DE2448036A1 - PYRIDYL ALKYLESTERS, THE METHOD OF MANUFACTURING THEIR PRODUCTS AND THE MEDICINAL PRODUCTS CONTAINING THEY - Google Patents

Description

Dr. Hans-Heinrich Willrath »- £££, i

Dr Dieter Weber Gust "v-Freyt.g-S" r "6eS5

Tx Γ7-1 C -CT -J. ® (06121) 37 27 M.

Dipl.-Phys. Klaus worries

PATENT LAWYERS _{Lß 4} ^ _-1

Astra-Bofors Nobelpharma Aktiebolag, S 151 85 Södertälje / Sweden

Pyridyl alkyl esters, processes for their preparation and pharmaceuticals containing them

Priority: October 24, 1973 in Sweden Note No .: 7314 402-4

The present invention relates to new compounds having a therapeutic effect and physiologically acceptable ones Salts of the same. The new compounds, which are pyridine derivatives of salicylic acid, have particularly advantageous ones Serum lipid concentration-lowering properties in combination with a very low level of side effects. The invention also relates to processes for the preparation of the compounds pharmaceutical preparations containing the compounds and a method of treating certain diseases by administering a therapeutically effective amount of a compound naqh der Jlrf.iiidxina in conjunction with a

ORIGINAL INSPECTED

! pharmaceutically acceptable carrier material.

The factors that cause arteriosclerosis and some other diseases cause in the vasculature are numerous and very complex. However, it seems perfectly clear that an increased serum lipid concentration is closely related to fundamental pathogenic mechanisms and that a reduction in the concentration of serum lipids has a positive effect on the treatment of such vascular diseases Has.

It has been found that nicotinic acid and some of its derivatives, which have been known for some time to be good have a dilating effect on the peripheral blood vessels, have a strong ability to increase the level of serum lipids, i.e. of cholesterol, phospholipids, triglycerides and free Fatty acids, reduce. However, this requires such high doses that side effects easily occur. One such side effect is the vasodilator effect, which is generally undesirable in this case and which is in the Form of blushing can be very bothersome.

As an example of these known compounds there can be mentioned the ester of salicylic acid and 3-hydroxymethylpyridine, which is described in British Patent 1,079,726 and has the following formula:

509820/1 107

< ^x >

This compound (hereinafter referred to as "I") possesses in addition to its good vasodilating properties, it is a very good effect in lowering the concentration of the Plasma cholesterol levels. In large dosages, however, which are necessary to raise the serum cholesterol level lower, the compound I causes severe flushing and also a high incidence of gastric destruction.

It has now surprisingly been found according to the invention, that compounds of the general formula

O-Q-R

wherein η denotes 1 or 2, R, when ή is 1, a branched one Alky! Group with 3 to 7 carbon atoms, the rest

Cl—

or the rest

(CH ₂ ) -

509820/1107

wherein ρ is O or 1, and R when η is 2 is one straight-chain or branched-chain alkyl group with 1 to 7 carbon atoms, the remainder

egg -

or the rest

he

wherein ρ can be 0 or 1 sain, and their physiological Compatible addition salts have a much more favorable ratio between the desired main effect, i.e. the Decrease in serum cholesterol, and its side effects, flushing and harmful effects on the stomach, own. Examples of compounds according to the invention are as follows:. '

00 - CH

OCO-C (CH ₃ ) ₂ 0 -

COO-CH

€ 0- (
50 98 20 / Π 07

COO-CH,

OCO

COO-CH ₂ CH

OCO

COO-CH,

OCO-CH,

COO-CH ₂ CH

OCO-C (CH

The following compounds represented by the above formula II are summarized, preferred compounds according to the invention are:

S ^ - (p-chlorophenoxy) -isobutyrylsalicylic acid-S-pyridylmethyl- «Ster of formula

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Acetylsalicylic acid S-pyridylethyl ester of the formula

COO-CH ₀ CH

nD

OCOCH

The new compounds according to the invention with the general my formula II can according to methods known per se be made like

a) _ by reacting a compound of the general formula

0-C-R

with a compound of the general formula

₂ ²

(I ¥ 3

where η and R have the above meanings and X is a carboxyl group or a functional derivative thereof, such as

_ * j - 509820/110?

functional group of a metal salt, an acid halide, an ester, an acid anhydride or mixed anhydride, and Y denotes a hydroxyl group, a halogen atom, an alkylsulfonyloxy group or arylsulfonyloxy group, or

b } by reacting a compound of the general formula

(V)

with a compound of the general formula

R-X (VI)

where R, η and X have the above meaning and Z is a hydrogen atom or an alkali metal or a quaternary Means ammonium ion. .

The compounds used as starting materials can be prepared by known methods.

The above-mentioned reactions can be carried out in aqueous or non-aqueous organic solvents will. In the case where the reaction between an acid halide and a hydroxyl compound is carried out, can the hydrogen halide, which is released during the reaction, with the help of a base, such as a tertiary amine,

for example pyridine or triethylamine, neutralized and the reaction can be catalyzed.

509820/1107

In clinical practice, the compounds of the present invention will normally be administered orally or by injection in the form of a pharmaceutical preparation, the active ingredient in the form of the original compound or optionally in the form of the free Base or a pharmaceutically acceptable salt thereof, usually in conjunction with a pharmaceutically acceptable one Comprises carrier material which is a solid, semi-solid or liquid diluent or an ingestible capsule may be, and such preparations constitute a further aspect of the invention. Usually the active substance makes 0.1 up to 99% by weight of the preparation, such as 0.5 to 20% for preparations for injection and 0.1 to 50% for preparations for oral administration.

In order to produce pharmaceutical preparations in the form of dosage units for oral administration which contain a compound according to the invention, the active ingredient can be mixed with a solid, powdery carrier material such as lactose, sucrose, sorbitol, mannitol, a starch such as potato starch, corn starch , Amylopectin, laminar powder or citrus pulp powder, a cellulose derivative or gelatin and also lubricants such as magnesium stearate or calcium stearate or a Carbowachs ^ ⁷ or other polyethylene glycol waxes and are compressed to form tablets or dragee cores. '' If coated tablets are required, the coated tablets can be coated, for example with concentrated sugar solutions,

509820/1107 " ⁹ "

containing gum arabic, talc and / or titanium dioxide
can, or instead with a varnish that comes in easily
volatile organic solvents or mixtures of organic solvents is dissolved. Can cover this
Dyes are added, such as to distinguish between different levels of active substance. For the production of soft gelatine capsules (pearl-shaped closed capsules), which are made from gelatine and

Jl "

wise consist of glycerine, or for the production of similar closed ones Capsules can contain the active substance with a

(R)
bowachs - to be mixed. Hard gelatin capsules can

Granules of the active substance with solid, powdery
Carrier materials such as lactose, sucrose, sorbitol, mannitol, starches. (Such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin
and also include magnesium stearate or stearic acid.

When using several layers of the active substance, which are separated from each other by slowly dissolving coatings
tablets are obtained with delayed release of active ingredient. Another way of producing tablets with delayed release of active ingredient is to distribute the dose of the active substance on granules with coatings of different thicknesses and to compress the granules together with the carrier substance to form tablets. The active substance can also be found in
Slowly dissolving tablets, which for example consist of fat and wax substances, can be incorporated, or they can be incorporated evenly in a tablet of an insoluble substance,

- Io -

5 09820/1107

like a physiologically inert plastic substance will.

Effervescent powders are made by mixing the active ingredient with non-toxic carbonates or hydrogen carbonates, such as calcium carbonate, potassium carbonate and potassium hydrogen carbonate, solid, non-toxic acids such as tartaric acid and citric acid, and for example flavorings produced.

Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, such as in the form of solutions containing about 0.1 to 20% by weight of active substance, sugar and a mixture of ethanol, Water, glycerin, propylene glycol and optionally flavoring, saccharin and / or carboxymethyl cellulose as dispersants contain.

For parenteral administration by injection, preparations can be an aqueous solution of a water-soluble, pharmaceutical compatible salt of the active acids according to the invention, expediently in a concentration of 0.5 to 10%, and optionally also comprise a stabilizing agent and / or a buffer substance in aqueous solution. Dosage units of the solution can advantageously be enclosed in ampoules.

Mineral acids, such as hydrochloric acid, for example, can be used as salt-forming agents. Sulfuric acid or phosphoric acid,

- 11 -

509820/1 107

or organic acids such as acetic acid, lactic acid, citric acid and various other acids that give physiologically acceptable addition salts can be used.

Administration by the oral route is primarily intended Administration form in clinical use.

The dosage used depends upon the individual requirements of each patient from, but the administration of from about 0.5 to 2 of the active substance may g three times daily as possible dosage at ⁰ therapeutic treatment of hypercholesterolemia in humans are viewed. This dosage is intended primarily for oral administration.

The invention is further explained below by means of exemplary embodiments. Except for the physical ones listed below and chemical characteristics, the NMR and IR spectra were also recorded for all end products. These spectra are in good agreement with the given structure.

example 1

<λ - (p-Chlorophenoxy) -isobutyrylsalicylic acid-3-pyridylmethyl ester

3-Fyridylmethyl salicylate (239 g) and triethylamine (104 g) were dissolved in 2.5 liters of toluene. The solution was cooled in an ice bath, and 239 g of ^ιΤ Χ- (p-chlorophenoxy) isobutyryl chloride were added with stirring over a period of three hours. The reaction mixture was stirred overnight at room temperature and finally refluxed for one hour. After the cooling

509820/1 10.7

244803S

len, the triethylamine hydrochloride that had formed was filtered off and the solution treated with activated charcoal, filtered and the solvent evaporated. The residue was recrystallized from ethyl ether to give 305 g (71%) of an almost white substance. Melting point: 83.5 to 84.5 ⁰ C.

Analysis; calc. 64.87% C, 4.73% H, 8.33% Cl, 3.29% N, found 65.0% C, 4.8% H, 8.4% Cl, 3.2% N.

Example 2
Pivalylsaltcylic acid-S-pyridylmethyl ester

24.1 g of pivalyl chloride were reacted with 45.8 g of 3-pyridylmethyl salicylate under the same conditions as given in Example 1. After the triethylamine chloride had been separated off, the reaction solution was washed twice with an aqueous solution of sodium hydrogen carbonate (1% strength) and then once with water and treated with activated charcoal and dried over magnesium sulfate. Evaporation of the solvent gave ~: a light brown oil, which was dissolved in 200 ml of dry ether. A product was precipitated by the dropwise addition of ether saturated with hydrochloric acid, which was recrystallized from 60 ml of dry acetone. The hydrochloride was shaken in 250 ml of dry benzene and neutralized with triethylamine. After the triethylamine hydrochloride had been separated off and evaporated in vacuo, 36.5 g (58%) of a pale yellow colored liquid were obtained, n ^ ² = 1.5382.

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Analysis: calc. 68.99% C, 6.11% H, 4.47% N, found. 69.1% C, 6.2% H, 4.5% N.

Example 3

Nicotinylsalicylic acid-3-pyridylmethylester'r

0.2 g of nicotinylsalicylic acid and 15 ml of thionyl chloride in 150 ml of dry benzene were left overnight at room temperature touched. Benzene and the excess thionyl chloride were evaporated in vacuo. Then benzene was added and the Evaporation repeated. The powdery residue was in 150 ml of dry pyridine was dissolved and cooled in an ice bath, followed by 3-pyridylmethanol (6 g) dropwise with stirring were added. The reaction mixture was allowed to reach room temperature and stand overnight. The pyridine was taking Evaporated in vacuo and the residue was poured into ice water. When neutralizing with sodium hydrogen carbonate ' solution separated an oil, which crystallized after cooling and separation. Recrystallization from 35 ml of toluene and 15 ml of ligroin gave 9 g (54%) of a white product. Melting point 74.5 to 75.5 ° C.

Analysis: calc. 68.26% C, 4.22% H, 8.38% N, found. 68.4% C, 4.3% H, 8.3% N.

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Example 4
Acetylsalicylic acid-S-pyridylethyl ester

To an ice-cold solution of acetylsalicylic acid chloride (9.5 g) in 100 ml of toluene was added dropwise while stirring Hour a solution of 3-pyridylethanol (5.9 g) and triethylamine (4.9 g) in 100 ml of toluene was added. Stirring was continued at room temperature overnight, after which the mixture was refluxed for one hour.

After cooling and separation of the precipitated 3-ethereal hydrochloride, the mixture was washed twice with sodium carbonate solution and finally with water. Drying over magnesium sulfate and evaporation of the solvent gave an oil which was dissolved in 175 ml of dry ether. The hydrochloride was precipitated with ether saturated with hydrochloric acid and carefully washed with ether. After dissolving in ice-cold water and neutralizing with sodium carbonate, the released base was extracted with ether. The ether solution was dried over magnesium sulfate and evaporated. A residue of 9 g (66%) of an almost colorless liquid was obtained. n £ ² = 1.5520.

Analysis: calc. 67, 36% C, 5.30% H, 4.91% N, found. 67.3% C, 5.2% H, 4.9% N.

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Example 5
S-pyridylacetylsalicylic acid-S-pyridylmethyl ester

75 g of 3-pyridyl acetic acid and 24 g of 3-pyridylmethyl salicylate in 500 ml of ethyl acetate were cooled to -25 ° C., after which a solution of 113 g of N, N ¹ -dicyclohexylcarbodiimide in 200 ml of ethyl acetate was added dropwise over one hour with stirring. After cooling for an additional four hours, the reaction mixture was allowed to reach room temperature overnight. The precipitate that had formed was separated and the solution was washed first with sodium hydrogen carbonate solution and then with water and then dried over magnesium sulfate, whereupon the solvent was evaporated. The remainder, a brownish oil, was mixed with a warm mixture of ethyl acetate and ligroin (1: 4). On cooling, a yellowish precipitate was obtained which, after recrystallization from ether, gave 31 g (49%) of a white product. Melting point 72.0 to 73.0 ° C.

Analysis: calc. 68.96% C, 4.63% H, 8.04% N. found. 68.8% C, 4.5%. H, 8.1% N.

The following examples illustrate how the compounds according to the invention are incorporated into pharmaceutical preparations can be.

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Example 6

Manufacture of soft gelatin capsules

500 g Ο <* - (p-Chlorophenoxy) -isobutyrylsalicylic acid-S-pyridylmethyl ester were mixed with 500 g of corn oil, after which the mixture was filled into soft gelatin capsules, each Capsule 500 ml of the mixture, (i.e. 250 mg of the active substance) contained.

φ, -

Example 7

Manufacture of soft gelatin capsules

500 g of 3-pyridylethyl acetylsalicylate were mixed with 750 g Peanut oil mixed, after which the mixture was filled into soft gelatin capsules, each capsule 500 mg of the mixture (i.e. 200 mg of active substance).

Example 8

Manufacture of tablets

5 kg ^ - (p-ChlorophenoxyJ-isobutyrylsalicylic acid-S-pyridylmethyl ester were mixed with 2 kg of silicon dioxide with the trade name Aerosil, after which 4.5 kg of potato starch and 5 kg Lactose were mixed in and the mixture was moistened with a starch paste made from 0.5 kg of potato starch and distilled water, after which the mixture was granulated through a sieve. The granules were dried and sieved, after which 0.2 kg of magnesium stearate was added became. Finally the mixture was made into tablets

he

presses "each weighing 699 mg.

Example 9

Making an emulsion

100 g of S-pyridylethyl acetylsalicylate were dissolved in 2500 g of peanut oil. An emulsion was prepared from the solution obtained in this way , 90 g of gum arabic, flavor and color (qs) and 2500 g of water.

Example 10

Making a syrup

100 g of ζΧ - (p-chlorophenoxy) -isobutyrylsalicylic acid 3-pyridylmethyl ester were dissolved in 300 g of 95% ethanol, after which 300 g of glycerin, flavor and color (q.s.) and 1000 ml of water were added. Such a syrup was obtained.

Example 11

Production of effervescent tablets

100 g of 'jÄ-tp-chlorophenoxyJ-isobutyrylsalicylic acid-S-pyridylmethyl ester, 140 g powdered citric acid, 100 g powdered sodium hydrogen carbonate, 3.5 g magnesium stearate and flavor (q.s.) were mixed, and the mixture was compressed into tablets, each containing 200 mg of active substance. ■

- 18 509820/1107

Example 12 Production of tablets with delayed release of active ingredients

200 g of acetylic acid 3-pyridylethyl ester were together with 50 g of stearic acid and 50 g of carnauba wax melted. That The mixture obtained in this way was cooled and ground to a particle size of at most 1 mm. The mass thus obtained was mixed with 5 g magnesium stearate and made into tablets, each weighing 610 mg. Each tablet thus contained 400 mg of active substance.

Pharmacological experiments The pharmacological effect of the compounds was determined according to the

evaluated using the following test methods:

Decrease in plasma cholesterol

Female rats weighing 160 to 190 g was starved for 2.5 days causing mild hypercholesterolemia. During this time, the animal received 5 times with a probe test compositions consisting of suspensions of the various substances to be examined in 1 t aqueous solutions of the sodium salt of carboxymethyl cellulose (CMC-Na) passed. A control group of Rats received the appropriate treatment using CMC-Na alone. Two hours after the last application. At the same time, plasma was removed for analysis of the total cholesterol content. The amount of test substance administered was 100 mg / kg for each administration. Five to ten

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Rats were examined per group. As comparison substances were nicotinic acid, Perycit ^ (Pentaerythrltoltetranikotlnat) and the compound "I" given above is used. The results are shown in Table I below. The decrease in plasma cholesterol was expressed as a percentage of the Calculated plasma cholesterol level in the control group.

Side effect; Blushing in guinea pigs The test substances were administered to starving white guinea pigs with a probe at a dose of 10 mg / kg. With HlkotineSure, this dose usually results in a flushing reaction in the ears and in sharks of guinea pigs. The test preparations were administered to the animals under coded names. The latitude of the reddening reaction was assessed under Verveaiiüse 94Bd ¹ point acela rait 0, 1/2, 1, 2 and 3 points every five minutes. These readings during one hour were added together. Twelve army pigs were tested per connection. The side effects of the compounds examined in the development of blushing were rated on the following scale:

+++ corresponds to 288 - 432 points «severe blushing ¹

++ "- 144 - 287 V .. - ..- ■ moderate flushing

+ ^M - 72 - 143 "- moderate flush

O "- O - 71" * no blushing

The number of animals / which showed blushing was also determined on the basis of the criterion that blushing was assumed if the animal followed at least three consecutively

- 2o -5 0 9 8 2 0/1107

2U8036

Readings gave at least one point on the scale used.

The results are shown in Table I below.

Side effect with salicylate-containing compounds: gastric irritation This test was carried out according to G.Aberg and KSLarsson, Acta Pharmacol.

• κ

et Toxicol., 1970, 28, p. 249. Starving rats received suspensions with a volume of 0.5 ml / 100 g body weight administered via a probe. The administered Dose of each substance was 100 mg / kg, and the suspensions were in the form of 1% aqueous solutions of CMC-Na manufactured. Three hours after the administration of the substance the animals were killed and their stomachs were with a Stereomicroscope examined, whereby the occurrence of small bleeding micro-destructions was observed. At least ten animals each group were examined, and the result was expressed as the number of guinea pigs with gastric disruptions. This experiment shows the irritative effect of salicylate-containing compounds on the stomach, with nicotinic acid or esters

Tr)

the same, like Perycit ^v - ^/ , do not result in gastric injuries under these conditions. CMC-Na, salicylic acid, acetylsalicylic acid and the above-mentioned compound "I" were used as comparison substances in the investigation. The results are shown in Table II below.

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Reduction of the
Plasma cholesterol 35 ^± 8 2448036; 11/12 +++ % (Middle
+ Deviation) 35 ± 9 9/12 ++ - 21 - Comparison substances 54 i 6 Reddening effect 9/12 ++ Tabel ] Nicotinic acid • Blush Pentaerythritol
tetranicotinate 50-10 Number of Frequency Bewer
used tung
animals 3/12 + Z Il TlI 50 ± 11 0/12 0 Lowering plasma cholesterol levels and Connection after
Example no. 35th ± 7th 10 7/12 + Test substance 1 10 4th 10 2 10 5 5

Table II
Side effects: stomach irritation

Test substance frequency of guinea pigs

with affected areas in the stomach

Comparative substances

CMC-Na 2/25

Salicylic acid 23/25

Acetylsalicylic acid 22/25

"I" 9/10

Connection according to example no.

1 6/18

3 509 8 20/1107 ⁵ / l5

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" ²² " 2U8036

It is clear from the tables that the new compounds according to the invention have a very good gholesterol level have a lowering effect, while at the same time causing side effects to a degree that is clearly below that of known compounds.

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Claims (9)

Claims I. Pyridyl alkyl esters of the general formula O-C-R wherein η is 1 or 2 and when h is 1, R is a branched one Alky! Group with 3 to 7 carbon atoms, the rest or the. rest wherein ρ is O or 1, and R, when η is 2, is a straight-chain or branched alkyl group having 1 to 7 carbon atoms, the remainder Cl- o-c-CH or the rest - 24 - 509820/1 107 2U8036 wherein ρ is 0 or 1, and their physiologically acceptable acid addition salts. 2. o * \ - (p-Chlorophenoxy) -isobutyrylsalicylic acid-S-pyridylmethyl ester of the formula COO- - Cl OCO-C (CH ₃ ) ₂ -0 and its physiologically compatible acid addition salts, 3. 3-pyridylmethyl pivalylsalicylic acid ester of the formula COO-CH, OCO-C (CH ₃ ) and its physiologically compatible acid addition salts, 4. Nicotinylsalicylic acid pyridylmethyl ester of the formula OCO - 25 - 509820/1 107 ~ ^2S ~ and its physiologically compatible acid addition salts, 5. Acetylsalicylic acid S-pyridylethyl ester of the formula and its physiologically acceptable acid addition salts. 6. S-pyridylacetylsalicylic acid-S-pyridylmethyl ester of the formula COO-CH OCO-CH ₂ and its physiologically acceptable acid addition salts. 7. ⁰ ^ - (p-Chlorophenoxy) -isobutyrylsalicylic acid-S-pyridylethyl ester of the formula COO-CH ₂ CH ^ 'OCO-C (CH ₃ ) ₂ -o - ^ / and its physiologically acceptable acid addition salts. - 26 - 509820/1 107 .. ₂₆ - 2U8036 8. Process for the preparation of pyridyl alkyl esters according to Claim 1 to 7, characterized in that one a) a compound of the general formula -X '■ · 1 TJ r ■ · with a compound of the general formula Y- (CH ₂ ) _n where η and R have the above meanings, X is a carboxyl group or a functional derivative thereof and Y represents a hydroxyl group, a halogen atom, an alkylsulfonyloxy group or is an arylsulfonyloxy group or b) a compound of the general formula with a compound of the general formula R-X, where R, η and X have the above meanings and Z is a Means hydrogen atom, an alkali metal or a quaternary ammonium ion, and - 27 · 509820/1107 optionally converting the bases obtained according to a) or b) into their physiologically acceptable acid addition salts convicted. 9. Medicaments containing at least one pyridyl alkyl ester according to claim 1 to 7, preferably in combination with a pharmaceutically acceptable carrier material, 5 0 9 8 20/1 1 07 ^: