate-isopropanol (95.5) and then again eluting with ethyl acetate-acetic acid (100-0.25).

 The residue 5.7 g is crystallized in ether, 2.48 g of the desired product F> 260il is obtained.

Analysis for: C17H11N3F3O2clS
C% H% N% w% F% S%% calculated 49.34 2.68 10.15 13.77 8.57 7.75% found 49.3 2.7 9.9 14.0 8.4 7 9
EXAMPLE 2 5-Ethyl-4-hydroxy-6-phenyl N- (2-thiazolyl) -2 (trifluoromethyl) -3-pyridinecarboxamide
Step A: 2-Ethyl-3-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

 The procedure is as in Step A of Example 1 using 44 cm3 of 2-bromobutyrate ethyl and 25.7 cm3 of benzonitrile. 44 g of desired product are obtained, mp = 148 ° C.

Stage B: 5-ethyl-4-phenyl 2- (trifluoromethyl) 6H-1,3-oxazin-6-one.

 The procedure is as in Step B of Example 1 from 20 g of the acid obtained in Step A. 18.4 g of desired product is obtained at 78.degree.-80.degree.

Stage C: 5-ethyl-4-hydroxy-6-phenyl N- (2-thiazolyl) -2-trifluoromethyl-3-pyridinecarboxamide.

 The procedure is as in Stage C of Example 1 starting from 14.8 g of the product obtained in Stage B. After chromatography on silica eluent ethyl acetate, 2.05 g of the desired product, mp = 242 C., is obtained.

Analysis for: C18H14N302F3S:
C% H% N% F% S%% calculated 54.96 3.59 10.68 14.49 8.15% found 54.8 3.6 10.7 14.7 8.2
EXAMPLE 3 4-Hydroxy-6-phenyl-5-propyl N- (2-thiazolyl) -2 (trifluoromethyl) 3-pyridinecarboxamide.

Step A: 3-Phenyl-2-propyl-3- (trifluoroacetyl) amino] 2-propenoic acid.

 The procedure is as in Stage A of Example 1 using 53 cm 3 of ethyl 2-bromopentanoate and 25.7 cm 3 of benzonitrile. 41 g of desired product are obtained F = 114-116C.

Step B: 4-phenyl-5-propyl 2- (trifluoromethyl) 6H-1,3-oxazin-6-one.

 The procedure is as in Step B of Example 1 from 20 g of acid obtained in Step A, 15.1 g of desired product F = 70-72 ° C.

Step C: 4-hydroxy-6-phenyl-5-propyl N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

 The procedure is as in Stage C of Example 1 starting from 14.7 g of product obtained in Stage B. After chromatography on silica, eluent ethyl acetate-methylene chloride (1-1), 7 g is obtained. of product which is taken up in ether, eliminates the insoluble matter and the filtrate is concentrated under reduced pressure, by crystallization from ether, 2.2 g of product 194-196C are isolated. The mother liquors eluting with ethyl acetate-hexane (5-5) are chromatographed on silica to give 400 mg of expected product. The 2 fractions of the product which are dissolved in 20 cm3 of ethyl acetate are reduced, 1.5 cm3 of 6.6 N aqueous hydrochloric ethanol are added and the mixture is drained.

2 g of product are obtained which is taken up in 50 cm3 of water, extracted with ethyl acetate and concentrated to dryness under reduced pressure. 1.82 g of expected product, mp 194-196 ° C., are obtained.

Analysis for: C19H16N3O2F3S
C% H% N%% calculated 56.01 3.46 10.31% found 56.4 4.1 10.4
EXAMPLE 4 5-hexyl-4-hydroxy-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

Step A: 2-hexyl-3-phenyl-3 - [(trifluoroacetyl) amino] 2-propenoic acid.

 The procedure is as in Step A of Example 1 using 75.34 g of ethyl 2-bromooctanoate and 25.7 cm3 of benzonitrile. 41.5 g of sought product F = 90-92C is obtained.

Stage B: 1-phenyl N- (trifluoroacetyl) 1-octenamine.

 A mixture of 20 g of the product obtained in Stage A and 200 mg of copper is maintained for 10 minutes in a bath at 180-200 ° C. It is cooled and chromatographed on silica eluting with ethyl acetate-hexane (1-9) to give 7 g of the desired product F-55C.

Stage C: N- (1-chloro-2,2,2-trifluoroethylidene) 1-phenyl-1-octenamine.

 To a solution heated under reflux for 2 hours, 7 g of the product obtained in Stage B, 60 cm 3 of methylene chloride, 6.55 g of triphenylphosphine and 2.5 cm 3 of carbon tetrachloride, are added: 3.275 g of triphenylphosphine and 1.25 cm3 of carbon tetrachloride and again maintains 2 hours at reflux. The solvents are removed under reduced pressure and the residue is chromatographed on silica eluent: hexane-methylene chloride (9-1) to give 6.5 g of the desired product.

Step D: [2,2,2-trifluoro-1 - [(1-phenyl-1-octenyl) imino] ethyl] malonate diethyl.

 To a suspension of 1.96 g of sodium hydride in 50% suspension in oil and 20 cm 3 of dimethyl formamide, 7.6 cm 3 of diethyl malonate and 25 cm 3 of diethyl malonate are added at 15 ° C./20 ° C. dimethyl formamide. A solution of 6.5 g of the product obtained in Stage C in 20 cm 3 of dimethylformamide is then added, between 15 and 20 ° C., the mixture is heated to 60 ° C., then cooled and poured into 500 cm 3 of 2N hydrochloric acid, and extracted. with ether and concentrated under reduced pressure, 14 g of desired product are obtained.

Stage E: Ethyl 5-hexyl 4-hydroxy 6-phenyl 2- (trifluoromethyl) 3-pyridinecarboxylate.

 14 g of the product obtained in Stage A are heated for 20 minutes in a flask immersed in a bath at 220 ° -240 ° C. Chromatography on silica, eluent ethyl acetate-hexane (2-8). 7.2 g of desired product are obtained, mp 50.degree.

Step F: 5-hexyl 4-hydroxy-6-phenyl N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

 To a mixture of 8.86 g of 2-aminothiazole and 160 cm3 of toluene is added at 20/26 ° C, 40 cm3 of a 1.1 M solution of triisobutyl aluminum in toluene and then 7 g of product obtained in stage E.

The mixture is refluxed for 4 hours, the solvent is eliminated under reduced pressure and the residue is taken up in 100 cm 3 of water and ice and 100 μl of concentrated hydrochloric acid, the mixture is extracted with ethyl acetate and the mixture is brought to dryness under pressure. scaled down. The residue (9 g) is concentrated in a mixture of ether and hexane (1-1). The product obtained 4.9 g is recrystallized from ethyl acetate. 4.25 g of sought product is obtained
Mp 194-196 ° C.

Analysis for: C22H21N302SF3
C% H% N% F% S%% calculated 58.92 4.72 9.37 12.71 7.14% found 58.6 4.9 9.2 12.5 7.4
EXAMPLE 5: 4-Hydroxy-5-isopropyl-6-phenyl N- (2-thiazolyl) -2 (trifluoromethyl) -3-pyridinecarboxamide.

Step A: 2-Isopropyl-3-phenyl-3 (trifluoroacetyl) amino] 2-propenoic acid.

The procedure is as in Stage A of Example 1, using 62.72 g of ethyl 2-bromo-isopropanolate and 25.7 cm 3 of benzonitrile. 27 g of desired product are obtained
F = 128-130BC.

 Stage B: 1-phenyl N- (trifluoroacetyl) 1-pentenamine.

 The operation is carried out as in Stage B of Example 4, starting from 22 g of product obtained in Stage A. 8.2 g of the desired product F = 80-82C are obtained.

Stage C: N- (1-chloro-2,2,2-trifluoroethylidene) 1-phenyl-pentenamine.

 The procedure is as in Step C of Example 4 from 8.2 g of the product obtained in Step B, 8.2 g of desired product is obtained.

Step D: Diethyl (2,2,2-trifluoro-1- (1-phenyl-pentenyl) imino) ethyl] malonate.

 The procedure is as in Step D of Example 4 from 8.2 g of the product obtained in Step C. 18 g of the desired product are obtained.

Stage E: 4-hydroxy 5-isopropyl 6-phenyl 2- (trifluoromethyl) 3-pyridinecarboxylate.

 The procedure is as in Step E of Example 4 from 18 g of product obtained in Step D, 6.3 g of desired product is obtained F = 104 -106C.

Step F: 4-Hydroxy-5-isopropyl-6-phenyl N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide.

 The procedure is as in Step F of Example 4 from 6.3 g of the product obtained as in Stage E, 3.9 g of desired product is obtained F = 254-256C.

Analysis for: ClgHl6N3F3O2S
C% H% N% F% S%% calculated 56.01 3.96 10.31 13.99 7.86% found 56.0 3.9 10.1 13.9 7.8
EXAMPLE OF PHARNACEUTICAL COMPOSITIONS
Tablets having the following formula were prepared - the product of Example 3 ...................... 50 mg - excipient qs for a tablet finished at. .. 350 mg (details of the excipient: lactose, talc, starch, magnesium stearate).

PHARNACOLOGICAL STUDY OF PRODUCTS
Anti-inflammatory activity: arthritis chronic with adjuvant (preventive treatment).

 The injection of Freund's adjuvant into a hind paw causes, in the rat, the rapid appearance of a primary inflammatory lesion in this paw, then, after a latency period of 13 to 15 days, the triggering of secondary arthritis affecting in particular the other hind paw. The test is practical in male rats aged 42 to 50 days, which receive an intraplantar injection, 0.1 ml of adjuvant type "Freund" (suspension in petrolatum oil of 6 mg per ml of mycobacterium butyricum killed ).

 The animals receive the product studied, orally, from day 0 (day of the injection of the adjuvant) until the day before the sacrifice, performed on day 17. Of the arthritic control animals, normal control animals receive only the vehicle. The criteria for assessing the activity of the substances studied are the volume increases of the injected hind legs (primary and secondary inflammation) and not injected (secondary inflammation) compared to the average volume of the corresponding legs of normal controls.

 DA50, i.e., the dose which decreases by 50% the volume increases of the hind legs of the treated animals relative to the control animals, is determined.

The results obtained were as follows

<tb> Product <SEP> of <SEP> Example <SEP> j <SEP> DA50 <SEP> in <SEP> mg / kg
<tb> 2 <SEP> 0.3
<tb> 3 <SEP> 3 <SEP> I <SEP> 1
<Tb>

Claims (7)

 in which R represents a 5- or 6-membered heterocyclic radical, optionally substituted with an alkyl radical containing from 1 to 5 carbon atoms, or R represents a phenyl radical optionally substituted by one or more radicals chosen from the group formed by the hydroxyl radical, the alkyl or alkoxy radicals containing from 1 to 5 carbon atoms, the trifluoromethyl radical, the nitro radical and the halogen atoms, R1A and R2A, which may be identical or different, represent an alkyl radical containing from 1 to 18 carbon atoms or a radical; 5- or 6-membered heterocyclic ring optionally substituted by an alkyl radical containing from 1 to 5 carbon atoms, or a phenyl or naphthyl radical optionally substituted by one or more alkyl or alkoxy radicals containing from 1 to 5 carbon atoms, the trifluoromethyl radical, the nitro radical and the halogen atoms, it being understood that at least one of the radicals R1 o R 2 represents an alkyl radical having from 6 to 18 carbon atoms, R 3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a radical of the - (CF 2) nCF 3 type, n representing a whole number between 0 and 4, as well as the addition salts of the products of formula (I) with acids and bases.

 1) Products related to the formula (I) of the main patent and corresponding to the general formula (IA) 2) Products corresponding to the general formula (I) of the main patent or related to this formula (I) and corresponding to the general formula (IA)

  in which R'A represents an alkyl radical having from 1 to 12 and preferably from 1 to 6 carbon atoms and X represents a hydrogen atom or a chlorine atom. 3) The products according to claim 2 whose names follow - 6- (4-chlorophenyl) 4-hydroxy-5-methyl N- (2-thiazolyl) 2 (trifluoromethyl) 3-pyridinecarboxamide. 5-ethyl-4-hydroxy-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide. 4-hydroxy-6-phenyl-5-propyl N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide. 5-hexyl-4-hydroxy-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide. 4-hydroxy-5-isopropyl-6-phenyl-N- (2-thiazolyl) -2- (trifluoromethyl) -3-pyridinecarboxamide. 4) The product of claim 2 whose name follows - 5-ethyl 4-hydroxy 6-phenyl N- (2-thiazolyl) 2- (trifluoromethyl) 3-pyridinecarboxamide. 5) As medicaments the products of general formula (IA) as defined in claim 1 and their addition salts with pharmaceutically acceptable acids. 6) As medicaments the products of general formula (I'A) as defined in one of claims 2 to 4, and their addition salts with pharmaceutically acceptable acids. 7) Pharmaceutical compositions containing as active principle at least one of the medicaments as defined in claims 5 and 6.