SE446863B - 5-SUBSTITUTED PICOLIC ACID DERIVATIVES, PROCEDURE FOR PREPARING THEREOF AND USING THE COMPOUNDS AS ACTIVE INGREDIENT IN AN ANTI-HYPERTENSIVE COMPOSITION - Google Patents

Description

446 863 patent application no. 838 180, filed September 30, 1977).

It has now been found that the compounds of the present invention finning has an antihypertensive activity that is comparable or superior to the 5-alkoxypicolinic acids in the Japanese patnntnnsükan no. 116641/1976 and lower toxicity than 5-alkoxy- the picolic acids according to Japanese application no. ll664l / 1976 and therefore, the compounds of the invention are useful for treatment of hypertension.

According to the invention, a new group of antihypertensive agents is provided. siva means.

An object of the present invention is to provide a new group of antihypertensive agents that are less toxic than The 5-alkoxypicolinic acids but comparable or superior to these regarding antihypertensive activity.

A further object of the invention is to provide a new process for the preparation of these antihypertensives siva means.

Thus, the present invention relates to 5-substituted picoline 'acid derivatives illustrated by formula (I): \ RZOC N wherein R 1 represents 4-chlorobutoxy, 3-chloropropoxy or 5,5,5-tri- fluoropentyloxy; and R 2 represents a -OM group, wherein M represents- hydrogen, sodium, potassium, calcium, aluminum or magnesium . ZR7. or an amino group of the formula -N -, wherein R7 and R8, R. 8 which may be the same or different, each denoting hydrogen, lower alkyl or phenyl. 446 863 The compounds illustrated by formula (II-a): \ (II-a) HOOC N wherein R1 has the meaning given above, can be prepared by a compound of formula (IV): / ou (IV) \ _ | 9 l wherein R 9 represents methyl or hydroxymethyl, may react with a R halide of formula (V): X (V) wherein R 1 is as defined above and X represents a halogen atom, in an organic solvent such as dimethylformamide, dimethyl sulfoxide, dimethylacetamide and the like in the presence of a inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate or the like or an organic base such as triethylamine, 1,1-dimethylaniline and similar to a compound illustrated by formula (VI): f oral IN \ N (V1) Rs » wherein R 9 and R 11 are as defined above.

This substitution reaction takes place selectively in the hydroxy group in the 5-position and no reaction of the -CH 2 OH group or bi- production of pyridinium salts is observed under the conditions according to the invention. This reaction takes place easily at a temperature between about 30-100 ° C and is completed in relatively short time such as about 1-20 hours.

The compounds of formula (II-a) according to the invention may prepared by oxidizing the intermediate described above 446 863 4 the product of formula (VI) using an oxidizing agent agents such as potassium permanganate, chromium anhydride, selenium dioxide, nitric acid, potassium bichromate or the like in a solution agents such as acetone, dioxane, pyridine, aqueous acetone, aqueous t-butanol, sulfuric acid and the like. Any impurities formed during the reaction can be easily removed by Solvent extraction, precipitation, crystallization or the like procedures. The reaction conditions for the oxidation varies with the type of oxidizing agent used and R9 the group in the compound of formula (VI). When the R9 group is one hydroxymethyl group are the reaction conditions for the oxidation in generally mild. When, for example, the compound of formula (VI) has a hydroxymethyl group as the R9 group is oxidized with potassium permanganate and uses about 1-2 moles of potassium permanganate per mol of compound of formula (VI) and the reaction time and reaction the temperature is about 5-20 ° C resp. 2-20 hours. When you oxidizes a compound of formula (VI) with a methyl group such as R9 group with potassium permanganate requires about 2-4 moles potassium permanganate per mole of the compound of formula (VI) at a reaction temperature of about 80-100 ° C and a reaction temperature time of about 4-10 hours. When a compound of formula (VI) with a methyl group such as R9 group is oxidized with chroman hydride approximately 2.5-3.5 moles of chroman hydride are used per mole of compound gene of formula (VI) in the presence of sulfuric acid in a reaction temperature of about 30-70 ° C and a reaction time of about 4-10 hours. When selenium dioxide was used as the oxidizing agent the oxidation reaction is carried out in the presence of pyridine in a amount of about 1.8-2.5 moles of selenium dioxide per mole of the compound of formula (VI) at reaction temperatures of about 100- 120 ° C for a reaction time of about 5-10 hours.

The 5-substituted picolinic acids obtained above can easily transferred to pharmaceutically acceptable salts thereof such as calcium salts, sodium salts, aluminum salts; magnesium sal- and potassium alterl The present invention relates to a further method of preparation of a 5-substituted picolinic acid ester or amide 446 865 illustrated by formula (III): / -ORI \ i R2010C N (III) wherein R1 has the meaning given above and Rzol represents one _ R. amino group of the formula -N '' '/, 7, wherein R7 and R8, which can Rs be the same or different, each denoting hydrogen, lower alkyl or phenyl, which is characterized by allowing a 5-substituent row of picolinic acid or a metal salt thereof illustrated / '-OR \ Û 1 MOOC N of formula (II): (II) wherein R 1 has the meaning given above and M represents a hydrogen atom (such as sodium, potassium, calcium, aluminum or magnesium) react with an amine of formula (XI): , * R7 \ Rs HN (X1) wherein R 7 and R 8 are as defined above in the presence of a acid catalyst or a condensing agent.

Alternatively, the compounds of formula (III) may be prepared by an acid halide of a 5-substituted picolinic acid illustrated by formula (XIII): / -ORI \ I XOC N (XIII) 446 863 wherein R 1 has the meaning given above and X represents a halogen atom, which is obtained by a 5-substituted picolinic acid illustrated by formula (II) may react with an acid halide reagent, is reacted with an amine of formula (XI): / R7 HN wherein R 7 and R 8 are as defined above, in the presence of a base.

The amide derivatives of the 5-substituted picolinic acid can be prepared by substituting 5-substituted picolinic acid of formula (II) is reacted with an amine of formula (XI) in an organic solution condensing agent in the presence of a condensing agent such as hexylcarbodiimide or the like or by reaction between a acid halide of a 5-substituted picolinic acid of the formula (XIII) with an amide of formula (XI) in a solvent such as methylene chloride, ethyl ether, chloroform, dioxane and the like.

The amide derivatives of the formula (III-b): R \ '(III-b) 7 \. \ Foc _ N R8 "r wherein R 1, R 7 and R 8 are as defined above, may also is prepared by adding the 5-substituted picolinic acid with formula (III-a): / '-OR - 1 lisïš fl (III-a) RZOZOC N wherein R1 has the meaning given above and RZOZ represents a straight, h branched or cyclic alkoxy group having 1-6 carbon atoms, an amino alkoxy group, a phenoxy group, a 5-indanyloxy group or a 446 865 acyloxyalkoxy group of the formula R , 5 -O-CHOCOR6 wherein R 5 represents a hydrogen atom or a methyl group and R 6 represents represents a lower alkyl group having 1-6 carbon atoms, a phenyl group or a substituted phenyl group is reacted with an amine with formula (XI) with or without a suitable solvent.

The present invention also relates to the use of a therapeutic economically effective amount of at least one 5-substituted pico- folic acid derivatives of formula (I) as described above, as active constituent of an antihypertensive composition.

The invention is further illustrated by the following examples, wherein the temperatures refer to degrees Celsius. Unless otherwise stated percent, parts, ratios and the like are calculated by weight.

Example 1 4.86 g of potassium salt of 5-hydroxy-2-hydroxymethylpyridine suspension was dissolved in 80 ml of dimethylformamide and 5.7 g of tetramethylene chloride and 1 g of potassium carbonate was added to the suspension, followed by stirring at 700 took place for 15 hours to effect reaction. Reactive The mixture was concentrated to dryness and to the residue. it was added 150 ml each of ethyl acetate and water to give of two layers. The ethyl acetate layer was separated and dried with anhydrous sodium sulphate, after which the to 5.4 g of a syrup of 5- (4-chlorobutoxy) -2-hydrogens roximethylpyridine. The unreacted material was found to remain in the water layer. 446 863 4.1 g of the product thus obtained were dissolved in a mixed solution. 35 ml of t-butanol and 12 ml of water and 30 ml of a aqueous solution containing 3.5 g of potassium permanganate tes dropwise to it for one hour. The reaction continued to further with a temperature of 5 - 1000 for 2 hours during stirring. The reaction mixture and the filter cake were washed with 50 ml warm 50% aqueous methanol solution (adjusted to pH 10 with sodium hydroxide). The filtrate and the washing product was combined, the mixture was concentrated to a volume of for 30 ml and the solvent was distilled off. The resulting the aqueous layer was adjusted to pH 1.5 with SN hydrochloric acid and extra was treated with 50 ml of chloroform. The chloroform layer was dried with water. sodium sulfate and concentrated to a volume of danger 3 ml. 10 ml of ethanol was then added to the concentrate and the mixture was allowed to stand at low temperature and the product crystallized was lysed. The crystals thus obtained were separated by filtration. and gave 3.5 g of white crystals of 5- (4-chlorobutoxy) pico- linic acid. melting point = 96 - 91 ° C.

Elemental analysis for C 10 H 12 N 3 NCl: C H 5 N O Cl Calculated (%): 52.29 5.23 6.10 29.92 15.47 Found (%): 52.18 5.92 6.15 15.32 Example 2, 4.3 g of potassium salt of 5-hydroxy-2-hydroxymethylpyridine suspension was dissolved in 50 ml of dimethyl sulfoxide and 4.4 g of 1,3-dichloropropane and 500 g of potassium carbonate were added to the suspension, after which the was carried out at 60 ° C for 10 hours to effect reaction.

The reaction mixture was concentrated to dryness and 100 ml each of chloroform and water were added to the residue formation of two layers. The chloroform layer was separated, dried with anhydrous sodium sulfate and concentrated immediately to dryness and gave 4.5 g of a syrup of 5- (3-chloropropoxy) -2-hydro- 446 863 roximethylpyridine.

The product thus obtained was oxidized in 50 ml of 70% aqueous containing acctone with potassium permanganate in the same manner as described Example 1 gives 3.7 g of white crystals of 5- (3-chloropro- poxy) picolinic acid. melting point = 120 - 121 ° c.

Elemental analysis for C H O NCl: 9 10 3 C H N 0 Cl Calculated (%) 1 50.12 4.64 6.50 22.27 16.47 Found (%) = 50.07 4.72 6.58 16.33 Exemgel 3 0.8 g of sodium hydroxide was added to a suspension of 4.63 g 5- (3-chlorophenoxy) picolinic acid in 180 ml of water, after which stirred until an aqueous solution of the sodium salt was obtained 5- (chloropropoxy) picolic acid. To this solution was added 20 ml of an aqueous solution containing 1.8 g of calcium acetate monohydrate to form a white precipitate. It so formed the precipitate was separated by filtration, washed with water and dried over phosphorus pentoxide to give 4.7 g of a calcium salt of 5- (3-chloropropoxy) picolinic acid as a white powder. melting point = above 22 ° C Elemental analysis of C 9 H 10 O 3 NCl-1 / 2Ca: C H N Cl Calculated (%): 45.86 4.25 5.94 15.07 Found (%). 44.72 4.31 5.73 14.25 Exemgel 4 8.15 g of potassium salt of 5-hydroxy-2-hydroxymethylpyridine suspension was dissolved in 120 ml of dimethylformamide and 10.5 g of 1,1,1-trifluoro-5- 446 865 l0 bromopentane was added to the suspension, then stirred in > at 65 ° C for 18 hours to effect reaction. Reactional the mixture was immediately concentrated to dryness and 200 ml of each chloroform and water were added to the residue to give of two layers. The chloroform layer was washed with water, dry with anhydrous sodium sulfate and immediately gave the dry 12.83 g of a syrup of 5- (5,5,5-trifluoropentyloxy) -2-hydro roximethylpyridine. 12.73 g of the product thus obtained were dissolved in 150 ml of a mixed solvent system of t-butanol-water (3: 1 calculated on the volume) and 110 ml of an aqueous solution containing 9.4 g of potassium permanganate were added dropwise thereto ice cooling over a period of 1.5 hours. Reaction mixture The mixture was further stirred at 10-20 ° C for a further 2 hours and filtered. The filter cake was washed with 150 ml of a hot 50% aqueous methanol solution (adjusted to pH 10 with sodium hydroxide). The filtrate and the washing product were combined, concentrated to a volume of approximately 100 ml, adjusted to pH 1.5 with 5N aqueous hydrochloric acid solution and extract was prepared with 200 ml of chloroform. The chloroform layer was dried with water. free sodium sulfate, concentrated to a volume of approx. for 20 ml, mixed with 30 ml of ethanol and allowed to stand at low temperature to form crystals, which were separated by filtration to give 9.1 g of white crystals of 5- (5,5,5-trifluoro- pentoxy) picolic acid. melting point = 99-110 ° C Elemental analysis for C 11 H 12 NO 3 F 3: C H N O -.F Calculated (%) (%): 50.19 4.56 5r32 49.92, 4.67 5.19 18.25 21.67 Found Example §_ 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, after which, refluxing took place for 3 hours. The reaction mixture was 446 863 11 was immediately concentrated to dryness and 20 ml of benzene was added to the remainder. The mixture was dried again to solidify to remove by-produced hydrochloric acid and sulfuric acid-containing gas and thereby gave an acid chloride of 5- (4-chlorobutoxy) picolinic acid (hydrochloride). The resulting acid chloride was dissolved in 40 ml 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 triethyl amine under ice-cooling over a period of 15 hours with stirring ning. The reaction was further continued at 5-10 ° C for 2 hours and then at room temperature for 2 hours. The reaction mixture dried to solidify and the residue was taken up in 200 ml of chloro- The mixture was washed successively with 50 ml each of one aqueous hydrochloric acid solution at pH 3, an aqueous alkali solution at pH 9 and distilled water. The chloroform layer is dry. with anhydrous sodium sulfate, concentrated to dryness and recrystallized from a mixed solvent of ethyl ether and hexane to give 5.6 g of crystals of 5-indanyl ester of 5- (4-chlorobutoxy) picolinic acid. melting point = 62 - 63 ° c Elemental analysis for C 19 H 20 NO 3 Cl: C H N Cl Calculated (%) 65.99 5.79 4.05 10.27 found (sa = 65.28 5.83 3.97 10.56 n The compounds of the present invention may at clinical use is administered orally in the form of tablets, capsules or dry syrup, commonly used as vehicles. Before- The ions can also be administered in the form of a subcutaneous injection.

In this case, derivatives with increased water solubility are suitably used. tet, e.g. a dimethylaminoethyl ester of 5- (4-chlorobutoxy) Pik ° 1in ' acid hydrochloride.

The compounds of the present invention may be used as single active agent or in combination with one or more others: physiologically active agents, especially diuretic antihypertensives average. .. -..___ -.-__-___ m fi -... s-aw-í. 446 863 12 The dosage amount of the compounds of the present invention is about 200-500 mg in one or two doses per day.

Example 6 The composition in this example is a tablet. A granulate produced by: Lactose 65 parts Corn starch 30 parts Polyvinylpyrrolidone 5 parts Water A sufficient amount The granules were dried and sieved. The following ingredients then mixed well together and pressed into tablets. weighing 250 mg containing 100 mg of the calcium salt.

Calcium 5- (4-chlorobutoxy) picolinate 100 g Lactose granules 97.5 g Magnesium stearate 2.5 g Example 7 The composition in this example is a capsule. The following stock parts were mixed and then introduced into clear gelatin capsules.

Calcium 5- (5,5,5-trifluoropentyloxy) picolinate 100 g Lactose 98 g Magnesium stearate 2 g The capsules obtained contained 100 mg of the calcium salt per dosage unit.

All compounds of the present invention as illustrated made of formula (I) above has an antihypertensive activity at oral or non-oral administration and may be considered useful as pharmaceuticals as shown in Examples 25 and 26 below.

Example 8_ Each of the compounds of the invention listed below was suspended in a 5% aqueous gum arabic solution and the suspension was administered orally (100 mg / kg) to group 13 446 865 per consisting of 3 spontaneously hypertensive rats (18-23 weeks old; blood pressure before administration): 170 ~ 190 mm fl g). Blood- the pressure changes were determined according to a direct E1od pressure ~ measurement method and the results obtained are shown in Table 1 below.

Each of the test compounds in was administered intraperitoneally. tonally to male mice (ICR strain, 5 weeks old) and The LD5 value was observed one week after administration and 0 the results in acute toxicity are also shown in Table 1 below.

TABLE 1 Maximum acute: widow Chemically dissolved bioa- Test pre-formula (LD50) pressure k 0 FLlSâISyrâ (mg / g) (o) <5 ~ butylpik ° linic acid) ec10H13No2 15-100 15.8 s- -b '- ~ 1' - _ S- (4-chlorobutoxy) - c H No cz 150-200 23.0 picolic acid 10 12 3 5- (3-kl ° rpr0p0Xi> - c9H10N0.cz 150-200 1s.z picolic acid J S ~ (S, S, S-tr1f1u0r- cllnlzmosvs 1s0-200 zs.7 pentyloxy) picolic acid Calcium salt of 5 '(4' C10H11NO3Cß- 800-1000 22.8 chlorobutoxy) picoline- ¿Approx syra ' Calcium salt of 5- (5 s s- c H No-P-- 000-900 26.9 trifluorpentyloxiï-,, ¿àå ll J ° z picolic acid 446 863 14 Example 9 J Each of the compounds of the invention listed below was suspended in a 5% aqueous gum arabic. solution and the suspension was administered orally to groups persistent spontaneously hypertensive rats (17 - 23 weeks old; blood pressure before administration: 170-190 mmHg). Blood pressure the changes were determined according to the tail cuff method (Tail Cuff Method) and the results obtained are shown in Table 2 below.

TABLE 2 Maximum lowering of blood Test compound Dose pressure '_' - (mg / kg) (%) 5- (fl-chlorobutaxi) picoli fi syraamia 1oo 21, s The oral LD50 value for the free acids according to the present invention the invention was 900 mg / kg for 5- (4-chlorobutoxy) picolinic acid. On the other hand, the oral LD50 value for amide The derivatives of the present invention for example 1500-1600 mg / kg for the 5- (4-chlorobutoxy) picolinic acid amide.

All the compounds of the present invention as illustrated in made of formula A above has a long-lasting antihypertensive activity during oral administration and may be considered pharmaceuticals as indicated in the following cleaning example.

Claims (3)

446 863 CLAIMS 1. 5-Substituted picolinic acids, salts and acid amides thereof, characterized in that they have the formula = '(I) R 2 O N wherein R 1 represents 4-chlorobutoxy, 3-chloropropoxy or 5,5,5-tri- fluoropentyloxy; and R 2 represents a -OM group, wherein M represents hydrogen, sodium, potassium, calcium, aluminum or magnesium - RV or an amino group of the formula -Nf 7, wherein R 7 and R 8, as R 8 may be the same or different, each represents hydrogen, lower alkyl or phenyl. Process, characterized in that a) for the preparation of 5-substituted picolinic acids of the formula (II-a): 1 'I ORI \ 1 HOOC N (II-a) wherein R1 represents 4-chlorobutoxy, 3-chloropropoxy or 5,5,5-trifluoropentyloxy, a compound of formula (IV): reacted with a halide of formula (V) wherein R 9 represents methyl or hydroxymethyl ; RX (V) 446 863 IG wherein R1 has the meaning given above and X represents halogen, to a compound of formula (VI): / -OR 1 - RN 9 wherein R1 and R9 have the meaning given above, and that the compound of formula (VI ) is oxidized with an oxidizing agent; or b) for the preparation of a 5-substituted picolinic acid amide of formula (III): - '| wherein R 1 has the meaning given above and R 20 represents an _ /, f R 7 amino group of the formula -N _ \ _, wherein R 7 and R 8, which may be - R 8 are the same or different, each represents hydrogen, lower alkyl or R 20 ° C phenyl, is given a 5-substituted picolinic acid or a metal salt thereof of the formula (II): Ûm fl (II) \ MOOC N wherein R 1 has the meaning given above and M represents hydrogen, sodium, potassium, calcium, aluminum or .magnesium, react with an amine of formula (XI): m1 / (xx) 446 863 I? wherein R 7 and R 5 are as defined above, in the presence of an acid catalyst or a condensing agent, or c) for the preparation of a 5-substituted picolinic acid amide of the formula (III): / -ORI \ I (III) R 20 above, an acid halide of a 5-substituted picolinic acid of formula (XIII) is obtained: _ / -fdR1 Wherein X 1 is as defined above and X is halogen, reacting with an amine of formula (XI): R 7 HN <(XI) Ra wherein R 7 and R 8 are as defined above, in the presence of a base , or d) for the preparation of a 5-substituted picolinic acid amide of the formula (III-b): "I / -oR1 R7 \ | (III-b) / NOC N Rs wherein R a 5-substituted picoline ester of the formula (III-a): 446 865 (III-a) R 2 D 2 OC N wherein R 1 is as defined above and R 2 O 2 represents a straight or branched chain or cyclic alkoxy group having 1 to 6 carbon atoms, aminoalkoxy, phenoxy, 5-indanyloxy or acyloxyalkyloxy of the formula: ifs -O-CHOCOR6 wherein R5 represents hydrogen or methyl and R6 represents lower alkyl having 1-6 carbon atoms, phenyl or substituted phenyl, react with an amine of formula (XI) : Rv /. Cxn wherein R7 and R8 have the meanings given above. Use of a therapeutically effective amount of at least one 5-substituted picolinic acid, a salt or an acid amide thereof of formula (I): (I) wherein R 1 represents 4-chlorobutoxy, 3-chloropropoxy or 5,5,5-tri - fluoropentyloxy; and R 2 represents a -OM - group, wherein M represents hydrogen, sodium, potassium, calcium, aluminum or magnesium R7, wherein R7 and R8, as or an amino group of the formula -N ::: - 'R 8 1,' J: 446 863 lq may be the same or different, each representing hydrogen, lower alkyl or phenyl; as an active ingredient in an antihypertensive composition. ._..-. » v-o-vnnuwnaw-v-