DE1926359A1 - oxylcanic acids - Google Patents

Description

T 46 662

AZIENDE -CHIMICHE RIIHTITB AN & ELIIII FRANCISCO ACRAI ¹ . Spa

Via Amelia 70, Rome, Italy

(Indazol-3-yl) oxyalkanoic acids

The present invention relates to compounds with pharmacological valuable properties. In particular, the present invention relates to (indazol-3-yl) oxyalkanoic acids and non-toxic ones Salts thereof having such pharmacological properties.

A wide variety of steroids have been found over the past few years which are useful as anti-inflammatory agents. However, these compounds also have undesirable side effects. There is therefore a need for anti-inflammatory agents that are non-steroid. The present invention concerns such agents.

The present invention relates to cosmetic preparations which, according to the invention, are characterized in that they (Indazol-3-yl) -oxyalkanoic acids of the general formula

CO (CH ₂ ) _η σ00Η R

where X is hydrogen, Cl, OCH ,, Nögi / öcHta "NHCOCH, R is hydrogen, phenyl, benzyl or substituted by methyl, methoxyl, halogen, trifluoromethyl and / or dimethylsulfamido

denotes phenyl, benzyl and η is 1 or 2 or contain their pharmaceutically acceptable salts. The present The invention further relates to a process for the production of these compounds as well as pharmaceutical and cosmetic ones Preparations containing these compounds.

The compounds of general formula I can be selected from the corresponding 3-oxy-indazoles are produced in that an alkali or alkaline earth salt of these 3-oxy-indazoles of the general Formula II is reacted with a halogen compound of the general formula III according to the following reaction scheme:

+ Haiog -

(H)

(in)

(IV)

a Journal of Medicinal Chemistry 9, 38 (1966).

In this reaction scheme, X, H and η have the same meanings as in formula I. Me denotes an alkali metal, R ¹ denotes a carboxyl, carbethoxy, nitrile or carboxyamide group and halogen denotes a halogen (preferably chlorine or Bromine). The reaction is suitably carried out in aqueous solution at an elevated temperature («iB 80-100 ° C) for a period of time

from 30 to 90 minutes.

-3-

009821/1950

If. R ^{f stands} for a group other than a carboxyl group, the reaction shown in the above reaction scheme is followed by hydrolysis of the ester, nitrile or amide of the general formula IV. The hydrolysis conditions are explained in Examples 2-4 below. Accordingly, conventional hydrolysis conditions can be used. For example, an alkyl halogen acetate can be reacted with a sodium or potassium salt of a 3-oxy-indazole to form the corresponding indazole-3-oxyacetic acid ester. The ester is purified by distillation and then hydrolyzed to the corresponding acid. Similarly, OhI or acetonitrile can be reacted with a sodium or potassium salt of a 3-oxy-indazole and the nitrile obtained can then be hydrolyzed.

In the special batch of compounds of the general formula I, where η stands for the number 2, the compounds can thereby be prepared that alkali salts of the general formula II reacted with Propiolac ^ ton in an aqueous medium at 50-100 ° G will. Typical conditions for this reaction are given in Example 5, for example.

Compounds of the general formula I in which R does not represent a phenyl group or a substituted phenyl group, are also from the corresponding (ihdazol-3-yl) -oxyalkane derivatives that do not have any substituents in the 1-position, obtainable by reaction in an alkaline aqueous medium with benzyl halides, optionally as indicated above can be substituted. For example, the acid in water can contain one gram equivalent of the benzyl halide and 2.5 grams equivalent alkali such as NaOH at elevated temperature (50 ° 0) are implemented for a period of several hours (2-3).

Compounds of the general formula I in which X is a nitro group means, can by nitration of the corresponding

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Compounds are obtained in which X is a hydrogen atom means. During this nitration, the nitro group enters the 5-position of the indazole ring. The nitro group can too an amino group can be reduced by using suitable reduction conditions for heterocyclic compounds. The nitration and reduction conditions are illustrated in Examples 6 and 7.

With reference to the reaction scheme shown above, halogen compounds of the formula III, in which R 'is a carboxyl group, are reacted with the alkali metal salts (preferably the sodium salt) of 5-oxyindazoles in aqueous solution, at a temperature and for a period of time determined by the Depending on the reaction components and are generally between 20 and 80 ° C or 1-5 hours. Another suitable method is the reaction of alkali metal salts of 3-oxyindazoles with a sodium salt of a chloroalkanoic acid in toluene or xylene suspension at the boiling point for a period of 1-5 hours. If R ^{1 is} a carbalkoxy, nitrile or carboxyamide group, the reaction is carried out with a compound of the formula II in an inert solvent (for example dioxane). The subsequent hydrolysis to the corresponding carboxyl derivative can be achieved using conventional hydrolysis conditions.

According to the reactions mentioned above, in addition to _ the compounds of the formulas I and IV, compounds of the formula V are prepared.

N-CH ₂ CO OH

(ν)

009821/1950

wherein the acetic acid radical (-CHpOOOH) is closer to the nitrogen atom in the 2-position as being attached to the oxygen.

By suitable selection of the reaction conditions, it is possible to essentially use compounds of the formulas I or IY pure state and in yields of 80 percent by weight. Non-polar solvents favor the formation of ν · η compounds of the formulas I and IV | polar solvents favor the formation of compounds of formula V.

The compounds of the formula I differ from the compounds of the formula II by the IR spectrum. They show an intense band at about 1550 cm, which is absent in the compounds of the formula V, while at about 1630 cm they have no band ₉ which the is the most intense band of the spectra of the compounds of the formula V. The melting points of the compounds of the formula I are generally lower than the melting points of the corresponding compounds of the formula V.

The following procedures were used to pharmacologically study the compounds of the invention.

The acute toxicity was determined in mice intraperitoneally, with that occurring within 5 days after treatment Mortality was recorded. Then a series of behavioral studies were carried out using the Irvin method (Pharmacological Techniques in Drug Evaluation, Year Book; Medical Publishers, Chicago, 1964 »pp 36-54). Neurovegetative effects were investigated "in vitro" using the reflex of using acetylecholine, and histamine Dimethylphenylpterazinium iodide (DMPP) stimulated from guinea pigs isolated intestines and registered "in vivo * * the arterial blood pressure and the reflex to the adrenaline injection and vagus stimulation was measured in the cat anesthetized with Ohloraloa (70 mg / kg i.p.). The analgesic The effect was then determined by the method of Siegmund et al (1957) investigated. "5_

009821/1950

The anti-edema effect in the mouse was then determined by that method von Winter et al (1962) and the anti-granuloma effect according to the method of Maier et al (1950).

The effect of these derivatives on serum albumin denaturation caused by heat (Mizushima, Acta Hheum. Scando £ ₉ JJ ₉ 1963; Mizushima and Suzuki, Arch. Int. Pharmacodyrio 157 _g 115 ₉ 1965; Del Basso and Silvestrini, Biochim, XT ₅ 198s »1966), it was determined»

The local "anti-inflammatory effect" was investigated ^ by applying the method of applying the products to the g-ranuloma (Winter et al, 1962) and applying the products in a 5 follow vaseline suspension to the urtics' ^ which were carried out by the method had been obtained from Parrat and West (1958) ο

The local lolerans was "determined by either application." on the skin tissue of the satiated or by subcutaneous injection of the satiated.

The compounds of formula I have very low acute toxicity, starting at about 300 mg / kg i.p. lies with the exception of the i-o-chlorobenzylindazole-3-oxyacetic acid, which is about twice that is toxic.

The effects on behavior include sedation at relative high doses (50 or 100 mg / kg i.p.); Prostration and convulsions at sub-toxic doses. There weren't any neurovegetative effects were observed, neither in these experiments nor in those made using isolated Organs and the blood pressure heflex in the cat became.

According to the test by Siegmund et al, no analgesic effect was observed with the exception of 1-m-chlorobenzylindazole »3-oxyeseetic acid, at a dose of 10 mg / kg a.c. a

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1928359

shows significant effect.

The anti-edema is absent. The effect on the granuloma is also low or absent.

On the other hand, compounds of the formula I have a contact anti-inflammatory effect that is comparable or higher than the effects of cortisone. In fact, they not only prevent granuloma growth after direct application the cotton pellet ("cotton pellet"), but they decrease pronounced the focal inflammatory responses when they can be applied as a $ 5 ointment.

These results are particularly interesting since, as far as is known, this is the first time that an anti-inflammatory has been used local effect has been described for substances that are not of the steroid type. One to create an irritation phenomenon capable concentration is 20-50 times higher than the lowest: active concentration.

The local anti-inflammatory effect is most likely related to the ability of these substances to protect serum albumin against heat denaturation. Ea however, it is known that in the course of an inflammatory process a denaturation of the proteins occurs, which in turn is responsible for the many phenomena that cause the inflammation process characterize.

Because on the other hand all known anti-rheumatic Drugs capable of preventing albumin heat denaturation, the substances mentioned can be considered suitable for this are considered to show therapeutic activity in rheumatic diseases in which actually im Blood appears the presence of abnormal proteins, analogous to those formed when albumin is heated "in vitro" will.

009821/1950

example 1 i-p-Chlorobenzyl-indazole-S-oxy-acetic acid

An aqueous solution of the potassium salt of i-p-chlorobenzyl-3-oxy-indazole is prepared by dissolving 25 x 8 g of the indazole in 200 ml of H $ -iger KOH solution. The aqueous solution is heated in a water bath and 35 g of monobromoacetic acid are added all at once with stirring. The stirring and heating is continued until the pH of the solution is about 7, which is about 1/2 level. After this The solution is cooled by filtration of any small undissolved residue that may be present freed and then acidified with dilute HCl. The resulting precipitate is collected, washed with water and in a dissolved aqueous 10% solution of KpCO *. Any minor undissolved substances are filtered off from the solution obtained. This is then acidified again with dilute HCl The 1-p-chlorobenzyl-indazole-3-oxyacetic acid formed is then dissolved in a slight excess of an aqueous saturated solution of sodium hydrogen carbonate. Acidification becomes failed again. The product is washed with water and crystallized from alcohol at 95 ° C. The substance possesses a melting point of 117 ° C. In the crystallization waters there are small amounts of the isomers i-p-chlorobenzyl-indazol-3-one-2-acetic acid before.

Example 2 1-m-chlorobenzyl-indazole-3-oxyacetic acid

25.8. g i-m-chlorobenzyl-3-oxy-indazole are in a sodium methylate solution dissolved, which was made from 2.3 g of sodium. Removal of the solvent leaves the sodium salt of i-m-chlorobenzyl-3-oxyindazole. This will be with 16.7 g of ethyl bromoacetate mixed and in 280 ml of 1,2-dimethoxy, ethati suspended. The reaction mixture obtained is stirred and heated to 100 ° C. for 3 hours with stirring. After cooling, the precipitate is filtered off and the one obtained The filtrate becomes dry under reduced pressure

009821/1960

evaporated. The residue is taken up again with ether and washed thoroughly first with very dilute aqueous STaOH solution and then with water. The solution is _{then dried over Ma 2} SO ^ and the solvent is removed. Distillation under reduced pressure produces a mixture of the strongly predominant 1-m-chlorobenzyl-indaol-3-oxyacetic acid ethyl ester and 1-m-chlorobenzyl -3 ^ra on-2 ~ ethyl acetate boiling at 218 ° C / 1.5 Torr »

Analyzes for C ₁₈ H ₁₁₇ ClF ₂ O ₅

calculated? C 62 »70 H 4.97 M" 8.13 found! 62.80 5 "19 8039"

The hydrolysis is carried out by treating the ester product with two equivalents of NaOH dissolved in 20 times the volume of water based on the ester weight and stirring it at 90 ° C. until a complete solution is obtained The reaction is ended. The reaction mixture is cooled and acidified with dilute HGl. A precipitate is collected. The precipitate is purified by dissolving it in 10 <$> Na ₂ COg and then removing a small amount of an insoluble residue from the resulting alkane solution obtained a mixture of two isomeric acids, in which, however, the 1-m-chlorobenzyl-3-on-2-acetic acid predominates Therefore, by treating one part by weight of the mixture with 5 parts by volume of ethyl alcohol, only 1-m-chlorobenzyl-indazole-3-oxyacetic acid ext rahiert, which is finally umkrietalliaiert from hexane. It has a melting point of 109 ° C.

Example 3 1-Benzyl-indazole-3-oxyacetic acid

11g of the sodium salt of i-benzyl-3-oxy-ynäaiol are in 70 ml of absolute ethanol by heating the resulting solution -9-

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Dissolved to the boiling point and stirring. 305 g of chloroacetonitrile dissolved in 5 ml of absolute alcohol are then added within 2-3 minutes. After 10 minutes a further portion of 1.7 g of chloroacetonitrile is added "The reaction is finally brought by additional 45 minutes long m heating to the boiling point of the end" Bas Reakti ons mixture is cool to room temperature allowed to "spell is filtered, the alcoholic solution under reduced pressure evaporated to dryness. The pike stand obtained is then taken up again with ether * and the ltherlösung is washed successively with dilute HCl, with water., And with MAOIs with water ge = "The solution is dried over Ia SO _0," and the solution-

e. 4th

solvents is then removed "The residue consists of (1-benzyl-indazol-3) -oxyacetonitrilp which is crystallized from methanol" It has the melting point .of 95 ° C ₀

Analysis: for ^C 1 6 ¹¹ I ₃ ¹ V. D. H 4th 98 I. 15o 96 calculated % C 72 .98 5o 25th 16. 03 found" 73 »21

1 g of (1-benzyl-indazol-3) -oxyaeet © Hxtril is pulverized and then added to 5 ml of concentrated HCl with stirring. When heated on a boiling water bath for a period of 2-3 minutes, the nitrile product melts and solidifies soon after. The precipitate is cooled, then filtered and washed well with water in a mortar, then dissolve in 10 # ITa ₂ CO, is again precipitated with dilute HCl. After crystallization from ethanol, 1-benzyl-indazole-3-oxyacetic acid is obtained. It has a melting point of 160 ° C.

Example 4 (1-Benzyl-indazol-3-yl) -oxyacetic acid

a) 246 g of sodium eel from 1-benzyl ~ 3 ~ oxy-indazole and 131 S. Chloracetamide are suspended in 1 liter of dioxane and the resulting Suspension is refluxed for 2 hours

The solvent (dioxane) is removed under reduced pressure, and the residue is crystallized from alcohol. In this way (1-benzyl-indazol-3-yl) -oxyacetic acid amide is obtained. It has a melting point of 135-7 ° C.

b) 155 g of the amide are mixed with a mixture for 2 hours from 300 ml of dioxane and 300 ml of concentrated hydrochloric acid heated under reflux. After cooling, 3 liters of water are added. An oil precipitates which solidifies immediately. It is recrystallized from acetone after a small amount of undissolved 1-Benzyl-3-oxy-indazole had been filtered off. The product is (1-benzylindazol-3-yl) -oxyacetic acid, which is at 160 ° C melts.

Example 5

Q- (1-Benzyl-indazol-3-yl) -oxypropionic acid

25 g of the sodium salt of 1-benzyl-3-oxy-indazole are in a solution of 3 g of HaOH dissolved in 75 ml of water. The resulting solution is heated to 65-70 ° C, and 11.7 g of Proptolac ton are slowly added with stirring. After the addition is complete, the solution is heated for a further 15 minutes, cooled to room temperature, acidified and extracted with ether. A small amount falls from the ethereal solution unreacted 1-benzyl-3-oxy-indazole from. The product is β- (1-Benzyl-alterazol-3-yl) -oxypropionic acid. This is filtered off and extracted with 5 $ bicarbonate solution and then Reprecipitated by acidification with HCl. It is made from benzene recrystallized. 15 g of the acid are obtained in this way. she has a melting point of 135 ° C.

Example 6 (1-Benzyl-5-nitro-indazol-3-yl) -oxyesBigBaic c

20 g of (1-benzyl-indazol-3-yl) -oxyacetic acid are poured into 200 ml There big acid anhydride suspended. The suspension is at 0 ° C cooled, and 3 · 5 ml HNO * (d ■ 1.52) are slowly added dropwise calmly. The mixture is then stirred for a further 3 hours, and

-11 -009 821/19 5 0

to be sure, to dissolve and then precipitate the received ITi t ro derivative to complete it. It is filtered washed with water and crystallized from benzene. The product has a melting point of 155 ° C.

Example 7

(5-Acetamino-1-benzyl-indazol-3-yl) -oxyacetic acid

a) 14 g of (1-benzyl-5-nitro-indazol-3-yl) -oxyacetic acid are added in portions to a _{stirred solution of 30 g of SnCl 2} »HpO in 30 ml of concentrated HCl, which is heated to 80 ° C. in a water bath . The oxyacetic acid goes into solution and then becomes partially insoluble. After the addition has ended, the desired reduction reaction is brought to completion by heating to 80 ° C. for 15 minutes. The reaction mixture is then cooled and a precipitate which forms is separated off. Crystallization of this precipitate from an alcohol-ether mixture gives (5-amino-1-benzyl-indazol-3-yl) -oxyacetic acid hydrochloride.

The hydrochloric acid mother liquors are diluted with water and adjusted to pH 8. A precipitate of an inorganic salt is deposited when the alkaline solution is neutralized to pH 6 with acetic acid. The precipitate formed will filtered off, washed and crystallized from dioxane-methanol (1: 1). This product is (5 ~ Amino-1-benzyl-indazol-3-yl) -oxyacetic acid, which melts at 217 ° G (decomposition).

b) 6 g of (5-amino-1-benzyl-indazol-3-yl) oxyeacetic acid in 24 ml of acetic anhydride are heated to 110 ° C. for 15 minutes. The resulting mixture is poured into 100 ml of HpO and the resulting solution is slowly made alkaline _{with aqueous Na 2 CO.} The alkaline solution is clarified with activated charcoal, then filtered and acidified with dilute HCl. The precipitate that forms is filtered off, _{washed neutral with H 2} O and crystallized from ethanol.

009821/19 50

The product thus obtained is (5-acetamino-i-benzylindazol-3-yl) -oxyacetic acid, which "melts at 238 ° C.

Example 8

/ T- (2,6-Dimethyl-3-dimethylsulfamoyl) -phenyl-indazol-3-ylj-

oxyacetic acid

6 g of N- (2,6-dimethyl-3-dimethylsulfamoyl) -phenyl-anthranilic acid are dissolved in 42 ml of acetic acid. Then β g of EaIO _{2 are} added. The solution obtained is left to stand overnight. It is poured into water and allowed to digest, when the precipitate that forms takes on a solid appearance. It is filtered off, washed with water and then repeatedly with benzene. The N ~ (2 ₅ 6-Dimethyl «> 3-dimethylsulfamoyl) phenyl» N-nitroso ~ anthranilic acid thus obtained has a melting point of 139 ° C (decomposition) »

507 g of zinc powder are suspended in 22 ml of water. While the temperature is kept between 10 and 20 ° C, a solution of 10 g of the nitroso derivative in 100 ml is stirred Acetic acid added slowly. After the addition is complete, the resulting solution is stirred for about a further 2 hours, then Heated to 80 ° C. for 10 minutes and poured into 150 ml of water. The pH of the solution is raised with solid sodium carbonate

6 brought, and the resulting precipitate is filtered off 1- (2,6-Dimethyl-3-dimethylsulfamoyl) -phenyl-3-oxy-indaz oil is crystallized from alcohol. It melts at 182 ° 0.

The oxy-indazole is converted into the sodium salt with the calculated Amount of sodium methylate transferred. An equivalent of this Salt, 1.1 equivalents of dry sodium chloroacetate and 11 Parts of xylene are heated to boiling point for 4-5 hours. The resulting mixture is cooled and washed with 1 # NaOH extracted. It is acidified with hydrochloric acid and extracted with ether. The ethereal solution becomes / T- (2,6-dimethyl-3-diatttoyleulfamoyl) -phenyl-indazol-3-yl7-oxy® acetic acid with

7 tiger sodium bicarbonate extracted. Duron acidifying the he «? -13 »

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holding bicarbonate extract falls the essentially pure Substance from and can be crystallized from ligroin. It has a melting point of 120-1 ° C.

Example 9

A certain amount of the acid prepared according to Example 3 is dissolved in aqueous sodium hydroxide containing a stoichiometric amount of sodium. The solution obtained is under Evaporated to dryness in vacuo. The sodium salt obtained in this way slowly decomposes instead of having a sharp melting point.

Example 10 Zinc salt

To an aqueous saturated solution of the sodium salt of i-benzyl-indazol-3-yl-oxyacetic acid (prepared according to Example 9) an equimolar amount of zinc chloride dissolved in water is added. It becomes an abundant colorless precipitate which is isolated by filtration. The precipitation is then dissolved in acetone and reprecipitated with water.

The dry salt has a melting point of 110 C, and its analysis corresponds to the formula (C ₁ 6 ^H 13 ^N 2 ° 3 ^ 2 ^Zn *

Using the same procedure, ^ become the following SaI ze also)? from the acid described in Example 3 manufactured t

Pb (C ₁₆ H ₁₃ N ₂ O _{3) 2} 170-173 ° F.

Al (O ₁₆ H ₁₃ N ₂ O ₃ I ₃ m. 160 °

Cd ( ⁰ I ₆ H ₁ 5 IT ₂ O ₃ ) ₂ F. 135-HO ⁰

Ca (O ₁₆ H ₁₃ N ₂ O ₃ ) ₂ m.p. 126-130 °

Sn (C ₁ 5H ₁ 3N ₂ O ₃ ) ₂ m.p. 80-90 °

Ag (Ci ₆ H ₁₃ N ₂ O ₃ ) m.p. 207 °

009821/1950 "~~~

Bi (C ₁₆ H ₁₅ Li ₂ O ₃ ) ₅ , m.p. 156 °

Example 11

According to the procedure described in Example 9 ", however the aqueous sodium hydroxide is replaced with ammonium hydroxide or an organic amine, the following salts are made up obtained the acid described in Example 3:

Ammonium salt, NH ₄ ^ C ₁₆ H ₁₅ N ₂ O ₅ , mp 155 ° »N-hydroxyethylmorpholine salt, C ₆ H ₁₅ NO ₂ O ₁₆ H ₁₄ N ₂ O ₅ , mp 95-97 °;

_15216142 piperazine salt, C ₄ H ₁₀ N ₂ * (C ₁₆ H ₁₄ N ₂ O ₅ ), m.p. 175 °; Triethanolamine salt, C ₆ H ₁₅ NO ₅ -C ₁₆ H ₁₄ N ₂ O ₅ , F. 87-89 ⁰ J Ethylenediamine salt, C ₂ HgN ₂ ⁴ C ₁₆ H ₁ XO, H ₂ Oj morpholine salt, C ₄ H ₉ NO- C ₁₆ H ₁₄ N ₂ O ₅ , F. 137 ° J diethanolamine salt, C ₄ H ₁₁ NO ₂ ^ C ₁₆ H ₁₄ N ₂ O ₅ , F. 99 ⁰ J The following salts are obtained from the acid described in Example 2:

Diisopropylamine salt, C ₆ H ₁₅ NC ₁₆ H _{15 ClN 2} O ₅ , m.p. 109 ° | Diethanolemine salt, C ₄ H ₁₁ NO ₂ -C ₁₆ H ₁₅ ClN ₂ O ₅ , m.p. 106 °.

In accordance with the procedures outlined above, are the following compounds manufactured:

- (2,6-Dimethylphenyl) indazol-3-yl7-oxyacetic acid, melting point 130 ° - (2,3-Dimethylphenyl) indazol-3-yl7-oxyacetic acid, mp 142 ° i-Phenyl-indazole-3-oxyacetic acid mp 164 °

1- _m -chlorophenyl-indazole-3-oxyacetic acid mp 148 °

(the new intermediate i-m-chlorophenyl-3-oxy-indazole has the melting point F * 240 °)

ß- (1-Phenyl-indazol-3-yl) -oxypropionic acid F. 131

β- (Indazol-3-yl) -oxypropionic acid mp 179 °

ß- (1-p-fluorophenyl-indazol-3-yl) -oxypropionic acid ___- ' F. 150-2 ° (the new intermediate 1-p-fluorophenyl-3-oxyindazole has a melting point of 250 °)
iO-chlorobenzyl-indazole ^ -oxyacetic acid m.p. 156 °

009821/1 950

926359

-X-

133 °

β- (1-m-bromophenyl-indazol-3-yl) -oxypropionic acid mp 89 ° (the new intermediate 1-m-bromophenyl-3-oxyindazole has a melting point of F. 242 °)

ß- (5-Methoxy-indazol-3-yl) -oxypropionic acid mp 184 °

(1-m-Trifluoromethyl phenyl-indazol ** 3-yl) -oxyacetic acid

157 ° F.

(the new intermediate 1-m-chlorophenyl-3-oxy-indazole has a melting point of 203 ° C)

(5-chloro-1-benzyl-indazol-3-yl) -oxyacetic acid mp 158 °

β- / T- (2,6-dimethyl) -phenyl-indazol-3-yl7-oxypropionic acid

(5-Amino-1-benzyl-indazol-3-yl) -oxyacetic acid hydrochloride F. 230 °

1-Benzyl-6-chloro-indazole-3-oxyacetic acid - m.p. 157 ° C.

The present invention is further illustrated with reference to the preparations described in the following examples, including Ointments and lotions.

Example 12

An ointment containing 1 to 3 # i-benzyl-indazol-3-yl-oxyacetic acid in 100 ml of a carrier, is prepared as follows:

vaseline
Paraffin oil
Cetyl alcohol
Stearyl alcohol
White wax
Sorbitol sesquiojeat
Methyl p-oxybenzoate
Propyl p-oxybenzoate
Water except for

40 G 20th G 2.5 G 2.5 G "5 G 10 G 0.18 G 0.02 G 100 G

-16-

00982 1/1950

Example 13 L 1 1926359 4th G -17- · - tff - ■ β G G -Benzyl- G An ointment that rorated 1 to 3 $ of the sodium salt contains questioner, will G indazol-3-yl-oxyacetic acid in 100 ml of a 13th G prepared as follows 4o G. Polyoxyethylene sorbitol monost earat 0. 18th G Polyoxyethylene mono st earat 9 02 G Stearic acid 10 g ο Paraffin oil 2 Isopropyl myristate 4o Cetostearyl alcohol 6th Glycerin Oo G Mipagine (methyl p-osybenzoate) Oo 9 G lipasol (propyl ^ f-oxybenzoate) 100 5 G Water up to G Example 14 G line lotion is prepared as follows G sodium salt of I ^ benzyl-indazole " 1 18th G 3-yl-osyes big acid 1o 02 -G Getyl alcohol 2o g Paraffin oil 1 Uodium lauryl sulfonate 5 Fluid Silicone 200/350 MS 5 Glycerin 0. G Uipagine 0. 5 G Kipasol 100 S. Water except for S. Example 15 5 G An ointment is prepared as follows! 1 ~ Benzyl-indazol-3-yl-oxyacetic- 3 acid 0. Neomycin sulfate 40 vaseline 20th Paraffin oil 2o oetyl alcohol

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-rf-

Stearyl alcohol 2.5 g

White wax 5 g

Sorbitol sesquioleate 10 g

Methyl p-oxybenzoate 0.18 g

Propyl p-oxybenzoate Oo02 g

Water Ms on 100 g.

The compounds according to the present invention can be used as active ingredients in pharmacological preparations and in preparations for body and beauty care, including beauty creams, beauty lotions, sunday ijotions and shampoos, toothpastes and mouthwashes _{or the like}

The present invention includes all acid addition and metal algae of (xndazol-3 ° yl) ~ O3 y ~ alkanoic acids. The generally known methods for the preparation of the salts can be used here & qs the above examples explained "Such salts can be prepared with pfcax-aseutically acceptable and pharmaceutically unacceptable acids _P metals and organic bases." As "pharmaceutically acceptable" are meant those salt-forming acids, metals and bases which have the idoxicity of the named Oxyahcaic acids do not increase significantly.

The pharmaceutically acceptable acid addition salts include also salts of mineral acids such as hydrochloric acid, hydriodic acid, Hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid as well as the salts with organic acids such as tartaric, lemon, apple, benzoin, glycol, glueon, Succinic and aryl sulfonic acid, e.g. p-toluenesulfonic acid. The pharmaceutical Unacceptable acid addition salts are, if they are not useful for therapy either, »valuable sur Isolation and purification of the new Oxjalkaaaäuren. aside from that they are useful in the preparation of pharmaceutically acceptable salts. From this group, "one @ n as usual® salts named those with fluoride acetabic acid and perehlor" ■ acids are formed. The acid alzs form calibrated when I for

-18-

009821/1980

stands.

Although all metal salts of the novel acids described above can be made and are useful for various purposes the pharmaceutically acceptable salts are particularly valuable because of their therapeutic utility Use. The pharmaceutically acceptable metals are, for example, sodium, potassium and alkaline earth metals with an ordinal number up to 20, i.e. magnesium and calcium, as well as aluminum, zinc, iron, manganese and cadmium.

Examples of pharmaceutically unacceptable metal salts are in particular the lithium salts and the salts with alkaline earth metals with an ordinal number above 20, i.e. barium and strontium. These are useful for isolation and cleaning of the oxyalkanoic acids.

Examples of pharmaceutically acceptable salts of organic The amines and the oxyalkanoic acids are the morpholine salts. Examples for pharmaceutically unacceptable salts are the o-, m- and p-toluidine salts, which are necessary for isolation and purification of the connections can be used.

The following additional examples are pertinent to those Preparations that are not used for pharmaceutical purposes:

Example 1 6

Hand ereme (O / W type) Lanolin alcohols 4th G 100 g contain: Acetylated Lanolin 2 G stearin 6th G Self-emulsifying glycerine monostearate 12th G Liquid paraffin 2 S. Nipagine 0.18 e Nipaeol 0.02 G

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Triethanolamine 1 G Example 17 Acetylated Lanolin Alcohols 10 Example 18 1.90 g G 1-benzyl-indazol-3-yl-oxy- Beauty cream (o / w type) Diethylene glycol monostearate 2 Hair lotion (O / W emulsion) 2.50 g G acetic acid 1 G 100 g contain: Acetylated Lanolin 2 100 ml contain: G Perfume q.s. Stearic acid 2 Cetyl alcohol G water 72.80 G Cetyl alcohol 2.50 Paraffin oil 5 g G pH = »7 · 2 - soft white cream, which easily from Nipagine 0.18 Fluid silicone (Dimethyl ρ ο Iy-. G is absorbed by the hands. Nipasol 0.02 siloxane) viscosity 200/300 G Triethanolamine 1 centistokes G 1-benzyl-indazol-3-yl-oxy- acetic acid 1 G Perfume q .. s. water 79.30 G pH β 7.2 - ivory-white soft and soften· de creme. -20-

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1926359 Sodium salt of 1-benzyl-indazole- Example 19 Dehymuls K (Aliphatic 1 p 25 g Sodium salt of 1-benzyl-indazöl- 1 g Example 20 5 g Water soluble sunburn 2 g -21- Sodium lauryl sulfate 1 g 3-yl-oxyacetic acid Baby cream (W / O type) 100 ml 10 g 3-yl-oxyacetic acid 47.80 g Sunburn lotion 20 g Pilter substance Glycerin 5 g Water except for 100 g contain? q. «s. 5 g water pH = 7.9 - white mass of ointment-like 100 ml contain « 2 g ÜTipagine 0.18 g Perfume Milk, suitable for 1 g Consistency. Glycerin Nipasol 0.02 g pH a 7-5 - Liquid white 10 g 95 ° alcohol the hair. 0.18 g Dihydroxyacetone 0.02 g mixed High molecular weight esters, W / O ~ type emulsifier base) Cetiol (decyl oleate) Paraffin oil Wi smuthsubni entered zinc oxide Nipagine Eipasol

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U ■ 0 Ü Sodium salt of 1-benzyl-indazole- 1 Example 21 Sorbitol monostearate 0. Sodium salt of 1-benzyl-indazöl- Example 22 Extract N 40 Texapon (solution t .18 > 359 mmOOmm 0 3-yl-oxyacetic acid 100 Sunburn Cream (O / W-T.vp) Polyoxyethylene sorbitol monostearate 4th 3-yl-oxyacetic acid shampoo from 27-28 j £ lauryl ether sodium CVJ .02 Nipagine Water except for q .. s. 100 g contain: Cetostearyl alcohol 5 Dihydroxyaeeton 100 g contain: eulfate) CVI G Mpasol Perfume for sunburn lotion pH »7 - clear solution, pale yellow» Cetyl alcohol 5 Sunburn filter substance Oieic acid diethanolamide 100 G Liquid paraffin 10 Water except for Undecylenic acid monoethanolamide q .. s. Isopropyl myristate CVJ Perfume for sunburn cream G Glycerin 6th pH * 6.9 - White cream. - - ml Nipagine 0. Nipasol 0. 6th 50 4th 5 S. CVJ G G S. S. 18th G 02 G G G G G G G S. e e

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1926359 Sodium salt of 1-benzyl-indazole- 1 Example 25 Sodium lauryl sulfonate 2 G Sodium salt of 1-benzyl-indazole- Example 24 Eutsnol G (2-Octyldodecanol) 1 G 33 5-yl-oxyacetic acid 100 toothpaste Sodium carboxymethyl cellulose 1 ml 5-yl-oxyacetic acid Deodorants (pen) Cetyl alcohol 100 G Hexachlorophene 1 Water except for q .. s. 100 g contain: Di calciumpho sphat 57.5 G Water except for 100 g contain: Glycerin q.o s. Isopropyl alcohol 2 Perfume pH β 6.9 - viscous clear liquid. uncompressed aerosil 2.5 Toothpaste Flavors stearin the no « G citric acid 0.10 Glycerin 50 G pH * 6.9 - Soft white paste, Hexachlorophene G Sodium saccharine G contains. 95 9 ^ ethyl alcohol Wipagine 5 air Uipasol 5 2 50 G 9.60 G G 0.20 G G 40 G G G G G 0.0025 g ml 0.18 -25- 0.02

0 0 9 8 2 1/19 5 0

Solution of 38 # sodium hydrate 4 g Sodium salt of 1-benzyl-indazöl-3-yl-oxyacetic acid 1g

Perfume q. s.

pH * 7.5 - Clear or slightly opaque stick.

With regard to some of the pharmacological tests mentioned, refer to the following literature «

MEIER, R., SGHULER, W. and DESAULLES, P. Experientia (Basel) 6_, 4691 1950;

PARRAT, J. R. and WEST, B. G. - Brit. J. Pharmacol ο 22 »65 * 1958;

SIEGMUED, E., GADMUS, R. and LU, G. - Proc. Soc Exp. Biol. (N.T.) O £, 729, 1957;

WINTER, G. A., RISLEY, E. A. and NUSS, G. W ..- Proc. Soc. Exp. Biol. (N.Y.), VM, 544, 1962.

Claims ι

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Claims (6)

192Ö359 -X- claims; 1. Cosmetic preparations, characterized in that that they are used as an anti-inflammatory agent indazole-3— oxyalkanoic acids of the general formula CO (CH ₂ ) _n COOH where X is hydrogen, Cl, OCH ₃ , NO ₂ , NH ₂ or EHCOCEz, B. hydrogen, phenyl, benzyl or by methyl, methoxyl, halogen, trifluoromethyl and / or or dirnethylsulfamido substituted phenyl / benzyl and η is 1 or 2, or contain their pharmaceutically acceptable salts. 2. Cosmetic preparations according to claim 1, characterized in that that the salts are metal salts. 5 · Cosmetic preparations according to Claims 1 to 2, characterized characterized in that they are the sodium salt of 1-benzyl-indazol-3-yl-oxyacetic acid contain. 4. Cosmetic preparations according to Claims 1 to 3i, characterized in that that they are intended for use on the surface of the human body »preferably as Oreme · 5. Cosmetic preparation according to claims 1 to 4 »characterized in that that it's a sunburn lotion. 6. Cosmetic preparation according to Claims 1 to 4 »characterized in that it is a shampoo. 7 · Cosmetic preparation according to claims 1 to 4, characterized indicated that it is a toothpaste. -25- 009821/1950 ORlGIiNlAL SMSPECTED , 10. Cosmetic preparation according to Claims 1 Ms 4, characterized indicated that it is a mouthwash. Cosmetic preparation according to Claims 1 Ms 4, characterized in that it is a deodorant. Cosmetic preparation according to claims 1 Ms 4, characterized in that characterized as being a hair lotion. ORIGINAL INSPECTED 0098 2 1/1950