DE2015265A1 - Arylalkanoic acids and processes for their preparation - Google Patents

Description

I ΜΪΕ NTAiJWRUE

DR.E.WIEGAND DIPL-ING. W. NIEMANN

DR. M. KÖHLER DIPL-ING. C. GERNHARDT 2015 265

MDNCHEN HAMBURG

SSSOi 8ΰοΰ Manche 15, -351 March 1970

TELEGRAMS: KARPATENT N USSBAUMSTRASSE IO

¥. 14 753/70 13 / never

Yoshitomi Pharmaceutical Industries ltd. Osaka (Japan)

Arylalkanoic acids and processes for their preparation

The invention relates to novel and therapeutically valuable 2-arylalkanoic acids.

The novel 2-arylalkanoic acids according to the invention are compounds of the general formula below

R-CHCOOH

■■)% 9 S 4 1 /; SQ R

where A is the group CO or CH _? , R is hydrogen or a lower alkyl group (eg CH ,, C ^ *) and X is hydrogen, a lower alkyl group (eg CH ,, C ₂ Hr) or a halogen (eg F, Cl), as well as their pharmaceutically acceptable acid addition salts. The 2-arylalkanoic acids of formula (I) and their pharmaceutically acceptable acid addition salts are useful, for example, as analgesics, anti-inflammatory drugs and anti-inflammatory agents.

The invention also provides procedures for the preparation of such new and useful 2-arylalkanoic acids and their salts created.

According to the invention, the compounds are prepared by one of the following procedures:

1. By hydrolysis of compounds of the formula

wherein Y is a CN _T CONH ₀ -, COOR ¹ - (wherein R 'is lower alkyl), or any a: \ dera fiiriktionalle group COOH to hydrolysis .-:, t represents · -.- ^ ri and A and X and R the V5rs ";« hen ^ ■ ^ ■ ^ ::;.:; =: ^< b'ii: ^ have meaning «

2. By hydrolysis of amides or thioamides, which after the Willgerodt-Kindler reaction from a Compound of formula

(III)

were manufactured.

3. By ring closure of a compound of the general formula below

COOH

R.
, CHCOOH

(IV)

The hydrolysis in procedures (1) and (2) is carried out in a solvent (e.g. water, aqueous methanol, aqueous dioxane) in the presence of an acid (e.g. sulfuric acid, hydrochloric acid) or an alkali (e.g. sodium hydroxide, Potassium hydroxide) carried out under reflux.

The Willgerodt-Kindler reaction in Arbeitswei se (2) is advantageously carried out with sulfur and morpholine at the reflux temperature of morpholine for 10 to 20 hours.

009841/1985

The ring closure, ie the condensation in procedure (3), is carried out in a solvent (e.g. benzene, nitrobenzene, dichloroethane, carbon disulfide) in the presence of a condensing agent (e.g. polyphosphoric acid, phosphoric anhydride, sulfuric acid, aluminum chloride, acetic anhydride, hydrochloric acid, boron trifluoride) at about 20 ⁰ C up to about 150 ⁰ C carried out. (The compounds of the general formula (I) in which R is a lower alkyl radical can also be prepared from the compounds of the general formula (I) in which R is hydrogen by customary alkylation.)

The compounds of formula (I) can usually into the corresponding acid addition salts with various inorganic or organic bases, e.g. Na, K, Ca, Mg, Ag, ammonium, triethylamine, diethylamine, Morpholine, piperazine and other derivatives.

The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof are analgesic and anti-inflammatory effects as shown, for example, by the following experiments in which the alphabetical designations A to D each represent the following compounds:

A: 9-0xoxanthen-2-yl-acetic acid

B: aluminum salt of 9-0xoxanthen-2-yl-acetic acid

C: 2- (9-0xoxanthen-2-yl) propionic acid

D: xanthene-2-y ! -Acetic acid

00M41 / 19IS

Anti-inflammatory effect: (Carregisnin-Edema method)

The experiment was essentially similar to that of Charles A, Winter et al. in Proceedings of the Society for Experimental Biology and Medicine, Vol. 111, pp. 544-547 (1962) carried out the procedure described. This was a 1% aqueous solution of Garraghenin (0.05 ml) subcutaneously into the hind paw of a Donryu rat (male, about 130 g) indicated. The experimental ver Binding was in a 1 ^ igen aqueous solution of poly Sorbat- 80 suspended and the suspension (5.ml/ 200 g Body weight) was administered orally 1 hour before the injection of carraghenin. The paw volume was measured after 3 hours and the increase in this volume as a percentage of control experiments was observed · The Results are shown in Table I below.

Table I ■ '.: Compound dose (mg / kg) per os inhibition (%)

A. 25th
50
100 32.7
41.6
50.6 B. 25th
50
100 26th
40
44 C. 50
100 23
30th D. 50
100 31
46 Metiadic acid 50
100
250 - 12
20th
21

0098 ~ 41/1985

Analgesic effect (chemical stimulation method):

The experiment was carried out according to the method described by LC Hedershot et al. in Journal of Pharmacology and Experimental Therapeutics, Vol. 125, pp. 237-240 (1959). A 0.02 % aqueous solution of benzoquinone (0.2 ml / 20 g body weight) was injected intraperitoneally into a dd mouse (male, about 20 g). The test compound was suspended in a 1% aqueous solution of polysorbate 80, and the suspension (0.1 ml / 10 g body weight) was administered orally 1 hour before the injection of benzoquinone. The EDc _Q value was determined as the dose containing the cumulative number of. . Twitches

(cumulative number of writhing) decreased to 50% for 30 min. The results are summarized in Table II below:

Table II g body weight) link ED ₅₀ (mg / k A. . 95 ■ B 110 C. 66 D. 220 aspirin 270

Acute toxicity (LD ^ ₀ ) of> 0x, oxaathen «2-yl-acetic acid is as given in Table III.

'ÖG3Ö41 / 1385

Table III

Animal: WistejvRatte dd mouse

Administration

chungsweg \ gender: male. female male

orally 1600 1650 > 640 subcutaneous 860 800 > 320 intraperi- toneal 540 540 > 320

009841/1985

With regard to the various investigations,

including those described above, the compounds of general formula (I) according to the invention and their pharmaceutically acceptable addition salts

τ- j 4 τ. ι α α. · ν .Analr ^ eticum reliable and safe as anti-inflammatory and anti-inflammatory drugs Agents as such or in the form of a pharmaceutical composition in admixture with one suitable and conventional carrier or adjuvant, orally, percutaneously or by injection without harm to the host or recipient (host).

The pharmaceutical compositions can or the like in the form of tablets, granules, powders, capsules. for oral administration, in the form of injectable solutions for subcutaneous or intramuscular administration or in the form of creams, ointments, gels or gels, suppositories or the like. for topical administration. The choice of carrier will depend on the preferred form administration, solubility of the compound and standard pharmaceutical practice.

Examples of compositions are given below, wherein a compound according to the invention for for pharmaceutical purposes.

(A) 25 mg capsules are made from the following composition :

Compound (I) (e.g. Compound A) 5o mg lactones 61 mg

Corn starch 61 mg

Methyl cellulose 1.5 mg

Magnesium sterate 1 ig

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(B) 50 mg capsules are made from the following composition manufactured: ■

Compound (I) (e.g. Compound B) 50 mg

Lactose 83rag

Corn starch 83 mg

Methyl cellulose -2 mg

Magnesium stearate 2 mg

(0) 25 mg tablets are made from the following composition manufactured:

Compound (I) (e.g. Compound G) 25 mg Lactose 75 »5 mg

Corn starch 12 rag

(Mow ^X 7 mg

Methyl cellulose 1.5 mg

IaIk 3.3 mg

Magnesium stearate 0.7 mg

The usual daily dose of the compound (I) or its salt is in the range of about 75 to 700 mg, in particular about 300 to 600 mg per adult.

The invention is illustrated below by way of examples explained in more detail:

Example 1 .

To a solution of 10 g of sodium hydroxide in 100 ml Ethanol plus 50 ml of water will produce 30 g of 9 ^ oxoxanthen-2-yl ~ acetonitrile added, and the mixture is for 8 hours. held at reflux. The ethanol is distilled off, and the residue is dissolved in 500 ml of water, the solution becomes

009841/1985

treated with activated charcoal, whereupon hydrochloric acid is added to give 10 g of 9-oxanthen-2-yl-acetic acid in the form of crystals with a melting point of 213 "to 216 ° 0.

To a solution of 3.5 g of 9-oxoxauthen-2-ylacetic acid in 100 ml of hot isopropanol, a solution of 2.82 g of aluminum isopropoxide in 30 ml of isopropyl alcohol given. After refluxing for 1 hour, the white crystals are collected and treated with isopropanol. wash, the aluminum salt of 9-0xoxanthen-2-yl- "acetic acid with a melting point of above 300 ° C is obtained.

Example 2

27 g of ethyl 9-oxaxanthen-2-yl acetate are added to a solution of 5 g of sodium hydroxide in 30 ml of water and 70 ml of ethanol, and the mixture is refluxed for one hour. The ethanol is distilled off and the resulting crystalline sodium salt is dissolved in about 200 ml of water. The solution is loaded with activated charcoal. acts, whereupon hydrochloric acid is added to obtain a precipitate, which is recrystallized from aqueous ethanol, 20 g of pale yellow crystals of 9-oxoxanthene-2-jrl-acetic acid ι
can be obtained.

Example 3

2-jrl-acetic acid with a melting point of 215 to 217 ° C

A mixture of 3 g of p ~ (o-carboxyphenoxy) phenylacetic acid and 30 g of polyphosphoric acid are heated at 70 ° C. for 3 hours with stirring. The reaction disagreement

009841/1985

is poured into ice water, and the precipitate is collected, washed with water and recrystallized from aqueous dioxane, wherein 1.3 g of white crystals of 9-oxoxanthen-2-yl-acetic acid with a melting point 217 "to 219 ° O can be obtained.

Example .4

A mixture of 13 g of 2-acetylxanthene, 3.2 g Sulfur and 34 ml of morpholine are refluxed in a nitrogen atmosphere for 18 hours; about half of the morpholine is distilled off, whereupon 100 ml of ethanol are added in the residue. Be there 8 g of crude g-oxoxanthene ^ -yl-thioacetomorpholide as Precipitation received.

A mixture of 2.5 g of the crude 9-0xoxanthen-2-ylthioacetomorpholids, 4 g of potassium hydroxide and 50 ml of ethanol are in a nitrogen atmosphere for 16 hours. held under reflux. The ethanol is distilled off, the residue is dissolved in water, the solution is with Treated activated carbon, whereupon hydrochloric acid is added. The precipitate is recrystallized from ethyl acetate, whereby 0.7 g of xanthen-2-yl-acetic acid with a melting point 189 to 190 ° 0 can be obtained.

Example 5

A mixture of 7 »5 g of ethyl a- (9-oxoxanthen-2-yl) propionate, 40 ml of ethanol, 1.3 g of sodium hydroxide and. 10 ml of water is heated at 60 to 270 ° C for one hour. After concentration, the residue is dissolved in water

009841/1985

dissolved, the solution treated with activated charcoal, whereupon hydrochloric acid is added. The precipitate is recrystallized from aqueous ethanol, 5 »35 g of α- (9-oxoxanthen-2-yl) propionic acid having a melting point of ^{165 °> is} 165 ° C. are obtained.

Example 6

Sodium amide is made in situ from a 50 ml liquid Ammonium and 1.6 g of metallic sodium are produced. To this 7.6 g of 9-oxoxanthen-2-yl-acetic acid are added. After stirring the mixture for 30 minutes, a mixture of 4.3 g of methyl iodide and 20 ml of ether is added dropwise in Added over a period of 30 minutes. Stirring is continued until the ammonia has completely evaporated, followed by water is added to the reaction mixture. The resulting mixture is treated with activated carbon, and then becomes Hydrochloric acid added. The precipitate is uracrystallized from aqueous ethanol, with 2 g of α- (9-oxoxanthen-2-yl) propionic acid with a melting point of 163 to 165 ° 0 can be obtained.

Examples 7 and 8

Using the procedures of Examples 1 to 6, but using equivalent amounts of other suitable starting materials , 8-methyl-9-oxoxanthene ε-yl-acylic acid having a melting point of 217 to 219 ° C and e-chlorine - ^ - oxoxanthen ^ -yl-acetic acid with a melting point of 239 to 241 ° C also produced.

Specific examples of the preparation of the starting materials of the general formulas (XI) ₁ (III) and (IT) are given below , for example:

009841/1985

2015 285

(II): a) To a solution of 25 g of potassium cyanite in 100 ml Water is 93 g of 2-bromomethyl-9-oxoxanthene, which is obtained by reacting 2-methyl-9-oxoxanthene with N-bromosuccinimide had been prepared, 1000 ml of dioxane and 100 ml of dimethylformamide added, and the mixture is heated with stirring. The reaction mixture will be in a large amount Poured water. The precipitate is collected by filtration, washed with water, dried and made from a Recrystallized mixture of ethyl acetate and dioxane, 60 g of 2-gyanmethyl-9-oxoxanthene having a melting point at 173 to 176 ° C. can be obtained.

b) Sodium amide is produced in situ from 150 ml of liquid ammonia and 1.27 g of metallic sodium. For this Hg ethyl 9-oxoxanthen2-yl acetate are given. After stirring the mixture for 1 hour, 100 ml of toluene is added and stirring is continued, whereby the ammonia is evaporated. Then 8 g of methyl iodide added gradually at 25-30 ° C. The resulting The mixture is kept at 30 ° for 5 hours and then left to stand overnight. Water is added, and the toluene layer is separated and dried. The toluene is distilled off, with 9 g of ethyl α- (9-0xoxanthen-2-yl) propionate in the form of an oil (n '£ = 1.6058).

(III): 33 g of anhydrous aluminum chloride are added in portions to a solution of 20 g of xanthene in 200 ml of tetrachloroethane plus 11.2 g of acetic anhydride while stirring. The entire mixture is kept at 20 to 25 ° C. for 4 hours and then poured into ice water. The tetrachloroethane is from the organic layer

009841/198 5

-H-

distilled off, and the residue is distilled, 10 g of 2-acetylxanthene having a boiling point of 170 to 180 ° C can be obtained.

(IV): A mixture of 48 g of methyl o- (p-tolyloxy) benzoate, 37 g N-bromosucciniraide, 0.5 g benzoyl peroxide and 200 ml Carbon tetrachloride is refluxed for 4 hours. After cooling it becomes the insoluble substance filtered off, and the solvent is distilled off, | wherein 66 g of crude methyl o- (p-bromomethylphenoxy) benzoate can be obtained.

To a solution of 17 »5 g of sodium cyanide in 30 ml 300 ml of dioxane, 50 ml of DenKthylformamid and water 66 g of said methyl o- (p-bromomethylphenoxy) benzoate and the mixture is heated with stirring for 4 hours. The reaction mixture is in a large Poured amount of water. After extraction with benzene, washing with water, drying and concentration, 50 g of methyl (p-cyanomethylphenoxy) benzoate are obtained with a boiling point of 210 to 220 ° 0 / 0.1 mmHg.

E ± ß Mixture of 5g of said methyl o- (pcyanmethylphenoxy) benzoate, 20 ml of concentrated hydrochloric acid and 30 ml of glacial acetic acid are refluxed for 3 hours. The reaction mixture is concentrated. The crystals obtained are recrystallized from aqueous acetic acid, 3 g of p- (o-0arboxyphenoxy) -pheny} .- acetic acid with a melting point of 172 to 175 ° C.

009841/1985

Claims (8)

- ₁₅ - Claims / T / Arylalkanoic acids of the general formula , X wherein A is the group CO or CHg, R is hydrogen or one lower alkyl radical and X hydrogen, a lower one Are alkyl or halogen, and their pharmaceutically acceptable salts. 2. 9-0xoxanthen-2-yl-acetic acid. 3. Aluminum salt of S-oxoxanthene-^ -yl acetic acid. 4 x 2- (9-0xoxanthen-2-yl) propionic acid. 5. Xanthen-2-yl-acetic acid. 6. A pharmaceutical composition consisting essentially of a therapeutically effective amount of a The arylalkanoic acid of claim 1 and a pharmaceutically acceptable inert carrier therefor. 7. Process for the preparation of arylalkanoic acids according to Claim 1, characterized in that compounds of the general formula 009 841/198 5 hydrolyzed, wherein Y is a functional group hydrolyzable to COOH, nB CN, CONH ₂ , COO-lower alkyl, CS-N (R ¹ ) (R ² ) '' -N (R ¹ ) (R ² ), namely an Arno- or substituted amino group, for example morpholino group. Or the like. and X, A and R are as defined above. 8. A process for preparing arylalkanoic acids according to claim 1, characterized in that compounds of the following formula is subjected to a ring closure, wherein X and R are as defined above ι _v -Λ — T BATH ORIGINAL 009841/1985