FI56680C - FOERFARANDE FOER FRAMSTAELLNING AV NYA THERAPEUTIC DISEASE INDOLYLATEXYRADERIVAT - Google Patents

Description

ΓΒ1 (111 NOTICE cccfift JRSi A (11) UTLÄGGN I NGSSKRIFT bOOCU

* WX C Patent .ayönrc tty 10 Λ3 1930 • (45) Patent meddelat> s— (51) Kv.ik. ’/ Int.ci. * C 0? D 209/26 C 07 D 411/06 C 07 H 405/06 FINLAND-FINLAND (21) Patent application - Patentansöicnlng 2036/71 (22) Application cloud —Anseknlngsdag 22.07.71 (23) Initial line — GUtlghetadag 22.07.71 (41) to the public - Bllvlt offentllg 01.02.7 2

Patent and Registry Administrators ..... . . .....

* (441 Date of issue and of issue |

Patent- och registerstyrelsen '' Ansökan utlagd och utl.skrlften publlcerad · ± χ '1 y w (32) (33) (31) Pyydetty etuoikeus — Begird prlorltet 31.07 · 70

Hungary-Hungary (HU) CI-1017 (71) Chinoin Pharmaceuticals and Chemicals Gyra Rt., T6 utca 1-5,

Budapest, Hungary-Hungary (HU) (72) Gäza T <5th, Budapest, Gäbor Szabo, Budapest, György Eibel, Budapest,

Eva Somfai, Budapest, Hungary-Hungary (HU) (74) Oy Kolster Ab (5 ^) Method for the preparation of new therapeutically active indolylacetic acid derivatives - Förfarande för framställning av nya therapeutiskt verksamma indolylätiksyraderivat

The invention relates to a process for the preparation of therapeutically active indolyl acetic acid derivatives of the formula 3?

Ev ^ .CHgCOOR

XXX »,

R

wherein R is a nitro-substituted furylcarbonyl group or a haloacyl-thiazol-U-ylcarbonyl group, R is a lower alkyl group, R is 3. . ...

a hydrogen atom or a lower alkyl group and R is a lower alkoxy group, and to prepare salts thereof.

The invention is characterized in that a compound prepared by direct acylation of hydrazine or hydrazone obtained by treatment with an oxo compound obtained from 2 S66O0 a) an arylhydrazine or a derivative thereof has the formula wherein R and R have the same meaning as above and R 1 represents two hydrogen atoms or alkylidene groups, is reacted with a compound of formula r 1 -co-ch 2 -ch 2 -coqr 2 (III). 1.2 wherein R and R are as defined above, and the free acid is, if desired, liberated from the compound obtained, or b) cyclizing a compound of formula R3 I CH2-CH2-COOH (IV) N-N = C-R1

R

1.3. . ...

wherein R, R and R are as defined above, or ^ c) a compound of formula χχ ^ 1-NH-SO 3 H (V)

R

O

wherein R and RJ are as defined above, are reacted with a compound of formula (HI), and the resulting compound is desalted or desalted, if desired.

The products according to the invention can be used as active ingredients in anti-inflammatory, analgesic, antipyretic or anti-calcifying pharmaceutical preparations.

3% 6680

A preferred embodiment of the process according to the invention is provided by option a), which, in addition to its simplicity and economy, has the advantage of providing intermediates which are easily isolated or can be immediately added to the indole synthesis and which as such are active compounds.

The process now developed for the preparation of N1-acyl-N4-arylhydrazines can be obtained from acetone, isopropylidene-2 having special properties. . ....

the group is used as a protecting group for the N atom.

2. . . . ....

This offers the following advantages: N-isopropylidene-arylhydrazine can be prepared simply and easily on an industrial scale, without distinguishing between readily degradable and difficult-to-handle by-products, making selective N1-acylation possible under simple conditions; it is suitable as such for indole synthesis; it can be easily exchanged for other oxo compounds suitable for indole synthesis; it can be immediately added to indole synthesis.

After N1-acylation, the compound can be converted to N4- (acyl) -N4- (aryl) -hydrazine or its hydrochloride in a simple manner by removing the isopropylidene group - without damaging the N1-acyl group.

Ring closure of N1-substituted phenylhydrazones is caused to occur under mild conditions, even at room temperature, and this results in a significant increase in yield.

Most arylhydrazines - and thus also p-methoxyphenylhydrazine - are fairly readily degradable compounds, so the desired intermediates can only be prepared in a very complex manner due to their separation and the hydrazone formed from the separated product. It has now been found that after hydrolysis of sodium p-methoxyphenylhydrazine sulfonic acids in an aqueous hydrochloric acid medium and subsequent neutralization of the reaction mixture with soda solution, the hydrazone can be obtained by adding the appropriate oxo compound, acetone, from an aqueous ethanol solution. If the hydrazone thus obtained is dissolved in a suitable solvent, the N1 acylation can be performed immediately after drying the solution.

Acetone-N1-acyl-N1-arylhydrazone obtained by treating the reaction mixture is also immediately useful in indole synthesis.

A further advantage of this method is that the isopropylidene group can be removed after acylation simply by adding aqueous hydrochloric acid to the reaction mixture, and using N, acyl-N-arylhydrazine hydrochloride can be obtained using a polar solvent.

The desired N-acylindole-3-acetic acid derivative can either be prepared. ... 1 L of the immediately obtained N-acyl-N-aryl-hydrazine hydrochloride or the desired N-acyl-indole-3-acetic acid derivative is prepared from the hydrochloride-liberated N1-acyl-N "* -arylhydrazine.

*. * 6680

The invention further relates to novel compounds of the formula I which have not yet been described in the chemical literature and are therefore to be regarded as novel. These compounds can be used as such or as their organotropic salts, tablets, granules, capsules, suppositories, powder mixtures, emulsions, suspensions, etc. parenterally, orally or rectally.

Certain representatives of these compounds may be used in veterinary medicine, e.g. for the prophylactic administration of animal diseases when administered in a Premix compound feed.

Therapeutic experiments:

The test compounds were: A = 1- (5-nitro-2-furoyl) -2-methyl-5-methoxyindolyl-3-acetic acid B = 1- (2-bromo-H-thiazolylcarbonyl) -2-methyl-5 -methoxyindolyl-3-acetic acid C = 1- (2-chloro-1,4-thiazolylcarbonyl) -2-methyl-5-methoxyindolyl-3-acetic acid D = 1- (2-furoyl ) -2-methyl-5-methoxyindolyl-3-acetic acid (known from FI patent Vf63 ^ I. Toxicity

Toxicity was studied in mice of both sexes weighing 22-25 g. Test compounds were administered orally to experimental animals and mortality was observed within 2 hours. 5 mice were used per dose. The LD 2 value was determined according to Behrens' formula. The results were: Compound LD ^ 0 mg / kg A> 1000 B> 1000 C 750 D (known) 975 II. Anti-inflammatory effect a) Inhibition of kaolin edema

The experiments were performed on female rats (weight 110-130 g) that had not been fed for 2b hours. 0.1 ml of a 5 ~ # kaolin suspension was injected into the sole of the right hind leg and the change in thigh circumference was measured after two and five hours. The test compound was administered orally to a group of 10 experimental animals 60 minutes before kaolin injection. The difference in leg circumference between control animals and test substance-treated animals is a measure of the inhibitory effect. Significance was calculated by Student's t test. Only significant values were considered.

Compound B produced 18 5? Inhibition at 100 mg / kg (significant). Compound C produced a $ 23 inhibition at a dose of 50 mg / kg (significant). The known commercially available anti-inflammatory agent sodium salicylate is ineffective 56680 at a dose of 50 mg / kg.

b) Prevention of carrageenan edema

The experiments were performed on female rats (110-130 g) that had not been fed for 2 h. 0.1 ml of a 0.5 / l carrageenan suspension was injected into the sole of the right hind leg and the change in thigh circumference was measured. Like kaolin, carrageenan caused considerable swelling in the thigh.

The results of the experiment were evaluated in the same way as in the kaolin experiment. The results were: Compound Dose mg / kg Inhibition%

^ C 100 18, U

D (known) 50 29.9

The lowest effective dose of sodium salicylate is 100 mg / kg.

c) Ptmpuligranuloma

The experiments were performed on male rats (10-10 g). One sterile cotton ball of 25 mg was placed subcutaneously in the back of the experimental animals under ether anesthesia on the honor side of the spine. Experimental animals were treated daily with the test compound. For each dose, 10-10 animals were used, with each group having a control animal that was not given the test substance. The animal's body forms cartilage around the spheres, while anti-inflammatory agents prevent this cartilage formation. Experimental animals were sacrificed after 8 days »Significance was calculated by Student's t test. Results were Compound Dose mg / kg Inhibition% C 100 18.1+ D (known) 50 28.8 sodium salicylate 100 29 d) UV erythema

The experiments were performed on female and male Albino guinea pigs (i + 00-600 g). The back of the experimental animals was depilated and after 2k hours the back was exposed to UV radiation for 3 1/2 minutes. The skin becomes inflamed at the site of irradiation and the inflammation is usually at its strongest after 2 hours. The intensity of the change was marked with different score values and the differences between the control group and the studied ai-. . Between the groups treated with 2 were evaluated by X test. Test compounds were administered orally and 10 experimental animals were used for each dose. Significant inhibitory values were

Compound Dose mg / kg Inhibition% C 100 33 D (known) 100 59.7 III. Antipyretic effect

The experiments were performed on female rats (130-150 g). The body temperature of the animals was measured from the rectum »The experimental animals were given subcutaneously 20- $ 6,56680 yeast suspensions. After 17 hours, a marked increase in body temperature was observed. The test substance was administered to the animals other than the control group, and after 60 minutes, the decrease in body temperature was measured.

The significant antipyretic doses obtained were:

Compound Dose mg / kg C 50 D (known) 25 IV. Alleviation of pain caused by inflammation

The experiments were performed on female rats (60-80 g) using the Randall-Selito method. The control animals were given 0.1 ml of 5 ~ # yeast suspension on the soles of the feet of the right hind leg. Under the influence of yeast, the foot becomes depressed. The reduction in tenderness was measured with a prescribed device and the numbing effect of pain was evaluated. Compound C produced a remarkable analgesic effect at a dose of 50 mg / kg administered via Summer.

The following examples are provided to illustrate the invention.

Example 1 80 g of suction filtration wet acetone (p-methoxyphenyl) hydrazone were dissolved in 700 ml of a 1: 1 mixture of benzene and toluene, dried over sodium sulfate, filtered and the filtrate was washed with 50 ml of benzene. After cooling the solution to 0 ° C, 10 ml of pyridine was added, then 87.5 ml (0.5 mol) of 5-nitro-2-furancarboxylic acid chloride were added dropwise at 0-5 ° C. After stirring for 30 minutes, the separated pyridine hydrochloride was filtered off, the solvent phase was washed with water and then shaken with 160 ml of 6N hydrochloric acid. The separated material was suction filtered, washed with benzene, then dissolved in water and neutralized with sodium carbonate. After the separated N- [5- (nitro-2-furoyl) -N- (5-nitro-2-furoyl) -N- (p-methoxy-phenyl) -hydrazine was filtered off with suction, it was washed with water. Yield: 67.5 g Melting point: 163-166 ° C.

A mixture of 5.1 g (0.162 g mol) of N- (5-nitro-2-furyl) -N- (p-methoxyphenyl) hydrazine, 160 ml of acetic acid, 27.8 ml of levulinic acid and - 2.8 ml of concentrated sulfuric acid were heated for one and a half hours at 80-85 ° C. After cooling, it was diluted with 158 ml of water, and the resulting 1- (5-nitro-2-furoyl) -2-methyl-5-methoxyindol-3-ylacetic acid was recrystallized from ethanol. Yield: 35.8 g, m.p .: 183-18 [deg.] C., 62% based on M - [- (5-nitro-2-furoyl) -N '- (p-methoxyphenyl) -hydrazine.

Example 2

A solution of 30 g of suction filtration wet acetone (p-methoxyphenyl) hydrazone in 300 ml of benzene was dried over sodium sulfate, filtered and the filtrate was washed with 30 ml of benzene. After cooling the solution to 5 ° C, 8 ml of Οί-picoline was added, then at 0-5 ° C a solution of τ S6680 was added, 8.8 g (0.08 g-moles) of 2-bromothiazole-U-carboxylic acid chloride was added. In 200 ml of toluene. The reaction mixture was stirred for 2 hours, then filtered, washed with water, and shaken with 120 ml of 1: 1 dilute hydrochloric acid. After separation of the aqueous phase, the solvent phase was evaporated to near dryness in vacuo. After cooling, the separated N1- (2-bromothiazol-U-ylcarbonyl) -N1- (p-methoxyphenyl) -hydrazine hydrochloride was filtered off with suction, washed with a small amount of benzene, air-dried, then dissolved in water and neutralized with sodium carbonate. Yield 12.6 g, m.p .: 125-126 ° C.

12.6 g of N1-2 (2-bromo-azol-U-ylcarbonyl) -N1- (p-methoxyphenyl) -hydrazine prepared as described above were dissolved in 50 ml of acetic acid, and 10 ml of levulinic acid and 2, U ml of concentrated sulfuric acid and then heated at 80-85 ° C for 2 hours. After cooling, the reaction mixture was diluted with 50 ml of water, the separated 1- (2-bromothiazol-6-ylcarbonyl) -2-methyl-5-methoxyindol-3 * ylacetic acid was filtered off with suction and recrystallized from ethanol. Yield: 8.18 g (13.7%), m.p .: 169-171 ° C.

Example 3

A solution of 21.5 g of wet filtration acetone- (p-methoxyphenyl) -hydrazone in 150 ml of benzene was dried over sodium sulfate, U ml of β-picoline was added, and a solution of 12 g (0 .0-5 moles) of 2-chlorothiazole-N-carboxylic acid chloride in 80 ml of benzene. After stirring for 2 hours, the reaction mixture was filtered, washed with water and shaken with 50 ml of hydrochloric acid diluted 1: 1 with water. The separated material was filtered using a suction filter, dissolved in water and neutralized with sodium carbonate. The separated N- (2-chlorothiazol-14-ylcarbonyl) -N1- (p-methoxyphenyl) hydrazine (5.8 g, m.p. 126 ° C) was heated in 16 ml of acetic acid after the addition of 6 ml of levulinic acid and 0.7 ml of concentrated sulfuric acid, for 2 hours at 80-85 ° C. After dilution with water, the separated product was recrystallized from ethanol. Yield: 5.22 g (19%) of 1- (2-chlorothiazol-1-ylcarbonyl) -2-methyl-5-methoxyindol-3-ylacetic acid, m.p .: 158-160 ° C.

The starting material used in Examples 1-3:

To a suspension of 128 g (0.5 g moles) of p-methoxyphenylhydrazine sulfonic acid sodium monohydrate in 500 ml of methanol was added 9h ml of concentrated hydrochloric acid at 60-65 ° C over about 10 minutes with stirring. After stirring for an additional 10 minutes, the mixture was cooled to room temperature and neutralized with 318 g of 20% sodium carbonate solution. To the resulting aqueous solution was poured 87 ml of acetone, after 30 minutes the acetone (p-methoxyphenyl) hydrazone separated as crystals was filtered off with suction and washed successively with methanol diluted 1: 1 with water and then with water. (After drying in vacuo, 80 g of acetone- (p-methoxyphenyl) -hydrazone were obtained. M.p .: 90%, m.p. 95-98 ° C, with decomposition).

8 56660

The product is used as a suction filtration wet starting material in Examples 1-3.

Example 1+

About 100 g of suction filtration wet acetone (p-methoxyphenyl) hydrazone obtained from 128 g (0.5 g mol) of p-methoxyphenylhydrazine sulfonic acid sodium monohydrate was dissolved in 700 ml of a 1: 1 mixture of benzene and toluene, dried over sodium sulfate, filtered and the filtrate was washed with 50 ml of benzene. After cooling the solution to 0 ° C, 1 + 0 ml of pyridine was added and then 87.5 ml (0.5 g-mol) of 5-nitro-2-furancarboxylic acid chloride were added dropwise. After stirring for 30 minutes, the solvent phase was washed with 1 + 00 ml of water, dried over sodium sulfate and evaporated in vacuo. As an oily residue, the remaining acetone-N1- (5-nitro-2-furoyl) -N1- (p-methoxyphenyl) hydrazone was dissolved in 300 ml of acetic acid and 1 + 0 ml of levulinic acid was added, followed by 5.5 ml of concentrated sulfuric acid and the mixture was heated at 80-85 ° C for 1 hour. After cooling, the mixture was diluted with water, and the precipitated 1- (5-nitro-2-furoyl) -2-methyl-5-methoxyindol-3-ylacetic acid was recrystallized from ethanol. The yield is 1 + 3 g (2 + 1% based on p-methoxyphenylhydrazine sulfonic acid sodium monohydrate), m.p. 179 ° C.

Example 5

To a solution of 27.7 g (0.1 g moles) of (5-nitro-2-furoyl) -N1- (p-methoxyphenyl) hydrazine in 150 ml of acetic acid was added 20 ml of levulinic acid. After standing for half an hour, a solution of levulinic acid-N- (5-nitro-2-furoyl) - (p-methoxyphenyl) -hydrazone was added dropwise with 5.5 ml of concentrated sulfuric acid, and the mixture was stirred for 1 hour at 80-85 ° C. , was then cooled and 100 ml of water were added. The separated 1- (5-nitro-2-furoyl) -2-methyl-5-methoxyindol-3-yl acetic acid was filtered off with suction and washed with 100 ml of 60 .mu.l of acetic acid and then with 10 ml. of water. The crude 1- (5-nitro-2-furoyl) -2-methyl-5-methoxyindol-3-ylacetic acid was recrystallized from 220 ml of 88/2 tert-butanol. Yield: 21.6 g (60.6%) 9 m.p. L8o 178 ° C.

Example 6 ^

To a solution of 25.8 g (0.1 mol) of p-methoxyphenylhydrazine sulfonic acid sodium monohydrate in a mixture of 112 ml of water and 1 + 8 ml of tert-butanol was added 17.1 * g (0.1 mol) 5-nitro-furan-2-carboxylic acid chloride. After stirring for 1 hour at room temperature and stirring for one hour in a water bath at 70-80 ° C, 17 ml of levulinic acid and 1.5 ml of concentrated sulfuric acid were added dropwise without separation, stirred for 1 hour at 80-85 ° C, cooled and added. 80 ml of water. The separated 1- (5-nitro-2-furoyl) -2-methyl-5-methoxyindol-3-ylacetic acid was filtered off with suction and washed with 80 ml of 60% acetic acid, then with 100 ml of water. The crude product was recrystallized from 170 ml of 88- $ tert-butanol, clarified with 5% Nort activated carbon, crystallized after cooling, 9 S6680 suction filtered, washed with 20 ml of 88- $ tert-butanol and dried. At 80 ° C to give 17 g of 1- (5-nitro-2-furoyl) -2-methyl-5-methoxyindol-3-ylacetic acid. Yield: 73.5% mp: 178-180 ° C.

Example 7

To a solution of 25.8 g (0.1 mol) of pmethoxyphenylhydrazine sulfonic acid sodium monohydrate in a mixture of 112 ml of water and U8 ml of tert-butanol was added 20 g (0.11 mol) of 2-chlorodiazole-1 + carboxylate. acid chloride. The mixture was stirred for 1 hour at room temperature and then for 1 hour at 70 ° C, and then - without separation of the product - * + 3.5 ml of levulinic acid and 5 ml of concentrated sulfuric acid were added, after heating for 1+ hours at 80 ° C, diluted the resulting reaction mixture with water, the separated product was filtered off with suction and recrystallized from tert-butanol to give 23 g of 1- (2-chlorothiazol-1 + -ylcarbonyl) -2-methyl-5-methoxyindol-3-yl- acetic acid. Yield: 65% mp: 158-160 ° C.

Claims (1)

10 & 6680 Patents: Process for the preparation of therapeutically active indolyl acetic acid derivatives of the formula b3x ^ ^ __ / CH2coor2 XXX., R wherein R is a nitro-substituted furylcarbonyl group or a halogen atom substituted 2 hydrogen 3. . ... an atom or a lower alkyl group and R is a lower alkoxy group, and for the preparation of their salts, characterized in that a) a compound of formula r3 \ XX prepared by direct acylation of hydrazine or hydrazone obtained by treatment with an oxo compound from an arylhydrazine or a derivative thereof. N-N = R ^ R _ 3 „. s wherein R and R are as defined above and R represents two hydrogen atoms or alkylidene groups are reacted with a compound of formula r1-co-ch2 ~ ch2-coor2 (III) 1 2 wherein R and R are as defined above, and free the acid is, if desired, liberated from the compound obtained, or (b) cyclization of a compound of formula «> 6660 (iv) I || ch2-ch2-cooh N-N = C-R1 R 1. 3 wherein R, R and R are as defined above, or c) a compound of formula 'Ok N-NH-SO-H R 3 wherein R and R are as defined above is reacted with a compound of formula (lii), and that the compound obtained is, if desired, salified or liberated from its salt. 56680 For the preparation of therapeutically active compounds of the indolylate mixture with the formulation of R 3 CH 2 CO 2 R 2 t jr T (i> i. R lägre alkyl- _ 2 .. 3 grupp, R ar en vateatom eller en lagre alkylgrupp och R ar en lagre alkoxy-grupp, och saiter.därav, kännetecknat därav, att en förening fram-ställd genom omedelbar acylering av en hydrazin eller hydrazon erhällen in the case of arylhydrazine or a derivative of a compound having an oxidation and in the form of R3 Tl NN = R5 R color R and R ^ in the form of an orthoglycine or in the form of an alkylidene group, in the case of a formulation of r1-co- ch2-ch2-coqr2 (III) 12. van R och and R har ovan angiven betydelse, och om sä önskas, den fna syran frigöres frän den erhällna föreningen, eller b) en förening med Formeln II CH, -CH, -COOH ( IV) R 1 3 is R, R and R har ovan angiven betydelse, cykliseras, eller c) en förening med formeln