CH637941A5 - DERIVATIVES OF PICOLINIC ACID SUBSTITUTED IN POSITION 5 AND ANTI-HYPERTENSIVE COMPOSITION CONTAINING THESE DERIVATIVES. - Google Patents

Description

The present invention relates to new picolini-55 ques acids substituted in position 5 and to the salts thereof, to esters and amides of picolinic acid substituted in position 5, as well as to pharmaceutical compositions containing these compounds.

It is known that hypertension often leads to cardiac disorders, apoplexy, etc., which requires intensive research 60 to supply new antihypertensive agents.

Fusaric acid (5-n-butylpicolinic acid) is known to be useful as an antihypertensive agent, as disclosed in "Jap. J. Pharmacol. ”, Vol. 25, 188 (1975); however, this fusaric acid has a butyl group in position 5 of the picolinic acid ring 65 and has a low LDS0 value. Thus, the search for new and improved antihypertensive agents has proved necessary.

British Patent No. 1502055 discloses that the 2- (1 H) -pyridone-6-carboxylic acid substituted in position 3 can be

3

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used as an antihypertensive agent, but the antihypertensive activity (i.e. maximum depression obtained in blood pressure) of it is weak and also required further research to provide more effective antihypertensive agents.

The present inventors have already synthesized 5-alkoxy-picolinic acids and evaluated these as antihypertensive agents,

as disclosed in Japanese patent application No. 116641/1976 (corresponding to USA patent application No. 838180, filed September 30, 1977).

The object of this invention therefore consists in providing new compounds having an antihypertensive activity equal to or greater than the 5-alkoxypicolinic acids disclosed in the aforementioned Japanese patent application No. 116641/1976 and having a toxicity lower than these acids, and which are therefore usable in compositions intended for the treatment of hypertension.

The object of this invention, aimed at achieving the aforementioned aim, consists of derivatives of picolinic acid substituted in position 5 represented by the general formula I:

(I)

R ^ OG

wherein R] represents a linear or branched C2 to C6 halogen substituted alkyl group or a substituted phenyl group of formula

-not

/ X

R,

R "

where R, and Rs, identical or different, each represent a hydrogen atom, a lower alkyl group or a phenyl group.

In formula I above, preferably R, represents a linear or branched C2 to C6 halogen substituted alkyl group, such as a 4-chlorobutyl group, a 4-bromobutyl group, a 3-chloropropyl group, a group 5 , 5,5-trifluoropentyl, 4,4,4-trifluorobutyl group, 3,4-dibromobutyl group, 5-chloro-3-methylpentyl group, etc .; or a substituted phenyl group of formula where R3 and R4, identical or different, each represent a hydrogen atom, a halogen atom (for example chlorine, bromine, fluorine, etc.), a lower C alkyl group, to C3 (for example a methyl group, an ethyl group, a propyl group, etc.), a lower C alkoxy group, to C3 (for example a methoxy group, an ethoxy group, a propoxy groups, etc.), a nitro group, amino group, amino group N-substituted alkyl in which the alkyl residue has from 1 to 3 carbon atoms (for example a dimethylamino group, a diethylamino group, etc.), a C2 to C4 acylamino group (for example an acetamido group, a propionylamino group, etc.), an acetyl group, a C2 to C4 acyloxy group (for example an acetoxy group, a propionyloxy group, etc.), a hydroxy group or an alkyl group C, to C3 halogen substituted (for example a trifiuoromethyl group, etc.), or else R3 and R4 represent, taken together, a chain p olymethylene having 3 to 5 carbon atoms, such as trimethylene, etc.

R2 represents a group - OM, where M represents a hydrogen atom, a sodium atom, a potassium atom, a calcium atom, an aluminum atom or a magnesium atom; a linear or branched alkoxy group at Q to C6 (for example a methoxy group, an ethoxy group, a propoxy group, an isobutoxy group, a cyclohexyloxy group, etc.); a C2 to C5 aminoalkoxy group (for example a diethylaminoethyloxy group, etc.); a phenoxy group (including a substituted phenoxy group as illustrated below with respect to the phenyl group); a 5-indanyloxy group; an acyloxyalkyloxy group of formula where r3 and r4, identical or different, each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, an N amino group substituted alkyl, an acylamino group, an acetyl group, an acyloxy group, a hydroxyl group or a halogen substituted alkyl group, or alternatively r3 and r4 represent, taken together, a polymethylene chain; and r2 represents an —om group, where m represents a hydrogen atom, a sodium atom, a potassium atom, a calcium atom, an aluminum atom or a magnesium atom, or r2 represents a linear alkoxy group , branched or cyclic having from 1 to 6 carbon atoms, an aminoalkoxy group, a phenoxy group, a 5-indanyloxy group, an acyloxyalkyloxy group of formula

Rs

I

-o-chocor6

where rs represents a hydrogen atom or a methyl group and r0 represents a lower alkyl group at c! to c6, a phenyl group or a substituted phenyl group, or r2 represents an amino group of formula

35

Rs

I

-o-chocor6

where R5 represents a hydrogen atom or a methyl group and R6 represents a lower C 1 -C 6 alkyl group (for example a methyl group, an ethyl group, a propyl group, an isobutyl group, a t-butyl group, etc.), a phenyl group or a substituted phenyl group, in which the substituent comprises a C 1 -C 3 alkyl group and a C 1 -C 3 alkoxy group (for example a p-tolyl group, a p-methoxyphenyl group, a 3,4,5-45 trimethoxyphenyl group, etc.); or an amino group represented by the formula

\

50

where R7 and R8, identical or different, each represents a hydrogen atom, a lower C 1 -C 4 alkyl group (for example a methyl group, an ethyl group, etc.), or a phenyl group.

The compounds represented by the formula IIa:

nu OC

(lia)

NOT

6o in which R10i represents a linear or branched alkyl group C2 to C6 halogen substituted can be prepared by reaction of a compound of formula IV:

65

(iv)

637,941

4

in which Rg represents a methyl group or a hydroxymethyl group, with a halide represented by the formula R, oiX (V), where R10i is as defined above and X represents a halogen atom, in an organic solvent such as dimethyl- formamide, dimethylsulfoxide, dimethylacetamide and the like, in the presence of an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate and the like or in an organic base such as triethylamine, N, N-dimethylaniline and the like, in order to obtain a compound of formula VI:

101

in which R9 and RI01 are as defined above.

This substitution reaction occurs selectively at position 5 of the hydroxy group, and no reaction of the group - CH 2 OH has been observed under the above conditions, nor formation of by-products of the pyridinium salts. The reaction easily takes place at a temperature between about 30 and 100 "C, and is completed in a relatively short time of about 1 to 20 h.

The compounds of formula IIa can be prepared by oxidation of the intermediate of formula VI as described above, using an oxidizing agent such as potassium permanganate, chromic anhydride, selenium dioxide, nitric acid, potassium dichromate and the like in a solvent such as acetone, dioxane, pyridine, hydrated acetone, hydrated t-butanol, sulfuric acid and the like. The impurities formed as by-products during the reaction can easily be removed by solvent extraction, precipitation, crystallization or the like. The reaction conditions for oxidation vary according to the nature of the oxidizing agent used and the R9 group of the compound of formula VI. When the Rq group is a hydroxymethyl group, the reaction conditions for the oxidation are generally mild. For example, when the compound of formula VI having a hydroxymethyl group as the R9 group is oxidized with potassium permanganate, about 1 to 2 mol of potassium permanganate per mole of compound VI are used, the reaction time and the reaction temperature being approximately 5 to 20 C and approximately 2 to 20 h respectively. In the case of the oxidation of the compound of formula VI having a methyl group as group R9 with potassium permanganate, approximately 2 to 4 mol of potassium permanganate per mole of compound VI are necessary at a reaction temperature of approximately 80 to 100 ° C. and for a reaction time of approximately 4 to 10 h. In the case of the oxidation of the compound of formula VI having a methyl group as group R9 with chromic anhydride, approximately 2.5 to 3.5 mol of chromic anhydride per mole of compound VI are used in the presence of sulfuric acid, at a reaction temperature of about 30 to 70 C and for a period of about 4 to 10 h. When selenium dioxide is used as an oxidizing agent, the oxidation reaction is carried out in the presence of pyridine, with an amount of about 1.8 to 2.5 mol of selenium dioxide per mole of the compound of formula VI, a reaction temperature of about 100 to 120 C and for a period of about 5 to 10 h.

The compounds represented by the formula Ilf:

HOOC

302

404

lower alkyl, lower alkoxy group, nitro group, amino group, amino group N-substituted alkyl, acylamino group, acetyl group or halogen substituted alkyl group, or R302 and R4.04 together represent a polymethylene chain , can be obtained by reacting the compound of formula IV or a metal salt thereof such as a potassium salt, a sodium salt, etc., with a substituted halobenzene derivative represented by the formula VIIa: _

302

(Vlla)

(VI)

404

Wherein R302 and R404 are as defined above and X is a halogen atom, in an organic solvent such as dimethylformamide, dimethylacetamide, pyridine, collidine and the like, preferably in the presence of a catalyst such as a copper powder, copper oxide, copper chloride and the like, in order to obtain a compound represented by the formula VIIlb:

R-

30 2

404

(VlIIb)

35

(Hf)

in which R302 and R404, identical or different, each represent a hydrogen atom, a halogen atom, a group in which R5, R302 and R404 are as defined above. Among the compounds of formula Vlla, those in which at least one of the groups R302 and R404 is a nitro group, this nitro group being in the ortho or para position of the halogen X, can be prepared under mild conditions such as at a reaction temperature of about 50 to 100: C and a reaction time of about 10 to 15 h, without catalyst.

The halobenzene derivative of formula VIIa is used in an amount of about 0.9 to 1.2 mol / mol of compound IV. The reaction requires a higher temperature than in the preparation of the compounds of formula IIa and is generally between about 90 and 180: C, the time required to complete the reaction being relatively long and between about 8 and 30 h. The reaction is generally carried out in a stream of nitrogen in order to prevent side reactions such as oxidation and polymerization. In the case of the use of copper powder as catalyst, approximately 5 to 15% by weight of copper powder relative to compound IV are used at a reaction temperature of approximately 100 to 150 C and for a period from around 10 a.m. to 8 p.m. In the case of the use of copper oxide or copper chloride as catalyst, approximately 0.2 to 0.3 mol of copper oxide or copper chloride per mole of compound IV is used at a temperature of reaction of about 50 to 130 to 160 C and for a reaction time of about 10 to 20 h. In the two aforementioned cases, the reaction is carried out in a stream of nitrogen gas.

Next, the compound of formula VIIb is oxidized in a solvent such as acetone, dioxane, hydrated acetone, pyridine, water, hydrated t-butanol 55, sulfuric acid and the like, using an oxidizing agent such as potassium permanganate, selenium dioxide, chromic anhydride, nitric acid, potassium dichromate and the like, so as to obtain the compound of formula Ilf. The oxidation conditions for this reaction are the same as those for the oxidation of the compound of formula VI obtained previously.

Among the compounds of formula VIIb, those in which at least one of the groups R302 and R404 is a nitro group can be prepared under the conditions employed for the preparation of the 65 compounds of formula IIa, since the reagent of formula Vlla is active.

Among the compounds of formula Ilf, those in which at least one of the groups R302 and R404 is a nitro group can be subjected

5

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reduction using tin or stannic chloride in hydrochloric acid or iron powder in hydrochloric acid, or catalytic reduction in alcohol, dioxane, hydrated alcohol, alcohol ammoniacal or an ammoniacal hydrated alcohol, in the presence of a catalyst such as platinum oxide, palladium, Raney nickel and the like, in order to obtain a compound of formula Ilh having at least one amino group on the nucleus phenoxy:

(Uh)

HOOC N

(Hj)

406

HOOC

405

where R405 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, an N-substituted amino group an acylamino group, an acetyl group or a substituted alkylhalogen group. In the case of the use of stannic chloride or iron powder as a reducing agent, approximately 3 mol of stannic chloride or 2.5 to 5 atoms of iron powder per mole of the compound Ilf are used under acidic conditions, generally in hydrochloric acid, at a reaction temperature between room temperature (about 15 to 30 C) and about 70 C, for a reaction time of about 5 to 20 h. In the case of catalytic reduction, the catalyst (for example platinum oxide, palladium, Raney nickel) is used in an amount of about 5 to 10% by weight relative to the weight of the compound of formula Ilf and the catalytic reduction is carried out under neutral or alkaline conditions at ambient temperature (approximately 15 to 30: C) and at atmospheric pressure, for a period of approximately 2 to 5 h.

When the catalytic reduction mentioned above is carried out in an acid anhydride or in a mixture of an acid anhydride and a corresponding organic acid, a compound of formula Ili containing an acylamino substituent is obtained:

NHCOR

kN

HOOC N

10

405

where X represents a halogen atom and R + 06 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a substituted N-alkyl amino group, an acylamino group, a group acetyl or a substituted alkylhalo group.

The compounds represented by the formula Ilk having at least one hydroxy group on the phenoxy ring:

15 OH

(iik)

HOOC

where R4 is as defined above, can be easily prepared by dealkoxylation of the compound Ilf in a hydrohalic acid and by heating, or by treatment of the diazonium salt of the compound Ilh with an aqueous dilute acid.

The compounds represented by formula VIII:

R-

30

(VIII)

in which R3,

35 are intermediates for the preparation of the compounds of formula IIb:

(Ili)

HOOC

(IIb)

where R, o represents a lower alkyl group and R405 is as defined above.

The compounds of formula Ilh can also be easily prepared by hydrolysis of the compound of formula Ili, as described above, using an acid or an alkali, then by deacylation.

The compound of formula Ilh as obtained above is dissolved in an aqueous solution containing a mineral acid such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like, and sodium nitrite is added to the ice-cooled mixture to form a diazonium salt of the compound Ilh. The diazotization is generally carried out in the presence of acid such as hydrochloric acid, sulfuric acid or hydrobromic acid using sodium nitrite (NaNO2) in an amount of about 1 to 1.2 mol / mol of the compound Ilh and at a reaction temperature of 0 to 10 C. The diazonium salt obtained can be chlorinated or brominated by treatment with mixtures of cuprous chloride / hydrochloric acid or cuprous bromide / hydrobromic acid, iodized by addition of potassium iodide or fluorinated by adding fluoroboric acid and by heating the diazonium fluoroborate obtained, in order to obtain a compound represented by the formula Ilj having at least one halogen atom on the phenoxy ring:

in which R3 and R4 are as defined above, can also be obtained by the following method.

The compound of formula IIb can be prepared by reaction of a compound of formula IX:

(IX)

in which X represents a halogen atom and R9 is as defined above, with a substituted phenol represented by the formula Xa:

302

(Xa)

4 Ili!

in which R302 and R404 are as defined above. The reaction takes place under the same conditions as those described in the case of the condensation reaction between the compound of formula IV and the compound of formula VIIa.

The picolinic acids substituted in position 5, as obtained as described above, can be easily transformed into salts

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6

of these pharmaceutically acceptable, such as the calcium, sodium, aluminum, magnesium and potassium salts.

There may also be mentioned a process for the preparation of an ester or an amide of the picolinic acid substituted in position 5 represented by the formula III:

, 0R,

ii) the reaction of a picolinic acid substituted in position 5 or of a metal salt thereof of formula Ilg with an acyloxyalkyl halide represented by formula XII:

Rs

X — CHOCORfi

(XII)

R201OC

(III)

in which R represents a linear or branched C2 to C6 halogen substituted alkyl group or a substituted phenyl group represented by the formula in which R5 and R6 are as defined above, and X represents a halogen atom, in the presence of a based.

More particularly, among the compounds of formula III, lower alkyl esters such as methyl, ethyl, pro-pylic and isobutyl esters and the like can easily be obtained by reaction of a picolinic acid substituted in position 5 represented by the If formula:

MO OC

(H)

where R3 and R4 are as defined above; and R20l represents a linear, branched or cyclic alkoxy group having from 1 to 6 carbon atoms, an aminoalkoxy group, a phenoxy group, a substituted phenoxy group, a 5-indanyloxy group, an acyloxyalkyloxy group represented by the formula

Rs I

-o-chocor6

3 °

where R5 and R6 are as defined above, or an amino group represented by the formula

R,

-NOT.

\

Rs where R7 and R8 are also as defined above, this method comprising:

i) the reaction of a picolinic acid substituted in position 5 or of a metal salt thereof, of formula IIg:

35

102

(Hg)

mooc in which R102 represents a linear or branched halogen substituted alkyl group (containing a halogen atom such as chlorine, bromine, iodine and fluorine) or a substituted phenyl group represented by formula d

302

in which R t and M are as defined above, with the corresponding aliphatic alcohol having from 1 to 6 carbon atoms, in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, p- acid toluenesulfonic and the like and at a temperature between 40 and 100 "C.

The 5-indanyl, phenyl and substituted phenyl esters of formula III can be obtained by reaction of the picolinic acid substituted in position 5 of formula II with 5-indanol, a phenyl or a substituted phenol (for example p-ethylphenyl, p-methylphenol, o-methylphenol and the like), respectively, in an organic solvent such as chloroform, dioxane, dimethylformamide, pyridine and the like, and in the presence of a condensing agent such as dicyclohexylcarbodiimide and the like.

Acyloxyalkyl esters of picolinic acid substituted in position 5 such as acetoxymetyl, pivaloyloxy-methyl, a-pivaloyloxyethyl, a-benzoyloxyethyl, a- (isovaleryloxy) ethyl, a- (3,4,5-trimethoxybenzoyloxy) ethyl esters the similar can be prepared by reacting the picolinic acid substituted in position 5 of formula II with an acyloxyalkyl halide represented by formula XII in a solvent such as dimethylformamide, dimethyl sulfoxide and the like in the presence of a base such as pyridine, triethylamine and the like in an amount of about 1 to 1.5 mol / mol of the picolinic acid substituted in position 5 of formula II. The reaction is carried out at a temperature between -20 and + 80 ° C for a period of 4 to 20 h.

On the other hand, the compound of formula III can be prepared by reaction of a halide of picolinic acid substituted in position 5 represented by formula XIII:

50

XOC

(xiii)

404

where R302 and R304 are as defined above; and M represents a hydrogen atom or a metallic atom (such as sodium, potassium, calcium, aluminum and magnesium), with a reagent chosen from the group comprising a C 1 -C 6 aliphatic alcohol, 5-indanol, phenol , substituted phenols and amines represented by formula XI:

/ R?

HN ^ (XI)

Rs where R7 and Rs are as defined above, in the presence of an acid catalyst or a condensing agent; or

55

wherein R, is as defined above and X represents a halogen atom, which is obtained by reaction of a picolinic acid substituted in position 5 of formula II with an acid halogenation reagent, with an aliphatic alcohol having 1 with 6 carbon atoms, 5-indanol, phenol, substituted phenols, amines represented by formula XI and acyloxyalkanols represented by formula XIV:

R <

ho-chocor6

(xiv)

65

in which Rs and R6 are as defined above, in the presence of a base.

The 5-indanyl, phenyl and substituted phenyl esters can be obtained by reaction of the acid halide of

637941

formula XIII with 5-indanol, phenyl and substituted phenol, respectively, in pyridine or in the presence of a base such as triethylamine, N, N-dimethylaniline and the like, in an organic solvent such as chloride methylene, ethyl ether, dimethylformamide, dioxane and the like. The two reactions are carried out at a temperature between -10 and + 50 ° C. and for a period of 2 to 10 hours.

The acyloxyalkyl esters can also be obtained by reaction of the acid halide of formula XIII with an acyloxy-alkanol of formula XIV in an organic solvent such as methylene chloride, chloroform, dioxane, dimethylformamide and the like, in the presence of a base such as triethylamine and the like or in pyridine. In this case, the reaction temperature is between -30 and +50 ° C and the duration of this reaction is between 1 and 10 h.

The amides of picolinic acid substituted in position 5 can be prepared by reacting picolinic acid substituted in position 5 of formula II with an amine of formula XI in an organic solvent in the presence of a condensing agent such as dicyclohexylcarbodiimide and the like or by reaction of a halide of picolinic acid substituted in position 5 of formula XIII with an amine of formula XI in a solvent such as methylene chloride, ethyl ether, chloroform, dioxane and the similar.

The amides of formula Illb:

R

R

7 \ 8 '

JU **

(IHb)

NOC N

in which R! is as defined above and R, and Rs, identical or different, each represent a hydrogen atom, a lower alkyl group or a phenyl group, can also be prepared by reaction of the ester of the picolinic acid substituted in position 5 of formula Illa:

R202 °°

wherein R] is as defined above and R202 represents a linear, branched or cyclic alkoxy group having from 1 to 6 carbon atoms, an aminoalkoxy group, a phenoxy group, a substituted phenoxy group, a 5-indanyloxy group or a acyloxyalkyloxy group of formula

Rs I

-o-chocor6

where rs represents a hydrogen atom or a methyl group and re represents a lower C1 to Cs alkyl group, a phenyl group or a substituted phenyl group, with an amine of formula XI, in the absence of solvent or in the presence of a suitable solvent.

The present invention also provides an antihypertensive composition containing, as active ingredient, a therapeutically effective amount of at least one derivative of picolinic acid substituted in position 5 of formula I as described above.

As another derivative of picolinic acid, one can also mention the 5-indanyl ester of 5-alkoxypicolinic acid represented by formula A:

RaO

^ ^ (A)

eoo in which Ra represents an alkyl group having from 1 to 6 carbon atoms.

The term "alkyl group having 1 to 6 carbon atoms" as used herein for Ra includes a linear or branched alkyl group, s for example methyl, ethyl, n-propyl, isopropyl, n-butyl, dry groups respectively. -butyl, tert.-butyl, n-pentyl, n-hexyl and the like.

This 5-indanyl ester of 5-alkoxypicolinic acid of the above-mentioned formula A can be prepared by a process which comprises reacting a 5-alkoxypicolinic acid or a metal salt thereof represented by formula B:

RaO

(B)

COOM

wherein Ra is as defined above and M is a hydrogen atom or a metal atom, with a 5-hydroxyindane (i.e. the compound of formula

),

in an organic solvent (for example dimethylformamide, dimethylsulfoxide and the like), in the presence of a base (for example pyridine, triethylamine, etc.), with a reaction temperature between about 0 and 40 C and a reaction time generally between approximately 3 and 10 h.

Another process for the preparation of this 5-indanyl ester of 5-alkoxypicolinic acid of formula A comprises the reaction of a halide of 5-alkoxypicolinic acid of formula C:

35

(Illa) 40

(vs)

COX

in which Ra is as defined above and X represents a halogen atom, with 5-hydroxyindane, in an organic solvent which (for example chloroform, methylene chloride, dimethylformamide, dioxane, etc.), in the presence of a base (for example pyridine, triethylamine, etc.), with a reaction temperature of between approximately -10 and approximately + 40 ° C. and with a reaction time generally of between approximately 3 and approximately 10 h. The present invention will now be illustrated in detail with reference to the following examples, in which, unless otherwise indicated, all percentages, parts, ratios and the like are by weight.

55 Example 1:

4.86 g of potassium salt of 5-hydroxy-2-hydroxymethyl-pyridine were suspended in 80 ml of dimethylformamide, and 5.7 g of tetramethylene chloride and 1 g of potassium carbonate were added to the suspension, then this was stirred at 60 ° 70 ° C for 15 h to carry out the reaction. The reaction mixture was concentrated to dryness, and 150 ml of ethyl acetate and 150 ml of water were added to the residue to form two phases. The ethyl acetate phase was separated and dried with anhydrous sodium sulfate, then immediately concentrated to obtain 5.4 g of a syrup of 5-65 (4-chlorobutoxy) -2-hydroxymethylpyridine. The unreacted products remained in the aqueous phase.

4.1 g of the product thus obtained were dissolved in a mixture of 35 ml of t-butanol and 12 ml of water, and 30 ml of an aqueous solution

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containing 3.5 g of potassium permanganate was added dropwise to the mixture for 1 h. The reaction was then continued at a temperature of 5 to 10 C for 2 h with stirring. The reaction mixture was then filtered and the filter cake was washed with 50 ml of hot 50% aqueous methanolic solution (adjusted to pH 10 with sodium hydroxide). The filtrate and the washing solution were combined and the mixture was concentrated to a volume of about 30 ml, then the solvent removed by distillation. The aqueous phase obtained was adjusted to a pH of 1.5 using 5N hydrochloric acid and extracted with 50 ml of chloroform. The chloroform phase was dried with anhydrous sodium sulfate and concentrated to a volume of about 3 ml. 10 ml of ethanol was then added to this concentrate, and the mixture was allowed to stand at low temperature to crystallize the product. The crystals thus obtained were separated by filtration to obtain 3.5 g of white crystals of 5- (4-chlorobutoxy) picolinic acid.

Melting point: 96-97 C.

Elementary analysis for C10H] 2N3NC1:

Calculated: C 52.29 H 5.23 N 6.10 0 29.92 Cl 15.47%

Found: C 52.18 H 5.92 N 6.15 Cl 15.32%

Example 2:

4.3 g of a potassium salt of 5-hydroxy-2-hydroxymethyl-pyridine were suspended in 50 ml of dimethyl sulfoxide, and 4.4 g of 1,3-dichloropropane and 500 mg of potassium carbonate were added to the suspension, then it was stirred at 60 ° C for 10 h to carry out the reaction. The reaction mixture was concentrated to dryness, and 100 ml of chloroform and 100 ml of water were added to the residue to form two phases. The chloroform phase was separated, dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 4.5 g of a syrup of 5- (3-chloropropoxy) -2-hydroxymethylpyridine.

The product thus obtained was oxidized in 50 ml of an aqueous 70% acetone solution with potassium permanganate in the same manner as described in Example 1, in order to obtain 3.7 g of white crystals of 5- (3-chloropropoxy) pycolinic acid.

• Melting point: 120-121: C.

Elementary analysis for C9H10O3NCl:

Calculated: C 50.12 H 4.64 N 6.50 0 22.27 Cl 16.47%

Found: C 50.07 H 4.72 N 6.58 Cl 16.33%

Example 3:

4.9 g of a potassium salt of 5-hydroxy-2-hydroxymethyl-pyridine were suspended in 90 ml of dimethylformamide, and 6.1 g of 4-bromonitrobenzene and 0.5 g of potassium carbonate were added to the suspension, and the reaction was carried out at 80 C for 18 h. The reaction mixture was immediately concentrated to dryness, and 200 ml of chloroform and 100 ml of water were added to the residue to form two phases. The chloroform phase was separated, dried with anhydrous sodium sulfate and immediately concentrated to obtain a crystalline residue. This residue was recrystallized from chloroform to yield 5.7 g of 5- (p-nitrophenoxy) -2-hydroxymethylpyridine crystals having a melting point of 129-130 ° C.

5 g of the product thus obtained were dissolved in 150 ml of acetone and 80 ml of an aqueous solution containing 3.8 g of potassium permanganate were added dropwise to the solution over a period of 1 h. The reaction was then continued at room temperature for 3 h, and the reaction mixture was filtered. The filter cake was washed with 80 ml of 50% hot aqueous methanol (adjusted to pH 10 using sodium hydroxide). The filtrate and the washing solution were combined, concentrated to a volume of about 40 ml, adjusted to a pH of 1.5 using hydrochloric acid and extracted with 100 ml of chloroform. The extract was dried with anhydrous sodium sulfate, concentrated to a volume of about 30 ml and allowed to stand at low temperature to allow the product to crystallize. The crystals thus formed were separated by filtration to give 4.2 g of crystals of 5- (p-nitrophenyl) picic acid.

Melting point: 188-189 C.

Elementary analysis for C, 2H805N2:

Calculated: C 55.38 H 3.08 N 10.77 O 30.77%

Found: C 55.47 H 3.12 N 10.68

Example 4:

7.35 g of a potassium salt of 5-hydroxy-2-methylpyridine were suspended in 20 ml of dimethylformamide, and 9.6 g of bro-mochlorobenzene and 800 mg of a copper powder were added to suspension. The reaction was carried out at a temperature of 120 C for a period of 18 h in a stream of nitrogen and with stirring. After the reaction mixture had cooled, it was diluted with 50 ml of methanol, then filtered. The filtrate was immediately concentrated to dryness, and 200 ml of chloroform and 100 ml of water were added to the dried product, and the mixture adjusted to a pH of 9 using 5N sodium hydroxide. The insoluble products were again separated by filtration. The chloroform phase obtained was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 8.2 g of oily 5- (p-chlorophenoxy) -2-methyl-pyridine. Analysis by gas chromatography revealed that the product thus obtained did not contain 5- (p-bromophenoxy) -2-methylpyridine.

4.7 g of the product obtained above were dissolved in 25 ml of pyridine, and 4.5 g of selenium dioxide were added to the solution, then the solution was stirred at 120 "C for 12 h to perform the oxidation. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The concentrate was dissolved in 200 ml of chloroform, then washed successively with 100 ml of an aqueous solution of hydrochloric acid at pH of 2 with 50 ml of water. The chloroform phase was dried with anhydrous sodium sulfate and immediately concentrated to crystallize the product, which was then recrystallized from ethanol to obtain 4.2 g of acid crystals 5 - (p-chloro-phenoxy) picolinic.

Melting point: 158-159.5: C.

Elementary analysis for C12H803NC1:

Calculated: C 57.72 H 3.21 N 5.61 0 19.24 Cl 14.23%

Found: C 57.63 H 3.26 N 5.53 Cl 14.19%

Example 5:

2.0 g of 5- (p-chlorophenoxy) -2-methylpyridine obtained in Example 4 were suspended in 60 ml of water, and a 1.53 g portion of potassium permanganate was added four times with suspension with stirring, at a temperature of 100 ° C and over a period of 10 h, in order to carry out the oxidation. The reaction mixture was filtered, and the filter cake was washed with 30 ml of hot water. The filtrate and the washing solution were combined, adjusted to a pH of 9.5 using 5N sodium hydroxide and washed with 30 ml of chloroform. The aqueous phase was adjusted to a pH of 1.5 using an aqueous solution of 5N hydrochloric acid, and extracted with 50 ml of chloroform. This chloroform phase was treated in the same manner as that described in Example 4, in order to provide 1.2 g of crystals of 5- (p-chlorophenoxy) picolinic acid.

Example 6:

7.4 g of a potassium salt of 5-hydroxy-2-methylpyridine, 8.5 g of p-bromotoluene and 500 mg of a copper powder were suspended in 25 ml of dimethylformamide, and the mixture was reacted in a stream of nitrogen at a temperature of 130 ° C and for 14 h with stirring. The reaction mixture was diluted with 70 ml of methanol and filtered. The filtrate was immediately concentrated, and 150 ml of chloroform was added to the residue. The

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The mixture was washed with 100 ml of a 0.01N aqueous sodium hydroxide solution, so as to transfer the unreacted 5-hydroxy-2-methylpyridine to the aqueous phase. The chloroform phase was washed with water, dried with anhydrous sodium sulfate and immediately dried to provide 8.9 g of the oily 5- (p-methylphenoxy) -2-methylpyridine.

4 g of the product thus obtained were dissolved in 20 ml of pyridine, and 4.3 g of selenium dioxide were added thereto, then the mixture was stirred at 120 C for 15 h to carry out the oxidation. The reaction mixture was then treated in the same manner as that described in Example 4 to provide 3.1 g of crystals of 5- (p-methylphenoxy) picolinic acid.

Melting point: 165-166 C.

Elementary analysis for C, 3H ,, 03N:

Calculated: C 68.12 H 4.80 N 6.11 0 20.96%

Found: C 68.17 H 4.72 N 6.19%

Example 7:

2.84 g of a potassium salt of 5-hydroxy-2-methylpyridine, 4.7 g of p-dibromobenzene and 400 mg of cuprous oxide were suspended in 10 ml of dimethylacetamide, and the mixture was was reacted, in a stream of nitrogen gas, at a temperature of 150 C and for 15 h. The reaction mixture was diluted with 30 ml of methanol, then filtered. The filtrate was immediately dried and the residue was taken up in 100 ml of chloroform and washed successively with a 3% aqueous sodium carbonate solution and with 50 ml of water. The chloroform phase was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 2.1 g of the oily 5- (p-bromophenoxy) -2-methylpyridine.

2.0 g of the product thus obtained were then subjected to oxidation in pyridine using selenium dioxide, in the same manner as that described in Example 6, to obtain 1.4 g of acid crystals 5 - (p-bromophenoxy) picolinic.

Melting point: 139-141 "3 C.

Elementary analysis for CI2H803NBr:

Calculated: C 49.00 H 2.72 N 4.76 0 16.33 Br 27.19%

Found: C 49.13 H 2.64 N4.81 Br 26.83%

Example 8:

2.2 g of 5- (p-nitrophenoxy) picolinic acid obtained in Example 3 were added to a solution of 6.1 g of stannous chloride in 16.2 ml of concentrated hydrochloric acid cooled to 5 ° C, then the mixture was stirred at room temperature for 16 h. The crystalline precipitate obtained was separated by filtration and dissolved in 12 ml of hot water. To the immediately solidified crystals were then added 12 ml of water, and the suspension obtained was filtered. The crude crystals obtained were washed with 25 ml of water, recrystallized from 75 ml of a mixture of concentrated hydrochloric acid and ethanol (3: 5 by volume), washed with 15 ml of ethanol and dried under reduced pressure to obtain 1.0 g of colorless crystals of 5- (p-aminophenoxy) picolinic acid dihydrochlorides.

Melting point: 221-230 ° C (decomposition).

Elementary analysis for C12H10N2O3 • 2HC1:

Calculated: C 47.52 H 3.96 N 9.24 0 15.84 Cl 23.43%

Found: C 47.61 H 3.72 N 9.36 Cl 23.40%

Example 9:

1.4 g of 5- (p-aminophenoxy) pico-linic acid dihydrochloride obtained in Example 8 above was suspended in 22 ml of concentrated hydrochloric acid, and 3 ml of a solution Aqueous containing 828 mg of sodium nitrite were added dropwise to the suspension over a period of 1 h and with ice cooling.

5.4 ml of an aqueous solution containing 760 mg of sodium metabisulfite and 480 mg of sodium hydroxide were added to 11 ml of a hot aqueous solution containing 3.4 g of copper sulphate pentahydrate and 2.9 g of sodium chloride to prepare a solution of cuprous chloride. The cuprous chloride solution was added to the diazonium salt solution as obtained above to form a solution, and 15 ml of concentrated hydrochloric acid were then added to the resulting solution, then the mixture was stirred at 10 C for 2 h, and then at room temperature for 16 h in order to carry out the reaction. The reaction mixture was diluted with 50 ml of water, adjusted to a pH of 1.5 using 5N sodium hydroxide and extracted with 100 ml of chloroform. The extract was dried with anhydrous sodium sulfate, concentrated to a volume of about 10 ml and allowed to stand at 3 "C to allow the formation of crystals, which were then separated by filtration to provide 0, 91 g of 5- (p-chlorophenoxy) picinic acid crystals.

Example 10:

3.68 g of a potassium salt of 5-hydroxy-2-methylpyridine were suspended in 10 ml of dimethylformamide, and 5.65 g of m-bromobenzotrifluoride and 300 mg of copper powder were added to the suspension, then the mixture was reacted under a stream of nitrogen at 120 ° C. and for 15 h, with stirring. After cooling, the reaction mixture was diluted with 40 ml of acetone and filtered. The filtrate was immediately dried to solidify, and 100 ml of chloroform and 50 ml of water were added thereto. The mixture was adjusted to pH 9 using 5N sodium hydroxide, and the insolubles were again separated by filtration. The chloroform phase obtained was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 4.1 g of the oily 5- (m-trifluoromethylphenoxy) -2-methylpyridine.

The product thus obtained was subjected to oxidation in pyridine using selenium dioxide in the same manner as described in Example 4. The product obtained was crystallized from 20 ml of ethyl scetate to give 2, 7 g of 5- (m-trifluoromethylphenoxy) picolinic acid crystals.

Melting point: 151-152 ° C.

Elementary analysis for C13H803NF3:

Calculated: C 55.12 H 2.83 N 4.95%

Found: C 53.68 H 2.72 N 4.79%

Example 11:

3 g of a potassium salt of 5-hydroxy-2-methylpyridine, 3.83 g of m-bromochlorobenzene and 200 mg of a copper powder were suspended in 8 ml of dimethylformamide, then the mixture was was reacted under a stream of nitrogen at a temperature of 130 ° C and for 13 h with stirring. The reaction mixture was diluted with 40 ml of ethanol and filtered. The filtrate was immediately concentrated, and 80 ml of chloroform was added to the residue. The mixture was then washed with 0.0IN aqueous sodium hydroxide solution, then the chloroform phase was washed with water, dried with anhydrous sodium sulfate and dried to solidify to provide 2.96 g of oily 5- (m-chlorophenoxy) -2-methylpyridine.

The product thus obtained was subjected to oxidation using potassium permanganate, in the same manner as that described in Example 5, in order to obtain 1.43 g of 5- (m-chlorophenoxy) acid crystals. ) picolinique.

Melting point: 138-139 ° C.

Elementary analysis for C12H803NC1:

Calculated: C 57.72 H 3.21 N 5.61 Cl 14.23%

Found: C 57.58 H 3.29 N5.38 Cl 13.82%

Example 12:

4 g of a potassium salt of 5-hydroxy-2-methylpyridine were suspended in 10 ml of dimethylacetamide, and 5.1 g of p-methoxybromobenzene and 450 mg of a copper powder were

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added to the suspension, then the mixture was reacted in a stream of nitrogen at a temperature of 140 C and for 14 h. The reaction mixture was diluted with 50 ml of methanol and filtered, then the filtrate was immediately dried to give a solid. 100 ml of ethyl acetate was added to the residue, and the mixture was washed with 50 ml of an aqueous solution of sodium hydroxide at pH 9. The ethyl acetate phase was washed with water and dried with anhydrous sodium sulfate to obtain 3.9 g of the oily 5- (p-methoxy-phenoxy) -2-methylpyridine.

The product thus obtained was subjected to oxidation in pyridine by means of selenium dioxide in the same manner as that described in Example 4, in order to obtain 1.8 g of crystals of 5- acid (p -methoxyphenoxy) picolinic.

Melting point: 170-172 'C.

Elementary analysis for CI3H,, 04N:

Calculated: C 63.67 H 4.49 N5.71%

Found: C 63.25 H 4.62 N 5.76%

Example 13:

4 g of a potassium salt of 5-hydroxy-2-methylpyridine, 5.2 g of o-bromochlorobenzene and 250 mg of copper powder were suspended in 10 ml of dimethylformamide, and the mixture was put in reaction in a stream of nitrogen at 115 ° C for 23 h and with stirring. The reaction mixture was diluted with 70 ml of methanol and filtered. The filtrate was then dried to give a solid, and 120 ml of chloroform was added to this residue. The mixture was washed with 70 ml of aqueous sodium hydroxide solution at pH 9. The solvent phase was washed with water, dried with anhydrous sodium sulfate and immediately dried to provide 2.8 g of oily 5- (o-chlorophenoxy) -2-methylpyridine.

The product thus obtained was subjected to oxidation in pyridine by means of selenium dioxide in the same manner as that described in Example 4, in order to provide 1.82 g of crystals of 5- (o- chlorophenoxy) picolinic.

Melting point: 178-179 ° C.

Elementary analysis for C12H803NC1:

Calculated: C 57.72 H 3.21 N 5.61 Cl 14.23%

. Found: C 57.67 H 3.15 N5.73 Cl 13.82%

Example 14:

4 g of a potassium salt of 5-hydroxy-2-methylpyridine were suspended in 10 ml of dimethylformamide and 6.15 g of p-bromobenzotrifiuoride and 500 mg of copper powder were added to the suspension, then the mixture was stirred in a stream of nitrogen at 125 C for 18 h to carry out the reaction. The reaction mixture was cooled, diluted with 50 ml of methanol and then filtered. The filtrate was immediately dried to give a solid, and 150 ml of chloroform and 100 ml of water were added to this residue. The resulting mixture was adjusted to pH 9.5 using 5N sodium hydroxide and the insolubles were removed again by filtration. The chloroform phase was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 5.6 g of the oily 5- (p-trifiuoromethylphenoxy) -2-methylpyridine.

The product thus obtained was subjected to oxidation in pyridine using selenium dioxide, in the same manner as that described in Example 4, to obtain 3.8 g of crystals of 5- (p- trifluoromethylphenoxy) picolinic.

Melting point: 150-151 ° C.

Elementary analysis for C13H803NF3:

Calculated: C 55.12 H 2.83 N4.95%

Found: C 54.63 H 3.02 N 4.81%

Example 15:

0.8 g of sodium hydroxide was added to a suspension of 4.63 g of 5- (3-chloropropoxy) picolinic acid in 180 ml of water,

then the mixture was stirred to obtain an aqueous solution of the sodium salt of 5- (3-chloropropoxy) picolinic acid. To this solution were added 20 ml of an aqueous solution containing 1.8 g of calcium acetate monohydrate to form a white precipitate. The precipitate thus formed was separated by filtration, washed with water and dried over phosphorus pentoxide to provide 4.7 g of a calcium salt of 5- (3-chloropropoxy) picolinic acid under the form of a white powder.

Melting point: above 220 C.

10 Elementary analysis for CQHI0O3NCl ■ l / 2Ca:

Calculated: C 45.86 H 4.25 N 5.94 Cl 15.07%

Found: C 44.72 H 4.31 N 5.73 Cl 14.25%

15 Example 16:

8.15 g of a potassium salt of 5-hydroxy-2-hydroxymethyl-pyridine were suspended in 120 ml of dimethylformamide, and 10.5 g of l, l, l-trifluoro-5-bromopentane were added with suspension, then the mixture was stirred at 65 ° C for 18 h to carry out the reaction. The reaction mixture was immediately concentrated to dryness, and 200 ml of chloroform and 200 ml of water were added to the residue to form two phases. The chloroform phase was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 12.83 g of a 5- (5,5,5-trifluoropentyloxy) -2-hydroxymethylpyridine syrup.

12.73 g of the product thus obtained were dissolved in 150 ml of a mixture of t-butanol and water (3: 1 by volume), and 110 ml of an aqueous solution containing 9.4 g of permanganate potassium were added dropwise to the mixture under ice and cooling over a period of 1.5 h. The reaction mixture was then stirred at 10-20 ° C for an additional 2 h, then filtered. The filter cake was washed with 150 ml of 50% warm aqueous methanol (adjusted to pH 10 using sodium hydroxide). The filtrate and the washing solution were combined, very concentrated to a volume of approximately 100 ml, adjusted to a pH of 1.5 using a solution of 5N aqueous hydrochloric acid and extracted with 200 ml of chloroform The chloroform phase was dried with anhydrous sodium sulphate, concentrated to a volume of approximately 20 ml, mixed with 30 ml of ethanol and left to stand at 40 low temperature to allow the formation of crystals, which were separated by filtration to provide 9.1 g of white crystals of 5- (5,5,5-trifluoropentyloxy) picolinic acid.

Melting point: 99-101 ° C.

Elementary analysis for Ct! H12N03F3:

Calculated: C 50.19 H 4.56 N 5.32 0 18.25 F 21.67%

Find: . C 49.92 H 4.67 N 5.19%

Example 17:

n / a 5 g of 5- (4-chlorobutoxy) picolinic acid were suspended in 30 ml of benzene, and 14 ml of thionyl chloride were added to the suspension, then the mixture was heated at reflux for 3 h. The reaction mixture was immediately concentrated to dryness, and 20 ml of benzene was added to the residue. The mixture was again dried to solidify and to remove hydrogen chloride and sulfurous acid gas formed as by-products, and thereby prepare an acid chloride of 5- (4-chlorobutoxy) acid. ) pico-linic (hydrochloride). The resulting acid chloride was dissolved in 40 ml of benzene, and the solution was added dropwise to 40 ml of a benzene solution containing 2.81 g of 5-hydroxyindane and 10.5 ml of triethylamine. under ice cooling and for a period of 15 min, with stirring. The reaction was then continued at 5-10? C for 2 h then at room temperature for 2 h. The reaction mixture was dried to solidify, and the residue was taken up in 200 ml of chloroform. The mixture was then washed successively with 50 ml of an aqueous hydrochloric acid solution at a pH of 3, with 50 ml of an aqueous alkaline solution at a pH of 9 and with 50 ml of distilled water. The chloroform phase was

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dried with anhydrous sodium sulfate, concentrated to dryness and recrystallized from a mixture of ethyl ether and hexane to yield 5.6 g of crystals of a 5- (4-chlorobutoxy) acid 5-indanyl ester -picolinic.

Melting point: 62-63 C.

Elementary analysis for C, qH2oN03C1:

Calculated: C 65.99 H 5.79 N 4.05 Cl 10.27%

Found: C 65.28 H 5.83 N 3.97 Cl 10.56%

Example 18:

1.5 g of 5- (p-chlorophenoxy) picolinic acid was dissolved in 40 ml of dried ethanol, and 0.15 ml of concentrated sulfuric acid was added to the solution, then the mixture was heated at reflux for 6 h. The reaction mixture was neutralized with sodium hydrogencarbonate and concentrated to dryness. The residue was dissolved in 50 ml of chloroform and washed with 30 ml of water, then the chloroform phase was discolored with a small amount of carbon powder, and immediately dried to solidify, then dissolved in ethyl ether and left to stand at low temperature to allow the formation of crystals. The crystals thus formed were separated by filtration to obtain 1.62 g of white crystals of an ethyl ether of 5- (p-chlorophenoxy) pico-linic acid.

Melting point: 75-76 C.

Elementary analysis for C14H12N03C1:

Calculated: C 60.54 H 4.32 N 5.05 Cl 12.79%

Found: C 60.42 H 4.51 N 5.13 Cl 13.02%

Example 19:

14 ml of 28% aqueous ammonia were added to 30 ml of a chloroform solution containing 2.37 g of 5- (o-trifluoromethylphenoxy) picolinic acid chloride (hydrochloride), and the mixture obtained was shaken vigorously for 2 h. The aqueous phase was removed, and the chloroform phase was washed with two 20 ml portions of water, dried with anhydrous sodium sulfate and concentrated to dryness to obtain a crystalline residue. Recrystallization from a mixture of ethanol and diethyl ether provided 2.1 g of white crystals of the amide of 5- (o-trifluoromethyl-phenoxy) picolinic acid.

Melting point: 137-138 ° C.

Elementary analysis for Ci5H12N03F3:

Calculated: C 57.88 H 3.86 N4.50 F 18.33%

Found: C 57.69 H 3.92 N 4.61%

Example 20:

1 g of 5- (p-chlorophenoxy) picolinic acid was dissolved in 20 ml of dimethylformamide and 1.22 g of α-pivaloyloxy-ethyl chloride and 1.12 ml of triethylamine were added to the solution, then the mixture was stirred at room temperature for 20 h. 3 ml of a water / ice mixture were added to the reaction mixture, which was left to stand for 1 h, then concentrated to dryness. 70 ml of ethyl acetate were added to the residue, and the mixture was washed successively with 40 ml of an aqueous solution of hydrochloric acid at pH 3, with 40 ml of an aqueous solution of sodium bicarbonate and with 40 ml of water. The ethyl acetate phase was dried with anhydrous sodium sulfate, dried to solidify and dissolved in 5 ml of diethyl ether. 10 ml of hexane were added to the solution, and the mixture was allowed to stand at low temperature to allow the product to crystallize. The crystals thus formed were separated by filtration in order to obtain 1.2 g of white crystals of an α-pivaloyloxyethyl ester of 5- (p-chlorophenoxy) picolinic acid. Melting point: 120-122 ° C.

Elementary analysis for C18H20NOSC1:

Calculated: C 59.10 H 5.47 N3.83 Cl 9.71%

Found: C 59.02 H 5.53 N 3.78 Cl 10.02%

Example 21:

10 ml of a dichloromethane solution containing 5- (o-chlorophenoxy) picolinic acid acid chloride (hydrochloride) were added dropwise to 20 ml of a dichloromethane solution containing 0.43 g of 5-hydroxyindane and 1.6 ml of triethylamine, under ice cooling and with stirring, over a period of 5 min. The reaction was continued at 0-5 C for 1 h, then at room temperature for 2 h. The reaction product was dried to solidify, then treated in the same manner as that described in Example 17 to obtain 1.32 g of white crystals of an indanyl ester of 5- (o -chlorophenoxy) picolinique.

Melting point: 100-102 C.

Elementary analysis for C2, H, 6N03C1:

Calculated: C 68.95 H 4.38 N 3.83 Cl 9.71%

Found: C 68.82 H 4.41 N 3.95 Cl 9.86%

Example 22:

1.3 g of the 5- (p-chlorophenoxy) pico-linic acid ethyl ester was dissolved in 6 ml of acetone, and 15 ml of 28% aqueous ammonia were added to the solution; the mixture was left to stand at room temperature for 23 h. The reaction mixture was cooled, and the precipitated crystals were separated by filtration and recrystallized from a mixture of ethanol and diethyl ether to obtain 1.1 g of 5- (p-chlorophenoxy) pico- acid amide crystals. linear.

Melting point: 173-174 "C.

Elementary analysis for C12H9N202C1:

Calculated: C 57.95 H 3.63 NI 1.27 Cl 14.29%

Found: C 58.02 H 3.71 N 11.25 Cl 14.18%

Example A:

3 g of 5-n-butyloxypicolinic acid were suspended in 30 ml of benzene and 8 ml of thionyl chloride were added to the suspension, then the mixture was stirred at 70 "C for 3 h. The solution The resulting solution was then concentrated to dryness, and 10 ml of benzene were added to the residue, then the solution obtained was concentrated to dryness. The addition of benzene (10 ml) and the dry concentration were repeated twice so removing hydrogen chloride and sulfur dioxide formed as by-products and, therefore, to form the acid chloride of 5-n-butyloxypicolinic acid (hydrochloride). The acid chloride thus obtained has was dissolved in 20 ml of benzene and the solution obtained was added dropwise to a solution of 2.1 g of 5-hydroxyindane, 7.7 ml of triethylamine and 30 ml of benzene, for 10 min under cooling with a mixture ice / water and stirring. The solution was then stirred for 1.5 h at 5-10 "C, then stirred further for ant 4 h at room temperature to complete the reaction. The reaction solution was then concentrated to dryness, and 100 ml of ethyl acetate were added to the residue, then the solution obtained was washed with 50 ml of a hydrochloric acid solution cooled to 5 C (pH 2 ) with 50 ml of an alkaline aqueous solution of sodium bicarbonate (pH 9) and with 50 ml of water, respectively. The ethyl acetate solution was dried over anhydrous sodium sulfate, then concentrated to dryness to obtain a crystalline residue. Recrystallization from di-ethyl / ether / hexane provided 4.5 g of crystals of the 5-indanyl ester of 5-n-butyloxypicolinic acid.

Melting point: 58-59 C.

Elementary analysis for C, 9H21N03:

Calculated: C 73.31 H 6.75 N 4.50%

Found: C 73.28 H 6.86 N 4.35%

For their clinical use, the compounds of formula I according to the invention can be administered orally in the form of tablets, capsules or dry syrup, usually used as vectors or excipients. These compounds I can also be administered

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very in the form of a subcutaneous injection. In this case, the derivatives having a high water solubility, for example the hydrochloride of the dimethylaminoethyl ester of 5- (4-chlorobutoxy) picolinic acid are used in an appropriate manner.

The compounds of formula I according to the invention can be used as active agent alone or in combination with one or more other physiologically active agents, more particularly with antihypertensive diuretic agents.

The amount of compound of formula I to be administered is between approximately 200 and approximately 500 mg / d in one or two doses.

Example 23:

Preparation of tablets

A granulation was prepared according to the following formulation:

65 parts 30 parts 5 parts in sufficient quantity

Lactose

Cereal starch

Polyvinylpyrrolidone

Water

This granulation was dried and sieved. Then the following ingredients were well mixed and compressed into tablets each weighing 250 mg and each containing 100 mg of the calcium salt.

5- (4-Chlorobutoxy) calcium picolinate Lactose granulation Magnesium stearate

100g

97.5 g 2.5 g

Example 24:

Preparation of capsules

The following ingredients were mixed and then introduced into standard clear gelatin capsules: 5 5- (5,5,5-Trifluoropentyloxy) calcium picoIinate 100 g Lactose 98 g

Magnesium stearate 2 g

The capsules obtained each contain 100 mg of the calcium salt per dosage unit.

All the compounds of formula I according to the invention exhibit antihypertensive activity by oral or non-oral administration and can be considered as useful pharmaceutical agents, as is apparent from Examples 25 and 26 below.

15 Example 25:

Each of the compounds of formula I indicated below were suspended in a 5% aqueous gum arabic solution and the suspension was administered orally (100 mg / kg) to groups formed by three spontaneously hypertensive rats (18 to 20 23 weeks of age; blood pressure before administration: 170-190 mmHg). The changes in blood pressure were determined by a direct method of measuring blood pressure, and the results obtained are shown in Table 1.

In addition, each of the test compounds was administered intraperitoneally to a male mouse 5 weeks of age (ICR breed) and the LD50 value was observed one week after administration, the results of acute toxicity being therefore also mentioned in table 1.

Table 1

Test compound

Chemical formula

Acute toxicity (LDS0) (mg / kg)

Maximum depression in the

blood pressure (%)

Fusarium acid c10h13no2

75-100

15.8

5-n-butoxypicolinic acid c10h13no3

100-150

16.6

5- (4-Chlorobutoxy) picolinic acid c10h12no3ci

150-200

23.0

5- (3-chloropropoxy) picolinic acid c9h10no3ci

150-200

18.2

5- (p-chlorophenoxy) picolinic acid c12h8no3ci

150-200

28.3

5- (p-methylphenoxy) picolinic acid c13h „no3

200-300

17.0

5- (p-amino-phenoxy) picolinic acid dihydrochloride

C12H10N2O3-2HCl

450-500

8.3

5- (m-trifluoromethylphenoxy) -picolinic acid c13h8no3f3

500-600

20.8

5- (p-bromophenoxy) picolinic acid

C12H8N03Br

150-200

27.5

5- (p-methoxyphenoxy) -picolinic acid c13h „no4

500-600

14.2

5- (m-chlorophenoxy) picolinic acid c12h8no3ci

300-400

16.7

5- (o-chlorophenoxy) picolinic acid c12h8no3ci

150-200

30.1

5- (p-acetylphenoxy) picolinic acid

C14HnN04

400-500

17.3

5- (p-trifluoromethylphenoxy) -picolinic acid c13h8no3f3

200-250

29.3

5- (2,4-Dimethylphenoxy) -picolinic acid c14h13no3

250-300

16.9

5- (o-trifluoromethylphenoxy) -picolinic acid c13h8no3f3

150-200

27.6

5- (2,4-Dimethoxyphenoxy) -picolinic acid c14h13nos

400-450

19.2

13

Table I (continued)

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Test compound

Chemical formula

Acute toxicity (LDS0) (mg / kg)

Maximum depression. in blood pressure (%)

5- (p-nitrophenoxy) picolinic acid ci2h8n2o5

500-600

15.1

Acid 5- (2,6-dichlorophenoxy) -

picolinique c12h7no3ci2

150-200

23.7

Acid 5- (2,4-ditrifluoromethylphenen-

oxy) picolinic c14h7no3f6

200-250

25.5

5- (2,4-Dichlorophenoxy) acid -

picolinique c12h7no3ci2

150-200

24.6

Acid 5- (5,5,5-trifluoropentyloxy) -

picolinic cmh12no3f 3

150-200

28.7

Acid calcium salt 5- (4-chloro-

butoxy) picolinic

C10H1INO3Cl- '/ 2Ca

800-1000

22.8

Acid calcium salt 5- (p-chloro-

phenoxy) picolinic

CI2H7N03C1- '/ 2Ca

350-400

23.5

Acid calcium salt 5- (5,5,5-tri-

fluoropentyloxy) picolinic

C1IHllN03F3 Vi Ca

800-900

26.9

Example 26:

Each of the compounds of formula I mentioned below were suspended in a 5% aqueous solution of gum arabic and the suspension was administered orally to groups of three spontaneously hypertensive rats (from 17 to 23 weeks of age;

30 blood pressure before administration: 170-190 mmHg). The changes in blood pressure were determined according to a method called Tail Cuff, and the results obtained are presented in Table 2.

Table 2

Depression

Dose (mg / kg)

maximum

Test compound in the

blood pressure (%)

5- (4-chlorobutoxy) picolinic acid indanyl ester

100

26.3

5- (4-Chlorobutoxy) picolinic acid amide

100

21.5

5- (p-chlorophenoxy) picolinic acid ethyl ester

100

. 23.3

5- (p-chlorophenoxy) picolinic acid indanyl ester

100

27.5

5- (p-Chlorophenoxy) acid a-pivaloyloxyethyl ester -

picnic

100

21.8

5- (p-chlorophenoxy) picolinic acid amide

100

23.7

5- (o-trifluoromethylphenoxy) picolinic acid indanyl ester

100

26.3

5- (o-trifluoromethylphenoxy) picolinic acid amide

100

20.7

5- (o-chlorophenoxy) picolinic acid indanyl ester

100

29.0

5- (o-chlorophenoxy) picolinic acid amide

100

19.6

The oral LD50 value of the free acids of formula I was 900 mg / kg for 5- (4-chlorobutoxy) picolinic acid and 400 to 600 mg / kg for 5- (p-chlorophenoxy) picolinic acid, for 5- (o-chlorophenoxy) picolinic acid and for 5- (o-trifiuoromethyl-phenoxy) picolinic acid. On the other hand, the respective oral LDS0 values of the indanylic, acyloxyalkyl esters and amide derivatives of the compounds of formula I have been found to be improved, and corresponded for example to 1600-1800 mg / kg for the indanyl ester of l 5- (4-chlorobutoxy) picolinic acid, at 700-800 mg / kg for the indanyl ester of 5- (p-chlorophenoxy) picolinic acid, at 900-1000 mg / kg for the a-pivaloyloxyethyl ester 5- (p-chlorophenoxy) picolinic acid, 1500-1600 mg / kg for the amide of 5- (4-chlorobutoxy) picolinic acid and 950 mg / kg for the amide of the acid 5- (o-trifluoromethylphenoxy) picolinic.

All the compounds of formula A according to the invention also exhibit a long-lasting hypertensive activity by administration

637,941

14

tion, and can be considered as pharmaceu- tive agents- groups of spontaneously hypertensive rats (from 15 to 20 weeks useful ticks, as shown in the example below. age; 3 rats per group; blood pressure before administration:

175-190 mmHg). The arterial blood pressure of concious SHR has

Example B: was recorded from the caudal artery via a trans-

Each of the compounds shown below was suspended in pressure transducer (Nihon Kohden MP-24T) on a recorder in an aqueous solution of 5% gum arabic gum containing graphics (Nihon Kohden RM-85).

2% Tween 80, and the suspension was administered orally to The results obtained are presented in Table 3.

Table 3

Test compound

Dose (mg / kg)

Maximum depression in blood pressure (%)

5-indanyl ester of 5-n-butyloxypicolinic acid

100

21.8

Fusaric acid * (control)

100

10.5

_ C. H

fY 9

Not a word

HOOC

The oral LDS0 value of fusaric acid (control) was 180 mg / kg, and the oral LD50 value of free acids 5-alkoxy- 30

picolinic such as 5-n-propyloxypicolinic acid and 5-n-butyloxypicolinic acid was 300 to 500 mg / kg. On the other hand, the value

Oral LDS0 of esters and 5-alkoxypicolinic acids was also improved, and corresponded for example to 800-1000 mg / kg with regard to the indanyl ester.

r

Claims (14)

637,941 1. Picicolinic acid substituted in position 5, as well as the salts, esters and amides thereof, represented by the general formula (I): (I) in which R represents a linear or branched C2 to C6 halogen substituted alkyl group or a substituted phenyl group of formula R3 '/ R, where r3 and r4, identical or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, an N-substituted amino amino group, a acylamino group, an acetyl group, an acyloxy group, a hydroxy group or a substituted alkyl halo group, or alternatively r3 and r4 represent, taken together, a polymethylenic chain; and r2 represents a group - om, where M represents a hydrogen atom, a sodium atom, a potassium atom, a calcium atom, an aluminum atom or a magnesium atom, or r2 represents a linear alkoxy group , branched or cyclic from Q to Cö, an aminoalkoxy group, a phenoxy group, a substituted phenoxy group, a 5-indanyloxy group, an acyloxyalkyloxy group of formula Rs I -o-chocor6 where rs represents a hydrogen atom or a methyl group and r6 represents a C1-C6 lower alkyl group, a phenyl group or a substituted phenyl group, or r2 represents an amino group of formula -NOT / \ r7 R " where R7 and Rs, identical or different, each represent a hydrogen atom, a lower alkyl group or a phenyl group. 2. Compound according to claim 1 represented by formula (II): MOOC in which R, is as defined for formula (I), and M represents a hydrogen atom, a sodium atom, a potassium atom, a calcium atom, an aluminum atom or a magnesium atom. 2 3. Compound according to claim 1 represented by formula (III): -GOLD, R201OC 4. 5- (4-Chlorobutoxy) picolinic acid and the salts thereof according to claim 1. 2o 5. 5- (3-Chloropropoxy) picölinic acid and the salts thereof according to claim 1. 6. 5- (5,5,5-Trifluoropentyloxy) picolinic acid and the salts thereof according to claim 1. 6 carbon atoms, aminoalkoxy group, phenoxy group, substituted phenoxy group, 5-indanyloxy group, acyloxyalkyloxy group of formula Rs i -o-chocor6 where r5 represents a hydrogen atom or a methyl group and re represents a lower C1-C6 alkyl group, a phenyl group or a substituted phenyl group or an amino group of formula -not / \ r, RR where R7 and R8, identical or different, each represent a hydrogen atom, a lower alkyl group or a phenyl group. 7. 5- (p-Chlorophenoxy) picolinic acid and the salts thereof according to claim 1. 8. 5- (o-Chlorophenoxy) picolinic acid and the salts thereof according to claim 1. 9. 5- (p-Trifluoromethylphenoxy) picolinic acid and the salts thereof according to claim 1. 30 10. 5- (o-trifluoromethylphenoxy) picolmic acid and the salts thereof according to claim 1, 11. 5- (4,4,4-Trifluorobutoxy) picolinic acid and the salts thereof according to claim 1. 12. Antihypertensive composition containing, as an active ingredient, a therapeutically effective amount of at least one picolinic acid substituted in position 5 or of a salt, ester, or amide thereof, represented by the formula general (I) according to claim 1. 13. Antihypertensive composition according to claim 12, ca-40 characterized by the fact that it contains, as active ingredient, a therapeutically effective amount of at least one picolinic acid substituted in position 5 or a salt thereof represented by the general formula (II), as defined in claim 2. 14. Antihypertensive composition according to claim 12, ca-45 characterized by the fact that it contains, as active ingredient, a therapeutically effective amount of at least one ester or amide of the picolinic acid substituted in position 5 represented by the general formula (III), as defined in claim 3. (") (III) in which R, is as defined for formula (I), and R20, represents a linear, branched or cyclic alkoxy group having from 1 to